Heterocyclic inhibitors of GLUT9 for the treatment of disease

Abstract

The present invention relates to heterocyclic compounds and methods that may be useful as inhibitors of GLUT9 for the treatment or prevention of hyperuricemia and gout.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 297,511, filed January 7, 2022, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing Reference This application has been submitted electronically in XML format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. A copy of said XML, created on December 27, 2022, is named 58651-602-601_SL.xml and is 11,787 bytes in size. [Background technology]

[0003] Disclosed herein are novel heterocyclic compounds and compositions for the treatment of diseases and their application as pharmaceuticals. Methods for inhibiting glucose transporter member 9 (GLUT9) activity in human or animal subjects are also provided for the treatment of diseases such as hyperuricemia and gout.

[0004] Uric acid is the final metabolic product in the human purine catabolic pathway. Under physiological pH conditions, uric acid exists predominantly as urate, the ionic form of uric acid. The amount of urate in the body depends on the balance between the amount of purine obtained through dietary intake, the amount of urate synthesized in the body, and the amount of urate excreted in urine or through the gastrointestinal tract. Hyperuricemia is a condition characterized by abnormally high levels of uric acid in the blood. In humans, the upper limit of the normal range for uric acid is approximately 360 μmol / L (approximately 6 mg / dL) for women and approximately 400 μmol / L (approximately 6.8 mg / dL) for men. When the concentration of uric acid exceeds the biochemical limit of solubility, e.g., a serum uric acid level of approximately 6.8 mg / dL, sodium urate crystals may precipitate in tissues. Hyperuricemia can lead to the accumulation of sodium urate crystals, causing gout symptoms such as acute inflammation of the joints (gout flares), the formation of gouty tophi, gouty arthritis, and uric acid nephropathy (including uric acid kidney stones). Gout is the most prevalent cause of arthritis in developed countries. Control of chronic gout requires maintaining serum uric acid (SUA) below 6 mg / dL.

[0005] High serum urate is associated with elevated body mass index, hypercholesterolemia, hypertriglyceridemia, increased fasting blood glucose level, and insulin resistance.In addition, increasing evidence has revealed the dose-effect of urate on the risk of metabolic syndrome, and elevated urate levels may have adverse cardiovascular effects.Furthermore, chronic kidney disease, hypertension, diabetes, heart disease (cardiovascular disease, heart failure, atrial fibrillation, etc.), arteriosclerotic disease, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and psoriasis are also associated with high serum urate levels.

[0006] Therefore, treatment of hyperuricemia is necessary. Currently, excessive production and insufficient excretion of uric acid are the main causes of hyperuricemia. More than 90% of hyperuricemia is caused by insufficient excretion of uric acid. Uric acid excretion depends on uric acid transporters such as uric acid transporter 1 (SLC22A12 / URAT1) and glucose transporter 9 (SLC2A9 / GLUT9). Therefore, URAT1 and GLUT9 have become important targets for the development of urate-lowering drugs.

[0007] Uric acid-lowering therapies include uricase, which breaks down uric acid; xanthine oxidase inhibitors, which block uric acid production; and uricosurics, which enhance uric acid excretion. Xanthine oxidase inhibitors, such as allopurinol and febuxostat, are widely used and administered orally. Uricase, such as pegloticase (KRYSTEXXA®), a pegylated recombinant mammalian uricase, is administered intravenously and used to treat gout that is resistant to conventional therapies, such as oral allopurinol. Most mammals, including humans, do not have functional uricase. Uricase breaks down uric acid into allantoin, a more soluble molecule that is easily excreted through the kidneys. However, despite significant advances in research, gout is not well controlled, and the condition can become chronic. Xanthine oxidase inhibitor therapy can cause hypersensitivity syndromes, and uricase therapy can cause immunogenicity, creating problems in gout management, for example.

[0008] Additional small molecule uricosuric drugs used in the clinic mainly include benzbromarone, probenecid, and lesinurad. Benzbromarone and probenecid can inhibit URAT1 and GLUT9, thus promoting uric acid excretion. However, due to the fulminant hepatitis caused by benzbromarone, it has been withdrawn from the market in most countries. Due to its low selectivity, probenecid may result in drug-drug interactions, thus limiting its clinical use. Lesinurad is a more selective URAT1 inhibitor developed by AstraZeneca and was approved by the FDA in October 2015 for the treatment of hyperuricemia, but it should be used in combination with a xanthine oxidase inhibitor (allopurinol / febuxostat). RDEA3170, derived from lesinurad, is currently in phase II clinical trials. In addition to the above drugs, losartan, fenofibrate, atorvastatin and others also have uric acid lowering effects, but their mechanisms have not been fully elucidated. Therefore, it is very meaningful to find new drugs for treating hyperuricemia.

[0009] Certain novel compounds and pharmaceutical compositions have been discovered that are found to inhibit GLUT9, along with methods for synthesizing and using the compounds, including methods for treating GLUT9-mediated disorders in patients by administering the compounds. Summary of the Invention [Means for solving the problem]

[0010] The compounds disclosed herein may have useful GLUT9 inhibitory activity and may be used in the treatment or prevention of diseases or conditions in which GLUT9 plays an active role.

[0011] In one aspect, provided herein is a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; X is selected from CH and N; Y is selected from CH, S, O, and N; Z is a bond and CR 7 Selected from; R 1 is selected from aryl and heteroaryl; R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or more R 6 may be optionally replaced by; R 3 teeth, alkyl optionally substituted with SO2-alkyl; alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl Selected from; Each R 4 is, independently, R 5 alkoxy optionally substituted with R 5 alkylamino optionally substituted with R 5 dialkylamino optionally substituted with SO2R 8a , Alkylthio, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, Hello, alkyl, and Haloalkyl Select from; or R 1 Two R on adjacent carbon atoms of 4the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy, and alkoxyalkoxy; Each R 6 are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, cyano, and tetrazolyl; R 7 is selected from hydrogen and halo; R 8a and R 8b are each independently selected from alkyl, amino, alkylamino, and dialkylamino; X and Y are not both CH).

[0012] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal via intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, transdermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal via oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0013] In any of the above aspects, there are further embodiments in which an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by inhalation; and / or (e) administered intranasally; and / or (f) administered by injection to a mammal; and / or (g) administered topically to a mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to a mammal; and / or (j) administered non-systemically or topically to a mammal.

[0014] In any of the above aspects, there are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments in which the compound is administered to the mammal once daily or in which the compound is administered to the mammal multiple times over a daily range. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0015] In any of the embodiments disclosed herein, the mammal is a human.

[0016] In some embodiments, the compounds provided herein are administered orally to humans.

[0017] Also described herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0018] Also described herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts thereof, for use in treating a condition selected from hyperuricemia and gout.

[0019] Also described herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of GLUT9.

[0020] Also described herein, in some embodiments, are methods of inhibiting GLUT9, comprising contacting GLUT9 with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] Also described herein, in some embodiments, is a method for treating a GLUT9-mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the disorder is selected from hyperuricemia, gout, and uncontrolled gout, including coexisting and associated disorders.

[0022] Also described herein, in some embodiments, are methods for treating a GLUT9-mediated disorder, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof; and another therapeutic agent. In some embodiments, the other therapeutic agent is selected from an inhibitor of uric acid synthesis, a uricosuric agent, and a uric acid catabolic agent. In some such embodiments, the uricosuric agent is selected from probenecid, lesinurad, benzbromarone, and sulfinpyrazone. In some such embodiments, the inhibitor of uric acid synthesis is selected from allopurinol and febuxostat. In some such embodiments, the uric acid catabolic agent is pegloticase. In some other embodiments, the other therapeutic agent is colchicine.

[0023] Also described herein, in some embodiments, are methods for lowering blood uric acid levels in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0024] Packaging materials, articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging materials, and labeling indicating that the compound or composition, or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used to inhibit GLUT9 or for the treatment, prevention, or amelioration of one or more symptoms of a disease or condition that would benefit from inhibiting GLUT9, are provided.

[0025] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and 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 disclosure will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0026] [Figure 1] 1 shows the nucleic acid sequence of human GLUT9B / GLUT9 variant 2 / Q96S37-2 / Glut9 isoform 2 (SEQ ID NO: 3). [Figure 2] 1 shows the amino acid sequence of human GLUT9B / GLUT9 variant 2 / Q96S37-2 / Glut9 isoform 2 (SEQ ID NO: 4). [Figure 3] The nucleic acid sequence of human URAT1 (SEQ ID NO: 5) is shown. [Figure 4] The amino acid sequence of human URAT1 (SEQ ID NO: 6) is shown. [Figure 5] The pIRESpuro vector from Takara Bio is shown. [Figure 6] Figure 1 shows the cloning strategy for GLUT9B and URAT1 to create a bicistronic vector for stable cell line generation. [Figure 7] 1 shows the conversion of uric acid to allantoin. [Figure 8]Figure 1 shows the Aspergillus oryzae uricase vector from GenScript. DETAILED DESCRIPTION OF THE INVENTION

[0027] The compounds disclosed herein may have useful GLUT9 inhibitory activity and may be used in the treatment or prevention of diseases or conditions in which GLUT9 plays an active role. Accordingly, in broad aspects, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for inhibiting GLUT9. Other embodiments provide methods for treating a GLUT9-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by GLUT9 inhibition.

[0028] Compounds of the Disclosure Disclosed herein are compounds useful for inhibiting GLUT9 activity. In some embodiments, the compounds described herein are useful in the treatment or prevention of diseases or conditions in which GLUT9 plays an active role.

[0029] In one aspect, provided herein is a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; X is selected from CH and N; Y is selected from CH, S, O, and N; Z is a bond and CR 7 Selected from; R 1is selected from aryl and heteroaryl; R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or more R 6 may be optionally replaced by; R 3 teeth, alkyl optionally substituted with SO2-alkyl; alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl Selected from; Each R 4 is, independently, R 5 alkoxy optionally substituted with R 5 alkylamino optionally substituted with R 5 dialkylamino optionally substituted with SO2R 8a , Alkylthio, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, Hello, alkyl, and Haloalkyl Select from; or R 1 Two R on adjacent carbon atoms of 4 the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy, and alkoxyalkoxy; Each R 6 are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, cyano, and tetrazolyl; R 7 is selected from hydrogen and halo; R 8a and R 8b are each independently selected from alkyl, amino, alkylamino, and dialkylamino; X and Y are not both CH).

[0030] For all embodiments, the substituents are selected from among a subset of the listed options. For example, in some embodiments, X is CH. In other embodiments, X is N.

[0031] In some embodiments, Y is CH or N. In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, Y is O. In some embodiments, Y is S.

[0032] In some embodiments, Z is a bond. In some embodiments, Z is CR 7 In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is halogen. In some embodiments, R 7 is F or Cl. In some embodiments, Z is a bond, CH, CF, or CCl. In some embodiments, Z is CH or CCl. In some embodiments, Z is a bond or CH. In some embodiments, Z is CH.

[0033] In some embodiments, X is CH; Y is S, O, or N.

[0034] In some embodiments, X is CH; Y is N; and Z is CR 7 In some embodiments, X is CH; Y is N; and Z is CH.

[0035] In some embodiments, X is N; and Y is CH, S, O, or N.

[0036] In some embodiments, X is N; Y is CH; and Z is CR 7 In some embodiments, X is N; Y is CH; and Z is CH.

[0037] In some embodiments, X is N; Y is N; and Z is CR 7 In some embodiments, X is N; Y is N; and Z is CH.

[0038] In some embodiments, X is selected from CH and N; Y is selected from CH and N; and Z is CR 7 In some embodiments, X is CH; Y is N; and Z is CR 7 or X is N; Y is CH; Z is CR 7 or X is N; Y is N; Z is CR 7 In some embodiments, X is CH; Y is N; and Z is CR 7 In some embodiments, X is N; Y is CH; and Z is CR 7 In some embodiments, X is N; Y is N; and Z is CR 7 In some embodiments, R 7 is hydrogen, F, or Cl. In some embodiments, R 7 is hydrogen. In some such embodiments, R 7 is F. In some such embodiments, R 7 is Cl.

[0039] In some embodiments, X is selected from CH and N; Y is selected from CH and N; and Z is CH. In some embodiments, X is CH; Y is N; Z is CH; or X is N; Y is CH; Z is CH; or X is N; Y is N; Z is CH. In some embodiments, X is CH; Y is N; Z is CH. In some embodiments, X is N; Y is CH; Z is CH. In some embodiments, X is N; Y is CH; Z is CH. In some embodiments, X is N; Y is N; Z is CH.

[0040] In some embodiments, the compound is a compound of formula (I'-A), or a pharmaceutically acceptable salt thereof: [ka] is.

[0041] In some embodiments, the compound is a compound of formula (I'-B) or formula (I'-C), or a pharmaceutically acceptable salt thereof: [ka] is.

[0042] In some embodiments, R 1 is aryl or heteroaryl. In some embodiments, R 1 is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, R 1 is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl, where the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring, or the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, R 1 is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, R1 is phenyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, or a bicyclic heteroaryl.

[0043] In some embodiments, R 1 is aryl. In some embodiments, R 1 is phenyl or naphthyl. In some embodiments, R 1 is phenyl.

[0044] In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is a monocyclic heteroaryl or a bicyclic heteroaryl. In some embodiments, R 1 is a monocyclic heteroaryl or a bicyclic heteroaryl, wherein the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring, or the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.

[0045] In some embodiments, R 1 is monocyclic heteroaryl. In some embodiments, R 1 is a 5-membered monocyclic heteroaryl or a 6-membered monocyclic heteroaryl. In some embodiments, R 1 is a 5-membered monocyclic heteroaryl or a 6-membered monocyclic heteroaryl, wherein the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring, or the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.

[0046] In some embodiments, R 1 is a 5-membered monocyclic heteroaryl. In some embodiments, R 1is a 5-membered monocyclic heteroaryl, wherein the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring, or the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, R 1 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, oxazolyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, or tetrazolyl.

[0047] In some embodiments, R 1 is a 6-membered monocyclic heteroaryl. In some embodiments, R 1 is a 6-membered monocyclic heteroaryl, wherein the heteroaryl contains 1 to 4 N atoms. In some embodiments, R 1 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0048] In some embodiments, R 1 is a bicyclic heteroaryl. In some embodiments, R 1 is a C2-C9 bicyclic heteroaryl. In some embodiments, R 1 is a bicyclic heteroaryl containing 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring system or 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring system. In some embodiments, R 1 is a bicyclic heteroaryl containing 1 O atom and 0 or 1 N atoms in the ring system. In some embodiments, R 1 is indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, tetrazolopyridazinyl, furopyridinyl, or pyrrolopyridinyl. 1is benzofuranyl or furopyridinyl. In some embodiments, R 1 is benzofuranyl.

[0049] In some embodiments, R 1are phenyl; 1H-indol-5-yl; 1H-indol-6-yl; thiophen-2-yl; thiazol-5-yl; 3-oxo-2,3-dihydrobenzofuran-5-yl; 2,3-dihydrobenzofuran-5-yl; furo[2,3-b]pyridin-5-yl; 2,3-dihydrofuro[2,3-b]pyridin-5-yl; pyridin-3-yl; pyridin-4-yl; benzo[d]oxazol-6-yl; 2,3-dihydrobenzo[b][1,4]dioxin-6-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4]dioxin-6-yl ]oxazin-6-yl;3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl;Furo[2,3-b]pyridin-5-yl;2,3-Dihydrobenzofuran-5-yl;2H-Indazol-6-yl;1H-Pyrrolo[2,3-b]pyridin-4-yl;[1,2,4]triazolo[1,5-a]pyridin-6-yl;Imidazo[1,2-a]pyrimidin-6-yl;2H-Indazol-6-yl;2H-Indazol-5-yl;Quinolin-3-yl;Quinolin-4-yl;1H-Pyrazol-5-yl;Thieno[3, 2-b]thiophen-2-yl;benzo[c][1,2,5]thiadiazol-5-yl;imidazo[1,2-a]pyridin-6-yl;4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;imidazo[1,5-a]pyridin-6-yl;imidazo[1,2-a]pyridin-7-yl;6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl;thieno[2,3-b]pyridin-5-yl;imidazo[1,2-b]pyridazin-6-yl;[1,2,4]triazolo[1,5-a]pyridin-7-yl; 2H-Indazol-7-yl; 1H-Pyrrolo[2,3-b]pyridin-4-yl; 2H-Indazol-4-yl; 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl; 1H-Pyrazolo[3,4-b]pyridin-5-yl; 2H-Pyrazolo[3,4-b]pyridin-5-yl; 3H-Imidazo[4,5-b]pyridin-6-yl; Imidazo[1,2-b]pyridazin-6-yl; Quinoline-4-yl; Benzo[b]thiophen-5-yl; Chroman-6-yl; 1-Oxo-1,3-dihydroisobenzofuran-5-yl;1,1-dioxide-2,3-dihydrobenzo[b]thiophen-5-yl; 1,1-dioxidethiochroman-6-yl; benzofuran-5-yl; or benzo[d][1,3]dioxol-5-yl.

[0050] In some embodiments, R 1 phenyl; 3-oxo-2,3-dihydrobenzofuran-5-yl; 2,3-dihydrobenzofuran-5-yl; 2,3-dihydrofuro[2,3-b]pyridin-5-yl; 2,3-dihydrobenzo[b][1,4]dioxin-6-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 2,3-dihydrobenzofuran-5-yl; benzo[b]thiophen-5-yl; chroman-6-yl; 1-oxo-1,3-dihydroisobenzofuran-5-yl; 1,1-dioxide-2,3-dihydrobenzo[b]thiophen-5-yl; 1,1-dioxidethiochroman-6-yl; benzofuran-5-yl; or benzo[d][1,3]dioxol-5-yl.

[0051] In some embodiments, m is an integer from 0 to 4. In some embodiments, m is 0 to 3. In some embodiments, m is 0 to 2. In some embodiments, m is 0 to 1. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 1 to 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0052] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with R 5 alkylamino optionally substituted with R 5dialkylamino optionally substituted with SO2R 8a , alkylthio, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl.

[0053] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl.

[0054] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C6 alkylamino optionally substituted with R 5 di-(C1-C6 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl.

[0055] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with SO2R 8a , C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl.

[0056] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl. In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl. In some embodiments, each R 4 is independently selected from alkoxy, haloalkoxy, and halo.

[0057] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5C1-C6 alkylamino optionally substituted with R 5 di-(C1-C6 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with SO2R 8a , C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 4 is independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, and halo. 4 is independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, F, and Cl.

[0058] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C4 alkylamino optionally substituted with R 5 di-(C1-C4 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C4 alkylamino optionally substituted with R 5di-(C1-C4 alkyl)-amino optionally substituted with C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 4 is independently selected from C1-C6 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl. 4 is independently selected from C1-C6 alkoxy, C1-C4 haloalkoxy, and halo.

[0059] In some embodiments, one R 4 SO2R 8a When R 8a is selected from C1-C6 alkyl, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino. 4 SO2R 8a When R 8a is selected from C1-C4 alkyl, amino, C1-C4 alkylamino, and di-(C1-C4 alkyl)-amino. 4 But SO2R 8a When R 8a is selected from —CH 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .

[0060] In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents are combined to form a fused heterocycloalkyl or a fused heteroaryl.

[0061] In some embodiments, R1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C4 alkoxy)-C1-C6 alkyl. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms, either of which may be optionally substituted with one or more C1-C4 alkyl, halo, C1-C4 alkoxy, or (C1-C4 alkoxy)-C1-C4 alkyl. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused dioxolane or furan ring, either of which may be optionally substituted with one or more C1-C4 alkyl, halo, C1-C4 alkoxy, or (C1-C4 alkoxy)-C1-C4 alkyl. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms. In some embodiments, R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused dioxolane or fused furan ring.

[0062] In some embodiments, R 1 is phenyl and R 1Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl. In some embodiments, R 1 is phenyl and R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C4 alkoxy)-C1-C6 alkyl. In some embodiments, R 1 is phenyl and R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms, either of which may be optionally substituted with one or more C1-C4 alkyl, halo, C1-C4 alkoxy, or (C1-C4 alkoxy)-C1-C4 alkyl. In some embodiments, R 1 is phenyl and R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused dioxolane or furan ring, either of which may be optionally substituted with one or more C1-C4 alkyl, halo, C1-C4 alkoxy, or (C1-C4 alkoxy)-C1-C4 alkyl. In some embodiments, R 1 is phenyl and R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms. In some embodiments, R 1 is phenyl and R 1 Two R on adjacent carbon atoms of 4The substituents combine to form a fused dioxolane or fused furan ring.

[0063] In some embodiments, each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy, and alkoxyalkoxy. In some embodiments, each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy. In some embodiments, each R 5 is selected from alkoxy, amino, alkylamino, and dialkylamino.

[0064] In some embodiments, each R 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 haloalkoxy, and (C1-C6 alkoxy)-C1-C6 alkoxy. 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C6 haloalkoxy, and (C1-C4 alkoxy)-C1-C6 alkoxy. In some embodiments, each R 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, and C1-C6 haloalkoxy.

[0065] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R 1 Two R on adjacent carbon atoms of 4The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; and m is an integer from 0 to 3.

[0066] In some embodiments, each R 4 is independently selected from alkoxy, haloalkoxy, and halo; or R 1 Two R on adjacent carbon atoms of 4 The substituents together form a fused heterocycloalkyl or a fused heteroaryl; m is an integer from 0 to 3.

[0067] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; and m is an integer from 0 to 3.

[0068] In some embodiments, each R 4 is independently selected from alkoxy, haloalkoxy, and halo; or R 1 Two R on adjacent carbon atoms of 4 The substituents together form a fused heterocycloalkyl or a fused heteroaryl; m is an integer from 0 to 3.

[0069] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, and halo; or R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl.

[0070] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a and halo; or R 1 Two R on adjacent carbon atoms of 4 The substituents are combined to form a fused heterocycloalkyl or a fused heteroaryl.

[0071] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C6 alkylamino optionally substituted with R 5 di-(C1-C6 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl; each R 5is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 haloalkoxy, and (C1-C6 alkoxy)-C1-C6 alkoxy.

[0072] In some embodiments, each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C4 alkylamino optionally substituted with R 5 di-(C1-C6 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C 6 selected from alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C4 alkoxy)-C1-C6 alkyl; each R 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C6 haloalkoxy, and (C1-C4 alkoxy)-C1-C6 alkoxy.

[0073] In some embodiments, each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, and halo; or two R 4 The substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkyl, or alkoxyalkyl. In some embodiments, each R4 are independently 5 alkoxy optionally substituted with SO2R 8a and halo; or two R 4 The substituents combine to form a fused heterocycloalkyl or heteroaryl. In some embodiments, R 4 is an alkoxy.

[0074] In some embodiments, R 3 is selected from alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl optionally substituted with SO-alkyl. In some embodiments, R 3 is selected from alkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl optionally substituted with SO-alkyl. In some embodiments, R 3 is selected from alkyl, alkoxyalkyl, haloalkyl, and haloalkoxyalkyl. In some embodiments, R 3 is selected from alkyl and alkoxyalkyl. In some embodiments, R 3 is alkoxyalkyl. In some embodiments, R 3 is alkyl. In some embodiments, R 3 is haloalkyl. In some embodiments, R 3 is haloalkoxyalkyl. In some embodiments, R 3 is selected from alkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl optionally substituted with SO2-alkyl.

[0075] In some embodiments, R 3is selected from C1-C6 alkyl optionally substituted with SO2-(C1-C6 alkyl), (C1-C6 alkoxy)-C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 haloalkoxy)-C1-C6 alkyl, (C3-C6 cycloalkyl)-C1-C6 alkyl, and (C3-C6 cycloalkoxy)-C1-C6 alkyl. 3 is selected from (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, (C1-C4 haloalkoxy)-C1-C6 alkyl, (C3-C6 cycloalkyl)-C1-C6 alkyl, and (C3-C6 cycloalkoxy)-C1-C6 alkyl. 3 is selected from (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, and (C1-C4 haloalkoxy)-C1-C6 alkyl. 3 is selected from (C1-C4 alkoxy)-C1-C6 alkyl and (C1-C4 haloalkoxy)-C1-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C1-C6 alkyl. In some embodiments, R 3-CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2CH2CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CH2CHF2, -CH2CH2CH2CH2CHF2 , -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2CH2CH2CF3, -CH2CH2CF2CF3, -CH2CH2CF2CH3, -CH2CH2CH2CHF2, -CH2CF2CH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH3, -CH2OCF3, -CH2OCF2CH3, -CH2OCF2CF3, -CH2CH2CH2OCF3, -CH2CH2CH2OCF2CH3, -CH2CH2CH2OCF2CF3, -CH2CH2CH2CH2OCF3, -CH2CH2CH2OCF3, -CH2CH2CH2OCF3, -CH2(cyclopropyl), -CH2CH2(cyclopropyl), -CH2CH2CH2(cyclopropyl), or -CH2CH2CH2CH2(cyclopropyl). In some embodiments, R 3 is -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2CH2CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CH2CH2CHF2, -CH2CH2CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2CH2CH2CF3, -CH2CH2CF2CF3, -CH2CH2CH2CHF2, -CH2CF2CH2CH3, -CH2CH2CH2CHF2, -CH2CF2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2CH2CH2OCF3, or -CH2CH2CH2CH2OCF3.

[0076] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or more R 6In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, either of which may be one or more R 6 In some embodiments, R 2 is a monocyclic or bicyclic heteroaryl, either of which may be one or more R 6 may be optionally replaced by

[0077] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which is selected from 1 to 3 R 6 In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of 1 to 3 R 6 In some embodiments, R 2 is a monocyclic or bicyclic heteroaryl, which is a heterocyclic group consisting of one to three R 6 may be optionally replaced by

[0078] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or two R 6 In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one or two R 6 In some embodiments, R 2 is a monocyclic or bicyclic heteroaryl, which is a heteroaryl group selected from one or two R 6 may be optionally replaced by

[0079] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be present at one R 6In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 In some embodiments, R 2 is a monocyclic or bicyclic heteroaryl, which is a heteroaryl group consisting of one R 6 is replaced by

[0080] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 In some embodiments, R 2 is a monocyclic heterocycloalkyl, a fused bicyclic heterocycloalkyl, a bridged bicyclic heterocycloalkyl, or a spiro bicyclic heterocycloalkyl, any of which may be substituted by one R 6 is replaced by

[0081] In some embodiments, R 2 is a monocyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 In some embodiments, R 2 is a monocyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 and heterocycloalkyl is a 3-, 4-, 5-, or 6-membered ring containing 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. 2 is a monocyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 and heterocycloalkyl is a 3-, 4-, 5-, or 6-membered ring containing 1-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. 2 is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, any of which may be present in the presence of one R 6 In some embodiments, R 2 is aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, any of which may be present in the presence of one R 6 In some embodiments, R2 is pyrrolidinyl or piperidinyl, either of which may be one R 6 In some embodiments, R 2 is pyrrolidinyl, which has one R 6 In some embodiments, R 2 is piperidinyl, which has one R 6 is replaced by

[0082] In some embodiments, R 2 is a fused bicyclic heterocycloalkyl, a bridged bicyclic heterocycloalkyl, or a spiro bicyclic heterocycloalkyl, any of which may be fused with one R 6 is replaced by

[0083] In some embodiments, each R 6 are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, cyano, and tetrazolyl. In some embodiments, each R 6 are independently hydroxyl, carboxyl, carboxyl alkyl, carboxyl alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl. In some embodiments, R 6 is carboxyl, carboxyl alkyl, C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl. In some embodiments, R 6 is selected from carboxyl, carboxylalkyl, and heterocycloalkyl.

[0084] In some embodiments, each R 6are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, cyano, and tetrazolyl. In some embodiments, each R 6 are independently carboxyl, carboxylalkyl, halo, alkyl, SO2R 8b , C(=O)NHSO2R 8b and tetrazolyl. In some embodiments, each R 6 are independently carboxyl, carboxylalkyl, halo, alkyl, SO2R 8b , C(=O)NHSO2R 8b and tetrazolyl. In some embodiments, R 6 is carboxyl.

[0085] In some embodiments, each R 6 are independently -C(=O)OH, -CH2C(=O)OH, -C(=O)O-C1-C6 alkyl, -C(=O)NHSO2R 8b and tetrazolyl. In some embodiments, R 6 is -C(=O)OH, -CH2C(=O)OH, -C(=O)O-C1-C4 alkyl, -C(=O)NHSO2R 8b and tetrazolyl. In some embodiments, R 6 is -C(=O)OH.

[0086] In some embodiments, one R 6 -C(=O)NHSO2R 8b When R 8b is selected from C1-C6 alkyl, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino. 6 -C(=O)NHSO2R 8b When R 8bis selected from C1-C4 alkyl, amino, C1-C4 alkylamino, and di-(C1-C4 alkyl)-amino. 6 But -C(=O)NHSO2R 8b When R 8b is selected from —CH 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .

[0087] In some embodiments, R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one or more R 6 Each R is replaced by 6 are independently hydroxyl, carboxyl, carboxyl alkyl, carboxyl alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl; R 8b is selected from alkyl, amino, alkylamino, dialkylamino.

[0088] In some embodiments, R 2 is a monocyclic heterocycloalkyl, which is a heterocyclic ring formed by one R 6 Replaced by ;R 6 is carboxyl, carboxyl alkyl, C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl; R 8b is selected from alkyl, amino, alkylamino, dialkylamino.

[0089] In some embodiments, R 2 is piperidinyl, which has one R 6 Replaced by ;R 6 is selected from carboxyl, carboxylalkyl, and heterocycloalkyl.

[0090] In some embodiments, the compound is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 3; R 2 is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one or more R 6 is replaced by; R 3 is selected from alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl optionally substituted with SO2-alkyl; Each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; Each R 6 are independently hydroxyl, carboxyl, carboxyl alkyl, carboxyl alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl; R 8b is selected from alkyl, amino, alkylamino, dialkylamino).

[0091] In some embodiments, R 2 is a monocyclic heterocycloalkyl, which is a heterocyclic group consisting of one R 6 is replaced by

[0092] In some embodiments, the compound is a compound of formula (V), or a pharmaceutically acceptable salt thereof: [ka] is.

[0093] In some embodiments, R 3 is selected from alkyl, alkoxyalkyl, haloalkyl, and haloalkoxyalkyl; Each R 4 is independently selected from alkoxy, haloalkoxy, and halo; or R 1 Two R on adjacent carbon atoms of 4 the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R 6 is carboxyl, carboxyl alkyl, C(=O)NHSO2R 8b , heterocycloalkyl, and tetrazolyl; R 8b is selected from alkyl, amino, alkylamino, dialkylamino.

[0094] In some embodiments, R 3 is selected from alkyl and alkoxyalkyl; Each R 4 is independently selected from alkoxy, haloalkoxy, and halo; or R 1 Two R on adjacent carbon atoms of 4 the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R 6 is selected from carboxyl, carboxylalkyl, and heterocycloalkyl.

[0095] In some embodiments, the compound is a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; Y is N or CH; R 3 teeth, C1-C6 alkyl optionally substituted with SO2-(C1-C6 alkyl); (C1-C6 alkoxy)-(C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 haloalkoxy)-C1-C6 alkyl, (C3-C6 cycloalkyl)-C1-C6 alkyl, and (C3-C6 cycloalkoxy)-C1-C6 alkyl; Each R 4 is, independently, R 5 C1-C6 alkoxy optionally substituted with R 5 C1-C6 alkylamino optionally substituted with R 5 di-(C1-C6 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, Hello, C1-C6 alkyl, and selected from C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which is optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C6 alkoxy)-C1-C6 alkyl; Each R 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 haloalkoxy, and (C1-C6 alkoxy)-C1-C6 alkoxy; R 6 is -C(=O)OH, -CH2C(=O)OH, -C(=O)O-C1-C6 alkyl, -C(=O)NHSO2R 8b and tetrazolyl; R 8a and R 8b are each independently selected from C1-C6 alkyl, amino, C1-C6 alkylamino, and di-(C1-C6 alkyl)-amino.

[0096] In some embodiments, R 3 is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0097] In some embodiments, Y is N or CH; R 3is selected from C1-C6 alkyl, (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, (C1-C4 haloalkoxy)-C1-C6 alkyl, (C3-C6 cycloalkyl)-C1-C6 alkyl, and (C3-C6 cycloalkoxy)-C1-C6 alkyl; Each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C4 alkylamino optionally substituted with R 5 di-(C1-C4 alkyl)-amino optionally substituted with SO2R 8a , C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which is optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C4 alkoxy)-C1-C6 alkyl; Each R 5 is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C6 haloalkoxy, and (C1-C4 alkoxy)-C1-C6 alkoxy; R 6 is -C(=O)OH, -CH2C(=O)OH, -C(=O)O-C1-C4 alkyl, -C(=O)NHSO2R 8b and tetrazolyl; R 8a and R 8b are each independently selected from C1-C6 alkyl, amino, C1-C4 alkylamino, and di-(C1-C4 alkyl)-amino.

[0098] In some embodiments, R 3is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0099] In some embodiments, the compound is a compound of formula (VI-1): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; Y is N or CH; R 3 is selected from C1-C6 alkyl, (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, (C1-C4 haloalkoxy)-C1-C6 alkyl, (C3-C6 cycloalkyl)-C1-C6 alkyl, and (C3-C6 cycloalkoxy)-C1-C6 alkyl; Each R 4 are independently 5 C1-C6 alkoxy optionally substituted with R 5 C1-C4 alkylamino optionally substituted with R 5di-(C1-C4 alkyl)-amino optionally substituted with C1-C6 haloalkoxy, C3-C6 cycloalkoxy, (C3-C6 cycloalkyl)-C1-C6 alkoxy, halo, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 the substituents combine to form a fused 5-membered heterocycloalkyl or a fused 5-membered heteroaryl, either of which is optionally substituted with one or more C1-C6 alkyl, halo, oxo, C1-C6 alkoxy, or (C1-C4 alkoxy)-C1-C6 alkyl; Each R 5 are independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)-amino, C1-C6 haloalkoxy, and (C1-C4 alkoxy)-C1-C6 alkoxy.

[0100] In some embodiments, R 3 is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0101] In some embodiments, the compound is a compound of formula (VI-2): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; Y is N or CH; R 3 is selected from C1-C6 alkyl, (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, and (C1-C4 haloalkoxy)-C1-C6 alkyl; Each R 4 is independently selected from C1-C6 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl; or R 1 Two R on adjacent carbon atoms of 4 The substituents combine to form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms, either of which may be optionally substituted with one or more C1-C4 alkyl, halo, C1-C4 alkoxy, or (C1-C4 alkoxy)-C1-C4 alkyl.

[0102] In some embodiments, R 3 is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0103] In some embodiments, the compound is a compound of formula (VI-3): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 2; Y is N or CH; R 3 is selected from C1-C6 alkyl, (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, and (C1-C4 haloalkoxy)-C1-C6 alkyl; Each R 4 are independently selected from C1-C6 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0104] In some embodiments, m is 0 or 1; R 4 is selected from C1-C6 alkoxy, C1-C4 haloalkoxy, and halo. 3 is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0105] In some embodiments, the compound is a compound of formula (VI-4): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 2; Y is N or CH; R 3 is selected from C1-C6 alkyl, (C1-C4 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, and (C1-C4 haloalkoxy)-C1-C6 alkyl; Each R 4 are independently selected from C1-C6 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0106] In some embodiments, m is 0 or 1; R 4 is selected from C1-C6 alkoxy, C1-C4 haloalkoxy, and halo. 3 is selected from C3-C6 alkyl, (C1-C4 alkoxy)-C3-C6 alkyl, C3-C6 haloalkyl, and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is selected from (C1-C4 alkoxy)-C3-C6 alkyl and (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 alkoxy)-C3-C6 alkyl. In some embodiments, R 3 is (C1-C4 haloalkoxy)-C3-C6 alkyl. In some embodiments, Y is N. In some embodiments, Y is CH.

[0107] In some embodiments, the compound is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 4; X is selected from CH and N; Y is selected from CH, S, O, and N; Z is a bond and CR 7 Selected from; R 1 is selected from aryl and heteroaryl; R 2 is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or more R 6 may be optionally replaced by; R 3 teeth, Alkyl optionally substituted with SO2-alkyl; alkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl Selected from; Each R 4 is, independently, R 5 alkoxy optionally substituted with SO2R 8a , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, and Halo Selected from or or two R's 4 the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkyl, or alkoxyalkyl; Each R 5 is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; Each R 6 are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO2R 8b , C(=O)NHSO2R 8b , heterocycloalkyl, cyano, and tetrazolyl; R 7 is selected from hydrogen and halo; R 8a and R 8b are each independently selected from alkyl, amino, alkylamino, and dialkylamino; X and Y are not both CH).

[0108] In some embodiments, the compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 3; R 2 is one or more R 6 is a monocyclic or bicyclic heterocycloalkyl optionally substituted with Each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a and halo, or two R 4 the substituents taken together form a fused heterocycloalkyl or heteroaryl; R 5 is selected from alkoxy, amino, alkylamino, dialkylamino; Each R 6 are independently carboxyl, carboxylalkyl, halo, alkyl, SO2R 8b , C(=O)NHSO2R 8b and tetrazolyl; R 8a and R 8bare each independently selected from alkyl, amino, alkylamino, and dialkylamino.

[0109] In some embodiments, the compound is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof (wherein m is an integer from 0 to 3; Each R 4 are independently 5 alkoxy optionally substituted with SO2R 8a and halo, or two R 4 the substituents taken together form a fused heterocycloalkyl or heteroaryl; R 5 is selected from alkoxy, amino, alkylamino, dialkylamino; R 6 is carboxyl, carboxyl alkyl, halo, alkyl, SO2R 8b , C(=O)NHSO2R 8b and tetrazolyl; R 8a and R 8b are each independently selected from alkyl, amino, alkylamino, and dialkylamino.

[0110] Also provided are embodiments in which any of the above embodiments may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.

[0111] As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment in which two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH.

[0112] That is, any combination of the groups described above for the various variables is contemplated herein. Throughout this specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0113] Exemplary compounds of the present invention include those set forth in the table below.

[0114] [Table 1]

[0115] [Table 2]

[0116] [Table 3]

[0117] [Table 4]

[0118] [Table 5]

[0119] [Table 6]

[0120] [Table 7]

[0121] [Table 8]

[0122] [Table 9]

[0123] Table 10

[0124]

Table 11

[0125]

Table 12

[0126]

Table 13

[0127]

Table 14

[0128]

Table 15

[0129] Table 16

[0130] Table 17

[0131] Table 18

[0132]

Table 19

[0133] Table 20

[0134] Table 21

[0135] Table 22

[0136] Table 23

[0137] Table 24

[0138] Table 25

[0139] Table 26

[0140] Table 27

[0141] Table 28

[0142] Table 29

[0143] [Table 30]

[0144] [Table 31]

[0145] [Table 32]

[0146] [Table 33]

[0147] [Table 34]

[0148] [Table 35]

[0149] [Table 36]

[0150] [Table 37]

[0151] [Table 38]

[0152] [Table 39]

[0153] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1.

[0154] Also provided herein is a compound selected from the examples disclosed herein.

[0155] definition As used herein, the following terms have the meanings indicated.

[0156] When a range of values ​​is disclosed, the notation "n1... to n2" or "between n1... and n2" is used, where n1 and n2 are numbers, and unless otherwise indicated, this notation is intended to include the value itself and the range therebetween. The range may be integer or continuous between and including the end values. As an example, the range "2 to 6 carbons" includes 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, comparing the range "1 to 3 μM (micromolar)," this includes 1 μM, 3 μM, and all significant figures therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0157] The term "about," as used herein, is intended to qualify the numerical value it modifies and indicates that such value is variable within a range. When a specific range is not recited, such as a margin of error or standard deviation for an average value given in a data chart, the term "about" should be understood to mean the greater of a range that includes the recited value and a range that also includes that number by rounding up or down taking into account significant digits, as well as a range that includes the recited value plus or minus 20%.

[0158] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bonded to the carbonyl was carbon. An "acetyl" group refers to a -C(=O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0159] The term "alkenyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0160] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0161] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like. In some embodiments, an alkoxy group refers to a (alkyl)-O- group, where alkyl is as defined herein. In some embodiments, an alkoxy group is a C1-C6 alkoxy, which refers to a (C1-C6 alkyl)-O- group.

[0162] An "alkyl" group refers to an aliphatic hydrocarbon group. The term "alkyl," as used herein, alone or in combination, refers to a straight- or branched-chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl will contain 1 to 10 carbon atoms. In further embodiments, the alkyl will contain 1 to 8 carbon atoms. An alkyl group can be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. In some embodiments, an alkyl is a C1-C6 alkyl. In one aspect, an alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH2-). In some embodiments, alkylene is a C1-C6 alkylene. In other embodiments, alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, alkylene is -CH2-. Unless otherwise specified, the term "alkyl" can include "alkylene" groups.

[0163]

[0033] "Alkoxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by an alkoxy group, as defined herein. In some embodiments, an alkoxyalkyl is a (C-C alkoxy)-C-C alkyl, which may also be considered a (C-C alkyl)-O-(C-C alkyl)- group. In some embodiments, an alkoxyalkyl is a (C-C alkoxy)-C-C alkyl, which may also be considered a (C-C alkyl)-O-(C-C alkyl)- group. Typical alkoxyalkyl groups include, but are not limited to, -CHOCH, -CHCHOCH, -CHCHCHOCH, -CHCHCHOCH, -CHCHCHCHOCH, -CHOCHCH, -CHCHCHOCHCH, -CHCHCHCHOCHCH, -CHCHCHCHOCHCH, and the like.

[0164] "Alkoxyalkoxyalkyl" refers to an alkoxyalkyl in which one hydrogen atom of the alkoxy group is replaced by a second alkoxy group, as defined herein. In some embodiments, an alkoxyalkoxyalkyl is a (C-C alkoxy)-(C-C alkoxy)-C-C alkyl, which can also be considered as a (C-C alkyl)-O-(C-C alkyl)-O-(C-C alkyl)- group. In some embodiments, an alkoxyalkoxyalkyl is a (C-C alkoxy)-(C-C alkoxy)-C-C alkyl, which can also be considered as a (C-C alkyl)-O-(C-C alkyl)-O-(C-C alkyl)- group. Typical alkoxyalkoxyalkyl groups include, -CH2OCH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH2CH2CH2OCH2CH2OCH3, -CH2CH2CH2CH2OCH2CH2OCH3, -CH2CH2CH2CH2OCH2CH2OCH3, -CH2OCH2CH2CH2CH2OCH3, -CH2CH2OCH2CH2CH2OCH3, -CH2CH2CH2OCH2CH2CH2OCH3, -CH2CH2CH2CH2OCH2CH2OCH3, -CH2CH2CH2CH2OCH2CH2OCH3, -CH2OCH2CH Examples include, but are not limited to, 2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH2OCH2CH3, -CH2OCH2CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH2CH2OCH2CH3 and the like.

[0165]

[0023] "Alkoxyalkoxy" refers to an alkoxy in which one hydrogen atom is replaced by an alkoxy group, as defined herein. In some embodiments, an alkoxyalkoxy is a (C1-C6 alkoxy)-C1-C6 alkoxy, which may also be considered a (C1-C6 alkyl)-O-(C1-C6 alkyl)-O- group. In some embodiments, an alkoxyalkyl is a (C1-C4 alkoxy)-C1-C6 alkoxy, which may also be considered a (C1-C4 alkyl)-O-(C1-C6 alkyl)-O- group. Typical alkoxyalkyl groups include, but are not limited to, -OCH2CHOCH3, -OCH2CH2CHOCH3, -OCH2CH2CH2CHOCH3, -OCH2CHOCH2CH3, -OCH2CHOCH2CH3, -OCH2CHOCH2CH3, -OCH2CHOCH2CH2CHOCH3, -OCH2CHOCH2CH2CH3, -OCH2CHOCH2CH2CHOCH3, and the like.

[0166] The term "amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form a heterocycloalkyl, any of which may themselves be optionally substituted. In one aspect, "amino," as used herein, refers to the group -NH.

[0167] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups are mono- or dialkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups. In some embodiments, the term "alkylamino" refers to -N(alkyl) x H yIn some embodiments, the term "alkylamino" refers to an -NH(alkyl) group, and the term "dialkylamino" refers to an -N(alkyl) group. In some embodiments, an alkylamino group is a C1-C6 alkylamino, which refers to an -NH(C1-C6 alkyl) group. In some embodiments, a dialkylamino group is a di-(C1-C6 alkyl)-amino, which refers to an -N(C1-C6 alkyl) group.

[0168] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (RS-) group, where the term alkyl is as defined above and sulfur can be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. In some embodiments, the term "alkylthio" refers to an -S-(alkyl) group. In some embodiments, the alkylthio group is a C1-C6 alkylthio, which refers to an -S-(C1-C6 alkyl) group.

[0169] The term "alkynyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH, -C≡CCHCH, and -CHC≡CH. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene [-C:::C-, -C≡C-]. Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0170] The terms "amido" and "carbamoyl," as used herein, alone or in combination, refer to an amino group, as defined below, attached to the parent molecular moiety through a carbonyl group (or vice versa). The term "C-amido," as used herein, alone or in combination, refers to a -C(=O)N(RR') group with R and R' as defined herein or by the specifically enumerated "R" groups specified. The term "N-amido," as used herein, alone or in combination, refers to a RC(=O)N(R')- group with R and R' as defined herein or by the specifically enumerated "R" groups specified. The term "acylamino," as used herein, alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(=O)NH-).

[0171] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (n ​​is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0172] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which all atoms forming the backbone of the ring are carbon atoms. Thus, this term distinguishes carbocycle from "heterocyclic" ring or "heterocycle," in which the ring backbone contains at least one atom that is different from carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycle includes aryl and cycloalkyl.

[0173] The term "aryl," as used herein, alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, and such polycyclic ring systems are fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C8 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0174] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0175] The terms "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0176] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0177] The terms "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0178] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refer to an acyl group derived from an aryl-substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropinoyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0179] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy. In some embodiments, aryloxy, as used herein, refers to an aryl-O- group. In some embodiments, aryloxy is a phenoxy or a phenyl-O- group.

[0180] The terms "benzo" and "benz," as used herein, refer to a fused bicyclic or polycyclic ring system formed with benzene as one of the rings. Examples include benzofuran, benzothiophene, and benzimidazole.

[0181] The term "cycloalkyl," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing 3 to 12 carbon atom ring members, and may optionally be a benzo-fused ring system, optionally substituted as defined herein. In some embodiments, cycloalkyl groups include groups having 3 to 10 ring atoms. In certain embodiments, the cycloalkyl will contain 5 to 7 carbon atoms. In certain embodiments, the cycloalkyl will contain 3 to 6 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. "Bicyclic" and "tricyclic," as used herein, are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. The latter type of isomer is commonly exemplified by bicyclo[1,1,1]pentane, camphor, adamantine, and bicyclo[3,2,1]octane. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is C3-C4 cycloalkyl.

[0182] The term "cycloalkyloxy," as used herein, alone or in combination, refers to a cycloalkyl group attached to the parent molecular moiety through an oxy. In some embodiments, cycloalkyloxy is a C-C cycloalkoxy, which refers to a (C-C cycloalkyl)-O- group.

[0183] "Cycloalkylalkyl" refers to an alkyl in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein. In some embodiments, the cycloalkylalkyl is (C-C cycloalkyl)-C-C alkyl.

[0184] "Cycloalkoxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by a cycloalkoxy group, as defined herein. In some embodiments, cycloalkoxyalkyl is a (C-C cycloalkoxy)-C-C alkyl, which refers to a (C-C cycloalkyl)-O-(C-C alkyl)- group.

[0185] "Cycloalkylalkoxy" refers to an alkoxy in which one hydrogen atom is replaced by a cycloalkyl group, as defined herein. In some embodiments, cycloalkylalkoxy is a (C-C cycloalkyl)-C-C alkoxy, which refers to the group (C-C cycloalkyl)-(C-C alkyl)-O-.

[0186] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiazole ... oranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidaziridinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The aforementioned groups are either C-bonded (or C-linked) or N-bonded where possible. For example, a group derived from pyrrole includes both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0187] The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the term "heteroaryl," as used herein, alone or in combination, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will contain 5 to 7 atoms. This term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like. In some embodiments, heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms in the ring.In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0188] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the term "heterocyclalkyl," as used herein, alone or in combination, refers to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group, respectively, containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will contain 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl will contain 3 to 7 ring members in each ring. In further embodiments, the heterocycloalkyl will contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and carbocyclic fused and benzofused ring systems; further, both terms also include systems in which a heterocycle is fused to an aryl group, as defined herein, or an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocyclic groups may be optionally substituted unless specifically prohibited. In one aspect, heterocycloalkyl is a C-C 10 In another embodiment, heterocycloalkyl is a C4-C 10Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0189] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), attached to the parent molecular moiety from either the nitrogen or the acid terminus, and which can be optionally substituted as defined herein.

[0190] The term "O-carbamyl," as used herein, alone or in combination, refers to an --OC(.dbd.O)NRR' group, with R and R' as defined herein.

[0191] The term "N-carbamyl," as used herein, alone or in combination, refers to an ROC(=O)NR'- group, with R and R' as defined herein.

[0192] The term "carbonyl," as used herein, alone includes formyl [-C(=O)H] and in combination is a -C(=O)- group.

[0193] The terms "carboxyl" or "carboxy," as used herein, refer to -C(=O)OH or the corresponding "carboxylate" anion, such as that present in a carboxylate. An "O-carboxy" group refers to an RC(=O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(=O)OR group, where R is as defined herein.

[0194] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0195] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0196] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0197] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0198] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above, in which one or more hydrogen atoms are replaced with halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups are included. For example, a monohaloalkyl group can have an iodo, bromo, chloro, or fluoro atom within the group. Dihalo and polyhaloalkyl groups can have two or more of the same halo atom or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like. In one aspect, haloalkyl is C1-C6 haloalkyl. In another aspect, haloalkyl is C1-C4 haloalkyl.

[0199] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In one aspect, a haloalkoxy is a C1-C6 haloalkoxy, which refers to a (C1-C6 haloalkyl)-O- group. In another aspect, a haloalkoxy is a C1-C4 haloalkoxy, which refers to a (C1-C4 haloalkyl)-O- group.

[0200]

[0033] "Haloalkoxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by a haloalkoxy group, as defined herein. In some embodiments, a haloalkoxyalkyl is a (C-C haloalkoxy)-C-C alkyl, which may also be considered a (C-C haloalkyl)-O-(C-C alkyl)- group. In some embodiments, an alkoxyalkyl is a (C-C haloalkoxy)-C-C alkyl, which may also be considered a (C-C haloalkyl)-O-(C-C alkyl)- group. Typical haloalkoxyalkyl groups include, but are not limited to, -CHOCF, -CHCHOCF, -CHCHCHOCF, -CHCHCHOCF, -CHOCHCF, -CHCHOCHCF, -CHCHCHOCHCF, -CHCHCHCHOCHCF, -CHCHCHCHOCHCF, and the like.

[0201] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable, straight or branched chain, or combination thereof, that is fully saturated or contains 1 to 3 degrees of unsaturation, consisting of the specified number of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, where the N heteroatom may optionally be quaternized. The heteroatom may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive (e.g., -CH-NH-OCH).

[0202] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., --NN--.

[0203] The terms "hydroxy" or "hydroxyl," as used herein, alone or in combination, refer to --OH.

[0204] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0205] The term "imino," as used herein, alone or in combination, refers to =N-.

[0206] The term "iminohydroxy," as used herein, alone or in combination, refers to ═N(OH) and ═NO—.

[0207] The phrase "in the backbone" refers to the longest continuous or contiguous chain of carbon atoms beginning at the point of attachment of a group to a compound of any one of the formulas disclosed herein.

[0208] The term "isocyanato" refers to an --NCO group.

[0209] The term "isothiocyanato" refers to the group -NCS.

[0210] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0211] The term "lower", as used herein, alone or in combination, means, unless otherwise defined, containing from 1 to 6 carbon atoms (i.e., C1-C6 alkyl).

[0212] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

[0213] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, of which 1 to 4 of said members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl in which each of the fused rings contains 5 or 6 ring members, of which 1 to 4 heteroatoms are selected from N, O, and S.

[0214] The term "lower cycloalkyl," as used herein, alone or in combination, refers to a monocyclic cycloalkyl having 3 to 6 ring members (i.e., a C3-C6 cycloalkyl). A lower cycloalkyl can be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0215] The term "lower heterocycloalkyl," as used herein, alone or in combination, refers to a monocyclic heterocycloalkyl having 3 to 6 ring members, 1 to 4 of which can be heteroatoms selected from N, O, and S (i.e., a C3-C6 heterocycloalkyl). Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. A lower heterocycloalkyl can be unsaturated.

[0216] The term "lower amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which may be optionally substituted.

[0217] The term "mercaptyl," as used herein, alone or in combination, refers to an RS-group, where R is as defined herein.

[0218] The term "nitro," as used herein, alone or in combination, refers to -NO2.

[0219] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0220] The term "oxo," as used herein, alone or in combination, refers to =O.

[0221] The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0222] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0223] The terms "sulfonate," "sulfonic acid," and "sulfonic acid-containing," as used herein, alone or in combination, refer to the -SO3H group, the anion of which, as sulfonic acid, is used in salt form.

[0224] The term "sulfanyl," as used herein, alone or in combination, refers to --S--.

[0225] The term "sulfinyl," as used herein, alone or in combination, refers to --S(.dbd.O)--.

[0226] The term "sulfonyl," as used herein, alone or in combination, refers to a -S(=O)2-, -S(=O)2R, or -S(=O)2R- group, with R as defined herein.

[0227] The term "sulfonamide," as used herein, alone or in combination, includes both N-sulfonamide and S-sulfonamide. The term "N-sulfonamide" refers to either an RS(=O)NR'- or an -S(=O)NR'- group, with R and R' as defined herein. The term "S-sulfonamide" refers to an -S(=O)NRRR' or an -S(=O)NR- group, with R and R' as defined herein.

[0228] The terms "thia" and "thio," as used herein, alone or in combination, refer to an -S- group or an ether where the oxygen is replaced by sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0229] The term "thiol," as used herein, alone or in combination, refers to a --SH group.

[0230] The term "thiocarbonyl," as used herein, alone includes thioformyl-C(S)H and in combination is a -C(S)- group.

[0231] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.

[0232] The term "O-thiocarbamyl" refers to an --OC(S)NRR' group, with R and R' as defined herein.

[0233] The term "thiocyanato" refers to the group -CNS.

[0234] The term "trihalomethanesulfonamide" refers to a X3CS(=O)2NR- group, with X being a halogen and R as defined herein.

[0235] The term "trihalomethanesulfonyl" refers to a X3CS(=O)2- group where X is a halogen.

[0236] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.

[0237] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with a group as listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0238] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the appendant of any such definition is that which is attached to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule via an alkyl group.

[0239] When a group is defined to be "null," what is meant is that said group is absent.

[0240] The term "optionally substituted" means that the preceding group may or may not be substituted. When substituted, the substituents on the "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or a specific set of specified groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower halo, lower alkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxy ester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(=O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic ring or a heterocyclic ring of 0 to 3 heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CF3). When substituents are listed without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is identified as "substituted," the substituted form is specifically intended. In addition, different sets of optional substituents for a particular moiety may be defined as necessary; in these cases, the optional substituent, as defined, will often immediately follow the phrase "optionally substituted with."

[0241] In some embodiments, the term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0242] The term R or R', when appearing alone and without a numbered designation, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, unless otherwise defined, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether or not an R group has a numbered designation, R, R', and R n All R groups, including where n = (1, 2, 3,...n), all substituents, and all terms should be understood to be independent of all others in terms of selection from groups. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in the chain of elements from either end as depicted. For example, an unsymmetrical group such as -C(=O)N(R)- may be attached to either the carbon or nitrogen parent moiety.

[0243] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the asymmetric carbon atom. It should be understood that the present invention encompasses all stereochemically isomeric forms, including diastereoisomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be synthetically prepared from commercially available starting materials containing asymmetric centers, or by separation after separation, such as preparation of a mixture of enantiomeric products followed by conversion to a mixture of diastereomers, by separation or recrystallization, by chromatographic techniques, by direct separation of enantiomers on a chiral chromatographic column, or by any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and appropriate mixtures thereof. In addition, compounds may exist as tautomers; all tautomeric isomers are provided by the present invention. In addition, compounds disclosed herein may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Generally, solvated forms are considered equivalent to unsolvated forms.

[0244] The term "bond" refers to a covalent bond between two atoms, or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0245] The term "disease," as used herein, is generally intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (medical condition), in that all reflect an abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by characteristic signs and symptoms, and reduces the duration or quality of the human or animal's life.

[0246] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0247] A "GLUT9 inhibitor" is an inhibitor of GLUT9 activity that has an IC50 or IC60 of about 100 μM or less, and more typically about 50 μM or less, with respect to GLUT9 activity, as measured in the GLUT9 assay generally described herein. 50 "IC" refers to a compound that exhibits 50 " is the concentration of inhibitor that reduces the activity of an enzyme (e.g., GLUT9) to half-maximal levels. Certain compounds disclosed herein have been found to exhibit inhibition against GLUT9. In certain embodiments, the compounds have an EC50 for GLUT9 of about 2 μM or less, as measured in the GLUT9 assay described herein. 50 In a further embodiment, the compound will exhibit an EC 50 In a further embodiment, the compound will exhibit an EC 50 This will show that.

[0248] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in treating a disease or disorder or in conducting a clinical endpoint.

[0249] The term "pharmaceutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0250] As used herein, "treating," "treatment," and the like refer to reducing, ameliorating, or eliminating one or more of a disease's cause, progression, severity, or symptoms in a subject, or otherwise beneficially altering the disease in a subject, so as to ameliorate the disease. In certain embodiments, references to "treating" a subject at risk of developing a disease or at risk of disease progression to a worse state or to "treatment" of a subject are intended to include prevention. Prevention of a disease may include complete protection from the disease, for example, in the case of prevention of infection by a pathogen, or may include prevention of disease progression, for example, from prediabetes to diabetes. For example, prevention of a disease may not mean the complete elimination of any effects associated with the disease at any level, but instead may mean the prevention of disease symptoms to a clinically significant or detectable level. Prevention of a disease may also mean the prevention of disease progression to a later stage of the disease.

[0251] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of mammals include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient or subject or mammal is a human.

[0252] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein may also exist as prodrugs as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003; T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems Vol. 14 of the ACS Symposium Series; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. In addition, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug may be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful in some situations because they may be easier to administer than the compound, or parent drug. For example, they may be bioavailable by oral administration whereas the parent drug is not. A prodrug may also have improved stability in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug would be a compound that is administered as an ester (the "prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0253] The compounds disclosed herein may exist as pharmaceutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the desired compound. Base addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich, Wiley-VCHA, Zurich, Switzerland, 2002).

[0254] The term "pharmaceutically acceptable salt," as used herein, refers to a salt or zwitterionic form of a compound disclosed herein that is water- or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. Salts can be prepared during the final isolation and purification of the compound or separately by reacting the free base form of the appropriate compound with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, and the like. Examples of suitable salts include methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, and the basic groups in the compounds disclosed herein may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.

[0255] The compounds provided herein may optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like.

[0256] Examples of inorganic acids that can be used to form pharmaceutically acceptable addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of organic acids that can be used to form pharmaceutically acceptable addition salts include oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of a compound with an alkali metal or alkaline earth metal. Thus, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0257] Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, or ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0258] Certain compounds provided herein containing a carboxylic acid functional group can optionally exist as pharmaceutically acceptable salts containing a non-toxic pharmaceutically acceptable metal cation and a cation derived from an organic base. Exemplary metals include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. In some embodiments, the pharmaceutically acceptable metal is sodium. Exemplary organic bases include benzathine, (N 1 ,N 2-dibenzylethane-1,2-diamine), chloroprocaine (2-(diethylamino)ethyl 4-(chloroamino)-benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine (2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certain pharmaceutically acceptable salts are listed in Berge, et. al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0259] Salts of compounds can be made by reacting the free base form of the appropriate compound with a suitable acid.

[0260] Acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds provided herein may form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0261] Additionally, the compounds described herein can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0262] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, the solvent contains a stoichiometric or non-stoichiometric amount of solvent, and is formed during the process of isolation or crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0263] In some embodiments, moieties on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0264] In another embodiment, the compounds described herein are isotopically (e.g., with a radioisotope) or by other means. The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, such as: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I,124 I, 125 I, 131 In one aspect, the isotopically labeled compounds described herein, for example, 3 H and 14 Incorporation of radioactive isotopes such as C is useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0265] In some embodiments, the compounds described herein contain one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, the compounds exist in the R configuration. In some embodiments, the compounds exist in the S configuration. The compounds provided herein include all diastereoisomeric forms, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0266] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on either non-chiral or chiral chromatographic columns, or crystallization or recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, compounds are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0267] Pharmaceutical Compositions and Formulations The formulations may be prepared by any suitable method, typically by uniformly admixing the active compound with a liquid or finely divided solid carrier, or both, in the required proportions, and then, if necessary, shaping the resulting mixture into the desired presentation.

[0268] Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral preparations can be in the form of dry powders that can be reconstituted with water or another suitable liquid medium before use. Additional additives, such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents, may be added to liquid preparations. Parenteral dosage forms can be prepared by dissolving the compounds provided herein in a suitable liquid medium, filter-sterilizing the solution before filling, and sealing it in an appropriate vial or ampoule. These are just a few examples of the many suitable methods well known in the art for preparing dosage forms.

[0269] The compound of the present invention can be formulated into pharmaceutical composition by using the method well known to those skilled in the art.Other suitable pharmaceutically acceptable carriers than those mentioned herein are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0270] For use in prophylaxis or treatment, the compounds provided herein may, in the alternative, be administered as the raw or pure chemical, although it is also preferable to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

[0271] Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation, insufflation, or transdermal patch. Transdermal patches dispense drugs at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure-sensitive adhesive layer, and a removable protective layer having a release liner. Those skilled in the art will understand and appreciate the appropriate techniques for manufacturing a desired and effective transdermal patch based on the needs of the artisan.

[0272] Thus, the compounds provided herein, together with conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical preparations and unit dosages thereof, and may be utilized in such forms as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels, or filled capsules, all for oral use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended daily dosage range to be utilized.

[0273] For oral administration, pharmaceutical compositions can be in the form of tablets, capsules, suspensions or liquids.Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredient.Examples of such dosage units are capsules, tablets, powders, granules or suspensions with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; and with lubricants such as talc or magnesium stearate.Active ingredient can also be administered by injection as a composition, and for example, physiological saline, dextrose or water can be used as a suitable pharmaceutically acceptable carrier.

[0274] The compounds provided herein, or salts, solvates, or hydrates thereof, can be used as active ingredients in pharmaceutical compositions, particularly as GLUT9 transporter modulators or inhibitors. The term "active ingredient," as defined in the context of a "pharmaceutical composition," refers to the component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to "non-active ingredients," which are generally recognized as not providing pharmaceutical benefit.

[0275] Dosages for the compounds provided herein can vary within wide limits and, as is customary and known to physicians and other clinicians, should be adjusted to the individual circumstances in each individual case. This depends, for example, on the nature and severity of the disease being treated, the condition of the patient, the compound being used, whether an acute or chronic disease state is being treated or prophylaxis is being performed, or whether additional active compounds are administered in addition to the compounds provided herein. Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Particularly when relatively large amounts are deemed necessary, multiple doses, such as 2, 3, or 4 doses, may be administered over the course of a day. Depending on the individual and as deemed appropriate by the healthcare provider, it may be necessary to deviate upward or downward from the doses set forth herein.

[0276] The amount of active ingredient or active salt or derivative thereof required for therapeutic use will vary not only depending on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. Generally, those skilled in the art understand how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some situations, these extrapolations may be based solely on the weight of the animal model compared to another, such as a mammal, preferably a human, but in most cases, these extrapolations are not simply based on weight but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicity profile of the particular compound used, whether a drug delivery system is used, whether an acute or chronic disease state is being treated or whether disease prophylaxis is being performed, or whether an additional active compound is administered in addition to the compound provided herein and as part of a drug combination. The dosing regimen for treating a disease state with the compounds and / or compositions provided herein is selected according to various factors, as cited above. Thus, the acute dosing regimen utilized may vary widely and may therefore deviate from the preferred dosing regimen, and those skilled in the art will recognize that dosages and dosing regimens outside these typical ranges may be tested and, if appropriate, used in the methods provided herein.

[0277] The desired dose can be conveniently provided as a single dose or as a divided dose that is administered at appropriate intervals, for example, 2, 3, 4 or more subdoses per day.The subdoses themselves can be further divided, for example, into several separate loosely separated administrations.Particularly when relatively large amounts are administered as deemed appropriate, a daily dose can be divided into several, for example, 2, 3 or 4 part administrations.In appropriate cases, depending on individual behavior, it may be necessary to deviate upward or downward from the specified daily dose.

[0278] The compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, hydrate, or solvate of a compound provided herein.

[0279] For preparing pharmaceutical compositions from the compounds provided herein, the selection of suitable pharmaceutically acceptable carriers can be either solid, liquid or a mixture of both.Solid form preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0280] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.

[0281] In tablets, the active ingredient is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.

[0282] Powders and tablets may contain varying percentage amounts of the active compound. A typical amount in a powder or tablet may contain 0.5 to about 90 percent of the active compound; however, one skilled in the art will recognize when amounts outside this range are necessary. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" refers to the formulation of the active compound with an encapsulating material as a carrier, resulting in a capsule in which the active ingredient, with or without the carrier, is surrounded by the carrier and thus associated therewith. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges may be used as solid forms suitable for oral administration.

[0283] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein as by stirring The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0284] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0285] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions. Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0286] Therefore, the compounds provided herein can be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion), and can be provided in unit dose form in ampoules, pre-filled syringes, small injections, or multi-dose containers with added preservatives.The pharmaceutical compositions can take the form of suspension, solution, or emulsion in oily or aqueous medium, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable medium before use, for example, sterile pyrogen-free water.

[0287] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents, as desired.

[0288] Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agent.

[0289] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0290] For topical administration to the epidermis, the compounds provided herein may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0291] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents.Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0292] Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0293] The solution or suspension is applied directly to the nasal cavity by conventional means, for example, by a dropper, a pipette or a spray.The formulation can be provided in the form of a single or multiple doses.In the latter case of a dropper or a pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of a spray, this can be achieved, for example, by a metering atomizing spray pump.

[0294] Administration to the respiratory tract can also be achieved by aerosol formulations in which the active ingredient is provided in a pressurized pack with a suitable propellant. When the compounds provided herein or pharmaceutical compositions containing them are administered as aerosols, for example, as nasal aerosols or by inhalation, this can be achieved using, for example, a spray, a nebulizer, a pump atomizer, an inhalation device, a metered-dose inhaler, or a dry powder inhaler. Pharmaceutical forms for administration of the compounds provided herein as aerosols can be prepared by processes well known to those skilled in the art. For their preparation, for example, solutions or dispersions of the compounds provided herein in water, water / alcohol mixtures, or suitable saline solutions can be utilized with conventional additives, such as benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, solubilizers, dispersants, and others, and, if appropriate, conventional propellants, such as carbon dioxide, CFCs, such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane. The aerosol can also advantageously contain a surfactant such as lecithin. The dose of drug may be controlled by the provision of a metered valve.

[0295] In the preparation intended to be administered to the respiratory tract, including intranasal preparation, compound generally has small particle size, for example, the particle size of the order of 10 microns or less.Such particle size can be obtained by the means known in the art, for example, by micronization.If desired, the preparation adapted to cause sustained release of active ingredient can be utilized.

[0296] Alternatively, the active ingredient may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives, e.g., hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example, in capsules or cartridges of, for example, gelatin, or blister packs, from which the powder may be administered by inhaler.

[0297] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, for example, packaged tablets, capsules, and powders in vials or ampoules.Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0298] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0299] Some embodiments include methods of making a pharmaceutical composition for "combination therapy" comprising mixing at least one compound according to any of the compound embodiments disclosed herein with at least one known pharmaceutical agent and a pharmaceutically acceptable carrier.

[0300] Treatment efficacy and methods Also provided herein are methods for treating a GLUT9-mediated disorder in a human or animal subject in need thereof, comprising administering to the subject an amount of a compound disclosed herein in combination with at least one additional agent known in the art for treating the disorder, effective to reduce or prevent the disorder in the subject. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for treating a GLUT9-mediated disorder.

[0301] GLUT9 inhibitors are considered to be drugs for treating or preventing conditions including high blood uric acid levels, particularly hyperuricemia, gout (e.g., gouty arthritis, gouty nephropathy, and gouty tophi), etc. Furthermore, they are considered to be potentially useful as drugs for treating or preventing conditions that are generally known to have complications with hyperuricemia and are particularly suggested to be associated with high uric acid, particularly chronic kidney disease (CKD), hypertension, diabetes, heart disease (e.g., cardiovascular disease, heart failure, and atrial fibrillation), arteriosclerotic disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), psoriasis, etc.

[0302] Particular diseases to be treated by the compounds, compositions, and methods disclosed herein include hyperuricemia and gout.

[0303] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0304] Thus, the present invention also relates to methods for inhibiting at least one GLUT9 function, comprising contacting GLUT9 with a compound as described herein. Changes in cell phenotype, cell proliferation, GLUT9 activity, biochemical output produced by active GLUT9, GLUT9 expression, or GLUT9 binding to a natural binding partner may be monitored. Such methods may be in the form of disease treatment, biological assays, cellular assays, biochemical assays, etc.

[0305] Also provided herein is a method for treating a GLUT9-mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, or a salt thereof.

[0306] GLUT9 inhibitors are considered to be drugs for treating or preventing conditions including high blood uric acid levels, particularly hyperuricemia, gout (e.g., gouty arthritis, gouty nephropathy, and gouty tophi), etc. Furthermore, they are considered to be potentially useful as drugs for treating or preventing conditions that are generally known to have complications with hyperuricemia and are particularly suggested to be associated with high uric acid, particularly chronic kidney disease (CKD), hypertension, diabetes, heart disease (e.g., cardiovascular disease, heart failure, and atrial fibrillation), arteriosclerotic disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), psoriasis, etc.

[0307] In certain embodiments, the condition is selected from hyperuricemia, gout, and uncontrolled gout, including coexisting and associated conditions.

[0308] In certain embodiments, the disease is selected from hyperuricemia and gout.

[0309] Also provided herein are compounds as disclosed herein for use as pharmaceuticals.

[0310] Also provided herein is a compound as disclosed herein for use as a medicament for the treatment of a GLUT9-mediated disease.

[0311] Also provided is the use of a compound as disclosed herein as a pharmaceutical.

[0312] Also provided is the use of a compound as disclosed herein as a pharmaceutical for the treatment of a GLUT9-mediated disease.

[0313] Also provided is a compound as disclosed herein for use in the manufacture of a medicament for the treatment of a GLUT9-mediated disease.

[0314] Also provided is the use of a compound as disclosed herein for the treatment of a GLUT9-mediated disease.

[0315] Also provided herein are methods of inhibiting GLUT9 comprising contacting GLUT9 with a compound as disclosed herein, or a salt thereof.

[0316] Also provided herein is a method for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as disclosed herein, or a salt thereof, wherein the effect is selected from cognitive enhancement.

[0317] In certain embodiments, the GLUT9-mediated disorder is selected from hyperuricemia and gout.

[0318] Also provided herein are methods for achieving an effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, wherein the effect is a reduction in blood uric acid levels.

[0319] Also provided is a method of modulating a GLUT9-mediated function in a subject, comprising administering a therapeutically effective amount of a compound as disclosed herein.

[0320] Also provided are pharmaceutical compositions comprising a compound as disclosed herein in association with a pharmaceutically acceptable carrier.

[0321] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0322] In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule.

[0323] Combination therapy In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if hypertension is one of the side effects experienced by a patient upon receiving one of the compounds described herein, it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., an adjuvant alone may have minimal therapeutic effect, but by combining it with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein together with another therapeutic agent (including a treatment regimen) that also has a therapeutic effect. By way of example only, in a treatment for diabetes that includes administration of one of the compounds described herein, an increased therapeutic effect may also be achieved by providing the patient with another therapeutic agent for diabetes. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0324] Specific non-limiting examples of possible combination therapies include the use of certain compounds of the present invention with inhibitors of uric acid synthesis, uricosurics, and uric acid catabolic agents.

[0325] In one embodiment, the uricosuric agent is selected from probenecid, lesinurad, benzbromarone, and sulfinpyrazone.

[0326] In one embodiment, the inhibitor of uric acid synthesis is selected from allopurinol and febuxostat.

[0327] In one embodiment, the uric acid catabolic agent is pegloticase.

[0328] In one embodiment, the other agent is colchicine.

[0329] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided singly, in a combined form, or in multiple forms (by way of example only, either as a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneously, the timing between the multiple doses can be anywhere from a few minutes to four weeks.

[0330] General synthetic scheme The following schemes can be used to practice the invention. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [Example]

[0331] The invention is further illustrated by the following examples: All IUPAC names were generated using CambridgeSoft's ChemDraw Ultra 11.0.1 or CambridgeSoft's ChemDraw Ultra 20.0.0.41.

[0332] I. Chemical synthesis List of commonly used abbreviations g (grams); mg (milligrams); L (liter); mL (milliliter); μL (microliter); psi (pounds per square inch); M (molar concentration); mM (millimolar concentration); μM (micromolar concentration); MHz (megahertz); mol (mole); mmol (millimol); rt(room temperature); hr(hour); min(minutes); TLC (thin layer chromatography); mp (melting point); THF (tetrahydrofuran); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); Et3N (triethylamine); NMP (N-methyl-2-pyrrolidine) CDCl3 (deuterated chloroform); N2(g) (nitrogen gas) DMSO (dimethyl sulfoxide); SOCl2 (thionyl chloride) SiO2 (silica); atm(atm); EtOAc (ethyl acetate); CHCl3 (chloroform); HCl (hydrochloric acid); Ac(acetyl); DMF (N,N-dimethylformamide); Me(methyl); Et(ethyl); t-Bu (tert-butyl); Pr(propyl); i-Pr (isopropyl); Cs2CO3 (cesium carbonate); EtOH (ethanol); MeOH (methanol); CD3OD (deuterated methanol); p-TsOH (p-toluenesulfonic acid); CDI (1,1'-carbonyldiimidazole); NaHCO3 (sodium bicarbonate); DCM (dichloromethane); DCE (1,2-dichloroethane); K2CO3 (potassium carbonate); Na2CO3 (sodium carbonate); ACN or CH3CN (acetonitrile); PE (petroleum ether); MTBE (methyl t-butyl ether); Hex(Hexane); H2SO4 (sulfuric acid); HCl (hydrochloric acid); TMSBr (bromotrimethylsilane); Na2SO4 (sodium sulfate); Boc(tert-butoxycarbonyl); DIPEA (diisopropylethylamine); IPA (isopropanol); HMDS (hexamethyldisilazane); NH4Cl (ammonium chloride); K3PO4 (tripotassium phosphate); (NH4)HCO3 (ammonium bicarbonate); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); NaOH (sodium hydroxide); DMAP (4-dimethylaminopyridine); TMSCl (chlorotrimethylsilane); NIS (N-iodosuccinimide); NCS (N-chlorosuccinimide); CuI (copper(I) iodide); KOAc (potassium acetate); KF (potassium fluoride); CsF (cesium fluoride); NaN3 (sodium azide); TMP (2,2,6,6-tetramethylpiperidine); K2OsO4 (potassium osmate); NaIO4 (sodium metaperiodate); DAST ((diethylamino)sulfur trifluoride); Pd(OAc)2 (palladium acetate); BF3·(OEt)2 (boron trifluoride diethyl etherate); CS2 (carbon disulfide); Tf2O (trifluoromethanesulfonic anhydride); TMSCN (trimethylsilyl cyanide); CDI (1,1'-carbonyldiimidazole); LiAlH4 (lithium aluminum hydride); TMSN3 (trimethylsilyl azide); DMA (N,N-dimethylacetamide); FA (formic acid); NH2OH·HCl (hydroxylamine hydrochloride); DEAD (diethyl azodicarboxylate); PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate); Pd(PPh3)2Cl2 (bis(triphenylphosphine)palladium chloride); Pd(dppf)Cl2 ([[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Pd(dppf)Cl2·CH2Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0).

[0333] Synthesis method The following intermediates and examples can be synthesized using the general synthetic procedures described in Schemes 1-10.

[0334] Intermediate 1. (E)-5-(but-1-en-1-yl)-3-chloropyrazin-2-amine [ka] To a mixture of 3-chloro-5-iodo-pyrazin-2-amine (18.0 g, 70.47 mmol, 1.0 equiv.) and 2-[(E)-but-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.0 g, 82.39 mmol, 1.2 equiv.) in HO (90 mL) and 1,4-dioxane (270 mL), Pd(dppf)Cl·CHCl (5.75 g, 7.05 mmol, 0.1 equiv.) and CsCO (68.88 g, 211.40 mmol, 3.0 equiv.) were added at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, diluted with HO (300 mL), and subsequently extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 3:1) to give (£)-5-(but-1-en-1-yl)-3-chloropyrazin-2-amine (22.4 g, 86% yield) as a yellow solid. 1 LCMS C8H 10 Calculated for ClN3: m / z = 183; Found: m / z = 184 (M+H).

[0335] Intermediate 2. (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate methyl [ka] To a solution of (E)-5-(but-1-en-1-yl)-3-chloropyrazin-2-amine (Intermediate 1) (4.0 g, 21.78 mmol, 1.0 equiv) in NMP (80 mL) was added methyl piperidine-4-carboxylate (31.19 g, 217.82 mmol, 10.0 equiv) at room temperature. The resulting reaction mixture was heated at 160° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with HO (100 mL), and subsequently extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (approximately 2 g). The aqueous phase was adjusted to pH 5 with saturated aqueous citric acid (5 mL) and subsequently extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylic acid (5 g, crude) as a yellow oil. The crude acid was dissolved in MeOH (500 mL), and the resulting solution was treated with SOCl (6.46 g, 54.28 mmol, 3.94 mL, 3.0 equiv). The resulting reaction mixture was heated to 70 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaHCO (50 mL), and the resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give additional crude methyl (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate, which was combined with the material obtained above and purified by silica gel column chromatography (PE: EtOAc = 50:1 to 15:1) to give pure methyl (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (3.5 g, 58% yield) as a yellow solid. 1H NMR(400MHz,CD3OD)δ 7.44(s,1H),6.57(m,1H),6.28(d,J=15.6,1H),3.72(s,3H),3.56(m,2H),2.58(m, 1H),2.36(m,2H),2.23(m,2H),2.09(m,2H),1.93(m,2H),1.10(t,J=7.2,3H);LCMS C 15 H 22 Calculated for N4O2: m / z = 290; Found: m / z = 291 (M+H).

[0336] Intermediate 3. Methyl 1-(3-amino-6-butylpyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of (E)-1-(3-amino-6-(but-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 2) (6.0 g, 20.66 mmol, 1.0 equiv.) in MeOH (50 mL) was added Pd / C (2.0 g, 10% wt.) at room temperature. The resulting reaction mixture was degassed under vacuum and purged multiple times with H(g). The reaction mixture was then stirred under H(15 psi) at room temperature for 12 h. The reaction mixture was then purged multiple times with N(g), filtered through a pad of Celite to remove the Pd catalyst, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 1:1) to give 1-(3-amino-6-butylpyrazin-2-yl)piperidine-4-carboxylate (4.3 g, 71% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.47(s,1H),4.50(s,br,2H),3.69(s,3H)3.51(m,2H),2.83(m,3H),2.55(t,J=7.6 ,2H),2.02(m,2H),1.85(m,2H),1.60(m,2H),1.33(m,2H),0.91(t,J=7.2,3H);LCMS C 15 H 24 Calculated for N4O2: m / z = 292; Found: m / z = 293 (M+H).

[0337] Intermediate 4. Methyl 1-(3-bromo-6-butylpyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(3-amino-6-butylpyrazin-2-yl)piperidine-4-carboxylate (Intermediate 3) (0.45 g, 1.54 mmol, 1.0 equiv) in dibromomethane (30 mL) was added isopentyl nitrite (198 mg, 1.69 mmol, 228 μL, 1.1 equiv) followed by a solution of TMSBr (259 mg, 1.69 mmol, 220 μL, 1.1 equiv) in dibromomethane (15 mL) under N (g) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was treated with HO (10 mL) followed by extraction with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (PE: EtOAc = 8:1) to give methyl 1-(3-bromo-6-butylpyrazin-2-yl)piperidine-4-carboxylate (0.6 g, 55% yield) as a yellow oil. 15 H 22 Calculated for BrN3O2: m / z = 355; Found: m / z = 356 (M+H).

[0338] Intermediate 5,5-butyl-3-chloropyrazine-2-amine [ka] To a solution of (E)-5-(but-1-en-1-yl)-3-chloropyrazin-2-amine (Intermediate 1) (3.0 g, 16.34 mmol, 1.0 equiv) in EtOAc (120 mL) was added PtO (370 mg, 1.63 mmol, 0.1 equiv) at room temperature under N(g). The suspension was degassed under vacuum and purged multiple times with H. The resulting reaction mixture was stirred under H(g) (15 psi) at room temperature for 3 h. The reaction mixture was purged multiple times with N(g), followed by filtration to remove the catalyst and concentration under reduced pressure to give 5-butyl-3-chloropyrazin-2-amine (3.0 g, crude) as a yellow liquid. LCMS C8H 12 Calculated for ClN3: m / z = 185; Found: m / z = 186 (M+H).

[0339] Intermediate 6. 2-Bromo-5-butyl-3-chloropyrazine [ka] To a solution of crude 5-butyl-3-chloropyrazin-2-amine (Intermediate 5) (3.0 g, 16.16 mmol, 1.0 equiv.) in dichloromethane (18 mL) under a N2(g) atmosphere at room temperature, was added isopentyl nitrite (3.79 g, 32.32 mmol, 4.35 mL, 2.0 equiv.) in one portion, followed by a solution of TMSBr (4.95 g, 32.32 mmol, 4.19 mL, 2.0 equiv.) in dibromomethane (27 mL). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then poured into HO (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 2-bromo-5-butyl-3-chloropyrazine (3.1 g, yield 78%) as a yellow liquid. 1 H NMR:(400MHz,CD3OD)δ 8.24(s,1H),2.76(t,J=7.6,2H),1.69(m,2H),1.38(m,2H),0.94(t,J=7.6,3H);LCMS C8H 10Calculated for BrClN2: m / z = 249; Found: m / z = 250 (M+H).

[0340] Intermediate 7. 5-Butyl-3-chloro-2-(4-methoxyphenyl)pyrazine [ka] To a mixture of 2-bromo-5-butyl-3-chloropyrazine (Intermediate 6) (2.5 g, 10.02 mmol, 1.0 equiv) and (4-methoxyphenyl)boronic acid (1.37 g, 9.02 mmol, 0.9 equiv) in dioxane (25 mL) and HO (5 mL) was added Pd(dppf)Cl·CHCl (818 mg, 1.00 mmol, 0.1 equiv) and KCO (2.77 g, 20.04 mmol, 2.0 equiv) at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with HO (100 mL), and subsequently extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 5-butyl-3-chloro-2-(4-methoxyphenyl)pyrazine (2.3 g, yield 83%) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ LCMS C 15 H 17 Calculated for ClNO: m / z = 276; Found: m / z = 277 (M+H).

[0341] Intermediate 8. Ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of 2,6-dichloropyrazine (20.00 g, 134.25 mmol, 1.0 equiv.) and ethyl piperidine-4-carboxylate (22.16 g, 140.96 mmol, 1.1 equiv.) in 1,4-dioxane (600 mL) was added EtN (14.94 g, 147.64 mmol, 1.1 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C under a N2(g) atmosphere with stirring for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the 1,4-dioxane. The residue was poured into HO (700 mL) and extracted with EtOAc (1400 mL). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to give ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (29.50 g, yield 74%) as a yellow oil. 1 LCMS C 12 H 16 Calculated for ClN3O2: m / z = 269; Found: m / z = 270 (M+H).

[0342] Intermediate 9. Ethyl 1-(6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of Zn (16.82 g, 257.23 mmol, 3.0 equiv) in THF (180 mL) was added 1,2-dibromoethane (3.16 g, 16.81 mmol, 1.27 mL, 0.2 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was heated to 80 °C, stirred for 5 h, and then cooled back to room temperature. This heating-cooling cycle was repeated three more times. Next, TMSCl (547 mg, 5.04 mmol, 0.06 equiv) was added to the mixture, and the resulting reaction mixture was stirred at room temperature for 10 min. Next, the reaction mixture was cooled to 0 °C, and a solution of 1,1,1-trifluoro-4-iodobutane (20 g, 84.04 mmol, 1.0 equiv) in THF (180 mL) was added dropwise to the mixture over 15 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 15 min. Next, a solution of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (9.56 g, 35.43 mmol, 1.0 equiv) in THF (300 mL) was added to the reaction mixture. The reaction mixture was degassed and purged with N2 (g) three times, followed by the addition of Pd(dppf)Cl2·CHCl2 (2.89 g, 3.54 mmol, 0.1 equiv). The resulting reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove THF. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give ethyl 1-(6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carboxylate (14 g, yield 60%) as a brown oil. 1 H NMR(400MHz,CDCl3)δ=8.13(s,1H),7.68(s,1H),4.26(d,J=13.6,2H),4.13(q,J=7.2,2H),3.12(m,2 LCMS C 16 H 22Calculated for F3N3O2: m / z = 345; Found: m / z = 346 (M+H).

[0343] Intermediate 10. Ethyl 1-(5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 9) (74 g, 214.26 mmol, 1.0 equiv) in DMF (1000 mL) was added TFA (24.44 g, 214.26 mmol, 1.0 equiv) and NIS (62.66 g, 278.56 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. Next, the reaction mixture was adjusted to pH = 8 with saturated aqueous NaHCO3, and then the reaction mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 5: 1) to give ethyl 1-(5-iodo-6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carboxylate (49 g, 45% yield) as a brown oil. 1 H NMR(400MHz, CDCl3)δ=7.77(s,1H),4.19(m,4H),3.05(m,2H),2.83(t,J=7.4,2H ),2.57(m,1H),2.19(m,2H),2.01(m,4H),1.73(m,2H),1.27(t,J=7.2,3H);LCMS C 16 H 21 Calculated for F3IN3O2: m / z = 471; m / z = 472 (M+H).

[0344] Intermediate 11. Ethyl 1-(3-chloro-5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 10) (44 g, 93.36 mmol, 1.0 equiv.) in DMF (500 mL) was added NCS (18.70 g, 140.06 mmol, 1.5 equiv.) and TFA (10.64 g, 93.36 mmol, 1.0 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and adjusted to pH = 8 with saturated aqueous NaHCO3, and the resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give ethyl 3-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate (49 g, 93% yield) as a yellow oil. 16 H 20 Calculated for ClF3IN3O2: m / z = 489; Found: m / z = 506 (M+H).

[0345] Intermediate 12. Ethyl 1-(3-chloro-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 11) (36 g, 73.19 mmol, 1.0 equiv) in EtOH (300 mL) was added 10% Pd / C (30 g) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 12 hours. The mixture was then purged with N2(g) three times and subsequently filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 3: 1) to give ethyl 1-(3-chloro-6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carboxylate (13 g, 45% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=7.72(s,1H),4.17(q,J=7.2,2H),3.95(d,J=13.6,2H),2.96(m,2H),2.7 5(t,J=7.2,2H),2.54(m,1H),2.18(m,2H),2.02(m,4H),1.90(m,2H),1.29(t,J=7.2,3H);LCMS C 16 H 21 Calculated for ClF3N3O2: m / z = 379; Found: m / z = 380 (M+H).

[0346] Intermediate 13. Ethyl 1-(6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a slurry of NaH (14.94 g, 373.44 mmol, 60% purity, 3.0 equiv) in THF (1125 mL) was added 2,2,2-trifluoroethanol (37.36 g, 373.44 mmol, 3.0 equiv) under a N2(g) atmosphere at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. The resulting reaction mixture was then recooled to 0 °C, and potassium trifluoro((2,2,2-trifluoroethoxy)methyl)borate (25.00 g, 124.48 mmol, 1.0 equiv) was added. The resulting reaction mixture was warmed to room temperature and stirred for 11 h. The reaction mixture was cooled to 0 °C and quenched with potassium bifluoride (200 mL, 4.5 M), and the resulting reaction mixture was stirred for 30 min. The suspension was concentrated under reduced pressure to provide a residue. The residue was triturated with MTBE (2 x 600 mL) at room temperature for 30 minutes. The resulting slurry was filtered, and the solid was collected and dried under vacuum. The crude product was triturated with acetonitrile (200 mL) at room temperature for 30 minutes. The resulting slurry was filtered, and the filtrate was concentrated in vacuo to give potassium (2,2,2-trifluoroethoxymethyl)trifluoroborate (27.00 g, crude) as a white solid. Next, to a solution of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (10.00 g, 37.07 mmol, 1.0 equiv.) and potassium (2,2,2-trifluoroethoxymethyl)trifluoroborate (12.23 g, 55.61 mmol, 1.5 equiv.) in 1,4-dioxane (100 mL) and HO (20 mL), Pd(dppf)Cl·CHCl (1.51 g, 1.85 mmol, 0.05 equiv.) and CsCO (36.24 g, 111.22 mmol, 3.0 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the dioxane. The residue was poured into H2O (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 1: 1) to give ethyl 1-(6-((2,2,2-trifluoroethoxy) methyl) pyrazin-2-yl) piperidine-4-carboxylate (9.5 g, yield 73%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.85(s,1H),4.58(s,2H),4.18(m,2H),4.07(m,2H),3.90(q,J=8.8,2 H),2.97(m,2H),2.51(m,1H),1.96(m,3H),1.68(m,2H),1.22-1.73(t,J=8.8,3H).

[0347] Intermediate 14. Ethyl 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 13) (1.50 g, 4.32 mmol, 1.0 equiv) in DMF (15 mL) was added NCS (519 mg, 3.89 mmol, 0.9 equiv) and TFA (49 mg, 431 μmol, 0.1 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was then heated at 60 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature. The residue was poured into HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 3:1) to give ethyl 1-(5-chloro-6-((2,2,2-trifluoroethoxy) methyl) pyrazin-2-yl) piperidine-4-carboxylate (720 mg, 43% yield) as a white solid. 15 H 19 Calculated for ClF3N3O3: m / z = 381; Found: m / z = 382 (M+H).

[0348] Intermediate 15. Ethyl 1-(5-chloro-3-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 14) (620 mg, 1.62 mmol, 1.0 equiv) in CHCl (10 mL) was added NIS (730 mg, 3.25 mmol, 2.0 equiv) and TFA (18 mg, 162 μmol, 12 μL, 0.1 equiv) at room temperature under a N (g) atmosphere. The resulting reaction mixture was then heated at 80° C. and stirred for 0.5 h. The reaction mixture was cooled to room temperature and then poured into HO (30 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 5: 1) to give ethyl 1-(5-chloro-3-iodo-6-((2,2,2-trifluoroethoxy) methyl) pyrazin-2-yl) piperidine-4-carboxylate (780 mg, 94% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.68(s,2H),4.10(q,J=7.2,2H),3.94(dd,J=8.4,16.8,2H),3.74(m,2H) ,2.88(m,2H),2.42(m,1H),1.98(m,2H),1.88(m,2H),1.21(t,J=7.2,3H).

[0349] Intermediate 16. Ethyl 1-(6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a suspension of Zn (10.74 g, 164.25 mmol, 3.0 equiv) in THF (45 mL) was added 1,2-dibromoethane (2.06 g, 10.95 mmol, 0.2 equiv) over 5 min at room temperature under a N2(g) atmosphere. After the addition was complete, the resulting reaction mixture was heated to 80 °C and stirred for 5 min, followed by cooling the reaction mixture to room temperature. This heating-cooling cycle was repeated three more times. Next, TMSCl (356 mg, 3.29 mmol, 0.1 equiv) was added to the mixture at room temperature, and the resulting reaction mixture was stirred for 10 min. The reaction mixture was cooled to 0 °C, followed by the dropwise addition of a solution of 1,1,1,2,2-pentafluoro-4-iodo-butane (15 g, 54.75 mmol, 1.0 equiv) in THF (45 mL) over 10 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 15 min. Ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (7.50 g, 27.81 mmol, 1.0 equiv.) was then added, followed by Pd(dppf)Cl.CHCl (2.30 g, 2.78 mmol, 0.1 equiv.). The resulting reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 15:1 to 1:1) to afford ethyl 1-(6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (10.5 g, 38% yield) as a yellow liquid. LCMS C 16 H 20 Calculated for F5N3O2: m / z = 381; Found: m / z = 382 (M+H).

[0350] Intermediate 17. Ethyl 1-(5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 16) (11.00 g, 28.85 mmol, 1.0 equiv) in DMF (110 mL) was added NIS (7.79 g, 34.61 mmol, 1.2 equiv) and TFA (3.29 g, 28.85 mmol, 1.0 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL). The mixture was then diluted with HO (300 mL) and extracted with EtOAc (3 x 400 mL). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give ethyl 1-(5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (11.00 g, yield 77%) as a brown solid. 1 LCMS C 16 H 19 Calculated for F5IN3O2: m / z = 507; Found: m / z = 508 (M+H).

[0351] Intermediate 18. Ethyl 1-(3-chloro-5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 17) (10.00 g, 19.71 mmol, 1.0 equiv) in DMF (100 mL) was added NCS (3.42 g, 25.63 mmol, 1.3 equiv) and TFA (2.25 g, 19.71 mmol, 1.0 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and quenched by the addition of saturated aqueous NH Cl (80 mL). The resulting solution was diluted with HO (300 mL) and extracted with EtOAc (3 × 400 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give ethyl 1-(3-chloro-5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (9.11 g, 96% yield) as a yellow liquid. 16 H 18 Calculated for ClF5IN3O2: m / z = 541; Found: m / z = 542 (M+H).

[0352] Intermediate 19. Ethyl 1-(3-chloro-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 18) (2.00, 3.69 mmol, 1.0 equiv) in MeOH (80 mL) was added Pd / C (0.60 g, 10% wt) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 12 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 30: 1 to 1: 1) to give ethyl 1- (3-chloro-6- (3,3,4,4,4-pentafluorobutyl) pyrazin-2-yl) piperidine-4-carboxylate (1.67 g, crude) as a yellow solid. 1 LCMS C 16 H 19 Calculated for ClF5N3O2: m / z = 415; Found: m / z = 416 (M+H).

[0353] Intermediate 20. Ethyl 1-(5-chloro-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl}piperidine-4-carboxylate (Intermediate 16) (2.50 g, 6.56 mmol, 1.0 equiv.) in DMF (10 mL) was added NCS (875 mg, 6.56 mmol, 1.0 equiv.) at room temperature. The resulting reaction mixture was heated to 60° C. and stirred for 7 h. The reaction mixture was then cooled to room temperature. The residue was poured into HO (70 mL) and dissolved in Et The resulting mixture was extracted with HCl (3 × 15 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give ethyl 1-(5-chloro-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (1.5 g, 55% yield) as a yellow solid. 1 LCMS C 16 H 19 Calculated for ClF5N3O2: m / z = 415; Found: m / z = 416 (M+H).

[0354] Intermediate 21. Ethyl 1-(5-chloro-3-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-chloro-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 20) (1.00 g, 2.41 mmol, 1.0 equiv) in CHCl (5 mL) was added NIS (1.08 g, 4.81 mmol, 2.0 equiv) and TFA (27 mg, 240 μmol, 0.1 equiv) at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 1.5 h. The reaction mixture was then cooled to room temperature. The residue was poured into HO (15 mL) and extracted with DCM (2 × 5 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1-(5-chloro-3-iodo-6-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (0.9 g, 70% yield) as a yellow solid. 16 H 18 Calculated for ClF5IN3O2: m / z = 541; Found: m / z = 542 (M+H).

[0355] Intermediate 22. Ethyl 1-(6-(cyclopropylethynyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (10.00 g, 37.07 mmol, 1.0 equiv.) in DMA (40 mL) was added CuI (706 mg, 3.71 mmol, 0.1 equiv.), DIPEA (47.92 g, 370.75 mmol, 10.0 equiv.), Pd(PPh)Cl (2.60 g, 3.71 mmol, 0.1 equiv.), and ethynylcyclopropane (12.25 g, 185.37 mmol, 5.0 equiv.) at room temperature. The resulting reaction mixture was heated to 60 °C under a N (g) atmosphere and stirred for 12 h. The reaction mixture was cooled to room temperature and then poured into HO (400 mL) and extracted with EtOAc (800 mL). The organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 15:1 to 10:1) to give ethyl 1-(6-(cyclopropylethynyl)pyrazin-2-yl)piperidine-4-carboxylate (18 g, 81% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD)δ 8.07(s,1H),7.73(s,1H),4.26(m,2H),4.12(q,J=7.2,2H),3.07(m,2H),2.65(m,1H),2. 00(m,2H),1.69(m,2H),1.53(m,1H),1.26(t,J=7.2,3H),0.95(m,2H),0.86(m,2H);LCMS C 17 H 21 Calculated for N3O2: m / z = 299; Found: m / z = 300 (M+H).

[0356] Intermediate 23. Ethyl 1-(6-(2-cyclopropylethyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(cyclopropylethynyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 22) (2.00 g, 6.68 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (1.00 g) at room temperature under a N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under a H2(g) atmosphere (15 psi) for 12 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to afford ethyl 1-(6-(2-cyclopropylethyl)pyrazin-2-yl)piperidine-4-carboxylate (2 g, crude) as a yellow solid. LCMS C 17 H 25 Calculated for N3O2: m / z = 303; Found: m / z = 304 (M+H).

[0357] Intermediate 24. Ethyl 1-(6-(2-cyclopropylethyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(2-cyclopropylethyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 23) (10.00 g, 32.96 mmol, 1.0 equiv) in DMF (100 mL) was added NIS (9.64 g, 42.85 mmol, 1.3 equiv) and TFA (1.88 g, 16.48 mmol, 0.5 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature under a N2(g) atmosphere for 1 h. The reaction mixture was quenched by the slow addition of saturated aqueous NaHCO3 (200 mL), poured into HO (500 mL), and extracted with EtOAc (1000 mL). The organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1-(6-(2-cyclopropylethyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (9.52 g, 67%) as a yellow oil. 17 H 24 Calculated for IN3O2: m / z = 429; Found: m / z = 430 (M+H).

[0358] Intermediate 25. Ethyl 1-(3-chloro-6-(2-cyclopropylethyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(2-cyclopropylethyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 24) (10.00 g, 23.29 mmol, 1.0 equiv) in DMF (100 mL) was added TFA (1.33 g, 11.65 mmol, 0.5 equiv) and NCS (3.42 g, 25.62 mmol, 1.1 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C under a N2(g) atmosphere and stirred for 1 h. The reaction mixture was cooled to room temperature, quenched by the slow addition of saturated aqueous NaHCO3 (100 mL), poured into HO (300 mL), and extracted with EtOAc (700 mL). The organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 15: 1) to give ethyl 1- (3-chloro-6- (2-cyclopropylethyl) -5-iodopyrazin-2-yl) piperidine-4-carboxylate (6.8 g, 63%) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ 4.16(q,J=6.8,2H),3.96(m,2H),3.04-2.80(m,4H),2.61(m,1H),2.01(m,2H),1.87- 1.59(m,4H),1.40(m,1H),1.28(t,J=6.8,3H),0.98(m,1H),0.80(m,1H),0.46(m,2H).

[0359] Intermediate 26. Ethyl 1-(3-chloro-6-(2-cyclopropylethyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-6-(2-cyclopropylethyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 25) (1.00 g, 2.16 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (700 mg) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 2 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 15: 1) to give ethyl 1-(3-chloro-6-(2-cyclopropylethyl)pyrazin-2-yl)piperidine-4-carboxylate (0.6 g, 83%) as a yellow oil. 17 H 24 Calculated for ClN3O2: m / z = 337; Found: m / z = 338 (M+H).

[0360] Intermediate 27. Ethyl 1-(5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 13) (15.00 g, 43.19 mmol, 1.0 equiv) in DMF (150 mL) was added NIS (12.63 g, 56.14 mmol, 1.3 equiv) and TFA (4.92 g, 43.19 mmol, 1.0 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was stirred for 1 h. The reaction mixture was poured into HO (1000 mL) and extracted with EtOAc (3 x 300 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 15: 1) to give ethyl 1-(5-iodo-6-((2,2,2-trifluoroethoxy) methyl) pyrazin-2-yl) piperidine-4-carboxylate (30 g, yield 75%). 1 H NMR(400MHz,CDCl3)δ 7.99(s,1H),4.71(s,2H),4.31(m,2H),4.25-4.05(m,4H),3.11(m,2H),2.71(m,1H),2.01(m,2H),1.73(m,2H),1.27(t,J=7.2,3H).

[0361] Intermediate 28. Ethyl 1-(3-chloro-5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 27) (8.00 g, 16.91 mmol, 1.0 equiv) in DMF (80 mL) was added NCS (2.93 g, 21.98 mmol, 1.3 equiv) and TFA (1.93 mg, 16.91 mmol, 1.0 equiv) at room temperature under a N2 (g) atmosphere. The resulting reaction mixture was then heated at 90 °C and stirred for 1 h. The reaction mixture was cooled to room temperature. The reaction mixture was then poured into HO (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 1:1) to give ethyl 1-(3-chloro-5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (8.00 g, 93% yield) as a yellow oil. 15 H 18 Calculated for ClF3IN3O3: m / z = 507; Found: m / z = 508 (M+H).

[0362] Intermediate 29. Ethyl 1-(3-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 28) (5.00 g, 9.85 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (600 mg) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 1 hour. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 40: 1 to 15: 1) to give ethyl 1-(3-chloro-6-((2,2,2-trifluoroethoxy) methyl) pyrazin-2-yl) piperidine-4-carboxylate (2.20 g, yield 54%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.94(s,1H),4.72(s,2H),4.13(q,J =7.2,2H),3.96(m,4H),2.94(m,2H),2.53(m,1H),2.01(m,2H),1.88(m,2H),1.25(t,J=7.2,3H).

[0363] Intermediate 30. Ethyl 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (2.00 g, 7.41 mmol, 1.0 equiv.) and potassium trifluoro(3,3,3-trifluoropropyl)borate (1.81 g, 8.90 mmol, 1.2 equiv.) in 1,4-dioxane (30 mL) and HO (6 mL), Pd(dppf)Cl·CHCl (605 mg, 741 μmol, 0.1 equiv.) and CsCO (7.25 g, 22.24 mmol, 3.0 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with HO (300 mL), and subsequently extracted with EtOAc (2 × 300 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 10:1) to give ethyl 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (2.09 g, 85% yield) as a yellow liquid. 1 H NMR(400MHz,CDCl3)δ 7.97(s,1H),7.69(s,1H),4.24(m,2H),4.13(q,J=7.2,2H),3.03(m,2H), 2.84(m,2H),2.53(m,3H)1.99(m,2H)1.74(m,5H)1.25(t,J=7.2,3H);LCMS C 15 H 20 Calculated for F3N3O2: m / z = 331; Found: m / z = 332 (M+H).

[0364] Intermediate 31. Ethyl 1-(5-chloro-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 30) (300 mg, 905 μmol, 1.0 equiv) in DMF (2 mL) was added NCS (121 mg, 905 μmol, 1.0 equiv) at room temperature. The resulting reaction mixture was heated to 60° C. under a N2(g) atmosphere and stirred for 1 h. The reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1-(5-chloro-6-(3,3,3-trifluoropropyl) pyrazin-2-yl) piperidine-4-carboxylate (170 mg, yield 51%) as a white solid. 1 LCMS C 15 H 19 Calculated for ClF3N3O2: m / z = 365; Found: m / z = 366 (M+H).

[0365] Intermediate 32. Ethyl 1-(5-chloro-3-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-chloro-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 31) (150 mg, 410 μmol, 1.0 equiv) in CHCl (5 mL) was added NIS (92 mg, 410 μmol, 1.0 equiv) and TFA (46 mg, 410 μmol, 1.0 equiv) at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1- (5-chloro-3-iodo-6- (3,3,3-trifluoropropyl) pyrazin-2-yl) piperidine-4-carboxylate (172 mg) as an oily yellow liquid. LCMS C 15 H 18 Calculated for ClF3IN3O2: m / z = 491; Found: m / z = 492 (M+H).

[0366] Intermediate 33. Ethyl 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 30) (10.00 g, 30.18 mmol, 1.0 equiv) in DMF (100 mL) was added TFA (344 mg, 3.02 mmol, 0.1 equiv) and NIS (6.79 g, 30.18 mmol, 1.0 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (70 mL). Subsequently, the reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (3 × 300 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (10.30 g) as a yellow solid. LCMS C 15 H 19 Calculated for F3IN3O2: m / z = 457; Found: m / z = 458 (M+H).

[0367] Intermediate 34. Ethyl 1-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 33) (4.65 g, 10.17 mmol, 1.0 equiv.) in DMF (45 mL) was added TFA (1.16 g, 10.17 mmol, 0.1 equiv.) and NCS (1.63 g, 12.20 mmol, 1.2 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was then cooled to room temperature, quenched by the addition of saturated aqueous NaHCO (50 mL), diluted with HO (300 mL), and extracted with EtOAc (3 × 400 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1- (3-chloro-5-iodo-6- (3,3,3-trifluoropropyl) pyrazin-2-yl) piperidine-4-carboxylate (4.65 g) as a yellow solid. LCMS C 15 H 18 Calculated for ClF3IN3O2: m / z = 491; Found: m / z = 492 (M+H).

[0368] Intermediate 35. Ethyl 1-(3-chloro-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 34) (1.30 g, 2.64 mmol, 1.0 equiv) in MeOH (50 mL) was added 10% Pd / C (0.50 g) at room temperature under an N2(g) atmosphere. The suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 12 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give ethyl 1-(3-chloro-6-(3,3,3-trifluoropropyl) pyrazin-2-yl) piperidine-4-carboxylate (0.73 g, 76%) as a yellow liquid. 1 LCMS C 15 H 18 Calculated for ClF3N3O2: m / z = 365; Found: m / z = 366 (M+H).

[0369] Intermediate 36. 1-(6-chloropyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 2,6-dichloropyrazine (5.00 g, 33.56 mmol, 1.0 equiv.) and piperidinium-4-carbonitrile hydrochloride (5.12 g, 34.90 mmol, 1.1 equiv.) in 1,4-dioxane (50 mL) was added EtN (3.74 g, 36.92 mmol, 1.1 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, diluted with HO (200 mL), and subsequently extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(6-chloropyrazin-2-yl) piperidine-4-carbonitrile (3.24 g, 43% yield) as a yellow solid. 10 H 11 Calculated for ClN4: m / z = 222; Found: m / z = 223 (M+H).

[0370] Intermediate 37. 1-(6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-chloropyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 36) (3.00 g, 13.47 mmol, 1.0 equiv.) and potassium trifluoro((2,2,2-trifluoroethoxy)methyl)borate (4.44 g, 20.21 mmol, 1.5 equiv.) in HO (4 mL) and 1,4-dioxane (20 mL), Pd(dppf)Cl·CHCl (1.10 g, 1.35 mmol, 0.1 equiv.) and CsCO (13.17 g, 40.41 mmol, 3.0 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with HO (200 mL), and extracted with EtOAc (2 × 300 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 10:1) to give 1-(6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (1.3 g, 32% yield) as a white solid. LCMS C 13 H 15 Calculated for F3N4O: m / z = 300; Found: m / z = 301 (M+H).

[0371] Intermediate 38. 1-(5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 37) (6.00 g, 19.98 mmol, 1.0 equiv) in DMF (40 mL) were added TFA (2.28 g, 19.98 mmol, 1.0 equiv) and NIS (5.84 g, 25.98 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched at room temperature by the addition of saturated aqueous NaHCO (100 mL), diluted with HO (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(5-iodo-6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (4.5 g, 55% yield) as a yellow solid. 13 H 14 Calculated for F3IN4O: m / z = 426; Found: m / z = 427 (M+H).

[0372] Intermediate 39. 1-(3-chloro-5-iodo-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(5-iodo-6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 38) (3.5 g, 8.21 mmol, 1.0 equiv) in DMF (35 mL) was added TFA (936 mg, 8.21 mmol, 1.0 equiv) and NCS (1.43 g, 10.68 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 3 h. The reaction mixture was then cooled to room temperature. The reaction mixture was quenched at room temperature by the addition of saturated aqueous NaHCO (50 mL), diluted with HO (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(3-chloro-5-iodo-6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (3.24 g, 86% yield) as a yellow solid. 13 H 13 Calculated for ClF3IN4O: m / z = 460; Found: m / z = 461 (M+H).

[0373] Intermediate 40. 1-(3-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(3-chloro-5-iodo-6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 39) (1.00 g, 2.17 mmol, 1.0 equiv) in MeOH (50 mL) was added Pd / C (0.50 g, 10% wt) at room temperature under an N2(g) atmosphere. The suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 12 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(3-chloro-6-(2,2,2-trifluoroethoxymethyl)pyrazin-2-yl)piperidine-4-carbonitrile (600 mg, 82% yield) as a yellow liquid. 13 H 14 Calculated for ClF3N4O: m / z = 334; Found: m / z = 335 (M+H).

[0374] Intermediate 41. 2-(7-Fluorobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 5-bromo-7-fluorobenzofuran (7.0 g, 32.56 mmol, 1.0 equiv.) and bis-pinacolatodiborane (13.23 g, 52.09 mmol, 1.6 equiv.) in 1,4-dioxane (98 mL), Pd(dppf)Cl·CHCl (5.32 g, 6.51 mmol, 0.2 equiv.) and KOAc (6.39 g, 65.11 mmol, 2.0 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, diluted with HO (500 mL), and subsequently extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 15: 1) to give 2-(7-fluorobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.35 g, 91%) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.84(d,J=2.0,2H),7.38(d,J=11.2,1H),6.95(m,1H),1.38(s,12H).

[0375] Intermediate 42. 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-chloropyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 36) (3.00 g, 13.47 mmol, 1.0 equiv.) and potassium trifluoro(3,3,3-trifluoropropyl)borate (3.02 g, 14.82 mmol, 1.1 equiv.) in 1,4-dioxane (30 mL) and HO (6 mL), Pd(dppf)Cl·CHCl (1.10 g, 1.35 mmol, 0.1 equiv.) and CsCO (13.17 g, 40.42 mmol, 3.0 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, diluted with HO (200 mL), and extracted with EtOAc (2 × 300 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 5:1) to give 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (3.7 g, 96% yield) as a brown liquid. LCMS C 13 H 15 Calculated for F3N4: m / z = 284; Found: m / z = 285 (M+H).

[0376] Intermediate 43. 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a suspension of 1-(6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 42) (3.20 g, 11.26 mmol, 1.0 equiv.) in DMF (32 mL) was added NIS (3.29 g, 14.63 mmol, 1.3 equiv.) and TFA (1.28 g, 11.26 mmol, 1.0 equiv.) at room temperature, and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (50 mL), diluted with HO (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (2.3 g, 50% yield) as a yellow oil. 13 H 14 Calculated for F3IN4: m / z = 410; Found: m / z = 411 (M+H).

[0377] Intermediate 44. 1-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 43) (2.00 g, 4.88 mmol, 1.0 equiv) in DMF (20 mL) was added TFA (556 mg, 4.88 mmol, 1.0 equiv) and NCS (846 mg, 6.34 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 3 h. The reaction mixture was then cooled to room temperature. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (50 mL), diluted with HO (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (1.9 g, 88% yield) as a yellow solid. 13 H 13 Calculated for ClF3IN4: m / z = 443; Found: m / z = 444 (M+H).

[0378] Intermediate 45. 1-(3-chloro-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(3-chloro-5-iodo-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 44) (1.80 g, 4.05 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (1.00 g) at room temperature under an N2(g) atmosphere. The suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2 atmosphere(g) (30 psi) for 12 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 1-(3-chloro-6-(3,3,3-trifluoropropyl)pyrazin-2-yl)piperidine-4-carbonitrile (1.23 g, 95% yield) as an oily yellow liquid. 13 H 14 Calculated for ClF3N4: m / z = 317; Found: m / z = 318 (M+H).

[0379] Intermediate 46. Ethyl 1-(6-vinylpyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (20.0 g, 74.15 mmol, 1.0 equiv.) and potassium trifluoro(vinyl)borate (11.92 g, 88.98 mmol, 1.2 equiv.) in THF (200 mL) and HO (40 mL) was added Pd(dppf)Cl·CHCl (3.03 g, 3.71 mmol, 0.05 equiv.) and KCO (20.50 g, 148.30 mmol, 2.0 equiv.) at room temperature. The resulting reaction mixture was heated at 80 °C under a N(g) atmosphere and stirred for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the THF. The residue was poured into HO (700 mL) and extracted with EtOAc (2 × 700 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 5:1) to give ethyl 1-(6-vinylpyrazin-2-yl)piperidine-4-carboxylate (16.8 g, 86% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.03(s,1H),7.80(s,1H),6.67(dd,J=10.8,17.2,1H),6.29(dd,J=2.0,17.2,1H),5.48(dd,J=2.0,10.8,1H), 4.32(m,2H),4.15(q,J=7.2,2H),3.04(m,2H),2.57(m,1H),2.04(m,2H),1.80(m,2H),1.27(t,J=7.2,3H);LCMS C 14 H 19 Calculated for N3O2: m / z = 261; Found: m / z = 262 (M+H).

[0380] Intermediate 47. Ethyl 1-(6-formylpyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-vinylpyrazin-2-yl)piperidine-4-carboxylate (Intermediate 46) (10.0 g, 38.27 mmol, 1.0 equiv.) in THF (100 mL) and HO (20 mL) was added KOsO (2.82 g, 7.65 mmol, 0.2 equiv.) at 0 °C, followed by NaIO (24.56 g, 114.80 mmol, 3.0 equiv.). The resulting reaction mixture was then warmed to room temperature and stirred for 12 h. The reaction mixture was poured into HO (700 mL) and extracted with EtOAc (2 × 700 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 2: 1) to give ethyl 1-(6-formylpyrazin-2-yl)piperidine-4-carboxylate (3.00 g, yield 29%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.96(s,1H),8.38(s,1H),8.33(s,1H),4.34(m,2H),4.14(q,J=7.2,2H),3. 16(m,2H),2.62(m,1H),2.08(m,2H),1.81(m,2H),1.29(t,J=7.2,3H);LCMS C 13 H 17 Calculated for N3O3: m / z = 263; Found: m / z = 264 (M+H).

[0381] Intermediate 48. (E)-1-(6-(5,5,5-trifluoropent-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate ethyl [ka] To a mixture of ethyl 1-(6-formylpyrazin-2-yl)piperidine-4-carboxylate (Intermediate 47) (2.50 g, 9.50 mmol, 1.0 equiv.) and triphenyl-(4,4,4-trifluorobutyl)phosphonium iodide (prepared by heating a solution of 1,1,1-trifluoro-4-iodobutane (5.00 g, 21.01 mmol, 1.0 equiv.) and PPh (5.51 g, 21.01 mmol, 1.0 equiv.) in toluene (50 mL) at 85 °C for 12 hours) (7.25 g, 14.43 mmol, 1.52 equiv.) in isopropyl acetate (25 mL), KCO (2.10 g, 15.19 mmol, 1.6 equiv.) was added at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with HO (400 mL), and extracted with EtOAc (2 × 400 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 8:1 to 2:1) to give ethyl (E)-1-(6-(5,5,5-trifluoropent-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (2.83 g) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.01(s,1H),7.73(s,1H),6.33(d,J=11.6,1H),5.88(m,1H),4.17(m,4H),3.11(m, 4H),2.58(m,1H),2.31(m,2H),2.05(m,2H),1.80(m,2H),1.30(t,J=7.2,3H);LCMS C 17 H 22 Calculated for F3N3O2: m / z = 357; Found: m / z = 358 (M+H).

[0382] Intermediate 49. Ethyl 1-(6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl (£)-1-(6-(5,5,5-trifluoropent-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 48) (1.20 g, 3.36 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (800 mg) at room temperature. The suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (15 psi) at room temperature for 3 hours. The reaction mixture was then purged with N(g) three times and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to give ethyl 1-(6-(5,5,5-trifluoropentyl)pyrazin-2-yl]piperidine-4-carboxylate (0.91 g, yield 76%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.97(s,1H),7.70(s,1H),4.27(m,2H),4.16(q,J=7.2,2H),3.04(dt,J=2.4,11.2,2H),2.64(t,J=7 .2,2H),2.53(m,1H),2.16(m,2H),2.03(m,2H),1.80(m,4H),1.63(m,2H),1.29(t,J=7.2,3H);LCMS C 17 H 24 Calculated for F3N3O2: m / z = 359; Found: m / z = 360 (M+H).

[0383] Intermediate 50. Ethyl 1-(5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 49) (2.00 g, 5.57 mmol, 1.0 equiv) in DMF (20 mL) was added NIS (1.38 g, 6.12 mmol, 1.1 equiv) and TFA (63 mg, 556 μmol, 0.1 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the slow addition of saturated aqueous NaHCO (20 mL), and then the reaction mixture was poured into HO (200 mL) and extracted with EtOAc (400 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 10: 1) to give ethyl 1-(5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (2.3 g, 85% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.76(s,1H),4.19(m,4H),3.03(dt,J=2.4,11.2,2H),2.79(t,J=7.2,2H),2.57 (m,1H),2.19-1.98(m,4H),1.78(m,4H),1.69(m,2H),1.27(t,J=7.2,3H);LCMS C 17 H 23 Calculated for F3IN3O2: m / z = 485; Found: m / z = 486 (M+H).

[0384] Intermediate 51. Ethyl 1-(3-chloro-5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 50) (2.50 g, 5.15 mmol, 1.0 equiv) in DMF (25 mL) was added NCS (894 mg, 6.70 mmol, 1.3 equiv) and TFA (58 mg, 515 μmol, 0.1 equiv) at room temperature. The resulting reaction mixture was heated at 100° C. and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into HO (200 mL), and extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 12: 1) to give ethyl 1-(3-chloro-5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (2.5 g, 93% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.16(q,J=7.2,2H),3.95(m,2H),3.01(dt,J=2.4,11.2,2H),2.83(t,J=7.2,2H),2.54(m ,1H),2.18(m,2H),2.04(m,2H),1.92-1.76(m,4H),1.66(m,2H),1.27(t,J=7.2,3H);LCMS C 17 H 22 Calculated for ClF3IN3O2: m / z = 519; Found: m / z = 520 (M+H).

[0385] Intermediate 52. Ethyl 1-(3-chloro-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 51) (1.00 g, 1.92 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (600 mg) at room temperature. The suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (30 psi) at room temperature for 0.5 h. The reaction mixture was then purged with N(g) and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 10: 1) to give ethyl 1-(3-chloro-6-(5,5,5-trifluoropentyl)pyrazin-2-yl)piperidine-4-carboxylate (900 mg, yield 79%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.71(s,1H),4.16(q,J=7.2,2H),3.93(m,2H),2.99(dt,J=2.4,11.2,2H),2.69(t,J=7.2,2H ),2.53(m,1H),2.16-2.01(m,4H),1.95-1.75(m,4H),1.62(m,2H),1.28(t,J=7.2,3H);LCMS C 17 H 23 Calculated for ClF3N3O2: m / z = 393; Found: m / z = 394 (M+H).

[0386] Intermediate 53. Ethyl 1-(6-(3-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] A mixture of ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 76) (15.0 g, 41.53 mmol, 1.0 equiv.), but-3-yn-2-ol (8.73 g, 124.59 mmol, 3.0 equiv.), PPh (2.18 g, 8.31 mmol, 0.2 equiv.), CuI (1.58 g, 8.31 mmol, 0.2 equiv.), and EtN (21.01 g, 208 mmol, 5.0 equiv.) in ACN (200 mL) was purged with N(g) three times. Pd(dppf)Cl (3.04 g, 4.15 mmol, 0.1 equiv.) was then added, and the resulting reaction mixture was heated to 60 °C and stirred under N(g) for 12 h. The reaction mixture was cooled to room temperature, diluted with H2O (200 mL), and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 3:1 to 1:1) to give ethyl 1-(6-(3-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (12.0 g, 83% yield) as a brown oil. LCMS C 16 H 21 Calculated for N3O3: m / z = 303; Found: m / z = 304 (M+H).

[0387] Intermediate 54. Ethyl 1-(6-(3-hydroxybutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 53) (15.2 g, 50.11 mmol, 1.0 equiv.) in MeOH (40 mL) was added 20% Pd(OH)2 / C (1.5 g, 50.11 mmol, 1.0 equiv.) under an N2(g) atmosphere. The suspension was degassed and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 4 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under vacuum to give ethyl 1-(6-(3-hydroxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (9.6 g, 55% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.99(s,1H),7.73(s,1H),4.18(m,4H),3.88(m,1H),3.04(m,2H),2.78(t,J=7 .2,2H),2.56(m,1H),2.02(m,2H),1.93-1.71(m,4H),1.27(t,J=7.0,3H);LCMS C 16 H 21 Calculated for N3O3: m / z = 307; Found: m / z = 308 (M+H).

[0388] Intermediate 55. Ethyl 1-(6-(3-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-hydroxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 54) (9.60 g, 31.23 mmol, 1.0 equiv) in DCM (120 mL) was added Dess-Martin periodinane (26.49 g, 62.46 mmol, 2.0 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to remove DCM. The residue was diluted with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give ethyl 1-(6-(3-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate (6.20 g, 53% yield) as a brown oil. 16 H 23 Calculated for N3O3: m / z = 305; Found: m / z = 306 (M+H).

[0389] Intermediate 56. Ethyl 1-(6-(3,3-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 55) (3.00 g, 9.82 mmol, 1.0 equiv) in DCE (30 mL) was added DAST (43.47 g, 196.48 mmol, 20.0 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0 °C and adjusted to pH = 8 with saturated aqueous NaHCO (100 mL). The reaction mixture was diluted with HO (100 mL), extracted with EtOAc (3 × 200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 2: 1) to give ethyl 1-(6-(3,3-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (1.20 g, yield 33%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.99(s,1H),7.73(s,1H),4.27(m,2H),4.17(q,J LCMS C 16 H 23 Calculated for F2N3O2: m / z = 327; Found: m / z = 328 (M+H).

[0390] Intermediate 57. Ethyl 1-(6-(3,3-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3,3-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 56) (1.7 g, 5.19 mmol, 1.0 equiv) in DMF (15 mL) was added TFA (593 mg, 5.19 mmol, 1.0 equiv) and NIS (1.52 g, 6.75 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH = 8 with saturated aqueous NaHCO3 (30 mL) and subsequently extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give ethyl 1-(6-(3,3-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (1.8 g, 76% yield) as a yellow oil. 16 H 22 Calculated for F2IN3O2: m / z = 453; Found: m / z = 454 (M+H).

[0391] Intermediate 58. Ethyl 1-(3-chloro-6-(3,3-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3,3-difluorobutyl)-5-iodo-pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 57) (1.5 g, 3.31 mmol, 1.0 equiv) in DMF (20 mL) was added TFA (378 mg, 3.31 mmol, 1.0 equiv) and NCS (663 mg, 4.96 mmol, 1.5 equiv) at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and adjusted to pH = 8 with saturated aqueous NaHCO (30 mL), followed by extraction with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 4: 1) to give ethyl 1-(3-chloro-6-(3,3-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (1.5 g, yield 77%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.18(q,J=7.0,2H),3.94(m,2H),2.98(m,4H),2.54(m,1H),2.31(m,2H) ),2.02(m,2H),1.88(m,2H),1.69(t,J=18.4,3H),1.28(t,J=7.2,3H).

[0392] Intermediate 59. Ethyl 1-(3-chloro-6-(3,3-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-6-(3,3-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 58) (1.2 g, 2.46 mmol, 1.0 equiv) in EtOH (30 mL) was added 10% Pd / C (2.5 g, 2.46 mmol, 1.0 equiv). The suspension was degassed and purged with H(g) three times. The resulting reaction mixture was stirred under H(g) (15 psi) at room temperature for 12 hours. The reaction mixture was then purged with N(g) and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 0: 1 to 3: 1) to give ethyl 1-(3-chloro-6-(3,3-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (920 mg, 83% yield) as a yellow oil. 16 H 22 Calculated for ClF2N3O2: m / z = 361; Found: m / z = 362 (M+H).

[0393] Intermediate 60. (E)-1-(6-(4-methoxybut-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate ethyl [ka] To a solution of ethyl 1-(6-formylpyrazin-2-yl)piperidine-4-carboxylate (Intermediate 47) (3.21 g, 12.19 mmol, 1.0 equiv.) in isopropyl acetate (45 mL) was added (3-methoxypropyl)triphenylphosphonium bromide (6.33 g, 15.24 mmol, 1.3 equiv.) at room temperature, followed by K2CO3 (2.02 g, 14.63 mmol, 1.2 equiv.). The resulting reaction mixture was heated to 80 °C and stirred for 48 h. The reaction mixture was then cooled to room temperature, diluted with HO (400 mL), and extracted with EtOAc (2 × 150 mL). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 2: 1) to give ethyl (E)-1-(6-(4-methoxybut-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (3.60 g, yield 92%) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.97(s,1H),7.77(s,1H),6.34(d,J=11.8,1H),6.01(m,1H),4.27(m,2H),4.17(q,J=8.0,2H),3.54(t, LCMS C 17 H 25 Calculated for N3O3: m / z = 319; Found: m / z = 320 (M+H).

[0394] Intermediate 61. Ethyl 1-(6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of (£)-1-(6-(4-methoxybut-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 60) (1.87 g, 5.85 mmol, 1.0 equiv) in EtOH (20 mL) was added 10% Pd / C (1.87 g) at room temperature under a N2(g) atmosphere. The resulting suspension was degassed and purged with H2 three times, and the mixture was then stirred at room temperature under a H2(g) atmosphere (15 psi) for 2 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 1-(6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (3.65 g, 97% yield) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.95(s,1H),7.70(s,1H),4.26(m,2H),4.16(q,J=8.0,2H),3.41(t,J=6.0,2H),3.33(s,3H),3.02(m, LCMS C 17 H 27 Calculated for N3O3: m / z = 321; Found: m / z = 322 (M+H).

[0395] Intermediate 62. Ethyl 1-(5-iodo-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 61) (3.45 g, 10.73 mmol, 1.0 equiv.) in DMF (75 mL) was added NIS (3.02 g, 13.42 mmol, 1.2 equiv.) at room temperature. The resulting reaction mixture was heated to 60 °C and stirred for 2 h under a N2(g) atmosphere in the absence of light. The reaction mixture was then cooled to room temperature and quenched by the addition of saturated aqueous Na2SO3 (10 mL), followed by dilution with EtOAc (200 mL) and HO (200 mL). The aqueous layer was extracted with EtOAc (3 × 150 mL). The organic layers were combined, washed with brine (2 × 150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 4: 1 to 2: 1) to give ethyl 1-(5-iodo-6-(4-methoxybutyl) pyrazin-2-yl) piperidine-4-carboxylate (3.57 g, yield 74%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.73(s,1H),4.19(m,2H),4.15(q,J=8.0,2H),3.42(t,J=6.0,2H),3.34(s,3H),3.01(m,2H),2. 77(t,J=6.0,2H),2.54(m,1H),2.01(m,2H),1.76(m,4H),1.68(m,2H),1.26(t,J=6.0,3H);LCMS C 17 H 26 Calculated for IN3O3: m / z = 447; Found: m / z = 448 (M+H).

[0396] Intermediate 63. Ethyl 1-(3-chloro-5-iodo-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 62) (2.37 g, 5.30 mmol, 1.0 equiv.) in DMF (23 mL) was added NCS (707 mg, 5.30 mmol, 1.0 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 4 h under a N2(g) atmosphere in the absence of light. The reaction mixture was then cooled to room temperature and quenched by the addition of saturated aqueous Na2SO3 (20 mL). The mixture was then diluted with EtOAc (300 mL) and HO (300 mL). The aqueous layer was extracted with EtOAc (2 × 300 mL). The organic layers were combined, washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 9: 1 to 4: 1) to give ethyl 1-(3-chloro-5-iodo-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (2.13 g, 83% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.16(q,J=8.0,2H),3.95(m,2H),3.43(t,J=8.0,2H),3.35(s,3H),2.98(m,2H),2.83(t,J=8.0, 2H),2.54(m,1H),2.04(m,2H),1.90(m,2H),1.77(m,2H),1.67(m,2H),1.28(t,J=6.0,3H);LCMS C 17 H 25 Calculated for ClIN3O3: m / z = 481; Found: m / z = 482 (M+H).

[0397] Intermediate 64. Ethyl 1-(3-chloro-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a suspension of 10% Pd / C (2.81 g, 2.65 mmol) in EtOH (140 mL) was added ethyl 1-(3-chloro-5-iodo-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 63) (2.81 g, 5.83 mmol, 1.0 equiv.) at room temperature under an N2(g) atmosphere. The suspension was degassed and purged with H2(g) three times. The mixture was stirred at room temperature under an H2(g) atmosphere (30 psi) for 4 hours. The reaction mixture was then purged with N2(g) and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove EtOH. The residue was partitioned between HO (200 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE: EtOAc = 9:1 to 4:1) to give ethyl 1-(3-chloro-6-(4-methoxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (1.57 g, yield 76%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.71(s,1H),4.17(q,J=8.0,2H),3.93(m,2H),3.40(t,J=8.0,2H),3.33(s,3H),2.94(m,2H),2.68(t, LCMS C 17 H 26 Calculated for ClN3O3: m / z = 355; Found: m / z = 356 (M+H).

[0398] Intermediate 65. Ethyl 1-(6-(4-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 76) (15.0 g, 41.53 mmol, 1.0 equiv.), but-3-yn-1-ol (4.37 g, 62.30 mmol, 4.72 mL, 1.5 equiv.), CuI (1.58 g, 8.31 mmol, 0.2 equiv.), PPh (2.18 g, 8.31 mmol, 0.2 equiv.), and EtN (21.01 g, 207.65 mmol, 28.90 mL, 5.0 equiv.) in ACN (150 mL) was added Pd(dppf)Cl (3.04 g, 4.15 mmol, 0.1 equiv.) under a N atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with HO (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 3:1 to 1:2) to give ethyl 1-(6-(4-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (11.0 g, 73% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.03(s,1H),7.89(s,1H),4.23(m,2H),4.15(q,J=7.2,2H),3.85(m,2H),3.02(m,2H), 2.73(t,J=6.4,2H),2.55(m,1H),2.01(m,2H),1.77(m,2H),1.26(t,J=7.2Hz,3H);LCMS C 16 H 21 Calculated for N3O3: m / z = 303; Found: m / z = 304 (M+H).

[0399] Intermediate 66. Ethyl 1-(6-(4-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a suspension of 20% Pd(OH) (15.0 g, 21.36 mmol) in EtOH (100 mL) was added ethyl 1-(6-(4-hydroxybut-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 65) (9.00 g, 29.67 mmol, 1.0 equiv.) at room temperature under a N(g) atmosphere. The resulting reaction mixture was degassed under vacuum, purged multiple times with H(g), and then stirred at room temperature under a H(g) atmosphere (30 psi) for 96 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give crude ethyl 1-(6-(4-hydroxybutyl)pyrazin-2-yl)piperidine-4-carboxylate (8.00 g, crude) as a yellow oil. In a separate flask, a solution of oxalyl chloride (8.67 g, 68.32 mmol, 5.98 mL, 3.0 equiv) in DCM (80 mL) was treated dropwise with DMSO (8.90 g, 113.86 mmol, 8.90 mL, 5.0 equiv) under a N2(g) atmosphere at −78 °C over 5 min, and the resulting reaction mixture was stirred for 0.5 h. Next, a solution of the crude 1-(6-(4-hydroxybutyl)pyrazin-2-yl)piperidine-4-carboxylate prepared above in DCM (20 mL) was added dropwise over 10 min, and the resulting reaction mixture was stirred at −78 °C for 1 h. Next, EtN (18.43 g, 182.18 mmol, 25.36 mL, 8.0 equiv) was added dropwise over 5 min, and the resulting reaction mixture was stirred at −78 °C for 0.5 h. The mixture was warmed to room temperature, diluted with HO (50 mL), and extracted with DCM (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5:1 to 1:1) to give ethyl 1-(6-(4-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate (3.60 g, 52%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 9.79(s,1H),7.99(s,1H),7.71(s,1H),4.26(m,2H),4.17(q,J=7.2,2H),3.05(m,2H),2.67(t,J =7.2,2H),2.60(m,1H),2.51(m,2H),2.08(m,2H),2.02(m,2H),1.76(m,2H),1.28(t,J=7.2,3H).

[0400] Intermediate 67. Ethyl 1-(6-(4,4-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(4-oxobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 66) (3.20 g, 10.48 mmol, 1.0 equiv) in DCM (30 mL) was added DAST (4.64 g, 20.96 mmol, 4.59 mL, 2.0 equiv) at −78° C. The resulting reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with saturated aqueous NaHCO (50 mL) and subsequently extracted with DCM (3×30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give ethyl 1-(6-(4,4-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (1.90 g, 55% yield) as a yellow oil. LCMS C 16 H 23 Calculated for F2N3O2: m / z = 327; Found: m / z = 328 (M+H).

[0401] Intermediate 68. Ethyl 1-(6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] A solution of ethyl 1-(6-(4,4-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 67) (2.00 g, 6.11 mmol, 1.0 equiv), TFA (696 mg, 6.11 mmol, 452 μL, 1.0 equiv), and NIS (1.79 g, 7.94 mmol, 1.3 equiv) in DMF (20 mL) was degassed at room temperature and purged with N (g) three times, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO (30 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 30: 1 to 10: 1) to give ethyl 1-(6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (2.16 g, yield 78%) as a yellow oil. 16 H 22 Calculated for F2IN3O2: m / z = 453; Found: m / z = 454 (M+H).

[0402] Intermediate 69. Ethyl 1-(3-chloro-6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] A solution of ethyl 1-(6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 68) (2.20 g, 4.85 mmol, 1.0 equiv), NCS (842 mg, 6.31 mmol, 1.3 equiv), TFA (553 mg, 4.85 mmol, 359 μL, 1.0 equiv) in DMF (20 mL) was degassed at room temperature and purged with N (g) three times, and the resulting reaction mixture was then heated to 100 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO (30 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to give ethyl 1-(3-chloro-6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (1.62 g, 68% yield) as a yellow oil. 16 H 21 Calculated for ClF2IN3O2: m / z = 487; Found: m / z = 488 (M+H).

[0403] Intermediate 70. Ethyl 1-(3-chloro-6-(4,4-difluorobutyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-6-(4,4-difluorobutyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 69) (1.50 g, 3.08 mmol, 1.0 equiv) in EtOH (15 mL) was added 10% Pd / C (3.00 g) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged multiple times with H2(g). The resulting reaction mixture was stirred at room temperature under an H2(g) atmosphere (15 psi) for 48 hours. The reaction mixture was purged multiple times with N2(g) and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 30: 1 to 10: 1) to give ethyl 1-(3-chloro-6-(4,4-difluorobutyl) pyrazin-2-yl) piperidine-4-carboxylate (975 mg, 87% yield) as a yellow oil. 16 H 22 Calculated for ClF2N3O2: m / z = 361; Found: m / z = 362 (M+H).

[0404] Intermediate 71. 1-(6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a mixture of zinc (6.44 g, 76.35 mmol, 3.0 equiv) in THF (75 mL) was added 1,2-dibromoethane (1.18 g, 6.30 mmol, 0.2 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was heated to 80 °C and stirred for 5 min. The reaction mixture was then cooled to room temperature. This heating and cooling cycle was repeated four times, after which TMSCl (205 mg, 1.89 mmol, 0.06 equiv) was added to the mixture. The resulting mixture was stirred at room temperature for 10 min and then cooled to 0 °C. A solution of 1,1,1-trifluoro-3-iodo-propane (7.50 g, 31.51 mmol, 1.0 equiv) in THF (75 mL) was then added dropwise over 10 min to the reaction mixture, and the resulting reaction mixture was stirred at 0 °C for 15 min. Next, 1-(6-chloropyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 36) (3.50 g, 15.72 mmol, 1.0 equiv.) in 5 mL of THF was added, followed by Pd(dppf)Cl.CHCl (1.28 g, 1.57 mmol, 0.1 equiv.). The resulting reaction mixture was heated at 60 °C with stirring for 12 h. The reaction mixture was cooled to room temperature and then poured into HO (300 mL) and extracted with EtOAc (2 × 300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give 1-(6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile (4.1 g, 87%) as a black oil. 1 H NMR(400MHz,CDCl3)δ 7.94(s,1H),7.69(s,1H),3.79(m,2H),3.52(m,2H),2.84(m,1H),2.64(t,J=7.2,2H),2.07(m,2H),1.92(m,6H).

[0405] Intermediate 72. 1-(5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 71) (3.10 g, 10.39 mmol, 1.0 equiv.) in DMF (30 mL) was added NIS (3.04 g, 13.51 mmol, 1.3 equiv.) and TFA (1.18 g, 10.39 mmol, 1 equiv.) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (60 mL), poured into HO (100 mL), and extracted with EtOAc (2 x 140 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 4: 1) to give 1-(5-iodo-6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carbonitrile (3.6 g, 81% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.72(s,1H),3.74(m,2H),3.51(m,2H),2.80(m,1H),2.72(m,2H),2.09(m,2H),1.94(m,6H).

[0406] Intermediate 73. 1-(3-chloro-5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 72) (3.30 g, 7.78 mmol, 1.0 equiv) in DMF (30 mL) was added NCS (1.14 g, 8.56 mmol, 1.1 equiv) and TFA (887 mg, 7.78 mmol, 1.0 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was heated at 100 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and subsequently quenched with saturated aqueous NaHCO3 (50 mL), poured into HO (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 6: 1) to give 1-(3-chloro-5-iodo-6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carbonitrile (3.1 g, 85% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 3.59(m,2H),3.32(m,2H),2.84(m,3H),2.16(m,2H),1.98(m,6H).

[0407] Intermediate 74. 1-(3-chloro-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(4,4,4-trifluorobutyl)pyrazin-2-yl)piperidine-4-carbonitrile (2.00 g, 4.36 mmol, 1.0 equiv) in MeOH (150 mL) was added 10% Pd / C (1.00 g) at room temperature. The suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (30 psi) at room temperature for 12 hours. The reaction mixture was then purged with N(g) three times and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 5: 1) to give 1-(3-chloro-6-(4,4,4-trifluorobutyl) pyrazin-2-yl) piperidine-4-carbonitrile (1.2 g, yield 80%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.70(s,1H),3.59(m,2H),3.31(m,2H),2.83(m,1H),2.70(m,2H),2.01(m,8H).

[0408] Intermediate 75. 2,6-Diiodopyrazine [ka] To a solution of 2,6-dichloropyrazine (50.00 g, 335 mmol, 1.0 equiv) in HI (250 mL, 48% purity) was added sodium iodide (65.40 g, 436 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 1 h. The mixture was then cooled to room temperature, diluted with HO (500 mL), and extracted with MTBE (3 × 500 mL). The combined organic layers were washed successively with saturated aqueous NaHCO (500 mL), NaSO (500 mL), and brine (500 mL), then dried over NaSO, filtered, and concentrated under reduced pressure to give 2,6-diiodopyrazine (102 g, crude) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.91(s,2H).

[0409] Intermediate 76. Ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of 2,6-diiodopyrazine (Intermediate 75) (60 g, 180 mmol, 1.0 equiv) in dioxane (800 mL) was added EtN (27.44 g, 271 mmol, 37.8 mL, 1.5 equiv) and ethyl piperidine-4-carboxylate (42.63 g, 271 mmol, 41.8 mL, 1.5 equiv) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The mixture was then cooled to room temperature, diluted with HO (500 mL), and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to give ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate (66 g, yield 96%) as a yellow oil. 1 LCMS C 12 H 16 Calculated for IN3O2: m / z = 361; Found: m / z = 362 (M+H).

[0410] Intermediate 77. Ethyl 1-(6-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 76) (10 g, 28 mmol, 1.00 equiv.) in ACN (100 mL) was added prop-2-yn-1-ol (3.35 g, 61 mmol, 2.20 equiv.), CuI (1.05 g, 5.6 mmol, 0.20 equiv.), PPh (1.45 g, 5.6 mmol, 0.20 equiv.), Pd(dppf)Cl (1.01 g, 1.4 mmol, 0.05 equiv.), and EtN (14.01 g, 138.5 mmol, 19 mL, 5.00 equiv.) at room temperature. The resulting reaction mixture was degassed and purged with N(g) three times. The reaction mixture was then heated to 60 °C and stirred under N(g) for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the ACN. The residue was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 1:1) to give ethyl 1-(6-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (7.50 g, 90% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 8.07(s,1H),7.95(s,1H),4.51(s,2H),4.23(m,2H),4.12(q,J=7.2,2H),3. 04(m,2H),2.56(m,1H),2.01(m,2H),1.77(m,2H),1.28(t,J=7.2,3H);LCMS C 15 H 19 Calculated for N3O3: m / z = 289; Found: m / z = 290 (M+H).

[0411] Intermediate 78. Ethyl 1-(6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-hydroxyprop-1-ynyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 77) (12 g, 41.48 mmol, 1.0 equiv.) in EtOH (100 mL) was added 20% Pd(OH)2 / C (15.0 g) at room temperature. The resulting suspension was degassed under vacuum and purged multiple times with H2(g). The reaction mixture was stirred at room temperature under an H2(g) atmosphere (15 psi) for 12 hours. The reaction mixture was then purged multiple times with N2(g). The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give ethyl 1-(6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (6.75 g, 55% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.00(s,1H),7.73(s,1H),4.21(m,2H),4.14(q,J=7.2,2H),3.71(t,J=6.0,2H),3.03(m,2H),2. 77(t,J=7.2,2H),2.58(m,1H),2.02(m,2H),1.96(m,2H),1.80(m,2H),1.27(t,J=7.2,3H);LCMS C 15 H 23 Calculated for N3O3: m / z = 293; Found: m / z = 294 (M+H).

[0412] Intermediate 79. Ethyl 1-(6-(3-hydroxypropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 78) (2.30 g, 8 mmol, 1.0 equiv) and NIS (2.29 g, 10 mmol, 1.3 equiv) in DMF (30 mL) was added TFA (179 mg, 1.57 mmol, 116 μL, 0.2 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to give ethyl 1-(6-(3-hydroxypropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (1.8 g, 55% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.77(s,1H),4.16(m,4H),3.71(t,J=7.2,2H),3.04(m,2H),2.90(t,J=7.2, 2H),2.56(m,1H),2.07-1.93(m,5H),1.76(m,2H),1.27(t,J=7.2,3H);LCMS C 15 H 22 Calculated for IN3O3: m / z = 419; Found: m / z = 420 (M+H).

[0413] Intermediate 80. Ethyl 1-(3-chloro-6-(3-hydroxypropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-hydroxypropyl)-5-iodo-pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 79) (1.3 g, 3 mmol, 1 equiv) and NCS (497 mg, 3.72 mmol, 1.2 equiv) in DMF (20 mL) was added TFA (71 mg, 620 μmol, 46 μL, 0.2 equiv) at room temperature. The resulting reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to room temperature, diluted with HO (30 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 3: 1) to give ethyl 1-(3-chloro-6-(3-hydroxypropyl)-5-iodo-pyrazin-2-yl) piperidine-4-carboxylate (1.0 g, yield 71%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ LCMS C 15 H 21 Calculated for ClIN3O3: m / z = 453; Found: m / z = 454 (M+H).

[0414] Intermediate 81. Ethyl 1-(3-chloro-6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-6-(3-hydroxypropyl)-5-iodo-pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 80) (1.1 g, 2.42 mmol, 1.0 equiv.) in EtOH (10 mL) was added 10% Pd / C (2.42 mmol, 1 equiv.). The resulting suspension was degassed under vacuum and purged multiple times with H(g). The reaction mixture was stirred at room temperature under an H(g) atmosphere (15 psi) for 16 hours. The reaction mixture was then purged with N(g). The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 2:1) to give ethyl 1-(3-chloro-6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (500 mg, 63% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.76(s,1H),4.18(q,J=7.2,2H),3.93(m,2H),3.71(m,2H),3.00-2.92(m,2H),2.81(t,J LCMS C 15 H 22 Calculated for ClN3O3: m / z = 327; Found: m / z = 328 (M+H).

[0415] Intermediate 82. Ethyl 1-(3-chloro-6-(3-oxopropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] A solution of oxalyl chloride (465 mg, 3.66 mmol, 320 μL, 3 equiv) in DCM (5 mL) was cooled to −78° C. To this solution was added DMSO (477 mg, 6.10 mmol, 476 μL, 5 equiv), and the resulting reaction mixture was stirred at −78° C. for 30 minutes. Next, a solution of ethyl 1-(3-chloro-6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 81) (400 mg, 1.22 mmol, 1 equiv) in DCM (5 mL) was added dropwise to the reaction mixture over 5 minutes, and the resulting reaction mixture was stirred at −78° C. for 1 hour. Next, EtN (988 mg, 9.76 mmol, 1.36 mL, 8 equiv) was added dropwise over 5 minutes at −78° C., and the resulting reaction mixture was stirred for 30 minutes, then warmed to room temperature, and stirred for an additional 15 minutes. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 1:1) to give ethyl 1-(3-chloro-6-(3-oxopropyl)pyrazin-2-yl)piperidine-4-carboxylate (380 mg, 69% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.89(s,1H),7.77(s,1H),4.18(q,J=7.2,2H),3.92(m,2H),3.05(m,2H),2.99 -2.84(m,4H),2.53(m,1H),2.03(m,2H),1.90(m,2H),1.29(t,J=7.2,3H);LCMS C 15 H 20 Calculated for ClN3O3: m / z = 325; Found: m / z = 326 (M+H).

[0416] Intermediate 83. Ethyl 1-(3-chloro-6-(4,4-difluorobut-3-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(3-chloro-6-(3-oxopropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 82) (911 mg, 2.80 mmol, 1.5 equiv), 2-((difluoromethyl)sulfonyl)pyridine (360 mg, 1.86 mmol, 1.0 equiv), and CsF (566 mg, 3.73 mmol, 138 μL, 2.0 equiv) in DMF (15 mL) was added bis(trimethylsilyl)amine (871 mg, 3.73 mmol, 2 equiv) at room temperature under a N2 (g) atmosphere. The resulting reaction mixture was stirred at room temperature for 11.5 hours. The mixture was cooled to 0 °C, and then saturated aqueous NH4Cl (100 mg, 1.86 mmol, 1 equiv.) and HCl (2 M, 13.98 mL, 15 equiv.) were added sequentially to the reaction mixture. The resulting reaction mixture was heated to 50 °C and stirred for 30 min. The reaction mixture was cooled to room temperature, diluted with HO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give ethyl 1-(3-chloro-6-(4,4-difluorobut-3-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (420 mg, 61% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.63(s,1H),4.11(m,3H),3.87(m,2H),2.90(m,2H),2.66(t,J=7.6,2H),2 .46(m,1H),2.34(m,2H),1.97(m,),1.85(m,2H),1.21(t,J=7.2,3H);LCMS C 16 H 20 Calculated for ClF2N3O2: m / z = 359; Found: m / z = 360 (M+H).

[0417] Intermediate 84. 5-Bromo-2-chloro-3-(methoxymethoxy)pyridine [ka] To a solution of NaH (2.49 g, 62.37 mmol, 60% purity, 1.30 equiv) in DMF (50 mL) was added 5-bromo-2-chloropyridin-3-ol (10.00 g, 47.98 mmol, 1.00 equiv) in DMF (50 mL) dropwise over 10 min at room temperature under a N2(g) atmosphere. The resulting reaction mixture was stirred at room temperature for 30 min, and MOMCl (4.83 g, 59.99 mmol, 4.56 mL, 1.25 equiv) was added. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (10.0 g, yield 81%) as a white solid.

[0418] Intermediate 85. 3-(6-chloro-5-(methoxymethoxy)pyridin-3-yl)prop-2-yn-1-ol [ka] 3-Methoxyprop-1-yne (12.21 g, 174.26 mmol, 14.37 mL, 2.00 equiv.), 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (Intermediate 84) (22.00 g, 87.13 mmol, 1.00 equiv.), CuI (1.66 g, 8.71 mmol, 0.10 equiv.), [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (CataCXium A Pd G3) (3.17 g, 4.36 mmol, 0.05 equiv) and CsCO (85.17 g, 261.39 mmol, 3.00 equiv) were degassed under vacuum and purged with N(g) three times. The reaction mixture was then heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was diluted with HO (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 50:1 to 10:1) to give 2-chloro-3-(methoxymethoxy)-5-(3-methoxyprop-1-yn-1-yl)pyridine (17.0 g, 80% yield) as a yellow solid. 1 LCMS C 11 H 12 Calculated for ClNO3: m / z = 241; m / z = 242 (M+H).

[0419] Intermediate 86. 2-Chloro-3-(methoxymethoxy)-5-(3-methoxypropyl)pyridine [ka] To a solution of 2-chloro-3-(methoxymethoxy)-5-(3-methoxyprop-1-ynyl)pyridine (13.00 g, 53.79 mmol, 1.0 equiv) in MeOH (10 mL) was added 5% Rh / C (6.00 g) at room temperature under a N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The reaction mixture was stirred under H2(g) (15 psi) at room temperature for 8 hours. The reaction mixture was then purged three times with N2(g), filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 30:1 to 10:1) to give 2-chloro-3-(methoxymethoxy)-5-(3-methoxypropyl)pyridine (10.00 g, 75% yield) as a yellow oil. LCMS C 11 H 16 Calculated for ClNO3: m / z = 245; Found: m / z = 246 (M+H).

[0420] Intermediate 87. 6-Bromo-4-fluorobenzo[d][1,3]dioxole [ka] To a solution of 5-bromo-3-fluoro-benzene-1,2-diol (200 mg, 966 μmol, 1.0 equiv) and bromo(chloro)methane (375 mg, 2.90 mmol, 3.0 equiv) in DMF (3 mL) was added CsCO (629 mg, 1.93 mmol, 2.0 equiv) at room temperature under a N(g) atmosphere. The resulting reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was then cooled to room temperature. The residue was poured into HO (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic phase was washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to give 6-bromo-4-fluorobenzo[d][1,3]dioxole (60 mg, 18% yield) as a clear liquid. 1H NMR(400MHz,CDCl3)δ 6.77(dd,J=9.2,1H),6.72(s,1H),5.95(s,2H).

[0421] Intermediate 88. 2-(7-fluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 6-bromo-4-fluoro-1,3-benzodioxole (340 mg, 1.55 mmol, 1.0 equiv) and (bis)pinacolatodiborane (591 mg, 2.33 mmol, 1.5 equiv) in dioxane (10 mL) was added Pd(dppf)Cl·CHCl (253 mg, 310 μmol, 0.2 equiv) and KOAc (304 mg, 3.10 mmol, 2.0 equiv) at room temperature under a N atmosphere. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, poured into HO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to give 2-(7-fluoro-1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mg, yield 58%) as a colorless transparent liquid. 1 H NMR(400MHz,CDCl3)δ 7.19(s,1H),7.09(s,1H),5.95(s,2H),1.27(s,12H).

[0422] Intermediate 89. Ethyl 1-(6-(3-methoxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 76) (25.0 g, 69.22 mmol, 1.0 equiv.) and 3-methoxyprop-1-yne (9.7 g, 138.44 mmol, 2.0 equiv.) in ACN (250 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (2.3 g, 3.46 mmol, 0.05 equiv.), CsCO3 (67.7 g, 207.65 mmol, 3.0 equiv.), and CuI (1.3 g, 6.92 mmol, 0.1 equiv.) under a N2 (g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the ACN. The residue was poured into HO (1 L) and extracted with EtOAc (3 × 1 L). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 5:1 to 3:1) to afford ethyl 1-(6-(3-methoxyprop-1-ynyl)pyrazin-2-yl)piperidine-4-carboxylate (13.1 g, 62% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 8.10(s,1H),7.97(s,1H),4.37(s,2H),4.27(m,2H),4.19(q,J=7.2,2H),3.49( s,3H),3.09(m,2H),2.56(m,1H),2.06(m,2H),1.81(m,2H),1.29(t,J=7.2,3H).

[0423] Intermediate 90. Ethyl 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-methoxyprop-1-ynyl)pyrazin-2-yl)piperidine-4-carboxylate (10.0 g, 32.96 mmol, 1.0 equiv) in EtOH (500 mL) was added 20% Pd(OH)2 / C (4.4 g) at room temperature. The suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred under H2(g) (15 psi) at room temperature for 3 h. The reaction mixture was then degassed under vacuum and purged with N2(g) three times, followed by filtration through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give ethyl 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (9.6 g, 91% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 7.89(s,1H),7.64(s,1H),4.19(m,2H),4.10(q,J=7.2,2H),3.35(t,J=6.4,2H),3.28(s,3H), 2.95(m,2H),2.64(t,J=11.2,2H),2.47(m,1H),1.95(m,4H),1.71(m,2H),1.20(t,J=7.2,3H).

[0424] Intermediate 91. Ethyl 1-(5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 90) (11.1 g, 36.18 mmol, 1.0 equiv.) in DMF (100 mL) was added NIS (8.1 g, 36.18 mmol, 1.0 equiv.) and TFA (4.1 g, 36.18 mmol, 1.0 equiv.) at room temperature under a N2 (g) atmosphere. The resulting reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was poured into HO (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give 1-95-iodo-6-(3-methoxypropyl) pyrazin-2-yl) piperidine-4-carboxylate (13.1 g, 84% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 7.67(s,1H),4.11(m,4H),3.40(t,J=6.4,2H),3.30(s,3H),2.97(m,2H),2.7 6(t,J=7.6,2H),2.50(m,1H),1.94(m,4H),1.71(m,2H),1.18(t,J=4.4,3H).

[0425] Intermediate 92. Ethyl 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 91) (32.0 g, 73.85 mmol, 1.0 equiv.) and NCS (9.9 g, 73.85 mmol, 1.0 equiv.) in DMF (320 mL) was added TFA (8.4 g, 73.85 mmol, 1.0 equiv.) at room temperature under a N2 (g) atmosphere. The resulting reaction mixture was heated to 100 °C and stirred for 3 h. The reaction mixture was then cooled to room temperature, poured into HO (1 L), and extracted with EtOAc (3 × 1 L). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give ethyl 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl]piperidine-4-carboxylate (32.0 g, yield 92%) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 4.11(q,J=7.2,2H),3.88(m,2H),3.39(t,J=6.4,2H),3.29(s,3H),2.82(m,2H) ,2.79(m,2H),2.51(m,1H),1.98(m,4H),1.92(m,2H),1.22-1.17(t,J=7.2,3H).

[0426] Intermediate 93. Ethyl 1-(3-chloro-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 92) (1.0 g, 2.1 mmol, 1.0 equiv.) in MeOH (100 mL) was added 10% Pd / C (500 mg) at room temperature. The resulting suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (30 psi) at room temperature for 3 hours. The reaction mixture was then degassed under vacuum, purged with N(g) three times, and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to afford ethyl 1-(3-chloro-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (750 mg) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 7.65(s,1H),4.13(q,J=7.2,2H),3.87(m,2H),3.34(t,J=6.4,2H),3.27(s,3H) ,2.98(m,2H),2.68(m,2H),2.50(m,1H),1.98-1.84(m,6H),1.21(t,J=7.2,3H).

[0427] Intermediate 94. 1-(6-iodopyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 2,6-diiodopyrazine (Intermediate 75) (10.00 g, 30.13 mmol, 1.0 equiv.) and piperidine-4-carbonitrile (4.99 g, 34.05 mmol, 1.1 equiv.) in dioxane (100 mL) was added EtN (4.57 g, 45.20 mmol, 1.5 equiv.) at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the dioxane. The residue was poured into HO (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1 to 2: 1) to give 1-(6-iodopyrazin-2-yl) piperidine-4-carbonitrile (17.0 g, yield 60%) as a black oil. 1 H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.94(s,1H),3.76(m,2H),3.54(m,2H),2.87(m,1H),1.91(m,4H).

[0428] Intermediate 95. 1-(6-(3-methoxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(6-iodopyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 94) (4.50 g, 14.33 mmol, 1.0 equiv.) and 3-methoxyprop-1-yne (2.01 g, 28.65 mmol, 2.0 equiv.) in ACN (45 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (479 mg, 720 μmol, 0.05 equiv.), CsCO3 (14.00 g, 42.98 mmol, 3.0 equiv.), and CuI (270 mg, 1.3 mmol, 0.1 equiv.) under a N2 (g) atmosphere at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the dioxane. The residue was poured into HO (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 50:1 to 2:1) to give ethyl 1-(6-(3-methoxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carbonitrile (2.4 g, 22% yield) as a black oil. 1 H NMR(400MHz,CDCl3)δ 8.11(s,1H),8.02(s,1H),4.38(m,2H),3.91(m,2H),3.58(m,2H),3.50(s,3H),2.97(m,1H),2.02(m,4H).

[0429] Intermediate 96. 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of ethyl 1-(6-(3-methoxyprop-1-yn-1-yl)pyrazin-2-yl)piperidine-4-carbonitrile (1.20 g, 4.68 mmol, 1.0 equiv) in MeOH (30 mL) was added 10% Pd / C (1.00 g) at room temperature. The suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (15 psi) at room temperature for 2 hours. The reaction mixture was then degassed under vacuum, purged with N(g), and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give ethyl 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (3.2 g, 87% yield) as a yellow oil. LCMS C 14 H 20 Calculated for NO: m / z = 260; Found: m / z = 261 (M+H).

[0430] Intermediate 97. 1-(5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of ethyl 1-(6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 96) (2.70 g, 10.37 mmol, 1.0 equiv.) in DMF (27 mL) was added NIS (2.80 g, 12.45 mmol, 1.2 equiv.) and TFA (1.18 g, 10.37 mmol, 1.0 equiv.) at room temperature under a N2 (g) atmosphere. The resulting reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was poured into HO (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 0: 1) to give ethyl 1-(5-iodo-6-(3-methoxypropyl) pyrazin-2-yl) piperidine-4-carbonitrile (3.8 g, yield 80%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 7.69(s,1H),3.73(m,2H),3.49(m,2H),3.40(t,J=6.8,2H),3.30(s,3H),2.86(m,1H),2.77(t,J=7.6,2H),1.91(m,6H).

[0431] Intermediate 98. 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of ethyl 1-(5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 97) (2.80 g, 7.25 mmol, 1.0 equiv) and NCS (1.16 mg, 8.70 mmol, 1.2 equiv) in DMF (28 mL) was added TFA (827 mg, 7.25 mmol, 1.0 equiv) at room temperature under a N2(g) atmosphere. The resulting reaction mixture was heated to 90 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature, poured into HO (200 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 0: 1) to give ethyl 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (3.0 g, yield 62%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 3.68(m,2H),3.46(t,J=6.4,2H),3.37(m,5H),2.90(m,3H),2.06-1.97(m,6H).

[0432] Intermediate 99. 1-(3-chloro-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of ethyl 1-(3-chloro-5-iodo-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carbonitrile (Intermediate 98) (1.00 g, 2.38 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (100 mg) at room temperature. The suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (30 psi) at room temperature for 1 hour. The reaction mixture was then degassed under vacuum, purged with N(g), and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 10: 1) to give 1-(3-chloro-6-(3-methoxypropyl) pyrazin-2-yl) piperidine-4-carbonitrile (250 mg, yield 73%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ7.82(s,1H),3.71(m,2H),3.46(t,J=6.4,2H),3.40(m,5H),2.93(m,1H),2.79(t,J=7.6,2H),2.11-2.00(m,6H).

[0433] Intermediate 100. Ethyl 1-(6-(3-cyanopropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a suspension of Zn (1.35 g, 20.65 mmol, 1.38 equiv) in N,N-dimethylacetamide (10 mL) was added I2 (190 mg, 748 μmol, 0.05 equiv) at room temperature. The mixture was stirred until the yellow color disappeared (1–2 min), followed by the addition of 4-bromobutanenitrile (2.22 g, 15.00 mmol, 1.00 equiv). The resulting reaction mixture was heated to 70 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, followed by the addition of ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 8) (910 mg, 3.37 mmol, 1.00 equiv). The resulting reaction mixture was degassed under vacuum and purged with N2(g) three times, followed by the addition of Pd(dppf)Cl2CHCl2 (552 mg, 674 μmol, 0.20 equiv). The resulting reaction mixture was heated to 60° C. and stirred under a N2(g) atmosphere for 12 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite to remove the catalyst. The filtrate was diluted with HO (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ethyl 1-(6-(3-cyanopropyl)pyrazin-2-yl)piperidine-4-carboxylate (530 mg, 28% yield) as a brown oil. 1 H NMR(400MHz,CD3OD)δ 8.02(s,1H),7.66(s,1H),4.33(m,2H),4.15(q,J=7.2,2H),3.12(m,2H),2.77(t,J=7.2,2 H),2.65(m,1H),2.51(m,2H),2.23,(m,2H),2.00(m,2H),1.69(m,2H),1.26(t,J=7.2,3H).

[0434] Intermediate 101. Ethyl 1-(6-(3-cyanopropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(6-(3-cyanopropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 100) (1.50 g, 4.96 mmol, 1.0 equiv) in DMF (15 mL) was added TFA (566 mg, 4.96 mmol, 1.0 equiv) and NIS (1.45 g, 6.45 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH = 8 with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 2: 1) to give ethyl 1-(6-(3-cyanopropyl)-5-iodopyrazin-2-yl) piperidine-4-carboxylate (1.78 g, yield 80%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.79(s,1H),4.30-4.08(m,4H),3.05(t,J=11.2,2H),2.92(t,J=7.2,2H),2.58(m,1H) ,2.47(t,J=7.2,2H),2.14(m,2H),2.02(m,2H),1.76(m,2H),1.28(t,J=7.2,3H);LCMS C 16 H 21 Calculated for IN4O2: m / z = 428; Found: m / z = 429 (M+H).

[0435] Intermediate 102. Ethyl 1-(3-chloro-6-(3-cyanopropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(6-(3-cyanopropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 101) (1.78 g, 4.16 mmol, 1.0 equiv) in DMF (20 mL) was added TFA (474 ​​mg, 4.16 mmol, 1.0 equiv) and NCS (833 mg, 6.23 mmol, 1.5 equiv) at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and adjusted to pH = 8 with saturated aqueous NaHCO (30 mL), followed by extraction with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 2: 1) to give ethyl 1-(3-chloro-6-(3-cyanopropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (1.56 g, 80% yield) as a yellow oil. 16 H 20 Calculated for ClIN4O2: m / z = 462; Found: m / z = 463 (M+H).

[0436] Intermediate 103. Ethyl 1-(3-chloro-6-(3-cyanopropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a mixture of ethyl 1-(3-chloro-6-(3-cyanopropyl)-5-iodopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 102) (780 mg, 1.69 mmol, 1.0 equiv) in EtOH (20 mL) was added 10% Pd / C (1.60 g, 1.69 mmol, 1.0 equiv) at room temperature. The resulting suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (15 psi) at room temperature for 12 hours. The reaction mixture was then degassed under vacuum and purged with N(g). The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 4: 1 to 2: 1) to give ethyl 1-(3-chloro-6-(3-cyanopropyl) pyrazin-2-yl) piperidine-4-carboxylate (600 mg, yield 48%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.74(s,1H),4.18(q,J=7.2,2H),3.95(m,2H),3.04-2.91(m,2H),2.83(t,J=7.2,2H),2.5 4(m,1H),2.45(t,J=7.2,2H),2.15(m,2H),2.04(m,2H),1.91(m,2H),1.29(t,J=7.2,3H).

[0437] Intermediate 104. 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-b]pyridine [ka] To a solution of 5-bromofuro[2,3-b]pyridine (4.00 g, 20.20 mmol, 1.0 equiv) and bis(pinacolato)diboron (6.16 g, 24.24 mmol, 1.2 equiv) in dioxane (40 mL) was added Pd(dppf)Cl·CHCl (1.65 g, 2.02 mmol, 0.1 equiv) and KOAc (5.95 g, 60.60 mmol, 3.0 equiv) at room temperature under a N atmosphere. The resulting reaction mixture was heated to 85 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into HO (150 mL), and extracted with EtOAc (3 × 150 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo[2,3-b]pyridine (6.4 g) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.64(s,1H),8.29(s,1H),7.62(d,J=2.8,1H),6.70(d,J=2.8,1H),1.30(s,12H).

[0438] Intermediate 105. 2-Methoxy-5-(3-methoxyprop-1-yn-1-yl)pyridine [ka] To a solution of 5-bromo-2-methoxypyridine (15.0 g, 79.78 mmol, 1.0 equiv.) and 3-methoxyprop-1-yne (11.18 g, 159.56 mmol, 2.0 equiv.) in acetone (300 mL) was added CuI (1.52 g, 7.98 mmol, 0.1 equiv.) and CsCO (77.98 g, 239.33 mmol, 3.0 equiv.) at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, poured into HO (500 mL), and extracted with EtOAc (3 × 300 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 0:1) to give methyl 2-methoxy-5-(3-methoxyprop-1-yn-1-yl)pyridine (32.0 g) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.20(d,J=2.4,1H),7.53(dd,,J=2.4,8.4,1H),6.62(d,J=8.4,1H),4.24(s,2H),3.87(s,3H),3.38(s,3H).

[0439] Intermediate 106. 2-Methoxy-5-(3-methoxypropyl)pyridine [ka] To a solution of 2-methoxy-5-(3-methoxyprop-1-yn-1-yl)pyridine (Intermediate 105) (10.0 g, 56.43 mmol, 1.0 equiv) in MeOH (300 mL) was added 10% Pd / C (10.0 g) at room temperature under a N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred at room temperature under a H2(g) atmosphere (15 psi) for 12 hours. The reaction mixture was then purged under vacuum, flushed with N2(g), and filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under vacuum to give crude ethyl 2-methoxy-5-(3-methoxypropyl)pyridine (19.0 g, 93% yield) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 7.91(d,J=2.0,1H),7.34(dd,J=2.0,8.4,1H),6.61(d,J=8.4,1H),3.84(s,3H),3.30(t,J=8.2,2H),3.26(s,3H),2.56(m,2H),1.77(m,2H).

[0440] Intermediate 107. 3-Bromo-2-methoxy-5-(3-methoxypropyl)pyridine [ka] To a solution of 2-methoxy-5-(3-methoxypropyl)pyridine (Intermediate 106) (6.50 g, 35.87 mmol, 1.0 equiv) in concentrated H2SO4 (65 mL) was added NBS (19.15 g, 107.60 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was heated to 60 °C and stirred for 2 h. The reaction was cooled to 0 °C and subsequently quenched by the addition of ice-water (500 mL). The resulting mixture was extracted with DCM (3 × 200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 10:1) to give 3-bromo-2-methoxy-5-(3-methoxypropyl)pyridine (2.80 g, 30% yield) as a colorless liquid. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=2.0,1H),7.68(d,J=2.0,1H)3.84(s,3H),3.28(t,J=8.2,2H),3.22(s,3H),2.51(t,J=8.2,2H),1.72(m,2H).

[0441] Intermediate 108. 1-(2-Methoxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile [ka] To a solution of 3-bromo-2-methoxy-5-(3-methoxypropyl)pyridine (Intermediate 107) (3.50 g, 13.45 mmol, 1.0 equiv.) and piperidine-4-carbonitrile (1.97 g, 13.45 mmol, 1.0 equiv.) in THF (35 mL), Pd(dba) (778 mg, 1.35 mmol, 0.1 equiv.), t-BuONa (3.88 g, 40.36 mmol, 3.0 equiv.), and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) (1.23 g, 1.35 mmol, 0.1 equiv.) were added at room temperature under a N atmosphere (g). The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and combined with another batch (500 mg). The mixture was then poured into H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 1:1) to give 1-(2-methoxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile (3.20 g, 72% yield) as a yellow liquid. LCMS C 16 H 23 Calculated for N3O2: m / z = 289; Found: m / z = 290 (M+H).

[0442] Intermediate 109. 1-(2-hydroxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(2-methoxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile (Intermediate 108) (2.90 g, 10.02 mmol, 1.0 equiv) in HCl (3.0 M, 29 ml, 8.7 equiv) was heated to 70 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, quenched by careful addition of saturated aqueous NaHCO (50 mL), poured into HO (400 ml), and extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=7:1 to 0:1) to give 1-(2-hydroxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile (2.00 g, yield 66%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.07(s,1H),6.62(s,1H),3.30(m,7H),3.02(m,2H),2.78(m,1H),2.40(m,2H),2.06(m,4H),1.74(m,2H).

[0443] Intermediate 110. 3-(4-cyanopiperidin-1-yl)-5-(3-methoxypropyl)pyridin-2-yl trifluoromethanesulfonate [ka] To a solution of 1-(2-hydroxy-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carbonitrile (Intermediate 109) (1.70 g, 6.17 mmol, 1.0 equiv) in DCM (17 mL) was added EtN (2.50 mg, 24.70 mmol, 4.0 equiv) and TfO (4.35 g, 15.44 mmol, 2.5 equiv) under a N atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into HO (200 mL) and extracted with DCM (3 × 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 0: 1) to give 3-(4-cyanopiperidin-1-yl)-5-(3-methoxypropyl) pyridin-2-yl trifluoromethanesulfonate (1.90 g, yield 64%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.77(d,J=2.0,1H),7.23(d,J=2.0,1H),3.33(t,J=6.0,2H),3.28(s,3H),3.17( m,2H),2.98(m,2H),2.81(m,1H),2.65(t,J=7.6,2H),2.02(m,4H),1.81(m,2H).

[0444] Intermediate 111. Ethyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of 2,3,5-trichloropyrazine (2.00 g, 10.90 mmol, 1.0 equiv) and ethyl piperidine-4-carboxylate (1.71 g, 10.90 mmol, 1.68 mL, 1.0 equiv) in ACN (37 mL) was added DIEA (4.23 g, 32.71 mmol, 5.70 mL, 3.0 equiv) at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove most of the ACN. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to give ethyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (1.30 g, yield 78%) as a white solid. 12 H 15 Calculated for Cl2N3O2: m / z = 303; Found: m / z = 304 (M+H).

[0445] Intermediate 112. Ethyl 1-(3-(benzofuran-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 111) (3.10 g, 10.19 mmol, 1.0 equiv.) and benzofuran-5-ylboronic acid (1.65 g, 10.19 mmol, 1.0 equiv.) in DME (90 mL) was added Pd(dba) (933 mg, 1.02 mmol, 0.1 equiv.), PPh (534 mg, 2.04 mmol, 0.2 equiv.), and NaCO (1 M, 20.38 mL, 2.0 equiv.) at room temperature. The resulting reaction mixture was heated to 80 °C under a N(g) atmosphere and stirred for 2 h. The reaction mixture was then cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give ethyl 1-(3-(benzofuran-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate (3.80 g, 96% yield) as a white solid. LCMS C 20 H 20 Calculated for ClN3O3: m / z = 385; Found: m / z = 386 (M+H).

[0446] Intermediate 113. Ethyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 111) (300 mg, 986 μmol, 1.0 equiv.) and benzo[d][1,3]dioxol-5-ylboronic acid (163 mg, 986 μmol, 1.0 equiv.) in DME (8 mL) was added Pd(dba) (90 mg, 98 μmol, 0.1 equiv.), PPh (51 mg, 197 μmol, 0.2 equiv.), and NaCO (1 M, 1.97 mL, 2.0 equiv.) under a N(g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was then cooled to room temperature, diluted with HO (10 mL), and extracted with EtOAc (3 × 15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 10:1) to afford ethyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate (340 mg, 88% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.07(s,1H),7.39(dd,J=1.6,8.2,1H),7.34(d,J=1.6,1H),6.89(d,J=8.2,1H),6.02(s,2H),4.17(q, LCMS C 19 H 20 Calculated for ClN3O4: m / z = 389; Found: m / z = 390 (M+H).

[0447] Intermediate 114. 2-(1-(3,6-dichloropyrazin-2-yl)piperidin-4-yl)methyl acetate [ka] To a solution of 2,3,5-trichloropyrazine (500 mg, 2.73 mmol, 1.0 equiv.) and methyl 2-(piperidin-4-yl)acetate hydrochloride (791 mg, 4.09 mmol, 1.5 equiv., HCl salt) in dioxane (10 mL) was added EtN (414 mg, 4.09 mmol, 1.5 equiv.) at room temperature under a N (g) atmosphere. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and combined with another batch (100 mg scale). The combined mixture was then poured into HO (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to give methyl 2-(1-(3,6-dichloropyrazin-2-yl)piperidin-4-yl)acetate (650 mg, yield 65%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.72(s,1H),4.03(m,2H),3.63(s,3H),2.85(dt,J=2.0,12.8,2H),2.24(d,J=7.2,2H),1.98(m,1H),1.18(m,2H),1.36(m,2H).

[0448] Intermediate 115. 2-(1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidin-4-yl)acetate methyl [ka] To a solution of methyl 2-(1-(3,6-dichloropyrazin-2-yl)piperidin-4-yl)acetate (Intermediate 114) (550 mg, 1.81 mmol, 1.0 equiv) and benzo[d][1,3]dioxol-5-ylboronic acid (300 mg, 1.81 mmol, 1.0 equiv) in DME (11 mL) was added Pd(dba) (166 mg, 180 μmol, 0.1 equiv), PPh (95 mg, 361 μmol, 0.2 equiv), and NaCO (1 M, 3.6 mL, 2.0 equiv) under a N(g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and combined with another batch (100 mg scale). The combined mixture was then poured into HO (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 5:1) to afford methyl 2-(1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidin-4-yl)acetate (800 mg, 96% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.97(s,1H),7.28(dd,J=1.6,8.4,1H),7.25(s,1H),6.80(d,J=8.4,1H),5.95(s,2H),3.63(m ,5H),2.65(dt,J=2.0,12.0,2H),2.20(d,J=7.2,2H),1.98(m,1H),1.64(m,2H),1.20(m,2H).

[0449] Intermediate 116. Ethyl 3-(1-(3,6-dichloropyrazin-2-yl)piperidin-4-yl)propanoate [ka] To a solution of 2,3,5-trichloropyrazine (743 mg, 4.05 mmol, 1.0 equiv) in ACN (7 mL) was added ethyl 3-(piperidin-4-yl)propanoate (750 mg, 4.05 mmol, 1.0 equiv) and EtN (2.05 g, 20.24 mmol, 5.0 equiv) at room temperature. The resulting reaction mixture was then heated to 80 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature, diluted with HO (15 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give ethyl 3- (1- (3, 6-dichloropyrazin-2-yl) piperidin-4-yl) propanoate (920 mg, yield 65%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.79(s,1H),4.17(q,J=7.2,2H),4.09(m,2H),2.90(dt,J=2.0,8.8,2H),2.37(t,J =7.6,2H),1.82(m,2H),1.66(m,2H),1.54(m,1H),1.37(m,2H),1.27(t,J=7.2,3H).

[0450] Intermediate 117. Ethyl 3-(1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidin-4-yl)propanoate [ka] To a solution of ethyl 3-(1-(3,6-dichloropyrazin-2-yl)piperidin-4-yl)propanoate (Intermediate 116) (880 mg, 2.65 mmol, 1.0 equiv) in DMF (10 mL) was added benzo[d][1,3]dioxol-5-ylboronic acid (440 mg, 2.65 mmol, 1.0 equiv), CsCO (1.73 g, 5.30 mmol, 2.0 equiv), and Pd(PPh) (307 mg, 265 μmol, 0.1 equiv) at room temperature under a N atmosphere (g). The resulting reaction mixture was then heated to 100 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, diluted with HO (15 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 1:1) to give ethyl 3-(1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidin-4-yl)propanoate (600 mg, 53% yield) as a yellow oil. LCMS C 21 H 24 Calculated for ClN3O4: m / z = 417; Found: m / z = 418 (M+H).

[0451] Intermediate 118. 3-Chloro-5-(3-methoxyprop-1-yn-1-yl)pyridin-2-amine [ka] To a solution of 5-bromo-3-chloro-pyridin-2-amine (10.0 g, 48.20 mmol, 1.0 equiv.) and 3-methoxyprop-1-yne (3.72 g, 53.02 mmol, 1.1 equiv.) in ACN (100 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (1.61 g, 2.41 mmol, 0.05 equiv.), CuI (918 mg, 4.82 mmol, 0.1 equiv.), and CsCO3 (47.12 g, 144.61 mmol, 3.0 equiv.) under a N2 (g) atmosphere at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into HO (500 mL), and extracted with EtOAc (3 × 500 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 3:1) to give 3-chloro-5-(3-methoxyprop-1-ynyl)pyridin-2-amine (6.2 g, 65% yield) as a white solid. LCMS calculated for C9H9ClNO: m / z = 196; found: m / z = 197 (M+H).

[0452] Intermediate 119. 3-Chloro-5-(3-methoxypropyl)pyridin-2-amine [ka] To a solution of 3-chloro-5-(3-methoxyprop-1-ynyl)pyridin-2-amine (Intermediate 118) (6.90 g, 35.09 mmol, 1.0 equiv) in MeOH (150 mL) was added 5% Rh / C (5.00 g) at room temperature under an N2(g) atmosphere. The resulting suspension was degassed under vacuum and purged with H2(g) three times. The resulting reaction mixture was stirred under H2(g) (15 psi) at room temperature for 2 hours. The reaction mixture was then purged under vacuum, flushed with N2(g), and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give crude 3-chloro-5-(3-methoxypropyl)pyridin-2-amine (4.40 g, 62% yield) as a white solid, which was used without further purification. LCMS C9H 13 Calculated for ClNO: m / z = 200; Found: m / z = 201 (M+H).

[0453] Intermediate 120. 3-Chloro-5-(3-methoxypropyl)-2-nitropyridine [ka] To a solution of 3-chloro-5-(3-methoxypropyl)pyridin-2-amine (Intermediate 119) (4.30 g, 21.43 mmol, 1.0 equiv) in concentrated HSO (43 mL) was added 30% H0 (24.92 g, 219.79 mmol, 10.3 equiv) at −10 °C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then poured into ice-water (400 mL) and subsequently extracted with EtOAc (3 × 300 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to give 3-chloro-5-(3-methoxypropyl)-2-nitropyridine (1.70 g, 34% yield) as a white solid. 1 LCMS C9H11 Calculated for ClN2O3: m / z = 230; Found: m / z = 231 (M+H).

[0454] Intermediate 121. Ethyl 1-(5-(3-methoxypropyl)-2-nitropyridin-3-yl)piperidine-4-carboxylate [ka] To a solution of 3-chloro-5-(3-methoxypropyl)-2-nitropyridine (Intermediate 120) (300 mg, 1.30 mmol, 1.0 equiv) in MeOH (3 mL) was added ethyl piperidine-4-carboxylate (3.06 g, 19.46 mmol, 15.0 equiv) at room temperature. The resulting reaction mixture was heated at 80 °C under a N (g) atmosphere and stirred for 3 h. The reaction mixture was cooled to room temperature, poured into HO (60 mL), and extracted with EtOAc (3 × 60 mL). The combined organic phases were washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO, PE: EtOAc = 1:1) to afford ethyl 1-(5-(3-methoxypropyl)-2-nitropyridin-3-yl)piperidine-4-carboxylate (380 mg, 83% yield) as a yellow oil. LCMS C 17 H 25 Calculated for N3O5: m / z = 351; Found: m / z = 352 (M+H).

[0455] Intermediate 122. Ethyl 1-(2-amino-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(5-(3-methoxypropyl)-2-nitro-3-pyridyl)piperidine-4-carboxylate (Intermediate 121) (380 mg, 1.08 mmol, 1.0 equiv) in MeOH (10 mL) was added 10% Pd / C (0.4 g) at room temperature. The resulting suspension was degassed under vacuum and purged with H(g) three times. The resulting reaction mixture was stirred under an H(g) atmosphere (15 psi) at room temperature for 2 hours. The reaction mixture was then purged under vacuum, flushed with N(g), and filtered through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to provide crude ethyl 1-(2-amino-5-(3-methoxypropyl)-3-pyridyl)piperidine-4-carboxylate (380 mg) as a yellow oil, which was used without further purification. 1 H NMR(400MHz,CD3OD)δ 7.38(s,1H),7.04(s,1H),4.05(q,J=7.2,2H),3.27(t,J=6.4,2H),3.21(s,3H),3.05(m,2H),2.54 (m,2H),2.43(m,2H),2.37(m,1H),1.91(m,2H),1.80(m,2H),1.68(m,2H),1.16(t,J=7.2,3H);LCMS C 17 H 27 Calculated for N3O3: m / z = 321; Found: m / z = 322 (M+H).

[0456] Intermediate 123. Ethyl 1-(2-bromo-5-(3-methoxypropyl)pyridin-3-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(2-amino-5-(3-methoxypropyl)-3-pyridyl)piperidine-4-carboxylate (Intermediate 122) (150 mg, 466 μmol, 1.0 equiv) in dibromomethane (1.6 mL) was added isopentyl nitrite (60 mg, 513 μmol, 1.1 equiv) at room temperature under a N2(g) atmosphere. Next, a solution of TMSBr (78 mg, 513 μmol, 1.1 equiv) in dibromomethane (1.5 mL) was added to the reaction. The resulting reaction mixture was stirred at room temperature for 12 h. Next, the reaction mixture was poured into HO (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2 , PE:EtOAc=2:1) ​​to give ethyl 1-(2-bromo-5-(3-methoxypropyl)-3-pyridyl)piperidine-4-carboxylate (70 mg, 38% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ 7.39(s,1H),7.27(s,1H),4.06(q,J=7.2,2H),3.29(t,J=6.4,2H),3.23(s,3H),2.67 (m,2H),2.59(m,2H),2.41(m,1H),1.94(m,2H),1.79(m,6H),1.17(t,J=7.2,3H);LCMS C 17 H 25 Calculated for BrN2O3: m / z = 384; Found: m / z = 387 (M+H).

[0457] Intermediate 124. Ethyl 1-(3-(4-hydroxyphenyl)-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3-chloro-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 93) (2.00 g, 5.85 mmol, 1.0 equiv) and (4-hydroxyphenyl)boronic acid (1.21 g, 8.78 mmol, 1.5 equiv) in THF (40 mL) and HO (8 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (391 mg, 585 μmol, 0.1 equiv) and KPO (3.10 g, 14.63 mmol, 2.5 equiv) under a N2 (g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (3 × 60 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 3:1) to give ethyl 1-(3-(4-hydroxyphenyl)-6-(3-methoxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (2.00 g, 85% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.68(d,J=6.8,2H),6.72(m,2H),6.29(m,1H),4.10(m,2H),3.63(m,2H),3.40(m,2 H),3.29(s,3H),2.67(m,4H),2.33(m,1H),1.98(m,2H),1.81(m,2H),1.66(m,2H),1.20(m,3H).

[0458] Intermediate 125. tert-Butyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of 2,3,5-trichloropyrazine (5.00 g, 27.26 mmol, 1.0 equiv) and tert-butyl piperidine-4-carboxylate (6.65 g, 29.99 mmol, 1.1 equiv) in dioxane (60 mL) was added EtN (8.28 g, 81.78 mmol, 11.38 mL, 3.0 equiv). The resulting reaction mixture was heated to 100 °C and stirred under a N (g) atmosphere for 12 h. The reaction mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1 to 10: 1) to give tert-butyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (9.00 g, 98% yield) as a yellow oil. 14 H 19 Calculated for Cl2N3O2: m / z = 331; Found: m / z = 332 (M+H).

[0459] Intermediate 126. tert-Butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of tert-butyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 125) (4.00 g, 12.04 mmol, 1.0 equiv.) and benzo[d][1,3]dioxol-5-ylboronic acid (1.95 g, 12.04 mmol, 1.0 equiv.) in DMF (50 mL) was added CsCO (11.77 g, 36.12 mmol, 3.0 equiv.) and Pd(PPh) (1.39 g, 1.20 mmol, 0.1 equiv.) at room temperature. The resulting reaction mixture was degassed under vacuum and purged with N(g) three times. The reaction mixture was then heated to 80 °C and stirred under a N(g) atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with HO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give tert-butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate (4.00 g, 75% yield) as a yellow solid. LCMS C 21 H 24 Calculated for ClN3O4: m / z = 417; Found: m / z = 418 (M+H).

[0460] Intermediate 127. (E)-1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate tert-Butyl [ka] To a solution of tert-butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 126) (8.00 g, 19.14 mmol, 1.0 equiv.) and (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (6.85 g, 22.97 mmol, 1.2 equiv.) in dioxane (80 mL) and HO (8 mL) was added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2) (640 mg, 957 μmol, 0.05 equiv) and Cs2CO3 (18.71 g, 57.43 mmol, 3.0 equiv) were added at room temperature. The resulting reaction mixture was degassed under vacuum and purged with N2(g) three times. The reaction mixture was then heated to 110 °C and stirred under a N2(g) atmosphere for 1 h. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1 to 10: 1) to give tert-butyl (E)-1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (9.00 g, 84% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.01(s,1H),7.62(m,H),7.49(m,H),7.43(d,J=1.6,H),6.90(m,1H),6.53(d,J=12.6,1H),6.01(s,2H),4.44(dd,J=2.0,4. LCMS C 30 H 43Calculated for N3O5Si: m / z = 553; Found: m / z = 554 (M+H).

[0461] Intermediate 128. tert-Butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of tert-butyl (E)-1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 127) (9.00 g, 16.25 mmol, 1.0 equiv) in MeOH (50 mL) was added 10% Pd / C (5.00 g). The resulting suspension was degassed under vacuum and purged with H(g) three times, and the reaction mixture was then stirred under an H(g) atmosphere (15 psi) at room temperature for 2 hours. The reaction mixture was then degassed under vacuum, purged with N(g), filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1 to 10: 1) to give tert-butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyrazin-2-yl)piperidine-4-carboxylate (7.00 g, 66% yield) as a yellow oil. LCMS C 30 H 45 Calculated for N3O5Si: m / z = 555; Found: m / z = 556 (M+H).

[0462] Intermediate 129. tert-Butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of tert-butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyrazin-2-yl)piperidine-4-carboxylate (Intermediate 128) (14 g, 25.19 mmol, 1.0 equiv) in THF (100 mL) was added TBAF (1 M, 37.78 mL, 1.5 equiv) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with saturated aqueous NaCO (100 mL) and subsequently extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with saturated NaCO (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 5: 1) to give tert-butyl 1-(3-(benzo[d][1,3]dioxol-5-yl)-6-(3-hydroxypropyl)pyrazin-2-yl)piperidine-4-carboxylate (8 g, 68% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.00(s,1H),7.45(d,J=8.4,1H),7.40(d,J=1.6,1H),6.89(d,J=8.4,1H),6.01(s,2H),3.75(t,J=6.0,2H),3.62 (m,2H),2.86(t,J=6.8,2H),2.73(m,2H),2.31(m,1H),2.01(m,2H),1.86(m,2H),1.69(m,2H),1.45(s,9H);LCMS C 24 H 31 Calculated for N3O5: m / z = 441; Found: m / z = 442 (M+H).

[0463] Intermediate 130. Ethyl 1-(6-chloro-3-(7-fluorobenzofuran-5-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of ethyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 111) (200 mg, 658 μmol, 1.0 equiv.) and 2-(7-fluorobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 41) (173 mg, 657 μmol, 1.0 equiv.) in DME (4 mL) and HO (0.8 mL) was added Pd(dba) (60 mg, 65 μmol, 0.1 equiv.), PPh (35 mg, 131 μmol, 0.2 equiv.), and NaCO (139 mg, 1.32 mmol, 2.0 equiv.) under a N (g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into HO (30 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1 to 5:1) to afford ethyl 1-(6-chloro-3-(7-fluorobenzofuran-5-yl)pyrazin-2-yl)piperidine-4-carboxylate (300 mg, 90% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.04(s,1H),7.82(s,1H),7.53(s,1H),7.36(m,1H),6.81(m,1H),4.07(q,J=7.2,2H),3.6 0(m,2H),2.74(t,J=11.2,2H),2.32(m,1H),1.82(m,2H),1.67(m,2H),1.19(t,J=7.2,3H).

[0464] Intermediate 131. tert-Butyl 1-(6-chloro-3-(7-fluorobenzofuran-5-yl)pyrazin-2-yl)piperidine-4-carboxylate [ka] To a solution of tert-butyl 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carboxylate (Intermediate 125) (1.00 g, 3.01 mmol, 1.0 equiv.) and 2-(7-fluorobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 41) (788 mg, 3.01 mmol, 1.0 equiv.) in DME (20 mL) was added Pd(dba) (275 mg, 301 μmol, 0.1 equiv.), PPh (157 mg, 602 μmol, 0.2 equiv.), and NaCO (1 M, 6.02 mL, 2.0 equiv.) under a N (g) atmosphere at room temperature. The resulting reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, poured into HO (60 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 19:1) to give tert-butyl 1-(6-chloro-3-(7-fluorobenzofuran-5-yl)pyrazin-2-yl)piperidine-4-carboxylate (850 mg, 65% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.03(s,1H),7.81(s,1H),7.66(m,1H),7.02(d,J =15.6 ,1H),6.80(s,1H),3.59(m,2H),2.74(m,2H),2.29(m,1H),1.75(m,2H),1.58(m,2H),1.36(s,9H).

[0465] Intermediate 132. 1-(6-chloro-3-(7-fluorobenzofuran-5-yl)pyrazin-2-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(3,6-dichloropyrazin-2-yl)piperidine-4-carbonitrile (1.00 g, 3.89 mmol, 1.0 equiv.) and 2-(7-fluorobenzofuran-5-yl)-4,4,5,5-tetramethyl-1...

Claims

1. Compounds of formula (I'): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 4; X is selected from CH and N; Y is selected from CH and N; Z is CR 7 ; R １ is selected from aryl and heteroaryl; R ２ is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which may be one or more R ６ may be optionally replaced with; R ３ teeth, SO ２ - alkyl optionally substituted with alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl Selected from: Each R ４ is, independently, R ５ alkoxy optionally substituted with R ５ alkylamino optionally substituted with R ５ dialkylamino optionally substituted with SO ２ R ８ａ 、 Alkylthio, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, Hello, alkyl, and Haloalkyl Selected from; or R １ Two R on adjacent carbon atoms of ４ the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R ５ is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy, and alkoxyalkoxy; Each R ６ are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, cyano, and tetrazolyl; R ７ is selected from hydrogen and halo; R ８ａ and R ８ｂ are each independently selected from alkyl, amino, alkylamino, and dialkylamino; X and Y are not both CH).

2. X is selected from CH and N; Y is selected from CH and N; Z is CH; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. X is CH; Y is N; Z is CH; or X is N; Y is CH; Z is CH; or X is N; Y is N; and Z is CH; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. X is N; Y is N; and Z is CH; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. R １ is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. R １ is phenyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. R １ is a bicyclic heteroaryl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. Each R ４ But independently, R ５ alkoxy optionally substituted with SO ２ R ８ａ , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or R １ Two R on adjacent carbon atoms of ４ the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R ５ is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; m is an integer from 0 to 3; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. Each R ４ is independently selected from alkoxy, haloalkoxy, and halo; or R １ Two R on adjacent carbon atoms of ４ the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; m is an integer from 0 to 3; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. R ３ But SO ２ - selected from alkyl optionally substituted with alkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. R ３ is selected from alkyl, alkoxyalkyl, haloalkyl, and haloalkoxyalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. R ３ is selected from alkyl and alkoxyalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

13. R ３ is alkoxyalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

14. R ２ is a monocyclic or bicyclic heterocycloalkyl, which is represented by one or more R ６ is replaced by; Each R ６ are independently hydroxyl, carboxyl, carboxyl alkyl, carboxyl alkoxy, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, and tetrazolyl; R ８ｂ is selected from alkyl, amino, alkylamino, dialkylamino; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

15. R ２ is a monocyclic heterocycloalkyl, which is ６ is replaced by; R ６ is carboxyl, carboxyl alkyl, C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, and tetrazolyl; R ８ｂ is selected from alkyl, amino, alkylamino, dialkylamino; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

16. R ２ is piperidinyl, which is one R ６ is replaced by; R ６ is selected from carboxyl, carboxylalkyl, and heterocycloalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

17. The compound is a compound of formula (IV): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 3; R ２ is a monocyclic or bicyclic heterocycloalkyl, which is a heterocyclic group consisting of one or more R ６ is replaced by; R ３ is SO ２ - selected from alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl optionally substituted with alkyl; Each R ４ are independently R ５ alkoxy optionally substituted with SO ２ R ８ａ , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, halo, alkyl, and haloalkyl; or in formula (I') where R 1 is phenyl, R １ Two R on adjacent carbon atoms of ４ the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R ５ is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; Each R ６ are independently hydroxyl, carboxyl, carboxyl alkyl, carboxyl alkoxy, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, and tetrazolyl; R ８ｂ is selected from alkyl, amino, alkylamino, dialkylamino.

18. R ２ is a monocyclic heterocycloalkyl, which is ６ is replaced by 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

19. The compound is a compound of formula (V), or a pharmaceutically acceptable salt thereof: 【Transformation 3】 18. The compound of claim 17, wherein:

20. R ３ is selected from alkyl, alkoxyalkyl, haloalkyl, and haloalkoxyalkyl; Each R ４ is independently selected from alkoxy, haloalkoxy, and halo; or in formula (I') where R 1 is phenyl, R １ Two R on adjacent carbon atoms of ４ the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R ６ is carboxyl, carboxyl alkyl, C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, and tetrazolyl; R ８ｂ is selected from alkyl, amino, alkylamino, dialkylamino; 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

21. R ３ is selected from alkyl and alkoxyalkyl; Each R ４ is independently selected from alkoxy, haloalkoxy, and halo; or R １ Two R on adjacent carbon atoms of ４ the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R ６ is selected from carboxyl, carboxylalkyl, and heterocycloalkyl; 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

22. m is an integer from 0 to 4; X is selected from CH and N; Y is selected from CH and N; Z is CR 7 ; R １ is selected from aryl and heteroaryl; R ２ is a monocyclic or bicyclic heterocycloalkyl or a monocyclic or bicyclic heteroaryl, either of which is selected from one or more R ６ may be optionally replaced with; R ３ But SO ２ - selected from alkyl optionally substituted with alkyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, and cycloalkoxyalkyl; Each R ４ But independently, R ５ alkoxy optionally substituted with SO ２ R ８ａ , haloalkoxy, cycloalkoxy, cycloalkylalkoxy, and halo; or R １ Two R on adjacent carbon atoms of ４ the substituents combine to form a fused heterocycloalkyl or a fused heteroaryl, either of which may be optionally substituted with one or more alkyl, halo, oxo, alkoxy, or alkoxyalkyl; Each R ５ is independently selected from hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and haloalkoxy; Each R ６ are independently hydroxyl, hydroxyalkoxy, carboxyl, methylcarboxyl, carboxylalkyl, carboxylalkoxy, halo, alkyl, alkoxy, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ , heterocycloalkyl, cyano, and tetrazolyl; R ７ is selected from hydrogen and halo; R ８ａ and R ８ｂ are each independently selected from alkyl, amino, alkylamino, and dialkylamino; X and Y are not both CH; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

23. The compound is a compound of formula (II): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 3; R ２ is one or more R ６ is a monocyclic or bicyclic heterocycloalkyl optionally substituted with Each R ４ are independently R ５ alkoxy optionally substituted with SO ２ R ８ａ and halo; or R １ Two R on adjacent carbon atoms of ４ the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R ５ is selected from alkoxy, amino, alkylamino, and dialkylamino; Each R ６ are independently carboxyl, carboxylalkyl, halo, alkyl, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ and tetrazolyl; R ８ａ and R ８ｂ are each independently selected from alkyl, amino, alkylamino, and dialkylamino.

24. The compound is a compound of formula (III): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 3; Each R ４ are independently R ５ alkoxy optionally substituted with SO ２ R ８ａ and halo, or two R １ the substituents taken together form a fused heterocycloalkyl or a fused heteroaryl; R ５ is selected from alkoxy, amino, alkylamino, and dialkylamino; R ６ is carboxyl, carboxyl alkyl, halo, alkyl, SO ２ R ８ｂ , C(=O)NHSO ２ R ８ｂ and tetrazolyl; R ８ａ and R ８ｂ are each independently selected from alkyl, amino, alkylamino, and dialkylamino.

25. The compound is a compound of formula (VI): 【Transformation 6】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 4; Y is N or CH; R ３ teeth, SO ２ -(C １ ~C ６ C optionally substituted with alkyl １ ~C ６ Alkyl, (C １ ~C ６ Alkoxy)-C １ ~C ６ Alkyl, (C １ ~C ６ alkoxy)-(C １ ~C ６ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, (C １ ~C ６ haloalkoxy)-C １ ~C ６ Alkyl, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ alkyl, and (C ３ ~C ６ Cycloalkoxy)-C １ ~C ６ alkyl; Each R ４ But independently, R ５ C optionally substituted with １ ~C ６ Alkoxy, R ５ C optionally substituted with １ ~C ６ alkylamino, R ５ di-(C １ ~C ６ alkyl)-amino, SO ２ R ８ａ 、 C １ ~C ６ Alkylthio, C １ ~C ６ haloalkoxy, C ３ ~C ６ cycloalkoxy, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ Alkoxy, Hello, C １ ~C ６ alkyl, and C １ ~C ６ haloalkyl; or R １ Two R on adjacent carbon atoms of ４ The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may contain one or more C １ ~C ６ Alkyl, halo, oxo, C １ ~C ６ Alkoxy, or (C １ ~C ６ Alkoxy)-C １ ~C ６ optionally substituted with alkyl; Each R ５ are independently hydroxyl, C １ ~C ６ Alkoxy, amino, C １ ~C ６ Alkylamino, di-C １ ~C ６ Alkylamino, C １ ~C ６ haloalkoxy, and (C １ ~C ６ Alkoxy)-C １ ~C ６ alkoxy; R ６ is -C(=O)OH, -CH ２ C(=O)OH, -C(=O)OC １ ~C ６ Alkyl, —C(═O)NHSO ２ R ８ｂ , heterocycloalkyl, and tetrazolyl; R ８ａ and R ８ｂ are each independently C １ ~C ６ Alkyl, amino, C １ ~C ６ Alkylamino, di-(C １ ~C ６ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of alkyl, aryl, aryl-,

26. m is an integer from 0 to 4; Y is N or CH; R ３ But C １ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, (C １ ~C ４ haloalkoxy)-C １ ~C ６ Alkyl, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ Alkyl, and (C ３ ~C ６ Cycloalkoxy)-C １ ~C ６ alkyl; Each R ４ But independently, R ５ C optionally substituted with １ ~C ６ Alkoxy, R ５ C optionally substituted with １ ~C ４ Alkylamino, R ５ di-(C １ ~C ４ alkyl)-amino, SO ２ R ８ａ , C １ ~C ６ Haloalkoxy, C ３ ~C ６ cycloalkoxy, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ Alkoxy, Halo, C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl; or R １ Two R on adjacent carbon atoms of ４ The substituents, taken together, form a fused heterocycloalkyl or a fused heteroaryl, either of which may contain one or more C １ ~C ６ Alkyl, halo, oxo, C １ ~C ６ Alkoxy, or (C １ ~C ４ Alkoxy)-C １ ~C ６ optionally substituted with alkyl; Each R ５ are independently hydroxyl, C １ ~C ６ Alkoxy, amino, C １ ~C ４ Alkylamino, di-(C １ ~C ４ alkyl)-amino, C １ ~C ６ haloalkoxy, and (C １ ~C ４ Alkoxy)-C １ ~C ６ alkoxy; R ６ -C(=O)OH, -CH ２ C(=O)OH, -C(=O)OC １ ~C ４ Alkyl, —C(═O)NHSO ２ R ８ｂ and tetrazolyl; R ８ａ and R ８ｂ However, each independently, C １ ~C ６ Alkyl, amino, C １ ~C ４ Alkylamino, di-(C １ ~C ４ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (alkyl)-amino.

27. The compound is a compound of formula (VI-1): 【Transformation 7】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 4; Y is N or CH; R ３ is C １ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, (C １ ~C ４ haloalkoxy)-C １ ~C ６ Alkyl, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ Alkyl, and (C ３ ~C ６ Cycloalkoxy)-C １ ~C ６ alkyl; Each R ４ are independently R ５ C optionally substituted with １ ~C ６ Alkoxy, R ５ C optionally substituted with １ ~C ４ Alkylamino, R ５ di-(C １ ~C ４ alkyl)-amino, C １ ~C ６ Haloalkoxy, C ３ ~C ６ cycloalkoxy, (C ３ ~C ６ Cycloalkyl)-C １ ~C ６ Alkoxy, Halo, C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl; or R １ Two R on adjacent carbon atoms of ４ The substituents, taken together, form a fused 5-membered heterocycloalkyl or a fused 5-membered heteroaryl, either of which may contain one or more C １ ~C ６ Alkyl, halo, oxo, C １ ~C ６ Alkoxy, or (C １ ~C ４ Alkoxy)-C １ ~C ６ optionally substituted with alkyl; Each R ５ are independently hydroxyl, C １ ~C ６ Alkoxy, amino, C １ ~C ４ Alkylamino, di-(C １ ~C ４ alkyl)-amino, C １ ~C ６ haloalkoxy, and (C １ ~C ４ Alkoxy)-C １ ~C ６ 26. The compound of claim 25, wherein the aryl group is selected from the group consisting of aryl, aryl alkoxy ...

28. The compound is a compound of formula (VI-2): 【Transformation 8】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 4; Y is N or CH; R ３ is C １ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, and (C １ ~C ４ haloalkoxy)-C １ ~C ６ alkyl; Each R ４ are independently １ ~C ６ Alkoxy, C １ ~C ４ Haloalkoxy, Halo, C １ ~C ４ Alkyl, and C １ ~C ４ haloalkyl; or in formula (I') where R 1 is phenyl, R １ Two R on adjacent carbon atoms of ４ The substituents together form a fused 5-membered heterocycloalkyl containing 1 or 2 O atoms or a fused 5-membered heteroaryl containing 1 O atom and 0 or 1 N atoms, either of which may contain one or more C １ ~C ４ Alkyl, halo, C １ ~C ４ Alkoxy or (C １ ~C ４ Alkoxy)-C １ ~C ４ 26. The compound of claim 25, wherein:

29. The compound is a compound of formula (VI-3): 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 2; Y is N or CH; R ３ is C １ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, and (C １ ~C ４ haloalkoxy)-C １ ~C ６ alkyl; Each R ４ are independently １ ~C ６ Alkoxy, C １ ~C ４ Haloalkoxy, Halo, C １ ~C ４ Alkyl, and C １ ~C ４ 26. The compound of claim 25, wherein the alkyl is selected from the group consisting of alkyl, haloalkyl, aryl ... and aryl.

30. The compound is a compound of formula (VI-4): 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 2; Y is N or CH; R ３ is C １ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, and (C １ ~C ４ haloalkoxy)-C １ ~C ６ alkyl; Each R ４ are independently １ ~C ６ Alkoxy, C １ ~C ４ Haloalkoxy, Halo, C １ ~C ４ Alkyl, and C １ ~C ４ 26. The compound of claim 25, wherein the alkyl is selected from the group consisting of alkyl, haloalkyl, aryl ... and aryl.

31. m is 0 or 1; R ４ But C １ ~C ６ Alkoxy, C １ ~C ４ haloalkoxy, and halo; 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof.

32. R ３ But C ３ ~C ６ Alkyl, (C １ ~C ４ Alkoxy)-C ３ ~C ６ Alkyl, C ３ ~C ６ haloalkyl, and (C １ ~C ４ haloalkoxy)-C ３ ~C ６ selected from alkyl, 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

33. R ３ However, (C １ ~C ４ Alkoxy)-C １ ~C ６ Alkyl, and (C １ ~C ４ haloalkoxy)-C ３ ~C ６ selected from alkyl, 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

34. Y is N; 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof. 【Request Item 35】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

37. A pharmaceutical composition described in claim 36 for inhibiting GLUT9, comprising contacting GLUT9 with the pharmaceutical composition.

38. The pharmaceutical composition of claim 36 for the treatment of a GLUT9-mediated disease in a mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition to a mammal in need thereof.

39. 39. The pharmaceutical composition of claim 38, wherein the disease is selected from hyperuricemia, gout, and uncontrolled gout, including comorbid and associated diseases.

40. A therapeutically effective amount of the pharmaceutical composition; and b. another therapeutic agent; 37. The pharmaceutical composition of claim 36 for the treatment of a GLUT9-mediated disease in a mammal, comprising administering to a mammal in need thereof.

41. The pharmaceutical composition of claim 40, wherein the other drug is selected from an inhibitor of uric acid synthesis, a uricosuric agent, and a uric acid catabolic agent.

42. 42. The pharmaceutical composition of claim 41, wherein the uricosuric agent is selected from probenecid, lesinurad, benzbromarone, and sulfinpyrazone.

43. 42. The pharmaceutical composition of claim 41, wherein the inhibitor of uric acid synthesis is selected from allopurinol and febuxostat.

44. 42. The pharmaceutical composition of claim 41, wherein the uric acid catabolic agent is pegloticase.

45. 41. The pharmaceutical composition of claim 40, wherein the other drug is colchicine.

46. A pharmaceutical composition described in claim 36 for lowering blood uric acid levels in a mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition to a mammal in need thereof.

Images