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WO2025240893A1 - 4-phenyl-1h-pyrazolo[3,4-b]pyridine-5-carboxamide derivatives as amylin and/or calcitonin receptor agonists for the treatment of type 2 diabetes, obesity or overweight - Google Patents

4-phenyl-1h-pyrazolo[3,4-b]pyridine-5-carboxamide derivatives as amylin and/or calcitonin receptor agonists for the treatment of type 2 diabetes, obesity or overweight

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Publication number
WO2025240893A1
WO2025240893A1 PCT/US2025/029816 US2025029816W WO2025240893A1 WO 2025240893 A1 WO2025240893 A1 WO 2025240893A1 US 2025029816 W US2025029816 W US 2025029816W WO 2025240893 A1 WO2025240893 A1 WO 2025240893A1
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WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
independently selected
substituents independently
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/029816
Other languages
French (fr)
Inventor
Renato A. BAUER
Ana Maria CASTAÑO
David Jesse ` CUMMINS
Sara GUTIERREZ HERNANDEZ
Jared T. Hammill
Celia Lafuente Blanco
Hani G. LAKKIS
Christina MARTINEZ BROKAW
William Thomas Mcmillen
Jose Miguel Minguez Ortega
Neda OJAGHLOU
Emmanuel ONOBUN
Gema Consuelo SANZ
Anne-Marie SCHMITT
Abigail Smith
Srilok Srinivasan
Xuelin Wang
Sodiq O. WAHEED
Eric WOERLY
Mahta BAREKATAIN
Maria Carmen DOMINGUEZ FERNANDEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of WO2025240893A1 publication Critical patent/WO2025240893A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • non-peptide compounds which are amylin and/or calcitonin receptor agonists. These compounds may be useful as therapeutic agents, either as a monotherapy or in combination with another therapeutic agent, for preventing or treating a disease or condition through the modulation of the amylin and/or calcitonin receptors. Specifically, disclosed herein are compounds for treating diabetes, obesity, metabolic dysfunction associated steatohepatitis (MASH) and/or dyslipidemia.
  • MASH metabolic dysfunction associated steatohepatitis
  • Amylin is a peptide hormone that is co-secreted with insulin from the pancreatic ⁇ - cells and is deficient in people with diabetes. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent.
  • An amylin analog, pramlintide is available to treat diabetic patients who use insulin because it lowers blood sugar levels.
  • Calcitonin is a hormone that is produced in the thyroid gland that plays a role in regulating levels of calcium and phosphate in the blood. Salmon calcitonin is available to treat conditions with high levels of calcium in the blood, such as hypercalcemia. Salmon calcitonin has a short half-life of less than two hours, so a patient needs to dose once a day or multiple times a day to use this peptide in therapy.
  • amylin and calcitonin receptors have positive effects such as lowering blood glucose levels and inducing weight loss (see, e.g., WO2016/034604, WO2015/071229 and WO2010/085700).
  • amylin and calcitonin receptor agonists are peptides and the natural half-life of these agonists is short, so an extended time action is desirable.
  • chemical modifications intended to extend activity time have also, thus far, shown a decrease in potency.
  • agonists of the amylin and calcitonin receptors have stability challenges due to their tendency to fibrillate and the presence of a labile disulfide bond at neutral pH.
  • the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the amylin and/or calcitonin receptor(s).
  • R 1 is selected from: (1) a C1-10 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C 1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C 1-10 alkyl, and R 1b is selected from H, C1-10 alkyl, -C(O)C1-10 al
  • R 1 is selected from: (1) a C1-6 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C 1-6 alkyl, and R 1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR 1c R 1d , wherein R 1c is selected from (i) H and (ii) a C 1-6 alkyl,
  • R 1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (ii) -NR 1a R 1b , wherein R 1a is selected from H and C1-4 alkyl, and R 1b is selected from H, C1-4 alkyl, and -C(O)C1-4 alkyl, (c) -NR 1c R 1d , wherein R 1c is selected from (i
  • R 1 is selected from: (1) a C 1-10 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C 3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C1-10 alkyl, and R 1b is selected from H, C 1-10 alkyl, -C(O)C 1-10 alkyl, -C(O)OC 1-10 alkyl, and -SO 2 C 1-10 alkyl, (c) -NR 1c R 1d , wherein R 1c is selected from (i) H and (ii) a
  • R 1 is selected from: (1) a C 1-10 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C 3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C1-10 alkyl, and R 1b is selected from H, C 1-10 alkyl, -C(O)C 1-10 alkyl, -C(O)OC 1-10 alkyl, and -SO 2 C 1-10 alkyl, (c) -NR 1c R 1d , wherein R 1c is selected from (i) H and (ii) a C1-10
  • R 1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from (i) H and (ii) a C1-6 alkyl, and R 1b is selected from (i) H, (ii) C 1-6 alkyl, (iii) -C(O)C 1-6 alkyl, (iv) -C(O)OC 1-6 alkyl, and (v) -SO2C1-6 alkyl, (c) -NR 1c R 1d , wherein
  • R 1 is selected from: (1) a C 1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (ii) -NR 1a R 1b , wherein R 1a is selected from H and C 1-4 alkyl, and R 1b is selected from H, C1-4 alkyl, and -C(O)C1-4 alkyl, (c) -NR 1c R 1d , wherein R 1c is selected from (
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (Ia): ; wherein: R 7 is a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) -OH, (2) a phenyl, and (3) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (2) and heteroaryl or heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or a C1-6 alkoxy, (iii) a C 1-6 alkoxy, and (iv) -CN; R 8 is selected from: (1) H and (2) a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b
  • R 7 is a C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) -OH, (2) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C 1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, and R 8 is selected from: (1) H and (2) a C 1-4 alkyl, optionally substituted with phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents independently selected from: (a) a C 1-4 alkyl, optionally substituted with -OH, and (b) a C1-4 alkoxy.
  • the compound is of formula (Ib): ; wherein: W is selected from O and S; R 2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-6 alkyl, optionally substituted with -OH; R 7 is a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C 1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens; and R 8 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with
  • R 1 is selected from: (1) a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and C1-6 alkyl, and R 1b is selected from H, C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, and -SO 2 C
  • R 1 is selected from: (1) a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and C1-6 alkyl, and R 1b is selected from H, C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, and -SO 2 C 1-6 alkyl
  • R 1 is selected from: (1) a C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and C1-6 alkyl, and R 1b is selected from H, C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, and -SO 2 C 1-6 alkyl
  • R 1 is selected from: (1) a C 1-4 alkyl, optionally substituted with a C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and C 1-4 alkyl, and R 1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, -C(O)OC1-4 alkyl, and -SO2C1-6 alkyl; and (2) a 5 to 10 membered heterocycl
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (Ic): ; wherein: R 7 is a C1-6 alkyl, optionally a selected from phenyl, pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C 1-6 alkoxy.
  • the compound is of formula (Id): ); wherein: R 7 is a C 1-6 alkyl, optionally substituted with a substituent selected from phenyl, pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C 1-6 alkoxy.
  • R 7 is a C 1-6 alkyl, optionally substituted with a substituent selected from phenyl, pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C 1-6 alkoxy.
  • R 7 is a C 1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (Ie): , wherein: R 2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C 1-6 alkyl, optionally substituted with -OH; and R 7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) C 1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens; R 8 is selected from (1) H, (2) halogen, and (3) a C1-6 alkyl, optionally substituted with -OH;
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (If): ; wherein: A 1 is selected from: (1) O, (2) -NR 8 , wherein R 8 is selected from (a) H and (b) a C 1-6 alkyl; and R 7 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C 1-6 alkoxy, and (b) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens.
  • a 1 is selected from: (1) O, (2) -NR 8 , wherein R 8 is selected from (a) H and (b)
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (Ig): ; wherein: A 2 is selected from: (1) N, and (2) CH, optionally substituted with a substituent selected from: (a) halogen, and (b) a C 1-6 alkyl; and R 7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C 1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens.
  • a 2 is selected from: (1) N, and (2) CH, optionally substituted with a substituent selected from: (a) halogen, and (b)
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (Ih): ; wherein: 7 R is a C 1-6 alkyl, optionally a selected from phenyl, pyridyl, and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C 1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN; and R 8 is a C 1-6 alkyl substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens.
  • R 1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C1-6 alkyl, and R 1b is selected from H, C 1-6 alkyl
  • R 3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C 1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C 1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR 3a R 3b , wherein: R 3a is selected from (i) H and (ii) a C1-4 alkyl, and R 3b is a C 1-4 alkyl, optionally substituted with a substituoride, and a substituents, and (c) -NR 3a R 3b , wherein: R 3a is selected from (i) H and (ii) a C1-4 alkyl, and R 3b is a C
  • R 6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is optionally substituted with 1 to 3 halogens.
  • R 1 is selected from: (1) a C 1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C1-4 alkyl, and R 1b is selected from H, C 1-4 alkyl
  • R 1 is selected from: (1) a C 1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR 1a R 1b , wherein R 1a is selected from H and a C1-4 alkyl, and R 1b is selected from H, C 1-4 alkyl, -C(O
  • R 7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C 1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1
  • R 7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C 1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN.
  • R 8 when present, is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH. In one embodiment, R 8 is H.
  • R 2 when present, is selected from (1) H and (2) halogen. In one embodiment, R 2 is H.
  • R 10 when present, is selected from (1) H and (2) halogen. In one embodiment, R 10 is H.
  • a compound selected from Examples 1-242, or a pharmaceutically acceptable salt thereof is a compound selected from Examples 1-133, or a pharmaceutically acceptable salt thereof.
  • a compound selected from Examples 8, 9, 10, 14, 57, 74, 75, 76, 77, 80, 102, 103, 104, and 105 or a pharmaceutically acceptable salt thereof.
  • the compound herein, or a pharmaceutically acceptable salt thereof may be a solvate, or a non-solvate.
  • the solvent contained in a solvate may be either water or an organic solvent.
  • Alcohols for example, MeOH, EtOH, n-propanol
  • dimethylformamide for example, ACN
  • acetone dimethylsulfoxide
  • the proportion of the solvent molecule for example a water molecule
  • the proportion may fluctuate by humidity, the production method, and the production season.
  • the solvate of a compound herein, or a pharmaceutically acceptable salt thereof may be obtained by a common method, such as precipitating the compound herein, or a pharmaceutically acceptable salt thereof, from a solvent.
  • a hydrate may be obtained by precipitating a compound herein, or a pharmaceutically acceptable salt thereof, from a water-containing organic solvent.
  • the solvate of a compound herein, or a pharmaceutically acceptable salt thereof may be transformed to the compound herein, or a pharmaceutically acceptable salt thereof, by a common method such as heating in vacuo.
  • a compound used as a pharmaceutical active agent is the compound per se (free form), a hydrate of the free form, a pharmaceutically acceptable salt of the free form, or a hydrate of the salt.
  • the compound herein, or a pharmaceutically acceptable salt thereof, or a solvate of either the compound or the salt of the compound may be used in the form of a crystalline material or in an amorphous state.
  • a compound herein, or a pharmaceutically acceptable salt thereof includes all stereoisomers of the compound, for example, an enantiomer, a diastereomer (including cis- and trans- geometric isomer), the racemic form of the isomers, and other mixtures.
  • the compound herein, or a pharmaceutically acceptable salt thereof may have one or more asymmetric centers.
  • the compound herein, or a pharmaceutically acceptable salt thereof includes an embodiment in which an atom constituting the compound molecule is an isotope, and includes an embodiment in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons).
  • the isotopes include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • the heavier hydrogen isotopic form of 2 H is also known as a deuterium or “D”.
  • a deuterated compound one or more hydrogens are replaced with deuterium isotope(s).
  • radioisotopes which emit radiation as they decay such as 3 H or 14 C, are useful in pharmaceutical preparations or in vivo topographic tests of compounds.
  • the stable isotope neither decays nor changes in their amount, nor have radioactivity, so they can be used safely.
  • the atom constituting the compound herein, or a pharmaceutically acceptable salt thereof is an isotope, it may be transformed according to the common method by replacing the reagent used in synthesis with a reagent containing the corresponding isotope.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof are amylin receptor agonists.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have Rel EC 50 values of less than about 5,000 nM in AMY3R functional activity assays (10-point format or 20-point-format).
  • compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 500 nM in AMY3R functional activity assays.
  • compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 100 nM in AMY3R functional activity assays. In one even more preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC 50 values of less than about 50 nM in AMY3R functional activity assays. [0055] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are calcitonin receptor agonists.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have Rel EC 50 values of less than about 5,000 nM in CTR functional activity assays (10-point format or 20-point-format). In one embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 500 nM in CTR functional activity assays.
  • compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 100 nM in CTR functional activity assays. In one even more preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 50 nM in CTR functional activity assays. [0056] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are both amylin receptor agonists and calcitonin receptor agonists.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have Rel EC 50 values of less than about 5,000 nM in AMY3R functional activity assays (10-point format or 20-point-format) and less than about 5,000 nM in CTR functional activity assays (10-point format or 20-point-format).
  • compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC 50 values of less than about 500 nM in AMY3R functional activity assays and less than about 500 nM in CTR functional activity assays.
  • compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 100 nM in AMY3R functional activity assays and less than about 100 nM in CTR functional activity assays.
  • compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof have Rel EC 50 values of less than about 50 nM in AMY3R functional activity assays and less than about 50 nM in CTR functional activity assays.
  • a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • PYY peptide tyrosine-tyrosine
  • an effective amount means an amount, concentration or dose of a compound described herein, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment.
  • An effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • an effective amount can be determined by one of ordinary skill in the art through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered including, but are not limited to, the size, age and general health of a subject; the specific disease or disorder involved; the degree of or involvement of or the severity of the disease or disorder; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. [0067]
  • the term “treat,” “treating,” or “to treat” means attenuating, restraining, slowing, stopping or reversing the progression or severity of an existing condition, disease, disorder or symptom.
  • Treating includes administering a compound herein or a composition comprising a compound herein to the subject to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom. Treating includes administering a compound or a composition comprising a compound herein to the individual to result in, for example, a reduced HbA1c level or a weight loss to the subject.
  • a pharmaceutically acceptable salt refers to a derivative of the compound herein, where a compound herein is modified by making an acid or a base salt thereof. Pharmaceutically acceptable salts, and processes for preparing the same, are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, L.V.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of a compound herein formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, cit
  • Pharmaceutically acceptable salts are those forms of a compound herein, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salt forms of a compound herein can be synthesized to contain a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, EtOH, isopropanol, or ACN are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH 2nd ed. 2011)).
  • a pharmaceutical composition means a composition having an effective amount of a compound herein in combination with at least one pharmaceutically acceptable excipient, such as a binder, a carrier, a diluent, a lubricant, a pharmaceutical flow agent, and/or other pharmaceutically acceptable excipients.
  • halogen means a fluorine, a chlorine, a bromine, or an iodine. In one embodiment, a halogen is selected from fluorine and chlorine. In one embodiment, a halogen is a fluorine.
  • alkoxy refers to the following chemical group: , wherein R is an alkyl group as defined herein and the point of attachment is For example, C1-10 alkoxy has 1 to 10 carbons with the following structure: . Similarly, C1-6 alkoxy has 1 to 6 carbons with the following . [0072]
  • C 1-10 alkyl means a straight chain or a branched chain alkyl group containing 1 to 10 carbons. Similarly, “C1-6 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 6 carbons.
  • Examples of a C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1- methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.
  • alkylene refers to an alkanediyl group, i.e., a divalent sat.
  • C1-6 alkylene means an alkylene group having 1 to 6 carbon atoms.
  • Exemplary C 1-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH 2 -CH 2 -CH 2 -, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -), or butylene (e.g., -CH2-CH2-CH2-CH2-).
  • cycloalkyl refers to a monovalent saturated or partially unsaturated (not aromatic) carbocyclic group of from 3 carbons to 10 carbons having a single cyclic ring or multiple condensed or spirocyclic rings.
  • cycloalkyl examples include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; bicyclic groups such as bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octyl, bicyclo[4.4.0]octanyl, and bicyclo[4.4.1]octanyl.
  • monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl
  • bicyclic groups such as bicyclo[1.1.1]pentanyl, bicyclo
  • Cycloalkyl also includes carbocyclic groups to which is fused an aryl ring, for example, indane and tetrahydronaphthalene.
  • aryl refers to an aromatic carbocyclic group and may contain a non- aromatic portion in addition to the aromatic portion.
  • the ring may be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic aryl ring.
  • Examples include, but are not limited to, phenyl, naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H- isoquinolin-3-onyl, and 1,3-dihydrobenzimidazol-2-onyl.
  • an aryl is a phenyl.
  • an aryl is a naphthyl.
  • heteroaryl refers to a monovalent aromatic ring containing 1 to 5 heteroatoms in the ring-forming atoms independently selected from N, O and S, and may be partially saturated. The saturated carbon atom(s) may be oxidized to form a carbonyl.
  • the ring may be a single ring or two fused rings (e.g., a bicyclic heteroaryl obtained by a fusion with a benzene ring or monocyclic heteroaryl ring).
  • a 5 to 10 membered heteroaryl contains 1 to 4 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms.
  • Examples of a “5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S” include, but are not limited to, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzoxazolyl group
  • a “5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S” is selected from furyl, isoxazolyl, pyridyl, pyrimidyl, oxazolyl, pyridazinyl, pyrazinyl, pyrazolyl, and thienyl.
  • heterocyclyl refers to a monovalent ring group, including monocyclic rings as well as bridged rings, spiro rings, and/or fused rings (which may be composed, e.g., of two or three rings), wherein said ring group contains one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated or partially unsaturated (i.e., unsaturated but not aromatic on the ring containing one or more heteroatoms).
  • the term “5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 4 heteroatoms independently selected from N, O, and S.
  • the ring may be a monocyclic ring, a bicyclic ring or a spiro ring.
  • Examples include, but are not limited to, azepanyl, oxetanyl, thietanyl, azetidinyl, chromanyl, dihydrobenzofuranyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 8-azabicyclo[3.2.1]octanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 2 ⁇ 2-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[
  • the compound herein, or a pharmaceutically acceptable salt thereof has an amylin and/or calcitonin receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the amylin and/or calcitonin receptor(s).
  • the disease or condition is selected from Type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, overweight, hypertension, dyslipidemia, metabolic syndrome, hyperinsulinemia, nighttime hypoglycemia, hyperlipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, brain infarction, non-alcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated steatohepatitis (MASH).
  • the compound disclosed herein, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a pharmaceutical composition in an effective amount by an appropriate administration method.
  • diabetes As used herein, treatment of a subject with obesity or overweight is also known as chronic weight management.
  • “Diabetes” herein is a state or a disease in which the metabolism for generating and using glucose becomes deficient due to a failure in maintaining an appropriate blood glucose level in the body, and encompasses insulin-dependent diabetes mellitus (Type 1 diabetes) and non-insulin-dependent diabetes mellitus (Type 2 diabetes).
  • “Hyperglycemia” refers to a state in which the plasma glucose level while fasting or after administration of glucose is higher than the normal value (e.g.80 to 110 mg/dL in human while fasting), and it is a typical symptom of diabetes.
  • “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.
  • “Diabetic complication” is a complication caused by diabetes or hyperglycemia, and may be acute complex or chronic complex.
  • the term “acute complex” includes, for example, ketoacidosis, and infectious disease (e.g. skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and the “chronic complex” includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene.
  • diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.
  • “Coronary heart disease” includes myocardial infarction and angina pectoris.
  • “Dementia” includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.
  • the administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.
  • a method for treating a disease or condition regulated by an amylin and/or calcitonin receptor(s) comprises administering an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
  • the effective amount to be administered may be appropriately determined according to the severity of the symptom, the age, the body weight, the relative health state, whether other drugs are combined, and the method of administration. A person of ordinary skill may determine an effective dose taking into account of these factors and the particular properties of a specific compound disclosed herein.
  • the compound herein is co-administered with a second active agent.
  • additional active agent is selected from, the second active agent is selected from the group consisting of a glucagon receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof.
  • the administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.
  • a pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound herein, or a pharmaceutically acceptable salt thereof, is formulated into a certain pharmaceutical formulation (dosage form).
  • Examples of such pharmaceutical formulations include a tablet, a capsule, granules, powders, subtle granules, pills, aqueous or non-aqueous solution or suspension.
  • the compound herein, or a pharmaceutically acceptable salt thereof may also be used in the form of various controlled release preparations.
  • Examples of such controlled release preparations include, for example, those to be imbedded in the body, those applied to the oral mucosa or nasal mucosa.
  • the solution or suspension may be filled in containers suited for dividing into respective administration amounts to be stored.
  • the various pharmaceutical formulations may be produced by a well-known method by mixing a compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • additives include, but are not limited to, an excipient, a lubricant, a binding agent, a disintegrator, a stabilizer, a dispersant, a diluent, a surfactant, or an emulsifier.
  • an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.
  • a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient.
  • Examples of a disintegrator include chemically modified starch and cellulose, such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and compounds that are the same as the above excipient.
  • Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth, methyl cellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.
  • Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc.
  • Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol.
  • the content of the compound herein, or a pharmaceutically acceptable salt thereof, in the pharmaceutical formulation can vary by the dosage form, and is generally from 0.01 to 90 wt%.
  • EXAMPLES [0103] The following examples are provided for illustration purposes only. Unless otherwise defined, the abbreviations used in the preparations and examples are as defined below. ACN acetonitrile Aq. or aq.
  • Scheme 1 preparation of compounds disclosed herein.
  • Compound 1a is first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K 2 CO 3 or Cs 2 CO 3 ) at RT or at an elevated temperature to give 2a.
  • a base e.g. NaH, K 2 CO 3 or Cs 2 CO 3
  • 1a can be alkylated by a reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give 2a.
  • a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD
  • Compound 2a can then be converted to 2b utilizing syngas (1:1 CO/H 2 ), palladium(II) acetate, butyldi-1-adamantylphosphine, and N,N,N',N'-tetramethylethylenediamine at an elevated temperature and pressure.
  • the reaction order can be reversed beginning with a conversion of bromide 1a to aldehyde 1b as described above with a subsequent alkylation of 1b to give 2b.
  • Scheme 2 [0106] Scheme 4a and aldehyde 5a can be condensed with ketonitrile 6a in a solvent such as 1,4-dioxane, THF or an alcohol such as EtOH or isopropanol to give the dihydropyrazolopyridine-5-carbonitrile intermediate 7a.
  • Intermediate 7a can be isolated and oxidized using an oxidant such as MnO2, CAN, or DDQ in a solvent such as DCM, MeOH, acetic acid, ACN, or acetone to give pyrazolopyridine-5-carbonitrile 9a.
  • intermediate 7a can be oxidized in situ after the condensation is complete to give 9a.
  • aminopyrazole 4a and aldehyde 5a can be condensed with ketoamide 6b in a solvent such as 1,4-dioxane, THF or an alcohol such as EtOH or isopropanol to give the dihydropyrazolopyridine-5-carboxamide intermediate 8a.
  • the condensation reactions can optionally be conducted in the presence of an additive such as ammonium acetate.
  • the dihydropyrazolopyridine-5-carboxamide intermediate 8a can be oxidized in situ or after isolation as described above to give compounds of Formula I.
  • pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated using H2O2 in DMSO in the presence of an inorganic base such as K2CO3 or NaOH to give compounds of Formula I.
  • pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated in the presence of acetaldoxime with an appropriate catalyst such as CuO or Wilkinson’s to give compounds of Formula I.
  • pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated using Ghaffar-Parkins Catalyst and water in an alcohol solvent such as EtOH at an elevated temperatures to give compounds of Formula I.
  • 10a is first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K2CO3 or Cs2CO3) at RT or at an elevated temperature to give 9a.
  • a base e.g. NaH, K2CO3 or Cs2CO3
  • 10a can be alkylated by reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give 9a.
  • a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD
  • 10a can be alkylated by reaction with an alcohol 3b in the presence of CMBP (Tsunoda reagent) in an appropriate solvent such as 1,4-dioxane at RT or an elevated temperature optionally with microwave heating to give 9a.
  • CMBP Teunoda reagent
  • an appropriate solvent such as 1,4-dioxane at RT or an elevated temperature optionally with microwave heating.
  • Compound 9a can be converted to compounds of Formula I as described in Scheme 2.
  • compound 11a can be alkylated with 3a or 3b under conditions as described above to give compounds of Formula I.
  • Scheme 4 [0114] of compounds disclosed herein.
  • Compound 12a is first reacted with alkylating agent 13a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K 2 CO 3 or Cs 2 CO 3 ) at RT or at an elevated temperature to give 14a.
  • alkylating agent 13a where x is an appropriate leaving group such as Cl or Br
  • a solvent such as THF, DMF, DMSO, or NMP
  • 12a can be alkylated by a reaction with an aldehyde 13b via a reductive amination reaction in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride and an organic acid such as acetic acid in a solvent such as MeOH or EtOH to give 14a.
  • a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride and an organic acid such as acetic acid in a solvent such as MeOH or EtOH
  • Compound 14a can be hydrated to compound 16a using the method described in Scheme 2.
  • compound 15a can be alkylated to give 16a directly using the same methods described for 12a.
  • 17a is reacted with 18a in a solvent such as 1,4-dioxane, in the presence of a catalyst such as tBuBrettPhos Pd G3 or Xantphos Pd G3 with the addition of a base such as cesium carbonate at RT or at an elevated temperature.
  • a catalyst such as tBuBrettPhos Pd G3 or Xantphos Pd G3 with the addition of a base such as cesium carbonate at RT or at an elevated temperature.
  • 17a is coupled with a boronic acid in a Suzuki type reaction.
  • 17a is reacted with 18b in a solvent such as 1,4-dioxane, in the presence of a catalyst such as PdCl2(dppf) with the addition of a base such as aq. sodium carbonate at RT or at an elevated temperature.
  • Compound 9a can be converted to compounds of Formula I as described in Scheme 2.
  • Compound 25a is contacted with 2-isocyano-2-methylpropane in the presence of a catalyst such as PtBu 3 Pd G4, a ligand combination such as tri-tert-butylphosphonium tetrafluoroborate and a base combination such as DABCO with potassium formate in a solvent such as DMF.
  • Compound 25a can be aminated by reaction with an aldehyde 18a via a reductive amination reaction in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride and an organic acid such as acetic acid in a solvent such as MeOH or EtOH to give compound 26a.
  • a catalyst such as PtBu 3 Pd G4
  • a ligand combination such as tri-tert-butylphosphonium tetrafluoroborate
  • a base combination such as DABCO
  • Compound 25a can be aminated by reaction with an aldehyde
  • Scheme 8 first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K 2 CO 3 or Cs 2 CO 3 ) at RT or at an elevated temperature to give compound 28a.
  • alkylating agent 3a where x is an appropriate leaving group such as Cl or Br
  • a solvent such as THF, DMF, DMSO, or NMP
  • 27a can be alkylated by a reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give an be alkylated by reaction with an alcohol 3b in the presence of CMBP (Tsunoda reagent) in an appropriate solvent such as 1,4-dioxane at RT or an elevated temperature optionally with microwave heating to give 28a.
  • CMBP Teunoda reagent
  • Compound 28a can be hydrated to compounds of Formula Ib by methods described in Scheme 2.
  • reaction mixture was stirred for 15 – 20 min under N2 atmosphere at 0 – 5 °C.
  • 3- Methylbutanoyl chloride 1000 g, 8.29 mol was slowly added into the reaction mixture at 0 – 5 °C over 30 to 40 min.
  • the reaction mixture was warmed to 20 – 25 °C and stirred for 2 – 3 h.
  • the reaction mixture was quenched with 1M aq. HCl solution (1500 mL) at below 20 °C.
  • the resulting mixture was stirred for 10 min. Layers were separated and aq. layer extracted with DCM (1500 mL). The combined organic layers were washed with water (2 ⁇ 3500 mL).
  • CMBP cyclopentadiene
  • CMBP cyclopentadiene
  • the solution was loaded onto an SCX column. The column was washed with 3 column volumes of MeOH. The product was released with 7M ammonia in MeOH. Fractions containing the desired product were combined and evaporated to give a residue that was purified by silica gel chromatography eluting with a gradient from 0-100% EtOAc in hexane to give the title compound (49 mg).
  • N,N'-carbonyldiimidazole (0.80 g, 0.51 mL, 5.0 mmol). Placed under nitrogen and continued to stir at 62 oC for 17.5 h. Cooled down and diluted the mixture with 25 mL water. Stirred at rt then collected the solid by vacuum filtration to give the title compound (1.16 g).
  • Racemic 2-(2,2-difluorocyclopropyl)-N-methoxy-N- methylacetamide [0158] To a suspension of racemic acetic acid (5.00 g, 36.7 mmol) in DMF (30 mL) was added g, mmol). The mixture was stirred at RT for 5 min. N,N-diisopropylethylamine (44.8 mL, 257 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (17.9 g, 184 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions water, one portion sat. aq.
  • the vial was capped and placed in a 100 oC heating block for 4 h. The mixture was cooled to RT. The solvent was evaporated, and the residue was dissolved in DCM. DDQ (299 mg, 1 Eq, 1.32 mmol) was added all at once. The reaction mixture was stirred at RT for 30 min, then filtered through paper and the solids washed with minimal DCM. The filtrate was split into 4 equal portions and loaded onto 4 separate 10 g SCX columns. The columns were washed with 3 column volumes of MeOH. The product was released with 7 M NH3 in MeOH. Fractions containing the desired product were combined from all columns and evaporated.
  • N,N-Diisopropylethylamine (11.0 mL, 63.0 mmol) was added followed by N,O- dimethylhydroxylamine hydrochloride (4.39 g, 45.0 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions water, one portion sat. aq. NaCl, dried over Na 2 SO 4 , filtered, and evaporated to give the title compound (759 mg) as an oil. ES-MS m/z 155.2 (M+H).
  • Racemic 4,4,4-Trifluoro-N-methoxy-N,3- dimethylbutanamide [0195] To a suspension of racemic 3-methylbutanoic acid (2.21 g, 13.0 mmol) in DMF (50 mL) was added g, 19.3 mmol). The mixture was stirred at RT for 5 min. N,N-diisopropylethylamine (16 mL, 92 mmol) was added followed by N,O- dimethylhydroxylamine hydrochloride (6.34 g, 65.0 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc.
  • the crude product was purification by reverse phase flash chromatography on a YMC-Triart Prep C18250*50 mm*10 ⁇ m column eluting with a gradient from 0-50% ACN in water (NH 3 H 2 O+NH 4 HCO 3 ) at a flow rate of 110 mL/min.
  • the afforded flows were combined, concentrated to remove ACN and extracted with ethyl acetate (100 mL x 3).
  • the combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9.8 g).
  • the reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere.
  • the reaction mixture was quenched by adding sat. aq. NH 4 Cl (15 mL) at 0 °C.
  • the mixture was extracted with EtOAc (20 mL ⁇ 3).
  • the combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product.
  • the crude product was purified by flash silica gel chromatography eluting with a gradient from 0-10% MeOH in DCM to give the title compound (1.14 g).
  • the autoclave was sealed, purged and pressurized to 75 psi with Synthesis gas.
  • the reactor was heated at 90 o C for 18 h then cooled to RT and vented.
  • the reactor was opened, and the reactor contents transferred to a bottle rinsing the solids out with toluene.
  • the solids were filtered through a celite and rinsed with EtOAc.
  • the filtrate was removed under reduced pressure.
  • H 2 O was added, and a precipitate formed.
  • the precipitate was collected by vacuum filtration and the filter cake washed with H2O (x3) and hexane (x3), and dried under high vacuum to give the title compound (16 g).
  • Each vial was capped and placed in a 100 o C heating block with stirring for 16 h.
  • manganese dioxide 214 mg, 2.47 mmol.
  • the vials were capped and stirred in a 100 o C heating block for 2 h.
  • the reaction vials were cooled to RT.
  • the reaction mixtures were combined and filtered through a pad of diatomaceous earth and rinsed with EtOAc.
  • the filtrate was concentrated.
  • the residue was purified by silica gel column chromatography eluting with a gradient from 40- 100% EtOAc in cyclohexane to give the title compound (2.73 g).
  • the vial was sealed with a screw cap lined with teflon and was placed in an aluminum heating block warmed to 100 o C and stirred for 5 min to dissolve all reaction components. The mixture was allowed to cool to RT. The homogeneous solution was then split into two 40-mL vials and re-capped. The vials were heated at 100 o C for 20 h. The reaction vials were cooled to RT and DDQ (725 mg, 1.02 Eq, 3.19 mmol) (split over 2 reaction vials) was added. The mixtures were stirred for 1 h at RT. The reactions were combined rinsing with MeOH and evaporated.
  • the reaction mixture was stirred at 100 °C for 16 h under air.
  • the mixture was cooled to RT and DDQ (535.2 mg, 2.311 mmol) was added to the mixture.
  • the reaction mixture was stirred at 20 °C for 0.5 h under air.
  • the reaction mixture was concentrated to remove most of the solvent.
  • the residue was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product.
  • the residence time of the solution in the flow reactor was 1 min.
  • the mixture was collected from the flow reactor into a solution of sat. aq. NH 4 Cl (200 mL).
  • the mixture was pH adjusted to about 8 with 1 M HCl.
  • the mixture was extracted with EtOAc (400 mL ⁇ 3).
  • the combined organic layers were washed with sat. aq. NaCl (500 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in hexanes to give the title compound (5.96 g).
  • the reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with sat. aq. NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the crude product.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 23% EtOAc in hexane to give the title compound (646 mg).
  • the vessel was degassed and purged with atmospheric pressure of carbon monoxide gas 3 times.
  • the mixture was heated at 80 °C for 16 h under CO atmosphere (50 psi).
  • the reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (50 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (40 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate concentrated under reduced pressure to give a residue.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (278 mg, 78%).
  • Racemic 2-methyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde [0252] To a solution of racemic 2-nitrophenoxy)propanoate (5.2 g, 16 mmol) in AcOH (55 mL) was added 0.16 mol) and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and the pH of the mixture was adjusted to ⁇ 7 with sat. aq. NaHCO 3 .
  • Racemic tert-butyl (trans)-4-hydroxy-3-methoxypiperidine- 1-carboxylate [0263] To a 2250 mL Parr® bottle 10% Pd/C (1.72 g, 16.2 mmol). The bottle was placed under a stream of N2. MeOH (250 mL) was added. racemic tert-butyl (trans)-4- (benzyloxy)-3-methoxypiperidine-1-carboxylate (7.04 g, 21.9 mmol) and MeOH (250 mL) were added. The bottle was placed on a Parr® shaker. The bottle was flushed with N25 times, and H 2 5 times.
  • the bottle was pressurized with H 2 (10 psi). The reaction was shaken for 20 h at RT. The reaction mixture was filtered over diatomaceous earth and the solids washed with MeOH to give a filtrate. The combined filtrate was concentrated under vacuum. The sample was re-filtered over diatomaceous earth and the solids washed with MeOH to give a filtrate. The filtrate was concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography using EtOAc to give the title compound (5.2 g). ES-MS m/z 176 (M-tBu+1).
  • Racemic tert-butyl (cis)-4- ) Racemic tert-butyl (cis)-4-hydroxy-3-methoxypiperidine-1- carboxylate
  • Racemic tert-butyl (cis)-4-hydroxy-3-methoxypiperidine-1- carboxylate To an oven dried 500 mL equipped with a magnetic stir bar was added racemic tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (9.50 g, 40.2 mmol) and THF (100 mL) successively at ambient temperature. The vessel was degassed and purged with atmospheric pressure N23 times.
  • Lithium tri-sec-butylborohydride (L-selectride), 1M in THF (60.3 mL, 60.3 mmol) was added dropwise to the reaction mixture at -60 °C.
  • the reaction mixture was stirred at -60 °C for 2 h.
  • the reaction mixture was quenched with sat. aq. NH 4 Cl (300 mL) at 0 °C.
  • the mixture was extracted with EtOAc (300 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (300 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate concentrated under reduced pressure to give a crude product.
  • Racemic tert-butyl (trans)-3-methoxy-4-((4- nitrobenzoyl)oxy)piperidine-1-carboxylate [0273] To an oven dried with a magnetic stirrer were added racemic tert-butyl (cis)-4-hydroxy-3-methoxypiperidine-1-carboxylate (9.61 g, 39.4 mmol), THF (120 mL), 4-nitrobenzoic acid (8.48 g, 49.2 mmol), and triphenylphosphine (32.1 g, 119 mmol) successively at 0 °C. The vessel was degassed and purged with atmospheric pressure of N 2 3 times.
  • the reaction mixture was stirred at 20 °C for 1 h.
  • the reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (300 mL ⁇ 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in hexanes to give the title compound (7.81 g).
  • Racemic 3-methoxypiperidin-4-ol hydrochloride Racemic 3-methoxypiperidin-4-ol hydrochloride
  • racemic tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate 7.59 g, 26.3 mmol
  • hydrogen chloride, 2M in EtOAc 60 mL, 0.12 mol
  • the reaction mixture was stirred at 20 °C for 16 h.
  • the reaction mixture was concentrated under reduced pressure to give the title compound (5.51 g).
  • Racemic tert-butyl 5-hydroxy-7-oxa-3- azabicyclo[4.1.0]heptane-3-carboxylate [0283] To a N 2 -filled 100 mL RBF stir bar was added racemic tert-butyl 3-hydroxy-3,6-dihydropyridine-1(2H)- (2.0 g, 9.8 mmol) and DCM (40 mL) successively at ambient temperature. The vessel was purged with N23 times. The reaction mixture was cooled to 0 °C and Na 2 CO 3 (1.1 g, 9.8 mmol) and mCPBA (3.0 g, 15 mmol) were added at 0 °C.
  • the reaction mixture was warmed to 20 °C and stirred at 20 °C for 16 h to give a white suspension.
  • the reaction mixture was diluted with DCM (50 mL) and the mixture filtered.
  • the filtrate was washed with sat. aq. Na2HCO3 (50 mL ⁇ 2) and sat. aq. NaCl (50 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated to give a crude product.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 20% EtOAc in cyclohexane to give the title compound (1.74 g).
  • the mixture was degassed with N 2 for 5 min and stirred at 100 °C for 16 h.
  • the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (20 mL ⁇ 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 30% EtOAc in hexanes to give the product.
  • racemic tert-butyl 5-hydroxy-7-oxa-3- azabicyclo[4.1.0]heptane-3-carboxylate 200 mg, 883 ⁇ mol was added.
  • the vessel was degassed with N2 for 5 min.
  • the reaction mixture was heated to 100 °C and stirred for 1 h.
  • To the reaction mixture was added water (20 mL) and the mixture was extracted with EtOAc (20 mL ⁇ 3).
  • the combined organic layers were washed with water (10 mL) and sat. aq. NaCl (10 mL), dried over anhydrous Na2SO4, and filtered.
  • the filtrate was concentrated under reduced pressure to give a crude product.
  • the crude product was purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm ⁇ 200 mm, 7 ⁇ m) column eluting with a gradient from 32-72% ACN in water (10 mM NH 4 HCO 3 ) over 20 min at a flow rate of 60 mL/min to give the title compound (79 mg).
  • Tetrabutylammonium fluoride (1M) (1.14 mL, 1.14 mmol) was added and the reaction was stirred at RT for 30 min. Water was added to the reaction, followed by EtOAc. The layers were separated. The aq. phase was further extracted with EtOAc (3 ⁇ 25 mL). The organic phase was washed with sat. aq. NaCl (3 ⁇ 50 mL). The organic phase was dried over MgSO 4 , filtered, and the filtrate concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (110 mg). ES-MS m/z 618 (M+H).
  • Racemic 4-(4-((5-chloro- -yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL CHIRALPAK IK (30 mm ⁇ 250 mm, 10 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 55%; End B: 55%; Flowrate (mL/min): 130) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column.
  • Isomer 1 ES-MS m/z 622 (M+H).
  • Isomer 2 ES-MS m/z 622 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak IK-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Begin B: 40 %; End B: 40 %; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 40 °C).
  • Isomer 1 98 %ee, enriched in peak 1, retention time 1.023 min.
  • Isomer 2 97%ee, enriched in peak 2, retention time 1.769 min.
  • Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL CHIRALPAK IG (30 mm ⁇ 250 mm, 10 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH (0.1% NH 3 H 2 O); Begin B: 60%; End B: 60%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column.
  • Isomer 1 ES-MS m/z 605 (M+H).
  • Isomer 2 ES-MS m/z 605 (M+H).
  • the products were analyzed by SFC (Column: Chiralpakl IG-3 (4.5 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% NH3(7M in MeOH)); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C).
  • Isomer 1 95%ee, enriched in peak 1, retention time 1.104 min.
  • Isomer 2 99%ee, enriched in peak 2, retention time 1.536 min.
  • the vial was sealed and heated at 80 °C for 17.5 h.
  • the reaction was allowed to cool to RT and then was slowly quenched by the adding the reaction mixture to an ice-cold solution of sat. aq. sodium bicarbonate.
  • the solution was extracted with EtOAc ⁇ 3.
  • the combined organic layers were dried over Na2SO4, filtered, and the filtrate concentrated.
  • the crude product was purified by reversed-phase chromatography on a Teledyne ISCO RediSep C18 Gold® (100g) column using a gradient of 0-100% ACN in water (10 mM NH4CO3) at a flow rate of 60 mL/min to give the title compound (192 mg).
  • Racemic 3- bromo-1,1,1-trifluoropropan-2-ol (20 ⁇ L, 0.19 mmol) was added as a liquid, followed by DMA (0.91 mL). The suspension was stirred until everything went into solution (1 min) and the solution was a dark teal. The reaction was sparged with N 2 for 5 min, and then zinc (35 mg, 0.54 mmol) was added. The vial was sealed with a crimp cap and heated at 65 °C for 17 h. The reaction was allowed to cool to RT and then filtered through diatomaceous earth with DCM and MeOH. The filtrate was concentrated under reduced pressure. The filtrate was taken up in MeOH and filtered through a syringe filter.
  • the mixture was bubbled with N 2 for 5 min and stirred at 100 °C for 16 h.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (10 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate concentrated under reduced pressure to give a crude product.
  • the crude product was purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm ⁇ 200 mm, 7 ⁇ m) column eluting with a gradient from 16-56% ACN in water (0.225% formic acid) over 20 min.
  • Isomer 1 ES-MS m/z 667 (M+H).
  • Isomer 2 ES-MS m/z 667 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: IPA (0.2% NH 3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.14 min.
  • Isomer 1 ES-MS m/z 667 (M+H).
  • Isomer 2 ES-MS m/z 667 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak IM-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% NH3(7M in MeOH)); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 1.48 min.
  • Isomer 2 98%ee, enriched in peak 2, retention time 1.78 min.
  • Isomer 1 ES-MS m/z 663 (M+H).
  • Isomer 2 ES-MS m/z 663 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.06 min.
  • Isomer 1 ES-MS m/z 679 (M+H).
  • Isomer 2 ES-MS m/z 679 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak IA-3 (4.6 mm ⁇ mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.15 min.
  • Isomer 1 ES-MS m/z 674 (M+H).
  • Isomer 2 ES-MS m/z 674 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 0.95 min.
  • the mixture was stirred at 80 °C for 2 h.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (10 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate concentrated under reduced pressure to give a crude product.
  • the product was purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm ⁇ 200 mm, 7 ⁇ m) column eluting with a gradient from 38-78% ACN in water (0.225% formic acid) over 19 mins to give the title compound (106 mg).
  • Isomer 1 ES-MS m/z 683 (M+H).
  • Isomer 2 ES-MS m/z 683 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak IG-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH (0.2% NH 3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.37 min.
  • Example 2 Racemic 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-1-(2,2-dimethylpiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 1:2 solvate with methanol [0342] A solution of racemic 4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-2,2-dimethylpiperidine-1- carboxylate (46 mg, 68 ⁇ mol) and TFA (1.5 mL, 19 mmol) in DCM (1.5 mL) was stirred at RT for 2 h.
  • Examples 3a and 3b 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-((cis)-2- (trifluoromethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer mixture 1 – 3a, and Isomer mixture 2 – 3b) [0343] The title compound of isomers in a manner analogous to the Preparation of Intermediate hydroxy-2- (trifluoromethyl)piperidine-1-carboxylate (mixture of isomers), followed by nitrile hydrolysis in a similar manner as described in the Preparation of Intermediate 14, followed by Boc de- protection in a similar manner as described in Example 2.
  • the isomers were separated by reverse phase flash chromatography using a gradient of 33 to 67% ACN in 10 mM aqueous ammonium bicarbonate with 5% MeOH to give Isomer mixture 1 (first-eluting, Example 3a) and Isomer mixture 2 (second-eluting, Example 3b). Both isomer mixtures: ES-MS m/z 612 (M+H).
  • Example 5 Cis 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 6-isobutyl-1-((3-(methylamino)cyclobutyl)methyl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0345] To a solution of cis 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1- yl)methyl)cyclobutyl)(methyl)carbamate (217 mg, 315 ⁇ mol) in DCM (2 mL) was added TFA (2 mL).
  • Example 7 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(2-fluoroethyl)piperidin-4-yl)- 6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0347] The title compound was obtained after hydrolysis of 4-(1-(3,4-difluorobenzyl)- 1H-indazol-5-yl)-1-(1-(2-fluoroethyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carbonitrile using General Procedure B.
  • Example 8 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- ((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0348] To a solution of 1-((3- oxy)methyl)bicyclo[1.1.1]pentan- 1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (2.2 g, 3.1 mmol) in 60 mL
  • Example 23 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0353] A mixture of ammonium mmol), 1-(1-methylpiperidin-4-yl)- 1H-pyrazol-5-amine (2.23 g, 12.4 mmol), 5-methyl-3-oxohexanamide (1.56 g, 10.9 mmol) and 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (3.00 g, 9.89 mmol) in EtOH (90 mL) was heated at 95 oC for 44 h in a 250
  • the product was re-purified by silica gel chromatography (MeOH in EtOAc and MeOH in DCM, 0 to 5% mixtures). The product was filtered through a 3 ⁇ m membrane (polish filtration). The combined organic solvents were reduced up to ⁇ 1/3 (ca.25 mL) and water (25 mL) was added dropwise and the mixture stirred for a further 30 min at RT. The resulting solid was filtered, washed with 7/3 water/MeOH mixture (25 mL) and water (25 mL), then dried under vacuum at 45 oC for 18 h to afford the title compound (2.86 g). ES-MS m/z 589 (M+H).
  • the title compound was prepared as follows. In an RBF under N 2 , a mixture of ammonium acetate (26.7 g, 346.2 mmol), 1-(1-methylpiperidin-4-yl)-1H-pyrazol- 5-amine (16.7 g, 93.5 mmol), 5-methyl-3-oxohexanamide (10.9 g, 76.2 mmol) and 4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (21.0 g, 69.2 mmol) in n-propanol (600 mL) was heated at 100 oC for 6 h.
  • Example 24 4-(1-(4-Chloro-3-fluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0355]
  • the title compound was prepared in a similar manner as described in General Procedure A using 5-methyl-3-oxohexanamide, 1-(4-chloro-3-fluorobenzyl)-1H-indazole-5- carbaldehyde, and 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-amine.
  • Example 25a and 25b 1-(1-Cyclopropylethyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 25a and Isomer 2 – Example 25 b) General Procedure H: MCR with [0356] To a vial with a stir bar was added 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (100
  • the vial was capped, placed in a 100 oC heating block, and stirred at 100 oC for 20 h.
  • the mixture was cooled down and concentrated under vacuum, and the residue was purified by reverse phase chromatography using a gradient of 40-77% ACN in 0.1% formic acid in water to give 124 mg of the title compound as a racemic mixture.
  • the isomers were separated by chiral HPLC (column: Chiralpak® IG 30 ⁇ 250 mm, 5 ⁇ m; mobile phase: 1:3 (MeOH + 0.5% DMEA) : CO2; flow rate: 100 mL/min; column temperature: 40 °C] to give Isomer 1 (first-eluting isomer, 54 mg) and Isomer 2 (second-eluting isomer, 56 mg) of the title compound. Both isomers: ES-MS m/z 560 (M+H).
  • Example 31 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- ((2,2-difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (Isomer 2) [0359] The title compound was to General Procedure G using racemic 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((2,2- difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile, followed by chiral SFC [column: Chiralpak® IG, 30 ⁇ 250
  • the reaction was stirred for 2 h, then poured into a separation funnel containing 200 mL EtOAc, 150 mL water, and 50 mL sat. aq. NaCl and separated phases.
  • the organic layer was washed with 1:1 water:sat. aq. NaCl (2 ⁇ 100 mL).
  • the combined aq. layers were back extracted with EtOAc (1 ⁇ 100 mL).
  • the organics were dried over MgSO4, filtered, and concentrated.
  • the residue was purified by reverse phase flash chromatography using a gradient of 0 to 100% ACN in 10 mM aq.
  • Example 39 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-3-(5-(hydroxymethyl)thiophen-2- yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0365]
  • the title compound manner as described in General Procedure J with 3-bromo-4-(1- - indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (5- (hydroxymethyl)thiophen-2-yl)boronic acid, followed by nitrile hydrolysis in a similar manner as described in the General Procedure B.
  • Example 40 4-(4-((5-Bromo-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide [0366] The title compound was manner as described in General Procedure G using 4-(4-((5-bromo-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carbonitrile.
  • Example 45a The product was purified by silica gel chromatography using a gradient of 0 to 10 % MeOH in DCM, giving the racemic mixture of the title compound (Example 45a).
  • the isomers were separated by chiral SFC [column: Lux Cellulose-4, 21 ⁇ 150 mm, 5 ⁇ m; mobile phase: solvent A – MeOH + 0.5% DMEA, solvent B – CO 2 , 15:85 solvent A : solvent B; column temperature: 40 °C] to give Isomer 1 (Example 45b) as the first-eluting isomer and Isomer 2 (Example 45c) as the second-eluting isomer.
  • Example 48 Racemic 4-(4-(3,4-Difluorobenzyl)-2-(2-(methylamino)-2-oxoethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 50 4-(4-((5-Chloropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide
  • Example 56 Racemic 1-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)-4-(4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0378] A solution of 4-(4-(3,4-difluorobenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (195 mg, 256 ⁇ mol) in 2 M HCl in 1,4-dioxane (3.0 m
  • Example 57 was prepare following steps. [0380] Step 1: MCR with tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1- carboxylate, 1-(3,4-difluorobenzyl)-1H-indazole-5-carbaldehyde, and 5-methyl-3- oxohexanenitrile according to General Procedure A was conducted to give tert-butyl 4-(5- cyano-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate.
  • Step 2 Boc deprotection with 2 M HCl in 1,4-dioxane in a similar manner as described in Example 56 was conducted to give 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)- 6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile.
  • Step 3 Reductive amination with 3,3-difluorocyclobutan-1-one in a similar manner as described in Example 6 with the addition of 1.5 equivalents of titanium tetraisopropoxide was performed.
  • Step 4 Nitrile hydrolysis in a similar manner as described in General Procedure B was performed to afford the title compound.
  • Example 58 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-(3- methoxycyclobutyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 58 was prepare er as described in Example 57, using 3-methoxycyclobutan-1-one in Step 3. ES-MS m/z 628 (M+H).
  • Example 59 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-((1- fluorocyclopropyl)methyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0385]
  • Example 59 was as described in Example 57, using 1-fluorocyclopropane-1-carbaldehyde, 3 equivalents of sodium triacetoxyborohydride, and 3 equivalents of acetic acid in place of sodium cyanoborohydride and titanium tetraisopropoxide in Step 3.
  • Example 60 was prepare ner as described in Example 57, using 1-methylcyclopropane-1-carbaldehyde, 3 equivalents of sodium triacetoxyborohydride, and 3 equivalents of acetic acid in place of sodium cyanoborohydride and titanium tetraisopropoxide in Step 3.
  • Example 61 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(3- (difluoromethyl)cyclobutyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (mixture of isomers) [0387]
  • Example 61 was as described in Example 57, using 3-(difluoromethyl)cyclobutan-1-one in Step 3.
  • Example 62 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide [0388]
  • Example 62 was following steps.
  • Step 1 To a mix of 6- 4-yl)-4-(3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and NaH (1.5 equivalents) in DMF was added 2-(chloromethyl)-3,5-difluoropyridine and the mixture stirred at RT overnight. Sat. aq. NaCl was added, and the mixture extracted with DCM.
  • Step 2 The nitrile was hydrolyzed in a similar manner as described in General Procedure G to afford the title compound. ES-MS m/z 590 (M+H).
  • Example 63 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide formate
  • Example 63 was prepa llowing steps.
  • Step 1 tert-Butyl 4-(5-carbamoyl-4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate was prepared in a similar manner as described in General Procedure A using tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate, 4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, and 5-methyl-3-oxohexanamide.
  • Step 2 Boc deprotection in a similar manner as described in Example 2, followed by reverse phase HPLC using ACN and aqueous formic acid.
  • ES-MS m/z 575 (M+H).
  • Example 64 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-methylpiperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 64 was as described in General Procedure H using 5-methyl-3-oxohexanamide, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-amine, and 1- (3,4-difluorobenzyl)-1H-indazole-5-carbaldehyde.
  • Example 65 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-methylpiperidin-4- yl)-3-(thiazol-2-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0395]
  • Example 65 was steps. [0396] Step 1: General was 2-amine. [0397] Step 2: Nitrile hydrolysis in a similar manner as described in General Procedure B was performed to afford the title compound. ES-MS m/z 656 (M+H).
  • Example 68 Racemic 1-(1-Cyclopropylethyl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0400] General Procedure A 1-(1-cyclopropylethyl)-1H-pyrazol- 5-amine, 5-methyl-3-oxohexanamide, and 4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde to afford the title compound.
  • Example 69 Racemic 1-(1-Cyclopropylethyl)-6-isobutyl-4-(3-oxo-4-(pyrazin-2-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0401]
  • Example 69 was following steps.
  • Step 1 A mixture of 3- -3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, acetic acid, and piperidine (1 equivalent of each) was stirred at 50 °C for 2 h, then racemic 1-(1- cyclopropylethyl)-1H-pyrazol-5-amine (1 equivalent) was added and the mixture stirred at 50 °C for 6 h. Water was added and the mixture was extracted with EtOAc. The organics were washed with sat. aq. NaCl, dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 The product from Step 1 was dissolved in DMSO, K 2 CO 3 (3 equivalents) and hydrogen peroxide (30 wt% in water, 15 equivalents) and the mixture was stirred at RT for 12 h. Water was added and the mixture was extracted with EtOAc.
  • Example 70 was prepa llowing steps.
  • Step 1 General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and racemic tert-butyl (trans)-4- hydroxy-2,6-dimethylpiperidine-1-carboxylate
  • Step 2 Nitrile hydrolysis using General Procedure G was performed following step 1.
  • Step 3 Then Boc deprotection with TFA afforded the title compound.
  • Example 71 was steps. [0409] Step 1: General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1,2-dimethylpiperidin-4-ol (mixture of diastereomers).
  • Step 2 General Procedure B was used to give 4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-1-((2S,4S)-1,2-dimethylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide.
  • ES-MS m/z 572 (M+H).
  • Example 73 was following steps.
  • Step 1 General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-ethylpiperidin-4-ol;
  • Step 2 General Procedure B was used to give 4-(1-(3,4-Difluorobenzyl)-1H- indazol-5-yl)-1-(1-ethylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide.
  • ES-MS m/z 572 (M+H).
  • Example 74.1 (1-Cyclobutylpiperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0415]
  • Example 74 was steps.
  • Step 1 General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate;
  • Step 2 General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0418] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-difluoropyridin- 2-y
  • Example 76 was prepared following steps. [0423] Step 1: General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate; [0424] Step 2: General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0425] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-di
  • Example 77 was prepare following steps. [0429] Step 1: General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate; [0430] Step 2: General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0431] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-di
  • Example 78 was prepared following steps. [0435] Step 1: The procedure of Intermediate 35 was utilized starting with 2- cyclopropylacetic acid; [0436] Step 2: The procedure of Intermediate 36 was used starting with 2-cyclopropyl-N- methoxy-N-methylacetamide; and [0437] Step 3: General Procedure A was used with 4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 4-cyclopropyl-3-oxobutanenitrile to afford the title compound. ES-MS m/z 587 (M+H).
  • Step 1 General Procedure K was used with methyl 7-bromo-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-5-carboxylate and 4-(bromomethyl)-1,2-difluorobenzene;
  • Step 2 The procedure of Intermediate 16 was utilized starting with methyl 7- bromo-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate;
  • Step 3 General procedure E was used with methyl 4-(3,4-difluorobenzyl)-7- formyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate, 5-methyl-3- oxohexanamide, and racemic 1-(1-cyclopropylethyl)-1H-
  • Example 8 0.7-(5-Carbamoyl-6-isobutyl-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-5-carboxylic acid [0443]
  • Example 80 was steps.
  • Step 1 General Procedure K was used with methyl 7-bromo-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-5-carboxylate and 4-(bromomethyl)-1,2-difluorobenzene;
  • Step 2 The procedure of Intermediate 16 was utilized starting with methyl 7- bromo-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate;
  • Step 3 The procedure of Intermediate 5 was used starting with 3- methylbicyclo[1.1.1]pentane-1-carbaldehyde;
  • Step 4 General procedure E was used with methyl 4-(3,4-difluorobenzyl)-7- formyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • Example 81 was steps.
  • Step 1 General Procedure K was used with 5-bromo-3,3-difluoroindolin-2-one and 4-(bromomethyl)-1,2-difluorobenzene;
  • Step 2 The procedure of Intermediate 28 was used with 5-bromo-1-(3,4- difluorobenzyl)-3,3-difluoroindolin-2-one;
  • Step 3 General Procedure H was used with 1-(3,4-difluorobenzyl)-3,3-difluoro-2- oxoindoline-5-carbaldehyde, 5-methyl-3-oxohexanamide, and rac-(R)-1-(1- cyclopropylethyl)-1H-pyrazol-5-amine to afford the title compound.
  • Example 82 was prepared according to the following steps. [0454] Step 1: General Procedure K was used with 5-bromo-1,2-dihydro-3H-indazol-3- one and 4-(bromomethyl)-1,2-difluorobenzene; [0455] Step 2: The procedure of Intermediate 28 was used with 5-bromo-1,2-bis(3,4- difluorobenzyl)-1,2-dihydro-3H-indazol-3-one; and [0456] Step 3: General Procedure H was used with 1,2-bis(3,4-difluorobenzyl)-3-oxo- 2,3-dihydro-1H-indazole-5-carbaldehyde, 5-methyl-3-oxohexanamide, and 1-(1- methylpiperidin-4-yl)-1H-pyrazol-5-amine to afford the title compound.
  • Step 1 General Procedure K was used with 5-bromo-1,2-dihydro-3H-indazol-3- one and 4-(bro
  • Example 83 was following steps.
  • Step 1 General Procedure C was used with (5-fluoropyridin-2-yl)methanol and 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one;
  • Step 2 The product from step 1 was treated with triethylsilane, triethylamine, and PdCl 2 (dppf)-CH 2 Cl 2 in DMF under an atmosphere of carbon monoxide to give 4-((5- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde;
  • Step 3 General Procedure A was used with 4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohex
  • Example 84.1 (1-Cyclopropylpiperidin-4-yl)-4-(4-((5-fluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0464]
  • Example 84 was following steps.
  • Step 1 General Procedure C was used with (5-fluoropyridin-2-yl)methanol and 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one;
  • Step 2 The product from step 1 was treated with triethylsilane, triethylamine, and PdCl2(dppf)-CH2Cl2 in DMF under an atmosphere of carbon monoxide to give 4-((5- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde;
  • Step 3 General Procedure A was used with 4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohe
  • Example 85 (R)-4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0471]
  • Example 85 was steps.
  • Step 1 General Procedure K was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde and 2-(chloromethyl)-3,5-difluoropyridine;
  • Step 2 General Procedure A was used with 4-((3,5-difluoropyridin-2-yl)methyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1H-pyrazol-3-amine;
  • Step 3 General Procedure K was used with 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[
  • Example 86 Racemic1-(1-cyclopropylethyl)-4-(1-(3,4-difluorobenzyl)-7- ((methylsulfonyl)carbamoyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0476]
  • Example 86 was prepared steps.
  • Step 1 General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene;
  • Step 2 The procedure of Intermediate 16 was utilized starting with methyl 5- bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate;
  • Step 3 General Procedure H was used with methyl 1-(3,4-difluorobenzyl)-5- formyl-1H-indazole-7-carboxylate, 5-methyl-3-oxohexanamide, and racemic 1-(1- cyclopropylethyl)-1H-pyrazol-5-amine;
  • Step 3 General Procedure L was used to give 5-(5-carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl
  • Example 87 was prepare following steps. [0483] Step 1: General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0484] Step 2: methyl 5-bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate was treated with DIBAL in toluene to give (5-bromo-1-(3,4-difluorobenzyl)-1H-indazol-7- yl)methanol; [0485] Step 3: (5-bromo-1-(3,4-difluorobenzyl)-1H-indazol-7-yl)methanol was treated with phosphorous tribromide in DCM to give 5-bromo-7-(bromomethyl)-1-(3,4- difluorobenzyl)-1H-indazole; [0486] Step 4: 5-bromo
  • Example 88 Racemic 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
  • Step 1 General Procedure K was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and racemic 3-bromo-2-methylpropan-1-ol; and [0491] Step 2: General Procedure G was used to give 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide to afford the title compound.
  • Example 89 was steps.
  • Step 1 General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene;
  • Step 2 The procedure of Intermediate 16 was utilized starting with methyl 5- bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate;
  • Step 3 General Procedure H was used with methyl 1-(3,4-difluorobenzyl)-5- formyl-1H-indazole-7-carboxylate, 5-methyl-3-oxohexanamide, and rac-(R)-1-(1- cyclopropylethyl)-1H-pyrazol-5-amine; and
  • Step 4 General Procedure L was used to give 5-(5-Carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyr
  • Example 90 was steps.
  • Step 1 General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and oxazol-4-ylmethanol; and [0499] Step 2: General Procedure G was used to give 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(oxazol-4-ylmethyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide.
  • Example 92 1-((3-Aminobicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0501] A solution of tert- (3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (580 mg, 777 ⁇ mol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at 25 °C for 1 h.
  • Example 93 Racemic tert-butyl (3-(1-(5-carbamoyl-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0502] The title compound as described in General Procedure G using racemic tert-butyl (3-(1-(5-cyano-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1- yl)ethyl)bicyclo[1.1.1]p
  • Example 94 was prepared according to the following steps. [0504] Example 94 was prepared utilizing the procedure for Example 6 starting with 1- ((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide. ES- MS m/z 615 (M+H).
  • Example 9 5.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- (methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0505]
  • Example 95 was steps.
  • Step 1 General Procedure A was used with 5-methyl-3-oxohexanenitrile, 1-(3,4- difluorobenzyl)-1H-indazole-5-carbaldehyde, and tert-butyl 4-(5-amino-1H-pyrazol-1- yl)piperidine-1-carboxylate;
  • Step 2 The procedure of Example 56 was used starting tert-butyl 4-(5-cyano-4- (1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate; and [0508] Step 3: The procedure of Example 55 was used starting with 4-(1-(3,4- difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-
  • Step 1 General Procedure C was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and tert-butyl 8-hydroxy-5- azaspiro[2.5]octane-5-carboxylate;
  • Step 2 General Procedure G was used to give tert-butyl 8-(5-cyano-4-(1-(3,4- difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5- azaspiro[2.5]octane-5-carboxylate; and [0513] Step 3: A procedure similar to that for Example 2 was used to give the title compound.
  • Step 1 The procedure essentially described in the Preparation of Intermediate 5 was used starting with 3-methylbicyclo[1.1.1]pentane-1-carbaldehyde;
  • Step 2 General Procedure H was used with 3-oxo-4-(pyrazin-2-ylmethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazol-5-amine; and
  • Step 3 General Procedure B was used to give the title compound.
  • Example 98 was steps.
  • Step 1 General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and pyridin-3-ylmethanol.
  • Step 2 General Procedure G was used to give the title compound. ES-MS m/z 583 (M+H).
  • Example 99 4-(2-Benzyl-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0521] The title compound ES-MS (m/z) of 679 (M+H). Example 100.
  • Step 1 General was (1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (S)-3-bromo-2-methylpropan- 1-ol; and [0524] Step 2: General Procedure B was used to give the title compound.
  • Example 101 Racemic 6-isobutyl-1-(1-(3-methylbicyclo[1.1.1]pentan-1-yl)ethyl)-4-(3-oxo- 4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0525]
  • Example 101 was steps.
  • Step 1 General Procedure A was used with 3-oxo-4-(pyrazin-2-ylmethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1H- pyrazol-3-amine;
  • Step 2 Racemic 1-(3-methylbicyclo[1.1.1]pentan-1-yl)ethan-1-ol was made utilizing methods similar to the synthesis of Intermediates 58 to 60;
  • Step 3 General Procedure F was used with 6-isobutyl-4-(3-oxo-4-(pyrazin-2- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile and rac-(R)-1-(3-methylbicyclo[1.1.1]pentan-1-
  • Example 10 2.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- (cis-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0530]
  • Example 102 was steps.
  • Step 1 General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (cis)-3-(hydroxymethyl)-1-(trifluoromethyl)cyclobutan-1-ol; and [0532] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 644 (M+H).
  • Step 1 General Procedure A was used with 5-methyl-3-oxohexanenitrile, 3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, and 1-(1-methylpiperidin-4-yl)-1H- pyrazol-5-amine;
  • Step 2 General Procedure K was used with 6-isobutyl-1-(1-methylpiperidin-4-yl)- 4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile and 4-(bromomethyl)-1-chloro-2-fluorobenzene utilizing sodium hydride in place of a carbonate base; and [0536] Step 3: General Procedure G was used to give the title compound.
  • Example 104.1 ((7-Oxabicyclo[2.2.1]heptan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0537]
  • Example 104 was steps.
  • Step 1 General Procedure K was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, and 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane; and [0539] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 602 (M+H).
  • Example 105 was following steps.
  • Step 1 General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-cyclobutylpiperidin-4-ol; and [0542] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 629 (M+H).
  • Example 106 was prepar e following steps.
  • Step1 General Procedure C was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, and 1-(oxetan-3-yl)piperidin-4- ol; and
  • Step 2 General Procedure G was used to give the title compound.
  • Example 107 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0546] In a 20-mL vial with a 4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (100 mg, 174 ⁇ mol), 3,3-difluorocyclobutan-1- one (75 mg,
  • Example 110 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 131a and 131b 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – 131a, Isomer 2 – 131b)
  • Racemic 4-(4-((3,5-Diflu ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by chiral HPLC (column: Chiralpak® IG 30 x 250 mm, 5 ⁇ m; mobile phase: 1:3 (MeOH + 0.5% DMEA) : CO2; flow rate: 100 mL/min; column temperature: 40 °C] to give Isomer 1 (first-eluting isomer, 9.1 mg) and Isomer 2 (second-eluting isomer, 9.2 mg) of the title compound.
  • Example 132 Racemic 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0555] To a 40-dram vial charged with 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- (5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H-
  • Example 133a, and 133b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – 133a, and Isomer 2 – 133b) [0556] Racemic 4-(4-((5- -3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine
  • Example 215 6-(Cyclopropylmethyl)-1-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0565] In a 25 mL vial with a (cyclopropylmethyl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (100 mg, 211 ⁇ mol) and 1-(3,3- difluorocyclobutyl)piperidin-4-ol (63.4
  • Triphenylphosphine 158 mg, 602 ⁇ mol
  • DBAD 146 mg, 634 ⁇ mol
  • the reaction was capped under N 2 and stirred at RT for 22 h. Additional triphenylphosphine (73.4 mg, 280 ⁇ mol) and DBAD (72.9 mg, 317 ⁇ mol) were added and the mixture was stirred at RT for 5 h.
  • the reaction mixture was loaded onto a 10 g SCX column that was equilibrated in 100 mL of MeOH. The column was flushed with 100 mL of MeOH followed by elution with 100 mL of 2 M NH3 in MeOH. Fractions containing product were combined and evaporated to give the crude product.
  • the crude product was purified by silica gel column chromatography using a gradient of 0 to 100% (25%EtOH in EtOAc) in cyclohexane.
  • the product was further purified by reverse phase chromatography on a Evo (30 mm ⁇ 100 mm, 5 ⁇ m) column eluting with a gradient from 38-58% ACN in water (10 mM NH4CO3) over 20 min to give the title compound (13.1 mg).
  • Example 216 Racemic 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(3,3,3-trifluoro-2- hydroxypropyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1) [0566] To a 8 mL sealed vial bar was added 4-(4-((5-chloro-3- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4-b]pyr
  • the mixture was stirred at 80 °C for 16 h.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL ⁇ 2).
  • the combined organic layers were washed with sat. aq. NaCl (10 mL ⁇ 2), dried over anhydrous Na2SO4, filtered, and filtrate concentrated under reduced pressure to give a crude product.
  • the crude product was purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm ⁇ 200 mm, 7 ⁇ m) column eluting with a gradient from 28-68% ACN in water (10 mM NH4CO3) at a flow rate of 50 mL/min to give the title compound (18.53 mg).
  • Example 220 6-(Cyclopropylmethyl)-1-((3R,4R)-1-(2,2-difluoroethyl)-3-methylpiperidin-4- yl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 221 Racemic 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
  • Example 222 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(cyclopropylsulfonyl)-3-methoxypiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 2)
  • Isomer 1 ES-MS m/z 688 (M+H).
  • Isomer 2 ES-MS m/z 688 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AD-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: Heptane (0.2% IPAm), mobile phase B: EtOH (0.2% IPAm); Begin B: 30%; End B: 30%; Flowrate (mL/min): 1; Run length: 8 min; Detection Method: UV; Detection Wavelength: 225, 250 nM).
  • Isomer 1 99%ee, enriched in peak 1, retention time 3.18 min.
  • Isomer 1 ES-MS m/z 743 (M+H).
  • Isomer 2 ES-MS m/z 743 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C;).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 0.90 min.
  • Isomer 1 ES-MS m/z 709 (M+H).
  • Isomer 2 ES-MS m/z 709 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak IH-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: MeOH (0.2% NH 3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 0.99 min.
  • Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-(methylthio)-1-(oxetan-3-yl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL Chiralpak IC (30 mm ⁇ 250 mm, 10 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH:ACN 3:1 (0.1% NH3H2O); Begin B: 55%; End B: 55%; Flowrate (mL/min): 140) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column.
  • Isomer 1 was repurified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm ⁇ 200 mm, 7 ⁇ m) column eluting with a gradient from 18-58% ACN in water (10 mM NH4CO3) over 20 min at a flow rate of 30 mL/min to give repurified Isomer 1.
  • Isomer 1 ES-MS m/z 677 (M+H).
  • Isomer 2 ES-MS m/z 677 (M+H).
  • Examples 229a and 229b 1-((Cis)-1-(3,3-difluorocyclobutyl)-3-methoxypiperidin-4-yl)-4-(4- ((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 229a and Isomer 2 – Example 229b)
  • Isomer 1 ES-MS m/z 679 (M+H).
  • Isomer 2 ES-MS m/z 679 (M+H).
  • the products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 0.86 min.
  • Isomer 2 99%ee, enriched in peak 2, retention time 1.15 min.
  • Examples 230a and 230b 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(oxetan-3-yl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 230a and Isomer 2 – Example 230b)
  • Isomer 1 ES-MS m/z 678 (M+H).
  • Isomer 2 ES-MS m/z 678 (M+H).
  • the products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 35%; End B: 35%; Flowrate (mL/min): 5; Run length: 5 min).
  • Isomer 1 99%ee, enriched in peak 1, retention time 0.95 min.
  • Isomer 2 98%ee, enriched in peak 2, retention time 1.31 min.
  • Examples 231a and 231b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3-difluorocyclobutyl)-3-methoxypiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 231a and Isomer 2 – Example 231b)
  • Isomer 1 ES-MS m/z 695 (M+H).
  • Isomer 2 ES-MS m/z 695 (M+H).
  • the products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 1.13 min.
  • Isomer 2 97%ee, enriched in peak 2, retention time 1.57 min.
  • Examples 232a and 232b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Example 232a – cis-isomer) and 4-(4-((5- Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1-((trans)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Example
  • Example 233a and 233b 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-ethyl-1-(oxetan-3-yl)piperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 233a and Isomer 2 – Example 233b)
  • Racemic 4-(4-((3,5-diflu ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-ethyl-1-(oxetan-3-yl)piperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OJ-H (21 mm ⁇ 150 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 80; BPR set point: 100 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 214, 225 nM) to give the separated enantiomers
  • Isomer 1 ES-MS m/z 660 (M+H).
  • Isomer 2 ES-MS m/z 660 (M+H).
  • the products were analyzed by SFC (Column: Chiralcel OJ-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 10%; End B: 10%; Flowrate (mL/min): 5; Run length: 5 min).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 1.68 min.
  • Isomer 2 >99%ee, enriched in peak 2, retention time 2.32 min.
  • Example 234a and 234b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6- (3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 234a and Isomer 2 – Example 234b)
  • Isomer 1 ES-MS m/z 699 (M+H).
  • Isomer 2 ES-MS m/z 699 (M+H).
  • the products were analyzed by SFC (Column: Lux Cellulose-4 (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 2.32 min.
  • Isomer 2 >99%ee, enriched in peak 2, retention time 3.32 min.
  • Example 235a and 235b 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6- (3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 235a and Isomer 2 – Example 235b)
  • Isomer 1 ES-MS m/z 700 (M+H).
  • Isomer 2 ES-MS m/z 700 (M+H).
  • the products were analyzed by SFC (Column: Lux Cellulose-4 (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% IPAm); Begin B: 20%; End B: 20%; Flowrate (mL/min): 5; Run length: 5 min).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 2.27 min.
  • Isomer 2 >99%ee, enriched in peak 2, retention time 2.89 min.
  • Example 236a and 236b 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-5-fluoro-3,3-dimethyl-1-(oxetan-3- yl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 236a and Isomer 2 – Example 236b)
  • Isomer 1 ES-MS m/z 678 (M+H).
  • Isomer 2 ES-MS m/z 678 (M+H).
  • the products were analyzed by SFC (Column: (S,S)-Whelk-0-1.8 (4.6 mm ⁇ 50 mm, 1.8 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.05% DEA); Begin B: 45%; End B: 4545%; Flowrate (mL/min): 2.2; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.21 min.
  • Example 237a and 237b 1-((Trans)-1-(3,3-difluoro-1-methylcyclobutyl)-3- methylpiperidin-4-yl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 237a and Isomer 2 – Example 237b)
  • Isomer 1 ES-MS m/z 677 (M+H).
  • Isomer 2 ES-MS m/z 677 (M+H).
  • the products were analyzed by SFC (Column: Chiralpak AS-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH (0.2% NH 3 (7M in MeOH)); Begin B: Gradient: from 5% to 40% of B in 1.5 min and hold 40% for 1 min, then 5% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C).
  • Example 238a and 238b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)-3,3-difluoropiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 238a and Isomer 2 – Example 238b)
  • Isomer 1 ES-MS m/z 701 (M+H).
  • Isomer 2 ES-MS m/z 701 (M+H).
  • the products were analyzed by SFC (Column: Lux i-Amylose-3 (4.6 mm ⁇ 100 mm, 3 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% IPAm); Begin B: 40%; End B: 40%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 0.94 min.
  • Isomer 2 >99%ee, enriched in peak 2, retention time 1.44 min.
  • Example 239a and 239b 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methyl-1-(oxetan-3-yl)piperidin- 4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 239a and Isomer 2 – Example 239b)
  • Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Daicel Chiralpak IBN (30 mm ⁇ 250 mm, 10 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column.
  • Example 240a and 240b 1-((Cis)-1-(3,3-difluorocyclobutyl)-3- methoxypiperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 240a and Isomer 2 – Example 240b)
  • Racemic 1-((cis)-1-(3,3- )-3-methoxypiperidin-4-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OD-H (21 mm ⁇ 150 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.5% DMEA); Begin B: 25%; End B: 25%; Flowrate (mL/min): 80; BPR set point: 110 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 310 nM) to give the separated enantiomers named Isome
  • Isomer 1 ES-MS m/z 696 (M+H).
  • Isomer 2 ES-MS m/z 696 (M+H).
  • the products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm ⁇ 100 mm, 5 ⁇ m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm ); Begin B: 25%; End B: 25%; Flowrate (mL/min): 4; Run length: 5 min).
  • Isomer 1 96%ee, enriched in peak 1, retention time 0.76 min.
  • Isomer 2 99%ee, enriched in peak 2, retention time 1.03 min.
  • Example 241a and 241b 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3,3-dimethyl-1-(oxetan-3-yl)piperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 241a and Isomer 2 – Example 241b)
  • Isomer 1 ES-MS m/z 660 (M+H).
  • Isomer 2 ES-MS m/z 660 (M+H).
  • the products were analyzed by SFC (Column: Chiralpakl IG-3 (4.6 mm ⁇ 50 mm, 3 ⁇ m); Condition: mobile phase A: CO 2 , mobile phase B: EtOH (0.05% DEA); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min).
  • Isomer 1 >99%ee, enriched in peak 1, retention time 0.54 min.
  • Isomer 2 >99%ee, enriched in peak 2, retention time 0.72 min.
  • Example 242 4-(1-((5-Cyanopyridin-2-yl)methyl)-1H-indazol-5-yl)-6- isobutyl-1-((3R,4R)-3-methyl-1-(3-methyloxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
  • Example 242 was prepar following steps.
  • Step 1 The method of Intermediate 6 was used with 1H-indazole-5-carbaldehyde and 6- (bromomethyl)nicotinonitrile.
  • Step 2 General Procedure A was used with 6-((5-formyl-1H-indazol-1- yl)methyl)nicotinonitrile, 5-methyl-3-oxohexanamide, and 1H-pyrazol-5-amine;
  • Step 3 Described as follows: To a 40 mL vial equipped with a magnetic stir bar was added 4-(1-((5-cyanopyridin-2-yl)methyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide (172 mg, 344 ⁇ mol) , (3R,4S)-3-methyl-1-(3-methyloxetan-3-yl)piperidin-4- ol (136 mg, 697
  • the resulting mixture was degassed with N 2 for 5 min and stirred at 100 °C for 1 h.
  • the reaction was cooled to RT.
  • the reaction mixture was concentrated under reduced pressure to give the residue.
  • the residue was purified by silica gel column chromatography using a gradient of 0 to 10% MeOH in DCM.
  • the product was further purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm x 200 mm, 7 ⁇ m) column eluting with a gradient from 20-60% ACN in water (10 mM NH4CO3) over 20 min.
  • the fractions were concentrated, and the residual aqueous mixture was lyophilized to give the title compound (4 mg).
  • AMY3R and CTR Functional Activity Assays and Data Functional activity was determined using cAMP formation in human AMY3R- expressing or CTR-expressing UMUC3 clonal cell lines. Each receptor cell line was treated with a compound to be tested or a reference peptide (rAMY peptide for AMY3R assays or hCT peptide for CTR assays) using 10-point concentration response curves with 3-fold direct dilutions or 20-point concentration response curves with 2-fold direct dilutions prepared with a Labcyte Echo Acoustic Liquid Handler in DMEM (Gibco Cat# 31053) supplemented with 1X GlutaMAX TM (Gibco Cat# 35050061), 0.1% bovine casein (Sigma Cat# C4765-10ML), 1 mM IBMX (Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630080) in a 20 ⁇ l assay volume.
  • DMEM Gibco
  • the intracellular cAMP was quantitatively determined using the cAMP Gs dynamic Kit (Revvity/Cisbio, Cat# 62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu 3+ -Cryptate, also in cell lysis buffer. The resulting competitive assay was incubated for at least 90 min at RT and then detected using a Pherastar Instrument (BMG Labtech) with excitation at 320 nm and emission at 665 nm and 620 nm.
  • BMG Labtech Pherastar Instrument
  • Raw data values were inversely proportional to the amount of cAMP present and were converted to cAMP (nM) per well using a cAMP standard curve.
  • the amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with rat Amylin ⁇ rAMY ⁇ for AMY3R assays or human Calcitonin ⁇ hCT ⁇ for CTR assays.
  • a relative EC50 (Rel EC50) and Emax value were derived by non-linear regression analysis using the percent maximal response vs. the concentration of the compound added, fitted to a four-parameter logistic equation.

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Abstract

Disclosed herein is a 4-phenyl-lH-pyrazolo[3,4-b]pyridine-5- carboxamide derivative of formula (I) as amylin and/or calcitonin receptor agonists for the treatment of type 2 diabetes, obesity or overweight.

Description

SUBSTITUTED 1H-PYRAZOLO[3,4-B]PYRIDINE COMPOUNDS AS AMYLIN RECEPTOR AGONISTS AND THEIR USE AS THERAPIES TECHNICAL FIELD [0001] Disclosed herein are non-peptide compounds which are amylin and/or calcitonin receptor agonists. These compounds may be useful as therapeutic agents, either as a monotherapy or in combination with another therapeutic agent, for preventing or treating a disease or condition through the modulation of the amylin and/or calcitonin receptors. Specifically, disclosed herein are compounds for treating diabetes, obesity, metabolic dysfunction associated steatohepatitis (MASH) and/or dyslipidemia. The compounds herein agonize the amylin and/or calcitonin receptor(s) and can therefore lower food intake, body weight, glucose, and/or triglycerides. BACKGROUND OF THE INVENTION [0002] Amylin is a peptide hormone that is co-secreted with insulin from the pancreatic β- cells and is deficient in people with diabetes. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. An amylin analog, pramlintide, is available to treat diabetic patients who use insulin because it lowers blood sugar levels. The elimination half- life of this medicine is less than an hour and it is used at mealtimes, so a patient needs multiple doses in one day to use this medicine in therapy. [0003] Calcitonin is a hormone that is produced in the thyroid gland that plays a role in regulating levels of calcium and phosphate in the blood. Salmon calcitonin is available to treat conditions with high levels of calcium in the blood, such as hypercalcemia. Salmon calcitonin has a short half-life of less than two hours, so a patient needs to dose once a day or multiple times a day to use this peptide in therapy. [0004] It has been shown that compounds which agonize the amylin and calcitonin receptors have positive effects such as lowering blood glucose levels and inducing weight loss (see, e.g., WO2016/034604, WO2015/071229 and WO2010/085700). These known amylin and calcitonin receptor agonists are peptides and the natural half-life of these agonists is short, so an extended time action is desirable. However, chemical modifications intended to extend activity time have also, thus far, shown a decrease in potency. In addition, agonists of the amylin and calcitonin receptors have stability challenges due to their tendency to fibrillate and the presence of a labile disulfide bond at neutral pH. [0005] There is a need for alternative compounds that agonize the amylin and/or calcitonin receptors especially small molecule amylin and/or calcitonin receptor agonists. SUMMARY OF THE INVENTION [0006] Disclosed herein is a compound of formula (I): , or a pharmaceutically acceptable R1, R2, R3, R4, R5, R6 and R10 are as defined herein. [0007] In one embodiment, the compound of formula (I) is an amylin and/or calcitonin receptor agonist(s). In one embodiment, the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the amylin and/or calcitonin receptor(s). DESCRIPTION OF THE INVENTION [0008] Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: , wherein: R1 is selected from: (1) a C1-10 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-10 alkyl, and R1b is selected from H, C1-10 alkyl, -C(O)C1-10 alkyl, -C(O)OC1-10 alkyl, and -SO2C1-10 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-10 alkyl, and R1d is selected from (i) H, (ii) a C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkoxy, (e) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-10 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, and (g) halogen, (2) a C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-10 alkyl, and (iii) C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and a C1-10 alkyl, and R1f is selected from (i) H and (ii) a C1-10 alkyl, and (b) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-10 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-10 alkyl, (c) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, (ii) halogen, and (iii) a C1-10 alkoxy, (d) -C(O)C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) -OH and (ii) halogen, (e) -C(O)OC1-10 alkyl, optionally substituted with 1 to 4 halogens, (f) -SO2C1-10 alkyl, optionally substituted with 1 to 4 halogens, (g) -SO2C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (h) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) a C1-10 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (j) -S-C1-10 alkyl, optionally substituted with 1 to 4 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (a) a C1-10 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-10 alkyl, and R3b is a C1-10 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-10 cycloalkyl; (5) a C3-10 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-6 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with a C1- 10 alkyl, (7) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with -OH; (8) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1- 10 alkoxy, and (9) a 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with a C1-10 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 7 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 7 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) -C(O)OC1-10 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-10 alkyl; and R4b is selected from (i) H, (ii) C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH, (iii) a C1-10 alkoxy, and (iv) -CN, and (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH or C1-10 alkoxy, and (iii) a C1-10 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R6 is a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substituted with 1 to 4 halogens, (3) -OH, and (4) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) halogen and (b) C1-10 alkyl; and R10 is selected from (1) H, (2) halogen, and (3) a C1-10 alkyl. [0009] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-6 alkyl, and R1d is selected from (i) H, (ii) a C1-6 alkyl, (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-6 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-6 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-6 alkyl, and R1f is selected from (i) H and (ii) a C1-6 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-6 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) a C1-6 alkoxy, (d) -C(O)C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH and (ii) halogen, (e) -C(O)OC1-6 alkyl, optionally substituted with 1 to 3 halogens, (f) -SO2C1-6 alkyl, optionally substituted with 1 to 3 halogens, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-6 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-6 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-6 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-6 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-6 alkyl, and R3b is a C1-6 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-6 alkoxy, and (6) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with a C1-6 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) -C(O)OC1-6 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-6 alkyl; and R4b is selected from (i) H and (ii) C1-6 alkyl (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, (iii) a C1-6 alkoxy, and (iv) -CN, (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or C1-6 alkoxy, (iii) a C1-6 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-6 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (6) a C1-6 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (5) a C1-6 alkyl, optionally substituted with -OH or -CN; R6 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl; and R10 is selected from (1) H and (2) halogen. [0010] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (ii) -NR1aR1b, wherein R1a is selected from H and C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, and -C(O)C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H, (ii) a C1-4 alkyl, (iii) -C(O)C1-4 alkyl, (iv) -C(O)OC1-4 alkyl, and (v) -SO2C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 4 to 10 membered heterocyclyl selected from pyrrolidinyl, piperidinyl, and 7- oxabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and (ii) a C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl, and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl and (ii) oxo, (i) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (6) a 5 to 6 membered heteroaryl selected from isoxazolyl and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, wherein the 5 or 6 membered ring formed by R4 and R2 or formed by R4 and R5 is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, (iii) a C1-4 alkoxy, and (iv) -CN, and (c) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, (iii) a C1-4 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl. [0011] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-10 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-10 alkyl, and R1b is selected from H, C1-10 alkyl, -C(O)C1-10 alkyl, -C(O)OC1-10 alkyl, and -SO2C1-10 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-10 alkyl, and R1d is selected from (i) H, (ii) a C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkoxy, (e) a 5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-10 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, (2) a C3-10 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-10 alkyl, and R1f is selected from H and a C1-10 alkyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-10 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-10 alkyl, (c) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, (ii) halogen, and (iii) a C1-10 alkoxy, (d) -C(O)C1-10 alkyl, (e) -C(O)OC1-10 alkyl, (f) -SO2C1-10 alkyl, and (g) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl, (ii) halogen, and (iii) oxo; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) a C1-10 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-10 alkyl, and R3b is a C1-10 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-10 cycloalkyl; (5) a C3-10 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-6 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with a C1- 10 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with - OH; (8) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1- 10 alkoxy, and (9) a 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with a C1-10 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) -C(O)OC1-10 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-10 alkyl; and R4b is selected from (i) H and (ii) C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH, (iii) a C1-10 alkoxy, and (iv) -CN, and (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH or C1-10 alkoxy, (iii) a C1-10 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R6 is a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substituted with 1 to 3 halogens; and R10 is selected from (1) H, (2) halogen, and (3) a C1-10 alkyl. [0012] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-10 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-10 alkyl, and R1b is selected from H, C1-10 alkyl, -C(O)C1-10 alkyl, -C(O)OC1-10 alkyl, and -SO2C1-10 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-10 alkyl, and R1d is selected from (i) H, (ii) a C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkoxy, (e) a 5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-10 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, (2) a C3-10 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-10 alkyl, and R1f is selected from H and a C1-10 alkyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-10 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-10 alkyl, (c) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, (ii) halogen, and (iii) a C1-10 alkoxy, (d) -C(O)C1-10 alkyl, (e) -C(O)OC1-10 alkyl, (f) -SO2C1-10 alkyl, and (g) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) a C1-10 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-10 alkyl, and R3b is a C1-10 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-10 cycloalkyl; (5) a C3-10 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-6 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with a C1- 10 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with - OH; (8) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1- 10 alkoxy, and (9) a 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with a C1-10 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) -C(O)OC1-10 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-10 alkyl; and R4b is selected from (i) H and (ii) C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH, (iii) a C1-10 alkoxy, and (iv) -CN, and (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH or C1-10 alkoxy, (iii) a C1-10 alkoxy, and (iv) -CN, (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R6 is a C1-10 alkyl, optionally substituted with a C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substituted with 1 to 3 halogens; and R10 is selected from (1) H, (2) halogen, and (3) a C1-10 alkyl. [0013] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from (i) H and (ii) a C1-6 alkyl, and R1b is selected from (i) H, (ii) C1-6 alkyl, (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-6 alkyl, and R1d is selected from (i) H, (ii) a C1-6 alkyl, (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (d) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-6 alkoxy, (e) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-6 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, (2) a C3-6 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-6 alkyl, and R1f is selected from H and a C1-6 alkyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-6 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) a C1-6 alkoxy, (d) -C(O)C1-6 alkyl, (e) -C(O)OC1-6 alkyl, (f) -SO2C1-6 alkyl, and (g) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) oxo; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-6 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-6 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-6 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-6 alkyl, and R3b is a C1-6 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (5) a C3-6 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-6 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with C1-6 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with - OH; (8) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-6 alkoxy, and (9) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with a C1-6 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-6 alkyl; and R4b is selected from (i) H and (ii) C1-6 alkyl (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (c) an aryl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, (iii) a C1-6 alkoxy, and (iv) -CN, (d) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or C1-6 alkoxy, (iii) a C1-6 alkoxy, and (iv) -CN, (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (5) a C1-6 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (5) a C1-6 alkyl, optionally substituted with -OH or -CN; R6 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens; and R10 is selected from (1) H and (2) halogen. [0014] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (ii) -NR1aR1b, wherein R1a is selected from H and C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, and -C(O)C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H, (ii) a C1-4 alkyl, (iii) -C(O)C1-4 alkyl, (iv) -C(O)OC1-4 alkyl, and (v) -SO2C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkoxy, (e) a 5 to 10 membered heterocyclyl selected from pyrrolidinyl, piperidinyl, and 7- oxabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, (2) a C3-6 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-4 alkyl, and R1f is selected from H and a C1-4 alkyl, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, and (g) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl and (ii) oxo; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (5) a C3-6 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-4 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl selected from pyrazolyl, optionally substituted with a C1-4 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with -OH; (8) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (9) a 5 to 6 membered heteroaryl selected from isoxazolyl and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, wherein the 5 or 6 membered ring formed by R4 and R2 or formed by R4 and R5 is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, and (iii) a C1-4 alkoxy, and (c) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, and (iii) a C1-4 alkoxy,, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens; and R10 is selected from (1) H and (2) halogen. [0015] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ia): ; wherein: R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) -OH, (2) a phenyl, and (3) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (2) and heteroaryl or heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or a C1-6 alkoxy, (iii) a C1-6 alkoxy, and (iv) -CN; R8 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a phenyl, and (c) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (b) and heteroaryl or heterocyclyl of (c) is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy; and R9 is selected from (1) H and (2) oxo. [0016] In one embodiment of the compound of formula (Ia), or a pharmaceutically acceptable salt thereof: R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) -OH, (2) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents independently selected from: (a) a C1-4 alkyl, optionally substituted with -OH, and (b) a C1-4 alkoxy. [0017] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ib): ; wherein: W is selected from O and S; R2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-6 alkyl, optionally substituted with -OH; R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens; and R8 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with -OH. [0018] In one embodiment of the compound of formula (Ib), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, and (d) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and (ii) a C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (f) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo, (g) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (h) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R2 is selected from (1) H and (2) halogen; R3 is selected from (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 2 halogens; R6 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl; R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens; and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH. In one embodiment of the compound of formula (Ib), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, and (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl; and (2) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, and (e) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo; R2 is selected from (1) H and (2) halogen; R3 is selected from (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 2 halogens; R6 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens; R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens; and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH. In one embodiment of the compound of formula (Ib), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, and (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl; and (2) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, and (iii) C1-4 alkoxy, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, and (e) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl and (ii) oxo; R2 is selected from: (1) H and (2) halogen; R3 is selected from: (1) H, and (2) a C1-6 alkyl, optionally substituted with 1 to 2 halogens, R6 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens; R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens; and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH. [0019] In one embodiment of the compound of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-4 alkyl, optionally substituted with a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, -C(O)OC1-4 alkyl, and -SO2C1-6 alkyl; and (2) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, and morpholinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, and (b) a C1-4 alkyl, optionally substituted with 1 to 3 halogens; R2 is H; R3 is H; R6 is a C1-4 alkyl; and R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 halogens R8 is selected from: (1) H and (2) methyl. [0020] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ic): ; wherein: R7 is a C1-6 alkyl, optionally a selected from phenyl, pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy. [0021] In one embodiment of the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Id): ); wherein: R7 is a C1-6 alkyl, optionally substituted with a substituent selected from phenyl, pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy. [0022] In one embodiment of the compound of formula (Id), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0023] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ie): , wherein: R2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-6 alkyl, optionally substituted with -OH; and R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens; R8 is selected from (1) H, (2) halogen, and (3) a C1-6 alkyl, optionally substituted with -OH; and R10 is selected from (1) H and (2) halogen. [0024] In one embodiment of the compound of formula (Ie), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0025] In one embodiment of the compound of formula (Ie), or a pharmaceutically acceptable salt thereof, wherein R10 is H. [0026] In one embodiment of the compound of formula (Ie), or a pharmaceutically acceptable salt thereof, wherein R10 is halogen. [0027] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (If): ; wherein: A1 is selected from: (1) O, (2) -NR8, wherein R8 is selected from (a) H and (b) a C1-6 alkyl; and R7 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (b) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens. [0028] In one embodiment of the compound of formula (If), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0029] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ig): ; wherein: A2 is selected from: (1) N, and (2) CH, optionally substituted with a substituent selected from: (a) halogen, and (b) a C1-6 alkyl; and R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 halogens. [0030] In one embodiment of the compound of formula (Ig), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0031] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ih): ; wherein: 7 R is a C1-6 alkyl, optionally a selected from phenyl, pyridyl, and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN; and R8 is a C1-6 alkyl substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0032] In one embodiment of the compound of formula (Ih), or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-4 alkyl, optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens. [0033] In one embodiment of the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkoxy, (e) a 5 to 10 membered heterocyclyl selected from pyrrolidinyl, piperidinyl, and 7- oxabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, (2) a C3-6 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-4 alkyl, and R1f is selected from H and a C1-4 alkyl, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, and (g) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo. [0034] In one embodiment of the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof: R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (5) a C3-6 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-4 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl selected from pyrazolyl and isoxazolyl, each of which is optionally substituted with a C1-4 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl selected from azetidinyl, piperidinyl, and pyrrolidinyl, each of which is optionally substituted with -OH; (8) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (9) a 5 to 6 membered heteroaryl selected from pyrazolyl, isoxazolyl, and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH. [0035] In one embodiment of the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof: R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens. [0036] In one embodiment of the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, -C(O)OC1-4 alkyl, and -SO2C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkoxy, (e) a 5 to 10 membered heterocyclyl selected from pyrrolidinyl, piperidinyl, and 7- oxabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, and (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, (2) a C3-6 cycloalkyl, optionally substituted with -NR1eR1f, wherein R1e is selected from H and a C1-4 alkyl, and R1f is selected from H and a C1-4 alkyl, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, and (g) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (5) a C3-6 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-4 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl selected from pyrazolyl, optionally substituted with a C1-4 alkyl, (7) -C(O)-R3e, wherein R3e is a 4 to 6 membered heterocyclyl selected from azetidinyl, optionally substituted with -OH; (8) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (9) a 5 to 6 membered heteroaryl selected from pyrazolyl, isoxazolyl, and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; and R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen and (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens. [0037] In one embodiment of the compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, -C(O)OC1-4 alkyl, and -SO2C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkoxy, (e) a 4 to 10 membered heterocyclyl selected from azepanyl, azetidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl selected from furyl, pyrazolyl, pyrazinyl, isoxazolyl, thienyl, oxazolyl, pyridyl, and pyrimidyl, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and a (ii) C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, piperidinyl, and pyrrolidinyl, each of which is optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (6) a 5 to 6 membered heteroaryl selected from furyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; and R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl. [0038] In one embodiment of the compound as described above, or a pharmaceutically acceptable salt thereof: R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN. [0039] In one embodiment of the compound as described above, or a pharmaceutically acceptable salt thereof: R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN. [0040] In one embodiment of the compound as described above, or a pharmaceutically acceptable salt thereof, R8, when present, is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH. In one embodiment, R8 is H. [0041] In one embodiment of the compound of formula as described above, or a pharmaceutically acceptable salt thereof, R2, when present, is selected from (1) H and (2) halogen. In one embodiment, R2 is H. [0042] In one embodiment of the compound as described above, or a pharmaceutically acceptable salt thereof, R10, when present, is selected from (1) H and (2) halogen. In one embodiment, R10 is H. [0043] In one embodiment, disclosed herein is a compound selected from Examples 1-242, or a pharmaceutically acceptable salt thereof. [0044] In one embodiment, disclosed herein is a compound selected from Examples 1-133, or a pharmaceutically acceptable salt thereof. [0045] In one embodiment, disclosed herein is a compound selected from Examples 8, 9, 10, 14, 57, 74, 75, 76, 77, 80, 102, 103, 104, and 105, or a pharmaceutically acceptable salt thereof. [0046] In one embodiment, the compound herein, or a pharmaceutically acceptable salt thereof, may be a solvate, or a non-solvate. The solvent contained in a solvate may be either water or an organic solvent. Alcohols (for example, MeOH, EtOH, n-propanol), dimethylformamide, ACN, acetone, dimethylsulfoxide may be used as the organic solvent. The proportion of the solvent molecule (for example a water molecule) against a single molecule compound herein or a pharmaceutically acceptable salt thereof, is, for example, 0.1 to 10, or more specifically, 0.5 to 6. Further, the proportion may fluctuate by humidity, the production method, and the production season. [0047] The solvate of a compound herein, or a pharmaceutically acceptable salt thereof, may be obtained by a common method, such as precipitating the compound herein, or a pharmaceutically acceptable salt thereof, from a solvent. Further, a hydrate may be obtained by precipitating a compound herein, or a pharmaceutically acceptable salt thereof, from a water-containing organic solvent. [0048] The solvate of a compound herein, or a pharmaceutically acceptable salt thereof, may be transformed to the compound herein, or a pharmaceutically acceptable salt thereof, by a common method such as heating in vacuo. [0049] A compound used as a pharmaceutical active agent is the compound per se (free form), a hydrate of the free form, a pharmaceutically acceptable salt of the free form, or a hydrate of the salt. [0050] The compound herein, or a pharmaceutically acceptable salt thereof, or a solvate of either the compound or the salt of the compound, may be used in the form of a crystalline material or in an amorphous state. [0051] A compound herein, or a pharmaceutically acceptable salt thereof, includes all stereoisomers of the compound, for example, an enantiomer, a diastereomer (including cis- and trans- geometric isomer), the racemic form of the isomers, and other mixtures. For example, the compound herein, or a pharmaceutically acceptable salt thereof, may have one or more asymmetric centers. [0052] The compound herein, or a pharmaceutically acceptable salt thereof, includes an embodiment in which an atom constituting the compound molecule is an isotope, and includes an embodiment in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons). Examples of the isotopes include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl. The heavier hydrogen isotopic form of 2H is also known as a deuterium or “D”. In a deuterated compound, one or more hydrogens are replaced with deuterium isotope(s). [0053] In one embodiment, radioisotopes which emit radiation as they decay, such as 3H or 14C, are useful in pharmaceutical preparations or in vivo topographic tests of compounds. The stable isotope neither decays nor changes in their amount, nor have radioactivity, so they can be used safely. When the atom constituting the compound herein, or a pharmaceutically acceptable salt thereof, is an isotope, it may be transformed according to the common method by replacing the reagent used in synthesis with a reagent containing the corresponding isotope. [0054] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are amylin receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 5,000 nM in AMY3R functional activity assays (10-point format or 20-point-format). In one embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 500 nM in AMY3R functional activity assays. In one preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 100 nM in AMY3R functional activity assays. In one even more preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 50 nM in AMY3R functional activity assays. [0055] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are calcitonin receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 5,000 nM in CTR functional activity assays (10-point format or 20-point-format). In one embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 500 nM in CTR functional activity assays. In one preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 100 nM in CTR functional activity assays. In one even more preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 50 nM in CTR functional activity assays. [0056] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are both amylin receptor agonists and calcitonin receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 5,000 nM in AMY3R functional activity assays (10-point format or 20-point-format) and less than about 5,000 nM in CTR functional activity assays (10-point format or 20-point-format). In one embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 500 nM in AMY3R functional activity assays and less than about 500 nM in CTR functional activity assays. In one preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 100 nM in AMY3R functional activity assays and less than about 100 nM in CTR functional activity assays. In one even more preferred embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 50 nM in AMY3R functional activity assays and less than about 50 nM in CTR functional activity assays. [0057] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in therapy. [0058] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity. [0059] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes. [0060] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity. [0061] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in the treatment of overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease. [0062] In one embodiment, disclosed herein is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease. [0063] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. [0064] Reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.” [0065] The term “about” means within a meaningful range of a value or values such as, a stated amount, activity, concentration, length, molecular weight, pH, time frame, temperature or volume, for example, to account for a statistical or instrument measuring sensitivity range. Such a value or range can be within an order of magnitude typically within 20%, or more specifically within 10%, or even more specifically within 5%, of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. [0066] The term “an effective amount” means an amount, concentration or dose of a compound described herein, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment. An effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. An effective amount can be determined by one of ordinary skill in the art through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered including, but are not limited to, the size, age and general health of a subject; the specific disease or disorder involved; the degree of or involvement of or the severity of the disease or disorder; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. [0067] The term “treat,” “treating,” or “to treat” means attenuating, restraining, slowing, stopping or reversing the progression or severity of an existing condition, disease, disorder or symptom. Treating includes administering a compound herein or a composition comprising a compound herein to the subject to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom. Treating includes administering a compound or a composition comprising a compound herein to the individual to result in, for example, a reduced HbA1c level or a weight loss to the subject. [0068] The term “a pharmaceutically acceptable salt” refers to a derivative of the compound herein, where a compound herein is modified by making an acid or a base salt thereof. Pharmaceutically acceptable salts, and processes for preparing the same, are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012). By way of examples, pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of a compound herein formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. Pharmaceutically acceptable salts are those forms of a compound herein, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salt forms of a compound herein can be synthesized to contain a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, EtOH, isopropanol, or ACN are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH 2nd ed. 2011)). [0069] The term “a pharmaceutical composition” means a composition having an effective amount of a compound herein in combination with at least one pharmaceutically acceptable excipient, such as a binder, a carrier, a diluent, a lubricant, a pharmaceutical flow agent, and/or other pharmaceutically acceptable excipients. [0070] The term “halogen” means a fluorine, a chlorine, a bromine, or an iodine. In one embodiment, a halogen is selected from fluorine and chlorine. In one embodiment, a halogen is a fluorine. [0071] The term "alkoxy" refers to the following chemical group: , wherein R is an alkyl group as defined herein and the point of attachment is For example, C1-10 alkoxy has 1 to 10 carbons with the following structure: . Similarly, C1-6 alkoxy has 1 to 6 carbons with the following . [0072] The term “C1-10 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 10 carbons. Similarly, “C1-6 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 6 carbons. Examples of a C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1- methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl. [0073] The term "alkylene" refers to an alkanediyl group, i.e., a divalent sat. acyclic hydrocarbon group which may be linear or branched. For example, a "C1-6 alkylene" means an alkylene group having 1 to 6 carbon atoms. Exemplary C1-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(- CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). [0074] The term "cycloalkyl" refers to a monovalent saturated or partially unsaturated (not aromatic) carbocyclic group of from 3 carbons to 10 carbons having a single cyclic ring or multiple condensed or spirocyclic rings. Examples of cycloalkyl include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; bicyclic groups such as bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octyl, bicyclo[4.4.0]octanyl, and bicyclo[4.4.1]octanyl. Cycloalkyl also includes carbocyclic groups to which is fused an aryl ring, for example, indane and tetrahydronaphthalene. [0075] The term “aryl” refers to an aromatic carbocyclic group and may contain a non- aromatic portion in addition to the aromatic portion. The ring may be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic aryl ring. Examples include, but are not limited to, phenyl, naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H- isoquinolin-3-onyl, and 1,3-dihydrobenzimidazol-2-onyl. In one embodiment, an aryl is a phenyl. In one embodiment, an aryl is a naphthyl. [0076] The term “heteroaryl” refers to a monovalent aromatic ring containing 1 to 5 heteroatoms in the ring-forming atoms independently selected from N, O and S, and may be partially saturated. The saturated carbon atom(s) may be oxidized to form a carbonyl. The ring may be a single ring or two fused rings (e.g., a bicyclic heteroaryl obtained by a fusion with a benzene ring or monocyclic heteroaryl ring). In one embodiment, a 5 to 10 membered heteroaryl contains 1 to 4 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms. Examples of a “5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S” include, but are not limited to, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzoxadiazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, a quinazolinyl group, a quinoxalinyl group, a benzodioxolyl group, an indolizinyl group, and an imidazopyridyl group. In one embodiment, a “5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S” is selected from furyl, isoxazolyl, pyridyl, pyrimidyl, oxazolyl, pyridazinyl, pyrazinyl, pyrazolyl, and thienyl. [0077] The term "heterocyclyl" refers to a monovalent ring group, including monocyclic rings as well as bridged rings, spiro rings, and/or fused rings (which may be composed, e.g., of two or three rings), wherein said ring group contains one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated or partially unsaturated (i.e., unsaturated but not aromatic on the ring containing one or more heteroatoms). The term “5 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 4 heteroatoms independently selected from N, O, and S. The ring may be a monocyclic ring, a bicyclic ring or a spiro ring. Examples include, but are not limited to, azepanyl, oxetanyl, thietanyl, azetidinyl, chromanyl, dihydrobenzofuranyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 8-azabicyclo[3.2.1]octanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 2γ2-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, 1,3- diazaspiro[4.4]nonanyl, 2-oxa-5,7-diazaspiro[3.4]octanyl, 8-oxa-1,3-diazaspiro[4.5]decanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, and tetrahydroindolinyl. [0078] The compound herein, or a pharmaceutically acceptable salt thereof, has an amylin and/or calcitonin receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the amylin and/or calcitonin receptor(s). In one embodiment, the disease or condition is selected from Type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, overweight, hypertension, dyslipidemia, metabolic syndrome, hyperinsulinemia, nighttime hypoglycemia, hyperlipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, brain infarction, non-alcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated steatohepatitis (MASH). In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to a subject in the form of a pharmaceutical composition in an effective amount by an appropriate administration method. [0079] As used herein, treatment of a subject with obesity or overweight is also known as chronic weight management. [0080] “Diabetes” herein is a state or a disease in which the metabolism for generating and using glucose becomes deficient due to a failure in maintaining an appropriate blood glucose level in the body, and encompasses insulin-dependent diabetes mellitus (Type 1 diabetes) and non-insulin-dependent diabetes mellitus (Type 2 diabetes). [0081] “Hyperglycemia” refers to a state in which the plasma glucose level while fasting or after administration of glucose is higher than the normal value (e.g.80 to 110 mg/dL in human while fasting), and it is a typical symptom of diabetes. [0082] “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion. [0083] “Diabetic complication” is a complication caused by diabetes or hyperglycemia, and may be acute complex or chronic complex. The term “acute complex” includes, for example, ketoacidosis, and infectious disease (e.g. skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and the “chronic complex” includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene. Major diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. [0084] “Coronary heart disease” includes myocardial infarction and angina pectoris. [0085] “Dementia” includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia. [0086] The administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream. [0087] In one embodiment, a method for treating a disease or condition regulated by an amylin and/or calcitonin receptor(s) comprises administering an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. [0088] In one embodiment, the effective amount to be administered may be appropriately determined according to the severity of the symptom, the age, the body weight, the relative health state, whether other drugs are combined, and the method of administration. A person of ordinary skill may determine an effective dose taking into account of these factors and the particular properties of a specific compound disclosed herein. [0089] In one embodiment, the compound herein is co-administered with a second active agent. In one embodiment, additional active agent is selected from, the second active agent is selected from the group consisting of a glucagon receptor agonist, a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof. [0090] The administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream. [0091] In one embodiment, a pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. [0092] In one embodiment, a pharmaceutical composition comprising a compound herein, or a pharmaceutically acceptable salt thereof, is formulated into a certain pharmaceutical formulation (dosage form). Examples of such pharmaceutical formulations include a tablet, a capsule, granules, powders, subtle granules, pills, aqueous or non-aqueous solution or suspension. Further, the compound herein, or a pharmaceutically acceptable salt thereof, may also be used in the form of various controlled release preparations. Examples of such controlled release preparations include, for example, those to be imbedded in the body, those applied to the oral mucosa or nasal mucosa. The solution or suspension may be filled in containers suited for dividing into respective administration amounts to be stored. [0093] The various pharmaceutical formulations may be produced by a well-known method by mixing a compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Examples of such additives include, but are not limited to, an excipient, a lubricant, a binding agent, a disintegrator, a stabilizer, a dispersant, a diluent, a surfactant, or an emulsifier. [0094] Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate. [0095] Examples of a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin. [0096] Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient. [0097] Examples of a disintegrator include chemically modified starch and cellulose, such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and compounds that are the same as the above excipient. [0098] Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid. [0099] Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth, methyl cellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester. [0100] Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc. [0101] Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol. [0102] The content of the compound herein, or a pharmaceutically acceptable salt thereof, in the pharmaceutical formulation can vary by the dosage form, and is generally from 0.01 to 90 wt%. EXAMPLES [0103] The following examples are provided for illustration purposes only. Unless otherwise defined, the abbreviations used in the preparations and examples are as defined below. ACN acetonitrile Aq. or aq. aqueous Boc or BOC tert-butoxycarbonyl CMBP cyanomethylenetributylphosphorane CV column volume D deuterium DABCO 1,4-diazabicyclo[2.2.2]octane DBAD bis(1,1-dimethylethyl)azodicarboxylate DCC N,N′-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DIPE diisopropylether DIPEA N, N-diisopropylethylamine (Hünig's base) DMAP dimethylaminopyridine DMEA dimethylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EDC N'-(ethylcarbonimidoyl)-N, N-dimethyl-1,3-propanediamine, monohydrochloride EDTA ethylenediaminetetraacetic acid ES-MS electrospray mass spectrometry Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Fmoc fluorenylmethoxycarbonyl g gram(s) h hour(s) H2O water HATU hexafluorophosphate azabenzotriazole tetramethyl uranium HCl hydrochloric acid HPLC high performance liquid chromatography IPA isopropanol LCMS liquid chromatography mass spectrometry MCR multi-component reaction Me methyl MeOH methanol Me-THF 2-methyltetrahydrofuran min minute(s) MgSO4 magnesium sulfate MTBE methyl tert-butyl ether m/z mass-to-charge ratio N2 nitrogen gas Na2SO4 sodium sulfate NMP N-methyl-2-pyrrolidone PEG polyethylene glycol RBF round bottom flask RP-HPLC reverse-phase high performance liquid chromatography RP-LCMS reverse-phase liquid chromatography mass spectrometry RT or rt room temperature Sat. or sat. saturated SCX strong cation exchange SFC supercritical fluid chromatography SOCl2 thionyl chloride TATU O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TCFH Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMAD N,N,N',N'-tetramethylazodicarboxamide TMEDA tetramethylethylenediamine Tris tris(hydroxymethyl)aminomethane V or v volume Wt or wt weight [0104] In the following schemes, R1, R1a, R1b, R2, R3, R3a, R3b, R4, R5, R6, R7, R8, R9, and W are as defined in Formula I. Scheme 1 [0105] Scheme 1 preparation of compounds disclosed herein. Compound 1a is first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K2CO3 or Cs2CO3) at RT or at an elevated temperature to give 2a. Alternatively, 1a can be alkylated by a reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give 2a. Compound 2a can then be converted to 2b utilizing syngas (1:1 CO/H2), palladium(II) acetate, butyldi-1-adamantylphosphine, and N,N,N',N'-tetramethylethylenediamine at an elevated temperature and pressure. Alternatively, the reaction order can be reversed beginning with a conversion of bromide 1a to aldehyde 1b as described above with a subsequent alkylation of 1b to give 2b. Scheme 2 [0106] Scheme 4a and aldehyde 5a can be condensed with ketonitrile 6a in a solvent such as 1,4-dioxane, THF or an alcohol such as EtOH or isopropanol to give the dihydropyrazolopyridine-5-carbonitrile intermediate 7a. Intermediate 7a can be isolated and oxidized using an oxidant such as MnO2, CAN, or DDQ in a solvent such as DCM, MeOH, acetic acid, ACN, or acetone to give pyrazolopyridine-5-carbonitrile 9a. Alternatively, intermediate 7a can be oxidized in situ after the condensation is complete to give 9a. In another variation, aminopyrazole 4a and aldehyde 5a can be condensed with ketoamide 6b in a solvent such as 1,4-dioxane, THF or an alcohol such as EtOH or isopropanol to give the dihydropyrazolopyridine-5-carboxamide intermediate 8a. The condensation reactions can optionally be conducted in the presence of an additive such as ammonium acetate. The dihydropyrazolopyridine-5-carboxamide intermediate 8a can be oxidized in situ or after isolation as described above to give compounds of Formula I. [0107] Alternatively, pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated using H2O2 in DMSO in the presence of an inorganic base such as K2CO3 or NaOH to give compounds of Formula I. [0108] Alternatively, pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated in the presence of acetaldoxime with an appropriate catalyst such as CuO or Wilkinson’s to give compounds of Formula I. [0109] In another variation, pyrazolopyridine-5-carbonitrile intermediate 9a can be hydrated using Ghaffar-Parkins Catalyst and water in an alcohol solvent such as EtOH at an elevated temperatures to give compounds of Formula I. Scheme 3 [0110] 10a is first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K2CO3 or Cs2CO3) at RT or at an elevated temperature to give 9a. [0111] Alternatively, 10a can be alkylated by reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give 9a. [0112] In another Mitsunobu variation, 10a can be alkylated by reaction with an alcohol 3b in the presence of CMBP (Tsunoda reagent) in an appropriate solvent such as 1,4-dioxane at RT or an elevated temperature optionally with microwave heating to give 9a. Compound 9a can be converted to compounds of Formula I as described in Scheme 2. [0113] Alternatively, compound 11a can be alkylated with 3a or 3b under conditions as described above to give compounds of Formula I. Scheme 4 [0114] of compounds disclosed herein. Compound 12a is first reacted with alkylating agent 13a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K2CO3 or Cs2CO3) at RT or at an elevated temperature to give 14a. [0115] Alternatively, 12a can be alkylated by a reaction with an aldehyde 13b via a reductive amination reaction in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride and an organic acid such as acetic acid in a solvent such as MeOH or EtOH to give 14a. Compound 14a can be hydrated to compound 16a using the method described in Scheme 2. [0116] Alternatively, compound 15a can be alkylated to give 16a directly using the same methods described for 12a. Scheme 5 described in the schemes above. In the first route, 17a is coupled with an amine 18a in a Buchwald type reaction to give 9a. 17a is reacted with 18a in a solvent such as 1,4-dioxane, in the presence of a catalyst such as tBuBrettPhos Pd G3 or Xantphos Pd G3 with the addition of a base such as cesium carbonate at RT or at an elevated temperature. [0118] Alternatively, 17a is coupled with a boronic acid in a Suzuki type reaction. 17a is reacted with 18b in a solvent such as 1,4-dioxane, in the presence of a catalyst such as PdCl2(dppf) with the addition of a base such as aq. sodium carbonate at RT or at an elevated temperature. Compound 9a can be converted to compounds of Formula I as described in Scheme 2. Scheme 6
[ (where X indicates a halogen such as Br or I) is first reacted in a carbonylation type reaction to give compound 20a. Compound 19a is reacted under a carbon monoxide atmosphere in the presence of a catalyst such as palladium(II) acetate, a ligand such as 1,1'- ferrocendiylbis(diphenylphosphine), and a base such as triethyl amine in a solvent such as MeOH or a mixture of MeOH and ACN at RT or at an elevated temperature. Compound 20a is then hydrated using techniques described above to give compound 21a. Ester 21a is then hydrolyzed to the carboxylic acid by utilizing a base such as aq. LiOH or NaOH in a solvent such as MeOH or EtOH or mixtures of solvents such as THF and MeOH at RT or at an elevated temperature to give 22a. Compound 22a is then converted to 23a through an amide coupling in an appropriate solvent such as DMF in the presence of a base such as triethyl amine or Hunig’s base and in the presence of an appropriate coupling reagent such as HATU or TATU at RT or at an elevated temperature. Scheme 7 compound 24a (where X indicates a halogen such as Br or I) is converted to aldehyde 25a. Compound 25a is contacted with 2-isocyano-2-methylpropane in the presence of a catalyst such as PtBu3 Pd G4, a ligand combination such as tri-tert-butylphosphonium tetrafluoroborate and a base combination such as DABCO with potassium formate in a solvent such as DMF. Compound 25a can be aminated by reaction with an aldehyde 18a via a reductive amination reaction in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride and an organic acid such as acetic acid in a solvent such as MeOH or EtOH to give compound 26a. Scheme 8 first reacted with alkylating agent 3a (where x is an appropriate leaving group such as Cl or Br), undergoing an alkylation in a solvent such as THF, DMF, DMSO, or NMP, in the presence of a base (e.g. NaH, K2CO3 or Cs2CO3) at RT or at an elevated temperature to give compound 28a. [0122] Alternatively, 27a can be alkylated by a reaction with an alcohol 3b via a Mitsunobu reaction in the presence of a phosphine such as triphenylphosphine and an azadicarboxylate such as DIAD, DBAD or DEAD to give an be alkylated by reaction with an alcohol 3b in the presence of CMBP (Tsunoda reagent) in an appropriate solvent such as 1,4-dioxane at RT or an elevated temperature optionally with microwave heating to give 28a. Compound 28a can be hydrated to compounds of Formula Ib by methods described in Scheme 2. Preparation of Intermediate 1: 5-(1-Hydroxy-3-methylbutylidene)-2,2-dimethyl-1,3-dioxane- 4,6-dione [0123] 2,2-Dimethyl-1,3-dioxane- 8.29 mol) and DCM (10 L) were charged into an RBF at RT. The cooled to 0 – 5 °C. 4- Dimethylaminopyridine (202.6 g, 1.65 mol) was added into the reaction mass at 0 – 5 °C. TEA (1340 mL, 9.50 mol) was slowly added into the reaction mixture at 0- 5 °C over 30-40 min. The reaction mixture was stirred for 15 – 20 min under N2 atmosphere at 0 – 5 °C. 3- Methylbutanoyl chloride (1000 g, 8.29 mol) was slowly added into the reaction mixture at 0 – 5 °C over 30 to 40 min. Upon addition, the reaction mixture was warmed to 20 – 25 °C and stirred for 2 – 3 h. The reaction mixture was quenched with 1M aq. HCl solution (1500 mL) at below 20 °C. The resulting mixture was stirred for 10 min. Layers were separated and aq. layer extracted with DCM (1500 mL). The combined organic layers were washed with water (2 × 3500 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure via rotary evaporator at 35 – 40 °C to afford the title compound (1790 g). TLC (EtOAc: petroleum ether = 3: 7) Rf = 0.30. Preparation of Intermediate 2: tert-Butyl (5-methyl-3-oxohexanoyl)carbamate [0124] 5-(1-Hydroxy-3- 1,3-dioxane-4,6-dione (1580 g, 6.92 mol), tert-butyl carbamate (811 g, 6.92 mol) and ACN (12.64 L) were charged into a flask at RT. The reaction mixture was warmed slowly to 80 – 85 °C and stirred for 4 – 6 h. Upon completion of the reaction, the reaction was cooled to below 40 °C and concentrated under reduced pressure at 40 – 45 °C to provide a residue that was purified by silica gel chromatography (8 – 10% EtOAc in petroleum ether) to afford the title compound (1300 g, TLC: EtOAc/ petroleum ether = 3: 7, Rf = 0.70),) as a solid. Preparation of Intermediate 3: 5-Methyl-3-oxohexanamide [0125] Tert-butyl (5-methyl-3- (2600 g, 10.68 mol) and DCM (18.2 L) were added to a flask. The reaction then cooled to below 10 °C. TFA (2880 mL, 37.4 mol) was added slowly to the reaction mixture over 30 to 40 min. The reaction mixture was stirred for 16 h at 20 – 25 °C. Upon completion of reaction, the mixture was concentrated under reduced pressure at 40 °C to provide a residue that was purified by silica gel chromatography eluting with 40% EtOAc in petroleum ether. The residue was slurred in petroleum ether (5 v) at RT for 20 min and then filtered to afford the title compound (952 g). EI-MS (m/z): 143 (M)+. Preparation of Intermediate 4: 5-Methyl-3-oxohexanenitrile [0126] To a solution of methyl 3- g, 1.72 mol) in THF (2 L, 0.85 M) was added acetonitrile (180 mL, 3.44 mol). The reaction was cooled to 0 °C. NaH (137.7 g, 3.44 mol) added into reaction mixture in 4 portions. The reaction was maintained at or below 5 °C. After the addition was complete, the reaction mixture was heated at 60 – 65 °C and stirred for 8 h. The reaction mixture was cooled to 10 °C. Water (20 v) was slowly added to the reaction mixture. The resultant mixture’s pH was adjusted to pH 7 by using 1M aq. HCl solution. The reaction mixture was then diluted with EtOAc (10 V). The layers were separated, and the aq. phase was further extracted with EtOAc (2 × 10 V). The combined organic extracts were washed with sat. aq. NaCl (5 V). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40 °C to give a crude product. The crude product was purified by column chromatography eluting with 10 – 12% ethyl acetate/petroleum ether. Combined all pure fractions and concentrated under reduced pressure at 40 °C to afford the title compound (220 g) as a liquid.1HNMR (DMSO-d6) δ 4.03 (s, 2H), 2.38 (d, 2H, j= 5.2 Hz), 2.03 (m, 1H), 0.864 (d, 6H, j= 13.2 Hz). Preparation of Intermediate 5: 1-(1-Methylpiperidin-4-yl)-1H-pyrazol-5-amine [0127] A mixture of 1-methylpiperidin- g, 310 mmol) and 2-cyanoethyl hydrazine (25.2 mL, 310 mmol) in EtOH (180 mL) for 3 h at 25 ºC. Then, the solvents were removed in vacuum to give a residue that was taken up in n-butanol (350 mL) and sodium 1- butanolate (173 mL, 20% Wt, in n-butanol, 310 mmol) was added, and the mixture stirred at 120 ºC for 16 h. On cooling to RT, the reaction was adjusted to pH = 8 with 1M HCl, then almost fully concentrated in vacuum to give a residue that was dissolved in water (350 mL). Then, 1M HCl was added dropwise till to pH = 2 and washed with DCM (2 × 700 mL). The water phase was adjusted to pH=14 with aq. K2CO3 and extracted with DCM (2 × 700 mL). The combined organic layers were concentrated in vacuum and the resulting residue was dissolved in THF (1000 mL). 4M HCl in EtOAc (2.0 eq) was added and the mixture stirred at 25 oC for 1 h. The resulting solid was filtered and then it was triturated from EtOAc/DCM/MeOH (10:10:1 mixture) (10 V) to give desired product as HCl salt (50 g). The free base was obtained after treatment with aq. K2CO3 (300 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were dried with Na2SO4 and the solvents concentrated in vacuum to give the title compound as a solid (30.5 g). ES-MS m/z 181 (M+H). Preparation of Intermediate 6: 1-(3,4-Difluorobenzyl)-1H-indazole-5-carbaldehyde [0128] To a solution of difluorobenzene (440 g, 2.13 mol) in DMF (2.64 L) was added 1H-indazole-5-carbaldehyde (311 g, 2.13 mol) and Cs2CO3 (1.04 kg, 3.19 mol). The reaction mixture was stirred at 30 ºC for 2 h under N2. After the reaction was complete by LCMS, the mixture was poured into water (11.0 L) with stirring. The precipitate was filtered, and the filter cake was washed with water (880 mL × 4). The solid was dried under vacuum, and then purified by silica gel chromatography (35%-60% DCM in petroleum ether) to give the title compound (260 g) as a solid. ES-MS m/z 273 (M+H). Preparation of Intermediate 7: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile General Procedure A: MCR with [0129] To a suspension of 1-(3,4- - indazole-6-carbaldehyde (1.00 g, 3.68 mmol) in 1,4-dioxane (7.0 mL) was added 5-methyl-3-oxohexanenitrile (354 mg, 2.83 mmol) followed by 1H-pyrazol-5-amine (305 mg, 3.68 mmol). The mixture was heated at 100 ºC for 3.5 h. The mixture was cooled to RT and the solvent was evaporated. The residue was dissolved in DCM (10 mL), and DDQ (642 mg, 2.83 mmol) was added. The mixture was stirred at RT for 15 min to give a crude product. The crude product was purified by column chromatography on silica gel eluting with a gradient from 0-100% EtOAc in hexane to give the title compound as a solid. The material was dissolved in EtOAc and washed 3 times with 1M NaOH. The organic solution was washed with sat. aq. NaCl, dried over Na2SO4, filtered, and evaporated to give the title compound (1.05 g, 84%) as a solid. ES-MS m/z 443 (M+H). Preparation of Intermediate 8: tert-Butyl (3-((5-cyano-4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate
[0130] 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (200 mg, 452 μmol) and triphenylphosphine (261 mg, 994 μmol) were dissolved in THF (3.01 mL) at RT. tert-Butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (106 mg, 497 μmol) was added. DIAD (193 μL, 994 μmol) was added dropwise. The reaction was stirred overnight. The solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient from 20-100% EtOAc in cyclohexane to give the title compound (96 mg). ES-MS m/z 635.8 (M-H). Preparation of Intermediate 9: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate [0131] In an RBF, to a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (5.0 g, 29.4 mmol) and N- g, 29.4 mmol) in THF (75 mL) was added dropwise isobutyl chloroformate (4.0 g, 29.4 mmol) at -10 ºC. After 2 h at that temperature, it was added sodium borohydride (3.3 g, 88.2 mmol) and MeOH (50 mL) slowly. The reaction mixture was allowed to reach RT. After 16 h, water was added to the reaction (200 mL) and organic solvents were removed under vacuum; the aq. phase was extracted with EtOAc (2 × 100 mL); organics were combined, dried over MgSO4, filtered, and evaporated to give the title compound as a solid (4.6 g). Rf = 0.1 (cyclohexanes/EtOAc 9:1, PMA stain).1H NMR (400MHz, CDCl3, ^ ppm): 4.55 (t, J = 5.5 Hz, 1H), 3.59 (s, 3H), 3.38 (d, J = 5.5 Hz, 2H), 1.85 (s, 6H). Preparation of Intermediate 10: Methyl 3-(((tert- butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate [0132] In an RBF under N2, to a bicyclo[1.1.1]pentane- 1-carboxylate (4.6 g, 29.4 mmol) and tert-Butyldimethylchlorosilane (5.5 g, 35.3 mmol) in DMF (45 mL) was added imidazole (4.2 g, 58.8 mmol). After 16 h at RT, to the mixture was added water (150 mL) and was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water and sat. aq. NaCl (100 mL each), dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography using cyclohexanes 100% to cyclohexanes/EtOAc 9:1 as eluent mixture, to afford the title compound as an oil (5.2 g). TLC Rf = 0.5 (cyclohexanes/EtOAc 9:1, phosphomolybdic acid stain).1H NMR (400MHz, CDCl3, ^ ppm): 3.67 (s, 3H), 3.60 (s, 2H), 1.95 (s, 6H), 0.88 (s, 9H), 0.03 (s, 6H). Preparation of Intermediate 11: (3-(((tert- Butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol [0133] To a solution at 4 ºC of butyldimethylsilyl)oxy)methyl) 1-carboxylate (5.2 g, 18.3 mmol) in THF (52 mL) was added dropwise lithium aluminum hydride 2.3 M in Me-THF (9.9 mL, 22.8 mmol). The reaction was stirred for 1 h at RT, then it was added slowly at 0 ºC water (50 mL) and EtOAc (50 mL) successively; phases were separated, and aq. phase was extracted with more EtOAc (50 mL). Organics were combined, dried over MgSO4, filtered, and evaporated to give the title compound as an oil (4.3 g). TLC Rf = 0.5 (cyclohexanes/EtOAc 1:1, phosphomolybdic acid stain).1H NMR (400MHz, CDCl3, ^ ppm): 3.61 (s, 2H), 3.60 (s, 2H), 1.60 (s, 6H), 0.89 (s, 9H), 0.03 (s, 6H). Preparation of Intermediate 12: Tert-Butyl (3-((5-carbamoyl-4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1- yl)carbamate H N O General Procedure B: oxime [0134] A suspension of tert-butyl (3-((5-cyano-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (140 mg, 220 μmol), acetaldehyde oxime (1.30 g, 22.0 mmol), and copper(II) oxide (69.9 mg, 878 μmol) in 4:11,4-dioxane/water (5 mL) was heated at 100 °C overnight. The mixture was cooled to RT. The solution was loaded onto a diatomaceous earth column. The column was washed with EtOAc until the UV active material stopped eluting. Fractions containing the desired product were combined and evaporated to give a solution that was diluted with water and then extracted with three portions of DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to give a residue that was purified by silica gel chromatography eluting with a gradient from 0-100% EtOAc in cyclohexane to give the title compound (96 mg, 57%). ES-MS m/z 653.8 (M-H). Preparation of Intermediate 13: Racemic tert-Butyl 4-(5-cyano-4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-2,2-dimethylpiperidine-1- carboxylate [0135] 4-(1-(3,4-Difluorobenzyl)- 1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (50 mg, 0.11 mmol) and racemic tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1- carboxylate (29 mg, 0.12 mmol) were dissolved in 1,4-dioxane (3 mL) in a microwave vial. (Tributylphosphoranylidene)acetonitrile (60 μL, 0.23 mmol) was added and the mixture was heated in a microwave at 150 °C for 8 h. The solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient from 0-60% EtOAc in cyclohexane to give the title compound (57 mg). ES-MS m/z 651.8 (M-H). Preparation of Intermediate 14: Racemic tert-butyl 4-(5-carbamoyl-4-(1-(3,4-difluorobenzyl)- 1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-2,2-dimethylpiperidine-1- carboxylate
[0136] A solution of racemic tert-b -(3,4-difluorobenzyl)-1H-indazol-5- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-2,2-dimethylpiperidine-1-carboxylate (57 mg, 87 μmol) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(II) (3.7 mg, 8.7 μmol) in EtOH (1 mL) and water (0.11 mL) was heated at 80 °C for 28 h. The mixture was cooled to RT. The mixture was diluted with EtOAc (10 mL) and Na2SO4 was added as a drying agent. The mixture was allowed to stand at RT overnight. The mixture was filtered and evaporated to give a residue that was purified by silica gel chromatography eluting with a gradient from 0-100% EtOAc in cyclohexane to give the title compound (46 mg). ES-MS m/z 672 (M+H). Preparation of Intermediate 15: 7-Bromo-4-(3,4-difluorobenzyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one [0137] In a 3-neck 500 mL RBF probe, to a suspension of 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (25.00 g, 109.6 mmol) and cesium carbonate (78.58 g, 241.2 mmol) in DMF (250 mL) was added dropwise over 15 min 4-(bromomethyl)- 1,2-difluorobenzene (24.96 g, 14.7 mL, 120.6 mmol). A slight exotherm was observed and the internal temperature rose up to 35 ºC. The mixture was stirred at RT for 3 h. Water (350 mL) was added dropwise, and the mixture stirred for 15 min at RT. The resulting solid was filtered, washed with water (200 mL) and dried under vacuum oven at 40 ºC overnight to give the title compound (33.15 g). ES-MS m/z 355 (M+H).1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.46 – 7.34 (m, 2H), 7.26 (d, J = 2.2 Hz, 1H), 7.19 – 7.09 (m, 2H), 6.94 (d, J = 8.7 Hz, 1H), 5.13 (s, 2H), 4.86 (s, 2H). Preparation of Intermediate 16: 4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde [0138] A mixture of 7-bromo-4-(3,4- -2H-benzo[b][1,4]oxazin-3(4H)-one (30.00 g, 84.71 mmol), di((3S,5S,7S)- (butyl)phosphane (4.56 g, 12.71 mmol), palladium diacetate (1.426 g, 6.353 mmol), and N,N,N′,N′- tetramethylethylenediamine (11.81 g, 15.30 mL, 101.7 mmol) in toluene (400 mL) was pressurized to 75 psi of SynGas (1:1 CO-H2 mixture) and heated at 95 ºC for 22 h. Upon heating the reaction pressure increased to 90 psi. After cooling to RT, the reaction mixture was filtered through diatomaceous earth and the solvents removed under vacuum. Purification of the residue by silica gel chromatography (0-30% EtOAc in DCM) followed by drying under vacuum at RT gave the title compound as a solid (20.65 g). ES-MS m/z 304 (M+H). [0139] Alternatively, the title compound was prepared as follows. To a solution of 3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (2.0 g, 9.7 mmol) and cesium carbonate (6.5 g, 19 mmol) in DMF (20 mL) was added 4-(bromomethyl)-1,2-difluoro- benzene (2.5 g, 12 mmol). The resultant mixture was stirred at 25 °C for 3 h before it was diluted with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with sat. aq. NaCl (100 mL × 1), dried over anhydrous Na2SO4, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography using a gradient of 0 ~ 50% EtOAc/petroleum ether to give the title compound (1.89 g, 82% purity) as a solid. ES-MS m/z 304.2 (M+H). Preparation of Intermediate 17: 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile General Procedure E: MCR with MnO [0140] A mixture of 5-methyl-3-oxohexanenitrile (2.72 g, 21.8 mmol), 1H-pyrazol-5-amine (2.14 g, 125.7 mmol) and 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (6.00 g, 19.8 mmol) in n-propanol (180 mL) was heated at 105 ºC for 3 h. Then, manganese dioxide (3.44 g, 39.6 mmol) was added portion- wise, and the mixture stirred for 20 h at 105 ºC. The mixture was filtered through diatomaceous earth and the solvents from the filtrate removed in vacuum to give a residue that was purified by silica gel chromatography (DCM/EtOAc 10 to 100% mixtures as eluants) to give the title compound as a solid (7.20 g) that was dried under vacuum at 40 ºC. ES-MS m/z 474 (M+H). Preparation of Intermediate 18: Cis tert-butyl (3-((5-cyano-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)cyclobutyl)(methyl)carbamate General Procedure C: Mitsunobu [0141] To a solution of 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (200 mg, 422 μmol), cis tert-butyl 3-(hydroxymethyl)cyclobutyl)(methyl)carbamate (100 mg, 465 μmol) and triphenylphosphine (244 mg, 929 μmol) in THF (3 mL) at 0 °C was added dropwise DIAD (181 μL, 929 μmol). The mixture was stirred overnight while warming to RT. The solvent was evaporated, and the residue was purified by silica gel chromatography eluting with a gradient from 0-60% EtOAc in cyclohexane to give the title compound (283 mg). ES-MS m/z 671.2 (M+H). Preparation of Intermediate 19: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(2- fluoroethyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile General Procedure D: Mitsunobu heating) [0142] 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (50 mg, 0.11 mmol) and 1-(2-fluoroethyl)piperidin-4-ol (18 mg, 0.12 mmol) were dissolved in 1,4-dioxane (3 mL). CMBP (55 mg, 60 μL, 0.23 mmol) was added and the mixture was heated at 150 °Cfor 4 h. CMBP (55 mg, 60 μL, 0.23 mmol) was added and the reaction was heated at 150 °C for an additional 8 h. The solution was loaded onto an SCX column. The column was washed with 3 column volumes of MeOH. The product was released with 7M ammonia in MeOH. Fractions containing the desired product were combined and evaporated to give a residue that was purified by silica gel chromatography eluting with a gradient from 0-100% EtOAc in hexane to give the title compound (49 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (d, J = 0.9 Hz, 1H), 8.27 (dd, J = 1.7, 0.8 Hz, 1H), 8.20 (s, 1H), 8.04 (dt, J = 8.8, 1.0 Hz, 1H), 7.80 (dd, J = 8.7, 1.7 Hz, 1H), 7.51 – 7.37 (m, 2H), 7.22 – 7.13 (m, 1H), 5.77 (s, 2H), 4.85 (td, J = 11.3, 5.6 Hz, 1H), 4.64 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 4.9 Hz, 1H), 4.04 (q, J = 7.1 Hz, 1H), 3.05 (dd, J = 15.9, 9.3 Hz, 4H), 2.75 (t, J = 4.9 Hz, 1H), 2.68 (t, J = 4.9 Hz, 1H), 2.38 – 2.27 (m, 3H), 2.30 – 2.16 (m, 2H), 2.00 (s, 3H), 1.18 (t, J = 7.1 Hz, 1H), 1.02 (d, J = 6.6 Hz, 6H). Preparation of Intermediate 20: 1-((3-(((tert- Butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile General Procedure F: heating) [0143] To a suspension of 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.0 g, 4.2 mmol) and (3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol (1.4 g, 5.1 mmol) in toluene (40 mL) was added dropwise CMBP (4.08 g, 16.9 mmol). The reaction mixture was heated at 80 ºC for 18 h. After cooling to RT, the solvent was removed under vacuum, and the residue was purified by silica gel chromatography using cyclohexane to cyclohexane/EtOAc 8:2 as an eluent mixture to provide the title compound as a solid (2.2 g). ES-MS m/z 698 (M+H). Preparation of Intermediate 21: 1-((3-(((tert- Butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide
General Procedure G: Nitrile hylphosphinous acid- kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) [0144] A suspension of 1-((3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1- yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.1 g, 3.0 mmol) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (0.26 g, 0.6 mmol) in EtOH (110 mL) and water (10 mL) was heated at 90 ºC for 18 h. After cooling to RT, solvents were removed in a rotavap. To the aq. residue was added water (30 mL) and EtOAc (30 mL). Phases were separated, aq. phase was extracted with more EtOAc (2 × 20 mL). Organics were combined, washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated to provide the title compound as an oil (2.2 g). ES-MS m/z 714 (M- H). Preparation of Intermediate 22: 1-Cyclopropylpiperidin-4-ol [0145] A solution of 1- (5.00 g, 35.9 mmol) in EtOH (50 mL) was stirred at 0 °C. Then, sodium borohydride (1.02 g, 26.9 mmol) was added portion-wise, and the mixture stirred at RT for 1 h. The mixture was cooled to 0 °C and 5% aq. citric acid solution (25 mL) was added. Then, 5M NaOH solution was added up to pH ~9 and the organic solvents removed in vacuum. The aq. phase was extracted with DCM (4 × 50 mL). The combined organic fractions were washed with sat. aq. NaCl (50 mL), dried over Na2SO4 and the solvents removed in vacuum to give the title compound as an oil (2.98 g). ES-MS m/z 142 (M+H). Preparation of Intermediate 23: 1-(1-Cyclopropylpiperidin-4-yl)-4-(4-(3,4-difluorobenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile [0146] A mixture of 4-(4-(3,4- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)-6-isobutyl-1H-pyrazolo[3,4-b] (2.50 g, 5.28 mmol), 1- cyclopropylpiperidin-4-ol (1.30 g, 9.24 mmol) and triphenylphosphine (3.46 g, 13.2 mmol) was stirred at RT for ca.5 min to achieve a clear solution. Then, DBAD (3.04 g, 13.2 mmol) was added portion-wise, and the mixture stirred for 1 h at RT. The solvents were removed in vacuum to give a residue that was purified by silica gel chromatography (0 to 5% MeOH in DCM) to give a solid (8.0 g) that was dried under vacuum. The solid was dissolved in MeOH (35 mL) and the material purified using a SCX cartridge previously conditioned with MeOH, eluting first with MeOH and then ammonia 2M in MeOH to give a solid (3.36 g) that was purified by silica gel chromatography (0 to 100% EtOAc in DCM) to give title compound as a solid (2.18 g). ES-MS m/z 597 (M+H). Preparation of Intermediate 24: 3-Bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0147] The title compound was prepa General Procedure A using 3-bromo-1H- pyrazol-5-amine and 5-methyl-3-oxohexanamide. ES-MS m/z 537/539 (M-H). Preparation of Intermediate 25: 3-Bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0148] The title compound was Procedure A using 3-bromo-1H- pyrazol-5-amine. ES-MS m/z 521/523 (M+H). Preparation of Intermediate 26: 1-(4-Chloro-3-fluorobenzyl)-1H-indazole-5-carbaldehyde [0149] A suspension of 1H- mg, 3.08 mmol), 4-chloro-3- fluorobenzyl bromide (453 μL, 3.39 mmol), and cesium carbonate (2.51 g, 7.70 mmol) was stirred in ACN at RT for 2 h. The mixture was filtered and concentrated to afford a residue that was purified by silica gel chromatography (15 to 100% EtOAc in cyclohexane) followed by reverse phase purification (40% to 60% ACN in aq. NH4CO2H containing 5% MeOH) to afford the title compound as a solid (339 mg). ES-MS m/z 289 (M+H). Preparation of Intermediate 27: 3-Oxo-4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde [0150] To a mixture of 3-oxo-3,4- [b][1,4]oxazine-7-carbaldehyde (800 mg, 4.335 mmol) in DMF (10 mL) was carbonate (4.324 g, 13.01 mmol), then 2-(chloromethyl)-1,4-diazine hydrochloride (730 mg, 4.335 mmol) in DMF (5 mL) was slowly added. The resultant mixture was stirred at 20 °C for 3 h, and then at 40 °C for 2 h. To the mixture was then added H2O (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of 0 to 45% EtOAc/petroleum ether to give the title compound (847.3 mg) as a solid. ES-MS m/z 269.8 (M+H). Preparation of Intermediate 28: 3-(3,4-Difluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6- carbaldehyde [0151] A mixture of 6-bromo-3- [d]oxazol-2(3H)-one (250 mg, 0.74 mmol), triethylenediamine (124 mg, 1.1 mmol), methanesulfonato(tri-t- butylphosphino)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (21.6 mg, 0.037 mmol), 2- isocyano-2-methylpropane (0.10 mL, 0.88 mmol), and triethylsilane (0.35 mL, 2.2 mmol) in DMF (3.7 mL) was stirred at 65 oC for 2.5 h. The reaction was quenched with 1 M aq. HCl solution (2.0 mL) and this solution was stirred at RT for 40 min. The mixture was then diluted with 1 M aq. NaOH solution (2.0 mL) and EtOAc (2.0 mL). The aq. layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with sat. aq. NaCl (1 × 2 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound. ES-MS m/z 290 (M+H). Preparation of Intermediate 29: 6-bromo-3-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione [0152] To a vial with stir bar was added 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (1.0 g, 4.1 mmol), THF (14 mL), and methanamine (0.68 g, 5.0 mmol). Capped, placed under nitrogen, and stirred at rt for 20 min, then placed in a 62 ºC heating block for 3 h 40 min. Cooled to rt and filtered the mixture into a new vial with stir bar. Added N,N'-carbonyldiimidazole (0.80 g, 0.51 mL, 5.0 mmol). Placed under nitrogen and continued to stir at 62 ºC for 17.5 h. Cooled down and diluted the mixture with 25 mL water. Stirred at rt then collected the solid by vacuum filtration to give the title compound (1.16 g). ES-MS m/z: 361/363 (M+H). Preparation of Intermediate 30: 6-bromo-1-(3,4-difluorobenzyl)-3-(4- methoxybenzyl)quinazoline-2,4(1H,3H)-dione [0153] To a vial with stir bar was added quinazoline- 2,4(1H,3H)-dione (200 mg, 554 μmol), potassium carbonate (253 mg, 1.83 mmol), DMF (2.77 mL), and 4-(bromomethyl)-1,2-difluorobenzene (138 mg, 664 μmol). Capped and stirred at rt for 19.5 h. Filtered the mixture through a pad of diatomaceous earth, rinsing with ACN. Concentrated on rotovap and dissolved the resulting residue in DCM and loaded onto a silica cartridge. Placed under vacuum to remove solvent. Purified the residue on silica gel column, eluting with 0-50% EtOAc in cyclohexane to give the title compound (210 mg). ES- MS m/z: 487/489 (M+H). Preparation of Intermediate 31: 1-(3,4-Difluorobenzyl)-3-(4-methoxybenzyl)-2,4-dioxo- 1,2,3,4-tetrahydroquinazoline-6-carbaldehyde [0154] A mixture of 6-bromo-1- -3-(4-methoxybenzyl)quinazoline- 2,4(1H,3H)-dione (210 mg, 0.43 , (78.4 mg, 0.70 mmol), methanesulfonato(tri-t-butylphosphino)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (30.1 mg, 0.051 mmol), 2-isocyano-2-methylpropane (0.060 mL, 0.53 mmol), and triethylsilane (0.21 mL, 1.31 mmol) in DMF (3.0 mL) was stirred at 65 oC for 1 h 50 min. The reaction was quenched with 1 M aq. HCl solution (2.0 mL) and this solution was stirred at RT for 1 h 5 min. The mixture was then diluted with 1 M aq. NaOH solution (2.0 mL), sat. aq. NaCl (10 mL), and EtOAc (10 mL). The aq. layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with sat. aq. NaCl (1 × 3 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound, which was used in crude form. ES-MS m/z 437 (M+H). Preparation of Intermediate 32: Racemic 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)- one [0155] A vial equipped with a stir the following: 2-amino-5- bromophenol (800 mg, 4.25 mmol), potassium carbonate (1.18 g, 8.51 mmol) and ACN (14.2 mL, 0.3 M). Then, racemic 2-chloropropanoyl chloride (0.41 mL, 4.25 mmol) was added dropwise. Gas evolution was noticed upon addition. After 10 min of stirring, the reaction was heated to 80 °C for 21 h. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated under reduced pressure to provide the title compound (1.09 g). ES-MS m/z 242/244 (M+H). Preparation of Intermediate 33: Racemic 7-bromo-4-(3,4-difluorobenzyl)-2-methyl-2H- benzo[b][1,4]oxazin-3(4H)-one [0156] An RBF equipped with a stir with racemic 7-bromo-2-methyl-2H- benzo[b][1,4]oxazin-3(4H)-one (1.09 , potassium carbonate (1.24 g, 9.01 mmol), 4-(bromomethyl)-1,2-difluoro-benzene (1.12 g, 0.69 mL, 5.40 mmol) and ACN (9.01 mL). The reaction mixture was heated to 80 °C for 18 h, then cooled to ambient temperature and filtered over a bed of diatomaceous earth. The filtrate was further diluted with EtOAc (50 mL), washed with sat. aq. NaCl (3 × 50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc/cyclohexane) to afford the title compound (1.50 g) as an oil. ES-MS m/z 368/370 (M+H). Preparation of Intermediate 34: Racemic 4-(3,4-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carbaldehyde [0157] A mixture of racemic 7- -2-methyl-2H- benzo[b][1,4]oxazin-3(4H)-one (1.4 g, 3.8 mmol), di((3S,5S,7S)-adamantan-1- yl)(butyl)phosphane (170 mg, 0.474 mmol), palladium diacetate (36 mg, 0.16 mmol), N,N,N′,N′-tetramethylethylenediamine (0.44 g, 0.57 mL, 3.8 mmol) in toluene (16 mL) was heated at 95 ºC under 75 psi of SynGas (1:1 CO-H2 mixture) for 22 h. After cooling to RT, the reaction mixture was filtered through diatomaceous earth and the solvents removed under vacuum to give a crude product. The crude product was purified by silica gel chromatography (10-40% EtOAc/cyclohexane) to afford racemic 4-(3,4-difluorobenzyl)-2- methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (1.38 g) as an oil. ES- MS m/z 318 (M+H). Preparation of Intermediate 35: Racemic 2-(2,2-difluorocyclopropyl)-N-methoxy-N- methylacetamide [0158] To a suspension of racemic acetic acid (5.00 g, 36.7 mmol) in DMF (30 mL) was added g, mmol). The mixture was stirred at RT for 5 min. N,N-diisopropylethylamine (44.8 mL, 257 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (17.9 g, 184 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions water, one portion sat. aq. NaCl, dried over Na2SO4, filtered, and evaporated to give a residue that was purified by column chromatography on silica gel eluting with a gradient from 0-15% EtOAc in hexane to give the title compound (6.95 g) as an oil. ES-MS m/z 180.0 (M+H). Preparation of Intermediate 36: Racemic 4-(2,2-Difluorocyclopropyl)-3-oxobutanenitrile [0159] To a solution of ACN (3.04 THF (30 mL) at -78 ºC was added n- butyllithium (29.1 mL, 1.6 molar in heptane, 46.5 mmol) dropwise. The mixture was stirred for 45 min after the addition was complete. A solution of racemic 2-(2,2- difluorocyclopropyl)-N-methoxy-N-methylacetamide (6.95 g, 38.8 mmol) in THF (30 mL) was added dropwise. The mixture was stirred at -78 ºC for 1 h when the cold bath was removed, and the mixture was stirred for an additional 1 h while warming to RT. The reaction was quenched with sat. aq. ammonium chloride. The layers were separated. The aq. layer was back extracted with two portions EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography eluting with a gradient from 0-50% EtOAc in cyclohexane to give the title compound as an oil. ES-MS m/z 157.8 (M-H). Preparation of Intermediate 37: Racemic 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-((2,2-difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0160] To a reaction vial with stir difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carbaldehyde (400 mg, 1.32 mmol), 1-(1-methylpiperidin-4-yl)- 1H-pyrazol-5-amine (238 mg, 1.32 mmol), racemic 4-(2,2-difluorocyclopropyl)-3- oxobutanenitrile (210 mg, 1.32 mmol), and 1,4-dioxane (6.60 mL). The vial was capped and placed in a 100 ºC heating block for 4 h. The mixture was cooled to RT. The solvent was evaporated, and the residue was dissolved in DCM. DDQ (299 mg, 1 Eq, 1.32 mmol) was added all at once. The reaction mixture was stirred at RT for 30 min, then filtered through paper and the solids washed with minimal DCM. The filtrate was split into 4 equal portions and loaded onto 4 separate 10 g SCX columns. The columns were washed with 3 column volumes of MeOH. The product was released with 7 M NH3 in MeOH. Fractions containing the desired product were combined from all columns and evaporated. The residue was purified by column chromatography on silica gel eluting with a gradient from 0-100% (10% 7N ammonia MeOH) in DCM to give the title compound (509 mg). ES-MS m/z 605 (M+H). Preparation of Intermediate 38: N-Methoxy-N-methyl-3-(methyl-d3)butanamide-2,2,3,4,4,4- d6 [0161] HATU (5.13 g, 13.5 mmol) w pension of 3-(methyl-d3)butanoic- 2,2,3,4,4,4-d6 acid (1.00 g, 8.99 mmol) in DMF (30 mL). The mixture was stirred at RT for 5 min. N,N-Diisopropylethylamine (11.0 mL, 63.0 mmol) was added followed by N,O- dimethylhydroxylamine hydrochloride (4.39 g, 45.0 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions water, one portion sat. aq. NaCl, dried over Na2SO4, filtered, and evaporated to give the title compound (759 mg) as an oil. ES-MS m/z 155.2 (M+H). Preparation of Intermediate 39: 5-(Methyl-d3)-3-oxohexanenitrile-4,4,5,6,6,6-d6 [0162] To a solution of ACN (371 THF (30 mL) at -78 ºC, was dropwise added n-butyllithium (3.55 mL, 1.6 molar, 5.69 mmol). The mixture was stirred for 45 min after the addition was complete. A solution of N-methoxy-N-methyl-3-(methyl- d3)butanamide-2,2,3,4,4,4-d6 (731 mg, 4.74 mmol) in THF (30 mL) was added dropwise. The mixture was stirred at -78 ºC for 1 h when the ice bath was removed, and the mixture was stirred for an additional 1 h while warming to RT. The reaction was quenched with sat. aq. ammonium chloride solution. The layers were separated. The aq. layer was back extracted with two portions EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to give a residue that was purified by column chromatography on silica gel eluting with a gradient from 0-100% EtOAc in cyclohexane to give the title compound as an oil. 1H NMR (CDCl3) δ (ppm): 3.45 (s, 2H). Preparation of Intermediate 40: 2-Cyclobutyl-N-methoxy-N-methylacetamide [0163] To a suspension of 2- g, 8.76 mmol) in DMF (30 mL) was added HATU (5.00 g, 13.1 mmol). The mixture was stirred at RT for 5 min. DIEA (7.93 g, 10.7 mL, 61.3 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (4.27 g, 43.8 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions water, one portion sat. aq. NaCl, dried over Na2SO4, filtered, and evaporated to give the title compound (1.44 g). ES- MS m/z 158 (M+H). Preparation of Intermediate 41: 4-cyclobutyl-3-oxobutanenitrile [0164] To a solution of ACN (368 mmol) in THF (33 mL) at -78 °C, was dropwise added n-butyllithium (460 mg, molar, 7.18 mmol). The mixture was stirred for 45 min. A solution of 2-cyclobutyl-N-methoxy-N-methylacetamide (940 mg, 5.98 mmol) in THF (6.6 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h. The ice bath was removed, and the mixture was stirred for an additional 1.75 h while warming to RT. The reaction was quenched with a solution of sat. aq. ammonium chloride. The layers were separated. The aq. layer was back extracted with two portions EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (EtOAc/Cyclohexane 0-50%) gave the title compound as an oil (280 mg). ES-MS m/z 136 (M-H). Preparation of Intermediate 42: 3-Bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6- isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0165] The title compound was manner as described in General Procedure F using 3-bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-methylpiperidin-4-ol. ES-MS m/z 618/620 (M+H). Preparation of Intermediate 43: Racemic 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-3-(2- (hydroxymethyl) azetidin-1-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile General Procedure I – Buchwald [0166] In a screw cap vial 3-bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1- (1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (70 mg, 0.11 mmol), racemic azetidin-2-ylmethanol (30 mg, 0.34 mmol), cesium carbonate (0.15 g, 0.45 mmol) and XantPhos Pd G3 (32 mg, 34 μmol) were dissolved in 1,4-dioxane (1.6 mL), previously degassed with N2 for 15 min. The reaction mixture was stirred and heated under N2 at 100 ºC overnight, then concentrated. The material was then added to a 5 g SCX column previously conditioned with MeOH. Eluted first with 2 column volumes of MeOH, followed by elution with 2 column volumes of 2N NH3 in MeOH. Basic fractions were combined and concentrated to give the title compound. ES-MS m/z 625.40 (M+H). Preparation of Intermediate 44: 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-3-(3,5- dimethylisoxazol-4-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile
General Procedure J - Suzuki couplin [0167] In a screw cap vial, (3,5-dime yl)boronic acid (32 mg, 0.23 mmol), 3- bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile (70 mg, 0.11 mmol), PdCl2(dppf)-CH2Cl2 adduct (23 mg, 28 μmol) and Na2CO3 (36 mg, 0.17 mL, 2 molar, 0.34 mmol) were dissolved in dioxane (0.7 mL). The mixture was flushed with N2 and heated at 90 ºC for 2 h. The reaction was concentrated. The residue was then added to a 5 g SCX column previously conditioned with MeOH. Eluted first with 2 column volumes of MeOH, followed by elution with 2 column volumes of 2N NH3 in MeOH. Basic fractions were combined and concentrated, and the residue was used in next step without additional purification. ES-MS m/z 635.4 (M+H). Preparation of Intermediate 45: 6-Isobutyl-1-(1-methylpiperidin-4-yl)-4-(3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0168] A suspension of 5-methyl-3- (70.7 mg, 564 μmol), 3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (100 mg, 564 μmol), and 1-(1- methylpiperidin-4-yl)-1H-pyrazol-5-amine (132 mg, 734 μmol) in 1,4-dioxane (1.88 mL) was heated at 100 °C for 22 h. The mixture was cooled to RT. The solvent was evaporated. The residue was dissolved in DCM and DDQ (128 mg, 564 μmol) was added at RT. The mixture was stirred at RT for 30 min. The mixture was diluted with ACN to get a clear solution. The mixture was loaded onto a 10 g SCX column. The column was washed with 3 column lengths MeOH and then the product was released with 7N ammonia MeOH solution. Fractions containing the desired product were combined and evaporated to give the title compound (274 mg). ES-MS m/z 443 (M-H). Preparation of Intermediate 46: 4-(4-((5-Bromo-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile General Procedure K – alkylation [0169] To a vial containing a stir bar, 6-isobutyl-1-(1-methylpiperidin-4-yl)-4-(3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (65 mg, 0.15 mmol) and cesium carbonate (150 mg, 460 μmol) in DMF (1.5 mL) were combined and 5-bromo-2-(chloromethyl)-3-fluoropyridine (40 mg, 0.18 mmol) was added. The mixture was flushed with N2 and stirred at RT for 1 h. The reaction mixture was passed over a 10-g SCX column previously conditioned with MeOH. Eluted first with 3 column volumes of MeOH, followed by elution with 2 CVs of 7 N NH3 in MeOH. Basic fractions were evaporated to provide the title compound (92 mg). ES-MS m/z 632/634 (M+H). Preparation of Intermediate 47: Methyl 5-bromo-1-(3,4-difluorobenzyl)-1H-indazole-7- carboxylate [0170] A mixture of methyl 5-bromo- -carboxylate (1.0 g, 3.9 mmol), K2CO3 (1.8 g, 13 mmol), DMF (9.8 mL), and 4-(bromomethyl)-1,2-difluorobenzene (0.97 g, 4.7 mmol) was stirred at RT overnight. The mixture was filtered through a pad of diatomaceous earth and rinsed with ACN. The filtrate was concentrated under vacuum and purified by reversed-phase flash chromatography using a gradient of 45 to 75% ACN in aq. NH4HCO3 + 5% MeOH to give the title compound (1.02 g). ES-MS m/z 381/383 (M+H). Preparation of Intermediate 48: Methyl 1-(3,4-difluorobenzyl)-5-formyl-1H-indazole-7- carboxylate [0171] A mixture of palladium mmol), butyldi-1-adamantylphosphine (170 mg, 474 μmol), and methyl 5-bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate (1.0 g, 2.6 mmol) in anhydrous toluene (17 mL) and tetramethylethylenediamine (0.5 mL, 3.3 mmol) was purged and pressurized to 75 psi with synthesis gas (1:1 CO:H2) and heated to 95 °C overnight. The mixture was cooled to RT and filtered through a pad of diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (652 mg). ES-MS m/z 331 (M+H). Preparation of Intermediate 49: tert-Butyl 4-((4-bromo-2-hydroxyphenyl)amino)-4-oxobut-2- enoate (mixture of isomers) [0172] A vial equipped with a stir 2-bromo-succinic acid 4-tert-butyl ester (2.42 g, 9.573 mmol), 2-amino-5-bromophenol (1.50 g, 7.98 mmol), and THF (39.9 mL). To this was added DCC (2.47 g, 12.0 mmol), and the reaction was stirred at ambient temperature. The reaction mixture was filtered over a bed of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was redissolved in ACN (39.82 mL) and K2CO3 (1.65 g, 11.97 mmol) was added. The reaction was heated to 55 °C for 40 min, then filtered over a bed of diatomaceous earth and the filtrate concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with 0-60% MTBE in cyclohexane to provide the title compound (1.71 g) as an oil. ES-MS m/z 342 (M+H). Preparation of Intermediate 50: Racemic tert-butyl 2-(7-bromo-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate [0173] To a mixture of tert-butyl 4-( amino)-4-oxobut-2-enoate (mixture of isomers, 1.4 g, 4.1 mmol) and 2-propanol (20 mL) was added piperidine (4.0 mL, 41 mmol) followed by acetic acid (2.3 mL, 41 mmol). The reaction was stirred at ambient temperature for 16 h, then concentrated under reduced pressure and the residue purified via silica gel chromatography (0-100% EtOAc/heptane) to provide the title compound as an oil (689.4 mg). ES-MS m/z 340/342 (M-H). Preparation of Intermediate 51: Racemic tert-butyl 2-(7-bromo-4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate [0174] A vial equipped with a stir ba ith racemic tert-butyl 2-(7-bromo-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (595 mg, 1.74 mmol), 4- (bromomethyl)-1,2-difluoro-benzene (223 μL, 1.74 mmol) and potassium carbonate (264 mg, 1.91 mmol). ACN (8.69 mL) was added. After stirring for 20 h at RT, additional 4- (bromomethyl)-1,2-difluoro-benzene (180 mg, 0.87 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added. The reaction was stirred for additional 5 days, then filtered over a bed of diatomaceous earth, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford the title compound (841 mg) as an oil. ES-MS m/z 466/468 (M-H). Preparation of Intermediate 52: Racemic tert-butyl 2-(4-(3,4-difluorobenzyl)-7-formyl-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate [0175] The title compound was manner as described in the Preparation of Intermediate 48 using racemic tert-butyl 2-(7-bromo-4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate. ES-MS m/z 462 (M-(tert-butyl)+H). Preparation of Intermediate 53: Racemic tert-butyl 2-(7-(5-carbamoyl-1-(cyclohexylmethyl)- 6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate N N [0176] A vial containing racemic -7-formyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] μmol) was charged with 2- cyclohexylmethyl-2H-pyrazol-3-ylamine (98.7 mg, 551 μmol), ammonium acetate (193 mg, 2.5 mmol) and 5-methyl-3-oxohexanamide (78.9 mg, 551 μmol), followed by the addition of 2-propanol (2.5 mL). The reaction mixture was heated to 95 °C. After stirring for 20 h, the reaction mixture was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc/cyclohexane) to afford the title compound (232 mg) as an oil. ES-MS m/z 702 (M+H). Preparation of Intermediate 54: Racemic 2-(7-(5-carbamoyl-1-(cyclohexylmethyl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetic acid [0177] A vial equipped with a stir racemic tert-butyl 2-(7-(5- carbamoyl-1-(cyclohexylmethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (82.7 mg, 118 μmol) and DCM (236 μL). At RT, TFA (236 μL) was added. The reaction was stirred at RT for 20 h. The reaction was then concentrated under reduced pressure and then concentrated with toluene (3 × 10 mL) to afford the title compound (82.1 mg). ES-MS m/z 646 (M+H). Preparation of Intermediate 55: Racemic tert-butyl 2-(7-(5-carbamoyl-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate [0178] A vial containing -7-formyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] mg, μmol) was charged with 1-(1- methylpiperidin-4-yl)-1H-pyrazol-5-amine (147 mg, 817 μmol), ammonium acetate (286 mg, 3.71 mmol) and 5-methyl-3-oxohexanamide (117 mg, 817 μmol), followed by the addition of 2-propanol (3.71 mL). The reaction mixture was heated to 95 °C. After stirring for 16 h, the reaction was concentrated under reduced pressure. The residue was purified via SCX column eluting first with MeOH and then with 2M NH3/MeOH. The basic fractions were combined to provide the title compound as an oil (732 mg). ES-MS m/z 703 (M+H). Preparation of Intermediate 56: Racemic 4-(5-carbamoyl-4-(2-(carboxymethyl)-4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridin-1-yl)-1-methylpiperidin-1-ium 2,2,2-trifluoroacetate [0179] A vial equipped with a tert-butyl 2-(7-(5- carbamoyl-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (240 mg, 341 μmol). DCM (683 μL) was added followed by TFA (683 μL) at ambient temperature. The homogeneous mixture was stirred at RT. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was concentrated down with toluene (3 × 20 mL) to provide the title compound (214 mg) as an oil. ES-MS m/z 647 (M+H). Preparation of Intermediate 57: tert-Butyl (3-((5-cyano-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0180] The title compound was as described in General Procedure C using tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate and 4- (4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile. The product was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound as a solid (1.32 g). ES-MS m/z 669 (M+H). Preparation of Intermediate 58: tert-Butyl (3- (methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0181] To a solution of 3-( [1.1.1]pentane-1-carboxylic acid (3.0 g, 13 mmol) in THF (25.0 mL) was added O,N-dimethyl-hydroxylamine HCl (3.7 g, 38 mmol), diisopropylethylamine (8.3 g, 11 mL, 63 mmol) and HATU (15 g, 38 mmol), the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (3.25 g) as a solid. ES-MS m/z 269 (M-H). Preparation of Intermediate 59: tert-Butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate [0182] To a solution of tert- bicyclo[1.1.1]pentan-1- yl)carbamate (3.0 g, 11 mmol) in added methylmagnesium bromide (3 M in diethyl ether, 13 mL, 39 mmol) at -78 °C over 1 h under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL) at 0 °C, then diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (50 mL) and sat. aq. NaCl (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give the title compound (2.7 g, 80% purity) as a solid. ES-MS m/z 224 (M-H). Preparation of Intermediate 60: Racemic tert-butyl (3-(1-hydroxyethyl)bicyclo[1.1.1]pentan- 1-yl)carbamate [0183] To a solution of tert-butyl pentan-1-yl)carbamate (500 mg, 80 wt%, 1.78 mmol) in THF (8.0 mL) was added sodium borohydride (340 mg, 8.81 mmol) at 0 °C, then stirred at 20 °C for 2 h. The reaction mixture was quenched with sat. aq. NH4Cl (20 mL) at 0 °C, then diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound (450 mg, 85% purity) as an oil. ES-MS m/z 226 (M-H). Preparation of Intermediate 61: Racemic tert-Butyl (3-(1-(5-cyano-4-(4-(3,4-difluorobenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0184] To a solution of 4-(4- dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6- pyridine-5-carbonitrile (230 mg, 452 μmol) and racemic tert-butyl (3-(1-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (242 mg, 904 μmol) in toluene (5.0 mL) was added CMBP (668 mg, 732 μL, 2.71 mmol). The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in petroleum ether to give the title compound (280 mg, 80% purity) as an oil. ES-MS m/z 683 (M+H). Preparation of Intermediate 62: 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0185] A solution of ammonium acetate in EtOH (12 mL) was distributed evenly to twelve reaction vials. A 1 mL aliquot of a solution of 1H-pyrazol-5- amine (395 mg, 4.75 mmol), 5-methyl-3-oxohexanamide (680 mg, 4.75 mmol), and 4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (1.44 g, 4.75 mmol) in EtOH (20 mL) was distributed to the twelve reaction vials. The remaining solution was distributed evenly to three reaction vials. The mixtures were stirred at 100 ºC for 19.5 h. All of the reactions were combined, diluted with EtOAc and washed with 2:1 sat. aq. NaCl:water (15 mL) and then water (10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2.6 g of the title compound as a solid (90% yield, 80% purity). ES-MS m/z: 492 (M+H). Preparation of Intermediate 63: 6-bromo-3-(3,4-difluorobenzyl)benzo[d]oxazol-2(3H)-one [0186] To a vial with stir bar was 2(3H)-one (1.5 g, 7.0 mmol), potassium carbonate (2.9 g, 21 , , and 4-(bromomethyl)-1,2- difluorobenzene (1.7 g, 8.4 mmol). Capped and placed in a 50 ºC heating block. After 2.5 h, Cooled to rt let at rt overnight., The mixture was filtered through diatomaceous earth, rinsing with ACN and concentrated the filtrate to give a solid. Suspended the solid in Et2O and collected by vacuum filtration, rinsing with Et2O. The solid was dried under vacuum to give the title compound (2.18 g). ES-MS m/z: 340/342 (M+H). Preparation of Intermediate 64: tert-Butyl 4-(5-cyano-6-isobutyl-4-(3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1-carboxylate [0187] A suspension of 5-methyl-3- (160 mg, 1.28 mmol), 3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (226 mg, 1.28 mmol), and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (409 mg, 1.53 mmol) in 1,4-dioxane (6.39 mL) was heated at 100 °C. After 17.5 h, the reaction mixture was cooled to RT and the solvent evaporated. The residue was dissolved in DCM (10 mL) and 4,5-dichloro-3,6- dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (290 mg, 1.28 mmol) was added. The mixture was stirred at RT for 3 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was poured into a separatory funnel and washed with 1N NaOH aqueous solution (x 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified via reverse phase column chromatography using a gradient of 10-100% ACN in water (10 mM ammonium bicarbonate with 5% MeOH) to give the title compound (387.6 mg). ES-MS m/z 529 (M-H). Preparation of Intermediate 65: tert-Butyl 4-(5-cyano-4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)piperidine-1-carboxylate [0188] Tert-butyl 4-(5-cyano-6- dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1-carboxylate (306 mg, 577 μmol), cesium carbonate (395 mg, 1.21 mmol), and 2-(chloromethyl)-3,5-difluoropyridine (104 mg, 78.0 μL, 634 μmol) were mixed with DMF (11.5 mL) under N2 and stirred at RT for 1 h. The reaction was quenched by the addition of water and diluted with EtOAc. Extracted with EtOAc (x 3). The combined organic layers were washed with water and sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated to give a residue that was purified via reverse phase column chromatography using a gradient of 10-100% ACN in water (10 mM NH4HCO3 with 5% MeOH) to give the title compound (306.9 mg). ES-MS m/z 658 (M+H). Preparation of Intermediate 66: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile, trifluoroacetate salt [0189] To an RBF with a stir cyano-4-(4-((3,5-difluoropyridin- 2-yl)methyl)-3-oxo-3,4- yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)piperidine-1-carboxylate (306.9 mg, 466.6 μmol), DCM (4.13 mL) and TFA (611.8 mg, 413.4 μL, 5.366 mmol). The vial was stirred under N2 for 2 h and then, the reaction was concentrated under reduced pressure and dried under vacuum to give the title compound (368 mg). ES-MS m/z 558 (M+H). Preparation of Intermediate 67: 1-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-4-(4- ((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0190] To an RBF equipped with a 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, trifluoroacetate salt (50 mg, 74 μmol), 3,3- difluorocyclobutan-1-one (16 mg, 12 μL, 0.15 mmol), acetic acid (27 mg, 26 μL, 0.45 mmol) and dichloroethane (1.5 mL). The reaction was stirred at RT for 30 min and then added sodium triacetoxyborohydride (47 mg, 0.22 mmol). After 1.5 hours the reaction was quenched by the addition of water and transferred to a separatory funnel and extracted with DCM (x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue (48 mg) containing the title compound. ES-MS m/z 648 (M+H). Preparation of Intermediate 68: 5-(2-Cyclopropyl-1-hydroxyethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione [0191] In a 2000 mL three atmosphere, 2- cyclopropylethanoic acid (60.0 g, 599 mmol) was dissolved in DCM (600 mL) and stirred in ice water bath. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137.86 g, 719 mmol) was added in one portion followed by DMAP (183 g, .498 mol) in one portion. The mixture was warmed to 25 oC and stirred for 0.5 h. Meldrum's acid (90.69 g, 629 mmol) was added in one portion and the mixture was stirred for 18 h at 25 oC. The mixture was adjusted to a pH=2 with 1M HCl. The aqueous phase was extracted with DCM (700 ml x 3). The combined organic extracts were washed with brine (700 mL). The organic phase was concentrated under vacuum to give a crude product. The crude product was triturated with petroleum ether (700 mL). The mixture was stirred for 2 h at 25 oC and then filtered. The filtrate was washed with 1M HCl (700 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (53 g).1H NMR (400MHz, CDCl3, ^ ppm): 15.31 (s, 1H), 5.78 (s, 6H), 2.99 (d, 2H, J = 5.5 Hz), 1.16 (m, 1H), 0.57 (m, 2H), 0.30 (m, 2H). Preparation of Intermediate 69: tert-Butyl (4-cyclopropyl-3-oxobutanoyl)carbamate [0192] In a 2000 mL three necked flask under nitrogen, 5-(2-cyclopropyl-1- hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (90.0 g, 398 mmol) was suspended in ACN (720 mL). tert-Butyl carbamate (46.6 g, 398 mmol) was added in one portion at 25 oC. The mixture was heated to 71 oC and stirred for 5 h. The mixture was cooled to RT and then concentrated under vacuum to give a crude product. The crude product was suspended in petroleum ether (100 mL) and the mixture was stirred for 18 h at 25 oC. The mixture was filtered, and the filter cake was washed with petroleum ether. The filter cake was dried in vacuum to give the title compound (75 g). 1H NMR (400MHz, DMSO-d6, ^ ppm) δ 10.37 (s, 1H), 3.70 (s, 2H), 2.37 (d, 2H, J = 6.8 Hz), 1.41 (2, 9H) 0.90 (m, 1H), 0.48 (m, 2H), 0.10 (m, 2H). Preparation of Intermediate 70: 4-Cyclopropyl-3-oxobutanamide [0193] In a 2000 mL three necked flask under a nitrogen atmosphere, tert-butyl (4- cyclopropyl-3-oxobutanoyl)carbamate (60.0 g, 249 mmol) was dissolved in HCl (4M in EtOAc) (600 mL, 2.40 mol). The mixture was stirred for 5 h at 25 oC and filtered, and the filter cake dried under vacuum to give a crude product. The crude was dissolved in aq. sodium bicarbonate (300 ml). The aqueous phase was extracted with EtOAc (300 mL x 3) and the combined organic extracts were washed with brine (300 mL). The organic phase was dried under vacuum to give the title compound (20 g). ES-MS m/z 142 (M+H). Preparation of Intermediate 71: 4-Cyclopropyl-3-oxobutanenitrile [0194] In a 500 mL three necked atmosphere, methyl 2- cyclopropylacetate (10.00 g, 87.61 mmol) was suspended in THF (100 mL) and stirred at -20 oC. ACN (6.86 mL, 131.4 mmol) was added to the mixture at -20 oC. NaHMDS (1M in THF) (131.4 mL, 131.4 mmol) was added dropwise at -20 oC. The mixture was stirred for 2 h at -20 oC. The mixture was quenched with aq. NH4Cl (100 mL) and the mixture stirred for 0.5 h at 25 oC. The mixture was adjusted to pH=3 with 1M HCl. Two phases were observed and the THF phase was separated. The aqueous phase was extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, evaporated, and dried under vacuum to give a crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0-30% EtOAc in petroleum ether to give the title compound (6.5 g). 1H NMR (400MHz, CDCl3, ^ ppm): 3.56 (s, 2H), 2.70 (d, 2H, J = 6.8 Hz), 0.99 (m, 1H), 0.65 (m, 2H), 0.19 (m, 2H). Preparation of Intermediate 72: Racemic 4,4,4-Trifluoro-N-methoxy-N,3- dimethylbutanamide [0195] To a suspension of racemic 3-methylbutanoic acid (2.21 g, 13.0 mmol) in DMF (50 mL) was added g, 19.3 mmol). The mixture was stirred at RT for 5 min. N,N-diisopropylethylamine (16 mL, 92 mmol) was added followed by N,O- dimethylhydroxylamine hydrochloride (6.34 g, 65.0 mmol). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc. The organic solution was washed with three portions of water, one portion brine, dried over Na2SO4, filtered, and evaporated to give a residue that was purified by column chromatography on silica gel eluting with 40% EtOAc in hexane to give the title compound (2.03 g) as an oil. ES-MS m/z 200 (M+H). Preparation of Intermediate 73: Racemic 6,6,6-trifluoro-5-methyl-3-oxohexanenitrile [0196] To a solution of ACN in THF (50 mL) at -78 ºC was added n-butyllithium (7.01 mL, 1.6 molar in heptane, 11.2 mmol) dropwise. The mixture was stirred for 45 min after the addition was complete. A solution of racemic 4,4,4-trifluoro- N-methoxy-N,3-dimethylbutanamide (2.03 g, 10.2 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -78 ºC for 1 h then the cold bath was removed, and the mixture was stirred for an additional 1 h while warming to RT. The reaction was quenched with sat. aq. ammonium chloride. The layers were separated. The aq. layer was back extracted with two portions of EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography eluting with a gradient from 0-50% EtOAc in cyclohexane to give the title compound as an oil. ES-MS m/z 178 (M-H). Preparation of Intermediate 74: tert-Butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1- carboxylate [0197] To a mixture of 2- g, 58 mmol) in 1,4-dioxane (70 mL) was added tert-butyl 4- g, 58 mmol) and the mixture stirred at 25 °C for 3 h under a nitrogen atmosphere. IPA (21 mL) and potassium tertbutoxide, 1 M in THF (58 mL, 58 mmol) were added to the mixture at RT. The reaction mixture was stirred at 80 °C for 3 h. To the mixture was added water (400 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with a gradient from 0-7% MeOH in DCM to give a crude product. The crude product was purification by reverse phase flash chromatography on a YMC-Triart Prep C18250*50 mm*10 ^m column eluting with a gradient from 0-50% ACN in water (NH3H2O+NH4HCO3) at a flow rate of 110 mL/min. The afforded flows were combined, concentrated to remove ACN and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9.8 g). ES-MS m/z 267 (M+H). Preparation of Intermediate 75: 1-(3,3-Difluorocyclobutyl)piperidin-4-one [0198] To a mixture of 1-ethyl-1- 1-ium iodide (5.65 g, 20.6 mmol) and 3,3-difluorocyclobutanamine (1.50 g, 13.7 mmol) in EtOH (15 mL) and H2O (15 mL) was added K2CO3 (2.52 g, 17.8 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to RT and diluted with H2O (50 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography eluting with a gradient from 0-8% MeOH in DCM to give the title compound (1.38 g). ES-MS m/z 190 (M+H). Preparation of Intermediate 76: 1-(3,3-Difluorocyclobutyl)piperidin-4-ol [0199] To a mixture of 1-(3,3- piperidin-4-one (1.38 g, 6.56 mmol) in MeOH (5.0 mL) was added sodium mg, 3.11 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The reaction mixture was quenched by adding sat. aq. NH4Cl (15 mL) at 0 °C. The mixture was extracted with EtOAc (20 mL × 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography eluting with a gradient from 0-10% MeOH in DCM to give the title compound (1.14 g). ES-MS m/z 192 (M+H). Preparation of Intermediate 77: 1,5-Dichloropentan-3-ol [0200] In a 250-mL RBF with a stir bar was dissolved 1,5-dichloropentan-3-one (5.00 g, 32.3 mmol) in MeOH (40 mL). The reaction was cooled to 0 oC in an ice bath. Sodium borohydride (1.22 g, 32.2 mmol) was added portion wise over 5 min and the reaction stirred was stirred for 3 h. The reaction was removed from the ice bath and partitioned between DCM (200 mL) and water (200 mL). The layers were separated, and the aq. layer extracted with more DCM (2 x 200 mL). The combined organic extracts were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated to give the title compound (3.95 g). 1H NMR (400MHz, CDCl3, ^ ppm): 4.16 (p, 1H, J = 6.3 Hz) 3.81 – 3.65 (m, 4H), 1.95 (dt, 4H, J = 6.9, 5.7 Hz), 1.86 (s, 1H). Preparation of Intermediate 78: Bicyclo[1.1.1]pentane-1,3-diylbis(methan-d2-ol) [0201] To a solution of 1,3- pentane-1,3-dicarboxylate (1.00 g, 5.16 mmol) in THF (10 mL) was (479 mg, 10.8 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction was cooled to 0 °C and Na2SO4•10H2O (500 mg) was added. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography eluting with a gradient from 0-3% MeOH in DCM to give the title compound (726 mg).1H NMR (400MHz, CDCl3, ^ ppm): 1.66 (s, 2H). Preparation of Intermediate 79: 7-Bromo-4-((3,5-difluoropyridin-2-yl)methyl)-2H- benzo[b][1,4]oxazin-3(4H)-one [0202] To a solution of (3,5- (12.6 g, 86.8 mmol), 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (30.3 g, 133 mmol), and triphenylphosphine (45.5 g, 174 mmol) in THF (400 mL) was added diisopropyl diazene-1,2-dicarboxylate (34.3 mL, 174 mmol) dropwise. The reaction was stirred at RT overnight. The reaction mixture was diluted with H2O and extracted with EtOAc (x3). The combined organics were washed with a sat. aq. solution of sodium chloride, dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by flash silica gel column chromatography eluting with a gradient from 0-40% EtOAc in heptane to give the title compound (31.2 g). ES-MS m/z 355, 357 (M+H). [0203] The following compound was prepared in a similar manner as described for Intermediate 79. Intermediate No. Chemical Name Structure ES-MS m/z 7-Bromo-4-((5-chloro-3- 371, 373 80 fluoropyridin-2-yl)methyl)-2H- - benzo[b][1,4]oxazine-7-carbaldehyde [0204] To a 2L Parr autoclave dip tube and pressure gauge was added Pd(OAc)2 (784 mg), di- (3.76 g), 7-bromo-4-((3,5- difluoropyridin-2-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (31 g), anhydrous toluene (550 mL) and TMEDA (14 mL). The autoclave was sealed, purged and pressurized to 75 psi with Synthesis gas. The reactor was heated at 90 oC for 18 h then cooled to RT and vented. The reactor was opened, and the reactor contents transferred to a bottle rinsing the solids out with toluene. The solids were filtered through a celite and rinsed with EtOAc. The filtrate was removed under reduced pressure. When the solvent was about 10% of its original volume, H2O was added, and a precipitate formed. The precipitate was collected by vacuum filtration and the filter cake washed with H2O (x3) and hexane (x3), and dried under high vacuum to give the title compound (16 g). ES-MS m/z 305 (M+H). [0205] Alternatively, a mixture of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carbaldehyde (55 g, 311 mmol) and 2-(chloromethyl)-3,5-difluoropyridine (56.4 g, 310.5 mmol) in NMP (400 mL) was stirred at RT. Then, cesium carbonate (101.2 g, 310.6 mmol) was added, and the mixture stirred for 4.5 h at RT. Water (1600 mL) was added dropwise and the mixture stirred for 1 h at RT. The resulting solid was filtered, washed with H2O (3000 mL), cyclohexane (500 mL) and dried under vacuum at 50 oC to give the titled compound as a solid (68.6 g). ES-MS m/z 305 (M+H). [0206] The following compound was prepared in a similar manner as described for Intermediate 81. Intermediate No. Chemical Name Structure ES-MS m/z 4-((5-Chloro-3-fluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro- H) - benzo[b][1,4]oxazine-7-carbaldehyde [0207] A solution of (5- (10.00 g, 69.18 mmol) and DMF (1 mL) in DCM (100 mL) was (7.573 mL, 103.8 mmol) was added dropwise and the mixture stirred for 2.5 h at RT. The solvents were removed in vacuum to give an oil that was stored overnight at 0 oC under nitrogen. The residue that was dissolved in DMF (150 mL) and 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (12.26 g, 69.20 mmol) was added and the mixture stirred for 5 min at RT and then, powdered K2CO3 (23.90 g, 172.9 mmol) was added. The mixture was stirred for a further 20 h at RT. Water (250 mL) was added dropwise and the mixture stirred for a further 30 min at RT. The resulting solid was filtered, washed with water (150 mL) and dried under vacuum at 40 oC to give the title compound (19.21 g). ES-MS m/z 304 (M+H). Preparation of Intermediate 84: 2-(Chloromethyl)-5-fluoropyrimidine hydrochloride [0208] To a solution of (5- methanol (40.40 g, 283.8 mmol) in DCM (500 mL) was added DMF (2.20 mL, 28.38 mmol) and the mixture was cooled down to 5 oC. Thionyl chloride (31.98 mL, 425.7 mmol) was added dropwise and the resulting suspension was stirred at RT for 15 h. The reaction was concentrated in a rotavap with no heating, and then in vacuo at RT to give the crude title compound as a thick oily solid (51 g) and used without purification. Preparation of Intermediate 85: 4-((5-Fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde [0209] To 2-(chloromethyl)-5- (51.03 g, 278.8 mmol) was added DMF (400 mL) and 3-oxo- [b][1,4]oxazine-7-carbaldehyde (38.00 g, 214.5 mmol). Fresh ground K2CO3 (88.93 g, 643.5 mmol) was added in portions and the mixture stirred at RT for 3 days. Additional 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (11.40 g, 64.35 mmol) was added and the mixture stirred for 24 h at RT. A mixture of ice/water (500 g) was added and the mixture was stirred for 5 min. The resulting solid was filtered, washed with water, and dried with air current for 2 h at RT to give the title compound as a solid (82.8 g). ES-MS m/z 288 (M+H). Preparation of Intermediate 86: tert-Butyl 4-(5-carbamoyl-6-(cyclopropylmethyl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridin-1-yl)piperidine-1-carboxylate [0210] To each of 4 separate with stir bars was added 4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (500 mg, 1.64 mmol), 4-cyclopropyl-3-oxobutanamide (232 mg, 1.64 mmol), tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (438 mg, 1.64 mmol), ammonium acetate (190 mg, 2.47 mmol), and ethanol (6.0 mL). Each vial was capped and placed in a 100 oC heating block with stirring for 16 h. To each vial was added manganese dioxide (214 mg, 2.47 mmol). The vials were capped and stirred in a 100 oC heating block for 2 h. The reaction vials were cooled to RT. The reaction mixtures were combined and filtered through a pad of diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with a gradient from 40- 100% EtOAc in cyclohexane to give the title compound (2.73 g). ES-MS m/z 674 (M+H). Preparation of Intermediate 87: tert-Butyl 4-(5-carbamoyl-4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)piperidine-1-carboxylate [0211] In a 40 mL vial added 5-methyl-3-oxohexanamide (672 mg, 4.69 mmol), 4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (950 mg, 3.13 mmol), tert-butyl 4-(5-amino-1H- pyrazol-1-yl)piperidine-1-carboxylate (1.00 g, 1.2 Eq, 3.75 mmol), ammonium acetate (600 mg, 2.49 Eq, 7.78 mmol, and isopropanol (10 mL). The vial was sealed with a screw cap lined with teflon and was placed in an aluminum heating block warmed to 100 oC and stirred for 5 min to dissolve all reaction components. The mixture was allowed to cool to RT. The homogeneous solution was then split into two 40-mL vials and re-capped. The vials were heated at 100 oC for 20 h. The reaction vials were cooled to RT and DDQ (725 mg, 1.02 Eq, 3.19 mmol) (split over 2 reaction vials) was added. The mixtures were stirred for 1 h at RT. The reactions were combined rinsing with MeOH and evaporated. The crude solid was partitioned between EtOAc (250 mL) and water (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography eluting with a gradient form 10-100% EtOAc in cyclohexane to give the title compound (2.02 g). ES-MS m/z 675 (M+H). Preparation of Intermediate 88: tert-Butyl 4-(4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-(cyclopropylmethyl)-1H-pyrazolo[3,4- b]pyridin-1-yl)piperidine-1-carboxylate [0212] To a mixture of 4-((5- methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7- mg, , 4-cyclopropyl-3- oxobutanenitrile (249.6 mg, 1.93 mmol) and tert-butyl 4-(5-amino-1H-pyrazol-1- yl)piperidine-1-carboxylate (523 mg, 1.93 mmol) in EtOH (10 mL) was added acetic acid (564.6 μL, 9.63 mmol). The reaction mixture was stirred at 100 °C for 16 h under air. The mixture was cooled to RT and DDQ (535.2 mg, 2.311 mmol) was added to the mixture. The reaction mixture was stirred at 20 °C for 0.5 h under air. The reaction mixture was concentrated to remove most of the solvent. The residue was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel column chromatography eluting with a gradient from 0-35% EtOAc in petroleum ether to give the title compound (1.09 g). ES-MS m/z 655 (M+H). Preparation of Intermediate 89: tert-Butyl 4-(5-cyano-4-(4-((5-fluoropyrimidin-2-yl)methyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate
[0213] To a 40-dram vial equip as charged with 5-methyl-3- oxohexanenitrile (131 mg, 1.04 mmol), 4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (250 mg, 870 μmol), tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (278 mg, 1.04 mmol), and ammonium acetate (335 mg, 4.35 mmol). To this was added the solvent 2-propanol (4.35 mL). The reaction was heated to 100 oC for 4 h. The reaction was cooled to RT. DDQ (198 mg, 870 μmol) was added along with 5 mL of MeOH. The reaction was stirred for 15 min. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to provide the title compound (548 mg). ES-MS m/z 585 (M-tBu+H). [0214] The following compound was prepared in a similar manner as described for Intermediate 89. Intermediate No. Chemical Name Structure ES-MS m/z H) Preparation of Intermediate 91: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0215] To a mixture of 5-methyl-3 itrile (1.34 g, 10.7 mmol), 1H-pyrazol-5- amine (888 mg, 10.7 mmol) and, 4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (2.50 g, 8.22 mmol) was added 1,4-dioxane (41 mL). The reaction was heated at 100 °C for 18 h. The reaction was cooled to RT. DDQ (2.798 g, 12.33 mmol) was added and the reaction was stirred for 45 min at RT. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0-50% EtOAc in cyclohexanes to give the title compound (3.26 g) as a foam. ES-MS m/z 475 (M+H). [0216] Alternatively, a mixture of 5-methyl-3-oxohexanenitrile (3.62 g, 28.9 mmol), 1H- pyrazol-5-amine (2.85 g, 34.3 mmol) and 4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (8.00 g, 26.3 mmol) in n-propanol (160 mL) was heated at 100 ºC for 1 h. Manganese dioxide (2.30 g, 26.5 mmol) was added portion wise, and the mixture heated at 105 ºC for 2 h. Additional manganese dioxide (2.30 g, 26.5 mmol) was added, and the mixture heated at 105 ºC for 4 h. Additional manganese dioxide (2.30 g, 26.5 mmol) was added, and the mixture heated at 105 ºC for 4 hours. Additional manganese dioxide (2.30 g, 26.5 mmol) was added, and the mixture heated at 105ºC overnight. The reaction was cooled to RT and filtered through diatomaceous earth. The filter cake was washed with EtOH (2 L). The filtrate was evaporated to give a crude product. The crude product was loaded onto a silica gel pad and the pad was eluted with 50% EtOAc in cyclohexane to give the title compound (9.5 g). ES-MS m/z 475 (M+H). [0217] The following compounds were prepared in a similar manner as described for Intermediate 91. Intermediate No. Chemical Name Structure ES-MS m/z 4-(4-((5-Chloro-3-fluoropyridin-2- H) H) p py y y , y - 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0218] To a vial equipped with a with 5-methyl-3-oxohexanenitrile (236 mg, 1.88 mmol), 1H-pyrazol-5-amine (156 mg, 1.88 mmol), 4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (440 mg, 1.45 mmol) and 1,4-dioxane (7.24 mL). The reaction was heated at 100 °C for 16 h. The mixture was cooled to RT. DDQ (329 mg, 1.45 mmol) was added, and the reaction was stirred for 1 h. The reaction mixture was diluted with a sat. aq. sodium bicarbonate solution and extracted with EtOAc (2 x 50 ml). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 20-30% (25% EtOH in EtOAc) in cyclohexanes to give the title compound (545 mg). ES-MS m/z 474 (M+H). [0219] Alternatively, a mixture of 1H-pyrazol-5-amine (22.03 g, 265 mmol), 5-methyl-3- oxohexanenitrile (28.09 g, 224 mmol) and 4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbal-dehyde (61.95 g, 204 mmol) in n-propanol (990 mL) was heated at 105 oC for 5 h. On cooling to RT, manganese dioxide (47.3 g, 544 mmol) was added portion wise and the mixture stirred for 23 h at 105 oC. On cooling to RT, the solvents were removed in vacuum to give a residue that was taken up in EtOAc (700 mL) and the resulting EtOAc mixture was filtered through a silica plug eluting with 10% MeOH in DCM to give a solid that was triturated from a 1/1 acetone/water (1000 mL). The resulting solid was filtered, washed with a 1/1 acetone/water (1000 mL) and dried under vacuum at 40 oC to give the titled compound as a solid (93.9 g). ES-MS m/z 474 (M+H). [0220] The following compound was prepared in a similar manner as described for Intermediate 94. Intermediate No. Chemical Name Structure ES-MS m/z H) Preparation of Intermediate 96: tert-Butyl (3R,4R)-4-(5-cyano-4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)-3-methylpiperidine-1-carboxylate
[0221] To a solution of tert-buty xy-3-methylpiperidine-1-carboxylate (476 mg, 2.21 mmol), 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (700 mg, 1.48 mmol) and triphenylphosphine (387 mg, 1.48 mmol) in THF (7.4 mL) at RT was added dropwise DIAD (430 μL, 2.21 mmol). The mixture was stirred at RT for 18 h. Additional tert-butyl (3R,4S)-4-hydroxy-3-methylpiperidine-1-carboxylate (476 mg, 2.21 mmol) and triphenylphosphine (387 mg, 327 μL, 1 Eq, 1.48 mmol) were added and the reaction mixture was stirred for an additional 6 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography eluting with a gradient from 10-65% EtOAc in cyclohexane to give the title compound (900 mg). ES-MS m/z 616. (M-tBu+H). [0222] The following compounds were prepared in a similar manner as described for Intermediate 96. Intermediate No. Chemical Name Structure ES-MS m/z ) Racemic tert-Butyl (trans)-4- ) ) ) tert-Butyl (3R,4R)-4-(5- cyano-4-(4-((5- ) ) Racemic 1-(1-(3,3- F F Difluorocyclobutyl)piperidin- H) Butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-((5-chloropyrimidin- 2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile [0223] To a mixture of 4-(4- methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (150 mg, 309.6 μmol) in toluene (5 mL) were added (3-(((tert- butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol (250 mg, 929 μmol) and CMBP (418 μL, 1.55 mmol). The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0-19% EtOAc in petroleum ether to give the title compound (140 mg). ES-MS m/z 698 (M+H). [0224] The following compounds were prepared in a similar manner as described for Intermediate 105. Intermediate No. Chemical Name Structure ES-MS m/z 1-((3-(((tert- ) )
4-(4-((5-Chloropyrimidin-2- yl)methyl)-3-oxo-3,4- ) , o- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile [0225] To a flask containing tert- (4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H- pyrazolo[3,4-b]pyridin-1-yl)-3-methylpiperidine-1-carboxylate (345 mg, 514 μmol) was added DCE (2.57 mL). To this was added TFA (200 μL, 2.60 mmol). The mixture was stirred at RT for 7 min. The reaction was then concentrated under reduced pressure and purified via SCX column chromatography eluting first with MeOH followed by 7N NH3/MeOH. The basic fractions were combined and concentrated under reduced pressure to give the title compound (157). ES-MS m/z 571 (M+H). [0226] The following compounds were prepared in a similar manner as described for Intermediate 109. Intermediate No. Chemical Name Structure ES-MS m/z ) ) ) 4-(4-((5-Fluoropyrimidin-2- ) ) ) ) 4-(4-((5-Chloro-3- fluoropyridin-2-yl)methyl)-3- H) , - 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0227] 4-(4-((5- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide 2,2,2-trifluoroacetate (1.3 g, 1.9 mmol) was dissolved in MeOH (5 mL) and loaded onto a pre-washed (MeOH x 3 CVs) 20-g SCX column. The column was eluted with MeOH (3 CVs). The product was released with 7N ammonia methanol (2 CVs). The basic fractions were evaporated, and the residue vacuum dried overnight to give the title compound (947 mg). ES-MS m/z 571 (M+H). Preparation of Intermediate 119: 6-(Cyclopropylmethyl)-4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide 2,2,2-trifluoroacetate
[0228] To a 1 L RBF conta l 4-(5-carbamoyl-6- (cyclopropylmethyl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1-carboxylate (2.7 g, 4.0 mmol) was added DCM (40 mL) and trifluoroacetic acid (3.1 mL, 40 mmol). The reaction mixture was stirred at RT for 1.25 h. TFA (1.5 mL) was added, and the mixture was stirred at RT for 30 min. The solvent was evaporated and the residue azeotroped with Et2O. The solid was collected by vacuum filtration and dried under vacuum to give the title compound (2.57 g). ES-MS m/z 571 (M+H). The following compounds were prepared in a similar manner as described for Intermediate 119. Intermediate No. Chemical Name Structure ES-MS m/z ) 4-(4-((5-Fluoropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro- H) H) repara on o nermedae 3: -(-((5-C oropyrmdn--y)me y)-3-oxo-3,-d ydro- 2H-benzo[b][1,4]oxazin-7-yl)-1-(1-((1R,3R)-3-fluorocyclobutyl)piperidin-4-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0229] In a 2 dram vile added sequentially 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(1,5- dichloropentan-3-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (87 mg, 0.14 mmol), sodium iodide (70 mg, 0.47 mmol), DMA (2 mL), Hunig's base (150 μL, 861 μmol) and (1R,3R)-3-fluorocyclobutan-1-amine hydrochloride (65 mg, 0.52 mmol). The vial was capped and placed in a heating block at 100 oC for 22 h. The mixture was cooled to RT and passed over a 10 g SCX cartridge (product did not stick well). Combined MeOH and ammoniated fractions and concentrated. Partitioned between EtOAc (100 mL) and sat. aq. sodium bicarbonate. Separated and washed EtOAc phase with brine (2 x 25 mL), dried over MgSO4, filtered and concentrated to give the title compound (123 mg) used without further purification. ES-MS m/z 629 (M+H). [0230] The following compounds were prepared in a similar manner as described for Intermediate 123. Intermediate No. Chemical Name Structure ES-MS m/z 4-(4-((5-Chloropyrimidin-2- ) repara on o n ermeda e 5: -( -((3,5- uoropyr dn- -y )me y)-3-oxo-3, -d ydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(oxetan-3-yl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0231] To a solution of 4-(4-( 2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile (125 mg, 219 μmol) and acetic acid (22.5 μL, 394 μmol) in dichloroethane (625 μL) was added oxentan-3-one (280 μL, 4.37 mmol). Sodium triacetoxyborohydride (46.3 mg, 219 μmol) was add and the reaction was heated at 50 °C for 1 h. Additional oxentan-3-one (280 μL, 4.37 mmol) followed by additional sodium triacetoxyborohydride (46.3 mg, 219 μmol) were added and the mixture was stirred for an additional 1h. The reaction was cooled to RT and stored in the freezer overnight. The reaction was added dropwise to sat. aq. sodium bicarbonate solution and diluted with DCM. The layers were separated. The DCM layer was washed with sat. aq. sodium bicarbonate solution and brine. The DCM layer was dried over MgSO4 and concentrated to give the title compound (161 mg) carried forward without further purification. ES-MS m/z 628 (M+H). [0232] The following compounds were prepared in a similar manner as described for Intermediate 125. Intermediate No. Chemical Name Structure ES-MS m/z H) H) Racemic 4-(4-((3,5- H) H) H) 4-(4-((5-Chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro- H) H) H) 4-(4-((5-Fluoropyrimidin-2- H) H) H) 1-((3R,4R)-1-(3,3- H) , o- 2H-benzo[b][1,4]oxazin-7-yl)-1-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0233] To a mixture of 1-((3-( oxy)methyl)bicyclo[1.1.1]pentan- 1-yl)methyl)-4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (140.2 mg, 180.7 μmol) in THF (2 mL) was added tetrabutylammonium fluoride (1M in THF) (542.1 μL, 542.1 μmol) and the mixture was stirred at 20 °C for 16 h. To the mixture was added sat. aq. ammonium chloride (10 mL) and the mixture was extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel column chromatography eluting with a gradient from 0-68% EtOAc in petroleum ether to give the title compound (65.7 mg). ES-MS m/z 584 (M+H). [0234] The following compounds were prepared in a similar manner as described for Intermediate 138. Intermediate No. Chemical Name Structure ES-MS m/z 4-(4-((5-Chloropyrimidin-2- ) , fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0235] To a vial equipped fluoropyrimidin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile (245 mg, 453 μmol) was added DCE (2.27 mL, 453 μmol). Hunig’s base (484 μL, 2.72 mmol) was added followed by 2,2-difluoroethyl trifluoromethanesulphonate (485 mg, 2.27 mmol) all at RT. The reaction was stirred at RT for 5 min. The reaction was diluted with sat. aq. ammonium chloride (30 mL) and DCM (25 mL). The layers were separated. The organic phase was further washed with sat. aq. ammonium chloride (25 mL). The organic extracts were then dried over MgSO4 and concentrated to give the title compound (546 mg) used without further purification. ES-MS m/z 605 (M+H). Preparation of Intermediate 141: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(1,1-dioxidothietan-3-yl)-3-methylpiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0236] A vial equipped with 4- 2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6- -3-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile (110 mg, 193 μmol) and a stir bar was charged with THF (1.28 mL), 1,1-dioxide-3-bromothietane (178 mg, 962 μmol) and DIPEA (200 μL, 1.15 mmol). The reaction mixture was heated to 60 oC for 2.25 h. The reaction mixture was quenched by the addition of sat. aq. ammonium chloride and extracted with EtOAc. The layers were separated, and the aqueous phase was further extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the title compound (125 mg) used without further purification. ES-MS m/z 675 (M+H). Preparation of Intermediate 142: 6,6-Difluoro-3-oxohexanenitrile [0237] The title compound was The following solutions were prepared: Solution 1 - ACN (15.2 mL, 284 mmol) and methyl 4,4-difluorobutanoate (20.0 g, 142 mmol) in THF (200 mL); and Solution 2 - lithium bis(trimethylsilyl)amide, 1.0 M in THF (213 mL, 213 mmol). Solutions 1 and 2 were pumped simultaneously at 60 mL/min into a flow reactor {perfluroalkoxy polymer coiled tubing 6.350 mm, 120 mL total volume, 20 °C}. The residence time of the solution in the flow reactor was 1 min. The mixture was collected from the flow reactor into a solution of sat. aq. NH4Cl (200 mL). The mixture was pH adjusted to about 8 with 1 M HCl. The mixture was extracted with EtOAc (400 mL × 3). The combined organic layers were washed with sat. aq. NaCl (500 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in hexanes to give the title compound (5.96 g). 1H NMR (400 MHz, CDCl3, ^ ppm): 5.96 (tt, J = 56.4, 3.9 Hz, 1H), 3.54 (s, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.22 (ttd, J = 18.0, 7.1, 3.9 Hz, 2H). [0238] The following compound was prepared in a similar manner as described for Intermediate 4. Intermediate Chemica NMR or No. l Name Structure ES-MS m/z *1H .6, 8.0 Preparation of Intermediate 144: Racemic 4,4,4-trifluorobutane-1,3-diol [0239] To a solution of ethyl (2.00 g, 10.9 mmol) in THF (40 mL) was added aluminum lithium hydride (2.5 M in THF) (13.0 mL, 32.6 mmol) dropwise at 0 °C under N2. The reaction mixture was warmed to 20 °C and stirred for 16 h. To the mixture was added Na2SO4•10H2O (2.00 g). The reaction mixture was filtered, and the filter cake was washed with DCM (20 mL × 3). The filtrate was concentrated under reduced pressure to give the title compound (1.70 g).1H NMR (400MHz, DMSO-d6, ^ ppm): 6.01 (s, 1H), 4.53 (s, 1H), 3.97 (t, J = 8.2 Hz, 1H), 3.49 (t, J = 5.1 Hz, 2H), 1.60 – 1.49 (m, 2H). Preparation of Intermediate 145: (3-(((tert- Butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol [0240] In a 40 mL vial containi ded tert-butyldiphenylchlorosilane (1.06 g, 3.85 mmol) to a solution of bicyclo[1.1.1]pentane-1,3-diyldimethanol (500 mg, 3.90 mmol) and imidazole (400 mg, 5.88 mmol) in DCM (20.0 mL). The mixture was stirred at RT for 21 h. The reaction was loaded onto an SiO2 loading cartridge. The crude product was purified by silica gel column chromatography using a gradient of 0 to 40% EtOAc in cyclohexane to give the title compound (768 mg). 1H NMR (400MHz, DMSO-d6, ^ ppm): 7.65 – 7.57 (m, 4H), 7.51 – 7.39 (m, 6H), 3.64 (s, 2H), 3.38 – 3.29 (m, 2H, under water peak), 1.49 (s, 6H), 1.01 (s, 9H). Preparation of Intermediate 146: Racemic methyl 2-bromo-3-((tert- butyldimethylsilyl)oxy)propanoate [0241] To a 50 mL RBF with a added racemic methyl 2-bromo-3- hydroxypropanoate (1.0 g, 5.4 mmol), DCM (15 mL), and imidazole (0.62 g, 8.9 mmol) successively at ambient temperature. tert-Butyldimethylchlorosilane (1.23 g, 8.00 mmol) was added at 0 °C. The reaction was allowed to warm to 20 °C and stirred for 16 h. The reaction mixture was concentrated to remove the solvent. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 4% EtOAc in hexanes to give the title compound (1.41 g). 1H NMR (400MHz, CDCl3, ^ ppm): 4.14 (dd, J = 8.7, 5.6 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.81 (dd, J = 10.2, 5.6 Hz, 1H), 3.71 (s, 3H), 0.79 (s, 9H), - 0.01 (d, J = 5.6 Hz, 6H). Preparation of Intermediate 147: Racemic methyl 3-((tert-butyldimethylsilyl)oxy)-2-(5- formyl-2-nitrophenoxy)propanoate [0242] To a 50 mL RBF with a was added 3-hydroxy-4- nitrobenzaldehyde (0.71 g, 4.2 mmol), DMF (10 mL), racemic methyl 2-bromo-3-((tert- butyldimethylsilyl)oxy)propanoate (1.35 g, 4.31 mmol) and potassium carbonate (1.3 g, 9.2 mmol) successively at ambient temperature. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was left at ambient temperature overnight. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with sat. aq. NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 23% EtOAc in hexane to give the title compound (646 mg). 1H NMR (400 MHz, CDCl3, ^ ppm): 9.92 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.56 – 7.37 (m, 2H), 4.86 (t, J = 4.8 Hz, 1H), 4.06 (d, J = 4.7 Hz, 2H), 3.69 (s, 3H), 0.77 (s, 9H), -0.02 (d, J = 12.1 Hz, 6H). Preparation of Intermediate 148: Racemic 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde [0243] To a 100 mL flask with a was added racemic methyl 3-((tert- butyldimethylsilyl)oxy)-2-(5-formyl-2-nitrophenoxy)propanoate (622.1 mg, 1.541 mmol), AcOH (10 mL) and iron (877.3 mg, 15.39 mmol) successively at ambient temperature. The reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL), then the pH of the mixture was adjusted to ~7 with sat. aq. NaHCO3. The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with sat. aq. NaCl (20 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the title compound (447 mg). ES-MS m/z 322 (M+H). [0244] The following compounds were prepared in a similar manner as described for Intermediate 15. Intermediate No. Chemical Name Structure ES-MS m/z Racemic 2-(((tert- ) ) ) ) ) ) Preparation of Intermediate 155: 6-Bromo-3-methylquinazoline-2,4(1H,3H)-dione [0245] To a mixture of 2-amino-5-bromo-N-methylbenzamide (2.0 g, 8.3 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 17 mmol) in THF (20 mL) was added CDI (2.7 g, 17 mmol). The reaction mixture was stirred at 25 °C for 4 days. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with sat. aq. NaCl (30 mL × 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude product was triturated with MeOH (40 mL) at 25 °C for 30 min. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title compound (1.55 g). ES-MS m/z (79Br/81Br) 253/255 (M-H). [0246] The following compounds were prepared in a similar manner as described for Intermediate 33. Intermediate No. Chemical Name Structure ES-MS m/z 6-Bromo-1-((5- ) Preparation of Intermediate 157: Racemic 6-bromo-3-((5-chloropyrimidin-2-yl)methyl)- 1,1a,3,7b-tetrahydro-2H-cyclopropa[c]quinolin-2-one [0247] To a 50 mL RBF with a was added trimethyl(oxo)sulfonium iodide (653 mg, 2.91 mmol), DMSO (5 mL), and 2-methylpropan-2-olate potassium in 1M THF solution (2.5 mL, 2.5 mmol) successively at ambient temperature. The reaction mixture was stirred at 20 °C for 1 h. A solution of 6-bromo-1-((5-chloropyrimidin-2- yl)methyl)quinolin-2(1H)-one (656 mg, 1.81 mmol) in DMSO (5 mL) was added to the above mixture and stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a gradient of 0 to 60% EtOAc in hexanes to give the title compound (286 mg). ES-MS m/z (79Br/81Br) 364/366 (M+H). Preparation of Intermediate 158: Racemic 3-((5-chloropyrimidin-2-yl)methyl)-2-oxo- 1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline-6-carbaldehyde [0248] To a 35 mL sealed with a magnetic stirrer were charged with racemic 6-bromo-3-((5- 2-yl)methyl)-1,1a,3,7b-tetrahydro-2H- cyclopropa[c]quinolin-2-one (466 mg, 1022 μmol), triethylsilane (676 μL, 4.15 mmol), TEA (731 μL, 5.14 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (86 mg, 0.10 mmol), and DMF (10 mL) successively at ambient temperature. The vessel was degassed and purged with atmospheric pressure of carbon monoxide gas 3 times. The mixture was heated at 80 °C for 16 h under CO atmosphere (50 psi). The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with sat. aq. NaCl (40 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (278 mg, 78%). ES- MS m/z 314 (M+H). [0249] The following compounds were prepared in a similar manner as described for Intermediate 28. Intermediate No. Chemical Name Structure ES-MS m/z ) 1-((5-Chloropyrimidin-2- yl)methyl)-3-methyl-2,4- ) ) ) [0 Intermediate 16. Intermediate No. Chemical Name Structure ES-MS m/z 4-((5-Chloropyrimidin-2- ) repara on o n ermed a e 6 : acemc me y -(5- ormy- -n rop enoxy)propanoate [0251] To a mixture of 3-hydroxy-4-nitrobenzaldehyde (5.0 g, 29 mmol) and K2CO3 (8.3 g, 59 mmol) in DMF (50 mL) was added racemic methyl 2-bromopropanoate (5.0 g, 29 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with sat. aq. NaCl (50 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 33% EtOAc in hexanes to give the title compound (5.2 g). ES-MS m/z 254 (M+H). Preparation of Intermediate 165: Racemic 2-methyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde [0252] To a solution of racemic 2-nitrophenoxy)propanoate (5.2 g, 16 mmol) in AcOH (55 mL) was added 0.16 mol) and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and the pH of the mixture was adjusted to ~ 7 with sat. aq. NaHCO3. The mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with sat. aq. NaCl (100 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 35% EtOAc in hexanes to give the title compound (3.2 g). ES-MS m/z 192 (M+H). [0253] The following compound was prepared in a similar manner as described for Intermediate 47. Intermediate No. Chemical Name Structure ES-MS m/z Racemic 4-((5- ) Preparation of Intermediate 167: 3-((5-Fluoropyrimidin-2-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]oxazole-6-carbaldehyde [0254] To a reaction mixture fluoropyrimidine (500 mg, 3.34 mmol) and 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (675 mg, 4.01 mmol) in DMF (6 mL) was added TEA (1.44 mL, 10.0 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with sat. aq. NaCl (10 mL × 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (580 mg). ES-MS m/z 274 (M+H). Preparation of Intermediate 168: 1-((5-Chloropyrimidin-2-yl)methyl)-2-oxo-1,2- dihydroquinoxaline-6-carbaldehyde [0255] In a dried 250 mL RBF, 1,2-dihydroquinoxaline-6- carbaldehyde (2.58 g, 14.1 mmol) in DMF (30 mL) was added sodium hydride, 60 % in mineral oil (682 mg, 17.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added 5-chloro-2-(chloromethyl)pyrimidine (2.95 g, 17.0 mmol) at 0 °C. The resulting mixture was warmed to 25 °C and stirred for 16 h. To the reaction mixture was added H2O (100 mL) and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with sat. aq. NaCl (50 mL × 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound. The product was further purified by reverse phase chromatography on a PrePulite XP tC18 (50 mm × 250 mm, 10 μm) column eluting with a gradient from 10-50% ACN in water (10 mM NH4CO3) over 20 min to give the title compound (540 mg). ES-MS m/z 301 (M+H). Preparation of Intermediate 169: 3,3-Dimethyl-4-((trimethylsilyl)oxy)-1,2,3,6- tetrahydropyridine [0256] To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (10.0 g, 43.1 mmol) in toluene (200 mL) were added TEA (25.3 mL, 172 mmol) and trimethylsilyl trifluoromethanesulfonate (16.8 mL, 86.2 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. To the reaction mixture was added water (100 mL) at 0 °C and the mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with water (100 mL) and sat. aq. NaCl (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (10.08 g). ES-MS m/z 200 (M+H). Preparation of Intermediate 170: tert-Butyl 3,3-dimethyl-4-((trimethylsilyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate [0257] To a solution of 3,3- oxy)-1,2,3,6-tetrahydropyridine (10.08 g, 35.39 mmol) in DCM (100 mL) was added DIEA (18.6 mL, 106.2 mmol) and di- tert-butyl dicarbonate (8.670 g, 38.93 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. To the reaction mixture was added sat. aq. citric acid (50 mL) at 0 °C. The mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with sat. aq. citric acid (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (14.8 g). 1H NMR (400MHz, CDCl3, ^ ppm): 4.45 – 4.27 (m, 1H), 3.71 (s, 2H), 3.07 (s, 2H), 1.27 (s, 9H), 0.81 (s, 6H), 0.00 (s, 9H). Preparation of Intermediate 171: Racemic tert-butyl 5-fluoro-3,3-dimethyl-4-oxopiperidine- 1-carboxylate [0258] To a solution of tert-butyl 3,3-dimethyl-4-((trimethylsilyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate (14.8 g, 34.6 mmol) in ACN (300 mL) was added Selectfluor™ (13.8 g, 38.1 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 10% EtOAc in hexane to give the title compound (8.26 g). ES-MS m/z 190 (M-tBu+H). Preparation of Intermediate 172: Racemic (trans)-1-benzyl-3-ethylpiperidin-4-ol [0259] In a 100 mL RBF, to a 3-ethylpiperidin-4-one (1.00 g, 4.60 mmol) in MeOH (3 mL) and water (7 mL) at -10 °C was dropwise added phosphoric acid (310 μL, 4.60 mmol). Sodium borohydride (174 mg, 4.60 mmol) was added in 5 portions over 30 mins at -10 °C. The mixture was stirred at -10 °C for 20 min after the last portion was added. The ice bath was then removed, and the reaction was stirred for 16 h at RT. The pH was adjusted to 9 with 1N NaOH. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and the filtrate evaporated to give the title compound (1.03 g). ES-MS m/z 220 (M+H). Preparation of Intermediate 173: Racemic tert-butyl (trans)-3-ethyl-4-hydroxypiperidine-1- carboxylate [0260] A pressure vessel containing -1-benzyl-3-ethylpiperidin-4-ol (1.00 g, 4.56 mmol), di-tert-butyl dicarbonate (1.09 g, 5.02 mmol), palladium on carbon (446 mg, 4.19 mmol) and EtOAc (5 mL) in MeOH (15 mL) was stirred under a 40 psi atmosphere of hydrogen for 16 h at RT. The mixture was filtered through a frit and the filtrate evaporated to give the title compound (979 mg). 1HNMR (400MHz, DMSO-d6, ^ ppm): 4.66 (d, J = 5.1 Hz, 1H), 3.73 (d, J = 23.4 Hz, 2H), 3.23 (s, 1H), 3.17 (d, J = 4.7 Hz, 1H), 2.89 (t, J = 12.0 Hz, 1H), 1.76 – 1.60 (m, 2H), 1.39 (s, 9H), 1.28 – 1.17 (m, 1H), 1.17 – 0.98 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). Preparation of Intermediate 174: Racemic tert-butyl (trans)-4-(benzyloxy)-3- hydroxypiperidine-1-carboxylate [0261] To a 1000 mL RBF was alcohol (16 mL, 0.15 mol) and NMP (200 mL). The mixture was cooled in an ice water bath. Sodium hydride (60% in mineral oil) (6.0 g, 0.15 mol) was added in 1 g portions and the reaction was stirred under ice bath cooling for 30 min. tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (15 g, 75 mmol) was added dropwise. The ice bath was removed, and the reaction was stirred at RT for 4 days. The reaction was quenched by the dropwise addition of sat. aq. NH4Cl (100 mL). Water was added until all solids were dissolved. The mixture was extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with three portions water, one portion sat. aq. NaCl, dried over Na2SO4, filtered, and the filtrate evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 10 to 40% EtOAc in cyclohexane to give the title compound (8 g). ES-MS m/z 208 (M-Boc+1). Preparation of Intermediate 175: Racemic tert-butyl (trans)-4-(benzyloxy)-3- methoxypiperidine-1-carboxylate [0262] In a 250 mL RBF containing tert-butyl (trans)-4-(benzyloxy)-3- hydroxypiperidine-1-carboxylate (8.00 g, 26.03 mmol) was added THF (80 mL). The mixture was cooled to 0 °C. NaH (60% Wt in mineral oil) (1.42 g, 35.5 mmol) was added in three portions. The mixture was stirred at 0 °C for 30 min when iodomethane (1.953 mL, 31.23 mmol) was added dropwise. The mixture was stirred for 30 min at 0 °C when the ice bath was removed. The reaction was stirred for 3 h after the ice bath was removed. The reaction mixture was quenched by the addition of sat. aq. NH4Cl (40 mL). Water was added until all solids were dissolved. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (7.24 g). ES- MS m/z 222 (M-Boc+1). Preparation of Intermediate 176: Racemic tert-butyl (trans)-4-hydroxy-3-methoxypiperidine- 1-carboxylate [0263] To a 2250 mL Parr® bottle 10% Pd/C (1.72 g, 16.2 mmol). The bottle was placed under a stream of N2. MeOH (250 mL) was added. racemic tert-butyl (trans)-4- (benzyloxy)-3-methoxypiperidine-1-carboxylate (7.04 g, 21.9 mmol) and MeOH (250 mL) were added. The bottle was placed on a Parr® shaker. The bottle was flushed with N25 times, and H25 times. The bottle was pressurized with H2 (10 psi). The reaction was shaken for 20 h at RT. The reaction mixture was filtered over diatomaceous earth and the solids washed with MeOH to give a filtrate. The combined filtrate was concentrated under vacuum. The sample was re-filtered over diatomaceous earth and the solids washed with MeOH to give a filtrate. The filtrate was concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography using EtOAc to give the title compound (5.2 g). ES-MS m/z 176 (M-tBu+1). Preparation of Intermediate 177: 3-Methylpiperidin-4-one hydrochloride [0264] To a 250 mL RBF with a bar was added tert-butyl 3-methyl-4- oxopiperidine-1-carboxylate (5.03 g, 22.9 mmol) and hydrogen chloride, 2.0 M in 1,4- dioxane (51 mL, 0.10 mol) successively at ambient temperature. The reaction mixture was stirred at 15 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with hexanes (100 mL × 3). The filter cake was dried under reduced pressure to give the title compound (3.46). ES-MS m/z 114 (M+H). Preparation of Intermediate 178: 1,1,3-Trimethyl-4-oxopiperidin-1-ium iodide [0265] To a 250 mL RBF with a bar was added 3-methylpiperidin-4-one hydrochloride (3.46 g, 22.0 mmol), acetone (40 mL), and potassium carbonate (9.41 g, 66.0 mmol) successively at 0 °C. To the above mixture was added methyl iodide (3.80 mL, 57.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was dissolved in MeOH (200 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (8.92 g). ES-MS m/z 142 (M+H). Preparation of Intermediate 179: 1-(3-Methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin- 4-one [0266] In a 100 mL round-bottom flas a magnetic stir bar, 3- methoxybicyclo[1.1.1]pentan-1-amine hydrochloride (1.2 g, 7.9 mmol) and 1,1,3-trimethyl-4- oxopiperidin-1-ium iodide (3.0 g, 6.7 mmol) were suspended in a biphasic mixture of toluene (9.0 mL) and sat. aq. NaHCO3 (5.6 mL). The reaction was topped with a reflux condenser, under air, and heated to 75 °C for 16 h. The reaction was stirred vigorously to ensure even mixing of the layers. The reaction mixture was cooled to RT. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were washed with sat. aq. NaCl (15 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in hexane to give the title compound (632 mg). ES-MS m/z 210 (M+H). [0267] The following compound was prepared in a similar manner as described for Intermediate 179. Intermediate No. Chemical Name Structure ES-MS m/z ) Preparation of Intermediate 181: Racemic tert-butyl 3-(methylthio)-4-oxopiperidine-1- carboxylate [0268] To an oven dried 500 mL with a magnetic stir bar was added racemic tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (10.1 g, 35.2 mmol), THF (100 mL), and sodium methanethiolate (3.84 g, 53.2 mmol) successively at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with sat. aq. NaCl (200 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 5% MeOH in DCM to give the title compound (5.29 g). ES-MS m/z 244 (M-H). Preparation of Intermediate 182: 1-(3-Methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin- 4-ol [0269] To a 50 mL RBF with a bar was added 1-(3- methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin-4-one (632 mg, 2.72 mmol) and THF (5.0 mL) at RT. The reaction mixture was cooled to 0 °C, and sodium borohydride (320 mg, 8.29 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 16 h. Glacial acetic acid (10 drops) was added, and the reaction was stirred for 15 min. The solvents were evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 11% MeOH in DCM to give the title compound (505 mg). ES-MS m/z 212 (M+H). [0270] The following compounds were prepared in a similar manner as described for Intermediate 182. Intermediate No. Chemical Name Structure NMR or ES-MS m/z Racemic tert-butyl 4- * H), 3. , , . , . , , . , . , , . , ., . , 1H), 2.94 (dd, J = 6.2, 3.4 Hz, 1H), 1.73 (dd, J = 12.9, 4.2 Hz, 1H), 1.57 (d, J = 12.1 Hz, 1H), 1.39 (d, J = 0.9 Hz, 9H). [0271] The following compounds were prepared in a similar manner as described for Intermediate 76. Intermediate No. Chemical Name Structure ES-MS m/z Racemic tert-butyl (cis)-4- ) ) Preparation of Intermediate 188: Racemic tert-butyl (cis)-4-hydroxy-3-methoxypiperidine-1- carboxylate [0272] To an oven dried 500 mL equipped with a magnetic stir bar was added racemic tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (9.50 g, 40.2 mmol) and THF (100 mL) successively at ambient temperature. The vessel was degassed and purged with atmospheric pressure N23 times. Lithium tri-sec-butylborohydride (L-selectride), 1M in THF (60.3 mL, 60.3 mmol) was added dropwise to the reaction mixture at -60 °C. The reaction mixture was stirred at -60 °C for 2 h. The reaction mixture was quenched with sat. aq. NH4Cl (300 mL) at 0 °C. The mixture was extracted with EtOAc (300 mL × 2). The combined organic layers were washed with sat. aq. NaCl (300 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (9.15 g). 1H NMR (400MHz, DMSO- d6, ^ ppm): 3.91 (s, 1H), 3.59 (q, J = 22.0 Hz, 2H), 3.45 (s, 4H), 3.36 – 3.19 (m, 2H), 1.81 (dtd, J = 14.0, 7.2, 3.9 Hz, 1H), 1.66 (s, 1H), 1.48 (s, 9H). Preparation of Intermediate 189: Racemic tert-butyl (trans)-3-methoxy-4-((4- nitrobenzoyl)oxy)piperidine-1-carboxylate [0273] To an oven dried with a magnetic stirrer were added racemic tert-butyl (cis)-4-hydroxy-3-methoxypiperidine-1-carboxylate (9.61 g, 39.4 mmol), THF (120 mL), 4-nitrobenzoic acid (8.48 g, 49.2 mmol), and triphenylphosphine (32.1 g, 119 mmol) successively at 0 °C. The vessel was degassed and purged with atmospheric pressure of N23 times. DIAD (24.0 mL, 120 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to 20 °C and stirred for 1 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with sat. aq. NaCl (300 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 17% EtOAc in hexane to give the title compound (15.23 g). ES-MS m/z 281 (M-Boc+H). [0274] The following compounds were prepared in a similar manner as described for Intermediate 189. Intermediate No. Chemical Name Structure ES-MS m/z Racemic (trans)-3- methoxy-1-(3- 190 meth loxetan-3- 351 P dine- 1-carboxylate [0275] To a 250 mL flask with a bar was charged with racemic tert-butyl (trans)-3-methoxy-4-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate (15.23 g, 36.03 mmol), THF (75 mL), and 1M LiOH (75.0 mL, 75.0 mmol) successively at ambient temperature. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with sat. aq. NaCl (300 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in hexanes to give the title compound (7.81 g). 1H NMR (400MHz, DMSO-d6, ^ ppm): 4.96 (d, J = 4.1 Hz, 1H), 3.52 (d, J = 13.6 Hz, 3H), 3.33 (s, 3H), 3.15 (s, 2H), 2.93 (td, J = 6.0, 3.3 Hz, 1H), 1.72 (ddt, J = 11.9, 9.1, 4.4 Hz, 1H), 1.40 (s, 9H), 1.32 – 1.22 (m, 1H). [0276] The following compounds were prepared in a similar manner as described for Intermediate 192. Intermediate No. Chemical Name Structure NMR or ES-MS m/z Racemic (trans)-3- 1 methoxy-1-(3- NMR* *1 2H), 3. , , . , . , . , . , , . , . , . , . , , .72 (ddd, J = 10.6, 4.6, 2.3 Hz, 1H), 2.39 (ddt, J = 11.3, 4.6, 2.6 Hz, 1H), 2.05 (td, J = 11.7, 2.6 Hz, 1H), 1.90 (ddt, J = 12.5, 5.4, 2.8 Hz, 1H), 1.79 (dd, J = 10.6, 9.7 Hz, 1H), 1.54 (tdd, J = 12.3, 11.1, 4.3 Hz, 1H), 1.28 (s, 3H). #1H NMR (400MHz, DMSO-d6, ^ ppm): 4.55 (d, J = 4.0 Hz, 1H), 3.77 (q, J = 3.8 Hz, 1H), 3.46 (s, 2H), 3.23 (s, 2H), 1.58 – 1.42 (m, 2H), 1.39 (s, 9H), 1.36 – 1.20 (m, 2H), 1.08 (d, J = 15.2 Hz, 1H), 0.87 (t, J = 7.2 Hz, 3H). Preparation of Intermediate 195: Racemic 3-methoxypiperidin-4-ol hydrochloride [0277] To an oven dried 100 mL with a magnetic stirrer was added racemic tert-butyl 4-hydroxy-3-methoxypiperidine-1-carboxylate (7.59 g, 26.3 mmol) and hydrogen chloride, 2M in EtOAc (60 mL, 0.12 mol) successively at ambient temperature. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (5.51 g). 1H NMR (400 MHz, DMSO-d6, ^ ppm): 9.50 (s, 1H), 8.77 (d, J = 56.4 Hz, 1H), 3.91 (dt, J = 6.8, 3.1 Hz, 1H), 3.74 – 3.63 (m, 1H), 3.50 (dt, J = 7.5, 3.0 Hz, 1H), 3.34 (s, 3H), 2.95 (tdd, J = 26.0, 12.9, 6.2 Hz, 3H), 1.95 – 1.56 (m, 2H). [0278] The following compound was prepared in a similar manner as described for Intermediate 195. Intermediate No. Chemical Name Structure ES-MS m/z (3S,4R)-3- 196 Methylpiperidin-4-ol 116 (M+H) Pr -3-yl)- 3-methylpiperidin-4-ol [0279] To a N2-filled 250 mL RBF stir bar was added (3R,4S)-3- methylpiperidin-4-ol hydrochloride (6.4 g, and DCM (120 mL) at ambient temperature. The mixture was cooled to 0 °C. TEA (19.3 mL, 136 mmol), oxetan-3-one (3.0 g, 41 mmol) and 1H-benzo[d][1,2,3]triazole (5.97 g, 48.6 mmol) were added successively at 0 °C. The reaction mixture was warmed to 15 °C and stirred at 15 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with DCM (120 mL). The filter cake was dried in reduced pressure to give the title compound (8.12 g). 1HNMR (400MHz, DMSO-d6, ^ ppm): 8.11 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (dd, J = 15.8, 8.1 Hz, 1H), 5.24 (dt, J = 10.7, 5.3 Hz, 2H), 5.13 – 5.00 (m, 2H), 4.21 (s, 1H), 3.47 (s, 1H), 2.60 (s, 1H), 2.40 (d, J = 11.5 Hz, 1H), 2.14 (s, 1H), 1.86 (s, 1H), 1.80 – 1.70 (m, 1H), 1.61 (td, J = 9.3, 3.7 Hz, 2H), 0.82 (d, J = 6.7 Hz, 3H). [0280] The following compound was prepared in a similar manner as described for Intermediate 197. Intermediate No. Chemical Name Structure NMR or ES-MS m/z *1 H), 7.56 (t, J = 7.6 Hz, 1H), 7.53 – 7.45 (m, 1H), 5.25 (dd, J = 7.0, 4.5 Hz, 2H), 5.09 (dd, J = 11.7, 6.9 Hz, 2H), 4.22 (s, 1H), 3.47 (s, 2H), 1.93 – 1.81 (m, 2H), 1.75 (dtt, J = 13.9, 6.7, 3.3 Hz, 3H), 1.60 (td, J = 9.9, 5.4 Hz, 2H), 0.87 (d, J = 6.9 Hz, 3H). Preparation of Intermediate 199: (3R,4S)-3-Methyl-1-(3-methyloxetan-3-yl)piperidin-4-ol [0281] To a N2-filled 500 mL three-neck RBF with a magnetic stir bar was added methylmagnesium chloride, 3.0 M in THF (37.0 mL, 111 mmol) at ambient temperature. The mixture was cooled to 0 °C. A mixture of (3R,4S)-1-(3-(1H-benzo[d][1,2,3]triazol-1- yl)oxetan-3-yl)-3-methylpiperidin-4-ol (7.12 g, 22.2 mmol) in 1,4-dioxane (140 mL) was added to the above mixture dropwise at 0 °C. The reaction mixture was heated at 50 °C for 3 h. To the reaction mixture was added sat. aq. NH4Cl (100 mL). The mixture was diluted with CHCl3/IPA (4:1) (100 mL). The mixture was filtered through diatomaceous earth and the cake was washed twice with CHCl3/IPA (4:1) (100 mL). The mixture was extracted with CHCl3/IPA (4:1) (100 mL × 3). The combined organic layers were washed with sat. aq. NaCl (200 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 6% MeOH in EtOAc to give the title compound (3.15 g). ES-MS m/z 186 (M+H). [0282] The following compounds were prepared in a similar manner as described for Intermediate 199. Intermediate No. Chemical Name Structure NMR or ES-MS m/z * .6, 1.8 Hz, 2H), 4.02 (s, 0.5H), 3.45 (d, J = 9.5 Hz, 3H), 3.42 – 3.36 (m, 1H), 3.17 (td, J = 9.1, 4.5 Hz, 0.5H), 2.80 (ddd, J = 10.7, 4.6, 2.2 Hz, 0.5H), 2.58 (s, 0.5H), 2.51 – 2.33 (m, 2H), 2.25 (s, 0.5H), 2.22 – 2.07 (m, 1H), 2.05 – 1.81 (m, 1.5H), 1.75 (s, 0.5H), 1.62 (qd, J = 12.0, 4.3 Hz, 0.5H), 1.37 (d, J = 4.3 Hz, 3H) as a mixture of diastereomers. Preparation of Intermediate 202: Racemic tert-butyl 5-hydroxy-7-oxa-3- azabicyclo[4.1.0]heptane-3-carboxylate [0283] To a N2-filled 100 mL RBF stir bar was added racemic tert-butyl 3-hydroxy-3,6-dihydropyridine-1(2H)- (2.0 g, 9.8 mmol) and DCM (40 mL) successively at ambient temperature. The vessel was purged with N23 times. The reaction mixture was cooled to 0 °C and Na2CO3 (1.1 g, 9.8 mmol) and mCPBA (3.0 g, 15 mmol) were added at 0 °C. The reaction mixture was warmed to 20 °C and stirred at 20 °C for 16 h to give a white suspension. The reaction mixture was diluted with DCM (50 mL) and the mixture filtered. The filtrate was washed with sat. aq. Na2HCO3 (50 mL × 2) and sat. aq. NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 20% EtOAc in cyclohexane to give the title compound (1.74 g). ES-MS m/z 160 (M-tBu+H). Preparation of Intermediate 203: (E)-3-(2-((3-Methylbicyclo[1.1.1]pentan-1- yl)methylene)hydrazineyl)propanenitrile [0284] To a 1000 mL flask added 3-hydrazineylpropanenitrile (28.7 g, 337 mmol), THF (370 mL), and 3-methylbicyclo[1.1.1]pentane-1-carbaldehyde (37.0 g, 336 mmol) sequentially at RT. The reaction mixture was stirred at RT for 2 h. The reaction was concentrated to give the title compound (60 g) used without further purification. ES-MS m/z 178 (M+H). Preparation of Intermediate 204: 1-((3-Methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazol- 5-amine [0285] To a 1000 mL flask equipp let was added (E)-3-(2-((3- methylbicyclo[1.1.1]pentan-1-yl)methy ene) ydrazineyl)propanenitrile (60.0 g, 270.80 mmol), n-BuOH (600 mL), and KOtBu (60.78 g, 541.7 mmol) sequentially at RT. The reaction mixture was heated at 120 °C for 2 h. The reaction mixture was cooled to RT. The reaction mixture was concentrated under vacuum at 45 °C to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 10 to 30% EtOAc in petroleum ehter to give the title compound (17.2 g). ES-MS m/z 178 (M+H). [0286] The following compound was prepared in a similar manner as described for Intermediate 73. Intermediate No. Chemical Name Structure ES-MS m/z ) [0 ] e o ow ng compoun was prepare n a s m ar manner as escr e or Intermediate 88. Intermediate No. Chemical Name Structure ES-MS m/z ) [0288] The following compounds were prepared in a similar manner as described for Intermediate 86. Intermediate No. Chemical Name Structure ES-MS m/z ) ) [0 g p p p Intermediate 87. Intermediate No. Chemical Name Structure ES-MS m/z ) [0290] The following compounds were prepared in a similar manner as described for Intermediate 91. Intermediate No. Chemical Name Structure ES-MS m/z Racemic 4-(2-(((tert- butyldimethylsilyl)oxy)meth ) ) ) ) Racemic 4-(3-((5- ) ) ) ) Racemic 4-(4-((5- ) ) ) ) 44 35Difl idi 2 ) ) ) ) H) dihydrobenzo[d]oxazol-6-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile N H N N [0291] A mixture of 3- 1.016 mmol), 5-methyl-3- oxohexanenitrile (129.7 mg, 1.016 mmol), and 3-((5-chloropyrimidin-2-yl)methyl)-2-oxo- 2,3-dihydrobenzo[d]oxazole-6-carbaldehyde (272.4 mg, 846.3 μmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 16 h under air. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (322 mg). ES-MS m/z 460 (M+H). [0292] The following compound was prepared in a similar manner as described for Intermediate 227. Intermediate No. Chemical Name Structure ES-MS m/z H) P -3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0293] To a 100 mL RBF under a N2 atmosphere was added 4- ((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carbaldehyde (1.30 g, 4.29 mmol) followed by dioxane (20 mL). Once the solids were all dissolved, racemic 6,6,6-trifluoro-5-methyl-3-oxohexanenitrile (1.00 g, 5.58 mmol) followed by 1H-pyrazol-5-amine (392 mg, 4.72 mmol) were added and the mixture heated at 100 °C for 1.5 h. The reaction was cooled to RT. The mixture was filtered through a fritted filter and the filter cake washed with EtOAc. The filtrate was evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 10 to 60% EtOAc in cyclohexane to give the title compound (1.69 g). ES-MS m/z 528 (M+H). Preparation of Intermediate 230: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile
[0294] To a solution of 4-(4-((5-c -2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile (4.0 g, 5.4 mmol) in THF (14 mL) was added 6N hydrogen chloride (14 mL, 81 mmol). The mixture was stirred at 25 °C for 2 h. The pH was adjusted to around 7 by progressively adding sat. aq. NaOH. The mixture was extracted with EtOAc (60 mL × 2). The combined organic layers were washed with sat. aq. NaCl (60 mL), dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give the title compound (3.1 g). ES-MS m/z 570 (M+H). [0295] The following compounds were prepared in a similar manner as described in General Procedure F. Intermediate No. Chemical Name Structure ES-MS m/z
Racemic tert-butyl (cis)- 4-(4-(4-((5-chloro-3- ) ) ) ) pyrazolo[3,4-b]pyridine- 5-carbonitrile ) ) ) Racemic 4-(4-((5-chloro- 3fl idi 2 ) ) )
tert-Butyl (3R4R)-4-(4- ) ) Racemic tert-butyl 4-(4- ) ) ) ) ) ) Racemic 4-(4-((5- hl i ii 2 ) ) ) 4-(4-((3,5- ) ) ) 4-(4-((5- hl i ii 2 ) ) ) tert-Butyl (3R,4R)-4-(4- ) ) ) b]pyridine-5- carboxamide ) ) ) [0296] The following compounds were prepared in a similar manner as described for Intermediate 23. Intermediate No. Chemical Name Structure ES-MS m/z ) ) ) R i t t tl i 4 ) ) )
) ) ) ) ) Racemic tert-butyl (3R,4R)- ) ) ) ) ) ) ) ) ) H) H) [0 297] The following compounds were prepared in a similar manner as described for Intermediate 96. Intermediate No. Chemical Name Structure ES-MS m/z ) 1-((3-(((tert- Butyldiphenylsilyl)oxy)m eth l)bic clo[111] entan H) , -2- yl)methyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl- 1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylpiperidine-1-carboxylate [0298] To a mixture of racemic 2-yl)methyl)-2-methyl-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (363 mg, 617 μmol), tert-butyl (3R,4S)-4-hydroxy-3-methylpiperidine-1- carboxylate (206 mg, 926 μmol), and tributyl phosphine (1.58 mL, 6.17 mmol) in toluene (6 mL) was added TMAD (1.10 g, 6.17 mmol). The mixture was degassed with N2 for 5 min and stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with sat. aq. NaCl (20 mL × 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 30% EtOAc in hexanes to give the product. The product was further purified by prep-TLC (hexanes: EtOAc= 3:1, Rf= 0.1). The product was further purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 60-100% ACN in water (10 mM NH4CO3) over 20 min. The product was further purified by prep-TLC (hexanes: EtOAc= 3:1, Rf= 0.1) to give the title compound (82 mg). ES-MS m/z 685 (M+H). [0299] The following compounds were prepared in a similar manner as described for Intermediate 292. Intermediate No. Chemical Name Structure ES-MS m/z ) )
H) P , ydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile (mixture of isomers) O N [0300] To a mixture of 4-(4-((5- 2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (205 mg, 411 μmol) in toluene (4.0 mL) was added racemic 1-(4-hydroxycyclohexyl)pyrrolidin-2-one (157 mg, 814 μmol), triphenylphosphine (558 mg, 2.06 mmol), and DBAD (492 mg, 2.07 mmol). The mixture was bubbled with N2 for 3 min and stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with sat. aq. NaCl (20 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in hexanes to give the title compound (196 mg). ES-MS m/z 639 (M+H). Preparation of Intermediate 297: Racemic tert-butyl 4-(5-cyano-4-(4-((5-fluoropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)-3,5-dihydroxypiperidine-1-carboxylate [0301] To a 20 mL sealed vial fluoropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4] - pyrazolo[3,4-b]pyridine-5- carbonitrile (300 mg, 610 μmol), DMSO (6 mL), and DBU (281 μL, 1.83 mmol) successively at ambient temperature. Then racemic tert-butyl 5-hydroxy-7-oxa-3- azabicyclo[4.1.0]heptane-3-carboxylate (200 mg, 883 μmol) was added. The vessel was degassed with N2 for 5 min. The reaction mixture was heated to 100 °C and stirred for 1 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water (10 mL) and sat. aq. NaCl (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 32-72% ACN in water (10 mM NH4HCO3) over 20 min at a flow rate of 60 mL/min to give the title compound (79 mg). ES-MS m/z 673 (M+H). Preparation of Intermediate 298: Racemic tert-butyl 4-(5-cyano-4-(4-((5-fluoropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)-3,5-difluoropiperidine-1-carboxylate
[0302] To a N2-filled 50 mL thr a magnetic stir bar was added racemic tert-butyl 4-(5-cyano-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,5- dihydroxypiperidine-1-carboxylate (200 mg, 294 μmol) and DCM (5 mL) successively at ambient temperature. The vessel was degassed and purged with N23 times. The mixture was cooled with dry ice-EtOH bath while keeping external temperature -70 °C. Then DAST (160 μL, 1.18 mmol) was added dropwise at -70 °C. The reaction mixture was stirred at 20 °C for 16 h. To the reaction mixture was added sat. aq. NaHCO3 at 0 °C to adjust the pH to ~8. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were washed with sat. aq. NaCl (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by reversed-phase chromatography on a SepaFlash Column, C18 (80 g) column using a gradient of 0-60% ACN in water at a flow rate of 50 mL/min to give the title compound (140 mg). ES-MS m/z 677 (M+H). Preparation of Intermediate 299: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-((2,2-difluorocyclopropyl)methyl)-1-((3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile
[0303] A vial equipped with a ert- butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-((5-chloropyrimidin- 2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((2,2- difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (488 mg, 570 μmol) was added THF (2.28 mL). Tetrabutylammonium fluoride (1M) (1.14 mL, 1.14 mmol) was added and the reaction was stirred at RT for 30 min. Water was added to the reaction, followed by EtOAc. The layers were separated. The aq. phase was further extracted with EtOAc (3 × 25 mL). The organic phase was washed with sat. aq. NaCl (3 × 50 mL). The organic phase was dried over MgSO4, filtered, and the filtrate concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (110 mg). ES-MS m/z 618 (M+H). Preparation of Intermediate 300: Racemic tert-butyl (trans)-4-(4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H- pyrazolo[3,4-b]pyridin-1-yl)-3-(methylsulfonyl)piperidine-1-carboxylate [0304] To a 100 mL RBF equipped with a magnetic stir bar was charged with racemic tert-butyl (trans)-4-(4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3- (methylthio)piperidine-1-carboxylate (995 mg, 1.33 mmol) and DCM (20 mL) successively at ambient temperature. m-CPBA (677.9 mg, 3.339 mmol) was added into the reaction mixture at 0 °C. The reaction mixture was warmed to RT and stirred for 2 h. The residue was poured into sat. aq. Na2SO3 solution (30 mL) and stirred for 15 min. The aq. phase was extracted with DCM (20 mL × 2). The combined organic phase was washed with sat. aq. NaCl (50 mL × 1), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under vacuum. The crude product was purified by silica gel column chromatography using a gradient of 0 to 46% EtOAc in hexanes to give the title compound (909 mg). ES-MS m/z 735 (M+H). Preparation of Intermediate 301 and 302: Racemic tert-butyl (trans)-4-(4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6- isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-(methoxymethyl)piperidine-1-carboxylate (Intermediate 301) and Racemic tert-butyl (cis)-4-(4-(4-((5-chloropyrimidin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-1-yl)-3-(methoxymethyl)piperidine-1-carboxylate (Intermediate 302) O [0305] Racemic tert-butyl 4-(4- 2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3- (methoxymethyl)piperidine-1-carboxylate was separated by SFC (Column: Daicel Chiralpak IM (50 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 200) to give the separated isomer mixtures. Intermediate 301: ES-MS m/z 701 (M+H). Intermediate 302: ES-MS m/z 701 (M+H). Preparation of Intermediate 303: Racemic 4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-(methylsulfonyl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0306] To a dried 100 mL RBF stirrer were added racemic tert- butyl (trans)-4-(4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-5-cyano-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3- (methylsulfonyl)piperidine-1-carboxylate (908.9 mg, 1.113 mmol), DCM (6 mL), and TFA (6.50 mL, 83.5 mmol) successively at ambient temperature. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to remove most of the solvents. The pH of the mixture was adjusted to ~ 8 with sat. aq. NaHCO3. The mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the title compound (762). ES-MS m/z 635 (M+H). [0307] The following compounds were prepared in a similar manner as described for Intermediate 303. Intermediate No. Chemical Name Structure ES-MS m/z Racemic 4-(4-((5-chloro-3- ) ) ) ) Racemic 4-(3-((5- ) ) ) ) 4-(4-((5-Chloropyrimidin- ) ) ) ) 4-(4-((5-Chloro-3- ) ) [0 308] The following compounds were prepared in a similar manner as described for Intermediate 109. Intermediate No. Chemical Name Structure ES-MS m/z ) Racemic 4-(4-((5-chloro- ) ) ) ) [0309] The following compounds were prepared in a similar manner as described for Intermediate 119. Intermediate No. Chemical Name Structure ES-MS m/z H 4-(4-((5-Chloro-3- N CF3CO2H ) ) ) 4-(4-((5- Chloropyrimidin-2- l)meth l)-3-oxo-34- ) ) ) ) Racemic 4-(4-((5- chloropyrimidin-2- ) ) ) ) Racemic 4-(4-((5- chloropyrimidin-2- l)meth l)-3-oxo-34- ) ) ) ) 4-(4-((5- Chloropyrimidin-2- ) ) ) ) Preparation of Intermediate 342: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0310] A 25-mL vial containing sequentially with tert-butyl (3R,4R)-4-(5-carbamoyl-4-(4-((5- methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylpiperidine-1- carboxylate (205 mg, 297 μmol), DCM (4 mL), and TFA (1 mL, 0.01 mol). The vial was flushed with N2 and sealed with a screw cap. The reaction was stirred at RT for 1 h. Cyclohexane (5 mL) was added and the mixture concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography on a Teledyne ISCO RediSep C18 Gold® (100 g) column using a gradient of 10-100% ACN in water (10 mM NH4CO3 + 5% MeOH) at a flow rate of 60 mL/min and then switching solvent A to 100% MeOH to give the title compound (161 mg). ES-MS m/z 589 (M+H). Preparation of Intermediate 343: Racemic 1-(3,5-difluoropiperidin-4-yl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile hydrochloride
[0311] To a N2-filled 50 mL R tir bar was added racemic tert-butyl 4-(5-cyano-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,5- difluoropiperidine-1-carboxylate (140 mg, 186 μmol) and 2M HCl in EtOAc (5.00 mL, 10.0 mmol) successively at ambient temperature. Then the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (125 mg). ES-MS m/z 577 (M+H). [0312] The following compound was prepared in a similar manner as described for Intermediate 343. Intermediate No. Chemical Name Structure ES-MS m/z ) Preparation of Intermediate 345a and 345b: 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Intermediate 345a and Isomer 2 – Intermediate 345b)
[0313] Racemic 4-(4-((5-chloro- -yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL CHIRALPAK IK (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 55%; End B: 55%; Flowrate (mL/min): 130) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 622 (M+H). Isomer 2: ES-MS m/z 622 (M+H). The products were analyzed by SFC (Column: Chiralpak IK-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Begin B: 40 %; End B: 40 %; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 40 °C). Isomer 1: 98 %ee, enriched in peak 1, retention time 1.023 min. Isomer 2: 97%ee, enriched in peak 2, retention time 1.769 min. Preparation of Intermediate 346a and 346b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Intermediate 346a and Isomer 2 – Intermediate 346b)
[0314] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL CHIRALPAK IG (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); Begin B: 60%; End B: 60%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 605 (M+H). Isomer 2: ES-MS m/z 605 (M+H). The products were analyzed by SFC (Column: Chiralpakl IG-3 (4.5 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% NH3(7M in MeOH)); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: 95%ee, enriched in peak 1, retention time 1.104 min. Isomer 2: 99%ee, enriched in peak 2, retention time 1.536 min. Preparation of Intermediate 347: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,7- dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[0315] To a 100 mL RBF equipped with a stir bar was added ethyl cyanoacetate (1.1 mL, 10 mmol) followed by EtOH (39.0 mL). To this solution was added piperidine (1.0 mL, 10 mmol) and 4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (3.00 g, 9.76 mmol). The reaction was capped, and heated at 45 °C for 30 h. To the reaction mixture was added 1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazol-5-amine (1.84 g, 10.2 mmol), EtOH (9.75 mL), and TEA (1.4 mL, 10 mmol). The vial was re-capped and heated at 80 ºC for 4 days. The reaction was cooled to RT. A solid crashed out and was filtered, and washed with EtOH to give the title compound (2.09 g). ES-MS m/z 529 (M+H). Preparation of Intermediate 348: 6-Chloro-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile [0316] To a pressure vial added 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (516 mg, 976 μmol), DMF (120 μL, 1.55 mmol), and SOCl2 (8.0 mL, 0.11 mol). The vial was sealed and heated at 80 °C for 17.5 h. The reaction was allowed to cool to RT and then was slowly quenched by the adding the reaction mixture to an ice-cold solution of sat. aq. sodium bicarbonate. The solution was extracted with EtOAc × 3. The combined organic layers were dried over Na2SO4, filtered, and the filtrate concentrated. The crude product was purified by reversed-phase chromatography on a Teledyne ISCO RediSep C18 Gold® (100g) column using a gradient of 0-100% ACN in water (10 mM NH4CO3) at a flow rate of 60 mL/min to give the title compound (192 mg). ES-MS m/z 547 (M+H). Preparation of Intermediate 349: Racemic 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-6- (3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0317] To a vial equipped chloro-4-(4-((3,5-difluoropyridin- 2-yl)methyl)-3-oxo-3,4-dihydro- 7-yl)-1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (50 mg, 91 μmol), pyridine-2,6-bis(carboximidamide) dihydrochloride (4.9 mg, 21 μmol), and nickel(II) chloride ethylene glycol dimethyl ether complex (4.6 mg, 21 μmol). Racemic 3- bromo-1,1,1-trifluoropropan-2-ol (20 μL, 0.19 mmol) was added as a liquid, followed by DMA (0.91 mL). The suspension was stirred until everything went into solution (1 min) and the solution was a dark teal. The reaction was sparged with N2 for 5 min, and then zinc (35 mg, 0.54 mmol) was added. The vial was sealed with a crimp cap and heated at 65 °C for 17 h. The reaction was allowed to cool to RT and then filtered through diatomaceous earth with DCM and MeOH. The filtrate was concentrated under reduced pressure. The filtrate was taken up in MeOH and filtered through a syringe filter. The crude product was purified by reversed-phase chromatography on a Teledyne ISCO RediSep C18 Gold® (50 g) column using a gradient of 10-100% ACN in water (10 mM NH4CO3) at a flow rate of 40 mL/min to give the title compound (45.6 mg). ES-MS m/z 625 (M+H). [0318] The following compound was prepared in a similar manner as described for Intermediate 349. Intermediate No. Chemical Name Structure ES-MS m/z 4-(4-((3,5-Difluoropyridin- 2-yl)methyl)-3-oxo-3,4- H) P -3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-1-(3,3-difluorocyclobutyl)-3- (methylsulfonyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0319] To a 40 mL vial stir bar was added racemic 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((trans)-3-(methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (400.7 mg, 567.8 μmol), Me-THF (5 mL), TFA (442.9 μL, 5.69 mmol), 3,3-difluorocyclobutan-1- one (246.5 mg, 2.28 mmol), and borane-2-methylpyridine complex (308.4 mg, 2.83 mmol) successively at ambient temperature. The reaction mixture was heated to 50 °C and stirred for 1 h. The reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 47% EtOAc in hexanes to give the title compound (295 mg). ES-MS m/z 725 (M+H). [0320] The following compounds were prepared in a similar manner as described for Intermediate 351. Intermediate No. Chemical Name Structure ES-MS m/z ) ) ) ) ) ) ) ) ) H) H) Preparation of Intermediate 363: Racemic 4-(4-((5-chloro-1,2-dihydropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3- difluorocyclobutyl)-3-methoxypiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile
F F [0321] In a 100 mL RBF ((5-chloropyrimidin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4] - 1-(3-methoxypiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile tris(2,2,2-trifluoroacetate) (329 mg, 354 μmol) was added Me-THF (5 mL). Once the material was completely dissolved, TFA (545 μL, 7.08 mmol) was added followed by borane-2-methylpyridine complex (568 mg, 5.31 mmol). The mixture was stirred for 10 min when 3,3-difluoro-cyclobutanone (375 mg, 3.54 mmol) was added and the mixture stirred for 1.5 h. Additional borane-2-methylpyridine complex (568 mg, 5.31 mmol) followed by 3,3-difluoro-cyclobutanone (375 mg, 3.54 mmol) were added and the mixture stirred for an additional 19 h. The reaction was quenched with water (30 ml) and then diluted with EtOAc (30 mL). The aq. solution was isolated and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and the filtrate evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane followed by a gradient from EtOAc to 10% MeOH in EtOAc to give the title compound (118 mg). ES-MS m/z 679 (M+H). Preparation of Intermediate 364: Racemic 4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3-difluorocyclobutyl)-3- methoxypiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[0322] To a solution of racemic 2-dihydropyrimidin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3-difluorocyclobutyl)-3- methoxypiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (118 mg, 174 μmol) in ACN (1 mL) was added manganese dioxide (120 mg, 1.38 mmol). The mixture was heated at 80 °C for 2 h. The reaction was cooled to RT. The mixture was filtered through a frit and the filter cake was washed with EtOAc. The filtrate was evaporated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (52 mg). ES-MS m/z 677 (M+H). Preparation of Intermediate 365: Racemic 4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-(methylthio)-1-(oxetan-3- yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[0323] To a 40 mL sealed vial equipped with a magnetic stir bar was charged racemic 4- (4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1-((trans)-3-(methylthio)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (285.6 mg, 450 μmol), MeOH (4 mL), and AcOH (140 μL, 2.32 mmol) successively at ambient temperature. Sodium cyanoborohydride (61.2 mg, 925 μmol) and oxetan-3-one (151.2 mg, 1.99 mmol) were added, and the resulting mixture was heated at 50 °C and stirred for 2 h. The residue was dissolved in DMF (5 mL) and purified by reversed phase chromatography on a SepaFlash C18 (25 g) column using a gradient of 5-72% MeOH in water at a flow rate of 30 mL/min to give the title compound (305 mg). ES-MS m/z 659 (M+H). [0324] The following compounds were prepared in a similar manner as described for Intermediate 365. Intermediate No. Chemical Name Structure ES-MS m/z H) H) ) ) ) R i 44 ) ) ) ) ) ) H) H) [0 325] The following compounds were prepared in a similar manner as described for Intermediate 125. Intermediate No. Chemical Name Structure ES-MS m/z
) ) ) Racemic 4-(4-((3,5- ) ) ) Racemic 4-(4-((5- ) ) ) H) [0 General Procedure D. Intermediate No. Chemical Name Structure ES-MS m/z H)
Racemic 4-(4-((5- H) Pr , , ydro- 2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(1,1-dioxidothietan-3-yl)-3-methylpiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0327] To a vial equipped with with 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (132 mg, 231 μmol) and 3- bromothietane 1,1-dioxide (107 mg, 578 μmol). THF (2 mL) was added followed by DIEA (150 μL, 861 μmol). The reaction was heated at 60 °C for 19 h. The reaction was diluted with EtOAc and sat. aq. sodium bicarbonate (10 mL each). The layers were separated. The aq. phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and the filtrate concentrated to give the title compound (155 mg). ES- MS m/z 676 (M+H). [0328] The following compound was prepared in a similar manner as described for Intermediate 392. Intermediate No. Chemical Name Structure ES-MS m/z H) P repara on o nerme ae : -(-((,- uoropyr n--y)me y)--oxo-,- ydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-(3-methoxybicyclo[1.1.1]pentan-1- yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0329] To an 8 mL sealed vial bar was added 3- methoxybicyclo[1.1.1]pentan-1-amine hydrochloride (81 mg, 0.53 mmol), sodium carbonate (58.7 mg, 543 μmol) and DMA (2 mL). The mixture was stirred at 20 °C for 2 h. To another 8 mL sealed vial with a magnetic stir bar was added 1-(1,5-dichloropentan-3-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (180.8 mg, 265.2 μmol), sodium iodide (103 mg, 673 μmol), DIPEA (104 mg, 789 μmol) and the above solution. The mixture was bubbled with N2 for 5 min and stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with sat. aq. NaCl (10 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 16-56% ACN in water (0.225% formic acid) over 20 min. The pH of the fraction was adjusted to ~ 8 by sat. aq. NaHCO3. The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with sat. aq. NaCl (20 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the title compound (61.2 mg). ES-MS m/z 654 (M+H). [0330] The following compounds were prepared in a similar manner as described in Intermediate 394. Intermediate No. Chemical Name Structure ES-MS m/z
) ) ) Preparation of Intermediate 399: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(2-hydroxy-2-methylpropanoyl)-3- methylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0331] To a 2-dram vial added 4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H- 7-yl)-6-isobutyl-1-((3R,4R)-3- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 2,2,2-trifluoroacetate (83 mg, 0.12 mmol), HATU (92 mg, 0.24 mmol), and DMF (1.2 mL). The reaction was capped and allowed to begin stirring. 2-Hydroxy-2-methylpropanoic acid (15 mg, 0.14 mmol) and DIPEA (70 μL, 0.40 mmol) were added. The vial was recapped and allowed to stir for 16 h. The reaction was diluted with water and EtOAc. The mixture was extracted with EtOAc (x2). The combined organic layers were washed with water (x2). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated to give a crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (60 mg). ES-MS m/z 657 (M+H). Preparation of Intermediates 400a and 400b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-1-(3- methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (Isomer 1 – Intermediate 400a and Isomer 2 – Intermediate 400b) and 4-(4-((5- Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1-((cis)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile (Isomer 2)
[0332] Racemic 4-(4-((5-chlorop ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-3- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALCEL OX (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 130) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 667 (M+H). Isomer 2: ES-MS m/z 667 (M+H). The products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.2% NH3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.14 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.48 min. Preparation of Intermediates 401a and 401b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-1-(3- methoxybicyclo[1.1.1]pentan-1-yl)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (Isomer 1 – Intermediate 401a and Isomer 2 – Intermediate 401b)
[0333] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-3- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALCEL OX (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); Begin B: 45%; End B: 45%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 667 (M+H). Isomer 2: ES-MS m/z 667 (M+H). The products were analyzed by SFC (Column: Chiralpak IM-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% NH3(7M in MeOH)); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.48 min. Isomer 2: 98%ee, enriched in peak 2, retention time 1.78 min. Preparation of Intermediates 402a and 402b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-2- methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(3,3-difluoropropyl)-1-((3R,4R)- 3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (Isomer 1 – Intermediate 402a and Isomer 2 – Intermediate 402b)
[0334] Racemic 4-(4-((5-chloro thyl)-2-methyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-(3,3-difluoropropyl)-1-((3R,4R)-3-methyl-1-(oxetan-3- yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALPAK AD (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1 % NH3H2O); Begin B: 45%; End B: 45%; Flowrate (mL/min): 140) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 663 (M+H). Isomer 2: ES-MS m/z 663 (M+H). The products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.06 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.45 min. Preparation of Intermediates 403a and 403b: 4-(4-((5-Fluoropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-3-methyl-1-(3-methyloxetan-3- yl)piperidin-4-yl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (Isomer 1 – Intermediate 403a and Isomer 2 – Intermediate 403b)
[0335] Racemic 4-(4-((5-fluorop thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-3-methyl-1-(3-methyloxetan-3-yl)piperidin-4-yl)-6- (3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALPAK IA (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 679 (M+H). Isomer 2: ES-MS m/z 679 (M+H). The products were analyzed by SFC (Column: Chiralpak IA-3 (4.6 mm × mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.15 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.37 min. Preparation of Intermediates 404a and 404b: 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(3- methyloxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (Isomer 1 – Intermediate 404a and Isomer 2 – Intermediate 404b)
[0336] Racemic 4-(4-((5-chloro- -yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(3-methyloxetan-3-yl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALPAK AD (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 674 (M+H). Isomer 2: ES-MS m/z 674 (M+H). The products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 0.95 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.27 min. [0337] The following compounds were prepared in a similar manner as described in General Procedure G. Intermediate No. Chemical Name Structure ES-MS m/z Racemic 4-(4-((5- ) ) ) Racemic 4-(4-((5- ) ) ) R mi trt-btl (i)-4- ) ) ) H) 3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0338] To a vial equipped with a 4-(4-((5-chloro-3-fluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4S)-3-fluoropiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 2,2,2-trifluoroacetate (66 mg, 93 μmol), DIEA (20 μL, 0.11 mmol), and THF (1.0 mL). Methanesulfonyl chloride (15 μL, 0.19 mmol) was added. The reaction was allowed to stir at RT for 10 min. The reaction was concentrated under reduced pressure and dried under vacuum to give a crude product. The crude product was purified by reversed-phase chromatography on a Teledyne ISCO RediSep C18 Gold® (30 g) column using a gradient of 10-100% ACN in water (0.1% formic acid) at a flow rate of 35 mL/min to give the title compound (57 mg). ES-MS m/z 670 (M+H). Preparation of Intermediate 416: Racemic 4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(3,3,3-trifluoro-2- hydroxypropyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [0339] To a 40 mL sealed vial bar was added 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((3R,4R)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (150 mg, 213 μmol), racemic 3-bromo-1,1,1-trifluoropropan-2-ol (65.8 mg, 324 μmol), ACN (5 mL) and potassium carbonate (62.0 mg, 440 μmol) successively at ambient temperature. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with sat. aq. NaCl (10 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a crude product. The product was purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 38-78% ACN in water (0.225% formic acid) over 19 mins to give the title compound (106 mg). ES-MS m/z 683 (M+H). Preparation of Intermediates 417a and 417b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(3,3,3-trifluoro- 2-hydroxypropyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (Isomer 1 – Intermediate 417a and Isomer 2 – Intermediate 417b)
[0340] Racemic 4-(4-((5-chloropy ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(3,3,3-trifluoro-2- hydroxypropyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile was separated by SFC (Column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); Begin B: 35%; End B: 35%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 683 (M+H). Isomer 2: ES-MS m/z 683 (M+H). The products were analyzed by SFC (Column: Chiralpak IG-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% NH3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.37 min. Isomer 2: 99%ee, enriched in peak 2, retention time 1.48 min. Example 1: 1-((3-Aminobicyclo[1.1.1]pentan-1-yl)methyl)-4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0341] To a solution of tert- -(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)bicyclo[1.1.1]pentan-1- yl)carbamate (96 mg, 0.15 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 1.5 h. The solvent was evaporated to give a residue that was purified by reverse phase HPLC using a gradient of 23 to 58% ACN in 10 mM aq. NH4HCO3 + 5% MeOH to give the title compound (52 mg). ES-MS m/z 556 (M+H). Example 2: Racemic 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-1-(2,2-dimethylpiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 1:2 solvate with methanol [0342] A solution of racemic 4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-2,2-dimethylpiperidine-1- carboxylate (46 mg, 68 μmol) and TFA (1.5 mL, 19 mmol) in DCM (1.5 mL) was stirred at RT for 2 h. The solvent was evaporated to give a residue that was purified by reverse phase HPLC using a gradient of 33 to 67% ACN in 10 mM aq. NH4HCO3 + 5% MeOH to give the title compound (35 mg). ES-MS m/z 572.2 (M+H). Examples 3a and 3b: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-((cis)-2- (trifluoromethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer mixture 1 – 3a, and Isomer mixture 2 – 3b) [0343] The title compound of isomers in a manner analogous to the Preparation of Intermediate hydroxy-2- (trifluoromethyl)piperidine-1-carboxylate (mixture of isomers), followed by nitrile hydrolysis in a similar manner as described in the Preparation of Intermediate 14, followed by Boc de- protection in a similar manner as described in Example 2. The isomers were separated by reverse phase flash chromatography using a gradient of 33 to 67% ACN in 10 mM aqueous ammonium bicarbonate with 5% MeOH to give Isomer mixture 1 (first-eluting, Example 3a) and Isomer mixture 2 (second-eluting, Example 3b). Both isomer mixtures: ES-MS m/z 612 (M+H). Example 4: Cis tert-butyl (3-((5-carbamoyl-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1- yl)methyl)cyclobutyl)(methyl)carbamate
[0344] A solution of Cis tert-butyl (3-((5-cyano-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)cyclobutyl)(methyl)carbamate (458 mg, 683 μmol) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (29 mg, 68.3 μmol) in EtOH (5 mL) and water (0.5 mL) was heated at 80 °C overnight. The reaction was cooled to RT. The mixture was diluted with EtOH and evaporated. The residue was co-evaporated three times with EtOH. The residue was purified by silica gel chromatography eluting with a gradient from 0-100% EtOAc in cyclohexane to give the title compound (223 mg). ES-MS m/z 689.4 (M+H). Example 5: Cis 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 6-isobutyl-1-((3-(methylamino)cyclobutyl)methyl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0345] To a solution of cis 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1- yl)methyl)cyclobutyl)(methyl)carbamate (217 mg, 315 μmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 1 h. The solvent was evaporated, and the residue was purified by reverse phase HPLC using a gradient of 35 to 60% ACN in 10 mM NH4HCO3 + 5% MeOH to give the title compound (160 mg). ES-MS m/z 589.2 (M+H). Example 6: Cis 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 1-((3-(dimethylamino)cyclobutyl)methyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide
[0346] To a mixture of cis 4-( 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3-(methylamino)cyclobutyl)methyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (155 mg, 263 μmol) in MeOH (2 mL) was added acetic acid (15.1 μL, 263 μmol) followed by formaldehyde (98.0 μL, 37% Wt, 1.32 mmol). The mixture was stirred for 1 h at RT. Sodium cyanoborohydride (36.4 mg, 579 μmol) was added all at once and the reaction was stirred for 3 h at RT. The mixture was concentrated, and the residue dissolved in water. The mixture was extracted with 3 portions DCM (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and evaporated to give a residue that was purified by reverse phase HPLC using a gradient of 40 to 55% ACN in 10 mM aq. NH4HCO3 + 5% MeOH to afford the title compound (62 mg). ES-MS m/z 603.2 (M+H). Example 7: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(2-fluoroethyl)piperidin-4-yl)- 6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0347] The title compound was obtained after hydrolysis of 4-(1-(3,4-difluorobenzyl)- 1H-indazol-5-yl)-1-(1-(2-fluoroethyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carbonitrile using General Procedure B. ES-MS m/z 590 (M+H). Example 8: 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- ((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0348] To a solution of 1-((3- oxy)methyl)bicyclo[1.1.1]pentan- 1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (2.2 g, 3.1 mmol) in 60 mL of THF at RT was added dropwise tetrabutylammonium fluoride 1M in THF (3.7 mL, 3.7 mmol). After 17 h, to the mixture were added sat. aq. NH4Cl (50 mL) and EtOAc (30 mL). Phases were separated. The aq. phase was extracted with more EtOAc (2 × 30 mL). Organics were combined, washed with water and sat. aq. NaCl (20 mL each), dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography eluting from cyclohexanes/EtOAc 7:3 to EtOAc 100% to afford the title compound as a solid that was dried in the vacuum oven at 40 ºC overnight (0.95 g). ES-MS m/z 602 (M+H). Example 9: 1-(1-Cyclopropylpiperidin-4-yl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0349] A mixture of 1-(1-cyclop yl)-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (2.17 g, 3.64 mmol) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (312 mg, 727.4 μmol) in EtOH (18 mL) and H2O (2 mL) was heated at 80 °C for 28 h. After cooling to RT, solvents were removed in vacuum to give a residue that was purified by silica gel chromatography (DCM/EtOAc; 30 to 60%) to give a solid that was triturated from water (20 mL) with stirring at RT for 30 min. The resulting solid was filtered, washed with water, and dried in the vacuum oven at 40 ºC for 18 h to give the title compound as a solid (1.87 g). ES-MS m/z 615 (M+H). [0350] The following compounds were prepared by Mitsunobu reaction in a similar manner as described in General Procedure D using the appropriate alcohol, followed by nitrile hydrolysis using General Procedure B. Example No. Chemical Name Structure ES-MS m/z ) ) ) )
4-(1-(34- lysis b. Nitrile hydrolysis was done using General Procedure G Example 21: 3-Bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0351] The title compound manner as described in General Procedure F using 3-bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide and (3-methylbicyclo[1.1.1]pentan-1-yl)methanol. ES-MS m/z 633/635 (M+H). Example 22: 3-Bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0352] The title compound was ilar manner as described in General Procedure F using 3-bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-methylpiperidin-4-ol, followed by nitrile hydrolysis in a similar manner as described in General Procedure B. ES-MS m/z 636/638 (M+H). Example 23: 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0353] A mixture of ammonium mmol), 1-(1-methylpiperidin-4-yl)- 1H-pyrazol-5-amine (2.23 g, 12.4 mmol), 5-methyl-3-oxohexanamide (1.56 g, 10.9 mmol) and 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (3.00 g, 9.89 mmol) in EtOH (90 mL) was heated at 95 ºC for 44 h in a 250 mL sealed tube. On cooling to RT, DDQ (1.12 g, 4.95 mmol) was added portion-wise and the mixture stirred for 7 h. The mixture was then stored at 4 ºC for 72 h under N2, then stirred at RT for 5 h. The solvents were removed under vacuum to give a dark brown oil that was purified by column chromatography (EtOH in EtOAc; 0 to 40% mixtures as eluent). The product was dissolved in MeOH (25 mL) and loaded onto SCX resin (50 g), which was eluted first with MeOH and then ammonia (2 M). The product was re-purified by silica gel chromatography (MeOH in EtOAc and MeOH in DCM, 0 to 5% mixtures). The product was filtered through a 3 µm membrane (polish filtration). The combined organic solvents were reduced up to ~1/3 (ca.25 mL) and water (25 mL) was added dropwise and the mixture stirred for a further 30 min at RT. The resulting solid was filtered, washed with 7/3 water/MeOH mixture (25 mL) and water (25 mL), then dried under vacuum at 45 ºC for 18 h to afford the title compound (2.86 g). ES-MS m/z 589 (M+H). [0354] Alternatively, the title compound was prepared as follows. In an RBF under N2, a mixture of ammonium acetate (26.7 g, 346.2 mmol), 1-(1-methylpiperidin-4-yl)-1H-pyrazol- 5-amine (16.7 g, 93.5 mmol), 5-methyl-3-oxohexanamide (10.9 g, 76.2 mmol) and 4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (21.0 g, 69.2 mmol) in n-propanol (600 mL) was heated at 100 ºC for 6 h. Manganese dioxide (12.0 g, 138.5 mmol) was added portion-wise and the mixture was heated an additional 2 h at 100 ºC. After cooling to RT, the mixture was filtered through diatomaceous earth and washed with EtOH (2 L). The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (DCM to DCM/MeOH 9:1). The product was triturated in cyclohexanes/EtOAc 9:1 (300 mL) over 1 h, and then filtered. The solid was dried under vacuum at 40 ºC overnight to afford the title compound (22.1 g) as a solid. ES-MS m/z 587 (M-H). Example 24: 4-(1-(4-Chloro-3-fluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0355] The title compound was prepared in a similar manner as described in General Procedure A using 5-methyl-3-oxohexanamide, 1-(4-chloro-3-fluorobenzyl)-1H-indazole-5- carbaldehyde, and 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-amine. The product was purified by reverse-phase chromatography using a gradient of 40 to 65% ACN in aq. NH4HCO3 + 5% MeOH. ES-MS m/z 574 (M+H). Example 25a and 25b: 1-(1-Cyclopropylethyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 25a and Isomer 2 – Example 25 b) General Procedure H: MCR with [0356] To a vial with a stir bar was added 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde (100 mg, 330 μmol), 5-methyl-3-oxohexanamide (47 mg, 330 μmol), racemic 1-(1-cyclopropylethyl)-1H-pyrazol-5-amine (50 mg, 330 μmol), ammonium acetate (76 mg, 989 μmol), and EtOH (2.2 mL). The vial was capped, placed in a 100 ºC heating block, and stirred at 100 ºC for 20 h. The mixture was cooled down and concentrated under vacuum, and the residue was purified by reverse phase chromatography using a gradient of 40-77% ACN in 0.1% formic acid in water to give 124 mg of the title compound as a racemic mixture. The isomers were separated by chiral HPLC (column: Chiralpak® IG 30 × 250 mm, 5 µm; mobile phase: 1:3 (MeOH + 0.5% DMEA) : CO2; flow rate: 100 mL/min; column temperature: 40 °C] to give Isomer 1 (first-eluting isomer, 54 mg) and Isomer 2 (second-eluting isomer, 56 mg) of the title compound. Both isomers: ES-MS m/z 560 (M+H). Example 26: 4-(3-(3,4-Difluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-6-isobutyl-1- (1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0357] The title compound was prepared in a similar manner as described in General Procedure A using 5-methyl-3-oxohexanamide, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5- amine, and 3-(3,4-difluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde. ES- MS m/z 575 (M+H). [0358] The following compounds were prepared in a similar manner as described in General Procedure H using 5-methyl-3-oxohexanamide and the appropriate aldehyde and aminopyrazole. Example No. Chemical Name Structure ES-MS m/z 1-(Cyclohexylmethyl)- a. S) column temperature: 40 °C] to give Isomer 1 (first-eluting isomer) and Isomer 2 (second- eluting isomer). Example 31: 4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- ((2,2-difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (Isomer 2) [0359] The title compound was to General Procedure G using racemic 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((2,2- difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile, followed by chiral SFC [column: Chiralpak® IG, 30 × 250 mm, 5 µm; mobile phase: 25% EtOH (+ 0.5% DMEA) : 75% CO2; column temperature: 40 °C] to give the title compound as the second-eluting isomer. ES-MS m/z 623 (M+H). [0360] The following examples were prepared by multicomponent cyclization in a similar manner as described in General Procedure A using 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5- amine, 4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, and the appropriate keto-nitrile intermediate, followed by nitrile hydrolysis in a similar manner as described in General Procedure G. Example No. Chemical Name Structure ES-MS m/z 32 4-(4-(3,4-Difluorobenzyl)-3- 598 Example 34: (R)-4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0361] To an RBF with 4-(4-(3 -oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (2.30 g, 4.7 mmol) was added potassium carbonate (2.36 g, 17.1 mmol), DMF (47 mL), and (S)-3-bromo- 2-methylpropan-1-ol (0.72 g, 4.7 mmol). The reaction mixture was placed under N2 and heated to 50 ºC for 16 h, when added 1.2 g of potassium carbonate and the temperature was increased to 60 ºC. The reaction was stirred for 2 h, then poured into a separation funnel containing 200 mL EtOAc, 150 mL water, and 50 mL sat. aq. NaCl and separated phases. The organic layer was washed with 1:1 water:sat. aq. NaCl (2 × 100 mL). The combined aq. layers were back extracted with EtOAc (1 × 100 mL). The organics were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase flash chromatography using a gradient of 0 to 100% ACN in 10 mM aq. ammonium bicarbonate with 5% MeOH, then re-purified by reverse phase HPLC using a gradient of 35 to 50% ACN in 10 mM NH4HCO3 in 5:95 MeOH:water to give the title compound (629 mg). ES-MS m/z 564 (M+H). Example 35: Racemic 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-3-(2- (hydroxymethyl)azetidin-1-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
[0362] In a screw cap vial, race robenzyl)-1H-indazol-5-yl)-3-(2- (hydroxymethyl) azetidin-1-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile (70 mg, 0.11 mmol), (E)-acetaldehyde oxime (460 mg, 7.8 mmol), and copper (II) oxide (18 mg, 0.22 mmol) were mixed in 1,4-dioxane (1.5 mL) and water (0.5 mL) and the reaction was heated at 90 ºC overnight. The reaction was concentrated. The resulting mixture was then added to a 5 g SCX column previously conditioned with MeOH. Eluted first with 2 column volumes of MeOH, followed by elution with 2 column volumes of 2N NH3 in MeOH. Basic fractions were combined and concentrated, and the residue was purified by reverse phase HPLC (Stationary Phase: Xbridge C18, mobile phase: ACN in 20 mM NH4CO3, pH 9) to give 17.7 mg of the title compound as a solid. ES-MS m/z 643.2 (M+H). [0363] The compounds below were prepared in a similar manner as described in General Procedure I using 3-bromo-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and the appropriate amine, followed by nitrile hydrolysis using General Procedure B. Example No. Chemical Name Structure ES-MS m/z Racemic 4-(1-(3,4- Difluorobenzl)-1H- xampe : -(-(,- uoroenzy)- -nazo--y)--(,- me y soxazo--y)-6- isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide N O [0364] In a screw cap vial, 4- -1H-indazol-5-yl)-3-(3,5- dimethylisoxazol-4-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (70 mg, 0.11 mmol), (E)-acetaldehyde oxime (7.7 mmol), and copper(II) oxide (0.22 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL) and the reaction was heated at 90 ºC overnight. The reaction was concentrated, and the residue was loaded onto a 5 g SCX column previously conditioned with MeOH. Eluted first with 2 column volumes of MeOH, followed by elution with 2 column volumes of 2N NH3 in MeOH. Basic fractions were combined and concentrated, and the residue was purified (Stationary Phase: Xbridge C18, Mobile phase: ACN in 20 mM NH4CO3 pH 9) to give 3.2 mg of the title compound as a solid. ES-MS m/z 653.2 (M+H). Example 39: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-3-(5-(hydroxymethyl)thiophen-2- yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0365] The title compound manner as described in General Procedure J with 3-bromo-4-(1- - indazol-5-yl)-6-isobutyl-1-(1- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (5- (hydroxymethyl)thiophen-2-yl)boronic acid, followed by nitrile hydrolysis in a similar manner as described in the General Procedure B. ES-MS m/z 670.2 (M+H). Example 40: 4-(4-((5-Bromo-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide [0366] The title compound was manner as described in General Procedure G using 4-(4-((5-bromo-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carbonitrile. The product was purified by reverse phase HPLC using a gradient of 45 to 65% ACN in (10 mM NH4HCO3 in 95:5 water:MeOH). ES-MS m/z 651/653 (M+H). [0367] The following compounds were prepared in a similar manner as described in General Procedure K using 6-isobutyl-1-(1-methylpiperidin-4-yl)-4-(3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and the appropriate alkyl chloride, followed by nitrile hydrolysis in a similar manner as described in General Procedure G. Example No. Chemical Name Structure ES-MS m/z , methylbicyclo[1.1.1]pentan-1-yl)methyl)-3-(piperidin-1-ylmethyl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0368] 3-Bromo-4-(1-(3,4- 5-yl)-6-isobutyl-1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (70 mg, 0.11 mmol), PtBu3 Pd G4 (3.2 mg, 5.5 μmol), tri-tert-butyl phosphonium tetrafluoroborate (1.6 mg, 5.5 μmol) and 1,4-diazabicyclo[2.2.2]octane (6 mg, 0.0530 mmol) were charged to a vessel. A stir bar and DMF (0.5 mL) were added, and the vessel was purged with N2. 2-Isocyano-2-methylpropane (13 mg, 17 μL, 0.15 mmol) was added, followed by potassium formate (19 mg, 0.22 mmol). N2 was passed into the vessel and the mixture was heated at 65 °C for 16 h. The crude reaction mixture was cooled down and 2M HCl was added to the crude. The mixture was stirred at RT for 6 h. The crude was then extracted with EtOAc. The organic fraction was separated, washed with sat. aq. NaCl, dried on MgSO4 and evaporated in vacuo to afford 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-3-formyl-6-isobutyl-1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (70 mg). ES-MS m/z 583 (M+H). [0369] To a solution of 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-3-formyl-6-isobutyl- 1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (70 mg, 0.12 mmol) in DCM (2 mL) was added piperidine (15 mg, 0.02 mL, 0.18 mmol) and the reaction was stirred for 15 min at RT. Then sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and the reaction was further stirred for 1 h. The reaction mixture was diluted in MeOH with a few drops of HCl (5 M in isopropanol). 5 g SCX-2 cartridge was conditioned with MeOH, then the compound solution was charged, and the cartridge was eluted successively with MeOH and MeOH (2N NH3). Basic elution that contained the final compound was evaporated in vacuo. The residue was purified by reverse phase HPLC [column: Xbridge™ C18 (19 × 150 mm, 5 um); mobile phase: solvent A = 20 mM aq. NH4HCO3 (pH 9), solvent B = ACN; gradient 70 to 95% B; column temperature: RT] to give the title compound (27 mg) as a solid. ES-MS m/z 652 (M+H). Examples 45a, 45b, and 45c: Methyl 5-(5-carbamoyl-1-(1-cyclopropylethyl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-4-yl)-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate (racemic mixture – 45a, Isomer 1 – 45b, and Isomer 2 – 45c) [0370] The title compound was manner as described in General Procedure H using 1-(1-cyclopropylethyl)-1H-pyrazol-5-amine (racemic mixture), 5-methyl- 3-oxohexanamide, and methyl 1-(3,4-difluorobenzyl)-5-formyl-1H-indazole-7-carboxylate. The product was purified by silica gel chromatography using a gradient of 0 to 10 % MeOH in DCM, giving the racemic mixture of the title compound (Example 45a). The isomers were separated by chiral SFC [column: Lux Cellulose-4, 21 × 150 mm, 5 µm; mobile phase: solvent A – MeOH + 0.5% DMEA, solvent B – CO2, 15:85 solvent A : solvent B; column temperature: 40 °C] to give Isomer 1 (Example 45b) as the first-eluting isomer and Isomer 2 (Example 45c) as the second-eluting isomer. Racemic mixture and both isomers: ES-MS m/z 587 (M+H). Example 46: 1-(1-Cyclopropylethyl)-4-(1-(3,4-difluorobenzyl)-7-(hydroxymethyl)-1H- indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (racemic mixture) [0371] To a vial with a stir bar methyl 5-(5-carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(3,4-difluorobenzyl)-1H- indazole-7-carboxylate (100 mg, 170 μmol) and EtOH (1.70 mL). Sodium borohydride (22 mg, 0.58 mmol) was added, and the mixture was stirred at RT under N2 for 1.5 h. Then, additional 30 mg NaBH4 were added and continued to stir at RT for 1 h. The reaction was quenched with dropwise addition of water and the resulting mixture was transferred to a separation funnel containing 20 mL 1:1 water:sat. aq. NaCl and 20 mL EtOAc. Shook and removed aq. layer. Extracted aq. layer with EtOAc (1 × 20 mL). Dried the organic layer over MgSO4. Filtered and concentrated on rotovap. The residue was purified via C18 reverse phase with 40 to 77% ACN in 0.1 % formic acid in water, to give 46.5 mg of the title compound. ES-MS m/z 559 (M+H). Example 47: Racemic 3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide
[0372] A vial equipped with ith racemic 2-(7-(5-carbamoyl-1- (cyclohexylmethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid (33.7 mg, 52.2 μmol) and HATU (25.8 mg, 67.8 μmol). To this was added DMF (261 μL) and DIPEA (45.5 μL, 261 μmol). Then, dimethylamine hydrochloride (6.38 mg, 78.3 μmol) was added. The reaction was stirred at RT for 16 h, then sat. sodium bicarbonate solution (5 mL), water (5 mL), and EtOAc (5 mL) were added. The layers were separated, and the aq. phase was further extracted with EtOAc (2 × 10 mL) and then the organic phase was washed with sat. aq. NaCl (2 × 10 mL). The organic extracts were dried over MgSO4 and concentrated. The residue was purified via reverse phase chromatography using a gradient of 52-86% ACN in 0.1 % aq. formic acid to afford the title compound (18.9 mg). ES-MS m/z 673 (M+H). Example 48: Racemic 4-(4-(3,4-Difluorobenzyl)-2-(2-(methylamino)-2-oxoethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide
and Example 49: Racemic Methyl 2-(7-(5-carbamoyl-6-isobutyl-1-(1-methylpiperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate [0373] To a vial equipped with racemic 2-(7-(5-carbamoyl-6- isobutyl-1-(1-methylpiperidin-4- - 4-yl)-4-(3,4-difluorobenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid trifluoroacetate (108 mg, 142 μmol) TCFH (59.8 mg, 213 μmol) and ACN (710 μL). To this was added methylamine hydrochloride (23.0 mg, 341 μmol) followed by 1-methylimidazole (67.6 μL, 852 μmol). The reaction was stirred at ambient temperature for 20 h. The reaction mixture was then concentrated under reduced pressure. It was purified using a SCX column, eluting first with MeOH and NH3/MeOH (2N). The basic fractions were concentrated under reduced pressure. The residue was further purified via reverse phase chromatography using a gradient of 40 to 77% ACN in 10 mM aq. NH4HCO3 (pH 10) + 5% MeOH to provide Example 48 (8 mg) as the first-eluting compound, ES-MS m/z 660 (M+H), and Example 49 (8 mg) as the second- eluting compound, ES-MS m/z 661 (M+H). Example 50: 4-(4-((5-Chloropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide
[0374] A vial equipped with a st with (5-chloropyridin-2-yl)methanol (68 mg, 0.47 mmol), 6-isobutyl-1-(1-methylpiperidin-4-yl)-4-(3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (70 mg, 0.16 mmol) and 1,4-dioxane (0.8 mL). Then, CMBP (0.11 g, 0.13 mL, 0.47 mmol) was added in one portion at RT. The reaction mixture was heated to 115 ºC. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified via SCX, eluting first with MeOH (2 CV), followed by 7 M NH3/MeOH. Basic fractions were combined and concentrated. To the residue was then added 1,4-dioxane (0.79 mL) and water (0.08 mL) followed by hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(II) (6.8 mg, 16 μmol). The reaction was heated to 100 ºC overnight and then concentrated. The resulting material was added to a SCX column and eluted first with MeOH and then ammonia in MeOH (2 N). Basic fractions were combined and concentrated and the residue was purified by C18 reverse phase chromatography using a gradient of 23 to 58% ACN in aq. NH4HCO3 (pH 10) + 5% MeOH to give the title compound (21.2 mg). ES-MS m/z 588 (M+H). Example 51: 5-(5-Carbamoyl-1-(1-cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylic acid (Isomer 1)
General Procedure L – LiOH ester h [0375] To a 25 mL vial containing a stir bar and methyl 5-(5-carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(3,4-difluorobenzyl)-1H- indazole-7-carboxylate -Isomer 1 (126 mg, 215 μmol) was added MeOH (5 mL) and LiOH (1 M aq. Solution, 0.7 mL, 0.7 mmol). The vial was capped, and the mixture was heated to 40 °C for 2 h, then citric acid (1 M aq. solution, 1.5 mL), water (5 mL), and EtOAc (10 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 5 mL). The organics were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC using a gradient of 14 to 48% ACN in 10 mM aq. NH4HCO3 + 5% MeOH to give the title compound 89.5 mg. ES-MS m/z 573 (M+H). [0376] The following compounds were prepared in a similar manner as described in General Procedure H using the appropriate substituted aminopyrazole, 5-methyl-3- oxohexanamide, and methyl 1-(3,4-difluorobenzyl)-5-formyl-1H-indazole-7-carboxylate, followed by ester hydrolysis using General Procedure L. Example No. Chemical Name Structure ES-MS m/z 52 5-(5-C rb m l-1- 601 53 5-(5-Carbamoyl-6-isobutyl- 599 1-((3- (M+H) meth lbic clo[111] entan- p , y , y , y 6- isobutyl-1-((3-(methylsulfonamido)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0377] To a solution of 1-( 1-yl)methyl)-4-(4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (90 mg, 90% Wt, 0.14 mmol) in DCM (2.0 mL) was added TEA (29 µL, 0.21 mmol) and methanesulfonic anhydride (37 mg, 0.21 mmol) at 25 °C, then the mixture was stirred at 25 °C for 16 h under N2. Water (20 mL) was added to the reaction and the mixture was extracted with EtOAc (20 mL × 3). The combined organics were dried over anhydrous Na2SO4, filtered and the filtrate concentrated. The residue was purified by reverse phase HPLC using a gradient of 20 to 62% ACN in 0.225% aq. formic acid, then re-purified by SFC [column: Daicel Chiralpak® IBN 250 mm × 30 mm, 10 µm; mobile phase: 40% (EtOH + 0.1% NH4OH) in CO2] to give the title compound (37.6 mg). ES-MS m/z 665 (M+H). Example 56: Racemic 1-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)-4-(4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0378] A solution of 4-(4-(3,4-difluorobenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (195 mg, 256 μmol) in 2 M HCl in 1,4-dioxane (3.0 mL) was stirred at 25 °C for 3 h. The pH was adjusted to around 7 by progressively adding NH4OH, then the mixture was purified by reverse phase HPLC using a gradient of 26 to 66% ACN in 10 mM aq. NH4HCO3 to give the title compound (63.5 mg) as a solid. ES- MS m/z 601 (M+H). Example 57: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(3,3- difluorocyclobutyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0379] Example 57 was prepare following steps. [0380] Step 1: MCR with tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1- carboxylate, 1-(3,4-difluorobenzyl)-1H-indazole-5-carbaldehyde, and 5-methyl-3- oxohexanenitrile according to General Procedure A was conducted to give tert-butyl 4-(5- cyano-4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate. [0381] Step 2: Boc deprotection with 2 M HCl in 1,4-dioxane in a similar manner as described in Example 56 was conducted to give 4-(1-(3,4-difluorobenzyl)-1H-indazol-5-yl)- 6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile. [0382] Step 3: Reductive amination with 3,3-difluorocyclobutan-1-one in a similar manner as described in Example 6 with the addition of 1.5 equivalents of titanium tetraisopropoxide was performed. [0383] Step 4: Nitrile hydrolysis in a similar manner as described in General Procedure B was performed to afford the title compound. ES-MS m/z 634 (M+H). Example 58: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-(3- methoxycyclobutyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0384] Example 58 was prepare er as described in Example 57, using 3-methoxycyclobutan-1-one in Step 3. ES-MS m/z 628 (M+H). Example 59: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-((1- fluorocyclopropyl)methyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0385] Example 59 was as described in Example 57, using 1-fluorocyclopropane-1-carbaldehyde, 3 equivalents of sodium triacetoxyborohydride, and 3 equivalents of acetic acid in place of sodium cyanoborohydride and titanium tetraisopropoxide in Step 3. ES-MS m/z 616 (M+H). Example 60: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-((1- methylcyclopropyl)methyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0386] Example 60 was prepare ner as described in Example 57, using 1-methylcyclopropane-1-carbaldehyde, 3 equivalents of sodium triacetoxyborohydride, and 3 equivalents of acetic acid in place of sodium cyanoborohydride and titanium tetraisopropoxide in Step 3. ES-MS m/z 612 (M+H). Example 61: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-(3- (difluoromethyl)cyclobutyl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (mixture of isomers) [0387] Example 61 was as described in Example 57, using 3-(difluoromethyl)cyclobutan-1-one in Step 3. ES-MS m/z 648 (M+H). Example 62: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide [0388] Example 62 was following steps. [0389] Step 1: To a mix of 6- 4-yl)-4-(3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and NaH (1.5 equivalents) in DMF was added 2-(chloromethyl)-3,5-difluoropyridine and the mixture stirred at RT overnight. Sat. aq. NaCl was added, and the mixture extracted with DCM. The organics were concentrated to give 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide. [0390] Step 2: The nitrile was hydrolyzed in a similar manner as described in General Procedure G to afford the title compound. ES-MS m/z 590 (M+H). Example 63: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide formate
[0391] Example 63 was prepa llowing steps. [0392] Step 1: tert-Butyl 4-(5-carbamoyl-4-(4-((5-chloropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate was prepared in a similar manner as described in General Procedure A using tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate, 4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, and 5-methyl-3-oxohexanamide. [0393] Step 2: Boc deprotection in a similar manner as described in Example 2, followed by reverse phase HPLC using ACN and aqueous formic acid. ES-MS m/z 575 (M+H). Example 64: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-methylpiperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0394] Example 64 was as described in General Procedure H using 5-methyl-3-oxohexanamide, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-amine, and 1- (3,4-difluorobenzyl)-1H-indazole-5-carbaldehyde. ES-MS m/z 558 (M+H). Example 65: 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-methylpiperidin-4- yl)-3-(thiazol-2-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0395] Example 65 was steps. [0396] Step 1: General was 2-amine. [0397] Step 2: Nitrile hydrolysis in a similar manner as described in General Procedure B was performed to afford the title compound. ES-MS m/z 656 (M+H). Example 66.4-(4-((5-Fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0398] General Procedure A [1.1.1]pentan-1- yl)methyl)-1H-pyrazol-5-amine, 5-methyl-3-oxohexanamide, and 4-((5-fluoropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde to afford the title compound. ES-MS m/z 570 (M+H). Example 67.1-(1-Cyclopropylpiperidin-4-yl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0399] General Procedure A 4-yl)-1H-pyrazol- 5-amine, 5-methyl-3- 2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde to afford the title compound. ES-MS m/z 599 (M+H). Example 68. Racemic 1-(1-Cyclopropylethyl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0400] General Procedure A 1-(1-cyclopropylethyl)-1H-pyrazol- 5-amine, 5-methyl-3-oxohexanamide, and 4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde to afford the title compound. ES-MS m/z 544 (M+H). Example 69. Racemic 1-(1-Cyclopropylethyl)-6-isobutyl-4-(3-oxo-4-(pyrazin-2-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0401] Example 69 was following steps. [0402] Step 1: A mixture of 3- -3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, acetic acid, and piperidine (1 equivalent of each) was stirred at 50 °C for 2 h, then racemic 1-(1- cyclopropylethyl)-1H-pyrazol-5-amine (1 equivalent) was added and the mixture stirred at 50 °C for 6 h. Water was added and the mixture was extracted with EtOAc. The organics were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated. The residue was taken up in ACN and water, ceric ammonium nitrate (2 equivalents) was added and stirred at RT for 1 h. Water was added and the mixture was extracted with EtOAc. The organics were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated. Silica gel chromatography using a gradient of 0 to 53% EtOAc in petroleum ether gave racemic 1-(1- cyclopropylethyl)-6-isobutyl-4-(3-oxo-4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile. [0403] Step 2: The product from Step 1 was dissolved in DMSO, K2CO3 (3 equivalents) and hydrogen peroxide (30 wt% in water, 15 equivalents) and the mixture was stirred at RT for 12 h. Water was added and the mixture was extracted with EtOAc. The organics were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated. Purification by reverse phase HPLC using a gradient of 24 to 64% ACN in aqueous formic acid gave the title compound. ES-MS m/z 526 (M+H). Example.70. Racemic 4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-((trans)-2,6- dimethylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 1:2 solvate with methanol
[0404] Example 70 was prepa llowing steps. [0405] Step 1: General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and racemic tert-butyl (trans)-4- hydroxy-2,6-dimethylpiperidine-1-carboxylate [0406] Step 2: Nitrile hydrolysis using General Procedure G was performed following step 1. [0407] Step 3: Then Boc deprotection with TFA afforded the title compound. ES-MS m/z 572 (M+H). Example 71.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1,2-dimethylpiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (mixture of diastereomers) [0408] Example 71 was steps. [0409] Step 1: General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1,2-dimethylpiperidin-4-ol (mixture of diastereomers). [0410] Step 2: General Procedure B was used to give 4-(1-(3,4-difluorobenzyl)-1H- indazol-5-yl)-1-((2S,4S)-1,2-dimethylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide. ES-MS m/z 572 (M+H). Example 72.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- ((2,2-difluorocyclopropyl)methyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (Isomer 1) [0411] From the method of isomer was collected to afford the title compound. ES-MS m/z 623 (M+H). Example 73.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(1-ethylpiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0412] Example 73 was following steps. [0413] Step 1: General Procedure D was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-ethylpiperidin-4-ol; [0414] Step 2: General Procedure B was used to give 4-(1-(3,4-Difluorobenzyl)-1H- indazol-5-yl)-1-(1-ethylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide. ES-MS m/z 572 (M+H). Example 74.1-(1-Cyclobutylpiperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0415] Example 74 was steps. [0416] Step 1: General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate; [0417] Step 2: General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0418] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-difluoropyridin- 2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 2,2,2-trifluoroacetate with the crude salt used without purification; [0419] Step 4: The procedure was in a similar manner as described in Example 57, using cyclobutanone, 3 equivalents of sodium cyanoborohydride and 6 equivalents of acetic acid in place of titanium tetraisopropoxide; [0420] Step 5: General Procedure G to give 1-(1-cyclobutylpiperidin-4-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide. ES-MS m/z 630 (M+H). Example 75.1-(1-(3,3-Difluorocyclobutyl)piperidin-4-yl)-4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0421] To a vial was added 1- piperidin-4-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (48 mg, 74 μmol), EtOH (1.3 mL), water (0.13 mL), and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(II) (3.2 mg, 0.1 Eq, 7.4 μmol). The reaction mixture was stirred at 80 °C for 19 h, then cooled to RT and concentrated under reduced pressure to give a residue that was purified via reverse phase column chromatography using a gradient of 10-100% ACN in water (10 mM NH4HCO3 with 5% MeOH), to give the title compound (18.7 mg). ES-MS m/z 666 (M+H). Example 76.1-(1-(2,2-Difluoroethyl)piperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide
[0422] Example 76 was prepared following steps. [0423] Step 1: General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate; [0424] Step 2: General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0425] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-difluoropyridin- 2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 2,2,2-trifluoroacetate with the crude salt used without purification; [0426] Step 4: General Procedure K was used with 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1,1-difluoro-2-iodoethane; and [0427] Step 5: General Procedure G was used to give the title compound. ES-MS m/z 640 (M+H). Example 77.1-(1-Cyclopropylpiperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide
[0428] Example 77 was prepare following steps. [0429] Step 1: General Procedure A was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5- amino-1H-pyrazol-1-yl)piperidine-1-carboxylate; [0430] Step 2: General Procedure K was used with tert-butyl 4-(5-cyano-6-isobutyl-4-(3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1- carboxylate and 2-(chloromethyl)-3,5-difluoropyridine; [0431] Step 3: The procedure of Example 2 was used to give 4-(4-((3,5-difluoropyridin- 2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 2,2,2-trifluoroacetate with the crude salt used without purification; [0432] Step 4: The procedure was in a similar manner as described in Example 57, using (1-ethoxycyclopropoxy)trimethylsilane, 2 equivalents of sodium cyanoborohydride and 1.1 equivalents of acetic acid in place titanium tetraisopropoxide; and [0433] Step 5: General Procedure G was used to give the title compound. ES-MS m/z 616 (M+H). Example 78.6-(Cyclopropylmethyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide
[0434] Example 78 was prepared following steps. [0435] Step 1: The procedure of Intermediate 35 was utilized starting with 2- cyclopropylacetic acid; [0436] Step 2: The procedure of Intermediate 36 was used starting with 2-cyclopropyl-N- methoxy-N-methylacetamide; and [0437] Step 3: General Procedure A was used with 4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 4-cyclopropyl-3-oxobutanenitrile to afford the title compound. ES-MS m/z 587 (M+H). Example 79.7-(5-Carbamoyl-1-(1-cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin- 4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylic acid [0438] Example 79 was steps. [0439] Step 1: General Procedure K was used with methyl 7-bromo-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-5-carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0440] Step 2: The procedure of Intermediate 16 was utilized starting with methyl 7- bromo-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate; [0441] Step 3: General procedure E was used with methyl 4-(3,4-difluorobenzyl)-7- formyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate, 5-methyl-3- oxohexanamide, and racemic 1-(1-cyclopropylethyl)-1H-pyrazol-5-amine; and [0442] Step 4: General Procedure L was used with rac-methyl (R)-7-(5-carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate replacing LiOH with trimethyltinhydroxide and using toluene as solvent to afford the title compound. ES-MS m/z 604 (M+H). Example 80.7-(5-Carbamoyl-6-isobutyl-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-5-carboxylic acid [0443] Example 80 was steps. [0444] Step 1: General Procedure K was used with methyl 7-bromo-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-5-carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0445] Step 2: The procedure of Intermediate 16 was utilized starting with methyl 7- bromo-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate; [0446] Step 3: The procedure of Intermediate 5 was used starting with 3- methylbicyclo[1.1.1]pentane-1-carbaldehyde; [0447] Step 4: General procedure E was used with methyl 4-(3,4-difluorobenzyl)-7- formyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate, 5-methyl-3- oxohexanamide, and 1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazol-5-amine; and [0448] Step 5: General Procedure L was used with methyl 7-(5-carbamoyl-6-isobutyl-1- ((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(3,4- difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate replacing LiOH with trimethyltinhydroxide and using toluene as solvent to afford the title compound. ES-MS m/z 630 (M+H). Example 81.1-(1-Cyclopropylethyl)-4-(1-(3,4-difluorobenzyl)-3,3-difluoro-2-oxoindolin-5- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0449] Example 81 was steps. [0450] Step 1: General Procedure K was used with 5-bromo-3,3-difluoroindolin-2-one and 4-(bromomethyl)-1,2-difluorobenzene; [0451] Step 2: The procedure of Intermediate 28 was used with 5-bromo-1-(3,4- difluorobenzyl)-3,3-difluoroindolin-2-one; and [0452] Step 3: General Procedure H was used with 1-(3,4-difluorobenzyl)-3,3-difluoro-2- oxoindoline-5-carbaldehyde, 5-methyl-3-oxohexanamide, and rac-(R)-1-(1- cyclopropylethyl)-1H-pyrazol-5-amine to afford the title compound. ES-MS m/z 580 (M+H). Example 82.4-(1,2-Bis(3,4-difluorobenzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl)-6- isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0453] Example 82 was prepared according to the following steps. [0454] Step 1: General Procedure K was used with 5-bromo-1,2-dihydro-3H-indazol-3- one and 4-(bromomethyl)-1,2-difluorobenzene; [0455] Step 2: The procedure of Intermediate 28 was used with 5-bromo-1,2-bis(3,4- difluorobenzyl)-1,2-dihydro-3H-indazol-3-one; and [0456] Step 3: General Procedure H was used with 1,2-bis(3,4-difluorobenzyl)-3-oxo- 2,3-dihydro-1H-indazole-5-carbaldehyde, 5-methyl-3-oxohexanamide, and 1-(1- methylpiperidin-4-yl)-1H-pyrazol-5-amine to afford the title compound. ES-MS m/z 700 (M+H). Example 83.1-(1-(2,2-Difluoroethyl)piperidin-4-yl)-4-(4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0457] Example 83 was following steps. [0458] Step 1: General Procedure C was used with (5-fluoropyridin-2-yl)methanol and 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one; [0459] Step 2: The product from step 1 was treated with triethylsilane, triethylamine, and PdCl2(dppf)-CH2Cl2 in DMF under an atmosphere of carbon monoxide to give 4-((5- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde; [0460] Step 3: General Procedure A was used with 4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate to afford the title compound; [0461] Step 4: Boc deprotection with 2 M HCl in 1,4-dioxane in a similar manner as described in Example 56 was conducted to give 4-(4-((5-fluoropyridin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile; [0462] Step 5: General Procedure K was used with 4-(4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carbonitrile and 2,2-difluoroethyl trifluoromethanesulfonate; and [0463] Step 6: General Procedure G was used to give the title compound and had an ES- MS (m/z) of 622 [M+H]. Example 84.1-(1-Cyclopropylpiperidin-4-yl)-4-(4-((5-fluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0464] Example 84 was following steps. [0465] Step 1: General Procedure C was used with (5-fluoropyridin-2-yl)methanol and 7- bromo-2H-benzo[b][1,4]oxazin-3(4H)-one; [0466] Step 2: The product from step 1 was treated with triethylsilane, triethylamine, and PdCl2(dppf)-CH2Cl2 in DMF under an atmosphere of carbon monoxide to give 4-((5- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde; [0467] Step 3: General Procedure A was used with 4-((5-fluoropyridin-2-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and tert-butyl 4-(5-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate to afford the title compound; [0468] Step 4: Boc deprotection with 2 M HCl in 1,4-dioxane in a similar manner as described in Example 56 was conducted to give 4-(4-((5-fluoropyridin-2-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile; [0469] Step 5: 4-(4-((5-Fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile was treated with cyclopropylboronic acid; copper(II) acetate, triethylamine, and pyridine in THF to give 1-(1-cyclopropylpiperidin-4-yl)-4-(4-((5-fluoropyridin-2-yl)methyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile; and [0470] Step 6: General Procedure B was used to give the title compound and had an ES-MS (m/z) of 598 (M+H). Example 85. (R)-4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0471] Example 85 was steps. [0472] Step 1: General Procedure K was used with 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carbaldehyde and 2-(chloromethyl)-3,5-difluoropyridine; [0473] Step 2: General Procedure A was used with 4-((3,5-difluoropyridin-2-yl)methyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1H-pyrazol-3-amine; [0474] Step 3: General Procedure K was used with 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carbonitrile and (S)-3-bromo-2-methylpropan-1-ol; and [0475] Step 4: General Procedure G was used to give (R)-4-(4-((3,5-Difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)- 6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide to afford the title compound. ES-MS m/z 565 (M+H). Example 86. Racemic1-(1-cyclopropylethyl)-4-(1-(3,4-difluorobenzyl)-7- ((methylsulfonyl)carbamoyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0476] Example 86 was prepared steps. [0477] Step 1: General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0478] Step 2: The procedure of Intermediate 16 was utilized starting with methyl 5- bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate; [0479] Step 3: General Procedure H was used with methyl 1-(3,4-difluorobenzyl)-5- formyl-1H-indazole-7-carboxylate, 5-methyl-3-oxohexanamide, and racemic 1-(1- cyclopropylethyl)-1H-pyrazol-5-amine; [0480] Step 3: General Procedure L was used to give 5-(5-carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-(3,4-difluorobenzyl)-1H- indazole-7-carboxylic acid; and [0481] Step 4: 5-(5-carbamoyl-1-(1-cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridin-4-yl)-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylic acid was treated with CDI followed by methylsulfonamide to give 1-(1-cyclopropylethyl)-4-(1-(3,4-difluorobenzyl)-7- ((methylsulfonyl)carbamoyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide to afford the title compound. ES-MS m/z 650 (M+H). Example 87. Racemic 4-(7-(Cyanomethyl)-1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0482] Example 87 was prepare following steps. [0483] Step 1: General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0484] Step 2: methyl 5-bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate was treated with DIBAL in toluene to give (5-bromo-1-(3,4-difluorobenzyl)-1H-indazol-7- yl)methanol; [0485] Step 3: (5-bromo-1-(3,4-difluorobenzyl)-1H-indazol-7-yl)methanol was treated with phosphorous tribromide in DCM to give 5-bromo-7-(bromomethyl)-1-(3,4- difluorobenzyl)-1H-indazole; [0486] Step 4: 5-bromo-7-(bromomethyl)-1-(3,4-difluorobenzyl)-1H-indazole was treated with sodium cyanide in DMSO to give 2-(5-bromo-1-(3,4-difluorobenzyl)-1H-indazol-7- yl)acetonitrile; [0487] Step 5: The procedure of Intermediate 28 was utilized starting with 2-(5-bromo-1- (3,4-difluorobenzyl)-1H-indazol-7-yl)acetonitrile; and [0488] Step 6: General Procedure H was used with 2-(1-(3,4-difluorobenzyl)-5-formyl- 1H-indazol-7-yl)acetonitrile, 5-methyl-3-oxohexanamide, and racemic 1-(1- cyclopropylethyl)-1H-pyrazol-5-amine to afford the title compound and had an ES-MS (m/z) of 568 (M+H). Example 88. Racemic 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
[0489] Example 88 was prepa ollowing steps. [0490] Step 1: General Procedure K was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and racemic 3-bromo-2-methylpropan-1-ol; and [0491] Step 2: General Procedure G was used to give 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3-hydroxy-2-methylpropyl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide to afford the title compound. ES-MS (m/z) of 564 (M+H). Example 89.5-(5-Carbamoyl-1-(1-cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin- 4-yl)-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylic acid [0492] Example 89 was steps. [0493] Step 1: General Procedure K was used with methyl 5-bromo-1H-indazole-7- carboxylate and 4-(bromomethyl)-1,2-difluorobenzene; [0494] Step 2: The procedure of Intermediate 16 was utilized starting with methyl 5- bromo-1-(3,4-difluorobenzyl)-1H-indazole-7-carboxylate; [0495] Step 3: General Procedure H was used with methyl 1-(3,4-difluorobenzyl)-5- formyl-1H-indazole-7-carboxylate, 5-methyl-3-oxohexanamide, and rac-(R)-1-(1- cyclopropylethyl)-1H-pyrazol-5-amine; and [0496] Step 4: General Procedure L was used to give 5-(5-Carbamoyl-1-(1- cyclopropylethyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-(3,4-difluorobenzyl)-1H- indazole-7-carboxylic acid to afford the title compound. ES-MS (m/z) of 573 (M+H). Example 90.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1-(oxazol-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0497] Example 90 was steps. [0498] Step 1: General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and oxazol-4-ylmethanol; and [0499] Step 2: General Procedure G was used to give 4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(oxazol-4-ylmethyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide. ES-MS m/z 573 (M+H). Example 91: tert-Butyl (3-((5-carbamoyl-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-
yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0500] The title compound as described in General Procedure G using tert-butyl cyano- -3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate. The product was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in petroleum ether to give the title compound as a solid (582 mg). ES-MS m/z 687 (M+H). Example 92: 1-((3-Aminobicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0501] A solution of tert- (3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (580 mg, 777 µmol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at 25 °C for 1 h. The reaction was quenched with saturated Na2CO3 aq. solution (20 mL) to adjust pH to 8, then the mixture was extracted with DCM (20 mL × 3). The organics were dried over anhydrous Na2SO4, filtered and the filtrate concentrated to give the title compound (460 mg) as a solid. ES-MS m/z 587 (M+H). Example 93: Racemic tert-butyl (3-(1-(5-carbamoyl-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate [0502] The title compound as described in General Procedure G using racemic tert-butyl (3-(1-(5-cyano-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1- yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate. The product was purified by silica gel chromatography using a gradient of 0 to 9% MeOH in DCM to give the title compound (195 mg) as a solid. ES-MS m/z 701 (M+H). Example 94.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- ((3-(dimethylamino)bicyclo[1.1.1]pentan-1-yl)methyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
[0503] Example 94 was prepared according to the following steps. [0504] Example 94 was prepared utilizing the procedure for Example 6 starting with 1- ((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide. ES- MS m/z 615 (M+H). Example 95.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1- (methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0505] Example 95 was steps. [0506] Step 1: General Procedure A was used with 5-methyl-3-oxohexanenitrile, 1-(3,4- difluorobenzyl)-1H-indazole-5-carbaldehyde, and tert-butyl 4-(5-amino-1H-pyrazol-1- yl)piperidine-1-carboxylate; [0507] Step 2: The procedure of Example 56 was used starting tert-butyl 4-(5-cyano-4- (1-(3,4-difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1- yl)piperidine-1-carboxylate; and [0508] Step 3: The procedure of Example 55 was used starting with 4-(1-(3,4- difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine- 5-carbonitrile to afford the title compound; and [0509] Step 4: General Procedure B was used to give 4-(1-(3,4-Difluorobenzyl)-1H- indazol-5-yl)-6-isobutyl-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide. ES-MS m/z 622 (M+H). Example 96.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(5-azaspiro[2.5]octan- 8-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide formate
[0510] Example 96 was prepa llowing steps. [0511] Step 1: General Procedure C was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and tert-butyl 8-hydroxy-5- azaspiro[2.5]octane-5-carboxylate; [0512] Step 2: General Procedure G was used to give tert-butyl 8-(5-cyano-4-(1-(3,4- difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5- azaspiro[2.5]octane-5-carboxylate; and [0513] Step 3: A procedure similar to that for Example 2 was used to give the title compound. ES-MS m/z 570 (M+H). Example 97.6-Isobutyl-1-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-4-(3-oxo-4-(pyrazin- 2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0514] Example 97 was steps. [0515] Step 1: The procedure essentially described in the Preparation of Intermediate 5 was used starting with 3-methylbicyclo[1.1.1]pentane-1-carbaldehyde; [0516] Step 2: General Procedure H was used with 3-oxo-4-(pyrazin-2-ylmethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1-((3- methylbicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazol-5-amine; and [0517] Step 3: General Procedure B was used to give the title compound. ES-MS m/z 552 (M+H). Example 98.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0518] Example 98 was steps. [0519] Step 1: General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and pyridin-3-ylmethanol. [0520] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 583 (M+H). Example 99.4-(2-Benzyl-4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin- 7-yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0521] The title compound ES-MS (m/z) of 679 (M+H). Example 100. (R)-4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-1-(3-hydroxy-2- methylpropyl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0522] Example 100 was following steps. [0523] Step 1: General was (1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (S)-3-bromo-2-methylpropan- 1-ol; and [0524] Step 2: General Procedure B was used to give the title compound. ES-MS m/z 533 (M+H). Example 101. Racemic 6-isobutyl-1-(1-(3-methylbicyclo[1.1.1]pentan-1-yl)ethyl)-4-(3-oxo- 4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0525] Example 101 was steps. [0526] Step 1: General Procedure A was used with 3-oxo-4-(pyrazin-2-ylmethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, 5-methyl-3-oxohexanenitrile, and 1H- pyrazol-3-amine; [0527] Step 2: Racemic 1-(3-methylbicyclo[1.1.1]pentan-1-yl)ethan-1-ol was made utilizing methods similar to the synthesis of Intermediates 58 to 60; [0528] Step 3: General Procedure F was used with 6-isobutyl-4-(3-oxo-4-(pyrazin-2- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile and rac-(R)-1-(3-methylbicyclo[1.1.1]pentan-1-yl)ethan-1-ol; and [0529] Step 4: General Procedure G was used to give the title compound. ES-MS m/z 566 (M+H). Example 102.4-(4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- (cis-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl)-6-isobutyl-1H-pyrazolo[3,4- b]pyridine-5-carboxamide [0530] Example 102 was steps. [0531] Step 1: General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and (cis)-3-(hydroxymethyl)-1-(trifluoromethyl)cyclobutan-1-ol; and [0532] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 644 (M+H). Example 103.4-(4-(4-Chloro-3-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)-6-isobutyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0533] Example 103 was prepar e following steps. [0534] Step 1: General Procedure A was used with 5-methyl-3-oxohexanenitrile, 3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde, and 1-(1-methylpiperidin-4-yl)-1H- pyrazol-5-amine; [0535] Step 2: General Procedure K was used with 6-isobutyl-1-(1-methylpiperidin-4-yl)- 4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile and 4-(bromomethyl)-1-chloro-2-fluorobenzene utilizing sodium hydride in place of a carbonate base; and [0536] Step 3: General Procedure G was used to give the title compound. ES-MS m/z 605 (M+H). Example 104.1-((7-Oxabicyclo[2.2.1]heptan-1-yl)methyl)-4-(4-(3,4-difluorobenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0537] Example 104 was steps. [0538] Step 1: General Procedure K was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, and 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane; and [0539] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 602 (M+H). Example 105.1-(1-Cyclobutylpiperidin-4-yl)-4-(4-(3,4-difluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0540] Example 105 was following steps. [0541] Step 1: General Procedure F was used with 4-(4-(3,4-difluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 1-cyclobutylpiperidin-4-ol; and [0542] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 629 (M+H). Example 106.4-(1-(3,4-Difluorobenzyl)-1H-indazol-5-yl)-6-isobutyl-1-(1-(oxetan-3- yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0543] Example 106 was prepar e following steps. [0544] Step1: General Procedure C was used with 4-(1-(3,4-difluorobenzyl)-1H-indazol- 5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile, and 1-(oxetan-3-yl)piperidin-4- ol; and [0545] Step 2: General Procedure G was used to give the title compound. ES-MS m/z 600 (M+H). Example 107: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0546] In a 20-mL vial with a 4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (100 mg, 174 μmol), 3,3-difluorocyclobutan-1- one (75 mg, 0.71 mmol), and sodium triacetoxyborohydride (75 mg, 0.35 mmol) in a mixture of DCE (4 mL) and acetic acid glacial (1 mL). The vial was sealed with a screw cap and placed in an aluminum block pre-warmed to 40 oC and stirred for 2 h. The temperature was increased to 50 oC and stirred overnight. The reaction was cooled to RT and the solvent evaporated to give a crude product. The crude product was purified by reverse phase column chromatography on a 50 g C18 column eluting with a gradient of 45-65% ACN in water (10 mM NH4HCO3 with 5% MeOH) to give the title compound (35.5 mg). ES-MS m/z 665 (M+H). [0547] The following compound was prepared in a similar manner as described for Example 107. Example No. Chemical Name Structure ES-MS m/z H) Example 109: 6-(Cyclopropylmethyl)-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide
[0548] To a 7 mL vial with stir clopropylmethyl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(piperidin- 4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2,2,2-trifluoroacetate (200 mg, 291 μmol), DCM (2.91 mL), diisopropylethylamine (200 μL, 1.16 mmol), and 2,2-difluoroethyl trifluoromethanesulfonate (74.7 mg, 349 μmol). The reaction vial was capped and stirred at RT for 20 min. 2,2-Difluoroethyl trifluoromethanesulfonate (15 ^L) was added and the mixture stirred for an additional 20 min. The reaction was quenched with sat. aq. ammonium chloride (1 mL). The mixture was stirred and the organic layer removed. The aqueous phase was extracted with DCM (1 x 1 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by reverse phase chromatography on a Phenomenex Kintex C18 (100x 30 mm, 5 ^) column eluting with a gradient from 14-48% ACN in 0.1% aq. formic acid to give the title compound (162 mg). ES-MS m/z 638 (M+H). Example 110: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0549] To a vial equipped with g 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3- methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (161 mg, 256 μmol) was charged with 1,4-dioxane (1.03 mL, 256 μmol), water (0.15 mL) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (27.5 mg, 64.1 μmol). The reaction was heated to 100 oC for 20 h. The reaction was diluted with water, extracted with EtOAc, dried over MgSO4 and concentrated to give a crude product. The crude product was purified by reverse phase chromatography on a Phenomenex Kintex C18 (100x 30 mm, 5 ^) eluting with a gradient from 23-58% ACN in water (10 mM NH4HCO3 with 5% MeOH) to give the title compound (59.6 mg). ES-MS m/z 646 (M+H). [0550] The following compounds were prepared in a similar manner as described for Example 110. Example No. Chemical Name Structure ES-MS m/z
4-(4-((5-Chloropyrimidin-2- H) H) H) 4-(4-((5-Chloropyrimidin-2- H) H) Example 116: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(3,3-difluorocyclobutyl)-3-methylpiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0551] In a 25-mL vial, a solution of hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (10 mg, 23 μmol) and 4-(4-((5-chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(3,3- difluorocyclobutyl)-3-methylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (123 mg, 186 μmol) was dissolved in EtOH (3 mL) and water (0.3 mL) at RT. The vial was placed into an aluminum heating block preheated to 100 oC and stirred for 6 h. The reaction was cooled to RT and concentrated under a stream of nitrogen. The residue was purified by reverse phase column chromatography on a 30 g C18 column using high pH, 10 mM ammonium bicarbonate in 95/5 water/MeOH, ACN over 20 min to give the title compound (104 mg). ES-MS m/z 679 (M+H). [0552] The following compounds were prepared in a similar manner as described for Example 116. Example No. Chemical Name Structure ES-MS m/z ) ) 4-(4-((5-Chloropyrimidin-2- yl)methyl)-3-oxo-34-dihydro- ) ) )
4-(4-((5-Chloropyrimidin-2- yl)methyl)-3-oxo-3,4-dihydro- ) ) ) 4-(4-((5-Chloropyrimidin-2- ) ) ) 4-(4-((5-Chloro-3- fluoropyridin-2-yl)methyl)-3- ) g , , , difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile Example 130: Racemic 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide
[0553] To a vial equipped with a ged with 4-(4-((3,5-difluoropyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((3R,4R)-3- methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (361 mg, 575 μmol). The material was dissolved in 1,4-dioxane (2.88 mL). To this was added water (0.28 mL) followed by hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (37.0 mg, 86.2 μmol). The reaction was placed in a 100 oC heating block for 20 h. Additional hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (37.0 mg, 86.2 μmol) was added and heating was continued for an additional 7 h. The reaction was cooled to RT and diluted with water (25 mL) and EtOAc (25 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over MgSO4 and concentrated to give a crude product. The crude product was purified by reverse phase chromatography on a Phenomenex Kintex C18 (100x 30 mm, 5 ^) eluting with a gradient from 23-58% ACN in water (10 mM NH4HCO3 with 5% MeOH) to give the title compound (24 mg). ES-MS m/z 646 (M+H). Example 131a and 131b: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – 131a, Isomer 2 – 131b)
[0554] Racemic 4-(4-((3,5-Diflu ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by chiral HPLC (column: Chiralpak® IG 30 x 250 mm, 5 µm; mobile phase: 1:3 (MeOH + 0.5% DMEA) : CO2; flow rate: 100 mL/min; column temperature: 40 °C] to give Isomer 1 (first-eluting isomer, 9.1 mg) and Isomer 2 (second-eluting isomer, 9.2 mg) of the title compound. Both isomers: ES-MS m/z 646 (M+H). Example 132: Racemic 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0555] To a 40-dram vial charged with 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- (5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (211 mg, 330 μmol) and 1,4-dioxane (3 mL). Hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (22 mg, 51 μmol) followed by water (0.16 mL, 330 μmol) were added and the reaction was heated to 100 oC for 16 h. Additional hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (22 mg, 51 μmol) was added and heating continued at 100 oC for an additional 5 h. The reaction removed from the heat. The reaction was diluted with water and ethyl acetate (20 mL each). The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over MgSO4 and concentrated to give a crude product. The crude product was purified by reverse phase chromatography on a Teledyne ISCO AccQPrep eluting with a gradient from 35-55% ACN in water (10 mM NH4HCO3 with 5% MeOH) to give the title compound (58 mg). ES-MS m/z 657 (M+H). Example 133a, and 133b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – 133a, and Isomer 2 – 133b) [0556] Racemic 4-(4-((5- -3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(5-(oxetan-3-yl)-5-azaspiro[2.5]octan-8-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by chiral HPLC (column: Chiralpak® IG230 x 250 mm, 5 µm; mobile phase: 35% (EtOH + 0.5% DMEA):65% CO2; flow rate: 120 mL/min; column temperature: 40 °C) to give Isomer 1 (first-eluting isomer 20.4 mg) and Isomer 2 (second-eluting isomer, 17.4 mg) of the title compound. Both isomers: ES-MS m/z 657 (M+H). Example 134: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-3- methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1) [0557] To a dried 8 mL sealed stir bar was added 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((cis)-1-(3-methoxybicyclo3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide -1-yl)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (Isomer 1) (40 mg, 58 μmol), potassium carbonate (35 mg, 0.25 mmol), DMSO (2 mL) and aq. hydrogen peroxide (30% Wt) (0.46 mL, 4.4 mmol) successively at ambient temperature. The reaction mixture was heated and stirred at 60 °C for 16 h. The reaction mixture was poured into sat. aq. Na2SO3 (10 mL). The residue was diluted with water (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with sat. aq. NaCl (6 mL), dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give a crude product. The product was purified by reverse phase chromatography on a F-Welch Xtimate C18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 28-68% ACN in water (10 mM NH4HCO3) over 20 mins at a flow rate of 60 mL/min to give the title compound (10.8 mg). ES-MS m/z 685 (M+H). [0558] The following compounds were prepared in a similar manner as described for Example 134. Example No. Chemical Name Structure ES-MS m/z ) ) ) ) ) ) ) , H- benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)-3,3-difluoropiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0559] To a mixture of 2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3,3-difluoropiperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide 2,2,2-trifluoroacetate (90 mg, 99 μmol) in Me-THF (2 mL) was added 3,3-difluoro-cyclobutanone (145 mg, 1.34 mmol) and borane-2- methylpyridine complex (241 mg, 2.21 mmol), the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the residue. The crude product was purified by silica gel column chromatography using a gradient of 0 to 70% EtOAc in hexane. The product was further purified by reverse phase chromatography on an F-Welch Xtimate C18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 32- 72% ACN in water (10 mM NH4CO3) over 20 min to give the title compound (28 mg). ES- MS m/z 701 (M+H). [0560] The following compounds were prepared in a similar manner as described for Example 110. Example No. Chemical Name Structure ES-MS m/z ) ) ) ) ) 4-(4-((5-Chloropyrimidin- 2-yl)methyl)-3-oxo-3,4- H) H) Example 150: Racemic 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-(cyclopropylmethyl)-1-((3R,4R)-3-methyl-1-(oxetan-3- yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [0561] A 20 dram vial charged with 4-(4-((5- chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- (cyclopropylmethyl)-1-((3R,4R)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (260 mg, 443 μmol). To this was added DCM (2.2 mL) followed by oxentan-3- on (169 mg, 2.34 mmol). Sodium triacetoxyborohydride (469 mg, 2.21 mmol) was added in one portion. The mixture was stirred at RT for 3 days. The reaction was quenched via the addition of sat. aq. NaHCO3 solution and diluted with DCM. The layers were separated. The aq. phase was further extracted with DCM. The combined organic phases were dried over MgSO4, filtered, and the filtrate concentrated to give a crude product. The crude product was purified by reverse phase chromatography on a LUNA (50 mm × 250 mm, 10 μm) column eluting with a gradient from 20-45% ACN in water (10 mM NH4CO3) at a flow rate of 120 mL/min to give the title compound (110 mg). ES-MS m/z 643 (M+H). [0562] The following compound was prepared in a similar manner as described for Example 150. Example No. Chemical Name Structure ES-MS m/z H) [0563] The following compounds were prepared in a similar manner as described for Example 116. Example No. Chemical Name Structure ES-MS m/z ) ) ) 4-(4-((5-Chloro-3- fluoropyridin-2- l)meth l)-3-oxo-34- ) ) ) ) ) ) 4-(4-((5-Chloropyrimidin- ) ) ) 4-(4-((5-Fluoropyrimidin- ) ) ) 4-(4-((5-Chloro-3- ) ) ) 4-(4-((5-Chloro rimidin- ) ) ) R i 44 5 ) ) ) ) ) ) Racemic 4-(4-((3,5- ) ) )
Racemic 4-(4-((3,5- ) ) ) 4-(4-((5-Chlr rimidin- ) ) ) R i 44 5 ) ) ) ) ) ) ) ) )
Racemic 1-((trans)-1-(3,3- ) ) )
4-(4-((5-Chloropyrimidin- ) ) ) ) ) ) ) ) ) ) 4-(4-((5-Chloropyrimidin- ) ) ) 4-(4-((5-Chloro-3- fluoropyridin-2- H) Ex , yl)-6- isobutyl-1-((3R,4R)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide [0564] To an 8 mL sealed vial bar was added 4-(1-((5- chloropyrimidin-2-yl)methyl)-2-oxo-1,2-dihydroquinoxalin-6-yl)-6-isobutyl-1-((3R,4R)-3- methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (32 mg, 41 μmol), EtOH (1 mL), water (0.1 mL) and hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (9.0 mg21 μmol) successively at ambient temperature. The mixture was bubbled with N2 for 3 min and stirred at 100 °C for 2 h. The reaction was cooled to RT. To the reaction mixture was added 4,5-dichloro-3,6- dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (12.2 mg, 52.1 μmol) at RT. The mixture was stirred at RT for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were washed with sat. aq. NaHCO3 (3 mL × 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography using a gradient of 0 to 5% MeOH in DCM to give the title compound. The product was further purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 16-56% ACN in water (10 mM NH4CO3) over 20 min to give the title compound (10 mg). ES-MS m/z 642 (M+H). Example 215: 6-(Cyclopropylmethyl)-1-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide [0565] In a 25 mL vial with a (cyclopropylmethyl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (100 mg, 211 μmol) and 1-(3,3- difluorocyclobutyl)piperidin-4-ol (63.4 mg, 332 μmol) were dissolved in THF (2.11 mL). Triphenylphosphine (158 mg, 602 μmol) and DBAD (146 mg, 634 μmol) were added in sequence. The reaction was capped under N2 and stirred at RT for 22 h. Additional triphenylphosphine (73.4 mg, 280 μmol) and DBAD (72.9 mg, 317 μmol) were added and the mixture was stirred at RT for 5 h. The reaction mixture was loaded onto a 10 g SCX column that was equilibrated in 100 mL of MeOH. The column was flushed with 100 mL of MeOH followed by elution with 100 mL of 2 M NH3 in MeOH. Fractions containing product were combined and evaporated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0 to 100% (25%EtOH in EtOAc) in cyclohexane. The product was further purified by reverse phase chromatography on a Evo (30 mm × 100 mm, 5 μm) column eluting with a gradient from 38-58% ACN in water (10 mM NH4CO3) over 20 min to give the title compound (13.1 mg). ES-MS m/z 647 (M+H). Example 216: Racemic 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(3,3,3-trifluoro-2- hydroxypropyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1) [0566] To a 8 mL sealed vial bar was added 4-(4-((5-chloro-3- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1) (41 mg, 63 μmol), racemic 3-bromo-1,1,1-trifluoropropan-2-ol (53 mg, 0.27 mmol), ACN (1.0 mL) and K2CO3 (22 mg, 0.15 mmol) successively at ambient temperature. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with sat. aq. NaCl (10 mL × 2), dried over anhydrous Na2SO4, filtered, and filtrate concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 28-68% ACN in water (10 mM NH4CO3) at a flow rate of 50 mL/min to give the title compound (18.53 mg). ES-MS m/z 724 (M+H). [0567] The following compounds were prepared in a similar manner as described for Example 216. Example No. Chemical Name Structure ES-MS m/z Racemic 4-(4-((5-Chloro- 3-fl r ridin-2- ) ) ) Example 220: 6-(Cyclopropylmethyl)-1-((3R,4R)-1-(2,2-difluoroethyl)-3-methylpiperidin-4- yl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0568] A 10 dram vial equippe charged with 6-(cyclopropylmethyl)- 4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1- ((3R,4R)-3-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (250 mg, 219 μmol) in DCM (2.2 mL). To the reaction was added DIPEA (200 μL, 1.15 mmol) followed by 2,2-sifluoroethyl trifluoromethanesulphonate (100 μL, 751 μmol) at RT for 3.5 h. The reaction was quenched via the addition of sat. aq. NH4Cl. The mixture was extracted with DCM. The combined organic phase was dried over MgSO4, filtered, and the filtrate concentrated. The product was purified by reverse phase chromatography on a LUNA (250 mm × 500 mm, 10 μm) column eluting with a gradient from 36-56% ACN in water (10 mM NH4CO3) at a flow rate of 120 mL/min to give the title compound (36.8 mg). ES-MS m/z 635 (M+H). Example 221: Racemic 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide
[0569] To a solution of 4-(4-((3, -2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5- carboxamide (200 mg, 347 μmol) in DCE (2 mL) was added 2-(trifluoromethyl)oxirane (38.9 mg, 347 μmol). The mixture was stirred at RT for 2 days. Additional 2- (trifluoromethyl)oxirane (38.9 mg, 347 μmol) was added and the mixture stirred for 16 h. Additional, 2-(trifluoromethyl)oxirane (38.9 mg, 347 μmol) was added and the mixture was stirred for 16 h. The solvent was evaporated. The crude product was purified by silica gel column chromatography using a gradient of 30 to 100% EtOAc in cyclohexane to give the title compound (88 mg). ES-MS m/z 688 (M+H). Example 222: 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(cyclopropylsulfonyl)-3-methoxypiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 2)
[0570] To a 8 mL sealed vial with a magnetic stir bar was added 4-(4-((5-chloro-3- fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1- ((cis)-3-methoxypiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 2) (50.2 mg, 76.7 μmol), DCM (1 mL), TEA (55.4 μL, 389 μmol) and cyclopropanesulfonyl chloride (34.5 mg, 238 μmol) successively at ambient temperature. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The product was purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 26-66% ACN in water (10 mM NH4CO3) over 20 min at a flow rate of 30 mL/min to give the title compound (29 mg). ES-MS m/z 726 (M+H). [0571] The following compounds were prepared in a similar manner as described for Example 222. Example No. Chemical Name Structure ES-MS m/z 4 4 5 Chl 3 ) ) a. 3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxypiperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 2) Examples 225a and 225b: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 225a and Isomer 2 – Example 225b) [0572] Racemic 4-(4-((3,5- -3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6- 2-hydroxypropyl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralpak AD-H (30 mm × 250 mm, 5 ^m); Condition: mobile phase A: Heptane (0.2% IPAm), mobile phase B: EtOH (0.2% IPAm); Begin B: 30%; End B: 30%; Flowrate (mL/min): 35) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 688 (M+H). Isomer 2: ES-MS m/z 688 (M+H). The products were analyzed by SFC (Column: Chiralpak AD-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: Heptane (0.2% IPAm), mobile phase B: EtOH (0.2% IPAm); Begin B: 30%; End B: 30%; Flowrate (mL/min): 1; Run length: 8 min; Detection Method: UV; Detection Wavelength: 225, 250 nM). Isomer 1: 99%ee, enriched in peak 1, retention time 3.18 min. Isomer 2: 95%ee, enriched in peak 2, retention time 4.38 min. Examples 226a and 226b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)piperidin- 4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 226a and Isomer 2 – Example 226b)
[0573] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)piperidin- 4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL Chiralpak AD (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 45%; End B: 45%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 743 (M+H). Isomer 2: ES-MS m/z 743 (M+H). The products were analyzed by SFC (Column: Chiralpak AD-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C;). Isomer 1: >99%ee, enriched in peak 1, retention time 0.90 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.33 min. Examples 227a and 227b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-2-(hydroxymethyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-1-(3,3-difluorocyclobutyl)-3- methylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 227a and Isomer 2 – Example 227b)
[0574] Racemic 4-(4-((5-chlorop ethyl)-2-(hydroxymethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((3R,4R)-1-(3,3-difluorocyclobutyl)-3- methylpiperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: ChiralPak IH (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.1% NH3H2O); Begin B: 35%; End B: 35%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 709 (M+H). Isomer 2: ES-MS m/z 709 (M+H). The products were analyzed by SFC (Column: Chiralpak IH-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% NH3 (7M in MeOH)); Gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 0.99 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.21 min. Examples 228a and 228b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-(methylthio)-1-(oxetan-3-yl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 228a and Isomer 2 – Example 228b)
[0575] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((trans)-3-(methylthio)-1-(oxetan-3-yl)piperidin-4- yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL Chiralpak IC (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH:ACN=3:1 (0.1% NH3H2O); Begin B: 55%; End B: 55%; Flowrate (mL/min): 140) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1 was repurified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 18-58% ACN in water (10 mM NH4CO3) over 20 min at a flow rate of 30 mL/min to give repurified Isomer 1. Isomer 1: ES-MS m/z 677 (M+H). Isomer 2: ES-MS m/z 677 (M+H). The products were analyzed by SFC (Column: Chiralpak IC-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH:ACN=3:1 (0.1% DEA); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.15 min. Isomer 2: >99%ee, enriched in peak 2, retention time 2.62 min. Examples 229a and 229b: 1-((Cis)-1-(3,3-difluorocyclobutyl)-3-methoxypiperidin-4-yl)-4-(4- ((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 229a and Isomer 2 – Example 229b)
[0576] Racemic 1-((cis)-1-(3,3-d )-3-methoxypiperidin-4-yl)-4-(4-((5- fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OD-H (20 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.5% DEA); Begin B: 20%; End B: 20%; Flowrate (mL/min): 80; BPR set point: 110 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 679 (M+H). Isomer 2: ES-MS m/z 679 (M+H). The products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM). Isomer 1: >99%ee, enriched in peak 1, retention time 0.86 min. Isomer 2: 99%ee, enriched in peak 2, retention time 1.15 min. Examples 230a and 230b: 4-(4-((5-Chloro-3-fluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(oxetan-3-yl)piperidin-4-yl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 230a and Isomer 2 – Example 230b)
[0577] Racemic 4-(4-((5-chloro- -yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methoxy-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OD-H (20 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.5% DEA); Begin B: 35%; End B: 35%; Flowrate (mL/min): 80; BPR set point: 110 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 678 (M+H). Isomer 2: ES-MS m/z 678 (M+H). The products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 35%; End B: 35%; Flowrate (mL/min): 5; Run length: 5 min). Isomer 1: 99%ee, enriched in peak 1, retention time 0.95 min. Isomer 2: 98%ee, enriched in peak 2, retention time 1.31 min. Examples 231a and 231b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3-difluorocyclobutyl)-3-methoxypiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 231a and Isomer 2 – Example 231b)
[0578] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((cis)-1-(3,3-difluorocyclobutyl)-3-methoxypiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OD-H (21 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.05% DEA); Begin B: 25%; End B: 25%; Flowrate (mL/min): 66; BPR set point: 100 bar; BPR Temperature: 25°C; Column Temperature: 40 °C) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 695 (M+H). Isomer 2: ES-MS m/z 695 (M+H). The products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM). Isomer 1: >99%ee, enriched in peak 1, retention time 1.13 min. Isomer 2: 97%ee, enriched in peak 2, retention time 1.57 min. Examples 232a and 232b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide (Example 232a – cis-isomer) and 4-(4-((5- Chloropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1-((trans)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Example 232b – trans-isomer)
[0579] 4-(4-((5-Chloropyrimidi oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-(4-(2-oxopyrrolidin-1-yl)cyclohexyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: (s,s) WHELK-O1 (30 mm × 250 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH:ACN=3:1 (0.1% NH3H2O); Begin B: 50%; End B: 50%; Flowrate (mL/min): 80) to give the cis-isomer (first-eluting isomer) and the trans-isomer (second-eluting isomer). The products were further purified by reverse phase chromatography on a F-PrePulite Perfect T3 (40 mm × 200 mm, 10 μm) column eluting with a gradient from 18-58% ACN in water (10 mM NH4CO3) over 20 mins at a flow rate of 30 mL/min. Cis-isomer: ES-MS m/z 657 (M+H). Trans-isomer: ES-MS m/z 657 (M+H). The products were analyzed by SFC (Column: (S,S)-Whelk-0-1.8 (4.6 mm × 50 mm, 1.8 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH:ACN=3:1 (0.1% DEA); Begin B: 45%; End B: 45%; Flowrate (mL/min): 2.5; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Cis-isomer: >99%ee, enriched in peak 1, retention time 1.29 min. Trans-isomer: >99%ee, enriched in peak 2, retention time 1.64 min. Preparation of Example 233a and 233b: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-ethyl-1-(oxetan-3-yl)piperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 233a and Isomer 2 – Example 233b)
[0580] Racemic 4-(4-((3,5-diflu ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-ethyl-1-(oxetan-3-yl)piperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamidewas separated by SFC (Column: Chiralcel OJ-H (21 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 80; BPR set point: 100 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 214, 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 660 (M+H). Isomer 2: ES-MS m/z 660 (M+H). The products were analyzed by SFC (Column: Chiralcel OJ-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm); Begin B: 10%; End B: 10%; Flowrate (mL/min): 5; Run length: 5 min). Isomer 1: >99%ee, enriched in peak 1, retention time 1.68 min. Isomer 2: >99%ee, enriched in peak 2, retention time 2.32 min. Preparation of Example 234a and 234b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6- (3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 234a and Isomer 2 – Example 234b)
[0581] Racemic 4-(4-((5-chlorop ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6-(3,3,3- trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Lux Cell-4 (21 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% DEA); Begin B: 25%; End B: 25%; Flowrate (mL/min): 80; BPR set point: 100 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 214, 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 699 (M+H). Isomer 2: ES-MS m/z 699 (M+H). The products were analyzed by SFC (Column: Lux Cellulose-4 (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% IPAm); Begin B: 25%; End B: 25%; Flowrate (mL/min): 5; Run length: 5 min). Isomer 1: >99%ee, enriched in peak 1, retention time 2.32 min. Isomer 2: >99%ee, enriched in peak 2, retention time 3.32 min. Preparation of Example 235a and 235b: 4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6- (3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 235a and Isomer 2 – Example 235b)
[0582] Racemic 4-(4-((3,5-difluo ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-6-(3,3,3- trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Lux Cell-4 (21 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% DEA); Begin B: 20%; End B: 20%; Flowrate (mL/min): 80; BPR set point: 110 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 214, 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 700 (M+H). Isomer 2: ES-MS m/z 700 (M+H). The products were analyzed by SFC (Column: Lux Cellulose-4 (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% IPAm); Begin B: 20%; End B: 20%; Flowrate (mL/min): 5; Run length: 5 min). Isomer 1: >99%ee, enriched in peak 1, retention time 2.27 min. Isomer 2: >99%ee, enriched in peak 2, retention time 2.89 min. Preparation of Example 236a and 236b: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-((trans)-5-fluoro-3,3-dimethyl-1-(oxetan-3- yl)piperidin-4-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 236a and Isomer 2 – Example 236b)
[0583] Racemic 4-(4-((3,5-diflu ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-((trans)-5-fluoro-3,3-dimethyl-1-(oxetan-3-yl)piperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: REGIS (s,s) WHELK-O1 (30 mm × 250 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% NH3H2O); Begin B: 50%; End B: 50%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 678 (M+H). Isomer 2: ES-MS m/z 678 (M+H). The products were analyzed by SFC (Column: (S,S)-Whelk-0-1.8 (4.6 mm × 50 mm, 1.8 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.05% DEA); Begin B: 45%; End B: 4545%; Flowrate (mL/min): 2.2; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.21 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.43 min. Preparation of Example 237a and 237b: 1-((Trans)-1-(3,3-difluoro-1-methylcyclobutyl)-3- methylpiperidin-4-yl)-4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 237a and Isomer 2 – Example 237b)
[0584] Racemic 1-((trans)-1-(3,3 ylcyclobutyl)-3-methylpiperidin-4-yl)- 4-(4-((5-fluoropyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL Chiralpak AS (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 677 (M+H). Isomer 2: ES-MS m/z 677 (M+H). The products were analyzed by SFC (Column: Chiralpak AS-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% NH3(7M in MeOH)); Begin B: Gradient: from 5% to 40% of B in 1.5 min and hold 40% for 1 min, then 5% of B for 0.5 min; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C). Isomer 1: >99%ee, enriched in peak 1, retention time 1.36 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.56 min. Preparation of Example 238a and 238b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)-3,3-difluoropiperidin-4- yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 238a and Isomer 2 – Example 238b)
[0585] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(1-(3,3-difluorocyclobutyl)-3,3-difluoropiperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralpak IG (30 mm × 250 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.5% DMEA); Begin B: 40%; End B: 40%; Flowrate (mL/min): 135; BPR set point: 100 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 215, 225 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 701 (M+H). Isomer 2: ES-MS m/z 701 (M+H). The products were analyzed by SFC (Column: Lux i-Amylose-3 (4.6 mm × 100 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.2% IPAm); Begin B: 40%; End B: 40%; Flowrate (mL/min): 5; Run length: 5 min; Detection Method: UV; Detection Wavelength: 225 nM). Isomer 1: >99%ee, enriched in peak 1, retention time 0.94 min. Isomer 2: >99%ee, enriched in peak 2, retention time 1.44 min. Preparation of Example 239a and 239b: 4-(4-((5-Chloropyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methyl-1-(oxetan-3-yl)piperidin- 4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 239a and Isomer 2 – Example 239b)
[0586] Racemic 4-(4-((5-chloro thyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1-((cis)-3-methyl-1-(oxetan-3-yl)piperidin-4-yl)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Daicel Chiralpak IBN (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.1% NH3H2O); Begin B: 40%; End B: 40%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. The products were both further purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm × 200 mm, 7 μm) column eluting with a gradient from 20-60% ACN in water (10 mM NH4HCO3) over 20 min to give the purified isomers. Isomer 1: ES-MS m/z 645 (M+H). Isomer 2: ES-MS m/z 645 (M+H). The products were analyzed by SFC (Column: Chiralpak IB N-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: IPA (0.05% DEA); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min; BPR set point: 103 bar; Column Temperature: 35 °C; Detection Method: UV; Detection Wavelength: 220 nM). Isomer 1: >99%ee, enriched in peak 1, retention time 1.78 min. Isomer 2: 98%ee, enriched in peak 2, retention time 1.85 min. Preparation of Example 240a and 240b: 1-((Cis)-1-(3,3-difluorocyclobutyl)-3- methoxypiperidin-4-yl)-4-(4-((3,5-difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 240a and Isomer 2 – Example 240b)
[0587] Racemic 1-((cis)-1-(3,3- )-3-methoxypiperidin-4-yl)-4-(4-((3,5- difluoropyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-isobutyl- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: Chiralcel OD-H (21 mm × 150 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.5% DMEA); Begin B: 25%; End B: 25%; Flowrate (mL/min): 80; BPR set point: 110 bar; BPR Temperature: 25 °C; Column Temperature: 40 °C; Detection Method: UV; Detection Wavelength: 310 nM) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 696 (M+H). Isomer 2: ES-MS m/z 696 (M+H). The products were analyzed by SFC (Column: Chiralcel OD-H (4.6 mm × 100 mm, 5 ^m); Condition: mobile phase A: CO2, mobile phase B: MeOH (0.2% IPAm ); Begin B: 25%; End B: 25%; Flowrate (mL/min): 4; Run length: 5 min). Isomer 1: 96%ee, enriched in peak 1, retention time 0.76 min. Isomer 2: 99%ee, enriched in peak 2, retention time 1.03 min. Preparation of Example 241a and 241b: 4-(4-((3,5-Difluoropyridin-2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1-(3,3-dimethyl-1-(oxetan-3-yl)piperidin-4-yl)-6- isobutyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (Isomer 1 – Example 241a and Isomer 2 – Example 241b)
[0588] Racemic 4-(4-((3,5-difluo ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7-yl)-1-(3,3-dimethyl-1-(oxetan-3-yl)piperidin-4-yl)-6-isobutyl-1H- pyrazolo[3,4-b]pyridine-5-carboxamide was separated by SFC (Column: DAICEL Chiralpak IG (30 mm × 250 mm, 10 ^m); Condition: mobile phase A: CO2, mobile phase B: ACN/EtOH (0.1% NH3H2O); Begin B: 45%; End B: 45%; Flowrate (mL/min): 80) to give the separated enantiomers named Isomer 1 and Isomer 2 according to their elution order from the column. Isomer 1: ES-MS m/z 660 (M+H). Isomer 2: ES-MS m/z 660 (M+H). The products were analyzed by SFC (Column: Chiralpakl IG-3 (4.6 mm × 50 mm, 3 ^m); Condition: mobile phase A: CO2, mobile phase B: EtOH (0.05% DEA); Begin B: 40%; End B: 40%; Flowrate (mL/min): 4; Run length: 3 min). Isomer 1: >99%ee, enriched in peak 1, retention time 0.54 min. Isomer 2: >99%ee, enriched in peak 2, retention time 0.72 min. Preparation of Example 242: 4-(1-((5-Cyanopyridin-2-yl)methyl)-1H-indazol-5-yl)-6- isobutyl-1-((3R,4R)-3-methyl-1-(3-methyloxetan-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4- b]pyridine-5-carboxamide
[0589] Example 242 was prepar following steps. Step 1: The method of Intermediate 6 was used with 1H-indazole-5-carbaldehyde and 6- (bromomethyl)nicotinonitrile. Step 2: General Procedure A was used with 6-((5-formyl-1H-indazol-1- yl)methyl)nicotinonitrile, 5-methyl-3-oxohexanamide, and 1H-pyrazol-5-amine; Step 3: Described as follows: To a 40 mL vial equipped with a magnetic stir bar was added 4-(1-((5-cyanopyridin-2-yl)methyl)-1H-indazol-5-yl)-6-isobutyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide (172 mg, 344 μmol) , (3R,4S)-3-methyl-1-(3-methyloxetan-3-yl)piperidin-4- ol (136 mg, 697 μmol), toluene (3 mL), and CMBP (420 mg, 1.71 mmol) successively at RT. The resulting mixture was degassed with N2 for 5 min and stirred at 100 °C for 1 h. The reaction was cooled to RT. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography using a gradient of 0 to 10% MeOH in DCM. The product was further purified by reverse phase chromatography on a F-Prepulite XP tC18 (40 mm x 200 mm, 7 μm) column eluting with a gradient from 20-60% ACN in water (10 mM NH4CO3) over 20 min. The fractions were concentrated, and the residual aqueous mixture was lyophilized to give the title compound (4 mg). ES-MS m/z 618 (M+H). AMY3R and CTR Functional Activity Assays and Data [0590] Functional activity was determined using cAMP formation in human AMY3R- expressing or CTR-expressing UMUC3 clonal cell lines. Each receptor cell line was treated with a compound to be tested or a reference peptide (rAMY peptide for AMY3R assays or hCT peptide for CTR assays) using 10-point concentration response curves with 3-fold direct dilutions or 20-point concentration response curves with 2-fold direct dilutions prepared with a Labcyte Echo Acoustic Liquid Handler in DMEM (Gibco Cat# 31053) supplemented with 1X GlutaMAXTM (Gibco Cat# 35050061), 0.1% bovine casein (Sigma Cat# C4765-10ML), 1 mM IBMX (Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630080) in a 20 µl assay volume. [0591] After a 30-min incubation at 37°C, the intracellular cAMP was quantitatively determined using the cAMP Gs dynamic Kit (Revvity/Cisbio, Cat# 62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu3+-Cryptate, also in cell lysis buffer. The resulting competitive assay was incubated for at least 90 min at RT and then detected using a Pherastar Instrument (BMG Labtech) with excitation at 320 nm and emission at 665 nm and 620 nm. Raw data values (emission at 665nm/620nm*10,000) were inversely proportional to the amount of cAMP present and were converted to cAMP (nM) per well using a cAMP standard curve. [0592] The amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with rat Amylin {rAMY} for AMY3R assays or human Calcitonin {hCT} for CTR assays. A relative EC50 (Rel EC50) and Emax value were derived by non-linear regression analysis using the percent maximal response vs. the concentration of the compound added, fitted to a four-parameter logistic equation. [0593] Data for the exemplified compounds and rAMY reference peptides in the AMY3R assay and CTR assay are shown in the tables below. Table. In Vitro Functional AMY3R Assay Results – 10-Point Format and 20-Point Format 10-Point Format 20-Point Format 10 43 89 11 260 104 2324 42 2540 47 217 68 118 65 90 394 89 91 b 16 87 10 100 3.39 93 2.44 95 7.9 103 11.2 105 240b 17 95 241a 11.2 102 Format 10-Point Format 20-Point Format Example No. Rel EC50 nM Emax, % Rel EC50, nM Emax, % 28b 73 82 29 16 83 16 79 388 83 8 93 4 94 150 8.99 99 151 18.5 94 192 44.3 92 193 111 93 229b 10.8 87 230a 6.77 85

Claims

CLAIMS 1. A compound having formula (I), or a pharmaceutically acceptable salt thereof: , wherein: R1 is selected from: (1) a C1-10 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (i) -OH, (ii) a C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-10 alkyl, and R1b is selected from H, C1-10 alkyl, -C(O)C1-10 alkyl, -C(O)OC1-10 alkyl, and -SO2C1-10 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-10 alkyl, and R1d is selected from (i) H, (ii) a C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-10 alkoxy, (e) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-10 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, and (g) halogen, (2) a C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-10 alkyl, and (iii) C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and a C1-10 alkyl, and R1f is selected from (i) H and (ii) a C1-10 alkyl, and (b) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-10 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-10 alkyl, (c) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, (ii) halogen, and (iii) a C1-10 alkoxy, (d) -C(O)C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) -OH and (ii) halogen, (e) -C(O)OC1-10 alkyl, optionally substituted with 1 to 4 halogens, (f) -SO2C1-10 alkyl, optionally substituted with 1 to 4 halogens, (g) -SO2C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (h) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) a C1-10 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (j) -S-C1-10 alkyl, optionally substituted with 1 to 4 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) -CN, (4) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from (a) a C1-10 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) a C1-10 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-10 alkyl, and R3b is a C1-10 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-10 cycloalkyl; (5) a C3-10 cycloalkyl, (6) -NR3cR3d, wherein R3c is H and R3d is selected from (a) a C1-6 alkyl, optionally substituted with -OH, and (b) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with a C1- 10 alkyl, (7) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with -OH; (8) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-10 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1- 10 alkoxy, and (9) a 5 to 6 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, optionally substituted with a C1-10 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 7 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 7 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) -C(O)OC1-10 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-10 alkyl; and R4b is selected from (i) H, (ii) C1-10 alkyl, (iii) -C(O)C1-10 alkyl, (iv) -C(O)OC1-10 alkyl, and (v) -SO2C1-10 alkyl, (d) an aryl, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH, (iii) a C1-10 alkoxy, and (iv) -CN, and (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) a C1-10 alkyl, optionally substituted with -OH or C1-10 alkoxy, (iii) a C1-10 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-10 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-10 alkyl, and R2b is selected from (a) H, (b) a C1-10 alkyl, and (c) -SO2C1-10 alkyl, and (6) a C1-10 alkyl, optionally substituted with -OH or -CN; R6 is a C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substituted with 1 to 4 halogens, (3) -OH, and (4) a 4 to 10 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) halogen and (b) C1-10 alkyl; and R10 is selected from (1) H, (2) halogen, and (3) a C1-10 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 4 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-6 alkyl, and R1d is selected from (i) H, (ii) a C1-6 alkyl, (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 2 substituents independently selected from (i) a C1-6 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-6 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-6 alkyl, and R1f is selected from (i) H and (ii) a C1-6 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-6 alkoxy, and (iv) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) a C1-6 alkoxy, (d) -C(O)C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH and (ii) halogen, (e) -C(O)OC1-6 alkyl, optionally substituted with 1 to 3 halogens, (f) -SO2C1-6 alkyl, optionally substituted with 1 to 3 halogens, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-6 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-6 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-6 alkoxy, (b) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-6 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (a) H and (b) a C1-6 alkyl, and R3b is a C1-6 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-6 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-6 alkoxy, and (6) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with a C1-6 alkyl optionally substituted with - OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the 5 or 6 membered ring formed by R4 and R2, or formed by R4 and R5, is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) -C(O)OC1-6 alkyl, (c) -C(O)-NR4aR4b, wherein R4a is selected from (i) H and (ii) C1-6 alkyl; and R4b is selected from (i) H and (ii) C1-6 alkyl (iii) -C(O)C1-6 alkyl, (iv) -C(O)OC1-6 alkyl, and (v) -SO2C1-6 alkyl, (d) an aryl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, (iii) a C1-6 alkoxy, and (iv) -CN, and (e) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or C1-6 alkoxy, (iii) a C1-6 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)OC1-6 alkyl, (5) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (6) a C1-6 alkyl, optionally substituted with -OH or -CN; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, (4) -C(O)NR2aR2b, wherein: R2a is selected from (a) H and (b) a C1-6 alkyl, and R2b is selected from (a) H, (b) a C1-6 alkyl, and (c) -SO2C1-6 alkyl, and (5) a C1-6 alkyl, optionally substituted with -OH or -CN; R6 is a C1-6 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-6 alkyl; and R10 is selected from (1) H and (2) halogen.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (ii) -NR1aR1b, wherein R1a is selected from H and C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, and-SO2C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H, (ii) a C1-4 alkyl, (iii) -C(O)C1-4 alkyl, (iv) -C(O)OC1-4 alkyl, and (v) -SO2C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 4 to 10 membered heterocyclyl selected from pyrrolidinyl, piperidinyl, and 7- oxabicyclo[2.2.1]heptanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and (ii) a C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl, and tetrahydrofuranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen and (iii) oxo, (i) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl, and (d) halogen; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (6) a 5 to 6 membered heteroaryl selected from isoxazolyl and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; R4 and R2, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl; or alternatively, R4 and R5, together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic or heteroaryl ring selected from imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, wherein the 5 or 6 membered ring formed by R4 and R2 or formed by R4 and R5 is optionally substituted with 1 to 4 substituents independently selected from: (1) halogen, (2) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, (iii) a C1-4 alkoxy, and (iv) -CN, and (c) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-4 alkyl, optionally substituted with -OH, (iii) a C1-4 alkoxy, and (iv) -CN, and (3) oxo; R2, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R5, when not forming a ring with R4, is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-4 alkyl, optionally substituted with -OH; R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl.
4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia): ; wherein: 7 R is a C1-6 alkyl, optionally independently selected from: (1) -OH, (2) a phenyl, and (3) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (2) and heteroaryl or heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH or a C1-6 alkoxy, (iii) a C1-6 alkoxy, and (iv) -CN; R8 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a phenyl, and (c) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (b) and heteroaryl or heterocyclyl of (c) is optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy; and R9 is selected from (1) H and (2) =O.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) -OH, (2) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, and (3) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl, pyrimidyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN, and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents independently selected from: (a) a C1-4 alkyl, optionally substituted with -OH, and (b) a C1-4 alkoxy.
6. The compound of any one of claims 1-2 having formula (Ib), or a pharmaceutically acceptable salt thereof: b); wherein: W is selected from O and S; R2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-6 alkyl, optionally substituted with -OH; R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl, pyrimidyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN; and R8 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with -OH. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: (1) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and C1-4 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, and (d) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and (ii) a C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl,
7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) C1-4 alkoxy, and (iv) a C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (f) a 4 to 6 membered heterocyclyl selected from oxetanyl, azetidinyl, piperidinyl and thietanyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo, (g) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (h) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (i) -OH; R2 is selected from (1) H and (2) halogen; R3 is selected from (1) H and (2) a C1-4 alkyl, optionally substituted with 1 to 2 halogens; R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl; R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, and (c) a C1-4 alkoxy, (d) -CN, and (2) a 5 to 10 membered heteroaryl or heterocyclyl selected from pyridyl and pyrimidyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN; and R8 is selected from: (1) H and (2) a C1-4 alkyl, optionally substituted with -OH.
8. The compound of any one of claims 1-2 having formula (Ic), or a pharmaceutically acceptable salt thereof: ; wherein: R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from phenyl, pyridyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN.
9. The compound of any one of claims 1-2 having formula (Id), or a pharmaceutically acceptable salt thereof: ; wherein: R7 is a C1-6 alkyl, optionally independently selected from phenyl, pyridyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN.
10. The compound of any one of claims 1-2 having formula (Ie), or a pharmaceutically acceptable salt thereof: R1 R6 N N , wherein: R2 is selected from: (1) H, (2) halogen, (3) -C(O)OH, and (4) a C1-6 alkyl, optionally substituted with -OH; and R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN; R8 is selected from (1) H, (2) halogen, and (3) a C1-6 alkyl, optionally substituted with -OH; and R10 is selected from (1) H and (2) halogen.
11. The compound of any one of claims 1-2 having formula (If), or a pharmaceutically acceptable salt thereof: ; wherein: A1 is selected from: (1) -O-, (2) -C(R15)(R15’)-, wherein each of C15 and R15’ is independently selected from (a) H, (b) C1-6 alkyl, and (c) halogen, (3) -N(R8)-, wherein R8 is selected from (a) H and (b) a C1-6 alkyl; and R7 is selected from: (1) H and (2) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (iv) -CN, (b) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, (c) a C1-6 alkoxy, and (d) -CN.
12. The compound of any one of claims 1-2 having formula (Ig), or a pharmaceutically acceptable salt thereof: ; wherein: A2 is selected from: (1) -N=, and (2) -CH=, optionally substituted with a substituent selected from: (a) halogen, and (b) a C1-6 alkyl; and R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) a phenyl, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) a C1-6 alkyl, optionally substituted with -OH, and (iii) a C1-6 alkoxy, and (2) a 5 to 10 membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy.
13. The compound of any one of claims 1-2 having formula (Ih), or a pharmaceutically acceptable salt thereof: ; wherein: R7 is a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from phenyl, pyridyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-6 alkyl, optionally substituted with -OH, and (c) a C1-6 alkoxy; and R8 is a C1-6 alkyl substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens.
14. The compound of any one of claims 4-6 and 8-13, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-6 alkyl, and R1b is selected from H, C1-6 alkyl, -C(O)C1-6 alkyl, -C(O)OC1-6 alkyl, and -SO2C1-6 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 5 to 10 membered heterocyclyl selected from azepanyl, azetidinyl, morpholinyl, oxetanyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl selected from oxazolyl, pyridyl, and pyrimidyl, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and (ii) a C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 5 to 10 membered heterocyclyl selected from azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5- azaspiro[2.5]octanyl, 7-oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, and (j) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens.
15. The compound of any one of claims 4-6 and 8-14, wherein: R3 is selected from: (1) H, (2) halogen, (3) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, piperidinyl, and pyrrolidinyl, each of which is optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl selected from morpholinyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (6) a 5 to 6 membered heteroaryl selected from pyrazolyl, isoxazolyl, and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH.
16. The compound of any one of claims 4-6 and 8-15, wherein: R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl.
17. The compound of any one of claims 4-6 and 8-13, wherein: R1 is selected from: (1) a C1-6 alkyl substituted with 1 to 3 substituents independently selected from: (a) -OH, (b) a C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH, and (iii) -NR1aR1b, wherein R1a is selected from H and a C1-4 alkyl, and R1b is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl, -C(O)OC1-4 alkyl, and -SO2C1-4 alkyl, (c) -NR1cR1d, wherein R1c is selected from (i) H and (ii) a C1-4 alkyl, and R1d is selected from (i) H and (ii) a C1-4 alkyl, (d) a phenyl, optionally substituted with 1 to 3 halogens, (e) a 4 to 10 membered heterocyclyl selected from azepanyl, azetidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 2 substituents independently selected from (i) a C1-4 alkyl and (ii) halogen, (f) a 5 to 10 membered heteroaryl selected from furyl, pyrazolyl, pyrazinyl, isoxazolyl, thienyl, oxazolyl, pyridyl, and pyrimidyl, and (g) halogen, (2) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) -NR1eR1f, wherein R1e is selected from (i) H, (ii) a C1-4 alkyl, and (iii) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and a C1-4 alkyl, and R1f is selected from (i) H and a (ii) C1-4 alkyl, and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) oxo, and (3) a 4 to 10 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, azepanyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 5-azaspiro[2.5]octanyl, 7- oxabicyclo[2.2.1]heptanyl, and 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1 to 5 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) -OH, (ii) halogen, (iii) a C1-4 alkoxy, and (iv) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl, (c) a C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) a C1-4 alkoxy, (d) -C(O)C1-4 alkyl, (e) -C(O)OC1-4 alkyl, (f) -SO2C1-4 alkyl, (g) -SO2C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (h) a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl, (ii) halogen, and (iii) oxo, (i) a C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (j) -S-C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (k) -OH; R3 is selected from: (1) H, (2) halogen, (3) a C1-4 alkyl, optionally substituted with 1 to 2 substituents independently selected from (a) a C1-4 alkoxy, (b) a 5 to 6 membered heterocyclyl selected from piperidinyl and pyrrolidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) a C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (c) -NR3aR3b, wherein: R3a is selected from (i) H and (ii) a C1-4 alkyl, and R3b is a C1-4 alkyl, optionally substituted with a substituent selected from (i) -OH and (ii) a C3-6 cycloalkyl; (4) -C(O)-R3e, wherein R3e is selected from (a) -NH2 and (b) a 4 to 6 membered heterocyclyl selected from azetidinyl, piperidinyl, and pyrrolidinyl, each of which is optionally substituted with -OH; (5) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) a C1-4 alkyl optionally substituted with -OH, (ii) -OH, and (iii) a C1-4 alkoxy, and (6) a 5 to 6 membered heteroaryl selected from furyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, and thienyl, each of which is optionally substituted with a C1-4 alkyl optionally substituted with -OH; and R6 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with 1 to 3 halogens, (3) -OH, and (4) a 4 to 6 membered heterocyclyl selected from azetidinyl, morpholinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) C1-4 alkyl.
18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: R7 is a C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from phenyl, pyridyl, pyrimidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, pyrazolyl, pyrazolidinyl, pyrrolidinyl, dihydropyrazolyl, hexahydropyrimidyl, and tetrahydropyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) a C1-4 alkyl, optionally substituted with -OH, (c) a C1-4 alkoxy, and (d) -CN.
19. The compound of claim 1, wherein the compound is selected from any one of Examples 1-242, or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound of any one of claims 1- 18, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
21. A method for treating a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity comprising administering an effective amount of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
22. A compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for use in therapy.
23. A compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity.
24. A compound or a pharmaceutically acceptable salt thereof, for use of claim 22, in the treatment of a type 2 diabetes.
25. A compound or a pharmaceutically acceptable salt thereof, for use of claim 22, in the treatment of obesity.
26. A compound or a pharmaceutically acceptable salt thereof, for use of claim 22, in the treatment of overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.
27. A compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose- dependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.
PCT/US2025/029816 2024-05-17 2025-05-16 4-phenyl-1h-pyrazolo[3,4-b]pyridine-5-carboxamide derivatives as amylin and/or calcitonin receptor agonists for the treatment of type 2 diabetes, obesity or overweight Pending WO2025240893A1 (en)

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Citations (4)

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WO2003076440A1 (en) * 2002-03-06 2003-09-18 Smithkline Beecham Corporation Condensed heterocyclic compounds as calcitonin agonists
WO2010085700A2 (en) 2009-01-22 2010-07-29 Unigene Laboratories Inc. Treatment for obesity
WO2015071229A1 (en) 2013-11-14 2015-05-21 Keybioscience Ag Calcitonin mimetics for treating diseases and disorders
WO2016034604A1 (en) 2014-09-04 2016-03-10 Novo Nordisk A/S Novel amylin and calcitonin receptor agonist

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WO2003076440A1 (en) * 2002-03-06 2003-09-18 Smithkline Beecham Corporation Condensed heterocyclic compounds as calcitonin agonists
WO2010085700A2 (en) 2009-01-22 2010-07-29 Unigene Laboratories Inc. Treatment for obesity
WO2015071229A1 (en) 2013-11-14 2015-05-21 Keybioscience Ag Calcitonin mimetics for treating diseases and disorders
WO2016034604A1 (en) 2014-09-04 2016-03-10 Novo Nordisk A/S Novel amylin and calcitonin receptor agonist

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