WO2025222000A1 - Substituted 1,1'-biphenyl compounds as glucagon receptor agonists - Google Patents

Substituted 1,1'-biphenyl compounds as glucagon receptor agonists

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Publication number
WO2025222000A1
WO2025222000A1 PCT/US2025/025163 US2025025163W WO2025222000A1 WO 2025222000 A1 WO2025222000 A1 WO 2025222000A1 US 2025025163 W US2025025163 W US 2025025163W WO 2025222000 A1 WO2025222000 A1 WO 2025222000A1
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WIPO (PCT)
Prior art keywords
optionally substituted
independently selected
alkyl
halogen
substituents independently
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/US2025/025163
Other languages
French (fr)
Inventor
Sarah May ANTHONY
Travis Lamonte BUCHANAN
Scott Eugene Conner
Jaime Nathan CORONADO
Steven J. GREEN
Rachel Rose KNAPP
Jack Lee
Jayana P. Lineswala
Tao Liu
Ifedi ORIZU
Elisabetta RONCHI
Farbod SALAHI
Tabitha Taylor SCHEMPP
Bishnu THAPA
Miguel Angel Toledo Escribano
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Eli Lilly and Co
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Eli Lilly and Co
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Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of WO2025222000A1 publication Critical patent/WO2025222000A1/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
    • C07D471/10—Spiro-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
    • A61P3/08—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

  • glucagon receptor agonists are glucagon 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 glucagon receptor.
  • T2D mellitus is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels caused by insulin resistance.
  • the current standard of care for T2DM includes diet and exercise, and treatment with oral and injectable medications including incretinbased therapies, such as glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and glucosedependent insulinotropic polypeptide receptor agonists (GIP RA). Incretin-based therapies such as GLP-1 RA and GIP RA have also been approved for treating obesity and overweight.
  • GLP-1 RA glucagon-like-peptide-1 receptor agonists
  • GIP RA glucosedependent insulinotropic polypeptide receptor agonists
  • Glucagon is a twenty nine amino acid peptide which is secreted from the cells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues.
  • Glucagon through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis.
  • the glucagon receptor GCGR is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors.
  • GLP-1 glucagon -like peptide- 1 receptor
  • GLP-2 glucagon-like peptide-2 receptor
  • gastric inhibitory polypeptide receptor gastric inhibitory polypeptide receptor.
  • the glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. Regulation of the glucagon receptor can play an important role in the treatment of T2DM, obesity or overweight, and other conditions modulated by this receptor.
  • glucagon agonists described herein have favorable properties allowing for administration of doses that provide sufficient activity at the glucagon receptor to provide the benefits of agonism of that receptor while avoiding unwanted side effects associated with too much activity.
  • the compound of formula (I) is a glucagon receptor agonist. In one embodiment, the compound of formula (I) is a glucagon receptor agonist which has potent activity at the glucagon receptor. In one embodiment, the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the glucagon receptor. DESCRIPTION OF THE INVENTION
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -C1-10 alkyl, and (c) -C(0)Ci-io alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • R g is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with -OH,
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-io alkyl,
  • R d is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 4 , R 4 , R 5 , and R y is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-io alkoxy,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • each of R A1 , R A2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from:
  • R 1 is selected from:
  • R s is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with Ci-6 alkyl optionally substituted with -OH,
  • Ci-6 alkoxy optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl, (4) -C(O)-R d , wherein R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 4 , R 4 , R 5 , and R 5 is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy,
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • R 1 is selected from:
  • R e is selected from:
  • R. 1 is selected from:
  • R g is 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 halogen and Ci-4 alkyl optionally substituted with -OH,
  • R 1 is selected from:
  • heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from:
  • R e is selected from (a) H and (b) -C1.4 alkyl
  • R 1 is selected from:
  • Ci-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; or a pharmaceutically acceptable salt thereof.
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -Ci-io alkyl, and (c) -C(0)Ci-io alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from: (a) H, (b) -Ci-io alkyl, and
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -C1-10 alkyl
  • R d is selected from (a) -C1-10 alkyl; (b) -OH, (c) -C1-10 alkoxy, and
  • each of R 4 , R 4 , R 5 , and R 5 is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) - Ci-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) - Ci-10 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -CMO alkyl, and (c) -C(0)Ci-io alkyl;
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-io alkyl,
  • R d is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 4 , R 4 , R 5 , and R 3 is independently selected from:
  • R 6 is an aryl, optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-io alkyl, (b) halogen, (c) -OH, and (d) -Ci-io alkoxy,
  • R 6e and R 6f are independently selected from (a) H, (b) -Ci-io alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (la):
  • each of R A1 , R A2 , R A3 , and R 44 is independently selected from:
  • each of R a and R h is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
  • R 1 is selected from: (1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R e is selected from:
  • R 1 is selected from:
  • R a and R b are independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl
  • R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 4 , R 4 , R 5 , and R y is independently selected from:
  • R 6 is selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy, (f) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci- 4 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 4 is -C1-4 alkyl, optionally substituted with 1 to 3 halogens
  • R 6 is selected from: (1) a phenyl
  • each of R A1 , R 2 , R A3 , and R A4 is independently selected from:
  • each of R a and R b is independently selected from (a) H and (b) - C(O)CH 3 ,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from: (1) H,
  • R 4 is selected from:
  • R 6 is selected from:
  • each of R A1 , R ⁇ , R A3 , and R A4 is independently selected from:
  • Ci-6 alkyl optionally substituted with 1 to 3 halogens
  • R a and R b are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl.
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • Ci-4 alkyl optionally substituted with 1 to 3 halogens
  • R a and R b are independently selected from (a) H, (b) -Ci-4 alkyl, and (c) -C(O)Ci-4 alkyl.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (le):
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (If):
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H and (b) -Ci-6 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • R a and R b are independently selected from (i) H and (ii) -C1-6 alkyl, and
  • R a and R b is independently selected from (a) H and (b) -C1-6 alkyl, (6) -C(O)NR a R b , wherein R a and R b is independently selected from (a) H and (b) -Ci-6 alkyl,
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl
  • R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • R 4 is selected from:
  • each of R 6a , R 6b , R 6e and R 6d is independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
  • R 6e and R 6t are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci- 4 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 4 is -Ci-4 alkyl, optionally substituted with 1 to 3 halogens; and each of R 6a , R 6b , R 6c and R 6d is independently selected from:
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • each of R a and R b is independently selected from (a) H and (b) methyl, (c) ethyl and (d) -C(O)CH ,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R 4 is selected from:
  • R 6a , R 6b , R 6c and R 6d is independently selected from:
  • (6) a 4-6 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) methyl, (ii) ethyl and (iii) halogen,
  • R 1 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is a monocyclic or a spiro bicyclic group,
  • heteroaryl (2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is a monocyclic or a fused bicyclic group,
  • R e is selected from (a) H and (b) -Ci-6 alkyl
  • R f is selected from:
  • R 1 is selected from:
  • R c is selected from (a) H and (b) -Ci-4 alkyl
  • R f is selected from:
  • R 1 is selected from:
  • R e is selected from (a) H and (b) -CH3;
  • R 1 is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R d is selected from (a) -C1.4 alkyl; (b) -C1-4 alkoxy, and (c) - NR 2c R 2f , wherein each of R 2c and R 2f is independently selected from (i) H and (ii) -Ci- 4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 2 is selected from (1) H, (2) -CH 3 and (3) -CH2OH;
  • R 3 is selected from (1) H, (2) -CH 3 and (3) -CH2OH.
  • each of R 4 , R 4 , R ⁇ and R 5 is independently selected from:
  • R 4 is selected from:
  • R 2 is selected from (1) H, (2) -CH3 and (3) -CH2OH;
  • R 3 is selected from (1) H, (2) -CH3 and (3) -CH2OH;
  • R 4 is selected from (1) -CH 3 , (2) -CH 2 OH, (3) -CHF 2 , and (4) -CF 3 .
  • R 2 is selected from (1) H and (2) -CH3;
  • R 3 is selected from (1) H and (2) -CH3;
  • R 4 is -CH 3 .
  • R 2 is -CH 3 ;
  • R 3 is -CH3
  • R 4 is -CH 3 .
  • R 6 is selected from:
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a phenyl optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
  • a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
  • R 6 is selected from:
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (g) a 5 or 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) -CH3 and (ii) halogen,
  • a phenyl optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
  • a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
  • R 6 is selected from:
  • each of R 6e and R 6f is independently selected from (i) H, (ii) - C1-2 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
  • a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, and (v) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) - OH, and (v) -OCH 3 .
  • R 6 is a phenyl, optionally substituted with 1 to 3 substituents independently selected from:
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -CH3, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a heteroaryl selected from (i) pyridyl, (ii) thiazolyl, (iii) isothiazolyl, and (iv) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
  • R 6 is phenyl, optionally substituted with 1 to 3 substituents independently selected from:
  • a pyridyl optionally substituted with 1 to 3 substituents independently selected from (i) - CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
  • 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, acetonitrile, 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.
  • 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.
  • 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).
  • isotopes examples 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 C1.
  • radioisotopes which emit radiation as they decay 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 glucagon receptor agonists.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have relative EC50 (Rel EC50) values of greater than 50,000 nM using Functional Assay I or Functional Assay II as described herein.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have relative EC50 (Rel EC 50) values of less than about 50,000 nM using Functional Assay I or Functional Assay II.
  • compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 25,000 nM using Functional Assay I or Functional Assay II. In one preferred embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 10,000 nM using Functional Assay I or Functional Assay II. [0049] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in the treatment of a type 2 diabetes.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in the treatment of obesity.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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
  • references 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.”
  • 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.
  • 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.
  • 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.
  • 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 HbAlc 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. Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012).
  • 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.
  • 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 acetonitrile 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.
  • a 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 through the oxygen.
  • R is an alkyl group as defined herein and the point of attachment is through the oxygen.
  • Ci-io j-o-c dlK? 1 alkoxy has 1 to 10 carbons with the following structure: ’ .
  • Ci-6 alkoxy has 1 to 6 carbons with the following structure:
  • Ci-io alkyl means a straight chain or a branched chain alkyl group containing 1 to 10 carbons.
  • Ci-6 alkyl means a straight chain or a branched chain alkyl group containing 1 to 6 carbons.
  • Ci-6 alkyl examples 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 saturated acyclic hydrocarbon group which may be linear or branched.
  • a "Ci-6 alkylene” means an alkylene group having 1 to 6 carbon atoms.
  • Ci-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH2- CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -), or butylene (e.g, -CH 2 - CH2-CH2-CH2-).
  • ethylene e.g., -CH2-CH2- or -CH(-CH 3 )-
  • propylene e.g., -CH2- CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -
  • butylene e.g, -CH 2 - CH2-CH2-CH2-
  • C 3 -6 cycloalkyl means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When two groups together form a C 3 -6 cycloalkane ring, the resulting group is bivalent. Non-limiting examples include cyclopropane- 1,1 -diyl, cyclobutane- 1,1 -diyl, cyclopentane-l,l-diyl, and cyclohexane- 1,1 -diyl.
  • aryl means an aromatic carbocyclic group, and it 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-lH-isoquinolin-3-onyl, and l,3-dihydrobenzimidazol-2-onyl.
  • an aryl is a phenyl.
  • an aryl is a naphthyl.
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises 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, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, for example, one, two, three, or four)
  • the term “5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S” means an heteroaryl group that contains 5 to 10 ring atoms including 1 to 3 hetero atoms independently selected from N, O, and S.
  • the ring may be a monocyclic heteroaryl, or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl ring.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imi
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring, and/or fused ring systems (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).
  • the term “5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 3 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, oxetanyl, azetidinyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 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 -benzodioxolyl, 1,3- diazaspiro[4.4]nonanyl, 2-oxa-5,7-diazaspiro[3.4]octanyl, 8-oxa-l,3-diazaspiro[4.5]decanyl, oxazolidinyl,
  • the compound herein, or a pharmaceutically acceptable salt thereof has a glucagon receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the glucagon receptor.
  • 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 non-alcoholic steatohepatitis.
  • 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.
  • treatment of a subject with obesity or overweight is also known as chronic weight management.
  • weight with at least one weight related comorbidity refers to a disease or condition of being overweight and at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.
  • a subject being overweight is defined as having a body mass index (BMI) of >25 to ⁇ 30.
  • 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.
  • Major diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.
  • Chronic heart disease includes myocardial infarction and angina pectoris.
  • ementia 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 a glucagon receptor agonist comprises administering an effective amount of a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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.
  • the effective daily amount is from 0.01 to 1000 mg, or more specifically, from 0.05 to 500 mg, or even more specifically, from 0.1 to 200 mg, or still more specifically, from 0.1 to 100 mg once daily.
  • the above effective amount is administered once daily or twice daily for a few days, a few weeks, a few months, or several years.
  • the above dosage is administered once daily for a few days, a few weeks, a few months, or several years.
  • 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-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • PYY peptide tyrosine-tyrosine
  • 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), (la), (lb), (Ic), (Id), (le), or (If), 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.
  • 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.
  • Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.
  • Examples of 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%.
  • R 1 , R 2 , R 3 , R 4 , R 4 ’, R 5 , R 5 , R 6 , R 6b , R 6c , R 7 , R A1 , R 42 , R 43 , R A4 , R a , and R b are as defined in Formula (I) and (la).
  • R 1 , R 2 , R 3 , R 4 , R 4 ’, R 5 , R 5 , R 6 , R 6b , R 6c , R 7 , R A1 , R 42 , R 43 , R A4 , R a , and R b are as defined in Formula (I) and (la).
  • Scheme 1 shows the preparation of intermediates (ii, iii, iv, v, vi, and vii) useful for the preparation of compounds of the present invention.
  • aryl or heteroaryl halide i, wherein “Y” is CH or N, “X” is a halogen such as Cl, Br, or F, and the carboxylic acid is optionally protected as an ester “-O-PG”, wherein “PG” is an alkyl group such as methyl
  • the halogen “X” can be substituted in a variety of ways.
  • Intermediate (i) can be coupled with boronic acids or esters using a palladum catalyst and an inorganic base.
  • a palladium catalyst such as Pd(dppf)C12
  • a carbonate base such as K2CO3
  • an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (iv)
  • a palladium on carbon catalyst under hydrogen gas at elevated temperatures to give (v).
  • (i) can be coupled with cyclopropaneboronic acid using a palladium catalyst such as Pd(OAc)2 and tri cyclohexylphosphine and an inorganic base such as K3PO4 at elevated temperatures in a mixture of toluene and water to give (vi).
  • a palladium catalyst such as Pd(OAc)2 and tri cyclohexylphosphine and an inorganic base such as K3PO4
  • Y is N
  • (i) can undergo nucleophilic aromatic substitution, for example with 3,3-difluoroazetidine hydrochloride and a carbonate base such as K2CO3 in a solvent such as DMF at elevated temperatures to give (vii).
  • Scheme 2 depicts the preparation of the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) beginning with a suitable protected amine (viii).
  • the PG moiety on the amine (viii) is a standard amine protecting group well known to a skilled artisan, including carbamate protecting groups such as Boc.
  • the amine (viii) is reacted with NFEOAc and KCN in an appropriate solvent, such as EtOH at elevated temperatures.
  • the resulting intermediate (ix) is reacted with a suitable acyl chloride (R 6 -C(O)C1) in the presence of an appropriate base, such as ISfeCCh, Nal ICO3 or EtaN, in a suitable solvent, such as DCM or THF.
  • an appropriate base such as ISfeCCh, Nal ICO3 or EtaN
  • a suitable solvent such as DCM or THF.
  • the amine (ix) is reacted under amide coupling conditions well known to a skilled artisan and include reacting an appropriate carboxylic acid (R 6 -CO2H) with the amine (ix) in a suitable solvent, such as DMF, with an appropriate coupling agent, such as HATU, in the presence of a suitable base, such as DIEA.
  • the intermediate (x) is cyclized to form the l,3,8-triazaspiro[4.5]dec-l-en-4-one core in the presence of an appropriate oxidizing agent, such as H2O2, and a suitable base, such as NaOH, in an appropriate solvent, such as EtOH, DMSO or MeOH, at 80 °C to give (xiii).
  • an appropriate oxidizing agent such as H2O2
  • a suitable base such as NaOH
  • the nitrile group of intermediate (ix) is first converted in the carbamoyl group under the aforementioned conditions for the formation of intermediate (xi).
  • the intermediate (xii) is obtained then by the sequential amidation (previously described) and cyclization conditions in the presence of a suitable base, such as PyO/Bu or KO/Bu, in an appropriate solvent, such as /-BuOH or EtOH, at 60 °C at least to give (xiii).
  • the removal of the PG moiety on (xiii) is achieved under conditions standard to the art.
  • the intermediate amine (xiv) is obtained by reacting a suitable acid, such as HC1 in 1,4-di oxane, in an appropriate solvent, such as DCM.
  • Halide (xv, where “X” is a halogen such as Br and “PG” is a protecting group such as Boc) is coupled with a heteroaryl boronic acid (or ester thereof) using a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) and a base such as K3PO4 in an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (xvi).
  • the protecting group is removed to give (xvii), under suitable conditions well known to the skilled artisan, e.g. HC1 in an organic solution to remove a -Boc group.
  • Scheme 5 illustrates the preparation of the biphenyl intermediate (xviii) beginning with a suitable aryl bromide (xxii).
  • the aryl boronic ester (xxiii) is produced from the reaction of (xxii) with bis(pinacolato)diborane and the appropriate catalyst system, such as Pd(OAc)2 and tris(4- methoxyphenyl)phosphine, in the presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, at elevated temperatures.
  • aryl boronic ester (xxiii) is reacted under Suzuki coupling conditions standard to the art and include a suitable substituted aryl bromide (xxiv) and the appropriate catalyst system, such as Pd(PPh3)4, in presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, stirred at 80 °C for 72 h to give biphenyl intermediate (xviii).
  • Scheme 6 shows the preparation of intermediate (xxx), which is useful for the preparation of compounds of Formula la.
  • Amide (xi) is cyclized to (xxv) using toluenesulfonic acid and 2,2- dimethoxypropane in an alcohol solvent such as EtOH at elevated temperature.
  • Amine (xxv) is reacted with halo-benzene (xxvi, wherein X is Br or Cl and X’ is I or Br) using lithium bis(trimethylsilyl)amide in a solvent such as 1,4-dioxane at elevated temperature to give (xxvii), which is then converted to amide-amine (xxviii) using aq. HC1 in MeOH and water at elevated temperature.
  • Amine (xxviii) is then reacted with an acid chloride R 6 -C(O)C1 using an amine base such as TEA in a solvent such as THF to give amide (xxix), which is then cyclized using a base such as aq. NaOH in MeOH at elevated temperature to give (xxx).
  • Compounds of Formula la may be prepared via the synthetic route presented in Scheme 7 by reacting the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) with an appropriate halo- benzene (xxxiv, wherein X is Br or Cl and X’ is I or Br) under Buchwald-Hartwig cross coupling conditions well known to a skilled artisan to give intermediate (xxx) wherein X is Br or Cl.
  • Such conditions include using a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2 l ,6'-bis(dimethylamino)-l , l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) and an alkoxide base such as sodium 2- methylbutan-2-olate at elevated temperature.
  • a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2 l ,6'-bis(dimethylamino)-l , l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) and
  • an aryl bromide can be reacted with lithium bis(trimethylsilyl)amide, followed by amine intermediate (xiv) in a solvent such as 1,4- dioxane at elevated temperature to give intermediate (xxx) wherein X is Cl, Br, or I.
  • amine (xiv) can also be reacted with (xxxiv) under SNAT reaction conditions using a base such as DIEA or K3PO4 in a solvent such as DMSO at elevated temperature.
  • the halogen in the resulting intermediate (xxx) may be reacted with a suitable aryl boronic ester (xxiii) or acid thereof under Suzuki coupling conditions, e.g.
  • a palladium catalyst such as Pd(PPh3)4, methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II), or l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloride, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as MeOH, THF, or 1,4-dioxane in water at elevated temperature.
  • a carbonate base such as K2CO3
  • an aqueous-organic solvent mix such as MeOH, THF, or 1,4-dioxane in water at elevated temperature.
  • (xxx) is converted to boronate (xxxiv) using conditions known to the skilled artisan e.g. using bis(pinacolato)diborane, a palladium catalyst such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) or chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl- l,l'-biphenyl) palladium(II), a base such as potassium acetate or K2CO3, a solvent such as methoxycyclopentane or 2-methyltetrahydrofuran at elevated temperature. Boronate (xiv) is then coupled with aryl hal
  • halo-phenol (xxxi, where R A4 is trimethyl silyl) is coupled with aryl boronic ester (xxiii) or ester thereof under Suzuki coupling conditions, e.g. using a palladium catalyst such as Pd(dppf)C12, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as 1,4-dioxane in water at elevated temperature to give (xxxii), which is converted to trifluoromethanesulfonate (xxxiii) using N-phenyl- bis(trifluoromethanesulfonimide) and K2CO3 in ACN at elevated temperature. Reaction of (xxxiii) with amine (xiv) using CsF and ACN at elevated temperature gives (xxxv), converting - R A4 to -H.
  • a palladium catalyst such as Pd(dppf)C12
  • a carbonate base such as K2CO3
  • H2O2 (63 mL, 50% Wt, 1000 mmol) was added slowly to a vigorously stirred solution of a mixture of diastereomers of tert-butyl (2S)-4-cyano-2-methyl-4-(2- (trifluoromethoxy)benzamido)piperidine-l -carboxylate (48.2 g, 112.8 mmol), NaOH (270 mL, 5 M, 1354 mmol) in EtOH (564 mL) at 80 °C. After 16 h, the reaction mixture was diluted with 500 mL of NH4CI sat. aq. solution and 30 mL of Na2S2O3 aq. solution.
  • the mixture was purged with nitrogen and heated to 110 °C for 2 days, then diluted with EtOAc (0.3 L) and 5% aq. NH4OH (0.3 L). The layers were separated and the organics were washed successively with 0.1 L of each of 5% aq. NH4OH and water, then 1 M aq. KH2PO4 (2 x 50 mL) and brine (50 m ). The organics were dried over MgSCU, filtered, then concentrated to a volume of 0.1 L. Heptane (0.4 L) was then added slowly and the mixture was stirred at RT for 1 h.
  • Tetrakis(triphenylphosphine)palladium(0) (0.238 g, 0.206 mmol) was added to a solution of l-bromo-3,5-difluoro-2-nitrobenzene (0.016 g, 0.69 mmol), 4-(3, 5-dimethyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (0.25 g, 0.76 mmol), and CS2CO3 (0.67 g, 2.06 mmol) in 1,4-di oxane (0.
  • DIEA (0.228 mb, 1.32 mmol) was added to a solution of (7S)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (mixture of diastereomers, 0.15 g, 0.44 mmol) and 4-(3',5'-difluoro-2,6-dimethyl-2'-nitro-[l,r-biphenyl]-4- yl)morpholin-3-one (0.160 g, 0.44 mmol) in DMSO (2.21 mL, 0.2 M) and stirred at 110 °C.
  • Oxalyl chloride (6.09 m , 69.4 mmol) was added to a stirred solution of 2-cyclopropyl- benzoic acid (10.0 g, 55.5 mmol) in DCM (100 mL) under nitrogen at ambient temperature.
  • EtsN 22 mL, 160 mmol was added to terz-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (14.42 g, 56.04 mmol) in DCM (100 mL) and stirred at ambient temperature under nitrogen in 500 mL RBF.
  • the free base of the title compound was prepared by stirring the hydrochloride salt in water and adding 2 M aq. K3PO4 to bring the pH to 11.7 and collecting the solid, washing with water, and drying the solid in a vacuum oven overnight.
  • reaction mixture was stirred at 55 °C for 2 h under irradiation with 395 nm (200 W) LED module in an integrated photoreactor under nitrogen.
  • the reaction mixture was poured into 500 mL water at 25 °C, and then extracted with EtOAc (800 mL x 3). The combined organic layers were washed with water (500 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in PE to give the title compound (14.4 g) as a solid.
  • the free base of the title compound was prepared by reverse-phase prep-HPLC of the dihydrochloride using a gradient of 1 to 50% ACN in 10 mM aq. NH4HCO3.
  • KCN (5.04 g, 77.4 mmol) was added to a mixture of 4-bromo-3,5-dimethylbenzaldehyde (10.0 g, 46.9 mmol) in water (50 mL).
  • Pd(dppf)C12 (3.4 g, 4.6 mmol) at 25 °C was added to a mixture of 2-(4-bromo-3,5- dimethylphenyl)-2-hydroxyacetamide (29 g, 110 mmol), potassium acetate (33 g, 330 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (31 g, 120 mmol) in 1,4-dioxane (300 mb) and the reaction mixture was stirred at 100 °C for 15 h.
  • Pd(dppf)Ch (3.20 g, 4.29 mmol) was added under nitrogen to a mixture of 2-chloro-6- (trifluoromethyl)nicotinic acid (10.00 g, 43.45 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (14.00 g, 65.31 mmol) in 1,4-dioxane (100 mL) and water (10 mL). K2CO3 (18.00 g, 130.2 mmol) was then added and the reaction mixture was heated to 110 °C with stirring under nitrogen for 16 h.
  • NBS (5.11 g, 27.3 mmol) was added to a -60 °C mixture of 4-(3'-hydroxy-2-methyl-2'- (trimethylsilyl)-[l,l'-biphenyl]-4-yl)morpholin-3-one (10.3 g, 22.6 mmol) in DCM (100 mL) and the reaction mixture was stirred vigorously at -60 °C for 1 h. The mixture was washed with water (100 mL) and extracted with DCM (3 x 50 mL). The organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure.
  • N-Phenyl-bis(trifluoromethanesulfonimide) (4.2 g, 11 mmol) at 0 °C was added to a mixture of 4-(4'-cyclopropyl-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l, l'-biphenyl]-4- yl)morpholin-3-one (1.2 g, 2.6 mmol) and K2CO3 (3.1 g, 21 mmol) in ACN (10 mL), and the reaction mixture was stirred vigorously at 80 °C. After 16 h, the mixture was poured into water (20 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL).

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Abstract

Disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Further disclosed herein is a method for preventing or treating a disease or condition through the modulation of the glucagon receptor using a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Description

SUBSTITUTED 1,1’-BIPHENYL COMPOUNDS AS GLUCAGON RECEPTOR AGONISTS
TECHNICAL FIELD
[0001] Disclosed herein are compounds which are glucagon 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 glucagon receptor.
BACKGROUND OF THE INVENTION
[0002] Over the past several decades, the prevalence of diseases such as type 2 diabetes, obesity, and overweight has continued to rise. T2D mellitus (T2DM) is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels caused by insulin resistance. The current standard of care for T2DM includes diet and exercise, and treatment with oral and injectable medications including incretinbased therapies, such as glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and glucosedependent insulinotropic polypeptide receptor agonists (GIP RA). Incretin-based therapies such as GLP-1 RA and GIP RA have also been approved for treating obesity and overweight. [0003] Despite the availability of these therapies, blood glucose levels in many patients with T2DM still remain inadequately controlled. Uncontrolled diabetes leads to several conditions that impact morbidity and mortality of patients. One of the main risk factors for T2DM is obesity or overweight. It is documented that a decrease in body adiposity leads to improvement in obesity-associated co-morbidities including hyperglycemia and cardiovascular events. Therefore, additional therapies effective in glucose control and weight reduction, for example, through the modulation of the glucagon receptor, are needed for better disease management. [0004] Glucagon is a twenty nine amino acid peptide which is secreted from the cells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma non-esterified fatty acid levels and somatostatin whereas glucagon secretion is increased in response to hypoglycemia and elevated plasma amino acid levels. Glucagon, through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis. [0005] The glucagon receptor GCGR is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors. Other related G-protein coupled receptors include glucagon -like peptide- 1 receptor (GLP-1), glucagon-like peptide-2 receptor (GLP-2) and gastric inhibitory polypeptide receptor. The glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. Regulation of the glucagon receptor can play an important role in the treatment of T2DM, obesity or overweight, and other conditions modulated by this receptor.
SUMMARY OF THE INVENTION
[0006] Despite advancement of T2DM and obesity therapies, there remains a need for treatments for T2DM with effective glucose control, and for weight loss benefits and a favorable side effect profile. Advantageously, glucagon agonists described herein have favorable properties allowing for administration of doses that provide sufficient activity at the glucagon receptor to provide the benefits of agonism of that receptor while avoiding unwanted side effects associated with too much activity.
[0007] Disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein variables R1, R2, R3, R4, R4 , R5, R5 , R6, R7, RA1, RA2, RA3, and RA4, are as defined herein.
[0008] In one embodiment, the compound of formula (I) is a glucagon receptor agonist. In one embodiment, the compound of formula (I) is a glucagon receptor agonist which has potent activity at the glucagon receptor. In one embodiment, the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the glucagon receptor. DESCRIPTION OF THE INVENTION
[0009] Disclosed herein is a compound of formula (I): wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -C 1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,
(3) halogen,
(4) -C i-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-10 cycloalkyl and (d) -C1-10 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -C1-10 alkyl, and (c) -C(0)Ci-io alkyl,
(6) -CN,
(7) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,
(8) oxo,
(9) -C(O)NH2,
(10) -C3-10 cycloalkyl, and
(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
R1 is selected from:
(1) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NRcRf, wherein:
Re is selected from:
(a) H,
(b) -Ci-io alkyl, and
(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; and
Rf is selected from:
(a) H,
(b) -Cuio alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Cuio alkyl;
(4) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Cuio alkyl, and
(iii) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Cuio alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rg is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with -OH,
(5) -SO2NH2, optionally substituted with 1 to 2 Cuio alkyl,
(6) -C(O)NH2, optionally substituted with 1 to 2 Ci-10 alkyl,
(7) -C(O)OH,
(8) H, and (9) C i-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) Ci-io alkyl, and (c) -OH; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -0-C(0)Ci-io alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H,
(2) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-io alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
(5) halogen; each of R4, R4 , R5, and Ry is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(3) -C3-10 cycloalkyl, and
(4) halogen;
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen, (b) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens,
(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-io alkoxy,
(f) -S-C i-io alkyl, optionally substituted with 1 to 3 halogens,
(g) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) -Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -Ci-io alkyl and (ii) halogen,
(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci -io alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) - Ci-io alkoxy,
(k) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, optionally substituted 1-3 halogens, and
(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is selected from:
(1) H,
(2) -Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound of formula (I) above, wherein: each of RA1, RA2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,
(3) halogen,
(4) -Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-6 cycloalkyl and (d) -C1-6 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
(6) -CN,
(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,
(8) oxo,
(9) -C(O)NH2,
(10) -C3-6 cycloalkyl, and
(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NReRf, wherein:
Re is selected from:
(a) H,
(b) -Ci-6 alkyl, and
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; and R1 is selected from:
(a) H,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (c) -C(0)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -Ci-6 alkyl;
(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Ci-6 alkyl, and
(iii) 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 halogen and Ci-6 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rs is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with Ci-6 alkyl optionally substituted with -OH,
(5) -SO2NH2,
(6) -C(O)NH2,
(7) -C(O)OH,
(8) H, and
(9) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-6 alkyl, (4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
(5) halogen; each of R4, R4 , R5, and R5 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(3) -C3-6 cycloalkyl, and
(4) halogen, wherein at least one of R4, R4 , R5, and R5 is not H;
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens,
(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy,
(f) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (g) -NR6eR6t, wherein each of R6e and R6t is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci- 6 alkoxy,
(k) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(l) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is selected from:
(1) H,
(2) -C1-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen; or a pharmaceutically acceptable salt thereof.
In one embodiment of the compound of formula (I) above, wherein:
R1 is selected from:
(1) a 5 to 10 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) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and
(b) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H, and (b) -Ci-4 alkyl, and
R.1 is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -Ci-4 alkyl;
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -C i-4 alkyl, and
(iii) 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 halogen and Ci-4 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rg is 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 halogen and Ci-4 alkyl optionally substituted with -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH,
(7) H, and
(8) C1.4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; or a pharmaceutically acceptable salt thereof.
In one embodiment of the compound of formula (I) above, wherein:
R1 is selected from:
wherein the heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from:
(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo,
(2) -NReRf, wherein:
Re is selected from (a) H and (b) -C1.4 alkyl; and
R1 is selected from:
(a) H,
(b) -C1-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(0)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -C1-4 alkyl; and
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(0)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -C 1.4 alkyl, and
(iii) 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 halogen and C1-4 alkyl optionally substituted with -OH, and
(c) -OH,
(4) -SO2NH2,
(5) -C(0)NH2, (6) -C(O)OH,
(7) H, and
(8) Ci-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; or a pharmaceutically acceptable salt thereof.
In one embodiment of the compound of formula (I), wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,
(3) halogen,
(4) -Ci-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-10 cycloalkyl and (d) -C1-10 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-io alkyl, and (c) -C(0)Ci-io alkyl,
(6) -CN,
(7) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,
(8) oxo,
(9) -C(O)NH2,
(10) -C3-10 cycloalkyl, and
(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NReRf, wherein:
Re is selected from: (a) H, (b) -Ci-io alkyl, and
(c) -C(O)Ci -10 alkyl, optionally substituted with 1 to 3 halogens; and
Rf is selected from:
(a) H,
(b) -Ci-io alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-io alkyl;
(4) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-io alkyl, and
(c) -OH,
(5) -SO2NH2,
(6) -C(O)NH2,
(7) -C(O)OH, and
(8) H; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with
1 to 4 substituents independently selected from:
(a) -Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-10 alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Re, wherein Rc is selected from (a) H and (b) -C1-10 alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -C1-10 alkyl; (b) -OH, (c) -C1-10 alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii)
-Ci-10 alkyl, and
(5) halogen; each of R4, R4 , R5, and R5 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(3) -C3-10 cycloalkyl, and
(4) halogen;
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens,
(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) - Ci-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy,
(f) -S-Ci-10 alkyl, optionally substituted with 1 to 3 halogens,
(g) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) - Ci-10 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -C1-10 alkyl and (ii) halogen, (i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci -io alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Cuio alkyl, (ii) halogen, (iii) -OH, and (iv) -Cn io alkoxy,
(k) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, optionally substituted 1-3 halogens, and
(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is selected from:
(1) H,
(2) -Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen; or a pharmaceutically acceptable salt thereof.
[0010] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -C 1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH and (c) -0-C(0)Ci-io alkyl,
(3) halogen,
(4) -C 1-10 alkoxy, and
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -CMO alkyl, and (c) -C(0)Ci-io alkyl;
R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, (3) -NRCR wherein:
Re is selected from:
(a) H,
(b) -Ci-io alkyl, and
(c) -C(O)Ci -10 alkyl, optionally substituted with 1 to 3 halogens; and
Rf is selected from:
(a) H,
(b) -Ci-io alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-io alkyl; and
(4) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-io alkyl; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C i-io alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-io alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
(5) halogen; each of R4, R4 , R5, and R3 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, (3) -C3-6 cycloalkyl, and
(4) halogen;
R6 is an aryl, optionally substituted with 1 to 3 substituents independently selected from:
(1) halogen,
(2) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -C i-io alkoxy, optionally substituted with 1 to 3 halogens,
(4) -O-aryl, optionally substituted with 1 to 3 halogens,
(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-io alkyl, (b) halogen, (c) -OH, and (d) -Ci-io alkoxy,
(6) -S-Ci-io alkyl, optionally substituted with 1 to 3 halogens,
(7) -NR6eR6f, wherein each of R6e and R6f is independently selected from (a) H, (b) -Ci-io alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(8) a 5 or 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) -Ci-io alkyl and (ii) halogen,
(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-io alkyl, (b) halogen, and (c) -OH, and
(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-io alkyl, (b) halogen, (c) -OH, and (d) -Ci-io alkoxy; and
R7 is selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen.
[0011] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (la):
(la).
[0012] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ib):
[0013] In one embodiment of the compound of formula (la) or (Ib), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, RA2, RA3, and R44 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,
(3) halogen,
(4) -Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-6 cycloalkyl and (d) -C1-6 alkoxy,
(5) -NRaRb, wherein each of Ra and Rh is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
(6) -CN,
(7) -C(O)NH2,
(8) -C3-6 cycloalkyl, and
(9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl and (b) halogen;
R1 is selected from: (1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NReRf, wherein:
Re is selected from:
(a) H,
(b) -Ci-6 alkyl, and
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; and
R1 is selected from:
(a) H,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-6 alkyl;
(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-6 alkyl, and
(c) -OH,
(5) -SO2NH2,
(6) -C(O)NH2,
(7) -C(O)OH, and
(8) H; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H, (2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-6 alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
(5) halogen; each of R4, R4 , R5, and Ry is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(3) -C3-6 cycloalkyl, and
(4) halogen, wherein at least one of R4, R4 , R5, and R5 is not H; and
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S; and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2) and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens,
(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy, (f) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(g) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci- 6 alkoxy,
(k) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(l) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens.
[0014] In one embodiment of the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-4 alkyl and (d) -CN,
(3) halogen,
(4) -Ci-4 alkoxy,
(5) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci-4 alkyl,
(6) -CN,
(7) -C(O)NH2,
(8) -C3-6 cycloalkyl, and
(9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl and (b) halogen; R1 is selected from:
(1) a 5 to 10 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) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H, and
(b) -Ci-4 alkyl, and
Rf is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-4 alkyl;
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-4 alkyl, and
(c) -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH, and
(7) H; each of R2 and R3 is independently selected from:
(1) H,
(2) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, and
(3) halogen;
R4 is -C1-4 alkyl, optionally substituted with 1 to 3 halogens; and
R6 is selected from: (1) a phenyl,
(2) a pyridyl, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the phenyl of (1), pyridyl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,
(d) a 4-6 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) -Ci-4 alkyl and (ii) halogen,
(e) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-4 alkyl, (ii) halogen, and (iii) -OH,
(f) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci- 4 alkoxy,
(g) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(h) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens.
[0015] In one embodiment of the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R 2, RA3, and RA4 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN,
(3) ethyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN,
(4) halogen,
(5) methoxy, (6) ethoxy,
(7) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H and (b) - C(O)CH3,
(8) -CN,
(9) -C(O)NH2,
(10) -C3-4 cycloalkyl, and
(11) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl and (b) halogen;
R1 is selected from:
(1) 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: (a) methyl, optionally substituted with 1 to 3 halogens, (b) ethyl, optionally substituted with 1 to 3 halogens, and (c) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H,
(b) methyl, and
(c) ethyl, and
Rf is selected from:
(a) H,
(b) methyl, optionally substituted with 1 to 3 halogens,
(c) ethyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)CH3, optionally substituted with 1 to 3 halogens;
(3) -C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C(O)NH2 and (c) -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH, and
(7) H; each of R2 and R3 is independently selected from: (1) H,
(2) methyl, optionally substituted with 1 to 3 halogens,
(3) ethyl, optionally substituted with 1 to 3 halogens, and
(4) halogen;
R4 is selected from:
(1) methyl, optionally substituted with 1 to 3 halogens, and
(2) ethyl, optionally substituted with 1 to 3 halogens; and
R6 is selected from:
(1) a phenyl,
(2) a pyridyl, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the phenyl of (1), pyridyl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) methyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) ethyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(d) methoxy, optionally substituted with 1 to 3 halogens,
(e) ethoxy, optionally substituted with 1 to 3 halogens,
(f) a 4-6 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) -Ci-4 alkyl and (ii) halogen,
(g) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci- 4 alkoxy,
(h) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(i) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens. [0016] In one embodiment of the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^, RA3, and RA4 is independently selected from:
(1) H,
(2) Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(3) halogen
(4) -Ci-6 alkoxy, and
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl.
[0017] In one embodiment of the compound of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(3) halogen
(4) -Ci-4 alkoxy, and
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-4 alkyl, and (c) -C(O)Ci-4 alkyl.
[0018] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ic):
[0019] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Id):
[0020] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (le):
[0021] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (If):
[0022] In one embodiment of the compound of formula (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,
(3) halogen,
(4) -Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-6 cycloalkyl and (d) -C1-6 alkoxy, (5) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
(6) -CN,
(7) -C(O)NRaRb, wherein Ra and Rb is independently selected from (a) H and (b) -Ci-6 alkyl,
(8) -C3-6 cycloalkyl, and
(9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NReRf, wherein:
Re is selected from:
(a) H,
(b) -Ci-6 alkyl, and
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; and
Rf is selected from:
(a) H,
(b) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -C1-6 alkyl;
(4) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -C1-6 alkyl, and
(c) -OH,
(5) -SO2NRaRb, wherein Ra and Rb is independently selected from (a) H and (b) -C1-6 alkyl, (6) -C(O)NRaRb, wherein Ra and Rb is independently selected from (a) H and (b) -Ci-6 alkyl,
(7) -C(O)OH, and
(8) H; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo ; each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-6 alkyl,
(4) -C(0)-Rd, wherein Rd is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
(5) halogen;
R4 is selected from:
(1) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(2) -C3-6 cycloalkyl, and
(3) halogen; and each of R6a, R6b, R6e and R6d is independently selected from:
(1) halogen,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(4) -O-aryl, optionally substituted with 1 to 3 halogens,
(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(6) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(7) -NR6eR6t, wherein each of R6e and R6t is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(8) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, and (c) -OH,
(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(11) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(12) H.
[0023] In one embodiment of the compound of formula (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-4 alkyl and (d) -CN,
(3) halogen,
(4) -C1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-4 cycloalkyl and (d) -C1-4 alkoxy,
(5) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci-4 alkyl,
(6) -CN,
(7) -C(O)NH2,
(8) -C3-6 cycloalkyl, and (9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-4 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 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) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H, and
(b) -Ci-4 alkyl, and
Rf is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-4 alkyl;
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-4 alkyl, and
(c) -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH, and
(7) H; each of R2 and R3 is independently selected from:
(1) H,
(2) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, and (3) halogen;
R4 is -Ci-4 alkyl, optionally substituted with 1 to 3 halogens; and each of R6a, R6b, R6c and R6d is independently selected from:
(1) halogen,
(2) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,
(4) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-4 alkyl, (b) halogen, (c) -OH, and (d) -Ci-4 alkoxy,
(6) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(7) H.
[0024] In one embodiment of the compound of formula (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN,
(3) ethyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -CN,
(4) halogen,
(5) methoxy,
(6) ethoxy,
(7) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H and (b) methyl, (c) ethyl and (d) -C(O)CH ,
(8) -CN,
(9) -C(O)NH2,
(10) -C3-4 cycloalkyl, and (11) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) methyl, (b) ethyl and (c) halogen;
R1 is selected from:
(1) 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: (a) methyl, optionally substituted with 1 to 3 halogens, (b) ethyl, optionally substituted with 1 to 3 halogens, and (c) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H,
(b) methyl, and
(c) ethyl, and
Rf is selected from:
(a) H,
(b) methyl, optionally substituted with 1 to 3 halogens,
(c) ethyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)CHs, optionally substituted with 1 to 3 halogens;
(3) -Ci-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C(0)NH2 and (c) -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH, and
(7) H; each of R2 and R3 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1 to 3 halogens,
(3) ethyl, optionally substituted with 1 to 3 halogens, and
(4) halogen;
R4 is selected from:
(1) methyl, optionally substituted with 1 to 3 halogens, and (2) ethyl, optionally substituted with 1 to 3 halogens; and each of R6a, R6b, R6c and R6d is independently selected from:
(1) halogen,
(2) methyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) ethyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(4) methoxy, optionally substituted with 1 to 3 halogens,
(5) ethoxy, optionally substituted with 1 to 3 halogens,
(6) a 4-6 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) methyl, (ii) ethyl and (iii) halogen,
(7) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) methyl, (b) ethyl, (c) halogen, (d) -OH, (e) methoxy and (f) ethoxy,
(8) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(9) H.
[0025] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is a monocyclic or a spiro bicyclic group,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is a monocyclic or a fused bicyclic group,
(3) -NReRf, wherein:
Re is selected from (a) H and (b) -Ci-6 alkyl; and
Rf is selected from:
(a) H,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-6 alkyl; and (4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from (i)
H and (ii) -Ci-6 alkyl, and
(c) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo.
[0026] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R1 is selected from:
(l) a 5 to 10 membered heterocyclyl selected from: (a) , (c)
(2) -NReRf, wherein:
Rc is selected from (a) H and (b) -Ci-4 alkyl; and
Rf is selected from:
(a) H,
(b) -Ci -4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -Ci-4 alkyl; and
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen, (b) -C(0)NRaRb , wherein each of Ra and Rb is independently selected from (i) H and (ii) -Ci-4 alkyl, and (c) -OH; wherein the heterocyclyl of (1) is optionally substituted 1 to 4 substituents independently selected from:
(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and (b) oxo.
[0027] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R1 is selected from:
(1) a 5 to 10 membered heterocyclyl selected from: , (c)
(2) -NReRf, wherein:
Re is selected from (a) H and (b) -CH3; and
R1 is selected from:
(a) H,
(b) -CH3, optionally substituted with 1 to 3 halogens,
(c) -C(O)CH3, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 substituents independently selected from (i) -CH3 and (ii) -CH2CH3; and
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C(0)NRa Rb , wherein each of Ra and Rb is independently selected from (i) H, (ii) methyl, and (iii) ethyl, and (c) -OH; wherein the heterocyclyl of (1) is optionally substituted with 1 to 3 substituents independently selected from:
(a) -CH3, optionally substituted with 1 to 3 halogens,
(b) -CH2CH3, optionally substituted with 1 to 3 halogens,
(c) -CH2OH,
(d) -CH2-OC(O)CH3, and
(e) oxo.
[0028] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -O-Rc, wherein Rc is selected from (a) H and (b) -C1-4 alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -C1.4 alkyl; (b) -C1-4 alkoxy, and (c) - NR2cR2f, wherein each of R2c and R2f is independently selected from (i) H and (ii) -Ci- 4 alkyl, and
(5) halogen.
[0029] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt thereof, each of R2 and R3 is independently selected from:
(1) H,
(2) -CH3,
(3) -CH2OH,
(4) -CF3,
(5) -CHF2,
(6) -OH,
(7) -OCH3,
(8) -C(O)CH3,
(9) -C(O)OCH3, and
(10) -C(O)N(CH3)2.
[0030] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt thereof:
R2 is selected from (1) H, (2) -CH3 and (3) -CH2OH; and
R3 is selected from (1) H, (2) -CH3 and (3) -CH2OH.
[0031] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, each of R4, R4 , R\ and R5 is independently selected from:
(1) H,
(2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(3) -C3-6 cycloalkyl, and
(4) halogen.
In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof: R4 is selected from:
(1) -C i-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(2) -C3-6 cycloalkyl, and
(3) halogen; and each of R4 , R5, and Ry is H.
[0032] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof:
R2 is selected from (1) H, (2) -CH3 and (3) -CH2OH;
R3 is selected from (1) H, (2) -CH3 and (3) -CH2OH; and
R4 is selected from (1) -CH3, (2) -CH2OH, (3) -CHF2, and (4) -CF3.
[0033] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt thereof:
R2 is selected from (1) H and (2) -CH3;
R3 is selected from (1) H and (2) -CH3; and
R4 is -CH3.
[0034] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof:
R2 is -CH3;
R3 is -CH3; and
R4 is -CH3.
[0035] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R6 is selected from:
(1) a phenyl,
(2) a naphthyl, and
(3) pyridyl, wherein each of the phenyl of (1), naphthyl of (2), and pyridyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -OCi-4 alkyl, optionally substituted with 1 to 3 halogens,
(d) -O-phenyl,
(e) -S-Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(f) -NR6eR6t, wherein each of R6e and R6t is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(g) a 5 or 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) -CH3 and (ii) halogen,
(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
(i) a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
[0036] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R6 is selected from:
(1) a phenyl and
(2) a naphthyl, wherein each of the phenyl of (1) and naphthyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -OC1-4 alkyl, optionally substituted with 1 to 3 halogens,
(d) -O-phenyl,
(e) -S-C1.4 alkyl, optionally substituted with 1 to 3 halogens,
(f) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (g) a 5 or 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) -CH3 and (ii) halogen,
(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
(i) a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
[0037] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R6 is selected from:
(1) a phenyl and
(2) a naphthyl, wherein each of the phenyl of (1) and naphthyl of (2) is optionally substituted with 1 to
3 substituents independently selected from:
(a) halogen,
(b) -C1-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -C1-3 alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-phenyl,
(e) -S-C1.2 alkyl, optionally substituted with 1 to 3 halogens,
(I) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) - C1-2 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(g) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen, and
(i) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, and (v) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) - OH, and (v) -OCH3.
[0038] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R6 is a phenyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -CH3, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -OCH3, optionally substituted with 1 to 3 halogens,
(d) -O-phenyl,
(e) -SCH3, optionally substituted with 1 to 3 halogens,
(f) -NR6eR6t, wherein each of R6e and R6t is independently selected from (i) H, (ii) -CH3, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(g) a 5 or 6 membered heterocyclyl selected from (i) morpholinyl and (ii) piperidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) - CH3 and (ii) halogen, and
(i) a heteroaryl selected from (i) pyridyl, (ii) thiazolyl, (iii) isothiazolyl, and (iv) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
[0039] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, R6 is phenyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -CH3, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -OCH3, optionally substituted with 1 to 3 halogens,
(d) -O-phenyl,
(e) a phenyl, (f) a thienyl, and
(g) a pyridyl, optionally substituted with 1 to 3 substituents independently selected from (i) - CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
[0040] 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, acetonitrile, 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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. [0046] 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 36C1.
[0047] 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.
[0048] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are glucagon receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have relative EC50 (Rel EC50) values of greater than 50,000 nM using Functional Assay I or Functional Assay II as described herein. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have relative EC50 (Rel EC 50) values of less than about 50,000 nM using Functional Assay I or Functional Assay II. In one embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 25,000 nM using Functional Assay I or Functional Assay II. In one preferred embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 10,000 nM using Functional Assay I or Functional Assay II. [0049] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in therapy.
[0050] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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 selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease. [00 1] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes.
[0052] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity. [0053] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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.
[0054] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), 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.
[0055] 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.
[0056] 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.” [0057] 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. [0058] 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.
[0059] 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 HbAlc level or a weight loss to the subject. [0060] 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 acetonitrile are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH 2nd ed. 2011)).
[0061] 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.
[0062] 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.
[0063] The term "alkoxy" refers to the following chemical group: , wherein R is an alkyl group as defined herein and the point of attachment is through the oxygen. For example, Ci-io j-o-c dlK? 1 alkoxy has 1 to 10 carbons with the following structure: ’ . Similarly, Ci-6 alkoxy has 1 to 6 carbons with the following structure:
[0064] The term “Ci-io alkyl” means a straight chain or a branched chain alkyl group containing 1 to 10 carbons. Similarly, “Ci-6 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 6 carbons. Examples of a Ci-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. [0065] The term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be linear or branched. For example, a "Ci-6 alkylene" means an alkylene group having 1 to 6 carbon atoms. Exemplary Ci-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-).
[0066] The term “C3-6 cycloalkyl” means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When two groups together form a C3-6 cycloalkane ring, the resulting group is bivalent. Non-limiting examples include cyclopropane- 1,1 -diyl, cyclobutane- 1,1 -diyl, cyclopentane-l,l-diyl, and cyclohexane- 1,1 -diyl. [0067] When the two groups on two carbon atoms are combined to form a C3-6 carbocyclic ring, the resulting ring forms a condensed ring. Non-limiting examples include ring structures such that the two carbon atoms are linked by -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. [0068] The term “aryl” means an aromatic carbocyclic group, and it 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-lH-isoquinolin-3-onyl, and l,3-dihydrobenzimidazol-2-onyl. In one embodiment, an aryl is a phenyl. In one embodiment, an aryl is a naphthyl.
[0069] The term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises 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, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). The term “5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S” means an heteroaryl group that contains 5 to 10 ring atoms including 1 to 3 hetero atoms independently selected from N, O, and S. The ring may be a monocyclic heteroaryl, or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl ring. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.
[0070] The term "heterocyclyl" refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring, and/or fused ring systems (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). The term “5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 3 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, oxetanyl, azetidinyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 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 -benzodioxolyl, 1,3- diazaspiro[4.4]nonanyl, 2-oxa-5,7-diazaspiro[3.4]octanyl, 8-oxa-l,3-diazaspiro[4.5]decanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, and tetrahydroindolinyl.
[0071] The compound herein, or a pharmaceutically acceptable salt thereof, has a glucagon receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the glucagon receptor. 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 non-alcoholic steatohepatitis. 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.
[0072] As used herein, treatment of a subject with obesity or overweight is also known as chronic weight management.
[0073] The term “overweight with at least one weight related comorbidity” refers to a disease or condition of being overweight and at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease. In one embodiment, a subject being overweight is defined as having a body mass index (BMI) of >25 to <30.
[0074] “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).
[0075] “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.
[0076] “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.
[0077] “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.
[0078] “Coronary heart disease” includes myocardial infarction and angina pectoris. [0079] “Dementia” includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.
[0080] 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. [0081] In one embodiment, a method for treating a disease or condition regulated by a glucagon receptor agonist comprises administering an effective amount of a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
[0082] 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. For example, the effective daily amount is from 0.01 to 1000 mg, or more specifically, from 0.05 to 500 mg, or even more specifically, from 0.1 to 200 mg, or still more specifically, from 0.1 to 100 mg once daily. In one embodiment, the above effective amount is administered once daily or twice daily for a few days, a few weeks, a few months, or several years. In one embodiment, the above dosage is administered once daily for a few days, a few weeks, a few months, or several years. [0083] 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-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof.
[0084] 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. [0085] In one embodiment, a pharmaceutical composition comprises a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. [0086] 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.
[0087] 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.
[0088] Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.
[0089] Examples of a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.
[0090] Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc. [0095] Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol.
[0096] 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
[0097] The following examples are provided for illustration purposed only. The abbreviations used in the preparations and examples are as defined below.
ACN acetonitrile
AcOH acetic acid aq. aqueous
Boc Zc 'Z-butoxycarbonyl
CSH charge surface hybrid
CV Column volume
DCM dichloromethane
DIEA diisopropylethylamine
DMF dimethylformamide
DMSO dimethylsulfoxide d.r. diastereomeric ratio
EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
ES-MS electrospray mass spectrometry
EtaN or TEA triethylamine
EtOAc ethyl acetate
EtOH ethanol
FA formic acid h hour(s)
HATU hexafluorophosphate azabenzotri azole tetramethyl uranium
HPLC high performance liquid chromatography
KO/Bu potassium Zcz7-butoxide
MeOH methanol min minute(s) m/z mass-to-charge ratio
NBS N-bromosuccinimide
NH4OAC ammonium acetate
Pd(OAc)2 palladium acetate
Pd(dppf)C12 l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride
Pd(PPhs)4 tetrakis(triphenylphosphine)palladium(0)
PE petroleum ether
PG protecting group prep-HPLC preparative high performance liquid chromatography prep-TLC preparative thin layer chromatography
PyOtBu pyridine ter/-butoxide
RBF round bottom flask
RP-HPLC reverse-phase high performance liquid chromatography RT or rt room temperature sat. saturated
SCX strong cation exchange
SFC supercritical fluid chromatography
/Bu Zc7 -butyl
/BuOH /c/7-butanol
THF tetrahydrofuran
TLC thin-layer chromatography
Wt or wt weight
[0098] In the schemes below, unless otherwise indicated, all substituents are as previously defined. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.
[0099] In the following schemes, R1, R2, R3, R4, R4’, R5, R5 , R6, R6b, R6c, R7, RA1, R42, R43, RA4, Ra, and Rb are as defined in Formula (I) and (la). [0100] A skilled artisan will appreciate that protecting groups employed in the preparation of compounds of Formula I may be removed as necessary or desired at any convenient point in the synthesis.
Scheme 1
[0101] Scheme 1 shows the preparation of intermediates (ii, iii, iv, v, vi, and vii) useful for the preparation of compounds of the present invention. Starting with an aryl or heteroaryl halide (i, wherein “Y” is CH or N, “X” is a halogen such as Cl, Br, or F, and the carboxylic acid is optionally protected as an ester “-O-PG”, wherein “PG” is an alkyl group such as methyl) the halogen “X” can be substituted in a variety of ways. Reacting (i) with l,3-dioxoisoindolin-2-yl 2-fluorocyclopropane-l -carboxylate using nickel(II) chloride and 2,2’ -bipyridine in a solvent such as DMF under electrolytic conditions gives (ii). Reacting (i) with tetrahydrofuran-2- carboxylic acid, 2-(/ert-butyl)-l,l,3,3-tetramethylguanidine, phthalimide, (4,4'-di-/-butyl-2,2'- bipyridine)bis[3, 5-difluoro-2-(5-tri fluoromethyl -2 -pyridinyl-K?V)phenyl-KC]iridium(III) hexafluorophosphate, and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine]nickel (II) di chloride with irradiation with 395 nm light at elevated temperature gives (iii). Intermediate (i) can be coupled with boronic acids or esters using a palladum catalyst and an inorganic base. For example, (i) can be coupled with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane using a palladium catalyst such as Pd(dppf)C12 and a carbonate base such as K2CO3 in an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (iv), which can then undergo reduction with a palladium on carbon catalyst under hydrogen gas at elevated temperatures to give (v). Additionally, (i) can be coupled with cyclopropaneboronic acid using a palladium catalyst such as Pd(OAc)2 and tri cyclohexylphosphine and an inorganic base such as K3PO4 at elevated temperatures in a mixture of toluene and water to give (vi). If “Y” is N, (i) can undergo nucleophilic aromatic substitution, for example with 3,3-difluoroazetidine hydrochloride and a carbonate base such as K2CO3 in a solvent such as DMF at elevated temperatures to give (vii).
[0102] In the transformations described above, if (i) is protected as an ester (“-O-PG”), an additional deprotection step after that transformation using conditions known to the skilled artisan gives the corresponding acid. For example, if the methyl ester of (i) is used, an additional hydrolysis step using a hydroxide base such as NaOH in an aqueous-organic solvent mix such as water and MeOH would give the corresponding acid intermediate (ii, iii, iv, v, vi, and vii).
Scheme 2
[0103] Scheme 2 depicts the preparation of the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) beginning with a suitable protected amine (viii). The PG moiety on the amine (viii) is a standard amine protecting group well known to a skilled artisan, including carbamate protecting groups such as Boc. The amine (viii) is reacted with NFEOAc and KCN in an appropriate solvent, such as EtOH at elevated temperatures. The resulting intermediate (ix) is reacted with a suitable acyl chloride (R6-C(O)C1) in the presence of an appropriate base, such as ISfeCCh, Nal ICO3 or EtaN, in a suitable solvent, such as DCM or THF. Alternatively, the amine (ix) is reacted under amide coupling conditions well known to a skilled artisan and include reacting an appropriate carboxylic acid (R6-CO2H) with the amine (ix) in a suitable solvent, such as DMF, with an appropriate coupling agent, such as HATU, in the presence of a suitable base, such as DIEA. The intermediate (x) is cyclized to form the l,3,8-triazaspiro[4.5]dec-l-en-4-one core in the presence of an appropriate oxidizing agent, such as H2O2, and a suitable base, such as NaOH, in an appropriate solvent, such as EtOH, DMSO or MeOH, at 80 °C to give (xiii).
[0104] Alternatively, the nitrile group of intermediate (ix) is first converted in the carbamoyl group under the aforementioned conditions for the formation of intermediate (xi). The intermediate (xii) is obtained then by the sequential amidation (previously described) and cyclization conditions in the presence of a suitable base, such as PyO/Bu or KO/Bu, in an appropriate solvent, such as /-BuOH or EtOH, at 60 °C at least to give (xiii).
[0105] The removal of the PG moiety on (xiii) is achieved under conditions standard to the art. For example, the intermediate amine (xiv) is obtained by reacting a suitable acid, such as HC1 in 1,4-di oxane, in an appropriate solvent, such as DCM.
Scheme 3
[0106] Scheme 3 shows the preparation of intermediate (xvii), which is useful for the preparation of compounds of Formula Ic (where “Y” in this scheme = CH) or Formula Id (where “Y” in this scheme = N). Halide (xv, where “X” is a halogen such as Br and “PG” is a protecting group such as Boc) is coupled with a heteroaryl boronic acid (or ester thereof) using a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) and a base such as K3PO4 in an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (xvi). The protecting group is removed to give (xvii), under suitable conditions well known to the skilled artisan, e.g. HC1 in an organic solution to remove a -Boc group.
Scheme 4
[0107] Compounds of Formula (la) my be prepared via the synthetic route presented in Scheme 4 by reacting intermediate (xiv) with biphenyl derivative (xviii) under SNAT conditions (e.g. using an organic base such as DIEA and an organic solvent such as DMSO at elevated temperature) to give intermediate (xix). The nitro group of intermediate (xix) is then converted to compound (xx) under nitro group reduction conditions, e.g. using zinc, acetic acid, and an alcohol solvent at 0 °C. Compound (xx) can be used to prepare compound (xxi), e.g. acylation conditions (e.g. acetic anhydride, organic base, and a solvent such as DCM) give compound (xxi) where Ra or Rb is -C(O)CH3.
Scheme 5
[0108] Scheme 5 illustrates the preparation of the biphenyl intermediate (xviii) beginning with a suitable aryl bromide (xxii). The aryl boronic ester (xxiii) is produced from the reaction of (xxii) with bis(pinacolato)diborane and the appropriate catalyst system, such as Pd(OAc)2 and tris(4- methoxyphenyl)phosphine, in the presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, at elevated temperatures. The resulting aryl boronic ester (xxiii) is reacted under Suzuki coupling conditions standard to the art and include a suitable substituted aryl bromide (xxiv) and the appropriate catalyst system, such as Pd(PPh3)4, in presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, stirred at 80 °C for 72 h to give biphenyl intermediate (xviii).
Scheme 6 xxix
[0109] Scheme 6 shows the preparation of intermediate (xxx), which is useful for the preparation of compounds of Formula la. Amide (xi) is cyclized to (xxv) using toluenesulfonic acid and 2,2- dimethoxypropane in an alcohol solvent such as EtOH at elevated temperature. Amine (xxv) is reacted with halo-benzene (xxvi, wherein X is Br or Cl and X’ is I or Br) using lithium bis(trimethylsilyl)amide in a solvent such as 1,4-dioxane at elevated temperature to give (xxvii), which is then converted to amide-amine (xxviii) using aq. HC1 in MeOH and water at elevated temperature. Amine (xxviii) is then reacted with an acid chloride R6-C(O)C1 using an amine base such as TEA in a solvent such as THF to give amide (xxix), which is then cyclized using a base such as aq. NaOH in MeOH at elevated temperature to give (xxx).
Scheme 7
[0110] Compounds of Formula la may be prepared via the synthetic route presented in Scheme 7 by reacting the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) with an appropriate halo- benzene (xxxiv, wherein X is Br or Cl and X’ is I or Br) under Buchwald-Hartwig cross coupling conditions well known to a skilled artisan to give intermediate (xxx) wherein X is Br or Cl. Such conditions include using a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2l,6'-bis(dimethylamino)-l , l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) and an alkoxide base such as sodium 2- methylbutan-2-olate at elevated temperature. Alternatively, an aryl bromide can be reacted with lithium bis(trimethylsilyl)amide, followed by amine intermediate (xiv) in a solvent such as 1,4- dioxane at elevated temperature to give intermediate (xxx) wherein X is Cl, Br, or I. If RA1 is - CN, amine (xiv) can also be reacted with (xxxiv) under SNAT reaction conditions using a base such as DIEA or K3PO4 in a solvent such as DMSO at elevated temperature. The halogen in the resulting intermediate (xxx) may be reacted with a suitable aryl boronic ester (xxiii) or acid thereof under Suzuki coupling conditions, e.g. using a palladium catalyst such as Pd(PPh3)4, methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II), or l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloride, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as MeOH, THF, or 1,4-dioxane in water at elevated temperature.
[0111] Alternatively, (xxx) is converted to boronate (xxxiv) using conditions known to the skilled artisan e.g. using bis(pinacolato)diborane, a palladium catalyst such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) or chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl- l,l'-biphenyl) palladium(II), a base such as potassium acetate or K2CO3, a solvent such as methoxycyclopentane or 2-methyltetrahydrofuran at elevated temperature. Boronate (xiv) is then coupled with aryl halide (xv) where X is Cl, Br, or I using Suzuki coupling conditions described above.
[0112] In another route to compounds of Formula la, halo-phenol (xxxi, where RA4 is trimethyl silyl) is coupled with aryl boronic ester (xxiii) or ester thereof under Suzuki coupling conditions, e.g. using a palladium catalyst such as Pd(dppf)C12, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as 1,4-dioxane in water at elevated temperature to give (xxxii), which is converted to trifluoromethanesulfonate (xxxiii) using N-phenyl- bis(trifluoromethanesulfonimide) and K2CO3 in ACN at elevated temperature. Reaction of (xxxiii) with amine (xiv) using CsF and ACN at elevated temperature gives (xxxv), converting - RA4 to -H.
PREPARATION OF INTERMEDIATES
Preparation of Intermediate 1 terz-Butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l-carboxylate (mixture of diastereomers)
[0113] NH4OAC (11.0 g, 140 mmol) was added to a stirred solution of tert-butyl (S)-2-methyl-4- oxopiperidine-l-carboxylate (20 g, 94 mmol), KCN (9.2 g, 140 mmol) in EtOH (31 L) and stirred at 80 °C. After 48 h, the reaction mixture was diluted with Na2COs sat. solution (300 mL) and was extracted with EtOAc (3 * 150 mL). The organic extracts were then washed with H2O (100 mL) and NaCl sat. solution (50 mL). The organic extracts were then filtered through MgSCh and the solution was concentrated to afford a mixture of diastereomers of the title compound.
Preparation of Intermediate 2
Zc/7-Butyl (2S)-4-cyano-2-methyl-4-(2-(trifluoromethoxy)benzamido)piperidine-l -carboxylate (mixture of diastereomers)
[0114] 2-(Trifluoromethoxy)benzoyl chloride (17.65 mL, 112.8 mmol) was added to a solution of /tv7-butyl (2S)-4-amino-4-cyano-2-methylpiperidine- l -carboxylate (mixture of diastereomers, 27.00 g, 112.8 mmol), Na2CO3 (23.92 g, 225.6 mmol) and NaHCCh sat. aq. solution (564.1 mL, 0.2 M) in DCM (564 mL) and stirred at RT. After 4 h, the reaction mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3 * 500 mL). The organic extracts were washed with water (1 L) then NaCl sat. aq. solution 500 mL. The organic layers were passed through a Na2SO4 column and concentrated to afford the title compound. ES-MS (m/z) 428 (M+H).
Preparation of Intermediate 3 zcz7-Butyl (7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-2-ene- 8-carboxylate (mixture of diastereomers)
[0115] H2O2 (63 mL, 50% Wt, 1000 mmol) was added slowly to a vigorously stirred solution of a mixture of diastereomers of tert-butyl (2S)-4-cyano-2-methyl-4-(2- (trifluoromethoxy)benzamido)piperidine-l -carboxylate (48.2 g, 112.8 mmol), NaOH (270 mL, 5 M, 1354 mmol) in EtOH (564 mL) at 80 °C. After 16 h, the reaction mixture was diluted with 500 mL of NH4CI sat. aq. solution and 30 mL of Na2S2O3 aq. solution. The mixture was extracted with 3 *200 mL of DCM. The organic extracts were passed through a Na2SO4 column and concentrated. The resulting residue was dissolved in EtOAc (1000 mL) and passed through a pad of silica gel (100 g), washed with EtOAc (2><250 mL) and DCM (3x250 mL). The resulting solution was concentrated to afford 4: 1 d.r. of the title compound. MS (m z) 428 (M+H).
Preparation of Intermediates 4 and 5 tert-Butyl (2S,4S)-4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (Intermediate 4) and
Z /V-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (Intermediate 5)
[0116] NaOH (20.5 mL, 5.00 M, 102.5 mmol) was added to a solution of a mixture of diastereomers of tert-butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l-carboxylate (22.72 g, 94.94 mmol) in MeOH (180 mL) and DMSO (11 mL) at 10 °C and stirred. After 5 min, H2O2 (10.5 mL, 35.5% Wt, 123.4 mmol) was slowly added over 15 min. After 1 h, Na2S20a sat. aq. solution (720 mL) was added and diluted with H2O (500 mL) and was extracted with DCM (3 x 100 mL). The organic layers were separated. All organic layers were combined and washed with NaCl sat. aq. solution (100 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-100% of a mixture of DCM and MeOH (9: 1) in DCM) to give the first eluting isomer (Intermediate 4) as a solid and the second eluting isomer (Intermediate 5) as a solid. Both isomers: ES-MS (m/z) 258 (M+H).
Preparation of Intermediate 6 tert-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(trifluoromethoxy)benzamido)piperidine-l-
[0117] A solution of 2-(trifluoromethoxy)benzoyl chloride (7.59 g, 33.8 mmol) in DCM (30 mb) was added to a stirred solution of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (9.13 g, 35.5 mmol) in DCM (300 mL) and EtaN (14.1 mL, 101 mmol) and was stirred. After 6 h, the reaction mixture was diluted with 2% citric acid aq. solution (300 mL) and heptane (300 mL) and stirred vigorously. After 30 min, a precipitate was collected by fdtration and the resulting cake was rinsed with a mixture of each H2O (100 mL) and 1 :2 DCM/heptane (1 :2), water (150 mL), heptane (150 mL) to result in a solid which was dried in vacuo overnight (50 °C) to give the title compound. ES-MS (m/z) 346 (M-Boc).
Preparation of Intermediate 7 tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l- ene-8-carboxylate
[0118] Potassium 2-methylpropan-2-olate IM in /-BuOH (77.5 mL, 77.5 mmol) was added dropwise to a suspension of tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-
(trifluoromethoxy)benzamido)piperidine-l -carboxylate (11.5 g, 25.8 mmol) in EtOH (152 mL) and stirred at 60 °C. After 30 min, solvent was removed. The residue was diluted with EtOAc and a 5% citric acid aq. solution. The aq. layer was separated, and organic layer was washed with H2O and NaCl sat. aq. solution, dried over anhydrous Na2SC>4, filtered and the solvent was removed in vacuo to afford a solid. The resulting solid was dried in vacuo at 35-40 °C to give the title compound. ES-MS (m z) 428 (M+H).
Preparation of Intermediate 8
/e/7-Butyl 4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0119] 2-(Trifluoromethoxy)benzoyl chloride (2.00 g, 8.60 mmol) was added to a solution of /c/'Z-butyl 4-amino-4-carbamoylpiperidine-l -carboxylate (2.00 g, 7.80 mmol) and EtsN (3.30 mL, 23.0 mmol) in THF (50 mL) at 0 °C and the mixture was stirred at 20 °C for 2 h. 2- Methylpropan-2-olate pyridine (4.50 g, 39.0 mmol) in Z-BuOH (30 mL) was added to the mixture and was stirred at 70 °C. After 3 h, the reaction mixture was diluted with H2O (150 mL) and extracted by EtOAc (3 x 45 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give the title compound as an oil. ES-MS (m/z) 414 (M+H).
Preparation of Intermediate 9
(5R, 7 S)-7 -Methyl-2-(2-(trifluoromethoxy)phenyl)- 1 , 3 , 8 -tri azaspiro[4.5 ]dec- 1 -en-4-one hydrochloride
[0120] HC1 in 1,4-dioxane (29.5 mL, 4 M, 118 mmol) was added dropwise to a solution of tert- butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy) phenyl)-!, 3, 8-triazaspiro [4.5]dec-l -ene- 8-carboxylate (11.2 g, 26.2 mmol) in DCM (87 mL) and stirred. After 4 h, the resulting solid was filtered, washed with DCM, dried in vacuo at 30-35 °C for 14 h to give the title compound as a solid. ES-MS (m/z) 328 (M+H).
Preparation of Intermediate 10
2-(2-(Trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride
[0121] HC1 in 1,4-di oxane (10 mL, 4 M, 26 mmol) was added to a solution of /e/7-butyl 4-oxo-2- (2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (1.40 g, 2.8 mmol) in DCM (10 mL) at 20 °C and the mixture was stirred. After 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound. ES-MS (m/z) 314 (M+H).
[0122] Alternatively, the title compound was partitioned between EtOAc and sat. aq. NaHCO3, then the organics were dried over MgSO4, filtered and concentrated to give the free base of the title compound.
[0123] Intermediate 11 in the following table was prepared essentially as described in the
Preparation of Intermediate 10 using the appropriate Boc-protected amine.
Preparation of Intermediate 12 (5R,7S)-8-(3-Bromophenyl)-7-methyl-2-(2-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec- 1-en -4-one
[0124] Sodium 2-methylpropan-2-olate (0.79 g, 8.06 mmol), l-bromo-3-iodo-benzene (1.00 g, 3.46 mmol), 2’-dicyclohexylphosphino-2-(A(iV-dimethylamino)biphenyl (0.096 g, 0.23 mmol) and tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) were added to a solution of (5R,7S)-7-methyl-2-(2-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (0.86 g, 2.31 mmol) in 1,4-di oxane (10 mL) at 20 °C and the mixture was heated at 100 °C in a microwave reactor. After 1 h, the residue was poured into H2O (20 mL). The aq. phase was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with NaCl sat. aq. solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (50-80% ACN in 10 mM aq. NH4HCO3) to give the title compound. ES-MS (m/z) 484 (M+2H).
Preparation of Intermediate 13
(7S)-8-(3-Chl oro-4-methoxyphenyl)-7-methyl-2-(2-(tri fluoromethoxy )phenyl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (Isomer 1)
[0125] To a mixture of (7S)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec- l-en-4-one hydrochloride (mixture of diastereomers, 1.03 g, 2.56 mmol) and lithium bis(trimethylsilyl)amide (1 M sol. in THF, 25.0 mL, 25.0 mmol) under argon was added 4- bromo-2-chl oro-1 -methoxybenzene (1.77 g, 7.99 mmol) as a solution in anhydrous 1,4-dioxane (24 mL). The mixture was stirred at 80 °C for 3 days, then diluted with EtOAc and water. The mixture was extracted three times with EtOAc, then the organics were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography using a gradient of 20 to 100% ACN in 0.1% aq. FA to give title compound as the first-eluting isomer. ES-MS rn/z 468 (M+H).
[0126] Intermediates 14-16 in the following table were prepared essentially as described in the Preparation of Intermediate 13 using (5R,7S)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one hydrochloride and the appropriate aryl bromide, using 1,4- di oxane as solvent, and heating the reaction for 12-16 h.
Preparation of Intermediate 17 4-(4-Bromo-3 , 5 -dimethylphenyl)morpholin-3 -one
[0127] To a mixture of 2,6-dimethyl-4-iodobromobenzene (14.97 g, 48.14 mmol) in 1,4-dioxane (0.12 L) was added morpholin-3-one (5.14 g, 50.8 mmol), K2CO3 (20.31 g, 147.0 mmol), racemic (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (5.45 g, 38.3 mmol), and cuprous iodide (1.86 g, 9.77 mmol). The mixture was purged with nitrogen and heated to 110 °C for 2 days, then diluted with EtOAc (0.3 L) and 5% aq. NH4OH (0.3 L). The layers were separated and the organics were washed successively with 0.1 L of each of 5% aq. NH4OH and water, then 1 M aq. KH2PO4 (2 x 50 mL) and brine (50 m ). The organics were dried over MgSCU, filtered, then concentrated to a volume of 0.1 L. Heptane (0.4 L) was then added slowly and the mixture was stirred at RT for 1 h. The solids were filtered and washed with 1 :4 EtOAc/heptane (50 mL) and heptane (50 mL). The filtrate and wash were concentrated and the residue was triturated with 1 :9 EtOAc/heptane (0.1 L). A second crop of solid was collected after 1 h, washed with 1 :9 EtOAc/heptane (25 mL), then heptane (25 mL). The first and second crops of the solid were combined to give the title compound. ES-MS m/z 284,286 (M+H).
Preparation of Intermediate 18
4-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one
[0128] A mixture of 4-(4-bromo-3,5-dimethylphenyl)morpholin-3-one (5.03 g, 16.2 mmol) in 1,4-dioxane (100 mL) was added to bis(pinacolato)diborane (5.65 g, 21.1 mmol), CS2CO3 (8.67 g, 25.3 mmol), tris(4-methoxyphenyl)-phosphine (0.64 g, 1.74 mmol) and Pd(OAc)2 (0.39 g, 1.68 mmol) and the mixture was stirred at 130 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in petroleum ether). The residue was further purified by using reverse phase HPLC (0-30% EtOH in heptane) to give the title compound as a solid. ES-MS (m/z) 332 (M+H).
Preparation of Intermediate 19 (2,6-Dimethyl-4-(3 -oxomorpholino)phenyl)boronic acid [0129] To a mixture of 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)morpholin-3-one (226.0 mg, 682.3 pmol) and acetone (3.0 mL) was added sodium periodate (448.4 mg, 2.096 mmol) and ammonium acetate (1 M aq. sol., 1.4 mL, 1.4 mmol). The reaction mixture was stirred at RT for 10 min, then at 30 °C for 3.5 h, then at 40 °C for 3 days, then at 60 °C for 7 days. The mixture was purified by reverse-phase flash chromatography (5 to 25% ACN in 10 mM aq. NH4HCO3 + 5% MeOH) to give the title compound. ES-MS m/z 250 (M+H).
Preparation of Intermediate 20
4-(3',5'-Difluoro-2,6-dimethyl-2'-nitro-[l,T-biphenyl]-4-yl)morpholin-3-one
[0130] Tetrakis(triphenylphosphine)palladium(0) (0.238 g, 0.206 mmol) was added to a solution of l-bromo-3,5-difluoro-2-nitrobenzene (0.016 g, 0.69 mmol), 4-(3, 5-dimethyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (0.25 g, 0.76 mmol), and CS2CO3 (0.67 g, 2.06 mmol) in 1,4-di oxane (0. 343 mL, 2 M) and H2O (2.29 mL, 0.3 M) and the mixture was stirred at 80 °C. After 72 h, the reaction mixture was directly loaded onto silica gel and purified via silica gel chromatography (0-100% EtOAc in heptane) to give the title compound. ES-MS (m/z) 363 (M+H).
[0131] Intermediates 21-22 in the following table were prepared essentially as described in the Preparation of Intermediate 20 by using appropriate aryl bromide.
Preparation of Intermediate 23
4-(3'-Fluoro-2,6-dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-2'-nitro-[l,r-biphenyl]-4-yl)morpholin-3-one (mixture of diastereomers)
[0132] DIEA (0.228 mb, 1.32 mmol) was added to a solution of (7S)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (mixture of diastereomers, 0.15 g, 0.44 mmol) and 4-(3',5'-difluoro-2,6-dimethyl-2'-nitro-[l,r-biphenyl]-4- yl)morpholin-3-one (0.160 g, 0.44 mmol) in DMSO (2.21 mL, 0.2 M) and stirred at 110 °C. After 24 h, the reaction mixture was diluted with H2O. The mixture was transferred to a centrifuge tube and was centrifuged for 5 min. The aq. layer was decanted and the solid was dissolved in DCM and purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound as an oil. ES-MS (m z) 670 (M+H).
[0133] Intermediates 24-25 in the following table were prepared essentially as described in the Preparation of Intermediate 23 by using appropriate aryl fluoride.
Preparation of Intermediate 26: 2-Cyclopropylbenzoyl chloride
[0134] Oxalyl chloride (6.09 m , 69.4 mmol) was added to a stirred solution of 2-cyclopropyl- benzoic acid (10.0 g, 55.5 mmol) in DCM (100 mL) under nitrogen at ambient temperature.
DMF (0.217 mL, 2.77 mmol) was then added. After 3 h, the mixture was concentrated under a stream of N2 to afford the title compound (10.7 g) as an oil.
Preparation of Intermediate 27: /c/7-Butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropylbenzamido)-2- methylpiperidine- 1 -carboxylate;
[0135] EtsN (22 mL, 160 mmol) was added to terz-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (14.42 g, 56.04 mmol) in DCM (100 mL) and stirred at ambient temperature under nitrogen in 500 mL RBF. A solution of 2-cyclopropylbenzoyl chloride (10.08 g, 52.24 mmol) in DCM (100 mL) was added. After 2 h, the mixture was diluted with 5% aq. citric acid (200 mL) and heptane (300 mL) and stirred vigorously. After 30 min, the mixture was filtered, and the filter cake was washed with water (200 mL) and heptane (100 m L). The solid was dried under reduced pressure overnight to give the title compound (18.03 g). ES-MS m/z 402 (M+H).
Preparation of Intermediate 28: tert-Butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-
1 , 3 , 8 -tri azaspi ro[4.5 ] dec- 1 -ene- 8 -carb oxy 1 ate
[0136] Sodium ethoxide (21 wt% in EtOH, 49 mL, 0.13 mol) was added to a stirred suspension of tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropylbenzamido)-2-methylpiperidine-l- carboxylate (18.0 g, 43.5 mmol) in EtOH (0.25 L) and the mixture was heated at 60 °C. After 4 h, the mixture was partially concentrated under reduced pressure at 50 °C to 0.1 L, then stirred at ambient temperature. Citric acid (5% aq. 0.50 L) was added and the mixture was extracted with EtOAc (0.30 L). The aqueous layer was extracted with a second portion of EtOAc (50 mL). The organics were combined, washed with 50 mL of 2 M aq. K^HPCUthen sat. aq. NaCl, dried over MgSO4 and fdtered. The organics were concentrated at 50 °C to afford the title compound (16.37 g) as a foam. ES-MS m/z 384 (M+H).
Preparation of Intermediate 29: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride
[0137] 4 M HC1 in 1 ,4-di oxane (34.47 mL, 137.9 mmol) was added to a 1 L RBF containing tert-butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8- carboxylate (13.22 g, 34.47 mmol) in DCM (344.7 mL) and stirred at RT overnight. 200 mL of DCM was added, and the mixture was filtered. The collected solid was dried for 2 h at 50 °C in a vacuum oven to give the title compound (10.35 g) as a solid. ES-MS m'z 284 (M+H).
[0138] The free base of the title compound was prepared by stirring the hydrochloride salt in water and adding 2 M aq. K3PO4 to bring the pH to 11.7 and collecting the solid, washing with water, and drying the solid in a vacuum oven overnight.
Preparation of Intermediate 30: to7-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine- 1 -carboxylate
[0139] To a mixture of 2-(trifluoromethyl)nicotinic acid (48.5 g, 249 mmol), HATU (243.05 g, 632.81 mmol) and DIEA (115.2 g, 155 mL, 882.4 mmol) in DMF (1500 mb) was added tert- butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (70.40 g, 273.6 mmol) portion wise. Upon complete addition, the mixture was stirred at 30 °C for 10 h under nitrogen. The reaction was quenched with water (4500 mL) and the filtered. The filter cake was washed with water (300 mL x 3) and concentrated under reduced pressure at 45 °C to give the title compound (107 g) as a solid. ES-MS m z 331 (M-Boc+H).
Preparation of Intermediate 31 : tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0140] To a solution of /crZ-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (107 g, 249 mmol) in DMSO (400 mL) and /c/7-butanol (1500 mL) was added NaOH (5 M aq. solution, 646 mL, 3228 mmol) and the mixture was heated to 100 °C for 20 h under nitrogen. The mixture was concentrated under reduced pressure to remove /c/v-butanol and then diluted with water (2.5 L) and extracted with EtOAc (900 mL x 4). The combined organics were washed with sat. aq. NaCl (2 L x 2), dried over Na2SO4, filtered, and concentrated to give the title compound (78.1 g) as a solid. ES-MS m,'z 357 (M-/Bu+H).
Preparation of Intermediate 32: (5R,7S)-7-Methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride
[0141] To a solution of te/7-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (78.1 g, 177 mmol) in DCM (400 mL) was added HC1 (4 M in 1,4-dioxane, 400 mL) dropwise at 20 °C. The mixture was stirred for 2 h under nitrogen, then concentrated under reduced pressure to give the title compound (63.2 g) as a solid. ES-MS w/z 313 (M+H).
Preparation of Intermediate 33: ze/7-Biityl (5R,7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7- methyl -4-oxo-l, 3, 8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0142] A mixture of 2-bromo-4-(trifluoromethoxy)benzoic acid (6.3 g, 22 mmol), /c/7-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (5.5 g, 21.0 mmol), HATU (12.2 g, 32.1 mmol) and DIEA (14 g, 18 mL, 4.9 Eq, 0.10 mol) in DMF (60 mL) was stirred at ambient temperature. After 16 h, the reaction mixture was diluted with 200 mL of EtOAc, washed with 100 mL of water, 100 mL of sat. aq. NaCl, dried over anhydrous MgSCh, filtered, and concentrated under reduced pressure to afford a solid. The solid was re-suspended in EtOH (150 mL) and potassium 2-methylpropan-2-olate (8.0 g, 71 mmol) was added and warmed to 80 °C and stirred. After 1 h, the reaction mixture was diluted with 50 mL of EtOAc and washed with 25 mL of water and 25 mL of sat. aq. NaCl, dried over anhydrous MgSO4, filtered, and partially concentrated under reduced pressure. The resulting slurry was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in cyclohexane to afford the title compound (8.6 g) as a solid. ES-MS m 'z 506, 508.
Preparation of Intermediate 34: tert-Butyl (5R,7S)-2-(2-(5-fluorothiophen-2-yl)-4-
(tri fluoromethoxy )phenyl)-7-methyl-4-oxo-l, 3, 8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0143] To a solution of K3PO4 (1.222 g, 7.015 mmol) in water (1 mL) was added /c/'Z-butyl (5R,7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l- ene-8-carboxylate (1.110 g, 2.192 mmol) in 1,4-dioxane (10 mL) and 2-(5-fluorothiophen-2-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.000 g, 4.385 mmol). The mixture was purged with nitrogen for 5 min and dichlorobis(triphenylphosphine)palladium (II) (0.185 g, 0.263 mmol) was added, then the reaction vessel was sealed and the reaction mixture was stirred at 82 °C for 16 h. The reaction was cooled and poured into water and extracted twice with EtOAc. The combined organics were washed with water, sat. aq. NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (0.87 g) as a solid. ES-MS m/z 528 (M+H).
Preparation of Intermediate 35: (5R,7S)-2-(2-(5-Fluorothiophen-2-yl)-4-
(trifluoromethoxy)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0144] Hydrogen chloride (4 M solution, 15.73 mL, 62.93 mmol) was added to a solution of tert- butyl (5R,7S)-2-(2-(5-fluorothiophen-2-yl)-4-(trifluoromethoxy)phenyl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (1.660 g, 3. 147 mmol) in DCM (50mL) via a syringe and stirred at ambient temperature. After 3 h, the solvent was removed under reduced pressure. The solid was taken up in MeOH and loaded onto 50 g SCX resin, which was eluted with 3 CV MeOH then 3 CV NH3 (2 M solution in MeOH) to give the title compound (1.17 g). ES-MS m/z' 428 (M+H).
Preparation of Intermediate 36: 2-(Tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)
[0145] A mixture of 2-chloro-6-(trifluoromethyl)-3-pyridinecarboxylic acid (50.0 g, 211 mmol), tetrahydrofuran-2-carboxylic acid (racemic mixture, 32.1 mL, 317 mmol), 2-( rt-butyl)-l, 1,3,3- tetramethylguanidine (69.2 g, 396 mmol) and phthalimide (37.6 mL, 306 mmol) in DMF (400 mL) was heated to 30 °C, and then (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (12.0 g,10.5 mmol) and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine]nickel (II) dichloride (1.2 g, 3.0 mmol) were added to the mixture. The reaction mixture was stirred at 55 °C for 2 h under irradiation with 395 nm (200 W) LED module in an integrated photoreactor under nitrogen. The reaction mixture was poured into 500 mL water at 25 °C, and then extracted with EtOAc (800 mL x 3). The combined organic layers were washed with water (500 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in PE to give the title compound (14.4 g) as a solid. ES-MS m/'z 262 (M+H).
Preparation of Intermediate 37: ZcvZ-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran-
2-yl)-6-(trifluoromethyl)nicotinamido)piperidine-l -carboxylate (mixture of isomers) [0146] A mixture of 2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture, 10.0 g, 38.2 mmol), tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (12.1 g, 45.3 mmol), DIEA (19.9 mL, 112 mmol), EDCI (11.2 g, 56.7 mmol) and 1-hydroxy-lH- benzotriazole (7.7 g, 55 mmol) in THF (100 mL) was reacted at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 16 h, then poured into 100 mL water and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with water (200 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give the title compound (15.3 g) as a solid. ES-MS m/z 501 (M+H).
Preparation of Intermediate 38: tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)- 6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers)
[0147] A mixture of tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (15.2 g, 20.0 mmol) and NaOH (12.0 g, 294 mmol) in MeOH (150 mL) and water (50 mL) was heated to 80 °C for 8 h with vigorous stirring. The mixture was cooled to 40 °C and concentrated under reduce pressure. The residue was diluted with 100 mL water and extracted with EtOAc (lOOmL x 3). The combined organic layers were washed with water (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in PE to give the title compound (8.1 g) as a solid. ES-MS m/z 483 (M+H).
Preparation of Intermediate 39: (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers) [0148] A mixture of tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (racemic mixture, 8.0 g, 16 mmol) and HC1 (4 M in 1,4-dioxane, 40 mL, 0.16 mol) in 1,4-dioxane (80 mL) was stirred vigorously at 27 °C for 6 h, then the mixture was concentrated under reduced pressure to give the title compound (6.5 g) as a solid. ES-MS m/z 383 (M+H).
[0149] The free base of the title compound was prepared by reverse-phase prep-HPLC of the dihydrochloride using a gradient of 1 to 50% ACN in 10 mM aq. NH4HCO3.
Preparation of Intermediate 40: (5R,7S)-8-(5-Chloro-3-fluoro-2-methoxyphenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0150] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 338 mg, 884 pmol) was dissolved in toluene (5 mL), then l-bromo-5-chloro-3-fluoro-2-methoxybenzene (427 mg, 1.78 mmol) was added. Nitrogen was bubbled through the solution for 10 min, then methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (CAS# 1810068-35-9, 104 mg, 91.2 pmol) was added, followed by a solution of sodium 2-methylbutan-2-olate (30 wt% in THF, 1.32 g, 1.45 mL, 3.59 mmol) via syringe. After this addition the mixture was allowed to further degas for 3 min then heated via microwave irradiation to 90°C for 5 h. The reaction mixture was loaded directly onto 10 g SCX resin, which was washed with MeOH, 1 :1 MeOH/DCM then again with MeOH. The resin was eluted with 7 M NH3 in MeOH and the eluate was collected and concentrated. The residue was purified by reverse phase flash chromatography using a gradient of 20 to 70% ACN in 0.1% aq. FA to give the title compound (110 mg). ES-MS m/z 542 (M+H).
Preparation of Intermediate 41 : 4-Bromo-3,5-dimethylbenzenesulfonamide
[0151] To a mixture of 4-bromo-3,5-dimethylbenzenesulfonyl chloride (300 mg, 1.04 mmol) in ACN (1 mb) was added ammonia (25 wt% aq. solution, 0.80 mL, 5.2 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with water (10 mL) and extracted with DCM (5 mL x 3). The organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (210 mg) as a solid. ES-MS m'z 262, 264 (M-H).
Preparation of Intermediate 42: 2-(4-Bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture)
[0152] KCN (5.04 g, 77.4 mmol) was added to a mixture of 4-bromo-3,5-dimethylbenzaldehyde (10.0 g, 46.9 mmol) in water (50 mL). A solution of Na2SCh (1.75 M aq., 49.6 mL, 86.8 mmol) was added to the reaction mixture at 0 °C, then the mixture was stirred at 22 °C over the weekend. The reaction mixture was filtered and washed with H2O (3 x 200 mL) to give a filter cake which was dried at 50 °C in a vacuum oven for 30 min to give the title compound (10.95 g) ^-NMR (500 MHz, MeOD) 5 9.93 (s, 1H), 7.67 (s, 2H), 2.52 (s, 6H), 2.42 (s, 1H).
Preparation of Intermediate 43: (R)-2-(4-Bromo-3,5-dimethylphenyl)-2-hydroxyacetamide (racemic mixture)
[0153] Aq. HC1 (12 M, 75 mL, 0.90 mol) at 0 °C was added dropwise to a vigorously stirred solution of 2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture, 58 g, 75 wt%, 0.18 mol) in HC1 (4 M solution in 1,4-dioxane, 300 mL). The reaction mixture was stirred at 20 °C. After 2 h, reaction mixture was diluted with aq. Na2CCL to pH 7, then poured into H2O (200 mb) and DCM (300 mL), stirred for 30 min, and filtered off the title compound (30 g) as a solid. ES-MS m/z 258, 260.
Preparation of Intermediate 44: 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (racemic mixture)
[0154] Pd(dppf)C12 (3.4 g, 4.6 mmol) at 25 °C was added to a mixture of 2-(4-bromo-3,5- dimethylphenyl)-2-hydroxyacetamide (29 g, 110 mmol), potassium acetate (33 g, 330 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (31 g, 120 mmol) in 1,4-dioxane (300 mb) and the reaction mixture was stirred at 100 °C for 15 h. The mixture was purified by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM, and the product was triturated with MTBE (150 mb) at 25 °C for 15 h, which upon filtration gave the title compound (20.50 g) as a solid. ES-MS m 'z 306 (M+H).
Preparation of Intermediate 45: 2-(3,6-Dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid;
[0155] Pd(dppf)Ch (3.20 g, 4.29 mmol) was added under nitrogen to a mixture of 2-chloro-6- (trifluoromethyl)nicotinic acid (10.00 g, 43.45 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (14.00 g, 65.31 mmol) in 1,4-dioxane (100 mL) and water (10 mL). K2CO3 (18.00 g, 130.2 mmol) was then added and the reaction mixture was heated to 110 °C with stirring under nitrogen for 16 h. The mixture was filtered and concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-80% EtOAc in hexane + 0.1% AcOH to give the title compound (5.50 g) as a solid. ES-MS m/z 274 (M+H). Preparation of Intermediate 46: 2-(Tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid
[0156] A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid (4.50 g, 15.6 mmol) in EtOAc (50 ml) was degassed with nitrogen, then palladium on carbon (4.50 g, 10 wt%, 4.23 mmol) was added. The reaction mixture was evacuated and backfilled three times with hydrogen. The mixture was stirred at 50 °C for 2 h under hydrogen (103 kPa). The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford the title compound (3.90 g) as a solid. ES-MS m/z 276 (M+H).
Preparation of Intermediate 47: te/7-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydro-2H- pyran-4-yl)-6-(trifluoromethyl)nicotinamido)piperidine-l -carboxylate
[0157] The title compound was prepared as described in the Preparation of Intermediate 30 using 2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid and tert-butyl (2S,4R)-4-amino- 4-carbamoyl-2-methylpiperidine-l-carboxylate, stirring the reaction at RT for 1 h. The reaction mixture was diluted with water and extracted three times with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated to give the title compound. ES-MS m/z 515 (M+H).
Preparation of Intermediate 48: Zc'/V-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate [0158] Potassium /cr/-butoxide (9.43 g, 84.1 mmol) was added to mixture of tert-butyl (2S,4R)- 4-carbamoyl-2-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (7.63 g, 81 wt%, 12.0 mmol) in EtOH (120 mL), and the mixture was heated to 80 °C with stirring for 16 h. The reaction mixture was cooled to RT, then water (500 mL), EtOAc (50 mL), and sat. aq. NaCl (50 mL) were added and layers were separated. The aqueous layer was extracted with EtOAc (3 * 100 mL). The organic layers were combined, dried with Na2SO4, and concentrated to give the title compound (5.89 g) as a solid. ES-MS m/z 497 (M+H).
Preparation of Intermediate 49: (5R,7S)-7-Methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-2-en-4-one dihydrochloride
[0159] HC1 (4 M solution in 1,4-di oxanes, 11.9 mL, 47.6 mmol) was added to tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-2-ene-8-carboxylate (5.89 g, 11.9 mmol) dissolved in DCM (119 mL) and the mixture was stirred at RT. After 16 h, EtOAc (200 mL) was added and the mixture was fdtered. The solid was dried for 2 h at 50 °C under reduced pressure to give the title compound (5.02 g) as a solid. ES-MS m/z 397 (M+H).
Preparation of Intermediate 50: 4-(4-Iodo-3-methylphenyl)morpholin-3-one
[0160] The title compound was prepared as described in the Preparation of Intermediate 17 using l-bromo-4-iodo-2-m ethylbenzene. ES-MS m/z 318 (M+H).
Preparation of Intermediate 51 : 4-(3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl )pheny l)morpholin-3 -one
[0161] The title compound was prepared as described in the Preparation of Intermediate 18 using 4-(4-i odo-3 -methylphenyl )morpholin-3 -one, stirring the reaction at 110 °C for 16 h, and purifying the product by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane. ES-MS m/z 318 (M+H).
Preparation of Intermediate 52: 3-Bromo-2-(trimethylsilyl)phenol
[0162] Bis(trimethylsilyl)amine (110 mL, 503 mmol) at 20 °C was added to a solution of 3- bromophenol (50 g, 270 mmol) in THF (500 mL) and the mixture was stirred at 50 °C. After 16 h, the reaction mixture was concentrated under reduced pressure, then THF (300 mL) was added followed by lithium diisopropylamide (410 mL, 2 M solution, 820 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h, then at 0 °C for 3 h. The mixture was quenched with sat. aq. NH4CI (1000 mL) and then extracted with EtOAc (3 x 500 mL). The organic layers were washed with sat. aq. NaCl (800 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel using a gradient of 0 to 5% EtOAc in PE to give the title compound (30.0 g) as an oil. ES-MS m 'z 243 (M-H).
Preparation of Intermediate 53: 4-(3'-Hydroxy-2-methyl-2'-(trimethylsilyl)-[l,r-biphenyl]-4- yl)morpholin-3 -one
[0163] Pd(dppf)Ch (2.64 g, 3.61 mmol) was added to a mixture of 3-bromo-2-
(trimethylsilyl)phenol (14.0 g, 36.0 mmol), 4-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)morpholin-3-one (14.2 g, 44.3 mmol), and K2CO3 (15.6 g, 107 mmol) in 1 ,4-di oxane (100 mL) and water (10 mL), and the system was de-gassed and refilled with nitrogen for three times. The reaction mixture was stirred and heated to 100 °C under nitrogen. After 16 h, the residue was poured into water (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with sat. aq. NaCl (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10 to 25% EtOAc in PE to give the title compound (10.3 g) as a solid. ES-MS m'z 356.
Preparation of Intermediate 54: 4-(4'-Bromo-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l,r- biphenyl]-4-yl)morpholin-3-one
[0164] NBS (5.11 g, 27.3 mmol) was added to a -60 °C mixture of 4-(3'-hydroxy-2-methyl-2'- (trimethylsilyl)-[l,l'-biphenyl]-4-yl)morpholin-3-one (10.3 g, 22.6 mmol) in DCM (100 mL) and the reaction mixture was stirred vigorously at -60 °C for 1 h. The mixture was washed with water (100 mL) and extracted with DCM (3 x 50 mL). The organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: Phenomenex luna C18 250mm x 100mm, 15 pm; mobile phase: solvent A - 0.2% aq. FA, solvent B - ACN; gradient: 40 to 75% solvent B in solvent A] to give the title compound (2.6 g) as a solid. ES-MS m/z 434, 436 (M+H).
Preparation of Intermediate 55: 4-(4'-Cyclopropyl-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l,T- biphenyl]-4-yl)morpholin-3-one
[0165] Chloro(crotyl)(tri-te/7-butylphosphine)palladium(II) (0.40 g, 0.91 mmol) was added to a mixture of 4-(4'-bromo-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l,T-biphenyl]-4-yl)morpholin- 3-one (2.00 g, 4.59 mmol), cyclopropylboronic acid (1.01 g, 11.2 mmol), and K2CO3 (2.65 g, 18.2 mmol) in 1,4-dioxane (20 mL). The reaction vessel was de-gassed and refilled with nitrogen three times. The reaction mixture was stirred and heated to 100 °C under nitrogen for 2 h, then washed with water (30 mL). The product was extracted with EtOAc (3 x 20 mL). The organic layers were washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25 to 60% EtOAc in PE gradient) to give the title compound (1.30 g) as a solid. ES-MS m z 396 (M+H).
Preparation of Intermediate 56: 4-Cyclopropyl-2'-methyl-4'-(3-oxomorpholino)-2- (trimethylsilyl)-[l, l'-biphenyl]-3-yl trifluoromethanesulfonate
[0166] N-Phenyl-bis(trifluoromethanesulfonimide) (4.2 g, 11 mmol) at 0 °C was added to a mixture of 4-(4'-cyclopropyl-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l, l'-biphenyl]-4- yl)morpholin-3-one (1.2 g, 2.6 mmol) and K2CO3 (3.1 g, 21 mmol) in ACN (10 mL), and the reaction mixture was stirred vigorously at 80 °C. After 16 h, the mixture was poured into water (20 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organics were washed with sat. aq. NaCl (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC using a gradient of 60 to 95% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.954 g) as a solid. ESMS m/z 528 (M+H).
Preparation of Intermediate 57: (5R,7S)-8-(5-Chloro-2-methoxyphenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers) [0167] To a vial containing toluene (10 mL) was added (5R,7S)-7-methyl-2-(2-(tetrahydrofuran- 2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 1010 mg, 2630 pmol). Next was added 2-bromo-4-chloro-l -methoxybenzene (1200 mg. 5310 umol), followed by sodium 2-methylbutan-2-olate in THF (5.30 mL, 30 wt%, 1330 umol) and methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'- bis(dimethylamino)-l,l'-biphenyl )(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (620 mg, 533 pmol) at 25 °C. The mixture was purged with nitrogen for 3 min before vigorously stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography using a 12 g silica column and eluent of 45 to 60% EtOAc/PE gradient. This gave the title compound (440 mg) as a solid. ES-MS m z 523 (M+H).
Preparation of Intermediate 58: (5R,7S)-8-(5-Chloro-4-fluoro-2-methoxyphenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one
(mixture of isomers)
[0168] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 600 mg, 1.44 mmol) was added to a vial containing toluene (6mL). Next, l-bromo-5-chloro-4-fluoro-2-methoxybenzene (530 mg, 2.17 mmol) and sodium 2-methylbutan-2-olate (30 wt% in THF, 1605 mg, 4.37 mmol) were added at 26 °C. The mixture was purged with nitrogen for 2 min before and after adding methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'- bis(dimethylamino)-l,l '-biphenyl )(2'-methylamino-l,T-biphenyl-2-yl)palladium(II) (338 mg, 0.29 mmol). The reaction mixture was then stirred vigorously at 100 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue which was purified by reverse phase prep-HPLC using a gradient of 15 to 55% ACN in 0.2% aq. FA to give the title compound (165 mg) as a solid. ES-MS m/z 541 (M+H). Preparation of Intermediate 59: 2-Bromo-l,3-dimethyl-5-vinylbenzene
[0169] A mixture of methyl triphenylphosphonium bromide (180 g, 499 mmol) and THF (400 mb) was cooled to -70 °C. The system was de-gassed by placing under vacuum then backfilled with nitrogen for three times. n-Butyllithium as a 2.5 M in THF (200 mL, 500 mmol) was added dropwise over the course of 50 min. The reaction mixture was stirred at -70 °C for 2 h under nitrogen, then a solution of 4-bromo-3,5-dimethylbenzaldehyde (75 g, 0.35 mol) in THF (100 mL) was added dropwise to the mixture at -70 °C over 50 min. The reaction mixture was warmed to 25 °C and stirred for 12 h, then quenched by adding 300 mL sat. aq. NH4CI solution at 0 °C under nitrogen, and then extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc / PE to give the title compound (35 g) as a liquid. ES-MS m/z 211 (M+H).
Preparation of Intermediate 60: (S)-l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol
[0170] AD-mix-alpha (Sigma-Aldrich catalog number 392758, 1860 mg) was added to a vial which was then placed under vacuum and backfilled with nitrogen three times before and after adding tert-butanol (10 mL) and H2O (10 mL). The reaction mixture was cooled to 0 °C, and 2- bromo-l,3-dimethyl-5-vinylbenzene (283 mg, 1.27 mmol) was added. The mixture was warmed to 27 °C and stirred for 12 h under nitrogen. The reaction mixture was poured into 20 mL H2O and then extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with sat. aq. NaCl (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc = 1/2, R/= 0.6) to give the title compound (175 mg) as a solid. 'H-NMR (400 MHz, CDCI3) 8 7.08 (s, 2H), 4.74 (dd, J = 3.5, 8.0 Hz, 1H), 3.81 - 3.71 (m, 1H), 3.69 - 3.59 (m, 1H), 2.43 (s, 6H). Preparation of Intermediate 61 : 4-Chloro-2-((5R,7S)-7-methyl-4-oxo-2-(2-((tetrahydrofuran-2- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (mixture of isomer)
[0171] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 4.0 g, 8.5 mmol) was added to a flask containing DMSO (50 mL). Next was added 4-chloro-2-fluoro-benzonitrile (1.65 g, 10.4 mmol) and K3PO4 (8.1 g, 46 mmol) at 20 °C. The mixture was purged with nitrogen for 2 min then stirred vigorously at 130 °C for 12 h. The reaction mixture was cooled to RT and filtered through diatomaceous earth, eluting with MeOH (20 mL). The filtrate was concentrated to give a residue that was purified using reverse phase prep-HPLC using a gradient of 40 to 90% ACN in 0.2% aq. FA to give the title compound (410 mg) as a solid. ES-MS m 'z 518 (M+H).
Preparation of Intermediate 62: 2-((5R,7S)-7-Methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (tri fluoromethyl )pyri din-3 -yl)-l, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-4-(4, 4, 5, 5-tetramethyl- 1,3, 2- dioxaborolan-2-yl)benzonitrile (mixture of isomers)
[0172] 4-Chloro-2-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (mixture of isomers, 400 mg, 767 pmol) was added to a vial containing methoxycyclopentane (5 mL). Next, bis(pinacolato)diborane (410 mg, 1.58 mmol) and potassium acetate (243 mg, 2.45 mmol) were added at 27 °C. The mixture was purged with nitrogen for 2 min and then methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'-methylamino-l,l'-biphenyl-2- yl)palladium(II) (89 mg, 0.10 mmol) was added and the reaction was heated to 80 °C and allowed to stir for 12 h under nitrogen. The reaction was then cooled to RT and filtered through diatomaceous earth. The filtrate was concentrated to give a residue which was purified by reverse phase prep-HPLC using a gradient of 45% to 85% ACN in 0.2% aq. FA to give the title compound (210 mg) as asolid. ES-MS m/r. 610 (M+H).
Preparation of Intermediate 63: 4-Bromo-2-fluoro-6-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)benzonitrile (mixture of isomers)
[0173] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 200 mg, 439 pmol) was dissolved in DMSO (1.5 mL). DIEA (383 pL, 2.20 mmol) was added to the mixture followed by 4-bromo-2,6-difluorobenzonitrile (134 mg, 615 pmol). The reaction was heated to 80 °C with stirring for 72 h, then purified directly by silica gel chromatography using a gradient of 0 to 55% EtOAc in heptanes to give the title compound (90 mg). ES-MS m z 580,582 (M+H).
Preparation of Intermediate 64: 4-Chloro-2-fluoro-6-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)benzonitrile (mixture of isomers)
[0174] To a 100 mL (1-neck) round bottom flask with a magnetic stir bar was charged with DMSO (20 mL) and (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3- yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 1.00 g, 2.12 mmol). 4-Chloro-2,6-difluoro-benzonitrile (814 mg, 4.64 mmol) was added to the mixture followed by DIEA (3.81 mL, 21.9 mmol) at 27 °C. The reaction mixture was stirred vigorously at 80 °C for 12 h, then filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 20 mL ACN. The filtrate was concentrated to give a 20 mL DMSO solution which was purified by reverse phase prep-HPLC using a gradient of 40 to 80% ACN in 0.2% aq. FA to give the title compound (350 mg) as a solid. ES-MS m/z 536 (M+H).
Preparation of Intermediate 65: l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol (racemic mixture)
[0175] To a 3 L 3-neck round bottom flask with a magnetic stir bar was charged with 2-bromo- l,3-dimethyl-5-vinylbenzene (35 g, 0.12 mol), tert-butanol (400 mL) and water (200 mL). Next, N-methylmorpholine-N-oxide (65 g, 0.53 mol) was added followed by potassium osmate (VI) dihydrate (53 g, 0.14 mol) at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 2 h. The reaction mixture was poured into 1 L sat. aq. Na2SOa water solution and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 45-60% EtOAc in PE to give the title compound (25 g) as a solid. ‘H-NMR (400 MHz, CDC13) 5 7.08 (s, 2H), 4.73 (dd, J = 3.5, 8.0 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.68 - 3.60 (m, 1H), 2.42 (s, 6H)
Preparation of Intermediate 66: l-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethane-l,2-diol (racemic mixture)
[0176] To a 250 mL (3-neck) round bottom flask was charged with l-(4-bromo-3,5- dimethylphenyl)ethane-l,2-diol (racemic mixture, 25 g, 0.10 mol) and DMF (140 mL). Next, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (55 g, 0.21 mol) was added followed by potassium acetate (33 g, 0.33 mol) at 25 °C. The system was de-gassed by placing under vacuum then backfilled with nitrogen three times before and after adding mesylate[(di(l- adamantyl)-n-butylphosphine)-2-(2'-amino-l,r-biphenyl)]palladium(II) (9.8 g, 13 mmol). The mixture was vigorously stirred at 120 °C for 2 h. The reaction mixture was poured into 1 L H2O at 25 °C and extracted with EtOAc (4 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 45-70% EtOAc in PE. The product was re-purified by reverse phase prep-HPLC using a gradient of 20 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (17 g) as a solid. 'H-NMR (400 MHz, CDCI3) 5 6.94 (s, 2H), 4.71 (dd, J = 3.6, 8.0 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.64 - 3.56 (m, 1H), 2.41 (s, 6H), 1.39 (s, 12H)
Preparation of Intermediate 67: Methyl 2-cyclopropyl-4-(trifluoromethyl)benzoate
[0177] To a 500 mL 3-neck round bottom flask was charged with toluene (250 mL) and water (30 mL), followed by the addition of methyl 2-bromo-4-(trifluoromethyl)benzoate (15.3 g, 53.0 mmol), cyclopropaneboronic acid (6.9 g, 79 mmol), tricyclohexyl phosphine, (1.54 g, 5.38 mmol), K3PO4 (33.7 g, 157 mmol) and Pd(OAc)2 (716 mg, 3.13 mmol) at 24 °C. The reaction mixture was de-gassed by evacuation under vacuum and refilling with nitrogen 3 times then stirred vigorously at 92 °C for 16 h. The reaction mixture was cooled to 24 °C and poured into water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with sat. aq. NaCl (120 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in PE to give the title compound (10.3 g) as an oil. ES-MS m/z 245 (M+H).
Preparation of Intermediate 68: 2-Cyclopropyl-4-(trifluoromethyl)benzoic acid [0178] To a 250 mL 3-neck round bottom flask was charged with MeOH (100 mL) and water (20 mL), followed by the addition of methyl 2-cyclopropyl-4-(trifluoromethyl)benzoate (10.2 g, 40.0 mmol) and lithium hydroxide monohydrate (4.76 g, 108 mmol) at 12 °C in an ice-water bath. The reaction mixture was stirred vigorously at 26 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue which was then diluted with 50 mL water and the pH was adjusted to 2 with 2 N aq. HC1 (76 mL). Precipitation was observed and the solid filtered via suction filtration, and the filter cake was washed with water (65 mL). The solid was dried under reduced pressure at 45 °C to give the title compound (9.1 g) as a solid. ES-MS mz 229 (M-H).
Preparation of Intermediate 69: /e/V-Butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-4- (trifluoromethyl)benzamido)-2-methylpiperidine- 1 -carboxylate
[0179] To a 100 mL 3-neck round bottom flask was charged with DMF (50 mL) and 2- cyclopropyl-4-(trifluoromethyl)benzoic acid (4.92 g, 20.2 mmol), followed by the addition of HATU (9.51 g, 24.8 mmol) and DIEA (9.6 mL, 54 mmol) at 15 °C. The reaction mixture was stirred vigorously at 15 °C for 15 min. Next, /c/7-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (6.26 g, 23.1 mmol) was added in portions over 2 min at 15 °C. The reaction mixture was stirred vigorously at 26 °C for 2 h. The reaction mixture was poured into 200 mL ice water and stirred for 30 min which resulted in the formation of a precipitate. The solid was filtered via suction filter and washed with 150 mL water. The solid was dried under reduced pressure at 45 °C to give the title compound (10.3 g) as a solid. ES-MS m/z 414 (M-tBu+H).
Preparation of Intermediate 70: /cvz-Butyl (5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)- 7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0180] To a 500 mL 3-neck round bottom flask was charged with THF (100 mL), followed by the addition of tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-4-(trifluoromethyl)benzamido)- 2-methylpiperidine-l -carboxylate (10.3 g, 19.6 mmol). A solution of potassium tert-butoxide in tert-butanol (1 M solution, 99.0 mL, 99.0 mmol) was added in one portion at 28 °C. The reaction mixture was stirred vigorously at 70 °C for 2 h, then cooled to 28 °C and concentrated. Ice water (220 mL) was added to the residue and extracted with DCM (3 * 110 mL). The combined organic layers were washed with sat. aq. NaCl (80 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0- 100% EtOAc in PE to give the title compound (8.4 g) as a solid. ES-MS m'z 452 (M+H).
Preparation of Intermediate 71: (5R,7S)-2-(2-Cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -en -4-one dihydrochloride
2HCI
[0181] To a 250 mL one-neck round bottom flask with a magnetic stir bar was charged with 1,4- di oxane (40 mL), followed by the addition of tert-butyl (5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (8.40 g, 17.6 mmol). A solution of HC1 in 1,4-dioxane (4 M, 60 mL, 0.24 mol) was added in one portion at 28 °C, then the mixture was stirred vigorously at 28 °C for 2 h. The reaction mixture was concentrated, then water (80 mL) was added and the mixture was lyophilized to give the title compound (7.6 g) as a solid. ES-MS m/'z 352 (M+H).
Preparation of Intermediate 72: 4-Bromo-2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzamide
[0182] To a 100 mL (3 -neck) round bottom flask was charged with DMSO (30 mL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (1.50 g, 3.23 mmol), 4-bromo-2,6- difluorobenzamide (924 mg, 3.84 mmol) and K2HPO3 (6.95 g, 39.5 mmol) at 22 °C. The reaction mixture was stirred vigorously at 145 °C for 24 h, then 100 mL ice water was added and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with sat. aq. NaCl (60 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in PE to give the title compound (523 mg) as a solid. ES-MS m/z 567, 569 (M+H).
Preparation of Intermediate 73 : Methyl 2-cyclopropyl-6-methoxynicotinate
[0183] To a 250 mL (1-neck) round bottom flask was charged with toluene (75 mL), 2-chloro-3- (methoxycarbonyl)-6-methoxypyridine (5.00 g, 24.6 mmol), cyclopropaneboronic acid (5.34 g, 61.5 mmol) and K2CO3 in H2O (2 M, 25.0 mL, 50.0 mmol). The system was de-gassed by applying vacuum then backfilled with nitrogen for three times before and after adding Pd(dppf)Ch (1.00 g, 1.35 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h under nitrogen. The reaction mixture was cooled to 27 °C then diluted with 100 mL H2O and 100 mL EtOAc. The mixture was extracted with EtOAc (100 mL x 2), then the combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (550 mg) as a solid. ESMS m z. 208 (M+H).
Preparation of Intermediate 74: 2-Cyclopropyl-6-methoxynicotinic acid
[0184] To a vigorously stirred MeOH (10 mL) and water (5 mL) solution of methyl 2- cyclopropyl-6-methoxyni cotinate (550 mg, 2.60 mmol) in a 100 mL (1-neck) round bottom flask was added NaOH (750 mg, 18.6 mmol) in one portion at 27 °C, and mixture was stirred at 27 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the solution was adjusted to pH=3 with 1 N HC1 (20 mL) with stirring resulting in a precipitate. The mixture was filtered, the filter cake was rinsed with 10 mL H2O, then the filter cake was collected and dried under reduced pressure at 45 °C to give the title compound (500 mg) as a solid. ES-MS m/z 194 (M+H).
Preparation of Intermediate 75: te/7-Butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- methoxynicotinamido)-2-methylpiperidine-l-carboxylate
[0185] To a 40 mL vial was charged with DMF (10 mL), followed by the addition of 2- cyclopropyl-6-methoxynicotinic acid (350 mg, 1.79 mmol), /cv7-butyl (2S,4R)-4-amino-4- carbamoyl-2-methylpiperidine-l -carboxylate (551 mg, 2.12 mmol), HATU (1.05 g, 2.73 mmol) and DIEA (940 pL, 5.41 mmol) at 27 °C. The reaction mixture was stirred vigorously at 27 °C for 6 h, then poured into 30 mL water, diluted with 30 mL EtOAc and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (30 mL x 2), then sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (711 mg) as a solid. ES-MS mz 433 (M+H).
Preparation of Intermediate 76: te/7-Butyl (5R,7S)-2-(2-cyclopropyl-6-methoxypyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0186] To a vigorously stirred solution of ter/-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- methoxynicotinamido)-2-methylpiperidine-l -carboxylate (711 mg, 1.53 mmol) in THF (20 mL) was added 2-methylpropan-2-olate potassium in tert-butanol (1 M solution, 8.50 mL, 8.50 mmol) in one portion at 27 °C. The reaction mixture was heated to 70 °C and stirred for 2 h then at RT overnight. The reaction mixture was poured into 40 mL water, diluted with 40 mL EtOAc and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with sat. aq. NaCl (40 mL), dried over NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (560 mg) as a solid. ES-MS m/z 415 (M+H).
Preparation of Intermediate 77: (5R,7S)-2-(2-Cyclopropyl-6-methoxypyridin-3-yl)-7-methyl- 1 ,3 ,8 -tri azaspiro [4.5]dec- 1 -en -4-one dihydrochlori de
[0187] To a 100 mL (1-neck) round bottom flask was charged with hydrogen chloride in 1,4- dioxane (4 M solution, 10 mL, 40 mmol), followed by the addition of /c/v-butyl (5R,7S)-2-(2- cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8- carboxylate (560 mg, 1.30 mmol) at 27 °C, and the reaction mixture was stirred vigorously at 27 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (500 mg) as a solid. ES-MS m,'z 315 (M+H).
Preparation of Intermediate 78: 4-Chloro-2-((5R,7S)-2-(2-cyclopropyl-6-methoxypyridin-3-yl)- 7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile
[0188] A vial was charged with DMSO (8 mL), followed by the addition of (5R,7S)-2-(2- cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (360 mg, 902 pmol), 4-chloro-2-fluoro-benzonitrile (361 mg, 2.30 mmol) and K2HPO3 (795 mg, 4.52 mmol) at 27 °C. The reaction mixture was stirred vigorously at 120 °C for 12 h, then filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL ACN. The filtrate was concentrated under reduced pressure to give an 8 mL DMSO solution which was purified by reverse phase prep-HPLC using a gradient of 35 to 75% ACN in 0.2% aq. FA to give the title (150 mg) as solid. ES-MS m/z 450 (M+H).
Preparation of Intermediate 79: 2-Bromo-6-chl oro-3 -methylphenol
[0189] To a vigorously stirred DCM (2000 mL) solution of 2-chloro-5-methylphenol (260 g, 1.79 mol) in a 10000 mL 3-neck round bottom flask was added diisopropylamine (630 mL, 4.5 mol) dropwise over 30 min at 0 °C. Next, a solution of NBS (257 g, 1.43 mol) in DCM (6000 mL) was added dropwise at 0 °C by peristaltic pump at a rate of 18 mL per min. The resulting mixture was then warmed to 25 °C and stirred for 16 h. The mixture was quenched with IM aq. NaHSCU (2000 mL) with stirring at 25 °C then layers were separated. The organics were extracted with IM aq. NaOH (1000 mL x 3). The aqueous phase was then acidified to pH 3 by the addition of concentrated H3PO4 and then extracted with cyclohexane (2000 mL x 2). The combined organic phases were washed with water then with sat. aq. NaCl (each 1000 mL), dried over Na SO4, filtered, and concentrated to give the title compound (380 g) as an oil. ES-MS m z 219 (M-H).
Preparation of Intermediate 80: (2-Bromo-6-chloro-3 -m ethylphenoxy )trimethyl silane
[0190] To a vigorously stirred solution of 2-bromo-6-chloro-3-methylphenol (380 g, 1.20 mol) in THF (1800 mL) was added bis(trimethylsilyl)amine (380 mb, 1.82 mol) in one portion at 25 °C. The resulting mixture was warmed to 70 °C and stirred for 16 h under nitrogen. The mixture was concentrated under reduced pressure to give the title compound (490 g) as an oil. 'H- MR (400 MHz, CDC13) 8 7.19 (d, 1H), 6.815 (d, 1H), 2.394 (s, 3H), 0.383 (s, 9H).
Preparation of Intermediate 81 : 6-Chloro-3-methyl-2-(trimethylsilyl)phenol
[0191] To a vigorously stirring THF (5000 mL) solution of (2-bromo-6-chloro-3- methylphenoxy)trimethyl silane (500 g, 1.11 mol) in a 10000 mL 3-neck round bottom flask was added n-butyllithium (1.6 M solution in hexanes, 1000 mL, 1.60 mol) dropwise over 60 min at - 70 °C and the mixture was stirred at -70 °C for 40 min under nitrogen. A solution of AcOH (100 mL, 1.75 mol) in THF (300 mL) was then added dropwise at -70 °C, over 20 min under nitrogen, and the resulting mixture was stirred at -70 °C for 10 min. The reaction was quenched at -70 °C with the addition of sat. aq. NaHCCL (5000 mL). The mixture was warmed to RT and poured into a separatory funnel where it was extracted with cyclohexane (2000 mL x 2). The combined organics were washed with water then with sat. aq. NaCl (each 1000 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE to give the title compound (230 g) as an oil. ES-MS m/z 213 (M-H).
Preparation of Intermediate 82: 6-Chloro-3-methyl-2-(trimethylsilyl)phenyl tri fluoromethanesulfonate [0192] A 5000 mL 3-neck bottle containing a mixture of 6-chloro-3-methyl-2- (trimethylsilyl)phenol (230 g, 1.02 mol) and DIEA (355 mL, 2.04 mol) in DCM (2000 mL) was treated with trifluoromethanesulfonic anhydride (260 mL, 1.53 mol) dropwise over 30 min at 0 °C. The mixture was then warmed to RT and stirred for 2 h. The mixture was transferred to a separating funnel along with 1000 mL heptane. The organic phase was washed with 2000 mL of 2 M aq. K2CO3, water, and sat. aq. NaCl (each 500 mL), dried over Na2SC>4, filtered, and concentrated. The product was triturated with cyclohexane 1000 mL at 25 °C with stirring for 10 min. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with PE to give the title compound (331.6 g) as an oil. 'H-NMR (400 MHz, CDCh) 8 7.33 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 2.45 (s, 3H), 0.46 - 0.41 (m, 9H).
Preparation of Intermediate 83: (5R,7S)-8-(5-Chloro-2-methylphenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0193] To a 40 mL vial with a magnetic stir bar was charged with ACN (20 mL), followed by the addition of (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 2.00 g, 4.60 mmol), 6- chloro-3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2.56 g, 7.01 mmol) and CsF (4.08 g, 26.3 mmol). The reaction mixture was bubbled with nitrogen for 4 min then stirred at 25 °C for 4 h under nitrogen. The reaction mixture was filtered through a pad of diatomaceous earth that was then rinsed with 10 mL ACN. The filtrate was concentrated under reduced pressure at 45 °C to give a residue which was purified by silica gel chromatography using a gradient of 0- 50% EtOAc in PE to give the title compound (1.7 g) as a solid. ES-MS m/z 507 (M+H). Preparation of Intermediate 84: (5R,7S)-7-Methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0194] To a 100 mL round bottom flask with a magnetic stir bar was charged with methoxy cyclopentane (20 mL), (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(2-(tetrahydrofuran-2- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 1.7 g, 2.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.30 g, 5.02 mmol) and potassium acetate (0.81 g, 7.8 mmol). The system was de-gassed by placing under vacuum then backfilled with nitrogen three times before and after adding methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (0.24 g, 0.27 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h under nitrogen. The mixture was filtered through a diatomaceous earth pad, washed with MeOH (15 mL x 3) and the filtrate was concentrated to give a product which was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in PE to give the title compound (1.2 g) as an oil. ES-MS m/z 599 (M+H).
Preparation of Intermediate 85: 2-(4-Bromo-3,5-difluorophenyl)-2-hydroxyacetonitrile (racemic mixture)
[0195] To a vigorously stirred mixture of H2O (5 mL) and 4-bromo-3,5-difluorobenzaldehyde (1.00 g, 4.30 mmol) in a 100 mL 3-neck round bottom flask was added sodium hydrogen sulfite (0.940 g, 8.58 mmol) in H2O (2.5 mL) dropwise over 5 min at 0 °C. Then NaCN (0.450 g, 8.72 mmol) in H2O (2.5 mL) was added dropwise to the reaction mixture over 5 min at 0 °C, then warmed to RT and stirred for 16 h. A precipitate formed which was filtered, then the filter cake was rinsed with 30 mL water, then collected to give the title compound (1.1 g) as a solid. 1H- NMR (400 MHz, DMSC ,) 8 7.37 (d, J = 7.6 Hz, 2H), 5.83 (s, 1H).
[0196] The intermediates in the following table were prepared as described in the Preparation of
Intermediate 85 using the appropriate aldehyde: a. Aqueous workup as follows: the reaction mixture was poured into water and extracted with DCM twice, and the organics were dried over Na2SC>4, filtered, and concentrated to give the product.
Preparation of Intermediate 88: 2-(4-Bromo-3,5-difluorophenyl)-2-hydroxyacetamide (racemic mixture)
[0197] A mixture of 1,4-dioxane (1 mL), 2-(4-bromo-3, 5 -difluorophenyl)-2-hydroxy acetonitrile (racemic mixture, 1.1 g, 2.2 mmol) and HC1 in 1,4-dioxane (4 M solution, 10 mL, 40 mmol) was obtained at 0 °C. The mixture was purged with nitrogen for 2 min then vigorously stirred at 25 °C for 2 h. The reaction mixture was quenched with 10 mL sat. aq. Na2COa at 0 °C, then diluted with 20 mL water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with sat. aq. NaCl (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with 5 mL DCM at 28 °C for 5 min, then the solid was filtered and rinsed with DCM, the filter cake was dried under reduced pressure to give the title compound (500 mg) as a solid. ES-MS m/z 266, 268 (M+H). Preparation of Intermediate 89: 2-(4-Bromo-3-fluoro-5-methylphenyl)-2-hydroxyacetamide (racemic mixture)
[0198] To a vigorously stirred solution of 2-(4-bromo-3-fluoro-5-methylphenyl)-2- hydroxyacetonitrile (racemic mixture, 1.01 g, 3.52 mmol) in water (0.2 mL) and 1,4-dioxane (1 mL) in a 100 mL 3-neck round bottom flask was added a solution of HC1 in 1,4-dioxane (4 M, 10 mL, 40 mmol) dropwise over 5 min at 0 °C. The mixture was warmed to 25 °C and stirred for 4 h. The reaction mixture was quenched by adding 50 mL sat. aq. sodium carbonate at 0 °C, then diluted with 20 mL water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over NazSCU, filtered and concentrated to give a residue which was triturated with 5 mL DCM with stirring for 30 min, then filtered and further rinsed with 5 mL DCM. The filter cake was dried under pressure to give the title compound (280 mg) as a solid. ES-MS m/z 262, 264 (M+H).
Preparation of Intermediate 90: 2-(4-Bromo-3-methylphenyl)-2-hydroxyacetamide (racemic mixture)
[0199] A 250 mL vial with a magnetic stir bar was charged with MeOH (50 mL) and DMSO (3.1 mL), followed by the addition of 2-(4-bromo-3-methylphenyl)-2-hydroxyacetonitrile (racemic mixture, 5.00 g, 16.6 mmol). A 5 N aq. solution of NaOH (17.3 mL, 86.3 mmol) was added at 25 °C. The reaction was then cooled to 0 °C and treated with H2O2 (8.58 mL, 30 wt%, 84.0 mmol) dropwise over 1 min. The reaction mixture was then warmed to 25 °C and stirred for 15 h. The reaction mixture was poured into a 0°C solution of sat. aq. NazSCL (200 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with sat. aq. NaCl (80 mL) and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in PE to give the title compound (1.50 g) as a solid. ES-MS m/z 244, 246 (M+H). Preparation of Intermediate 91: 2-Hydroxy-2-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)acetamide (racemic mixture)
[0200] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with 1,4- dioxane (30 mL) followed by the addition of 2-(4-bromo-3-methylphenyl)-2-hydroxy acetamide (racemic mixture, 1.50 g, 5.51 mmol), potassium acetate (1.685 g, 16.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.584 g, 6.113 mmol), and Pd(dppf)Ch (0.253 g, 339 pmol) at 25 °C. The system was placed under vacuum then backfilled with nitrogen three times. The reaction mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was then filtered and concentrated to give a residue which was purified by silica gel chromatography using a gradient of 0 to 50% of EtOAc in PE to give a product that was further purified via re-crystallization from PE (20 mL) at 25 °C. The solid was filtered and dried to give the title compound (1.30 g) as a solid. ES-MS m'z 292 (M+H).
Preparation of Intermediate 92: /crt-Butyl 4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (racemic mixture)
[0201] To a vial was charged with DMF (20 mL), followed by the addition of tert-butyl 4- amino-4-carbamoyl-piperidine-l-carboxylate (1 g, 4 mmol), 2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinic acid (racemic mixture, 0.95 g, 3.6 mmol) and DIEA (3 mL, 0.02 mol) at 25 °C. Next, HATU (5 g, 0.01 mol) was added into the mixture at 0 °C. The reaction mixture was then warmed back to RT and stirred vigorously for 4 h. The reaction mixture was quenched by adding 30 mL H2O at 25°C, and then diluted with 30 mL EtOAc and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with aqueous NH4CI (30 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was dissolved in EtOH (10 mL) and 2- methylpropan-2-olate potassium in /c'/V-butanol (I M solution, 10 mL, 10 mmol) was added at 25 °C. The reaction mixture was stirred vigorously at 70 °C for 6 h then at RT overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in PE to give the title compound (400 mg) as a solid. ESMS m/z 413 (M-zBu+H).
Preparation of Intermediate 93: 2-(2-(Tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyri din-3 -yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (racemic mixture)
[0202] To a vial was charged with EtOAc (4 mL), followed by the addition of Zc/'Z-butyl 4-oxo- 2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8- carboxylate (racemic mixture, 400 mg, 854 pmol) and HC1 in 1,4-dioxane (4 M solution, 2.74 mL, 11.0 mmol) at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 2 h, then concentrated under reduced pressure to give the title compound (420 mg) as a solid. ES-MS m z 369 (M+H).
Preparation of Intermediate 94: 8-(5-Chloro-2-methylphenyl)-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (racemic mixture)
[0203] A mixture of ACN (4 mL), 2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (racemic mixture, 420 mg, 863 pmol), 6- chloro-3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (450 mg, 1.23 mmol) and CsF (585 mg, 3.83 mmol) was stirred vigorously at 25 °C for 3 h. The reaction mixture was filtered through a pad of diatomaceous earth and rinsed with ACN (10 mL). The filtrate was concentrated and the residue was purified by reverse phase prep-HPLC using a gradient of 55- 85% ACN in 10 mM aq. NH4HCO3 to give the title compound (150 mg) as a solid after lyophilization. ES-MS m/z' 493 (M+H).
Preparation of Intermediate 95: te/7-Butyl 2-ethyl-4-oxopiperi dine- 1 -carboxylate (Isomer 1)
[0204] Step 1 - Preparation of l-benzyl-2-ethylpiperidin-4-one (2R,3R)-2, 3- bis(benzoyloxy)succinate (Isomer 1): A mixture of l-benzyl-2-ethylpiperidin-4-one (racemic mixture, 20.00 g, 92.03 mmol) and ACN (300 mb) was heated to 45 °C for 10 min, then (-)- dibenzoyl-L-tartaric acid (14.60 g, 40.75 mmol) was added and the mixture was stirred for 1 h at 45 °C. The mixture was cooled to 25 °C over 0.5 h and then stirred for 16 h. The mixture was filtered and the filter cake was washed with ACN (20 mL). The solid was dried at 45 °C under reduced pressure, then recrystallized from 20:0.5 methyl ethyl ketone : water (595 mL) by dissolving the solid at 65 °C and cooling to 25 °C over 16 h. The mixture was filtered and the filter cake was washed with methyl ethyl ketone (20 mL) and dried under reduced pressure at 45 °C for 1 h to give a first crop (13.0 g) of l-benzyl-2-ethylpiperidin-4-one (2R,3R)-2,3- bis(benzoyloxy)succinate (Isomer 1). The mother liquors from the salt formation and recrystallization were combined and the freebase of the starting material (16 g) was recovered using 5% aq. Na2COs. To this material was added ACN (240 mL) and the mixture was stirred for 10 min at 45 °C. The salt formation (with (-)-dibenzoyl-L-tartaric acid, 14.60 g, 40.75 mmol), crystallization, solid collection, and recrystallization from 20:0.5 methyl ethyl ketone : water (410 mL) steps were repeated as described above to give a second crop (10.5 g) of 1- benzyl-2-ethylpiperidin-4-one (2R,3R)-2,3-bis(benzoyloxy)succinate (Isomer 1).
[0205] Step 2 - Preparation of l-benzyl-2-ethylpiperidin-4-one (Isomer 1): to a mixture of 1- benzyl-2-ethylpiperidin-4-one (2R,3R)-2,3-bis(benzoyloxy)succinate (Isomer 1, 23.5 g, 40.8 mmol) in water (50 mL) was added 5% aq. Na2CO3 to adjust the pH to 10. The mixture was extracted with EtOAc (3 x 200 mL), then the combined organics were dried over Na2SO4, filtered, and concentrated to give 1 -benzyl -2-ethylpiperidin-4-one (Isomer 1, 8.5 g). [0206] Steps 1 and 2 were repeated starting with 54.0 g of l-benzyl-2-ethylpiperidin-4-one (racemic mixture) to give 1 -benzyl -2-ethylpiperidin-4-one (Isomer 1, 21.9 g).
[0207] Step 3 - Preparation of tert-butyl (S)-2-ethyl-4-oxopiperidine-l -carboxylate: to a 1000 mL flask equipped with a H2 inlet was added l-benzyl-2-ethylpiperidin-4-one (Isomer 1, 24.50 g, 112.7 mmol) followed by EtOAc (245 mL). The solution was then treated with di -tert-butyl dicarbonate (49.50 g, 226.8 mmol) and palladium on carbon (12.50 g, 10 wt%, 11.75 mmol).
The resulting suspension was stirred at 25 °C, under H2 at 345 kPa for 16 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated, and purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in PE to give the title compound (28.0 g) as an oil. ES-MS m z 172 (MrtBu+H).
Preparation of Intermediate 96: tert-Butyl (2S)-4-amino-4-carbamoyl-2-ethylpiperidine-l- carboxylate (mixture of isomers)
[0208] A 1000 mL three necked flask was fitted with a nitrogen outlet connected to an aq. NaOH trap, magnetic stirrer and thermometer, then to the flask was added tert-butyl 2-ethyl-4- oxopiperidine-l-carboxylate (Isomer 1, 22.0 g, 96.79 mmol) and MeOH (176 mL). The resulting solution was treated with ammonium acetate (63.5 g, 823.8 mmol) followed by KCN (9.50 g, 146 mmol) at 25°C. The reaction was stirred for 16 h at 40 °C then DMSO (12 mL) was added and the mixture was cooled to 10 °C and treated with a solution of NaOH in water (154.9 mL, 5 molar, 774.3 mmol). The reaction mixture was stirred for 10 min then H2O2 in water (12.85 mL, 30 wt%, 125.8 mmol) was added dropwise. The mixture was stirred for 4 h at 25 °C then quenched by the addition of added sat. aq. sodium thiosulfate (200 mL) and stirring continued for 10 min. The reaction was then partially concentrated to remove MeOH and the remaining solution was extracted with DCM (200 mL x 3). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and the filtrate concentrated to give the title compound (34 g). ES-MS m z 272 (M+H). Preparation of Intermediate 97: /c/7-Butyl 4-amino-4-carbamoyl-2-ethylpiperidine-l-carboxylate (Isomer 1)
[0209] To a 250 mL three necked flask was added /c/7-butyl 4-amino-4-carbamoyl-2- ethylpiperidine-1 -carboxylate (mixture of isomers, 26 g, 96 mmol) in MTBE (130 mL) to give a white suspension which was stirred at 25 °C for 16 h. The mixture was cooled down to 0 °C and stirred for 2 h. The solid was filtered and washed with MTBE (26 mL). The solid was triturated with MTBE (28 mL * 2) at 0 °C with 2 h of stirring, then purified by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give the title compound (7 g). ES-MS m z 272 (M+H).
Preparation of Intermediate 98: Zc'/V-Butyl 4-carbamoyl-2-ethyl-4-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l-carboxylate (mixture of isomers)
[0210] To a 100 mL round bottom flask was charged with DMF (40 mL), followed by the addition of 2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture, 2.02 g, 7.69 mmol), te/7-butyl 4-amino-4-carbamoyl-2-ethylpiperidine-l-carboxylate (Isomer 1, 2.07 g, 7.63 mmol), HATU (4.42 g, 11.5 mmol) and DIEA (4.10 mL, 23.3 mmol) at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 2 h. The reaction mixture was quenched by adding 60 mL water at 25 °C, and then diluted with 40 mL water and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in PE to give the title compound (4.35 g) as a solid. ES-MS m,'z 515 (M+H). Preparation of Intermediate 99: iter/-Butyl 7-ethyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers)
[0211] A mixture of THF (40 mL), te/7-butyl 4-carbamoyl-2-ethyl-4-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (racemic mixture, 4.35 g, 7.63 mmol) and KO/Bu (I M solution in Zc/7-butanol, 40 mL, 40 mmol) was stirred vigorously at 80 °C for 12 h. The reaction mixture was quenched by adding 80 mL water at 25 °C, and then further diluted with 80 mL water and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, fdtered, and the fdtrate was concentrated. The residue was purified by silica gel chromatography using a 40 g silica column and eluting with a gradient of 0 to 40% EtOAc in PE to give the title compound (2.86 g) as a solid. ES-MS m,'z 497 (M+H).
Preparation of Intermediate 100: 7-Ethyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin- 3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0212] A mixture of 1,4-dioxane (10 mL), /c77-butyl 7-ethyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)- 6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers, 2.86 g, 5.70 mmol) and 4 M HC1 in 1,4-dioxane (19 mL, 76 mmol) was stirred vigorously at 25 °C for 12 h The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase prep-HPLC using a gradient of 20 to 50% MeOH in water to give the title compound (1.80 g) as a solid. ES-MS m'z 397 (M+H). Preparation of Intermediate 101 : 8-(5-Chloro-3-fluoro-2-methoxyphenyl)-7-ethyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0213] A mixture of toluene (10 mL), 7-ethyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 500 mg, 1.24 mmol), l-bromo-5-chloro-3-fluoro-2 -methoxybenzene (760 mg, 3.14 mmol), sodium 2- methylbutan-2-olate (30 wt% in THF, 2.49 mL, 6.244 mmol) and methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (290 mg, 249 pmol) was purged with nitrogen for 2 min then vigorously stirred at 100 °C for 3 h under nitrogen. The reaction mixture was cooled to RT, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in PE to give the title compound (170 mg) as a solid. ES-MS m/z 555 (M+H).
Preparation of Intermediate 102: (5R,7S)-8-(5-Chloro-2-fluorophenyl)-7-methyl-2-(2- (trifhjoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0214] To a resealable tube under nitrogen atmosphere was charged with (5R,7S)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (100.4 mg, 321.5 pmol), anhydrous toluene (1.072 mL), methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l, l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (CAS# 1810068-35-9, 37.1 mg, 31.9 pmol) and 2- bromo-4-chl oro-1 -fluoro-benzene (138.8 mg, 643.0 pmol). The tube was purged with nitrogen, then sodium 2-methylbutan-2-olate in THF (2.5 M solution, 514.4 pL, 1.286 mmol) was added and the mixture was stirred at RT while purging with nitrogen for 2 min. The tube was sealed, and the mixture was stirred at 100 °C. After 8 h, the reaction was cooled to RT and diluted with aq. citric acid (5%) and EtOAc. The aqueous layer was separated, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous sodium sulphate, fdtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 20 to 40 % EtOAc in DCM to give the title compound (8.5 mg) as a solid. ES-MS m/z 441, 443 (M+H).
Preparation of Intermediate 103: (5R,7S)-8-(5-Chloro-2-methylphenyl)-7-methyl-2-(2-
(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0215] To a mixture of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (1.09 g, 2.83 mmol) suspended in ACN (20 mL) with CsF (2.58 g, 17.0 mmol) was added 6-chloro-3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1.47 g, 4.24 mmol) and the mixture was stirred at RT under nitrogen for 8 h. The mixture was concentrated under reduced pressure, then diluted with water and extracted three times into EtOAc. The combined organics were washed with sat. aq. NaCl, dried over Na SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (550 mg). ESMS m/z 437 (M+H).
Preparation of Intermediate 104: (5R,7S)-7-Methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one
[0216] A mixture of bis(pinacolato)diborane (350 mg, 1.38 mmol), K2CO3 (299 mg, 2.17 mmol), (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (430 mg, 984 pmol), chloro(crotyl)(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l,r-biphenyl) palladium(II) (XPhos Pd(crotyl)Cl, CAS# 1798782-02-1, 33.2 mg, 49.2 pmol) and 2-methyltetrahydrofuran (10 mL) was purged with nitrogen for 10 min, then 2-ethyl hexanoic acid (7.10 mg, 7.84 pL, 49.2 pmol) was added and the mixture was heated to 50 °C for 12 h. The reaction mixture was filtered through a pad of diatomaceous earth and rinsed with EtOAc (3 x 15 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 50 to 100% EtOAc in cyclohexanes to give the title compound (454 mg). ES-MS m/'z 529 (M+H).
Preparation of Intermediate 105: Methyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzoate
[0217] To a 500 mL round bottom flask was added 1,4-di oxane (250 mL), methyl 4-bromo-3,5- dimethylbenzoate (10.0 g, 39.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (11.0 g, 41.2 mmol) and potassium acetate (12.0 g, 116 mmol). The system was de-gassed and backfilled with nitrogen three times before and after adding bis(triphenylphosphine)palladium(II) chloride (1.50 g, 2.03 mmol). Then the reaction mixture was heated to 90 °C and allowed to stir for 16 h under nitrogen. The reaction mixture was poured into water (500 mL) at RT and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in PE to give the title compound (5 g) as a solid. ES-MS m/z 291 (M+H).
Preparation of Intermediate 106: l,3-Dioxoisoindolin-2-yl (lS,2S)-2-fluorocyclopropane-l- carb oxy late [0218] To a 1000 mL three-neck round bottom flask containing a mixture of (lS,2S)-2- fluorocyclopropane-1 -carboxylic acid (50.0 g, 471 mmol) in DCM (500 mL) was added di cyclohexylcarbodiimide (104 g, 479 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min, then 2-hydroxyisoindoline-l, 3-dione (101 g, 588 mmol) was added. The mixture was de-gassed and backfilled with nitrogen three times, then stirred at 25 °C for 12 h under nitrogen. The reaction mixture was quenched by adding 500 mL H2O at 25 °C, and then extracted with DCM (300 mL x 3). The combined organic layers were washed with sat. aq. NaCl (500 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 45% EtOAc in PE to give the title compound (51 g) as a solid. ES-MS m/z 250 (M+H).
Preparation of Intermediate 107: 2-((2S)-2-Fluorocyclopropyl)-6-(trifluoromethyl)nicotinic acid (Isomer 1)
[0219] To a mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (23.2 g, 97.7 mmol), 1,3- dioxoisoindolin-2-yl (lS,2S)-2-fluorocyclopropane-l-carboxylate (20.0 g, 64.6 mmol), 2,2'- bipyridine (2.16 g, 13.1 mmol), and nickel(II) chloride hexahydrate (3.22 g, 12.9 mmol) was added anhydrous DMF (300 mL). The mixture was stirred until all solids were dissolved, then silver nitrate (5.61 g, 31.4 mmol) was then added. The reaction vessel was closed with a magnesium sacrificial anode and a CF cathode (3 mm x 7 mm x 51 mm). The vial was then placed on an UCA ElectraSyn 2.0 stir plate and electrolysis was set to 12 mA, 0.4 mmol, 2.5 F/mol providing 5.4 A/m2 current density. The mixture was stirred at 26 °C for 4 h, then left at RT over the weekend. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC using a gradient of 30 to 60% ACN in 0.1% aq. tri fluoroacetic acid to give the title compound (2.2 g) as a solid. ES-MS m z 248 (M+H).
Preparation of Intermediate 108: 2-((2S)-2-Fluorocyclopropyl)-6-(trifluoromethyl)nicotinoyl chloride (Isomer 1)
[0220] To thionyl chloride (12 mL, 0.16 mol) was added 2-((2S)-2-fhiorocyclopropyl)-6- (trifluoromethyl)nicotinic acid (Isomer 1, 1.00 g, 3.95 mmol) at 26 °C. The system was degassed and refdled with nitrogen three times. Then the reaction mixture was allowed to stir vigorously at 26 °C for 2 h under nitrogen, then concentrated under reduced pressure to give the title compound (1.1 g) as a solid. A sample dissolved in MeOH shows ES-MS m/z 264 (methyl ester M+H).
Preparation of Intermediate 109: (5R,7S)-2,2,7-Trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride
[0221] To a mixture of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (60.0 g, 233 mmol) dissolved in EtOH (1000 mL) was added 2,2-dimethoxypropane (74.4 g, 700 mmol) and toluenesulfonic acid (9.06 g, 46.7 mmol) and the mixture was heated at 80 °C. After 16 h, the reaction was cooled to RT and HCI (4 M solution in 1,4-dioxane, 176 mL, 704 mmol) was added. The mixture was stirred at 20 °C for 16 h, and the solvent was removed under reduced pressure. After 2/3 of the liquid was removed from the flask a solid precipitate formed in the solution. 1000 mL of EtOAc was added and more material precipitated. The solid was fdtered off and dried for 30 min to give the title compound (65 g) as a solid. ES-MS m/z' 198 (M+H).
Preparation of Intermediate 110: (5R,7S)-8-(5-Iodo-2-methylphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5 ]decan-4-one [0222] To a solution of (5R,7S)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (30.0 g, 85.7 mmol) and 2-bromo-4-iodo-l -methylbenzene (94 g, 0.31 mol) in 1,4-dioxane (300 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 1.00 L, 1.00 mol) dropwise over 30 min at 25 °C. The reaction vessel was de-gassed and refdled with nitrogen three times. The resulting mixture was stirred at 80 °C for 2 h with a refluxing condenser. The reaction mixture was left at RT overnight, then poured into 1000 mL H2O at 25 °C, and then extracted with EtOAc (400 mL x 3). The combined organic layers were washed with sat. aq. NaCl (500 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in PE to give the title compound (14 g) as a solid. ES-MS m z 414 (M+H).
Preparation of Intermediate 111 : (2S,4R)-4-Amino-l-(5-iodo-2-methylphenyl)-2- methylpiperidine-4-carboxamide
[0223] To a 500 mL three-neck round bottom flask containing a mixture of (5R,7S)-8-(5-iodo-2- methylphenyl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (12.0 g, 28.7 mmol) in MeOH (100 mL) and water (100 mL) was added HC1 in water (40 mL, 1 molar, 40 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 2 days with a refluxing condenser. The reaction mixture was adjusted to pH=9 with 1 M NH3 in MeOH at 25 °C, then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH in DCM to give the title compound (4.9 g) as a solid. ES-MS m/z 374 (M+H).
Preparation of Intermediate 112: N-((2S,4R)-4-Carbamoyl- l-(5-iodo-2-methylphenyl)-2- methylpiperidin-4-yl)-2-((2S)-2-fluorocyclopropyl)-6-(trifluoromethyl)nicotinamide (Isomer 1) [0224] To a mixture of (2S,4R)-4-amino-l-(5-iodo-2-methylphenyl)-2-methylpiperidine-4- carboxamide (1.0 g, 2.4 mmol) and TEA (1.74 mL, 11.9 mmol) in THF (10 mL) was added a solution of 2-((2S)-2-fluorocyclopropyl)-6-(trifluoromethyl)nicotinoyl chloride (1.1 g, 2.5 mmol) in THF (10 mL) dropwise at 0 °C under nitrogen over 10 min. The system was de-gassed and refilled with nitrogen three times, then stirred at 25 °C for 1 h under nitrogen. The reaction mixture was quenched by adding 20 mL H2O at 25 °C, and then extracted with EtOAc (7 mL x 3). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (1.5 g) as a solid. ES-MS m 'z 605 (M+H).
Preparation of Intermediate 113: (5R,7S)-2-(2-((2S)-2-Fluorocyclopropyl)-6- (trifhioromethyl)pyridin-3-yl)-8-(5-iodo-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l- en-4-one (Isomer 1)
[0225] To a mixture of N-((2S,4R)-4-carbamoyl-l-(5-iodo-2-methylphenyl)-2-methylpiperidin- 4-yl)-2-((2S)-2-fluorocyclopropyl)-6-(trifluoromethyl)nicotinamide (Isomer 1, 1.50 g, 814 pmol) in MeOH (15 mL) was added NaOH in H2O (4.2 mL, 1 molar, 4.2 mmol) at 25 °C. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH at 40 °C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaCl (50 mL) and dried over Na2SO4. The Na2SO4 was filtered off and further washed with EtOAc (10 mL x 3). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in PE to give the title compound (360 mg) as a solid. ES-MS m 'z 587 (M+H).
Preparation of Intermediate 114: l,3-Dioxoisoindolin-2-yl (lR,2R)-2-fluorocyclopropane-l- carb oxy late
[0226] The title compound was prepared as described in the Preparation of Intermediate 106 using (lR,2R)-2-fluorocyclopropane-l-carboxylic acid. ES-MS m 'z 250 (M+H).
Preparation of Intermediate 115: 2-((2R)-2-Fluorocyclopropyl)-6-(trifluoromethyl)nicotinic acid (Isomer 1)
[0227] The title compound was prepared as described in the Preparation of Intermediate 107 using l,3-dioxoisoindolin-2-yl (lR,2R)-2-fluorocyclopropane-l-carboxylate. ES-MS OTZZ 248 (M+H).
Preparation of Intermediate 116: 2-((2R)-2-Fluorocyclopropyl)-6-(trifluoromethyl)nicotinoyl chloride (Isomer 1)
[0228] The title compound was prepared as described in the Preparation of Intermediate 109 using 2-((2R)-2-fhiorocyclopropyl)-6-(trifluoromethyl)nicotinic acid (Isomer 1). A sample dissolved in MeOH shows ES-MS m/z 264 (methyl ester M+H).
Preparation of Intermediate 117: N-((2S,4R)-4-Carbamoyl-l-(5-iodo-2-methylphenyl)-2- methylpiperidin-4-yl)-2-((2R)-2-fluorocyclopropyl)-6-(trifluoromethyl)nicotinamide (Isomer 1) [0229] The title compound was prepared as described in the Preparation of Intermediate 112 using 2-((2R)-2-fhiorocyclopropyl)-6-(trifluoromethyl)nicotinoyl chloride (Isomer 1). ES-MS m/z 605 (M+H).
Preparation of Intermediate 118: (5R,7S)-2-(2-((2R)-2-Fluorocyclopropyl)-6-
(tri fluoromethyl )pyridin-3-yl)-8-(5-iodo-2-methylphenyl)-7-methyl-l, 3, 8-triazaspiro[4.5]dec-l- en-4-one (Isomer 1)
[0230] The title compound was prepared as described in the Preparation of Intermediate 113 using N-((2S,4R)-4-carbamoyl-l-(5-iodo-2-methylphenyl)-2-methylpiperidin-4-yl)-2-((2R)-2- fluorocyclopropyl)-6-(trifluoromethyl)nicotinamide (Isomer 1). The product was purified by silica gel chromatography using a gradient of 40 to 80% EtOAc in PE. ES-MS m/z 587 (M+H).
Preparation of Intermediate 119: 4-Chloro-2-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H- pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile
[0231] A mixture of (5R,7S)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-2-en-4-one dihydrochloride (600 mg, 1.28 mmol), 4-chloro-2-fluorobenzonitrile (219 mg, 1.41 mmol), DIPEA (891 pL, 5.11 mmol) in NMP (1.28 mL) was heated at 150 °C in a microwave for 90 min, then heated overnight at 150 °C. The reaction mixture was diluted with EtOAc and organic layer was washed with sat. aq. NaHCO.i. The aqueous layer was extracted with EtOAc and the combined organics were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5 to 80% EtOAc in hexane over 20 min to give the title compound (114 mg). ES-MS m/z 532 (M+H). Preparation of Intermediate 120: 2-(3,3-Difluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinic acid
[0232] A mixture of DMF (800 mL), 2-chloro-6-(trifluoromethyl)nicotinic acid (40 g, 0.17 mol), 3,3-difluoroazetidine hydrochloride (39 g, 0.30 mol) and K^CCh (101 g, 727 mmol) was stirred vigorously at 90 °C for 16 h. The reaction mixture was poured into 500 mL water at 0 °C. The mixture was adjusted to pH<3 with 3 N aq. HC1 with stirring and then extracted with EtOAc (500 mL x 3). The combined organic layers were washed with sat. aq. NaCl 200 mL, dried over Na2SO4, fdtered and concentrated under reduced pressure to give the title compound (45 g) as a solid. ES-MS m/z 283 (M+H).
Preparation of Intermediate 121 : 4-Bromo-2-((5R,7S)-2,2,7-trimethyl-4-oxo-l,3,8- triazaspiro[4.5]decan-8-yl)benzonitrile
[0233] To a mixture of (5R,7S)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (1 g, 4 mmol) and K2HPO4 (4.25 g, 24.3 mmol) in DMSO (10 mL) was added 4- bromo-2-fluorobenzonitrile (1.02 g, 5.00 mmol) at 28 °C. The reaction vessel was purged with nitrogen for 1 min and the mixture was stirred at 120 °C for 16 h. The reaction mixture was poured into 20 mL water at RT, and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (0.7 g) as a solid. ES-MS m 'z 377, 379 (M+H).
Preparation of Intermediate 122: (2S,4R)-4-Amino-l-(5-bromo-2-cyanophenyl)-2- methylpiperidine-4-carboxamide
[0234] To a 40 mb vial with a magnetic stir bar was charged with ACN (7 mb) and H2O (0.7 mb), followed by the addition of 4-bromo-2-((5R,7S)-2,2,7-trimethyl-4-oxo-l,3,8- triazaspiro[4.5]decan-8-yl)benzonitrile (700 mg, 1.83 mmol) and 2-naphthalenesulfonic acid (555 mg, 2.61 mmol) at 27 °C. The resulting mixture was stirred at 90 °C for 16 h then concentrated under reduced pressure. Water (5 mL) was added adjusted to pH>8 with sat. NaHCCh with stirring, then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl (10 mL) and dried over ISfeSCU. The Na2SC>4 was filtered off and further washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give the title compound (350 mg) as a solid. ES-MS m/z 337, 339 (M+H).
Preparation of Intermediate 123: N-((2S,4R)-l-(5-Bromo-2-cyanophenyl)-4-carbamoyl-2- methylpiperidin-4-yl)-2-(3,3-difluoroazetidin-l-yl)-6-(trifluorornethyl)nicotinamide
[0235] A mixture ofDMF (3 mL), 2-(3,3-difluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinic acid (250 mg, 835 pmol), DIEA (224 mg, 302 pL, 1.70 mmol), HATU (493 mg, 1.27 mmol) and (2S,4R)-4-amino-l-(5-bromo-2-cyanophenyl)-2-methylpiperidine-4-carboxamide (345 mg, 944 pmol) was purged with nitrogen for 2 min then vigorously stirred at 27 °C for 16 h. The reaction mixture was quenched by adding H2O (10 mL) at 20 °C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with 20 mL sat. aq. NaCl, and dried over Na2SO4. The Na2SO4 was filtered off and further washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (500 mg) as a solid. ES-MS m z 601, 603 (M+H).
Preparation of Intermediate 124: 4-Bromo-2-((5R,7S)-2-(2-(3,3-difluoroazetidin-l-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile
[0236] A mixture of THF (5 mL), N-((2S,4R)-l-(5-bromo-2-cyanophenyl)-4-carbamoyl-2- methylpiperi din-4-yl)-2-(3,3-difluoroazeti din- 1 -yl)-6-(trifluoromethyl)ni cotinamide (500 mg, 806 pmol) and potassium 2-methylpropan-2-olate (1 M solution in /-BuOH, 8.06 mL, 8.06 mmol) was purged with nitrogen for 2 min then stirred vigorously at 80 °C for 3 h. The reaction mixture was poured into 10 mL water at RT, and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), and dried over Na2SO4. The Na2SO4 was filtered off and further washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (150 mg) as a solid. ES-MS m z 583, 585 (M+H).
Preparation of Intermediate 125: (5R,7S)-8-(5-Chloro-2-iodophenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0237] A mixture of DME (60 mL), (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 10.0 g, 24.1 mmol), 3-bromo-2-iodobenzo[b]thiophene (12.8 g, 37.0 mmol), KF (2.17 g, 875 pL, 37.0 mmol) and 18-crown-6 (9.87 g, 37.0 mmol) was degassed and purged with nitrogen 3 times. Then 5-chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (6.20 g, 18.5 mmol) in DME (60 mL) was added dropwise over 15 min at 24 °C under nitrogen. Then the reaction mixture was allowed to stir vigorously at 24 °C for 3 h under nitrogen. The reaction mixture was poured into H2O (200 mL) at 20 °C and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with sat. aq. NaCl (200 mL), and dried over Na2SO4. The Na2SO4 was filtered off and further washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to give the title compound (0.80 g) as a solid. ES-MS m/z 619 (M+H).
Preparation of Intermediate 126: (5R,7S)-8-(5-Chloro-2-(l-trityl-lH-pyrazol-4-yl)phenyl)-7- methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l- en-4-one (mixture of isomers)
[0238] A mixture of 1,4-dioxane (1 mL), H2O (0.1 mL), (5R,7S)-8-(5-chloro-2-iodophenyl)-7- methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l- en-4-one (mixture of isomers, 50 mg, 81 pmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1-trityl-lH-pyrazole (53 mg, 0.12 mmol), and K3PO4 (51 mg, 0.24 mmol) was purged with nitrogen for 1 min, then l,l -bis(di-cyclohexylphosphino)ferrocene palladium dichloride (12 mg, 16 pmol) was added at 20 °C under nitrogen. The reaction vessel was purged with nitrogen for 1 min, then the reaction mixture was heated to 80 °C and allowed to stir for 1 h under nitrogen. The reaction mixture was cooled down to RT and then poured into 10 mL H2O at 20 °C, then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl (5 mL) and dried over Na SO4. The Na2SC>4 was filtered off and further washed with EtOAc (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (2: 1 EtOAc : PE, Ry = 0.4) to give the title compound (30 mg) as a solid. ES-MS m/'z 801 (M+H).
Preparation of Intermediate 127: (5R,7S)-8-(5-Chloro-2-(isoxazol-4-yl)phenyl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0239] A mixture of 1,4-dioxane (15 mL), H2O (3 mL), (5R,7S)-8-(5-chloro-2-iodophenyl)-7- methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l- en-4-one (mixture of isomers, 600 mg, 968 pmol), CS2CO3 (1610 mg, 4.892 mmol), 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (387 mg, 1.94 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with DCM, 255 mg, 297 pmol) was purged with nitrogen for 1 min, then vigorously stirred at 50 °C for 1 h. The reaction mixture was left at RT for 3 days, then poured into 20 mL H2O at 20 °C, and then extracted with EtOAc (10 mL x 4). The combined organic layers were washed with sat. aq. NaCl (10 mL x 2), and dried over IS^SCU. The I feSCL was filtered off and further washed with EtOAc (10 mL x 2). The filtrate was concentrated under reduced pressure to give the title compound (900 mg) as a solid. ES-MS m 'z 560, 562 (M+H).
Preparation of Intermediate 128: 2-(4-Chloro-2-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran- 2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)phenyl)acetonitrile (mixture of isomers)
[0240] A mixture of DMF (9 mL), H2O (9 mL), (5R,7S)-8-(5-chloro-2-(isoxazol-4-yl)phenyl)-7- methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l- en-4-one (mixture of isomers, 900 mg, 945 pmol) and KF (281 mg, 4.79 mmol) was stirred vigorously at 90 °C for 2 h, then at RT overnight. The reaction mixture was poured into 50 mL H2O at 20 °C, and then extracted with EtOAc (30 mL x 4). The combined organic layers were washed with sat. aq. NaCl (10 mL x 2), dried over Na2SO4, then the Na2SO4 was filtered off and further washed with EtOAc (10 mL x 2). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in PE to give the title compound (290 mg) as a solid. ES-MS m/z 532, 534 (M+H). Preparation of Intermediate 129: 2-(2,6-Dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'- (l-trityl-lH-pyrazol-4-yl)-[l,l'-biphenyl]-4-yl)-2-hydroxyacetamide (mixture of isomers)
[0241] A mixture of 1,4-dioxane (1 mL), H2O (0.1 mL), (5R, 7S)-8-(5-chloro-2-(l -trityl- 1H- pyrazol-4-yl)phenyl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 30 mg, 33 pmol), 2-(3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 17 mg, 50 pmol), K2CO3 (16 mg, 0.11 mmol) was purged with nitrogen for 1 min. Then chloro(crotyl)(tri-/e/7-butylphosphine)palladium(II) (3 mg, 7 pmol) was added to the mixture at 15 °C under nitrogen. The system was purged with nitrogen for 1 min, then the reaction mixture was heated to 100 °C and allowed to stir for 1 h under nitrogen. The reaction mixture was cooled down to RT, and the reaction mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 5 mL EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC using a gradient of 70 to 90% ACN in 0.2% aq. FA to give the title compound (23 mg) as a solid. ES-MS m.'z 944 (M+H).
Preparation of Intermediate 130: 2-bromo-6-chloro-3-methylphenol
[0242] To a vigorous stirring DCM (2.0 L) solution of 2-chloro-5-methylphenol (260 g, 1787 mmol) was added diisopropylamine (450 g, 4500 mmol) dropwise over 30 mins at 0 °C. Then NBS (257 g, 1429 mmol) in DCM (6.0 L) was added dropwise at 0 °C by peristaltic pump over 18 mL/min. The resulting mixture was stirred at 25 °C for 16 h, then NaHS04 (1.0 M in H2O, 2.0 L) was added under stirring at 25 °C. The organic phase was obtained by separating the liquid and then extracted with NaOH (1.0 M in H2O, 1.0 L * 3), then H3PO4 (85% Wt in H2O) was added to pH = 3, further extracted with cyclohexane (2.0 L x 2). The cyclohexane organic phase was washed with H2O (1.0 L) then with brine (1.0 L), dried over Na2SO4 and fdtered. The filtrate was concentrated under reduced pressure to give the title compound (380 g, 70 wt% purity) as an oil. ES-MS m,'z 219, 221 (M-H).
Preparation of Intermediate 131 : (2-bromo-6-chloro-3-methylphenoxy)trimethylsilane
[0243] To a vigorous stirring THF (1.8 L) solution of 2-bromo-6-chloro-3-methylphenol (380 g, 70 wt% purity, 1201 mmol) was added hexamethyldisilazane (293 g, 1820 mmol) in one portion at 25 °C. The resulting mixture was stirred at 70 °C for 16 h under N2, concentrated under reduced pressure to give the title compound (490 g, 70 wt% purity) as an oil. 'H-NMR (400 MHz, CHLOROFORM-^ ) 8 7.14 - 7.08 (m, 1H), 6.73 (d, J= 8.2 Hz, 1H), 2.31 (s, 3H), 0.29 (s, 9H).
Preparation of Intermediate 132: 6-chl oro-3 -methyl-2-(trimethylsilyl)phenol
[0244] To a vigorous stirring THF (5.0 L) solution of (2-bromo-6-chloro-3- methylphenoxy)trimethylsilane (500 g, 70 wt% purity, 1106 mmol) in a 10 L 3-neck round bottom flask was added n-butyllithium (1.6 M in hexane, 1.0 L, 1600 mmol) dropwise over 60 mins at -70 °C under N2. The resulting mixture was stirred at -70 °C for 40 mins. A solution of AcOH (104.9 g, 100 mL, 1747 mmol) in THF (300 mL) was added dropwise at -70 °C over 20 mins under N2. The resulting mixture was stirred at -70 °C for 10 mins, then sat. aq. NaHCCh (5.0 L) and H2O (5.0 L) were added at -70 °C. The mixture was extracted with cyclohexane (2.0 L x 2). The cyclohexane organic phase was washed with H2O (1.0 L) and brine (1.0 L), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to give the residue. TLC (petroleum ether) R/= 0.5. The residue was purified by column chromatography using 100% petroleum ether to give the title compound (230 g) as an oil. ES-MS m z 213, 215 (M-H)
Preparation of Intermediate 133: 6-chloro-3-methyl-2-(trimethylsilyl)phenyl tri fluoromethanesulfonate
[0245] In a 5 L 3-neck bottle was charged DCM (2.0 L), followed by the addition of 6-chloro-3- methyl-2-(trimethylsilyl)phenol (230 g, 1017 mmol) and DIPEA (267 g, 355 mL, 2040 mmol), then trifluoromethanesulfonic anhydride (437.1 g, 1534 mmol) was added dropwise over 30 mins at 0 °C. The mixture was stirred at 25 °C for 2 h, transferred to a separating funnel, and heptane (1 .0 L) was added. The organic phase was separated and washed with K2CO3 (2.0 M in H2O, 2.0 L), H2O (500 mL) and brine (500 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was triturated with cyclohexane (1.0 L) at 25 °C for 10 mins. Then the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. TLC (petroleum ether) R, = 0.8. The residue was purified by column chromatography using 100% petroleum ether to give the title compound (331.6 g) as an oil. ES-MS m z 345, 347 (M-H)
Preparation of Intermediate 134: (5R,7S)-8-(5-chloro-2-methylphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one
[0246] To a solution of (5R,7S)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (60.5 g, 222 mmol) and cesium fluoride (170.5 g, 1122 mmol) in ACN (1.0 L) was added a solution of 6-chloro-3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (105.6 g, 289.3 mmol) in ACN (1.0 L) in one portion at 27 °C, then stirred at 30 °C for 12 h, cooled down to 25 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) R = 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the crude product, which was purified by reversed-phase HPLC using a gradient of 30 to 65% H2O in MeOH to give the title compound (30.5 g) as a solid. ES-MS m z 322, 324 (M+H).
Preparation of Intermediate 135: (5R,7S)-8-(5-iodo-2-methylphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5 ]decan-4-one
[0247] To a solution of (5R,7S)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (30.0 g, 85.7 mmol) and 2-bromo-4-iodo-l -methylbenzene (94 g, 317 mmol) in 1,4-dioxane (300 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.0 L, 1000 mmol) dropwise over 30 mins at 25 °C. The mixture was de-gassed and refilled with N2 for three times, stirred at 80 °C for 2 h, poured into H2O (1.0 L) at 25 °C, and then extracted with EtOAc (400 mL x 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography using a gradient of 0 to 40% EtOAc in petroleum ether to give a crude product. The crude product was further purified by reverse phase prep-HPLC using a gradient of 40 to 65% ACN in 10 mM aq. HCOONELto give the title compound the title compound (14 g) as solid. ES-MS m/z 413 (M+H).
Preparation of Intermediate 136: (2S,4R)-4-amino-l-(5-iodo-2-methylphenyl)-2- methylpiperidine-4-carboxamide
[0248] To a mixture of (5R,7S)-8-(5-iodo-2-methylphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (12.0 g, 28.7 mmol) in MeOH (100 mL) and H2O (100 mL) was added HC1 (1.0 M in H2O, 40 mL, 40 mmol) at 25 °C, then stirred at 100 °C for 2 days. The reaction mixture was adjusted to pH = 9 with NH3 (1.0 M in MeOH) at 25 °C, then concentrated under reduced pressure to give the residue. TLC (10:1 DCM : MeOH) R/= 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 5% MeOH in DCM to give the title compound (4.9 g, 88.4 wt% purity) as solid. ES-MS m/z 373 (M+H).
Preparation of Intermediate 137: (2S,4R)-4-amino-l-(5-chloro-2-methylphenyl)-2- methylpiperidine-4-carboxamide
[0249] To a 3 L 1-neck round bottom flask with a magnetic stir bar was charged with MeOH (600 m ) and H2O (600 mb), followed by the addition of (5R,7S)-8-(5-chloro-2-methylphenyl)- 2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (20.3 g, 61.8 mmol) and HC1 (1.0 M in H2O, 3.5 g, 95 mb, 95 mmol) at 27 °C, then stirred at 100 °C for 3 days, cooled to 27 °C, adjusted to pH = 8 by sat. aq. NaHCCh (200 mL). The aqueous phase was extracted with DCM (1.0 L x 2). The combined organic phase was washed with brine (1.0 L), dried with anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) Ry = 0.1. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (15.3 g) as a solid. ES-MS m/z 282, 284 (M+H)
Preparation of Intermediate 138 (Alternative deprotection procedure): (2S,4R)-4-amino-l-(5- chloro-2-methylphenyl)-2-methylpiperidine-4-carboxamide naphthalene-2-sulfonate
[0250] A mixture of (5R,7S)-8-(5-chloro-2-methylphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (3.92 g,12.2 mmol) and 2-Naphthalenesulfonic acid (6.31 g, 30.3 mmol) in acetonitrile (180 mL) and water (400 pL, 22.2 mmol) was heated at reflux in a 500 mL RBF w a reflux condenser open to air. The reaction was heated at reflux for 4 days and then allowed to stir at RT for 2 days to give a suspension. The suspension was heated to reflux and then allowed to cool slightly and the solids were removed by fdtration and washed with acetonitrile 3X (20 mL ea.) to give the product that was used directly in the next synthetic step. The filtrate was heated at reflux ON in a 500 mL RGF at reflux under a reflux condenser open to the air. Added 2-Naphthalenesulfonic acid (6.31 g, 2.49 Eq, 30.3 mmol) and continued heating ON. The reaction was concentrated. The residue was partitioned between IN NaOH (200 mL) and EtOAc (200 mL). Some solids in aqueous phase. The layers were separated. The aqueous layer was extracted 2X EtOAc. The combined organic phases were extracted IX with water (20 mL), IX with brine, dried Na2SO4, filtered and concentrated to a tan solid. Carried directly into the next synthetic step. ES-MS m/z 282 (M+H).
Preparation of Intermediate 139: l,3-dioxoisoindolin-2-yl 1-fluorocyclopropane-l-carboxylate
[0251] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with DCM (50 mL), followed by the addition of 1 -fluorocyclopropane- 1 -carboxylic acid (5.0 g, 47 mmol) and N,N’-di cyclohexylcarbodiimide (11 g, 52 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 mins, then 2-hydroxyisoindoline-l,3-dione (7.9 g, 47 mmol) was added, stirred at 25 °C for 16 h, then quenched by H2O (100 mL) and extracted with EtOAc (30 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. TLC (10: 1 petroleum ether : EtOAc) R/= 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (6.2 g, 88 wt% purity) as solid. ES-MS m/z 250 (M+H).
Preparation of Intermediate 140: 2-(l-fluorocyclopropyl)-6-(trifluoromethyl)nicotinic acid
[0252] To an 250 mL ElectraSyn vial was added l,3-dioxoisoindolin-2-yl 1-fluorocyclopropane- 1 -carboxylate (6.2 g, 22 mmol), 2-chloro-6-(trifluoromethyl)nicotinic acid (6.20 g, 88 wt% purity, 26.1 mmol), 2,2'-bipyridine (0.72 g, 4.4 mmol), and Nickelous chloride hexahydrate (1.10 g, 4.40 mmol), then DMF (90 mL) was added via syringe, stirred until all solids were dissolved. Silver nitrate (2.1 g, 12 mmol) was then added to the reaction mixture. The vial was closed with an ElectraSyn vial cap along with a magnesium sacrificial anode and a CF cathode (3 mm x 7 mm x 51 mm). The vial was then placed on an IKA ElectraSyn 2.0 stir plate and the electrolysis was set to 12 mA, 0.4 mmol, 2.5 F/mol providing 5.4 A/m2 current density. The mixture was stirred at 20 °C for 4 h, then concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 30 to 60% MeCN in 0.2% aq. FA to give the title compound (0.29 g) as solid. ES-MS m/z 250 (M+H).
Preparation of Intermediate 141 : 2-cyclopropyl-6-methoxynicotinic acid
[0253] To a 250 mL 1-neck round bottom flask with a magnetic stir bar was charged with EtOH (50 mL) and H2O (5 mL), followed by the addition of 2-chloro-6-methoxy-nicotinic acid (5.07 g, 26.8 mmol), cyclopropaneboronic acid (5.81 g, 67.0 mmol) and K2CO3 (11.3 g, 80.9 mmol). The mixture was de-gassed and backfdled with N2 for three times before and after adding tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (2.48 g, 2.68 mmol). Then the reaction mixture was stirred at 70 °C for 5 h under N2, cooled down to ambient temperature, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 30 to 55% MeCN in 0.2% aq. FA to give the title compound (0.90 g) was obtained as solid. ES-MS m/z 194 (M+H).
Preparation of Intermediate 142: 2-(3-fluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinic acid
[0254] In a 250 mL round bottom flask with a magnetic stir bar was added 2-chloro-6- (trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol), potassium fluoride (1.5 g, 27 mmol), DMSO (8.9 mL, 4.4 mmol), and 3 -fluoroazetidine hydrochloride (0.49 g, 4.4 mmol). The reaction was heated to 90 °C and monitored by LCMS. Upon complete consumption of the starting material, the reaction was taken of the heating block and allowed to cool to room temperature. The material was diluted in EtOAc and washed with water 3 times. The organic layer was collected and dried with sodium sulfate. The 2-(3-fluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinic acid (1.33 g) was isolated as a solid. ES-MS m/z 263 (M-H).
Preparation of Intermediate 143: 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid
[0255] To a mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (5.0 g, 22 mmol), cyclobutanecarboxylic acid (3.4 g, 33 mmol), Phthalimide (4.9 g, 33 mmol), 2-(tert-butyl)- 1,1,3,3-tetramethylguanidine (7.7 g, 45 mmol) in DMF (100 mL) was added (4,4'-Di-t-butyl-2,2'- bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (0.26 g, 0.23 mmol), [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) di chloride (0.46 g, 1.1 mmol) in one portion at 28 °C, under N2. The resulting solution was pumped by Pump 1 { S 1, Pl, 0.458 mL/min}to flow reactorl {FLR1,FEP, Coils reactor, 3.175(1/8”) mm, 55 mL,55 °C}. The residence time of flow reactor 1 was {FLR1,12O min }. Turned on the 395 nm ELD light (200W*2) and started pump 1. The back pressure regulator was adjusted to 100 kPa 5. The residence time of flow reactor 1 was FLR1,12O min. Started to collect the reaction mixture after running 120 min. The reaction mixture was left at room temperature over the night. The reaction mixture was filtrated and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch X timate C18 250*100mm#10um; mobile phase: [A: H2O (0.2%FA);B: ACN]; B%: 35.00%-
70.00%, 20.00 min; flow rate:300.00 ml/min), and the collected fraction underwent lyophilization to get the desired product. Compound 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid (2.7 g,) was obtained as a solid. ES-MS m/z 245.9 (M+H).
Preparation of Intermediate 144: 4-amino-l,l,l-trifluorobut-3-en-2-one NH2 [0256] A solution of 4-Ethoxy-l,l,l-trifluorobut-3-en -2-one (80 g, 450 mmol), Ammonia in methanol (250 mL, 7 N, 1750 mmol) was stirred vigorously at 25 °C for 16 h. The mixture was concentrated under reduced pressure to obtain the crude material as a yellow oil. The oil was taken to the next step without purification.
Preparation of Intermediate 145: ethyl 2-cyclobutyl-6-(trifluoromethyl)nicotinate
[0257] A solution of 4-amino-l,l,l-trifluorobut-3-en-2-one (67 g, 80 wt%, 390 mmol), ethyl 3- cyclobutyl-3-oxopropanoate (110 g, 633 mmol), TFA (47 mL, 600 mmol) in Toluene (500 mL) was stirred vigorously at 110 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated to a residue. The residue was suspended in EtOAc (500 mL) and a 15% Na2CO? solution. After separation, the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organics were washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography on silica gel (0-40% EtOAc in n-hexane) to afford the title compound (44 g) as a liquid.
Preparation of Intermediate 146: 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid
[0258] NaOH (10 g, 240 mmol), was added to a solution of ethyl 2-cyclobutyl-6- (trifluoromethyl)nicotinate (44 g, 157 mmol) in THF (150 mL), MeOH (150 mL), water (150 mL) and stirred at 20 °C for an hour. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in water (200 mL), then the pH was adjusted to 3-4 by addition of 4 N HC1. The formed precipitate was filtered and rinsed with water (5 x 100 mL) to afford the title compound (34 g) as a solid. Preparation of Intermediate 147: rac-2-(oxetan-2-yl)-6-(tri fluoromethyl) nicotinic acid (racemic mixture)
[0259] To a 250 mL 1-neck round bottom flask with a magnetic stir bar was charged with DMF (120 mL), followed by the addition of rac-2-chloro-6-(trifluoromethyl) nicotinic acid (6 g, 26.1 mmol) and rac-oxetane-2-carboxylic acid (racemic, mixture, 4.21 g, 40.4 mmol) and 2-(tert- butyl)-l,l,3,3-tetramethylguanidine (7.05 g, 40.7 mmol) at 25 °C. The mixture was de-gassed and backfilled with N2 for three times before and after adding (4,4'-Di-t-butyl-2,2'-bipyridine) bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN) phenyl-kC] iridium (III) hexafluorophosphate (0.83 g, 0.73 mmol) and [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (0.61 g, 1.5 mmol) at 25 °C. The mixture was stirred at 40 °C for 5 h under irradiation with 440 nm LED module (50 W) in an integrated photoreactor. The crude reaction mixture was directly concentrated under reduced pressure to give the crude product, which was purified by reverse phase prep-HPLC using a gradient of 2 to 20% ACN in 0.04% aq. HC1 to give the title compound (1.6 g, 86.2 wt% purity) as oil. ES-MS m/z 248 (M+H).
Preparation of Intermediate 148: rac-3-(tetrahydrofuran-2-yl)-2-(trifluoromethyl)isonicotinic acid; (racemic mixture)
[0260] To a mixture of 3-chloro-2-(trifluoromethyl)isonicotinic acid (9.8 g, 43 mmol), tetrahydrofuran-2-carboxylic acid (7.81 g, 65.9 mmol), phthalimide (9.52 g, 64.1 mmol), 2-(tert- butyl)-l,l,3,3-tetramethylguanidine (15.3 g, 88.4 mmol) in DMF (200 mL) was added (4,4'-Di-t- buty 1 -2 , 21 -b i py ri di ne)bi s [3 , 5 -di fluoro-2-(5 -tri fluoromethyl -2-pyri di ny 1 -kN)phenyl - kC]iridium(III) hexafluorophosphate (0.50 g, 0.4 mmol) and [4,4'-Bis(l,l-dimethylethyl)-2,2'- bipyridine] nickel (II) dichloride (0.88 g, 2.2 mmol) at 28 °C under N2. Then the mixture was pumped by Pump 1(0.458 mL/min) to flow reactor 1 (FEP, Coils reactor, 3.175 (1/8”) mm, 55 mb, 55 °C). The residence time of flow reactor 1 was 2 h with 395 nm LED light (200W x 2). The back pressure regulator was adjusted to 100 kPa. The reaction mixture was filtrated and concentrated under reduced pressure to give a residue, which was purified by reverse phase prep- HPLC using a gradient of 1 to 20% ACN in 10 mM aq. NH4HCO3 to give a crude product. The crude product was further purified by reverse phase prep-HPLC using a gradient of 10 to 50% ACN in 0.2% aq. FA to give the title compound (0.206 g) as solid. ES-MS m/z 262 (M+H).
Preparation of Intermediate 149: rac-(R)-2,2-difluoro-4-(tetrahydrofuran-2- yl)benzo[d][l,3]dioxole-5-carboxylic acid
[0261] In a 25 m microwave vial, 4-bromo-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid (470 mg, 1.67 mmol), Nickel(II) acetylacetonate (52.0 mg, 202 pmol), 4,4'-di-tert-butyl-2,2'- bipyridine (50.9 mg, 190 pmol), (4-methoxyphenyl)(4-(trifluoromethyl)phenyl)methanone (83 mg, 0.30 mmol), sodium carbonate (481 mg, 4.54 mmol) and THF (22.3 mb) were combined along with a stir bar. The flask was sealed with a septum, and the headspace in the vial was evacuated and backfilled with nitrogen x 3 before the pale green heterogeneous reaction mixture was placed in a double Hepatochem reactor equip with 2 x 390 nm Kessil lamps. After 3 hours of irradiation, the reaction was allowed to sit at room temperature. The contents of the vessel were filtered over celite and concentrated under reduced pressure. The material was concentrated under reduced pressure. The residue was then taken up in EtOAc and a solid persisted. The isolated solid and the filtrate were combined and concentrated. The material was taken up in IN NaOH and transferred to a separatory funnel. The material was washed with Et2O (2X). The aqueous layer was acidified with 5N HC1 and then extracted with CH2C12 (3X). The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified using RP-HPLC low pH method using 25-60% CAN in 0.1% formic acid and pooled fractions were concentrated under reduced pressure to yield 65 mg of rac-(R)-2,2- difluoro-4-(tetrahydrofuran-2-yl)benzo[d][l,3]dioxole-5-carboxylic acid as a solid. ES-MS m z 271 (M-H).
Preparation of Intermediate 150: 4-bromo-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid
[0262] To a vigorous stirring THF (500 mL) solution of 2,2-difluorobenzo[d][l,3]dioxole-5- carboxylic acid (50.0 g, 245 mmol) in a 3000 ml 3-neck round bottom flask was added n- butyllithium in THF (250 mL, 2.5 molar, 625 mmol) dropwise over 30 min at -70 °C. The mixture was stirred at -70 °C for 10 min and stirred at 0 °C for 1 hour, then NBS (222 g, 1.23 mol) in THF (500 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 2 hours. The reaction mixture was poured into H2O (500 ml) slowly at 15 °C and add 2N HC1 solution until pH=2~3. Then the mixture was extracted with EtOAc 1200 ml (400 mL * 3). The combined organic layers were washed with brine 600 ml (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was detected by TLC (PE: EA =1: 1, AcOH, Rf=0.65) and purified by column chromatography (Biotage; 330 g Agela Silica Flash Column, Eluent of 60-100% PE/EA gradient @ 200 mL/min). The fractions were concentrated under reduced pressure at 35 °C to give the desired product. The above product was triturated with 100 mL MTBE at 25 °C for 30 min. And the mixture was filtered and rinsed with petroleum ether, the filter cake was concentrated under pressure to give a product. The product 4-bromo-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid (24 g,) was obtained as a solid. ES-MS m/z 280 (M-H).
Preparation of Intermediate 151 : methyl l-butyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxylate
[0263] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMF (20 mL), followed by the addition of methyl 3-(trifluoromethyl)-lH-pyrazole-4-carboxylate (2.0 g, 10 mmol), n-butyl bromide (1.8 g, 1.4 mL, 13 mmol) and K2CO3 (3.8 g, 27 mmol) at 20 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 50 °C for 2 h, then cooled to ambient temperature and fdtered through a pad of celite under reduced pressure. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 40 to 70% ACN in 0.2% aq. FA to give the title compound (1.2 g) as oil. ES-MS m/z 251 (M+H).
Preparation of Intermediate 152: l-butyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid
[0264] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with MeOH (15 mL), followed by the addition of methyl l-butyl-3-(trifluoromethyl)-lH-pyrazole-4- carboxylate (1.2 g, 4.8 mmol) and NaOH (1.0 M in H2O, 15 mL, 15 mmol) at 25 °C. Then the reaction mixture was stirred at 25 °C for 4 h. The mixture was concentrated under reduce pressure to give a residue. The residue was dissolved in H2O (10 mL), adjusted to pH = 5 ~ 6 with HC1 (1.0 M in H2O) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.95 g) as oil. ES-MS m/z 237 (M+H).
Preparation of Intermediate 153: ethyl 2-butyl-4-(trifluoromethyl) thiazole-5-carboxylate
[0265] To a 100 m 1-neck round bottom flask with a magnetic stir bar was charged with EtOH (20 mL), followed by the addition of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (1.7 g, 7.6 mmol) and pentanethioamide (0.90 g, 8 mmol) at 15 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 80 °C for 12 h, then cooled to ambient temperature and concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane : EtOAc) R/= 0.5.
The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.60 g) as oil. ES-MS m/z 282 (M+H).
Preparation of Intermediate 154: 2-butyl-4-(trifluoromethyl) thiazole-5-carboxylic acid
[0266] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with THF (15 mL) and H2O (5 mL), followed by the addition of ethyl 2-butyl-4-(trifluorom ethyl) thiazole- 5-carboxylate (0.60 g, 2.1 1 mmol) and LiOH monohydrate (0.23 g, 5.4 mmol) at 16 °C. Then the reaction mixture was stirred vigorously at 16 °C for 15 h. The mixture was diluted with H2O (20 mL) and washed with EtOAc (20 mL). The aqueous phase was adjusted to pH = 3~4 with HC1 (2.0 M in H2O) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, then was concentrated under reduced pressure to give the title compound (0.49 g, 78.0 wt% purity) as solid. ES-MS m/z 254 (M+H).
Preparation of Intermediate 155: methyl 6-chloro-2-cyclopropylnicotinate
[0267] To a 2 L 3 -neck round bottom flask with a magnetic stir bar was charged with 1,4- dioxane (500 mL) and H2O (50 mL), followed by the addition of methyl 2-bromo-6- chloronicotinate (50.0 g, 189.6 mmol), cyclopropylboronic acid (42 g, 460 mmol) and K2CO3 (80 g, 579 mmol). The mixture was de-gassed and backfdled with N2 for three times before and after adding chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (CAS# 1334497-00-5, 5 g, 12 mmol). Then the reaction mixture was stirred at 90 °C for 4 h, cooled down to ambient temperature, filtered and the filtrate was poured into H2O (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (10: 1 n- hexane: EtOAc) R = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (22.6 g) as oil. ES-MS m/z 211, 213 (M+H).
Preparation of Intermediate 156: methyl 2-cyclopropyl-6-isopropoxynicotinate
[0268] To a 100 ml 3-neck round bottom flask with a magnetic stir bar was charged with IPA (30 mL), followed by the addition of methyl 6-chloro-2-cyclopropylnicotinate (3.0 g, 13.7 mmol) and sodium propan-2-olate in THF (20% Wt, 17 mL, 36 mmol). The mixture was de-gassed and refilled with N2 for three times before vigorously stirring at 80 °C for 12 h, then adjusted to pH = 7 with HC1 (1.0 M in H2O, 40 mL) with stirring at 15 °C. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (5: 1 n-hexane: EtOAc) R/= 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (1.8 g, 88 wt% purity) as oil. ES-MS m z 236 (M+H).
Preparation of Intermediate 157: 2-cyclopropyl-6-isopropoxynicotinic acid
[0269] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with MeOH (10 mL), followed by the addition of methyl 2-cyclopropyl-6-isopropoxynicotinate (1.8 g, 88 wt% purity, 6.7 mmol) and NaOH (1.0 M in H2O, 10 mL, 10 mmol) at 15 °C. Then the reaction mixture was stirred at 15 °C for 12 h, then adjusted to pH = 2~3 with HC1 (1.0 M in H2O, 11 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (40 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.40 g, 89.1 wt% purity) as solid. ES-MS m/z 222 (M+H). Preparation of Intermediate 158: methyl 6-butoxy-2-cyclopropylnicotinate
[0270] To a 250 ml 3-neck round bottom flask was charged with n-butanol (100 mL), then Na (1.62 g, 70.5 mmol) was added in portions over 10 mins at 20 °C. The mixture was stirred at 20 °C for 2 h, then methyl 6-chloro-2-cyclopropylnicotinate (4.20 g, 18.7 mmol) in n-butanol (20 mL) was added at 20 °C. The resulting mixture was stirred at 70 °C for 16 h, cooled down to ambient temperature, and concentrated under reduced pressure to give the title compound (4.20 g, 25.3 wt% purity) as oil. ES-MS m/z 250 (M+H).
Preparation of Intermediate 159: 6-butoxy-2-cyclopropylnicotinic acid
[0271] To a 100 mLl-neck round bottom flask with a magnetic stir bar was charged with MeOH (20 mL), followed by the addition of methyl 6-butoxy-2-cyclopropylnicotinate (4.20 g, 25.3 wt% purity, 4.26 mmol) and LiOH (4.0 M in water, 20 mL, 80 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h, then adjusted to pH = 6~7 with HC1 (2.0 M in H2O). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4. filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (5:1 petroleum ether: EtOAc) R/= 0.4. The residue was purified by flash silica gel chromatography using a gradient of 10 to 45% EtOAc in petroleum ether to give the title compound (1.0 g, 88.7 wt% purity) as solid. ES-MS m/z 236 (M+H).
Preparation of Intermediate 160: methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate
[0272] Methyl 2-chloro-6-(trifluoromethyl)nicotinate (25.28 g, 96% Wt, 101.3 mmol) and Potassiumcyclopropyltrifluoroborate (22.02 g, 148.8 mmol) were charged to a 1 L, 3-neck RBF with stir bar and temperature probe and condenser with nitrogen inlet. The flask was mounted in a metal heating block (ambient temp) and Toluene (0.25 L) and potassium carbonate (2.0 M aq) (55 g, 0.20 L, 2.00 molar, 0.40 mol) were added and a condenser with nitrogen inlet was fitted. Stirring started. Purged with nitrogen for ca. 10 min (sub-surface sparge with needle) before addition of bis(triphenylphosphine)palladium(II) di chloride (3.65 g, 5.20 mmol). The purge was continued for ca. 5 min more, then the purge needle was removed. Heating started with setpoint 70 °C (block). After 3 h, added more potassiumcyclopropyltrifluoroborate (7.26 g, 49.1 mmol) and continued heating overnight. The next day, heating stopped, left to cool. The mixture was transferred to a separating funnel, and the aqueous drained off. The organics were washed with 2 M aq. K2CO3 (2 x 50 mL) then with brine (50 mL), dried over MgSCh and filtered. Aqueous discarded. The organics were concentrated on RFE to a minimum of 40 mbar at 40 °C (20 min at 40 mbar pressure once most solvent had been removed; did not reduce further given likely volatility of product) to afford crude product 36.08 g red liquid that was used directly in the next reaction.
Preparation of Intermediate 161 : 2-cyclopropyl-6-(trifluoromethyl)nicotinic acid
[0273] Methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (36.08 g, 65% Wt, 95.64 mmol) was taken up in Tetrahydrofuran (0.15 L) and Methanol (0.15 L) with stirring in a 1 L RBF with stir bar. A solution of lithium hydroxide (6.872 g, 286.9 mmol) in Water (0.15 L) was added.
Stirred in a 40 °C metal heating block under a positive pressure of nitrogen overnight (start 1900 h). Heating stopped after one hour and then left to cool & stir at ambient overnight. Celite (~5 g) was added to the near-black mixture, stirred 5 min, then filtered through a pad of celite. The cake was rinsed with water (50 mL) and then discarded. Clear orange filtrate, single phase. The filtrate was concentrated on RFE at 50 °C to a minimum of 130 mbar, to remove most of the organic solvent. Grey precipitate formed in the mixture. The bulk mixture was filtered through celite as before, and the cake rinsed with water (50 mL). Cake discarded. Filtrate was clear brown, but as the rinse mixed with the filtrate, it clouded once more. The filtrate was extracted with MTBE (0.20 L). Both phases clear yellow, with a small amount of black material at the interface that was discarded. The aqueous was extracted with EtOAc (0.20 L). Both phases yellow. The aqueous was extracted with DCM (0.20 L). The aqueous was washed with a second portion of DCM (50 mL), mainly because droplets of the first wash were still visible on separating funnel walls. Left to settle thoroughly to minimize residual DCM mixed with aqueous. All organic extracts made to this point were discarded. The aqueous was stirred at ambient temperature, and 5 M aq. HC1 (60 mL) added. Solid formed immediately. Aq. pH -1. The mixture was stirred for approx. 30 min, then the solid was collected by filtration (8 cm paper filter on porcelain funnel, very rapid) and washed with 0.5 M HC1 (50 mL) then with water (2 x 0.10 L). The solid was dried in a vacuum oven (40 °C, 10 mbar) for 12 hours. Isolated 2- cyclopropyl-6-(trifluoromethyl)nicotinic acid (19.76 g) as a solid. ES-MS 230 m/z (M-H).
Preparation of Intermediate 162: methyl 2-cyclopropyl-6-methoxynicotinate
[0274] To a 5000 mL 3 neck RBF (with a refluxing condenser) with a magnetic stir bar was charged with Potassium phosphate, tribasic (278 g, 1.30 mol) and H2O (200 mL), the mixture was allowed to stir for 15 min (exothermic, thick slurry) and cooled to room temperature.
Toluene (2500 mL) was added followed by the addition of methyl 2-chloro-6-methoxynicotinate (100 g, 471 mmol), cyclopropylboronic acid (85 g, 0.95 mol), phosphine, tricyclohexyl- (28 g, 95 mmol) at 18 °C (external, no exothermic phenomenon). The system was bubbled with N2 for 15 min. Palladium diacetate (12 g, 95% Wt, 0.11 Eq, 51 mmol) was added. The reaction mixture was sparged with N2 for another 5 min and reaction mixture was stirred vigorously at 115 °C (external) for 3 hours under N2. The reaction mixture was left at RT, after 16 h, the organic layer was carefully decanted to another 5L flask, the remaining reaction mixture (-500 ml) was transferred to a separation funnel to remove the aqueous phase (two layers were easy to separate), the organic layer in the separation funnel was combined into the 5L flask, and filtered through a Celite pad, washed with EtOAc (200 ml *2) and the filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (Biotage®; 330 g Agela Silica Flash Column, Eluent of 0~50% Ethyl acetate/n-hexane gradient @ 190 mL/min). The fraction was concentrated under reduced pressure to give the desired product (88 g) as grey solid. ES-MS m 'z 208 (M+H).
Preparation of Intermediate 163: 2-cyclopropyl-6-ethoxynicotinic acid
[0275] To a 2 L RBF was charged with EtOH (500 m ) and methyl 2-cyclopropyl-6- methoxynicotinate (88 g, 0.41 mol), the mixture was sonicated for 10 min. Sodium ethanolate in EtOH (1000 mL, 20% wt, 62.55 mol) at 18 °C (external temperature) was added. The resulting mixture was stirred at 80 °C (external) for 30 min and was pumped into the column oven (220 °C, external temperature) at the speed of 2.75 ml/min with the residential time of 20 min. (Note: the back pressure regulator was set at 5 bar.) After 240 min the reaction mixture was adjusted to pH=2~3 with IM HC1 aq. with stirring at 0 °C (external temperature), during which white of precipitate crashed out of the solution. The product was collected through filtration via Buchner funnel under reduced pressure, and the filter cake was further washed with 200 ml H2O and dried in high vac. The 2-cyclopropyl-6-ethoxynicotinic acid (67 g,) was obtained as a solid. ES-MS mz 208 (M+H).
Preparation of Intermediate 164: 2-cyclobutyl-6-(trifluoromethyl)nicotinoyl chloride
[0276] To a vigorous stirring DCM (5 mL) solution of 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid (250 mg, 949 pmol)in a 100 ml 3-neck round bottom flask was added N,N-
Dimethylformamide (10 pL, 0.13 mmol) and Oxalyl chloride (129 pL, 1.44 mmol) dropwise at 0 °C. The mixture was stirred at 28 °C for 2 hours. A sample MeOH solution was made from the reaction mixture for the LCMS monitoring, shown the methyl ester peak at RT=2.779 min, M+l=260.0, and no carboxylic acid signal was detected. The reaction mixture was filtrated and concentrated under reduced pressure to give a residue. The crude product was used into next step without further purification. Compound 2-cyclobutyl-6-(trifluoromethyl)nicotinoyl chloride (280 mg, was obtained as an oil. ES-MS m/z 260 (methyl ester peak).
Preparation of Intermediate 165: 2-(l-fluorocyclopropyl)-6-(trifluoromethyl)nicotinoyl chloride
[0277] To a solution of 2-(l-fhjorocyclopropyl)-6-(trifluoromethyl)nicotinic acid (0.298 g, 1.12 mmol) and oxalyl di chloride (0.20 g, 1.54 mmol) in THF (6 mL) was added DMF (0.008 g, 0.1 mmol) at 0 °C, then stirred at 20 °C for 0.5 h, concentrated under reduced pressure to give the title compound (0.30 g, 82 wt% purity) as oil. LCMS was detected with MeOH, which gave the methyl ester mass. ES-MS m/z 263 (M+H).
Preparation of Intermediate 166: 2-bromo-4-(trifluoromethoxy)benzoyl chloride
[0278] To a 500 ml 3-neck round bottom flask with a magnetic stir bar was charged with DCM (150 mL), followed by the addition of 2-bromo-4-(trifluoromethoxy)benzoic acid (15.0 g, 51.6 mmol) and DMF (0.452 g, 6.06 mmol) at 25 °C. The mixture was degassed and refilled with N2 for three times. Then oxalyl chloride (14.5 g, 112 mmol) was dropwise added to the mixture at 0 °C over 10 min. The reaction mixture was stirred vigorously at 25 °C for 1 h, then was concentrated under reduced pressure to give the title compound (15.7 g) as oil, which was immediately used to next step without further purification. ES-MS m/z 299, 301 (M+H, methyl ester).
Preparation of Intermediate 167: 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride
Oxalyl chloride (1.3 g, 0.90 mL, 10 mmol) was added to a stirred suspension of 2-cyclopropyl-6- (trifluoromethyl)nicotinic acid (2.00 g, 8.65 mmol) in Di chloromethane (20 mL) at ambient temperature.. Trace off gassing. N,N-Dimethylformamide (32 mg, 34 uL, 0.43 mmol) was added; moderate off gassing. All solids had dissolved within 10 min, off gassing continued. After two hours, no more off gassing. The mixture was concentrated on RFE at 40 °C to a minimum of 100 mbar, to afford 2.32 g the title compound.
Preparation of Intermediate 168: N-((2S,4R)-4-carbamoyl-l-(5-chloro-2-methylphenyl)-2- methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide
[0279] To a DCM (20 mL) solution of (2S,4R)-4-amino-l-(5-chloro-2-methylphenyl)-2- methylpiperidine-4-carboxamide (1.6 g, 5.5 mmol) and TEA (2.2 g, 3.0 mL, 20 mmol) was added 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (1.6 g, 6.2 mmol) in DCM (2 mL) dropwise over 2 mins at 0 °C. The mixture was stirred at 15 °C for 12 h, then filtered. The filtrate was directly concentrated under reduced pressure to give the title compound (3.5 g, 68.7 wt% purity) as an oil. ES-MS m z 495, 497 (M+H)
[0280] The intermediates in the following table were prepared as described in the Preparation of Intermediate 168 using the appropriate carbonyl chloride and (2S,4R)-4-amino-l-(5-chloro-2- methylphenyl)-2-methylpiperidine-4-carboxamide.
Preparation of Intermediate 173: (5R,7S)-8-(5-chloro-2-methylphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0281] To a 100 ml 3-neck round bottom flask with a magnetic stir bar was charged with THF (10 mL), followed by the addition of N-((2S,4R)-4-carbamoyl-l-(5-chloro-2-methylphenyl)-2- methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide (3.5 g, 68.7 wt% purity, 4.9 mmol) and KO/Bu (1.0 M in /-BuOH, 50 mL, 50 mmol). The mixture was de-gassed and refilled with N2 for three times, then stirred at 80 °C for 4 h under N2, cooled down to ambient temperature, quenched by adding H2O (10 mL) at 25 °C, and then diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. TLC (5: 1 n-hexane: EtOAc) R/= 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in n-hexane to give the title compound (1.8 g) as solid. ES-MS m ,'z 477, 479 (M+H).
[0282] The Intermediates in the following table were prepared essentially as described in the preparation of Intermediate 173 using the appropriate precursor and dehydration reaction.
Preparation of Intermediate 176: (5R,7S)-8-(5-chloro-2-methylphenyl)-2-(2,2-difluoro-4-((RS)- tetrahydrofuran-2-yl)benzo[d][l,3]dioxol-5-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one;
[0283] Into a 20mL vial, Di isopropyl ethyl amine (93.9 mg, 125 pL, 3.56 Eq, 726 pmol) was added to rac-(R)-2,2-difluoro-4-(tetrahydrofuran-2-yl)benzo[d][l,3]dioxole-5-carboxylic acid (65 mg, 0.24 mmol), (2S,4R)-4-amino-l -(5-chloro-2-methylphenyl)-2-methylpiperidine-4- carboxamide naphthalene-2-sulfonate (100 mg, 204 pmol) and HATU (100 mg, 263 pmol) in N,N-Dimethylformamide (2 mL) with mechanical stirring, under nitrogen and at it. The reaction was allowed to continue stirring at rt overnight. The reaction was poured into sat aq NaHCO3 and extracted with EtOAc (3X). The combined organics were washed with water and brine. The material was then dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown gel. The material was transferred to a 25mL vial and was dissolved in Ethanol (4 mL). 2-methylpropan-2-olate pottasium (164 pL, 1.43 mmol) was then added with stirring and under nitrogen. The vial was capped and heated to 85°C external temperature for 2hrs. The reaction was cooled to rt and concentrated under reduced pressure to a minimal volume of solvent. The mixture was diluted with EtOAc (50mL) and poured into sat aq NH4C1. The layers were separated and the aq extracted two additional time with EtOAc. The combined organics were washed with sat aq NaHCO3 and brine. The material was dried over MgSO4, filtered and concentrated. The residue was then purified via flash chromatography (SiO2, 12g, 0-40% EtOAc/cyHex, gradient) to yield 102 mg of (5R,7S)-8-(5-chloro-2- methylphenyl)-2-(2,2-difluoro-4-((RS)-tetrahydrofuran-2-yl)benzo[d][l,3]dioxol-5-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one as a foam. ES-MS m z 515.8/517.8 (M-l doublet) (M-H).
[0284] Intermediates in the following table were prepared essentially as described in the preparation of Intermediate 176 using the appropriate amino-amide and carboxylic acid two-step procedure.
Preparation of Intermediate 184: (5R,7S)-2-(2-(l-fluorocyclopropyl)-6-(trifluoromethyl)pyridin- 3-yl)-8-(5-iodo-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0285] To a 40 mL vial with a magnetic stir bar was charged with MeOH (4.5 mL), followed by the addition of N-((2S,4R)-4-carbamoyl-l-(5-iodo-2-methylphenyl)-2-methylpiperidin-4-yl)-2- (l-fluorocyclopropyl)-6-(trifluoromethyl)nicotinamide (0.45 g, 41 wt% purity, 0.30 mmol) and NaOH (1.0 M in H2O, 1.9 mL, 1.9 mmol). The mixture was stirred at 70 °C for 12 h, then concentrated under reduced pressure, and MeOH (2 mL) was added. The mixture was fdtered, and the filtrate was purified by reverse phase prep-HPLC using a gradient of 50 to 90% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.104 g) as solid. ES-MS m/z 587 (M+H). Preparation of Intermediate 185: tert-butyl (5R,7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7- methyl -4-oxo- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -ene-8-carboxylate
[0286] To a 1 L 3-neck bottle with a magnetic stir bar was charged with THF (150 mL) followed by the addition of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (12.9 g, 49.8 mmol) and TEA (14.6 g, 142.2 mmol) at 25 °C. The reaction mixture was degassed and refilled with N2 for three times. Then a solution of 2-bromo-4- (trifluoromethoxy)benzoyl chloride (15.7 g, 49.7 mmol) in THF (50 mL) was dropwise added at 0 °C over 10 min. The reaction mixture was stirred at 25 °C for 2 h. Then KO/Bu (1.0 M in THF, 260 mL, 260 mmol) was dropwise added to the mixture at 25 °C, stirred at 70 °C for 5 h, poured into H2O (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (150 mL), dried with Na2SC>4, filtered and concentrated under reduced pressure to give a residue. TLC (2: 1 petroleum ether : EtOAc) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 20 to 50% EtOAc in petroleum ether to give the title compound (16.5 g, 86 wt% purity) as solid. ES-MS m/z 506, 508 (M+H).
Preparation of Intermediate 186: tert -butyl (5R,7S)-7-methyl-4-oxo-2-(2-(thiophen-2-yl)-4-
(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0287] To 1 L 3-neck round bottom flask with a magnetic stir bar was charged with 1,4-dioxane (300 mL), H2O (30 mL), tert-butyl (5R,7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7-methyl- 4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (15.0 g, 86 wt% purity, 25.5 mmol), thiophen-2-ylboronic acid (5.48 g, 42.0 mmol), CS2CO3 (24.1 g, 72.5 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (CAS# 95464-05-4, 4.25 g, 5.1 mmol). The mixture was degassed and refilled with N2 for three times, stirred at 110 °C for 2 h, then filtered and concentrated under reduced pressure to give a residue. TLC (2: 1 petroleum ether : EtOAc) Ry = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 20 to 50% EtOAc in petroleum ether to give the title compound (7.1 g) as solid. ES-MS m/z 509 (M+H).
Preparation of Intermediate 187: (5R,7S)-7-methyl-2-(2-(thiophen-2-yl)-4- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride
[0288] To a mixture of tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(thiophen-2-yl)-4- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (7.1 g, 12.8 mmol) in EtOAc (40 mL) was added HC1 (4M in 1,4-di oxane, 55.6 mL, 222 mmol) at 25 °C. The mixture was stirred at 25 °C for 5 h, then concentrated under reduced pressure to give the title compound (6.5 g, 85 wt% purity) as solid, which was immediately used to next step without further purification. ES-MS m/z 409 (M+H).
Preparation of Intermediate 188: (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(2-(thiophen- 2-yl)-4-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en -4-one
[0289] To a 250 ml round bottom flask with a magnetic stir bar was charged with MeCN (60 mL), followed by the addition of (5R,7S)-7-methyl-2-(2-(thiophen-2-yl)-4- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (6.0 g, 11.4 mmol), cesium fluoride (8.91 g, 85 wt% purity, 57.5 mmol) and 6-chloro-3-methyl-2- (trimethylsilyl)phenyl trifluoromethanesulfonate (5.44 g, 14.9 mmol) in one portion at 25 °C, then stirred at 25 °C for 15 h, poured into H2O (200 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. TLC (5: 1 petroleum ether : EtOAc) R = 0.3. The residue was purified by flash silica gel chromatography using a gradient of 0 to 20% EtOAc in petroleum ether to give the title compound (4.2 g, 71 wt% purity) as an off-solid. ES-MS m!z 533, 535 (M+H).
Preparation of Intermediate 189: (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(3- (tetrahydrofuran-2-yl)-2-(trifluoromethyl)pyridin-4-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)
[0290] To a 10 mL 1-neck round bottom flask with a magnetic stir bar was charged with /-BuOH (1 mL), followed by the addition of N-((2S,4R)-4-carbamoyl-l-(5-chloro-2-methylphenyl)-2- methylpiperidin-4-yl)-3-((RS)-tetrahydrofuran-2-yl)-2-(trifluoromethyl)isonicotinamide (mixture of isomers, 0.263 g, 54.2 wt% purity, 0.272 mmol) and KO/Bu (1.0 M in z-BuOH, 5.1 mL) at 28 °C, then stirred at 88 °C for 12 h, poured into H2O (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a crude product, which was purified by prep-TLC (SiC>2, 1 : 1 petroleum ether : EtOAc, R/= 0.6, UV), then the SiO2 powder was soaked with MeOH (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.021 g) as a solid. ES-MS m/z 507, 509 (M+H).
Preparation of Intermediate 190: tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-((RS)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinamido)piperidine-l -carboxylate
To a 250 ml round bottom flask with a magnetic stir bar was charged with THF (100 mL), followed by the addition of rac-(R)-2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (10.0 g, 38.2 mmol), tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (12.1 g, 45.3 mmol), DIEA (19.9 mL, 112 mmol), l-(3-Dimethylaminopropyl)-3- ethylcarbodiimideHydrochloride(EDCI) (11.2 g, 56.7 mmol)and 1-Hydroxy-lH-benzotriazole (7.7 g, 7.8 mL, 55 mmol) at 25 °C. Then the reaction mixture was allowed to stir vigorously at 25 °C fori 6 hour. The reaction mixture was poured into 100 mL H2O at 25 oC, and then extracted with EtOAc (200 mL * 2). The combined organic layers were washed with H2O (200 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue used to next step without further purification. Compound tert-butyl (2S,4R)-4- carbamoyl-2-methyl-4-(2-((RS)-tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (15.3 g) was obtained as a solid. ES-MS m 'z 501 (M+H).
Preparation of Intermediate 191 : tert-butyl 4-carbamoyl-4-(2-cyclopropyl-6-ethoxynicotinamido) piperidine- 1 -carboxylate
[0291] To a 250 mL one-neck round bottom flask was charged with THF (70 mL), followed by the addition of 2-cyclopropyl-6-ethoxynicotinic acid (5.0 g, 82.0 wt% purity, 20 mmol), EDCI (6.9 g, 35 mmol), DIPEA (11 g, 15 mL, 84 mmol) and HOBt (4.8 g, 35 mmol) at 10 °C. The mixture was stirred at 10 °C for 10 min. Then tert-butyl 4-amino-4-carbamoylpiperidine-l- carboxylate (6.1 g, 25 mmol) was added. The mixture was de-gassed and refilled with N2 for three times before vigorously stirring at 40 °C for 12 h, diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4. and filtered. The obtained filtrate was concentrated under reduced pressure to give the title compound (13.6 g, 46.5 wt% purity) as solid. ES-MS m/z 433 (M+H).
Preparation of Intermediate 192: tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- ethoxynicotinamido)-2-methylpiperidine-l -carboxylate
[0292] To a 1 L 1-neck round bottom flask with a magnetic stir bar was charged with DMF (300 mL), followed by addition of 2-cyclopropyl-6-ethoxynicotinic acid (50 g, 0.20 mol), DIEA (0.12 0.65 mol), HATU (95 g, 0.24 mol) and tert-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (58 g, 0.21 mol) at 16 °C (external temperature). The system was de-gassed and refilled with N2 for three times before vigorously stirring at 36 °C (external temperature) for 2 hours under N2. The reaction mixture was cooled down to r.t. and pour into IL ml H2O, white solids crashed out. The mixture was stirred for another 10 mins. The white precipitate was collected via filtration through the Buchner funnel, and the filter cake was washed with 200 ml H2O. tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- ethoxynicotinamido)-2-methylpiperidine-l-carboxylate (76 g) was obtained as white solid. ESMS m'z 447 (M+H).
Preparation of Intermediate 193: tert -butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- methoxynicotinamido)-2-methylpiperidine-l -carboxylate
[0293] To a 40 mL vial with a magnetic stir bar was charged with DMF (10 mL), followed by the addition of 2-cyclopropyl-6-methoxynicotinic acid (0.90 g, 4.61 mmol), tert-butyl (2S,4R)-4- amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (1.45 g, 5.58 mmol), HATU (2.68 g, 6.98 mmol) and DIPEA (1.84 g, 14.1 mmol) at ambient temperature, then stirred at 27 °C for 12 h. The reaction mixture was poured into H2O (50 mL) and then extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and then concentrated under reduced pressure to give the title compound (2.01g, 89 wt% purity) as solid. ES-MS m/z 433 (M+H). Preparation of Intermediate 194: tert-butyl 4-carbamoyl-4-(2-cyclopropyl-4- (trifluoromethyl)benzamido)piperidine-l -carboxylate
[0294] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMF (60 mL), followed by the addition of 2-cyclopropyl-4-(trifluoromethyl)benzoic acid (5.8 g, 24.8 mmol), DIPEA (6.8 g, 50.1 mmol), HATU (14.5 g, 37.4 mmol) and tert-butyl 4-amino-4- carbamoylpiperidine-1 -carboxylate (7.7 g, 30.1 mmol) at 20 °C. The mixture was de-gassed and refilled with N2 and stirred at 20 °C for 2 h, poured into ice water (50 mL) and stirred for 10 mins, then a lot of precipitate was observed and filtered. The filter cake was dried under reduced pressure to give the title compound (10.2 g, 46.2 wt% purity) as solid. ES-MS m/z 454 (M-H).
Preparation of Intermediate 195: tert-butyl 4-carbamoyl-4-(2-cyclopropyl-6-(trifluoromethyl) nicotinamido)piperidine-l -carboxylate
[0295] To a vigorous stirring DCM (40 mL) solution of tert-butyl 4-amino-4- carbamoylpiperidine-1 -carboxylate (5.85 g, 23.3 mmol) and TEA (5.90 g, 57.2 mmol) in a 100 ml 3-neck round bottom flask was added 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (5.00 g, 19.4 mmol) in DCM (10 mL) dropwise over 2 mins at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 100 mL (H2O) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (9.2 g, 52.9 wt% purity) as solid. ES-MS m 'z 457 (M+H).
Preparation of Intermediate 195 (Alternative Procedure): tert-butyl 4-carbamoyL4-(2- cyclopropyl-6-(trifluoromethyl)nicotinamido)piperidine-l-carboxylate
[0296] Tert-butyl 4-amino-4-carbamoylpiperidine-l -carboxylate (2.21 g, 9.08 mmol) was taken up in a mixture of Tetrahydrofuran (20 mL) and Sodium carbonate (2.0 M aqueous) (4.2 g, 20 mL, 2.00 molar, 4.6 Eq, 40 mmol) in a 250 mL RBF with stirring. Clear biphasic mixture. A solution of 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (2.16 g, 8.65 mmol) in Tetrahydrofuran (10 mL) was added over ca. 2 min. Some exotherm observed, flask slightly warmed to the touch. After two hours, a solid had formed in the mixture, which remained fully stirring, diluted to ca. 0.12 L with water. The mixture became thick but freed up with increased stir rate. The next day, the solid was collected by filtration (6 cm paper filter on porcelain funnel, moderate rate) and washed with water (0.2 L). Dried in the vacuum oven at 50 °C for 8 hours to provide tert-butyl 4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (3.21 g). ES-MS m/z 457 (M+H).
Preparation of Intermediate 196: tert-butyl 2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo- l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate
[0297] To a 250 mL one-neck round bottom flask with a refluxing condenser with a magnetic stir bar was charged with EtOH (60 mL), followed by the addition of tert-butyl 4-carbamoyl-4- (2-cyclopropyl-4-(trifluoromethyl)benzamido)piperidine-l-carboxylate (10.2 g, 46.2 wt% purity, 10.3 mmol) and KO/Bu (6.22 g, 6.4 mL, 54.3 mmol) in one portion at 20 °C. Then the reaction mixture was stirred vigorously at 80 °C for 1 h, cooled down to RT, poured into H2O (100 mL) at 20 °C and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane: EtOAc, UV) R/= 0.6. The residue was purified by flash silica gel chromatography using a gradient of 20 to 60% EtOAc in n-hexane to give the title compound (3.9 g) as solid. ES-MS m z 438 (M+H).
[0298] The following intermediates were prepared essentially the same as in Preparation 196 and using the appropriate precursor and dehydration reaction.
Preparation of Intermediate 204: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride
[0299] A solution of HC1 (50 mL, 9.1 g, 5 M, 250 mmol) in 1,4-Dioxane was added to a solution of tert-butyl (5R, 7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyri din-3-yl)-7-m ethyl -4-oxo-l, 3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (12.6 g, 27.8 mmol) in 1,4-Dioxane (250 mL) under N2 atmosphere and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the tittle compound (12.5 g) as a solid. ES-MS m/z 352 (M+H).
The following intermediates were prepared in essentially the same way as for intermediate 204.
Preparation of Intermediate 208: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 7 -methyl- 1,3, 8-triazaspiro[4.5 ] dec- 1 -en-4-one
[0300] To a 250 mL 1-neck round bottom flask with a magnetic stir bar was charged with EtOAc (20 mL), followed by the addition of tert -butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluorom ethyl) pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (6.2 g, 13 mmol) and HC1 (4.0 M in EtOAc, 60 mL) at 0 °C. Then the reaction mixture was stirred vigorously at 10 °C for 12 h, concentrated under reduced pressure directly to give a residue. The residue was adjusted to pH = 7~8 with sat. aq. NaHCOs at 10 °C and further purified by reverse phase prep- HPLC using a gradient of 10 to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (4.0 g) as solid. ES-MS m/z 353 (M+H).
The following intermediates were prepared in essentially the same way as for intermediate 208.
Preparation of Intermediate 215: 4-chloro-2-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzonitrile
[0301] To a 40 mL vial with a magnetic stir bar was charged with DMSO (5 mL), followed by the addition of 2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.50 g,1.46 mmol), 4-chloro-2,6-difluorobenzonitrile (0.29 g, 1.61 mmol) and DIPEA (0.56 g, 0.75 mL, 4.25 mmol) at 20 °C. The mixture was purged with N2 and stirred at 80 °C for 16 h under N2. The reaction mixture was quenched by adding H2O (10 mL) and extracted with EtOAc (10 mL x 3) The combined organic layers were washed with brine (15 mb), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (3: 1 n- hexane: EtOAc, UV) Ry = 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.45 g) as a solid. ES-MS m/z 491, 493 (M+H).
[0302] The following intermediates were prepared in essentially the same way as for intermediate 215 using the appropriate aryl fluoride and amine.
Preparation of Intermediate 230: 4-bromo-2-((5R,7S)-2,2,7-trimethyl-4-oxo-l,3,8- triazaspiro[4.5]decan-8-yl)benzonitrile
[0303] To a 500 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMSO (200 mL), followed by the addition of (5R,7S)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one dihydrochloride (20 g, 87.7 wt% purity, 65 mmol), 4-bromo-2- fluorobenzonitrile (24 g, 120 mmol) and K2HPO4 (92 g, 528 mmol) at 28 °C. Then the reaction mixture was stirred at 130 °C for 12 h, cooled down to ambient temperature, then diluted with H2O (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (10: 1 DCM : MeOH) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 80% MeOH in DCM to give the title compound (11.1 g) as solid. ES-MS m z 376, 378 (M+H).
Preparation of Intermediate 231 : 8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl) pyridin-3-yl)-l,3,8-triazaspiro [4.5] dec-l-en-4-one
[0304] To a 40 ml vial with a magnetic stir bar was charged with toluene (4 mL), 2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.44 g, 1.14 mmol), l-bromo-5-chloro-3-fluoro-2-methoxybenzene (0.558 g, 2.28 mmol) and sodium 2- methylbutan-2-olate (30% Wt in THF, 2 mL, 5 mmol). The mixture was purged with N2 for 2 mins before and after adding Methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)- 3,6-dimethoxy-2',6'-bis(dimethylamino)-l,T-biphenyl) (2'-methylamino-l,T-biphenyl-2-yl) palladium (II) (FrankenPhos Palladacycle Gen. 4, CAS# 1810068-35-9, 0.265 g, 0.228 mmol). Then the reaction mixture was stirred at 100 °C for 2 h under N2, cooled down to RT, then directly concentrated under reduced pressure to give a residue. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the crude product. TLC (1 : 2, EtOAc : n-hexane, UV) R/= 0.5. The crude product was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to give the title compound (0.090 g) as solid. ES-MS m z 497, 499 (M+H).
Preparation of Intermediate 231 (Alternative Procedure): 8-(5-chloro-3-fluoro-2- methoxyphenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l- en-4-one
[0305] 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (442 mg, 1.07 mmol) was first converted to the freebase by dissolving in MeOH and loading onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each), then eluted, collected, and concentrated 7 M NH3 in MeOH to give a residue, which was slurried in toluene (10 mL). l-Bromo-5-chl oro-3 -fluoro-2-m ethoxybenzene (415 mg, 1.73 mmol) was added and N2 was bubbled through the solution for 15 min. Added sodium 2-methylbutan-2-olate in 2-Me- THF (1.59 g, 1.75 mL, 30% Wt, 4.34 mmol) while continuing to bubble N2 until mixture was a homogenous solution. Added FrankenPhos Pd G4 (125 mg, 110 pmol), sealed and heated via microwave irradiation to 90°C for 6 hours. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction SCX2 containing the desired product. Concentrated to a residue that was further purified by reverse phase prep-HPLC using a gradient of 40 to 80% ACN in 0.1% formic acid in water to give the title compound (0.255 g) as a solid. ES-MS m/z 497 (M+H).
[0306] The following intermediates were prepared essentially the same way as for intermediate 231 using the appropriate amine and aryl bromide.
Preparation of Intermediate 237: 8-(5-bromo-3-fluoro-2-(hydroxymethyl) phenyl)-2-(2- cyclopropyl-6-ethoxypyridin-3-yl)-l,3,8-triazaspiro [4.5] dec-l-en-4-one
[0307] To 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DCM (20 mL), followed by the addition of methyl 4-bromo-2-(2-(2-cy cl opropyl-6-ethoxypyri din-3 - yl)-4-oxo-l,3,8-triazaspiro [4.5] dec-l-en-8-yl)-6-fluorobenzoate (2.2 g, 3.7 mmol) at -68 °C. Then diisobutylaluminum hydride (4.0 M in toluene, 15 mL, 15 mmol) was added dropwise at - 68 °C. The reaction mixture was stirred vigorously at -68 °C for 2 h, quenched by adding HC1 (1.0 M in H2O, 15 mL) at 0 °C and then diluted with H2O (100 mL) and extracted with DCM (50 mL x 3) The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The obtained filtrate was concentrated under reduced pressure to give a residue. TLC (1: 1 n-hexane: EtOAc) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (1.1 g, 87.8 wt% purity) as solid. ES-MS m/z 517, 519 (M+H).
Preparation of Intermediate 238: 8-(5-bromo-3-fluoro-2-(hydroxymethyl) phenyl)-2-(2- cyclopropyl-6-ethoxypyridin-3-yl)-3-(4-methoxybenzyl)-l,3,8-triazaspiro [4.5] dec-l-en-4-one
[0308] To a 100 mL one-neck round bottom flask with a magnetic stir bar was charged with DMF (10 mL), followed by the addition of 8-(5-bromo-3-fluoro-2-(hydroxymethyl) phenyl)-2- (2-cyclopropyl-6-ethoxypyridin-3-yl)-l,3,8-triazaspiro [4.5] dec- 1-en -4-one (0.60 g, 87.8 wt% purity, 1.02 mmol), l-chloromethyl-4-methoxy-benzene (0.32 g, 2.04 mmol) and K2CO3 (0.42 g, 3.03 mmol). Then the reaction mixture was stirred vigorously at 50 °C for 6 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and fdtered. The obtained filtrate was concentrated under reduced pressure to give a crude product. TLC (1 : 1 n-hexane: EtOAc) Ry = 0.4. The crude product was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (0.60 g, 87.3 wt% purity) as solid. ES-MS m'z 637, 639 (M+H).
Preparation of Intermediate 239: 8-(5-bromo-2-((difluoromethoxy)methyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-ethoxypyridin-3-yl)-3-(4-methoxybenzyl)-l,3,8-triazaspiro [4.5] dec-l-en-4-one
[0309] To a 40 mb vial with a magnetic stir bar was charged with DCM (5 mb), followed by the addition of 8-(5-bromo-3-fluoro-2-(hydroxymethyl) phenyl)-2-(2-cyclopropyl-6-ethoxypyridin- 3-yl)-3-(4-methoxybenzyl)-l,3,8-triazaspiro [4.5] dec-l-en-4-one (0.60 g, 87.3 wt% purity, 0.82 mmol), (bromodifluoromethyl)trimethylsilane (0.34 g, 1.67 mmol) and potassium bifluoride (0.26 g, 3.36 mmol). Then the reaction mixture was stirred vigorously at 19 °C for 12 h, diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over ISfeSCL and filtered. The obtained filtrate was concentrated under reduced pressure to give a crude product which was purified by prep-TLC (SiC>2, 1 :2 EtOAc: n-hexane, R/= 0.4, UV), then the SiCh powder was soaked with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.055 g, 85.8 wt% purity) as solid. ES-MS m/z 687, 689 (M+H).
Preparation of Intermediate 240: rac-2-(3'-(2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-3-(4- methoxybenzyl)-4-oxo-l, 3, 8-tri azaspiro [4.5] dec-l-en-8-yl)-4'-((difluoromethoxy)methyl)-5'- fluoro-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2-hydroxyacetamide (racemic mixture)
[0310] To an 8 mL vial with a magnetic stir bar was charged with 1,4-Di oxane (1 mL), H2O (0.2 mL), 8-(5-bromo-2-((difluoromethoxy)methyl)-3-fluorophenyl)-2-(2-cyclopropyl-6- ethoxypyridin-3-yl)-3-(4-methoxybenzyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.055 g, 85.8 wt% purity, 0.69 mmol), 7zzc-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.025 g, 0.080 mmol) and potassium carbonate (0.032 g, 0.23 mmol). The mixture was purged with N2 for 1 min before and after adding methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.006 g, 0.007 mmol). Then the reaction mixture was stirred at 80 °C for 1 h under N2. The crude reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiCh, 1 : 1 EtOAc: n-hexane, Ry = 0.4, UV), then the SiCh powder was soaked with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.060 g, 38.7 wt% purity) as oil. ES-MS m z 786 (M+H).
Preparation of Intermediate 241 : (2S,4R)-4-amino-l-(5-bromo-2-cyanophenyl)-2- methylpiperidine-4-carboxamide
[0311] To a 1 L 1-neck round bottom flask with a magnetic stir bar was charged with MeOH (300 mL) and H2O (100 mL), followed by the addition of 4-bromo-2-((5R,7S)-2,2,7-trimethyl-4- oxo-l,3,8-triazaspiro[4.5]decan-8-yl)benzonitrile (11.1 g, 28.4 mmol) and HC1 (1.0 M in H2O, 55 mL, 55 mmol) at 10 °C. The reaction mixture was stirred at 100 °C for 24 h, cooled down to ambient temperature, then adjusted to pH = 8 with sat. aq. NaHCOs. The mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (10: 1 DCM : MeOH) Ry = 0.3. The residue was purified by flash silica gel chromatography using a gradient of 0 to 60% MeOH in DCM to give the title compound (8.1 g) as solid. ES-MS m/z 336, 338 (M+H).
Preparation of Intermediate 242: (2S,4R)-4-amino-l-(5-bromo-2-cyano-3-fluorophenyl)-2- methylpiperidine-4-carboxamide
[0312] To a 500 mL 1-neck round bottom flask with a refluxing condenser with a magnetic stir bar was charged with MeOH (100 mL) and H2O (100 mL), followed by the addition of 4-bromo- 2-fluoro-6-((5R,7S)-2,2,7-trimethyl-4-oxo-l,3,8-triazaspiro [4.5] decan-8-yl) benzonitrile (2.95 g, 7.32 mmol) and HC1 (1.0 M in H2O, 11 mL, 11 mmol) at 22 °C. Then the reaction mixture was stirred vigorously at 100 °C for 2 days, then adjusted to pH = 8 by sat. aq. NaHCCL (30 mL). The aqueous phase was extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (200 mL), dried with NazSCU and filtered. The filtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) R = 0.15. The residue was purified by flash silica gel chromatography using a gradient of 0 to 80% EtOAc in petroleum ether to give the title compound (1.86 g) as solid. ES-MS m z 355, 357 (M+H).
Preparation of Intermediate 243: (5R,7S)-8-(5-chloro-3-fluoro-2-methoxyphenyl)-2,2,7- trimethyl-l,3,8-triazaspiro[4.5]decan-4-one
[0313] Dissolved (5R,7S)-8-(5-chloro-3-fluoro-2-methoxyphenyl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (345 mg, 970 pmol) in MeOH (10 mL). Added Water (10 mL) which caused a slurry to form. Added HC1 (5M in water) (300 pL, 5 molar, 1.50 mmol). Returned to a solution. Heated to 95 °C with reflux condenser attached and under N2 for 3 days, then increased heat to 100°C. Continued overnight, then cooled to RT. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction SCX2. Concentrated to a crude residue that was purified by reverse phase prep-HPLC using a gradient of 25 to 60% ACN in 10 mM NH4HCO3 to give the title compound (0.108 g) as a solid. ES-MS m z 616 (M+H). Preparation of Intermediate 244: (2S,4R)-l-(5-bromo-2-cyanophenyl)-4-(2-cyclopropyl-4-
(trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide
[0314] To a 100 m 3-neck round bottom flask with a magnetic stir bar was charged with DMF (15 mL) and (2S,4R)-4-amino-l-(5-bromo-2-cyanophenyl)-2-methylpiperidine-4-carboxamide (1.50 g, 4.36 mmol), followed by the addition of HATU (2.06 g, 5.36 mmol) and DIPEA (1.70 g, 2.29 mL, 13.0 mmol) at 20 °C. The mixture was stirred for 15 mins at 20 °C and then 2- cyclopropyl-4-(trifluoromethyl) benzoic acid (1.16 g, 4.75 mmol) was added. The mixture was vigorously stirred at 20 °C for 16 h. Then the reaction mixture was added to ice water (100 mL) under stirring and filtered. The obtained solid was dried under reduced pressure to give the title compound (2.1 g, 82.6 wt% purity) as a solid. ES-MS m/z 549, 551 (M+H).
[0315] The following intermediates were prepared essentially the same as for intermediate 244 using the appropriate carboxylic acid and amino-amide.
Preparation of Intermediate 250: 5-chloro-2-(trimethylsilyl)phenol
[0316] To a vigorous stirring THF (500 mL) solution of 2-bromo-5-chlorophenol (50.0 g, 229 mmol) in a 2 L 1-neck bottle was added HMDS (187 g, 1149 mmol) at 20 °C. The mixture was stirred at 80 °C for 14 h, cooled down to ambient temperature and then concentrated under reduced pressure to give a residue. The residue was added in a 2 L 3 -neck round bottom flask with THF (500 mL), purged with N2 for 3 times. Then n-butyllithium (2.5 M in hexane, 137 mL) was added dropwise over 50 mins at -70 °C under N2. The resulting mixture was stirred at - 70 °C for 1.5 h, then poured into sat. aq. NH4CI (1.0 L) at 0 °C and then extracted with EtOAc (1.0 L x 3). The combined organic layer was washed with brine (1.0 L), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (5: 1 n- hexane : EtOAc) Ry = 0.7. The residue was purified by flash silica gel chromatography using a gradient of 0 to 15% EtOAc in n-hexane to give the title compound (34 g, 89.4 wt% purity) as oil. ES-MS m/z 199, 201 (M-H). Preparation of Intermediate 251 : 5-chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate
[0317] To a 1 L 3-neck round bottom flask with a magnetic stir bar was charged with DCM (340 mL), followed by the addition of 5-chloro-2-(trimethylsilyl)phenol (34 g, 89.4 wt% purity, 151 mmol) and DIPEA (39.3 g, 301 mmol) at 20 °C. Then trifluoromethanesulfonic anhydride (64.7 g, 227 mmol) was added dropwise over 20 mins at 0 °C. The reaction mixture was stirred vigorously at 20 °C for 2 h, poured into H2O (600 mL) at 20 °C and then extracted with DCM (600 mL x 3). The combined organic layer was washed with brine (600 mL), dried over ISfeSCU, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 75 to 95% ACN in 10 mM aq. NH4HCO3 to give the title compound (30.5 g) as oil. ES-MS m/z 331 (M-H).
Preparation of Intermediate 252: (5R,7S)-8-(5-chloro-2-iodophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0318] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with DME (50 mL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyri din-3 -yl)- 7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (5.0 g, 14.0 mmol), 3-bromo-2- iodobenzo[b]thiophene (5.34 g, 15.4 mmol), potassium fluoride (1.65 g, 28.1 mmol) and 18- crown-6 (7.49 g, 28.1 mmol) at 20 °C. Then 5-chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (5.14 g, 15.4 mmol) in DME (50 mL) was added dropwise over 10 min at 20 °C. The suspension was degassed and purged with N2 for 3 times. The reaction mixture was stirred vigorously at 20 °C for 3 h, poured into H2O (200 mL) at 20 °C and then extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (200 mL), dried over ISfeSCU, fdtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 60 to 98% MeCN in 10 mM aq. NH4HCO3 to give the title compound (0.80 g) as solid. ES-MS m/z 589, 591 (M+H).
Preparation of Intermediate 253: (5R,7S)-8-(5-chloro-2-ethylphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0319] To a 40 mL vial with a magnetic stir bar was charged with 1,4-dioxane (10 mL), followed by the addition of cobaltousphthalocyaninate (0.434 g, 0.752 mmol), (SP-4-2)-[4,4’-bis(l, l- dimethylethyl)-2,2’-bipyridine-KNl,KNr]dibromo-Nickel (0.018g, 0.037 mmol) in glovebox. Then (5R,7S)-8-(5-chloro-2-iodophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.24 g, 0.373 mmol) and iodoethane (0.354g, 2.25 mmol) was added to the mixture. The vial was sonicated until the mixture was a uniform suspension, then brought back into the glovebox. Tetrakis(dimethylamino)ethylene (0.304 g, 1.50 mmol) was added. The mixture was stirred at 80 °C for 1 h, diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 60 to 90% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.060 g) as solid. ES-MS m/z 491, 493 (M+H).
Preparation of Intermediate 254: 2-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile [0320] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with methoxycyclopentane (20 mL) and 4-bromo-2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (1.54 g, 87.0 wt% purity, 2.52 mmol), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (1.10 g, 4.25 mmol), KO Ac (0.985 g, 9.23 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l, T-biphenyl)(2'-methylamino- l, T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.243 g, 0.276 mmol) at 17 °C. The mixture was de-gassed and backfilled with N2 for three times before vigorously stirring at 80 °C for 2 h, then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure at 45 °C to give a crude product. TLC (2: 1 petroleum ether : EtOAc) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (1.3 g) as solid. ESMS m z 497 (boronic acid, M+H).
[0321] The following intermediates were made essentially the same as intermediate 254 using the appropriate aryl halide.
Preparation of Intermediate 258: methyl 3'-((5R,7S)-2-(l-butyl-3-(trifluoromethyl)-lH-pyrazol- 4-yl)-7-methyl-4-oxo-l,3,8-triazaspiro [4.5] dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,l'- biphenyl]-4-carboxylate
[0322] To a 40 mL vial with a magnetic stir bar was charged with MeOH (5 mL), followed by addition of 4-bromo-2-((5R,7S)-2-(l -butyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (0.40 g, 84.8 wt% purity, 0.631 mmol), methyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.21 g, 0.717 mmol), K2CO3 (0.264 g, 1.89 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri- i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.061 g, 0.069 mmol) at 15 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 80 °C for 2 h, then cooled to ambient temperature and concentrated under reduced pressure to give the residue. The residue was dissolved in H2O (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL * 2), dried over N^SCL, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.41 g, 49.6 wt% purity) as solid. ES-MS m/z 621 (M+H).
[0323] The following intermediates were prepared essentially the same as intermediate 258 using the appropriate aryl halide.
Preparation of Intermediate 262: methyl 4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,T- biphenyl]-4-carboxylate
[0324] To a 10 ml 1-neck round bottom flask with a magnetic stir bar was added 2-((5R,7S)-2- (2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (0.25 g, 0.419 mmol), methyl 4- bromo-3,5-dimethylbenzoate (0.16 g, 0.638 mmol), K3PO4 (0.283 g, 1.32 mmol), 1,4-dioxane (3 mb) and H2O (0.3 mL) at 12 °C. The mixture was de-gassed and backfilled with N2 for three times before and after adding methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl- l,r-biphenyl)(2'-methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.04 g, 0.046 mmol) in one portion at 12 °C, then stirred at 100 °C for 1 h, cooled to ambient temperature and quenched by H2O (5 mL). Then the mixture was diluted with EtOAc (5 mL) and extracted with EtOAc (10 mL * 2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by prep-TLC (SiO2, 1 :2 EtOAc : n-hexane, Rf = 0.5, UV), then the SiO2 powder was soaked with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.15 g) as solid. ES-MS mz 615 (M+H).
Preparation of Intermediate 263: (R)-l-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)ethane- 1 ,2-diol
[0325] 1 L round bottom flask with a magnetic stir bar was charged (R)-l-(4-bromo-3,5- dimethylphenyl)ethane-l,2-diol (5.22 g, 21.3 mmol), bis(pinacolato)diboron (7.99 g, 31.5 mmol), 1,4-dioxane (60 mL) and sparged with N2. Potassium acetate (6.26 g, 63.8 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.53 g, 2.09 mmol) were added and the reaction mixture was warmed to 100 °C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a pad of celite. The resulting solution was concentrated under reduced pressure to a residue. The residue was diluted with EtOAc, washed with water (500 mL). The aqueous solution was extracted with EtOAc (5 x 100 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography on silica gel (40-80% EA in cyclohexane) to afford the tittle compound (3.75 g). ES-MS m/z 293 (M+H).
Preparation of Intermediate 264: (R)-l-(4-bromo-3,5-dimethylphenyl)ethane-l,2-diol
[0326] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with AD- mix-beta (2.1 g, 98% wt, 1.3 mmol), the system was de-gassed and backfilled with N2 for three times before and after adding t-BuOH (10 mL) and H2O (10 mL). Then the reaction mixture was cooled to 0 °C, then slowly added 2-bromo-l,3-dimethyl-5-vinylbenzene (302 mg, 94.8% Wt, 1.36 mmol). The mixture was warmed to 27 °C stirred for 12 h under N2. The reaction mixture was poured into 20 mL H2O at 25 °C, and then extracted with ethyl acetate (15 mL * 3). The combined organic layers were washed with brine (15 mL * 1), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The water phase was quenched by added Na2SOs solution (IN in water) 20 mL, then was discarded. The residue was purified by prep- TLC (SIO2, petroleum ether/ethyl acetate = 1/2, Rf = 0.6), then the SiCh powder was soaked with 30 ml ethyl acetate, and filtered via suction filter, the filter cake was rinsed with 15 mL DCM. The (R)-l-(4-bromo-3,5-dimethylphenyl)ethane-l,2-diol (187 mg) was obtained as a solid after evaporation. Optical rotation analytical report is consistent with desired product OR, -49.29. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.00 (s, 2H), 4.66 (dd, J = 3.6, 8.0 Hz, 1H), 3.73 - 3.63 (m, 1H), 3.62 - 3.51 (m, 1H), 2.34 (s, 6H).
Preparation of Intermediate 265: N-(4-bromo-3,5-dimethylphenyl)-4-chlorobutanamide
[0327] To a solution of 4-bromo-3,5-dimethylbenzenamine (3.00 g, 15.0 mmol) in DCM (25 mL) was added Na2CO3 (1.27 g, 12.0 mmol) and 4-chlorobutanoyl chloride (2.18 mL, 19.5 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was added H2O (50 mL), then extracted with EtOAc (50 mL * 3), the combined organic layer was washed with brine (100 mL), dried over anhydrous Nai CM, filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound N-(4-bromo-3,5-dimethylphenyl)-4- chlorobutanamide (4.42 g) was obtained as a solid and used directly in the next step. ES-MS m/z 304, 306 (M+H). Preparation of Intermediate 266: l-(4-bromo-3,5-dimethylphenyl)pyrrolidin-2-one
[0328] To a solution of N-(4-bromo-3,5-dimethylphenyl)-4-chlorobutanamide (2.00 g, 5.03 mmol) in THF (20 mL) was added 2-methylpropan-2-olate potassium (1.16 mL, 10.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a solid. The reaction mixture was added H2O (lOOmL) and extracted with EtOAc (50 mL * 3), the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~9% EA/PE @ 50 mL/min). (TLC: PE/EA=5:1, Rf=0.2, UV) The title compound (1.233 g) was obtained as a solid. ES-MS m z 268/270 (M+H).
Preparation of Intermediate 267: 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzamide
[0329] To a 250 mL 1-neck round bottom flask with a refluxing condenser with a magnetic stir bar was charged with 1,4-dioxane (50 mL), 4-bromo-3,5-dimethyl-benzamide (5 g, 21.7 mmol), KOAc (6.44 g, 60.4 mmol) and bis(pinacolato)diboron (7.25 g, 28.3 mmol). The mixture was de-gassed and backfilled with N2 for three times before and after adding [1,1- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS# 72287-26-4, 1.61 g, 2.18 mmol). Then the reaction mixture was stirred at 100 °C for 12 h under N2, then cooled down to 25 °C, filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) Ry = 0.45. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the crude product, which was purified by normal phase prep-HPLC using a gradient of 0 to 20% EtOH in heptane to give the title compound (3.55 g) as solid. ES-MS m z 276 (M+H).
Preparation of Intermediate 268: (4-bromo-3,5-dimethylphenyl)methanol
[0330] To a vigorous stirring MeOH (1400 mL) solution of 4-bromo-3,5-dimethylbenzaldehyde (136 g, 631.9 mmol) in a 2 L 3-neck round bottom flask was added NaBH4(50.1 g, 1300 mmol) in portions at 0 °C. The mixture was stirred at 15 °C for 2 h, quenched by adding HC1 (1.0 M in H2O, 1.2 L) at 15 °C to pH = 7, and then extracted with DCM (800 mL * 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (134 g) as solid. 1 H-NMR (400 MHz, DMSO-t/e) 8 7.11 (s, 2H), 5.19 (t, J = 5.7 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 2.35 (s, 6H).
Preparation of Intermediate 269: 2-bromo-5-(chloromethyl)-l,3-dimethylbenzene
[0331 ] To a 2 L 3-neck round bottom flask with a magnetic stir bar was charged with DCM (1.34 L) and DMF (7 mL), followed by the addition of (4-bromo-3,5-dimethylphenyl)methanol (134 g, 578 mmol) and thionyl chloride (209 g, 128 mL, 1740 mmol) at 0 °C. Then the reaction mixture was stirred vigorously at 15 °C for 2 h, concentrated under reduced pressure to give the title compound (145 g, 77.7 wt% purity) as oil. TLC (5 : 1 n-hexane : EtOAc, UV) R = 0.7.
Preparation of Intermediate 270: 2-(4-bromo-3,5-dimethylphenyl)acetonitrile
[0332] To a 3 L 1-neck round bottom flask with a magnetic stir bar was charged with DMSO (1400 mL), followed by the addition of 2-bromo-5-(chloromethyl)- 1,3 -dimethylbenzene (145 g, 77.7 wt % purity, 482 mmol), KCN (103 g, 1566 mmol) at 25 °C. The mixture was stirring at 25 °C for 16 h. The reaction mixture was quenched by added to H2O (2.0 L) at ambient temperature, and then diluted with EtOAc (800 mL) and extracted with EtOAc (800 mL * 2). The aqueous phase was added to adjust pH = 13 and then poured to aq. NaClO (10%, 5 L). The combined organic layer was washed with brine (500 mL), dried over Na2SC>4 and filtered. The obtained filtrate was concentrated under reduced pressure to give the title compound (135 g, 80 wt% purity) as solid. 'H-NMR (400 MHz, DMSO-t/6) 5 7.16 (s, 2H), 3.95 (s, 2H), 2.36 (s, 6H).
Preparation of Intermediate 271 : 2-(4-bromo-3,5-dimethylphenyl)acetamide
[0333] To a 3 L 3 -neck round bottom flask with a magnetic stir bar was charged with DMSO (1.4 L), followed by the addition of 2-(4-bromo-3,5-dimethylphenyl)acetonitrile (135 g, 80 wt% purity, 481 mmol) and K2CO3 (80.2 g, 574 mmol) at 20 °C. Then H2O2 (30% Wt in H2O, 100 mL, 979 mmol) was added dropwise for 10 min at 10 °C. The reaction mixture was stirred at 20 °C for 16 h, quenched by adding H2O (4.5 L) at 20 °C, then filtered. The filter cake was rinsed with H2O (1.0 L), then collected and dried under reduced pressure at 45 °C to give a crude product, which was triturated with MTBE (2.0 L) at 20 °C for 2 h to give the title compound (122.9 g, 80.5 wt% purity) as solid. ES-MS m/z 242, 244 (M+H).
Preparation of Intermediate 272: methyl 2-(4-bromo-3,5-dimethylphenyl)acetate
[0334] To a 100 mL one-neck round bottom flask with a magnetic stir bar was charged with MeOH (20 mL), followed by the addition of 2-(4-bromo-3,5-dimethylphenyl)acetamide (2.0 g, 80.5 wt% purity, 6.6 mmol) at 15 °C. Then HC1 (4.0 M in MeOH, 20 mL, 80 mmol) was added at 15 °C. The reaction mixture was stirred at 80 °C for 2 h, cooled down to ambient temperature, concentrated under reduced pressure directly to give the residue. The residue was diluted with 10 mL (H2O) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.7 g, 84.9 wt% purity) as solid. 'H-NMR (400 MHz, CHLOROFORM-c/) 8 7.00 (s, 2 H), 3.70 (s, 3 H), 3.53 (s, 2 H), 2.40 (s, 6 H).
Preparation of Intermediate 273: 2-(4-bromo-3,5-dimethylphenyl)ethan-l-ol
[0335] To a vigorous stirring THF (10 mL) solution of methyl 2-(4-bromo-3,5- dimethylphenyl)acetate (0.50 g, 84.9 wt% purity, 1.65 mmol) in a 100 ml three-neck round bottom flask was added aluminum lithium hydride (2.5 M in THF, 1.0 mL, 2.5 mmol) dropwise over 2 mins at 0 °C. The reaction mixture was de-gassed and refdled with N2 for three times, stirred at 18 °C for 2 h, then poured into aq. NaOH (10%, 10 mL) at 0 °C and extracted with EtOAc (8 mL x 3). The combined organic layer was washed with brine (15 mL), dried over Na2SC>4 and fdtered. The filtrate was concentrated under reduced pressure to give the title compound (0.40 g, 74.8 wt% purity) as oil. ’HNMR (400 MHz, DMSO-t/6) 8 7.02 (s, 2 H), 4.62 (t, J= 5.26 Hz, 1 H), 3.57 (td, J= 6.91, 5.38 Hz, 2 H), 2.57 - 2.68 (m, 2 H), 2.32 (s, 6 H).
Preparation of Intermediate 274: rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture)
[0336] To a 2 L 3-neck round bottom flask with a magnetic stir bar was charged with H2O (500 mL), followed by the addition of 4-bromo-3,5-dimethylbenzaldehyde (100 g, 460 mmol) and NaCN (55.27 g, 1099 mmol) at 20 °C. Then a solution of NaHSCL (110 g, 1037 mmol) in H2O (500 mL) was added dropwise at 0 °C over 40 min. The reaction mixture was stirred at 20 °C for 15 h, then filtered. The filtrate was adjusted to pH = 11 with NaOH (1.0 M in H2O), and poured into aq. NaClO (10%, 2 L) to quench the unreacted NaCN. The filter cake was washed with H2O (300 mL x 3) to give the title compound (120 g, 85 wt% purity) as solid. 'H-NMR (400 MHz, DMSO-t >) 8 7.70 (s, 1H), 7.28 (s, 2H), 5.67 (s, 1H), 2.39 (s, 6H).
Preparation of Intermediate 275: rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetamide (racemic mixture)
[0337] To a mixture of rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture, 120 g, 85 wt% purity, 425 mmol) in a 2 L 3-neck round bottom flask was added HC1 (4.0 M in 1,4-dioxane, 1.0 L) dropwise over 30 mins at 0 °C. The reaction mixture was stirred at 20 °C for 2 h, adjusted to pH = 7 with sat. Na2CCh and many solids precipitated. The mixture was filtered and the filter cake was triturated with H2O (100 mL) and MTBE (100 mL) at 25 °C for 30 mins, filtered and the filter cake was dried under reduced pressure to give the title compound (86 g) as solid. ES-MS m'z 257, 259 (M+H).
Preparation of Intermediate 276: rac-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2 -hydroxyacetamide (racemic mixture)
[0338] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with 1,4- dioxane (100 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-2- hydroxyacetamide (racemic mixture, 10.0 g, 36.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (11.1 g, 42.8 mmol), KOAc (10.5 g, 98.4 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (CAS# 72287-26-4, 1.43 g, 1.92 mmol) at 25 °C. The mixture was de-gassed and refilled with N2 for three times, stirred at 100 °C for 15 h, cooled down to ambient temperature and filtered. The filtrate was poured into H2O (200 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (10: 1 DCM : MeOH) R/= 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 25% MeOH in DCM to give a residue, which was triturated with MTBE (20 mL) at 20 °C for 30 mins, filtered and the filter cake was the title compound (4.30 g) as solid. ES-MS m/z 305 (M+H).
Preparation of Intermediate 277: 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide
[0339] A mixture of 4-bromo-3,5-dimethylbenzamide (3.1 g, 1 Eq, 14 mmol) 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.2 g, 1.2 Eq, 17 mmol),palladium(II) acetate (0.7 g, 0.2 Eq, 3 mmol),tris(4-methoxyphenyl)phosphane (1.0 g, 0.21 Eq, 2.8 mmol)and cesium carbonate (13.2 g, 3.0 Eq, 40.5 mmol). 1,4-di oxane (68 mL) was sparged with argon for 30 seconds, and the reaction was heated to 70 °C. Reaction was cooled to RT. The reaction was diluted with water (100 mL), extracted with EtOAc (30mLx3) and the organics were combined and concentrated onto celite. The residue was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in heptane to give the title compound (2.6 g). ES-MS m/z 276(M+H).
Preparation of Intermediate 278: l-bromo-5-chloro-3,4-difluoro-2-methoxybenzene;
[0340] Dissolved 6-Bromo-4-chloro-2,3-difluorophenol (515 mg, 2.12 mmol) in DMF (15 mL). Added potassium carbonate (618 mg, 4.47 mmol) and stirred at RT for 2-3 min, then added methyl iodide (2M in MTBE) (1.60 mL, 2.0 molar, 3.20 mmol). Stirred at RT overnight. Poured into NaHCC>3(aq) and extracted with EtOAc (3x). Washed the combined organic layers with brine, dried over MgSO4, filtered and concentrated. The sample was dissolved in minimal DCM and loaded onto a 12g silica gel loading column then purified using a 40g silica gel column that was eluted with a 0-10-25% Ethyl Acetate/Cyclohexanes gradient to give the title compound (0.445 g). 'H-NMR (400 MHz, DMSO-tL) 8 7.86 (dd, J = 7.5, 2.5 Hz, 1H), 3.95 (d, J = 1.7 Hz, 3H).
Preparation of Intermediate 279: 3-(4-bromo-3,5-dimethylphenoxy)propane-l,2-diol
[0341] A 100 mL RBF was charged with 1 -Bromo- 1 -deoxy glycerol (0.95 g, 0.54 mL, 6.1 mmol), 3,5-Dimethyl-4-bromophenol (1.00 g, 4.97 mmol), ACN (10 mL) and stirred at 90 °C (external) for and stirred for 1 h. The reaction mixture was allowed to continue stirring for 17 hours. The reaction was quenched with 10 mL of a 1 N HC1 solution and stirred for 20 min. The resulting solution was extracted twice with EA (30 mL), the combined organic layers were washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a colorless oil. The oil was purified by flash chromatography on silica gel (0-60% EA in cyclohexane) to afford the title compound (963.7 mg) as a solid. !H NMR (400 MHz, DMSO) 5 6.80 (s, 2H), 4.93 (d, J= 5.0 Hz, 1H), 4.66 (t, J= 5.6 Hz, 1H), 3.96 (dd, J = 9.7, 4.1 Hz, 1H), 3.80 (ddd, .7= 25.8, 10.4, 5.8 Hz, 2H), 3.43 (s, 2H), 2.32 (s, 6H).
Preparation of Intermediate 280: 2-(4-bromo-3,5-dimethylphenyl)acetic acid
[0342] To a 3000 ml 3-necked flask, equipped with N2 protection and a magnetic stirrer at 25°C, added 2,6-Dimethyl-4-iodobromobenzene (150.5 g, 484.0 mmol), DMSO (1 L), ethyl, 3- oxobutanoate (189.50 g, 1.4561 mol), potassium phosphate, tribasic (308.5 g, 1.453 mol), EtOH anhydrous (85 mL,1.5 mol), Cui (18.8 g, 98.7 mmol) (green and white suspension), and then purged with N2 for 3 times. Slowly warmed to 80°C and stirred at 80°C for 48 h. Added ethanol (20 mL, 484.0 mmol) dropwise. The reaction mixture was stirred at 80°C for another 24 h. Cooled to RT and the reaction mixture was filtered through celite to remove the insoluble and washed with THF (0.5 L.) To a 3000 ml 3-necked flask, equipped with a thermometer and a magnetic stirrer at 25°C, the filtrate was added followed by NaOH, 2M in water (486 mb, 2 molar, 972 mmol). Stirred at 25°C for 6 h. Added NaOH, 2M in water (240.0 mL, 2 molar, 480.0 mmol) and stirred at 25°C for another 16 h. Cooled to RT. The reaction mixture was quenched with water/NH4OH (1000 ml, 10: 1). (pH=13-14 by pH paper). Extracted with MTBE (500 ml*2). The water phase was adjusted to pH=2-3 by addition 4M HC1 (500 ml) and a brown solid precipitated. Filtered through a filter paper and washed with water (200 ml). The filter cake was then triturated with heptane/DCM (10: 1, 600 ml) for 2 h at 25°C. Filtered through a filter paper and washed with heptane (100 ml). The filter cake was concentrated to dryness to give the title compound (60.6 g) as a solid. ES-MS m/z 288 (M+H).
Preparation of Intermediate 281 : 2-(4-bromo-3,5-dimethylphenyl)-N-(tetrahydro-2H-pyran-4- yl)acetamide
[0343] A 20 mL vial was charged with 2-(4-bromo-3,5-dimethylphenyl)acetic acid (257.8 mg, 1.060 mmol), HATU (675.0 mg, 1.775 mmol), DMF (6 mL), tetrahydro-2H-pyran-4-amin (107.3 mg, 1.061 mmol), diisopropylethylamine (0.82 mL, 4.8 mmol) and stirred at ambient temperature for 4 h. The reaction mixture was diluted with 40 mL of EA, washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (334.1 mg) as a solid. The solid was taken to the next step without further purification. ES-MS m z 326.2/328.2 (M+H).
[0344] The following intermediate was prepared essentially the same as intermediate 281 using the appropriate amine.
EXAMPLES
Examples 1 and 2: 4-(2'-Amino-3'-fluoro-2,6-dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2- (tri fluoromethoxy )phenyl)- 1,3, 8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin-
3 -one (Isomer 1 - Example 1 and Isomer 2 - Example 2)
[0345] Zinc (0.049 g, 0.75 mmol) was added to a mixture of diastereomers of 4-(3'-fluoro-2,6- dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2-(trifluorom ethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l- en-8-yl)-2'-nitro-[l,r-biphenyl]-4-yl)morpholin-3-one (0.050 g, 0.075 mmol) in MeOH (0.75 mb) and AcOH (0.15 mL) at 0 °C and the reaction mixture was stirred. After completion, the reaction was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by reverse phase using reverse phase HPLC [column: XSelect® CSH™ C18 (30 mm * 150 mm, 5 pm); mobile phase: 5-95% ACN in 0.1% FA H2O; flow rate: 40 mL/rnin] to give Isomers 1 and 2 of the title compounds (Isomer 1 - first eluting isomer and Isomer 2 - second eluting isomer, respectively). Both isomers: ES-MS (m/z) 640 (M+H).
Examples 3 and 4: 4-(2'-Amino-2,6-dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2-
(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin- 3 -one (Isomer 1 - Example 3 and Isomer 2 - Example 4)
[0346] The title compounds were prepared essentially as described in Examples 1 and 2 using 4- (2, 6-dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec- l-en-8-yl)-2'-nitro-[l,T-biphenyl]-4-yl)morpholin-3-one (mixture of diastereomers). Using the purification method described in Examples 1 and 2 gave Isomer 1 - first eluting isomer and Isomer 2 - second eluting isomer. Both isomers: ES-MS m/z 622 (M+H).
Examples 5 and 6: 4-(6'-Amino-2'-fluoro-2,6-dimethyl-3'-((7S)-7-methyl-4-oxo-2-(2-
(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin- 3 -one (Isomer 1 - Example 5 and Isomer 2 - Example 6)
[0347] The title compounds were prepared essentially as described in Examples 1 and 2 using 4- (2'-fluoro-2,6-dimethyl-3'-((7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-6'-nitro-[l,T-biphenyl]-4-yl)morpholin-3-one. Using the purification method described in Examples 1 and 2 gave Isomer 1 - first eluting isomer and Isomer 2 - second eluting isomer. Both isomers: ES-MS m/z 640 (M+H).
Example 7: 4-(2,6-Dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5 ]dec- 1 -en-8-yl)-[ 1 , 1 '-biphenyl]-4-yl)morpholin-3 -one
[0348] K2CO3 (0.02 g, 0.15 mmol), 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)morpholin-3-one (0.025 g, 0.074 mmol) and chloro(crotyl)(tri-/er/- butylphosphine)palladium(II) (0.002 g, 0.005 mmol) were added to a solution of (5R,7S)-8-(3- bromophenyl)-7-methyl-2-(2-(trifluorom ethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-4-one (0.03 g, 0.049 mmol) in 1,4-dioxane (3 mL) and H2O (0.3 mL) at 15 °C and stirred at 100 °C. After 5 h, the reaction mixture was poured into H2O (3 mL). The aq. phase was extracted with EtOAc (3 x 3 mL). The organic phases were combined, washed with NaCl sat. aq. solution (5 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in petroleum ether), then re-purified by reverse phase HPLC using a gradient of 35-65% ACN in 10 mM aq. NH4HCO3) to give the title compound. ES-MS (m/z) 607 (M+H).
Example 8: A-(6-Fluoro-2',6'-dimethyl-5-((7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-
1 ,3 ,8-triazaspiro[4.5]dec- 1 -en-8-yl)-4'-(3 -oxomorpholino)-[ 1 , 1 '-biphenyl]-2-yl)acetamide
[0349] To a mixture of 4-(6'-amino-2'-fluoro-2,6-dimethyl-3'-((7S)-7-methyl-4-oxo-2-(2-
(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l, T-biphenyl]-4-yl)morpholin- 3-one (20 mg, 31 pmol) was added DCM (0.31 mL) followed by triethylamine (3.2 mg, 4.4 pL, 31 pmol) and acetic anhydride (32 mg, 30 pL, 0.31 mmol). The reaction was left with stirring at RT for 4 h, then the organics were extracted with EtOAc and concentrated to give the title compound. ES-MS m/z 683 (M+H).
Example 9: 4-(4'-Methoxy-2,6-dimethyl-3'-(4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin-3-one
[0350] A mixture of tris(dibenzylideneacetone)dipalladium(0) (17.5 mg, 19.2 pmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 21.1 mg, 38.3 pmol) was blanketed with argon, then toluene (255 pL) was added. The mixture was stirred for 5 min at RT, then 2- (2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (80.0 mg, 255 pmol) and 4- bromo-2-iodophenyl methyl ether (32.4 mg, 255 pmol) were added and the mixture was again blanketed with argon. Sodium 2-methylpropan-2-olate (2 M solution in THF, 255 pL, 511 pmol) was added and the mixture was heated to 100 °C for 2.5 h under argon. The pH was adjusted to 1-3 by the addition of HC1 (1 M aq. sol., 450 pL) and the mixture was loaded onto 2 g strong cation exchange (SCX) resin. The resin was eluted with DCM and the eluent was discarded. The resin was then eluted with NH3 (7 N sol. in MeOH) and the eluent was concentrated. The residue was purified by reverse-phase HPLC (33 to 67% ACN in 10 mM aq. NH4HCO3 + 5% MeOH) to give 33 mg of 8-(5-bromo-2-methoxyphenyl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one.
[0351] A mixture of 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)morpholin-3-one (27 mg, 81 pmol), 8-(5-bromo-2-methoxyphenyl)-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (27 mg, 54 pmol), 1,4-dioxane (0.27 mb), l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloride (5.7 mg, 8.7 pmol) and 3M CS2CO3 (3 M aq. sol., 60 pL) was sparged for 3 min with argon. The mixture was stirred for 4 h at 90 °C, then diluted with water (75 pL), DCM (300 pL) and HC1 (1 M aq., 250 pL) and loaded onto 2 g SCX resin. The resin was eluted with DCM and the eluent was discarded. The resin was then eluted with NH3 (7 N sol. in MeOH) and the eluent was concentrated. The residue was purified by reverse-phase HPLC (33 to 67% ACN in 10 mM aq. NH4HCO3 + 5% MeOH) to give the title compound. ES-MS m/z 623 (M+H).
[0352] Compounds 10-21 in the following table were prepared essentially as described in Example 9 using the appropriate aryl halide.
Example 22: 4-(2'-Methoxy-2,6-dimethyl-5'-((7S)-7-methyl-4-oxo-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-yl)morpholin- 3 -one
[0353] A mixture of (7S)-8-(3-chloro-4-methoxyphenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-!, 3, 8-triazaspiro[4.5]dec-l-en-4-one (Isomer 1, 91.9 mg, 196 pmol), (2,6-dimethyl-4-(3-oxomorpholino)phenyl)boronic acid (54 mg, 0.22 mmol), diacetoxypalladium (12.8 mg, 57.0 pmol), 2-(diphenylphosphino)-2',4',6'-triisopropylbiphenyl (76.5 mg, 165 pmol) and K3PO4 (185.6 mg, 874.4 pmol) was evacuated and backfilled with argon three times, then DMSO (1 mL) and water (300 gL) were added. The mixture was heated to 130 °C for 3 h, then diluted with EtOAc and sat. aq. NaCl. The mixture was extracted with EtOAc, and the organics were washed with sat. aq. NaCl three times. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography using a gradient of 20 to 35% ACN in 0.1% aq. FA to give the title compound. ES-MS m/z 637 (M+H).
Example 23 : 4-(2,3',6-Trimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin-3-one
[0354] The title compound was prepared essentially as described in Step 2 of the preparation of Example 9, using (5R,7S)-8-(3-bromo-5-methylphenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one and using K2CO3 as base. Upon completion, water was added to the reaction mixture and it was extracted with EtOAc, and the organics were concentrated. The residue was purified by reverse-phase HPLC (10 to 50% ACN in 0.2% aq. FA) to give the title compound. ES-MS m/z 621 (M+H).
Example 24: 4-(2,2',6-Trimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)morpholin-3-one
[0355] To a mixture of (5R,7S)-8-(3-chloro-4-methylphenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (50 mg, 0.11 mmol) in DMF (1 mL) and water (0.1 mL) was added 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)morpholin-3-one (75 mg, 0.22 mmol) at 25 °C under N2, followed by K3PO4 (70 mg, 0.32 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3, 20 mg, 23 pmol). The mixture was stirred at 110 °C forl2 h, then poured into water (5 mb). The mixture was extracted with EtOAc (3 x 5 mL). The organics were washed with sat. aq. NaCl (5 mb), dried over Na2SC>4, fdtered, and concentrated. The residue was purified by preparative TLC (EtOAc) and then by reversephase HPLC (50 to 85% ACN in 10 mM aq. NH4HCO3) to give the title compound as a solid. ES-MS m/z 621 (M+H)
Example 25: 4-(2,4',6-Trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T-biphenyl]-4-yl)morpholin-3-one
[0356] The title compound was prepared essentially as described in Step 2 of the preparation of Example 9, using (5R,7S)-8-(5-iodo-2-methylphenyl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one and using K2CO3 as base. Upon completion water was added to the reaction mixture and it was extracted with EtOAc, and the organics were concentrated. The residue was purified by reverse-phase HPLC (40 to 75% ACN in 10 mM aq. NH4HCO3) to give the title compound. ES-MS m/z 621 (M+H).
Example 26: 2-(3'-Fluoro-4'-methoxy-2,6-dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)-2 -hydroxyacetamide (mixture of isomers) [0357] A mixture of 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (racemic mixture, 88.9 mg, 291 pmol) and (5R,7S)-8-(5-chloro-3-fluoro-2- methoxyphenyl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 110 mg, 203 pmol) in MeOH (2.0 mL) was purged by bubbling nitrogen through the reaction. K2CO3 (86 mg, 0.62 mmol) was added followed by water (0.20 mL), and nitrogen was bubbled through the mixture for 15 min.
Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,r-biphenyl-2-yl)palladium(II) (21 mg, 24 pmol) was added, and the reaction mixture was sealed and heated via microwave irradiation to 85°C for 3 h. The reaction mixture was loaded onto 10 g SCX resin. The resin was eluted with MeOH, 1 : 1 MeOH/DCM then again with MeOH and collected as a first fraction. Then the resin was eluted with 7 M NH3 in MeOH and collected as a second fraction. The second fraction was concentrated under reduced pressure, and the residue was purified by reversed phase HPLC using a gradient of 40 to 55% ACN in aq. NH4HCO3 to give the title compound (52.8 mg). ES-MS m/z 684 (M+H).
Example 27: 2-Hydroxy-2-(4'-methoxy-2,6-dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T- biphenyl]-4-yl)acetamide (mixture of isomers)
[0358] (5R,7S)-8-(5-chloro-2-methoxyphenyl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 400 mg, 709 pmol) was added to a reaction vessel containing MeOH (8 mL) and water (1.6 mL). Next, to the mixture were added sequentially, 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2 -hydroxyacetamide (racemic mixture, 240 mg, 764 pmol), K2CO3 (260 mg, 1.86 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l, l'-biphenyl)(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (140 mg, 159 pmol). The mixture was purged with nitrogen for 2 min at 25 °C then vigorously stirred at 80 °C for 2 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by prep-TLC (EtOAc, R/= 0.2). The product was repurified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 10 mM aq. NH4HCO3 to give the title compound (197 mg). ES-MS m/z 666 (M+H).
Example 28: 2-(2'-Fluoro-4'-methoxy-2,6-dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)-2 -hydroxyacetamide (mixture of isomers)
[0359] (5R,7S)-8-(5-Chloro-4-fluoro-2-methoxyphenyl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 165 mg, 296 pmol) was added to a mixture of MeOH (5 mL) and water (1 mL). 2-(3,5-Dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 141 mg, 457 pmol) and K2CO3 (125 mg, 895 pmol) were added and the mixture was purged with nitrogen for 2 min before and after adding methanesulfonato(2-dicyclohexylphosphino-2',4',6'- tri-i-propyl-l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (55 mg, 63 pmol). The mixture was stirred vigorously at 80 °C for 2 h, then filtered. The filtrate was concentrated and the residue was purified by prep-TLC (DCM/MeOH = 10/1, R/= 0.4). The product was repurified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3), solvent B - ACN; gradient: 30%-60% solvent B in solvent A) to give the title compound (23.4 mg) as a solid. ES-MS m z 684 (M+H).
Example 29: 4'-((S)-l,2-Dihydroxyethyl)-2',6'-dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-carbonitrile (mixture of isomers)
[0360] 2-((5R,7S)-7-Methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (mixture of isomers, 70 mg, 0.11 mmol) was added to a mixture of 1,4-dioxane (1 mL) and water (0.1 mL). (S)-l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol (43 mg, 0.17 mmol), K2CO3 (60 mg, 0.43 mmol) and chloro(crotyl)(tri-te/7-butylphosphine)palladium(II) (6 mg, 0.01 mmol) were added, and then the mixture was purged with N2 for 2 min then vigorously stirred at 80 °C for 1 h. The reaction mixture was cooled to RT then filtered through diatomaceous earth rinsing with approximately 3 mL of EtOAc. The filtrate was then concentrated and the residue was purified by prep-TLC (EtOAc/PE = 1/1, R = 0.3), then further purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30mm, 10 pm); mobile phase: solvent A - 10 mM aq. NH4HCO3), solvent B - ACN; gradient: 30%-60% solvent B in solvent A) to give the title compound (32 mg) as a solid. ES-MS m z 648 (M+H).
Example 30: 4'-(Hydroxymethyl)-2',6'-dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2-
(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-carbonitrile (mixture of isomers)
[0361] 2-((5R,7S)-7-Methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (mixture of isomers, 50 mg, 80 pmol) was added to a vial containing MeOH (1 mL) and water
(0.1 mL). Next was added (4-bromo-3,5-dimethylphenyl)methanol (22 mg, 97 pmol), K2CO3 (32 mg, 0.23 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r- biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (8 mg, 9 pmol) at 26 °C. The mixture was purged with N2 for 2 min then vigorously stirred at 80 °C for 1 h. The reaction mixture was cooled to RT then fdtered through diatomaceous earth which was eluted with 2 mb MeOH. The filtrate was concentrated and purified via prep-TLC (EtOAc/PE = 1/1, R/= 0.4). The product was then further purified via prep-HPLC (column: Waters Xbridge BEH Cl 8 100 x 30mm, 10 pm); mobile phase: solvent A - lOmM aq. NH4HCO3), solvent B - ACN; gradient: 30%-60% solvent B in solvent A) to give the title compound (22.6 mg) as a solid. ES-MS m/z 618 (M+H).
Example 31 : 2-(4'-Cyano-3'-fluoro-2,6-dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T- biphenyl]-4-yl)-2 -hydroxyacetamide (mixture of isomers)
[0362] To a solution of 4-bromo-2-fluoro-6-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (mixture of isomers, 90 mg, 0.16 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added 2-(3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 60 mg, 0.20 mmol) followed by K2CO3 (65 mg, 0.47 mmol) and 1, l'-bis(di-t- butylphosphino)ferrocene palladium dichloride (25 mg, 38 pmol). The solution was sparged with argon for 30 seconds then heated to 40 °C in a sealed pressure release vial overnight. The reaction was diluted with 10 mL of water and extracted 3 times with 10 mL of EtOAc. The combined organic layers were concentrated. The residue was purified via prep-HPLC (column: XSelect CSH C18 150mm x 30mm, 5 pm; mobile phase: solvent A - 0.1% aq. FA, solvent B - ACN; gradient: 40%-95% solvent B in solvent A) to give the title compound (20.2 mg). ES-MS m/z 679 (M+H). Example 32: 4'-(l,2-Dihydroxyethyl)-3-fluoro-2',6'-dimethyl-5-((5R,7S)-7-methyl-4-oxo-2-(2- ((SR)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)-[ 1 , 1 '-biphenyl]-4-carbonitrile (mixture of isomers)
[0363] 4-Chloro-2-fluoro-6-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (mixture of isomers, 200 mg, 369 pmol) was added to a mixture of THF (3 m ) and water (0.3 m ). 1 -(3,5- Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethane-l,2-diol (racemic mixture, 139 mg, 476 pmol) was added followed by Pd(PPh3)4 (74 mg, 63 pmol) and K2CO3 (220 mg, 1.58 mmol) at 25 °C. The mixture was purged with N2 for 2 min then vigorously stirred at 80 °C for 48 h. The residue was purified by prep-TLC (EtOAc/PE = 2/1, Ry = 0.2), then repurified by reverse phase prep-HPLC (WePure Biotech XP tC 18 150 * 40, 7 pm; mobile phase: solvent A - 1 OmM aq. NH4HCO3), solvent B - ACN]; gradient: 30 to 60% solvent B in solvent A) to give the title compound (50 mg) as a solid. ES-MS m/z 666.3 (M+H).
Examples 33 and 34: 4'-(2 -Amino- l-hydroxy-2-oxoethyl)-3-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5-fluoro-2',6'- dimethyl-[l,l'-biphenyl]-4-carboxamide (Isomer 1 - Example 33, and Isomer 2 - Example 34)
[0364] To a mixture of THF (6 mb) and H2O (1.2 mb) was added 4-bromo-2-((5R,7S)-2-(2- cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl -4-oxo- 1,3, 8-triazaspiro[4.5]dec-l -en-8-yl)-6- fluorobenzamide (243 mg, 388 pmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 163 mg, 519 pmol), K2CO3 (305 mg, 2.18 mmol) and P(Ph3)4 (106 mg, 89.9 pmol) at 22 °C. The mixture was purged with nitrogen for 1 min and then vigorously stirred at 80 °C for 8 h. Then reaction was cooled to 22 °C and stirred for 12 h. Water (3 mL) was added at 22 °C, and then the mixture was extracted with EtOAc (3 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc/PE = 5/1, Ry = 0.3), then re-purified by reverse phase prep-HPLC using a gradient of 20 to 50% ACN in 10 mM aq. NH4HCO3 to give the title compound (121 mg) as a solid.
[0365] 62 mg of the mixture of isomers was purified by chiral HPLC (column: Whelk-0 (S,S) 30 mm x 250 mm, 5 pm; mobile phase: 100% MeOH) to give Isomer 1 (first-eluting isomer, 21 mg) and Isomer 2 (second-eluting isomer, 15 mg). Both isomers - ES-MS m,'z 666 (M+H).
Examples 35 and 36: 3-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-((RS)-l,2-dihydroxyethyl)-5-fluoro-2',6'-dimethyl-[l,r- biphenyl]-4-carboxamide (Isomer 1 - Example 35, and Isomer 2 - Example 36)
[0366] The title compound was prepared as described in Example 33 and 34 using l-(3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethane-l,2-diol (racemic mixture). The mixture of isomers was purified by prep-TLC (EtOAc/PE = 5/1, R/= 0.3), then repurified by reverse phase prep-HPLC using a gradient of 25 to 55% ACN in 10 mM aq. NH4HCO3. The mixture of isomers was then purified by chiral SFC (column: Chiralpak IM 30 mm x 250 mm, 5 pm; mobile phase: isocratic 40% (10 mM ammonium acetate in MeOH) in CO2) to give Isomer 1 (first-eluting isomer) and Isomer 2 (second-eluting isomer). Both isomers - ES-MS m!z 653 (M+H). Example 37: 2-(4'-Cyano-3'-((5R,7S)-2-(2-cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-4-oxo- 1, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2-hydroxy acetamide
[0367] To a mixture of THF (5 mL) and water (1 mL) was added 4-chloro-2-((5R,7S)-2-(2- cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)benzonitrile (160 mg, 352 pmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 165 mg, 525 pmol), K3PO4 (230 mg, 1.07 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2- aminoethyl)phenyl]palladium(ii) chloride (XPhos Palladacycle, 60 mg, 75 pmol) at 27 °C. The mixture was purged with N2 for 2 min then vigorously stirred at 80 °C for 2 h. The reaction mixture was directly concentrated under reduced pressure. The residue was purified by prep- TLC (EtOAc= 1/0, R/= 0.4), then re-purified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 10 mM aq. NH4HCO3 to give the title compound (82 mg) as a solid. ES-MS m'z 593 (M+H).
Example 38: 2-(2,6-Difluoro-4'-methyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-
6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-yl)-2- hydroxyacetamide (mixture of isomers)
[0368] To a mixture of 1,4-dioxane (4 mL) and H2O (1 m ) was added (5R,7S)-7-methyl-8-(2- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 195 mg, 229 pmol), 2-(4-bromo-3,5-difluorophenyl)-2-hydroxyacetamide (racemic mixture, 50 mg, 178 pmol) and K2CO3 (90 mg, 0.64 mmol). The mixture was purged with N2 for 2 min before and after adding methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (16 mg, 18 pmol). The reaction mixture was heated to 80 °C and stirred for 2 h under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (DCM/MeOH = 10/1, Ry = 0.4), then repurified by reverse phase prep-HPLC using a gradient of 10% to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (25 mg) as a solid. ES-MS m/z 658 (M+H).
Example 39: 2-(2-Fluoro-4',6-dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)- 6-(tri fluoromethyl )pyridin-3-yl)-l, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)-2- hydroxyacetamide (mixture of isomers)
[0369] To a mixture of 1,4-dioxane (4 mL) and H2O (1 mL), was added 2-(4-bromo-3-fluoro-5- methylphenyl)-2-hydroxyacetamide (racemic mixture, 280 mg, 876 pmol), (5R,7S)-7-methyl-8- (2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 739 mg, 869 pmol), methanesulfonato(2-dicyclohexylphosphino-2',4',6l-tri-i-propyl-l,T-biphenyl)(2l- methylamino-l,T-biphenyl-2-yl)palladium(II) (78 mg, 89 pmol) and K2CO3 (365 mg, 2.61 mmol) at 26 °C. The mixture was purged with N2 for 2 min then vigorously stirred at 80 °C for 2 h. The reaction mixture was cooled to RT, then filtered through a pad of diatomaceous earth eluting with 5 mL ACN. The filtrate was concentrated under reduced pressure at 45 °C and the residue was purified by reverse phase prep-HPLC using a gradient of 20 to 50% ACN in 0.2% aq. FA to give the title compound (33.8 mg) as a solid. ES-MS m/z 654 (M+H). Example 40: 2-(2,4'-Dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-yl)-2- hydroxyacetamide (mixture of isomers)
[0370] A mixture of MeOH (2 mL) and water (0.4 mL), then added (5R,7S)-8-(5-chloro-2- methylphenyl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyri din-3-yl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 80 mg, 0.11 mmol), 2-hydroxy-2-(3-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (racemic mixture, 45 mg, 0.14 mmol) and K2CO3 (50 mg, 0.35 mmol) was de-gassed and refilled with N2 three times.
Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) (12 mg, 13 pmol) was added at 25 °C and the reaction mixture was bubbled with N2 for 1 min. Then the reaction mixture was stirred at 80 °C for 1 h under N2, cooled to RT, and filtered through a pad of diatomaceous earth which was rinsed with 2 mL MeOH. The filtrate was concentrated to give a residue which was purified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 10 mM aq. NH4HCO3 to give the title compound (20.5 mg) as a solid. ES-MS m'z 636 (M+H).
Example 41 : 2-Hydroxy-2-(2,4',6-trimethyl-3'-(4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4- yl)acetamide (mixture of isomers)
[0371] A mixture of MeOH (2 mL), water (0.2 mL), 8-(5-chloro-2-methylphenyl)-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (racemic mixture, 80 mg, 0.15 mmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 65 mg, 0.21 mmol) and K2CO3 (62 mg, 0.45 mmol) was purged with nitrogen for 1 min before and after adding methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,r-biphenyl-2-yl)palladium(II) (35 mg, 40 pmol). Then the reaction mixture was heated to 80 °C and allowed to stir for 4 h under nitrogen. The reaction mixture was quenched by adding 2 mb H2O at 25°C, and then diluted with 2 mb EtOAc and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with aq. NH4CI (2 mL x 3), dried over ISfeSCL, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc/PE = 1/1, Ry = 0.6), then repurified by reverse phase prep-HPLC using a gradient of 50 to 80% ACN in 10 mM aq. NH4HCO3 to give the title compound (26.3 mg) a solid. ES-MS m 'z 636.3 (M+H).
Example 42: 2-(3'-((5R,7S)-7-Ethyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-4'-methoxy-2,6- dimethyl-[l, l'-biphenyl]-4-yl)-2-hydroxyacetamide (mixture of isomers)
[0372] To a mixture of 8-(5-chloro-3-fluoro-2-methoxyphenyl)-7-ethyl-2-(2-(tetrahydrofuran-2- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 160 mg, 270 pmol) and 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 2-hydroxyacetamide (racemic mixture, 160 mg, 509 pmol) in THF (5 mL) and water (1 mL) was added K3PO4 (212 mg, 989 pmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,T- biphenyl)[2-(2-aminoethyl)phenyl]palladium(ii) chloride (XPhos Palladacycle, 42 mg, 52 pmol) in one portion at 25 °C under nitrogen. The mixture was purged with nitrogen for 2 min then vigorously stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by prep-TLC (EtOAc/PE = 1/0, R/= 0.4), then repurified by prep-HPLC using a gradient of 40 to 70% ACN in 10 mM aq. NH4HCO3 to give the title compound (56.66 mg) as a solid. ES-MS m/z 698.1 (M+H). Example 43 : (5R,7S)-8-(4'-(Hydroxymethyl)-2',4,6'-trimethyl-[l,r-biphenyl]-3-yl)-7-methyl-2-
(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0373] To a mixture of (4-bromo-3,5-dimethylphenyl)methanol (24 mg, 0.10 mmol), K2CO3 (36 mg, 0.26 mmol), (5R,7S)-7-methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (55 mg, 0.10 mmol), and Pd(dppf)Ch (complex with DCM, 4.3 mg, 5.2 pmol) was added 1,4-dioxane (1 mL). The mixture was purged with nitrogen, then water (0.3 mL) was added and nitrogen purging continued. The reaction vessel was sealed and heated to 50 °C for 2 h, then at RT overnight. The mixture was fdtered through diatomaceous earth and rinsed twice with 50 mL EtOAc, and the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH in EtOAc, then repurified by reverse phase prep-HPLC using a gradient of 40 to 70% ACN in 0.1% aq. FA to give the title compound (26.9 mg). ES-MS m/z 537 (M+H).
Example 44: 2,4',6-Trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-sulfonamide
[0374] To a mixture of 4-bromo-3,5-dimethylbenzenesulfonamide (50 mg, 0. 18 mmol) and (5R,7S)-7-methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (230 mg, 222 pmol) in 1,4- dioxane (1 mL) and water (0.1 mL) was added K3PO4 (120 mg, 554 pmol), methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (16 mg, 18 pmol) and di-terLbutyl dicarbonate (40 mg, 0.18 mmol) at 25 °C. The resulting mixture was stirred at 100 °C for 1 h. The mixture was quenched with water (10 mL). The product was extracted with DCM (5 mL x 3). The organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC 35 to 70% ACN in 0.2% aq. FA to give the title compound (11.35 mg) as a solid. ES-MS m>z 586.3 (M+H).
Example 45: N-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)acetamide
[0375] Pd(dppf)Ch (complex with DCM, 0.005 g, 5.7 mmol) was added to a mixture of K2CO3 (0.039 g, 0.28 mmol), (5R,7S)-7-methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.060 g, 0.11 mmol), and N-(4-bromo-3,5-dimethylphenyl)acetamide (0.027 g, 1 Eq, 0.11 mmol) in 1,4- di oxane (2 mL). The mixture was purged with nitrogen at RT for 5min, then water (0.5 mL) was added with continued purging. The mixture was heated to 55°C for 1 h, then filtered through diatomaceous earth and rinsed with twice with 50 mL EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH in EtOAc, then repurified by reverse phase prep HPLC using a gradient of 33 to 67% ACN in 0.1% aq. FA to give the title compound (0.020 g). ES-MS m/z 564 (M+H).
Example 46: 2,4',6-Trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-carboxamide
[0376] The title compound was prepared as described in Example 45 using 4-bromo-3,5- dimethylbenzamide. ES-MS m'z 550 (M+H). Example 47: 2-(4'-Fluoro-2,6-dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-yl)-2- hydroxyacetamide (mixture of isomers)
[0377] A resealable tube under nitrogen atmosphere was charged with K2CO3 (8.5 mg, 62 pmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 11.4 mg, 37.4 pmol), (5R,7S)-8-(5-chloro-2-fluorophenyl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (8.5 mg, 19 pmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) (3.4 mg, 3.9 pmol). The tube was purged with nitrogen and then methanol (0.18 m ) and water (18 pL) were added. The tube was sealed and the mixture was stirred at 80 °C. After 2 h, the reaction was cooled to RT, then diluted with aq. citric acid and EtOAc. The aqueous layer was discarded, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous Na2SCU, filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOH in EtOAc to give the title compound (8.3 mg) as a solid. ES-MS m/z 584 (M+H).
Example 48: 3'-((5R,7S)-2-(2-((2S)-2-Fluorocyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,r-biphenyl]-4-carboxylic acid (Isomer 1)
[0378] Step 1 : To a 40 mL vial containing a solution of (5R,7S)-2-(2-((2S)-2- fluorocyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)-8-(5-iodo-2-methylphenyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one (Isomer 1, 180 mg, 291 pmol) in MeOH (5 mL) and H2O (0.5 mL) was added methyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (137 mg, 466 pmol), K2CO3 (135 mg, 928 pmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2- yl)palladium(II) (86 mg, 95 pmol) at 25 °C. The system was purged with nitrogen for 1 min. The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding 15 mL H2O at 25 °C, and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over N 2SO4, then the Na2SO4 was filtered off and further washed with EtOAc (10 mL x 2). The obtained filtrate was concentrated under reduced pressure.
[0379] Step 2: To the residue from Step 1 was added MeOH (3 mL) and IM LiOH in water (1.44 mg, 60.0 pL, 1 molar, 60.0 pmol) at 25 °C. The mixture was purged with nitrogen for 2 min before vigorously stirring at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-TLC (SIO2, EtOAc/PE = 1/1, Rf = 0.41), then the SiO2 powder was soaked with 20 mL MeOH, and filtered via suction filter, rinsed with 20 mL MeOH. The filtrate was concentrated under pressure to give a crude product. The crude product was purified by prep-HPLC, and the collected fractions underwent lyophilization to get the title compound as a solid. ES-MS m z 609 (M+H).
Example 49: 3'-((5R,7S)-2-(2-((2R)-2-Fluorocyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,r-biphenyl]-4-carboxylic acid (Isomer 1)
[0380] The title compound was prepared in two steps as described in Example 48 starting with (5R,7S)-2-(2-((2R)-2-fluorocyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)-8-(5-iodo-2- methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (Isomer 1). ES-MS m/z 609 (M+H). Example 50: 2',6'-Dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T-biphenyl]-4-carbonitrile
[0381] To a mixture of 4-chloro-2-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (54 mg, 0.10 mmol), 2,6-dimethylbenzeneboronicacid (23 mg, 0.15 mmol) and K2CO3 (56 mg, 0.41 mmol), was added 1,4-dioxane (0.68 mL, 0.10 mmol) and water (0.15 m , 0.10 mmol). The mixture was de-gassed with sub-surface nitrogen for 5 min. [1, 1 '-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)C12, 13 mg, 20 pmol) was added, then the vessel was sealed and heated to 80 °C for 16 h. The reaction was diluted with EtOAc and water and extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 5 to 50% EtOAc in cyclohexane to give the title compound (31 mg). ES-MS n 'z 602 (M+H).
Example 51 : 2',6'-Dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifhioromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T-biphenyl]-4- carboxamide
[0382] 2',6'-Dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-carbonitrile (31 mg, 52 pmol) was dissolved in EtOH (0.52 mL) and then KOH (43 mg, 0.77 mmol) dissolved in water (0.52 mL) was added at RT. The mixture was heated to 90 °C for 3 days.
The reaction was then concentrated and the residue was purified using reverse phase prep-HPLC using a gradient of 45 to 77% ACN in (5% MeOH in 10 mM aq. NH4HCO3) to give the title compound (10 mg) as a solid. ES-MS m'z 620 (M+H).
Example 52: 4-(4'-Cyclopropyl-3'-((5R,7S)-2-(2-(5-fluorothiophen-2-yl)-4- (trifluoromethoxy)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2-methyl-[l,r- biphenyl]-4-yl)morpholin-3-one
[0383] CsF (0.090 g, 0.59 mmol) was added to a mixture of (5R,7S)-2-(2-(5-fluorothiophen-2- yl)-4-(trifluoromethoxy)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.050 g, 0.12 mmol) in ACN (0.006 mL, 0.1 mmol). 4-Cyclopropyl-2'-methyl-4'-(3-oxomorpholino)-3- (trimethylsilyl)-[l,r-biphenyl]-2-yl trifluoromethanesulfonate (0.095 g, 0.18 mmol) was added and reaction mixture was stirred vigorously at RT. After 16 h, the reaction was diluted with H2O (3 mL) and EtOAc (3 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 3 mL). The combined organic layers were dried, fdtered, and concentrated. The residue was purified by prep-HPLC (column: XSelect CSH C18, 30 mm x 150 mm, 5 pm; mobile phase: solvent A: 10 mM aq. ammonium acetate, solvent B - ACN; gradient - 0 to 95% solvent B in solvent A) to give the title compound (0.014 g) as a solid. ES-MS m 'z 733 (M+H).
Example 53: 4'-Cyano-3'-((5R,7S)-2-(2-(3,3-difluoroazetidin-l-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,l'-biphenyl]-4- carboxylic acid [0384] Step 1 : To a mixture of MeOH (5 mL) and H2O (0.5 mL) was added 4-bromo-2- ((5R,7S)-2-(2-(3,3-difluoroazetidin-l-yl)-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (150 mg, 248 pmol), methyl 3,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (86 mg, 0.29 mmol), K2CO3 (103 mg, 730 pmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'- methylamino-l,l'-biphenyl-2-yl)palladium(II) (21 mg, 24 pmol) at 27 °C. The mixture was purged with nitrogen for 2 min then vigorously stirred at 80 °C for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 2 mL MeOH. The filtrate was concentrated under reduced pressure at 45 °C. The residue was purified by reverse phase prep-HPLC using a gradient of 45 to 85% ACN in 0.2% aq. FA to give methyl 4'-cyano-3'-((5R,7S)-2-(2-(3, 3-difluoroazeti din- l-yl)-6-(tri fluoromethyl )pyridin-3-yl)-7-methyl- 4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,T-biphenyl]-4-carboxylate (80 mg) as a solid. ES-MS m/z 667 (M+H).
[0385] Step 2: To a mixture of MeOH (1 mL) and H2O (1 mL) was added methyl 4'-cyano-3'- ((5R,7S)-2-(2-(3,3-difluoroazetidin-l-yl)-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,T-biphenyl]-4-carboxylate (80 mg, 0.12 mmol) and NaOH (7 mg, 0.2 mmol) at 27 °C. The mixture was purged with nitrogen for 2 min then vigorously stirred at 27 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase prep-HPLC using a gradient of 45 to 85% ACN in 0.2% aq. FA to give the title compound (10.6 mg) as a solid. ES-MS m z 653 (M+H).
Example 54: 2-(2,6-Dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6-
(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-(lH-pyrazol-4-yl)-[l,l'- biphenyl]-4-yl)-2 -hydroxyacetamide (mixture of isomers) [0386] A mixture of 2-(2,6-dimethyl-3l-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-(l-trityl-lH-pyrazol-4-yl)- [l,l'-biphenyl]-4-yl)-2-hydroxyacetamide (mixture of isomers, 20 mg, 19 pmol) and formic acid in H2O (0.5 mL, 88% wt, 0.01 mol) was heated at 30 °C for 1 h. The reaction mixture was cooled down to RT, and filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 5 mL EtOAc. The filtrate was concentrated and the residue was purified by reverse phase prep-HPLC using a gradient of 20 to 50% ACN in 10 mM aq. NH4HCO3 to give the title compound (6 mg), as a solid. ES-MS m/z 702 (M+H).
Example 55: 2-(4'-(Cyanomethyl)-2,6-dimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-
(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)-2 -hydroxyacetamide (mixture of isomers)
[0387] A mixture of 1,4-dioxane (2 mL), H2O (0.4 mL), 2-(4-chloro-2-((5R,7S)-7-methyl-4- oxo-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en- 8-yl)phenyl)acetonitrile (200 mg, 369 pmol), K2CO3 (153 mg, 1.10 mmol) and 2-(3,5-dimethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 172 mg, 503 pmol) was purged with nitrogen for 1 min. Chloro(crotyl)(tri-/c7 - butylphosphine)palladium(II) (30 mg, 71 ymol) was then added at 13 °C under nitrogen. The system was purged with nitrogen for 1 min, then the reaction mixture was heated to 100 °C and allowed to stir for 2 h under nitrogen. The reaction mixture was cooled down to RT, and poured into 20 mL H2O at 24 °C, then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with sat. aq. NaCl (15 mL), and dried over Na2SO4. Then the Na2SO4 was filtered off and further washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC (EtOAc/PE = 1/0, R/= 0.4), then re-purified by reverse phase prep-HPLC using a gradient of 40 to 70% ACN in 10 mM aq. NH4HCO3 to give the title compound (50 mg) as a solid. ES-MS m/z 675 (M+H).
Example 56: 2-(3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo- 1 ,3 , 8-triazaspiro[4.5]dec- 1 -en-8-yl)-2,4',6-trimethyl-[ 1 , 1 '-biphenyl]-4-yl)-N-(tetrahydro-2H- pyran-4-yl)acetamide
[0388] A 5 mL MWV was charged with (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (60.5 mg, 106 pmol), 2-(4-bromo-3,5-dimethylphenyl)-N- (tetrahydro-2H-pyran-4-yl)acetamide (47.3 mg, 145 pmol), potassium carbonate (29.9 mg, 216 pmol), XPhos Pd G4 (16.3 mg, 18.9 pmol), MeOH (2.5 mL), water (0.25 mL), sparged with N2 for 5 minutes. The vial was sealed, transferred to an 80 °C pre-heated heating block and stirred for an hour. The reaction mixture was cooled to ambient temperature, acidified and loaded onto a 10 g SCX cartridge. The cartridge was flushed with MeOH and the product eluted with a 2N NH3 in MeOH solution. The ammonia solution was concentrated under reduced pressure to a beige solid. The solid was further purified using reverse phase purification using high pH (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 40 to 70% ACN to obtain the title compound (7.8 mg) as a solid. 1H NMR (400.15 MHz, DMSO): 11.62-11.60 (m, 1H), 8.18-8.15 (m, 1H), 8.06 (d, J= 7.6 Hz, 1H), 7.84-7.83 (m, 1H), 7.30 (d, J= 7.8 Hz, 1H), 6.98 (s, 3H), 6.94- 6.91 (m, 1H), 6.86-6.85 (m, 1H), 3.82 (dt, J= 11.2, 3.6 Hz, 3H), 3.77-3.70 (m, 1H), 3.51-3.50 (m, 1H), 3.05-3.02 (m, 1H), 2.93-2.92 (m, 1H), 2.80-2.76 (m, 1H), 2.36-2.34 (m, 5H), 2.13-2.09 (m, 1H), 1.96 (d, J= 1.6 Hz, 8H), 1.78-1.66 (m, 7H), 1.45-1.36 (m, 3H), 1.24 (s, 15H), 1.09-1.04 (m, 5H), 0.88-0.83 (m, 6H). ES-MS m/z 688 (M+H). Example 57: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(4'-(2-(3- (hydroxymethyl)azetidin-l-yl)-2-oxoethyl)-2',4,6'-trimethyl-[l,l'-biphenyl]-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0389] A 5 mL MWV was charged with (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-8-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (62.2 mg, 1.0 Eq, 109 pmol), 2-(4-bromo-3, 5 -dimethylphenyl)- 1- (3-(hydroxymethyl)azetidin-l-yl)ethan-l-one (43.0 mg, 1.26 Eq, 138 p ol), potassium carbonate (31.9 mg, 2.11 Eq, 231 pmol), XPhos Pd G4 (19.0 mg, 0.202 Eq, 22.1 pmol), MeOH (2.5 mL), water (0.25 mL), sparged with N2 for 5 minutes. The vial was sealed, transferred to an 80 °C pre-heated heating block and stirred for an hour. LC-MS analysis (CAE-C01525-619-RM-1) of an aliquot of the reaction mixture indicated product formation. The reaction mixture was cooled to ambient temperature, acidified and loaded onto a 10 g SCX cartridge. The cartridge was flushed with MeOH and the product eluted with a 2N NH3 in MeOH solution. The ammonia solution was concentrated under reduced pressure to a beige solid. The solid was further purified using reverse phase purification using high pH (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 40 to 70% ACN to obtain the title compound (26.1 mg) was returned as a solid. 1H NMR (400 MHz, DMSO) 8 11.53 (s, 1H), 8.17 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.96 (s, 2H), 6.92 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.18 (t, J = 8.4 Hz, 1H), 4.10 (q, J = 5.2 Hz, 2H), 3.92 (dd, J = 8.5, 5.4 Hz, 1H), 3.83 (t, J = 9.0 Hz, 1H), 3.58 (dd, J = 9.6, 5.5 Hz, 1H), 3.52 (t, J = 5.6 Hz, 2H), 3.44 (s, 2H), 3.33 (s, 1H), 3.18 (d, J = 5.1 Hz, 4H), 2.97 (d, J = 12.8 Hz, 2H), 2.87 (d, J = 11.5 Hz, 1H), 2.75 (dd, J = 11.2, 5.3 Hz, 1H), 2.69 - 2.59 (m, 1H), 2.55 (s, 2H), 2.36 (s, 3H), 2.06 (s, 1H), 1.96 (d, J = 2.3 Hz, 6H), 1.74 (t, J = 11.9 Hz, 1H), 1.63 (d, J = 13.1 Hz, 1H), 1.57 (s, 1H), 1.09 - 1.00 (m, 4H), 0.83 (d, J = 5.8 Hz, 3H). ES-MS m/z 674 (M+H). Example 58: (Racemic) 3-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-(2,3-dihydroxypropoxy)-5-fluoro-2',6'-dimethyl-[l,r- bi phenyl ] -4-carb onitri 1 e
[0390] A 5 mL MWV was charged with 2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (51.8 mg, 86.9 pmol), 3-(4-bromo-3,5- dimethylphenoxy)propane-l,2-diol (36.4 mg, 132 pmol), potassium carbonate (30.5 mg, 221 pmol), XPhos Pd G4 (8.9 mg, 0.12 Eq, 10 pmol), dioxane (2.0 mL), water (0.20 mL), sparged with N2 for 5 min. The vial was sealed, transferred to an 80 °C pre-heated heating block and stirred for 1 h. The reaction mixture was cooled to ambient temperature, acidified and loaded onto a 10 g SCX cartridge. The cartridge was flushed with MeOH and the product eluted with a 2N NH3 in MeOH solution. The ammonia solution was concentrated under reduced pressure to a beige solid. The solid was further purified using reverse phase purification using high pH (l OmM ammonium bicarbonate with 5% MeOH in water and ACN) 40 to 100% ACN to obtain the title compound. 1H NMR (400 MHz, DMSO) 5 11.42 (s, 1H), 7.68 (t, J = 7.1 Hz, 2H), 7.37 (s, 1H), 7.14 - 7.04 (m, 2H), 6.72 (s, 2H), 4.93 (d, J = 5.1 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 3.99 (dd, J = 9.9, 4.3 Hz, 1H), 3.82 (ddd, J = 29.7, 10.2, 5.8 Hz, 2H), 3.59 (s, 1H), 3.44 (t, J = 5.6 Hz, 2H), 3.24 (s, 1H), 3.22 - 3.15 (m, 1H), 2.42 (ddd, J = 13.8, 8.6, 5.3 Hz, 1H), 2.11 (td, J = 12.2, 5.0 Hz, 1H), 1.98 (d, J = 2.3 Hz, 6H), 1.83 - 1.72 (m, 1H), 1.63 (t, J = 13.0 Hz, 2H), 0.97 (d, J = 5.9 Hz, 5H), 0.75 (q, J = 3.5 Hz, 2H). ES-MS m/z 665 (M+H).
Example 59: (Racemic) (RS)-2-(3'-((5R,7S)-2-(l-butyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,l'-biphenyl]-4-yl)-2- hy droxy acetami de
[0391] An 8 mL MWV was charged with (5R,7S)-2-(l-butyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)-8-(5-chloro-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (146 mg, 303 pmol), rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (229.6 mg, 752.3 pmol), potassium carbonate (142.3 mg, 1.030 mmol), XPhos Pd G4 (54.2 mg, 62.9 pmol), methanol (4 mL), water (0.4 mL), sparged with N2 for 5 min. The vial was sealed, transferred to a pre-heated 80°C block and stirred for 16 h. The reaction mixture was acidified and loaded unto an SCX and flushed with a 50% DCM in MeOH solution, then eluted with 50 mL of a 2 N ammonia in methanol solution. The ammonia solution was concentrated under reduced pressure to an oil. The oil was purified by reverse phase chromatography using high pH (lOmM ammonium bicarbonate with 5% MeOH in water and ACN) 5 to 95% ACN to obtain to obtain the title compound (43.3 mg) as a foam. 1H NMR (400.15 MHz, DMSO): 1 1.28 (s, 1H), 8.40 (s, 1H), 7.39 (dd, J= 2.3, 6.3 Hz, 1H), 7.32 (t, J= 8.1 Hz, 2H), 7.20-7.13 (m, 6H), 6.90-6.87 (m, 2H), 6.83-6.79 (m, 1H), 5.93-5.91 (m, 1H), 4.80-4.79
(m, 2H), 4.32-4.23 (m, 3H), 3.48-3.44 (m, 1H), 3.04-2.97 (m, 1H), 2.93-2.90 (m, 2H), 2.35-2.34
(m, 5H), 2.00-1.98 (m, 9H), 1.84-1.73 (m, 5H), 1.58-1.48 (m, 3H), 1.31-1.22 (m, 3H), 0.92-0.88
(m, 5H), 0.82-0.78 (m, 5H). ES-MS m/z 625 (M+H).
Example 60: (Racemic) (RS)-2-(3'-((5R,7S)-2-(2 -butyl -4-(trifluoromethyl)thiazol-5-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,T-biphenyl]-4-yl)-2- hydroxyacetamide [0392] An 8 mL MWV was charged with (5R,7S)-2-(2-butyl-4-(trifluoromethyl)thiazol-5-yl)-8- (5-chloro-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (100 mg, 200 pmol), rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (142 mg, 2.32 Eq, 465 pmol), potassium carbonate (102.9 mg, 744.6 pmol), XPhos Pd G4 (33.3 mg, 38.7 pmol), methanol (4 mL), water (0.4 mL), sparged with N2 for 5 minutes. The vial was sealed, transferred to a microwave reactor (100 °C, 70 min). The reaction mixture was acidified, loaded unto an SCX cartridge and flushed with a 50% DCM in MeOH solution, then eluted with 50 mL of a 2 N ammonia in methanol solution. The ammonia solution was concentrated under reduced pressure to an oil. Purified by reverse phase chromatography. The solid was further purified using reverse phase purification using high pH (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 5 to 95% ACN to obtain the title compound (32.6 mg) as a solid. 1H NMR (400.15 MHz, DMSO): 11.62 (s, 1H), 7.36 (d, J= 1.9 Hz, 1H), 7.32-7.29 (m, 1H), 7.18-7.15 (m, 3H), 6.88 (s, 1H), 6.80 (dd, J= 1.3, 7.7 Hz, 1H), 5.93- 5.91 (m, 1H), 4.78 (d, J= 4.5 Hz, 1H), 3.43-3.39 (m, 1H), 3.12-3.06 (m, 2H), 2.97-2.84 (m, 2H), 2.35-2.34 (m, 3H), 2.13-2.01 (m, 1H), 1.97 (d, J= 2.8 Hz, 6H), 1.76-1.65 (m, 3H), 1.60-1.54 (m, 2H), 1.41-1.33 (m, 2H), 0.92 (t, J= 7.3 Hz, 3H), 0.82 (d, J= 6.0 Hz, 3H); 19F{ 1H] NMR (DMSO): singlet, -59.95 ppm; ES-MS m/z 642 (M+H).
Example 61 : Racemic 4'-((R)-l,2-dihydroxyethyl)-2',6'-dimethyl-3-((5R,7S)-7-methyl-4-oxo-2- (2-((RS)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)-[ 1 , 1 '-biphenyl] -4-carbonitrile
[0393] To a 8 mL vial with a magnetic stir bar was charged with 1,4-Dioxane (1 mL) and H2O (0.1 mL), followed by the addition of 2-((5R,7S)-7-methyl-4-oxo-2-(2-((RS)-tetrahydrofuran-2- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile (70 mg, 0.11 mmol), (R)-l-(4-bromo-3,5- dimethylphenyl)ethane-l,2-diol (32 mg, 0.13 mmol), K2CO3 (45 mg, 0.32 mmol)and chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (5 mg, 0.01 mmol) at 26 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 80 °C for 1 h. Allowed the reaction mixture to cool down to RT, then the crude reaction mixture was filtered through a pad of celite under reduce pressure and rinsed with 3 ml EtOAc. The filtrate was concentrated under reduced pressure at 40 °C to give a residue. The residue was purified by prep-TLC (SIO2, Ethyl acetate/Petroleum ether = 1/1, Rf = 0.4), then the SiCh powder was soaked with 20 ml DCM, and filtered via suction filter, rinsed with 10 ml DCM. The filtrate was concentrated under pressure to give the crude product. The crude product was purified by prep-HPLC using high pH (lOmM ammonium bicarbonate with 5% MeOH in water and ACN) 35 to 70% ACN and the collected fraction underwent lyophilization to get the desired product. The title compound (28.87) was obtained as a solid. 1H NMR (400 MHz, DMSO-d6) 8 = 11.76 - 11.13 (m, 1H), 8.26 (br d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.87 (br d, J = 7.9 Hz, 1H), 7.21 (br d, J = 5.6 Hz, 1H), 7.09 (br s, 3H), 5.55 (td, J = 6.6, 11.0 Hz, 1H), 5.17 (d, J = 3.8 Hz, 1H), 4.69 (t, J = 5.6 Hz, 1H), 4.49 (br d, J = 5.3 Hz, 1H), 4.00 - 3.87 (m, 1H), 3.85 - 3.74 (m, 1H), 3.55 (br dd, J = 3.3, 6.3 Hz, 1H), 3.44 (br t, J = 5.6 Hz, 2H), 3.19 (br d, J = 7.0 Hz, 2H), 2.33 - 2.25 (m, 1H), 2.17 - 2.03 (m, 2H), 1.97 (br d, J = 3.0 Hz, 6H), 1.92 - 1.78 (m, 2H), 1.77 - 1.53 (m, 3H), 0.93 (br dd, J = 6.1, 8.8 Hz, 3H). ES-MS m/z 648 (M+H).
[0394] The pure enantiomers were separated using chiral SFC chromatography. Chiral Preparative Method: Chiralpak IM 30 mm x 250 mm, 5 um, 100% MeOH for 9 min at 25.5 mL/min to produce two isomers.
Example 61 A: (Isomer l)-4'-((R*)-l,2-dihydroxyethyl)-2',6'-dimethyl-3-((5R,7S)-7-methyl-4- oxo-2-(2-((R*)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-
1 -en-8-yl)-[ 1 , 1 '-biphenyl]-4-carbonitrile
Example 6 IB: (Isomer 2)-4'-((R*)-l,2-dihydroxyethyl)-2',6'-dimethyl-3-((5R,7S)-7-methyl-4- oxo-2-(2-((S*)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec- l-en-8-yl)-[l,l'-biphenyl]-4-carbonitrile
Example 62: Racemic 2-(3'-((5R,7S)-2-(2-(3-fluoroazetidin-l-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-2-en-8-yl)-2,4',6-trimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0395] Combined (5R,7S)-8-(5-chloro-2-methylphenyl)-2-(2-(3-fluoroazetidin-l-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-2-en-4-one (1.10 g 2.1,6 mmol), rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (987 mg, 3.24 mmol), potassium phosphate (1.37 g, 6.47 mmol) in a 20 mL MRV and added MeOH (10 mL)water (1.0 mL). Then added Methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (558 mg, 647 pmol) capped the vessel. The vial was heated to 70 °C and monitored by LCMS. After 14 h, the reaction was allowed to cool to RT. Once cooled to RT, the reaction was diluted EtOAc and fdtered through celite to obtain a solid. The solid was purified using RP-HPLC on high pH (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 50 to 70% ACN and the collected fraction underwent lyophilization to get the title compound, a solid (0.3340 g) ES-MS m/z 651 (M+H). The enantiomers were isolated using chiral SFC chromatography.
Chiral Chromatography Conditions 152 mg racemic was separated to provide the following.
Chiral Preparative Method:
Column: Whelk-0 (S,S) 30 mm x 250 mm, 5 um Mobile phase: B: Methanol Flow rate: 25mL/min for 8 minutes
Example 62 A: (Isomer 1)- (R*)-2-(3'-((5R,7S)-2-(2-(3-fluoroazetidin-l-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-2-en-8-yl)-2,4',6- trimethyl-[l,r-biphenyl]-4-yl)-2-hydroxy acetamide
Example 62B: (Isomer 2)- (R*)-2-(3'-((5R,7S)-2-(2-(3-fluoroazetidin-l-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-2-en-8-yl)-2,4',6- trimethyl-[l,r-biphenyl]-4-yl)-2-hydroxy acetamide
Example 63: Racemic - (RS)-2-(3'-((5R.7S)-2-(2-cvclobutvl-6-(trifluoromethvl)pvridin-3-vl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0396] To an 8 mb vial with a magnetic stir bar was charged with MeOH (2 m ) and water (0.2 mb), followed by the addition of (5R,7S)-8-(5-chloro-2-methylphenyl)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (51 mg, 0.10 mmol), rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (38 mg, 0.12 mmol), Potassium carbonate (44 mg, 0.31 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2l-methylamino- l,T-biphenyl-2-yl)palladium(II) (19 mg, 21 pmol) at 28 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 80 °C for 1 h. The reaction mixture was fdtrated and fdtrate was concentrated under reduced pressure to give a residue. The crude was purified by prep-TLC (SIO2, ethyl acetate/petroleum ether = 3/1, Rf = 0.4), then the SiO2 powder was soaked with 20 ml MeOH, and filtered via suction filter, rinsed with 5 ml MeOH. The filtrate was concentrated under pressure to give a product. The residue was purified by Prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [A: H2O (lOmM NH4HCO3); B: ACN]; B%: 40.00%-75.00%,8.00 min; flow rate:60.00ml/min), and the collected fraction underwent lyophilization to get the desired product. The title compound (22.68 mg) was obtained as a solid. 1H NMR (400 MHz, DMSO-d6) 5 = 11.58 - 11.31 (m, 1H), 8.31 - 8.16 (m, 1H), 7.91 (br d, J = 7.8 Hz, 1H), 7.36 (br d, J = 2.3 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.17 (br s, 1H), 7.13 (s, 2H), 6.92 (br s, 1H), 6.80 (br d, J = 7.9 Hz, 1H), 5.91 (d, J = 4.6 Hz, 1H), 4.77 (d, J = 4.5 Hz, 1H), 4.36 - 4.18 (m, 1H), 3.53 - 3.44 (m, 1H), 3.09 - 2.97 (m, 1H), 2.90 (br d, J = 9.8 Hz, 1H), 2.36 (s, 3H), 2.35 - 2.27 (m, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.03 (m, 1H), 1.97 (d, J = 2.1 Hz, 6H), 1.93 - 1.82 (m, 1H), 1.80 - 1.68 (m, 2H), 1.64 - 1.47 (m, 2H), 0.84 (br d, J = 5.1 Hz, 3H). ES-MS m 'z 634 (M+H).
[0397] The two enantiomers were separated by chiral SFC chromatography. The spectra of SFC showed (t(R): Isomer 1 1.226 min, Isomer 2 1.340 min; Column: (S,S)-WHELK-O1, 50*4.6mm I.D., 3.5um Mobile phase:A:CO2 B:ACN:EtOH=l :l(0.1% IPAm,v/v), 3.4 mL/min, 254 nm).
Example 63A: (Isomer 1)- (R*)-2-(3'-((5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-
7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,r-biphenyl]-4-yl)-2- hy droxy acetami de
Example 63B: (Isomer 2)- (R*)-2-(3'-((5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)- 7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,r-biphenyl]-4-yl)-2- hydroxy acetamide Example 64: 2',6'-dimethyl-3-((5R,7S)-7-methyl-4-oxo-2-(2-((RS)-tetrahydrofuran-2-yl)-6- (trifhioromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-(2-oxopyrrolidin-l-yl)- [l,l'-biphenyl]-4-carbonitrile
[0398] Used pre-sparged MeOH and a 3M CS2CO3 solution in water that was presparged. Created a stock solution of the 280 mg 2-((5R,7S)-7-methyl-4-oxo-2-(2-((RS)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (35 mg, 57 pmol) with 4 mL dry, sparged MeOH. To a vial was added l-(4-bromo-3,5-dimethylphenyl)pyrrolidin-2-one (7.3 mg, 91 pmol), XPhos Pd G4 (7.4 mg, 8.6 pmol), 510uL of the Boronate stock solution and 3.0M Cs2CO3 in water (56 mg, 57 pL, 3.0 molar, 0.17 mmol), then sparged for 2-3 min with Argon. Placed in 77 °C heating block with stirring. After 3 h, removed from heat and transferred to new vial using ~5 mL DCM and 2 mL water. The resulting mixture was quenched with IN HC1 to pH ~8. Added 40 mg Silicycle MetS-Thiol and 60mg Silicycle MetS-DMT Pd scavengers to the mixture and the mixture was shaken at 40 °C for 30-40 min, then transferred the organic layer from the Pd scavenging mixtures was added to a SCX-2 SPE cartridge. The cartridge was eluted with 30mL DCM (Fl), 30mL 25% MeOH/DCM (F2) and 30mL 7M NH3/MeOH (F3). The elution was concentrated and then purified using Prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [A: H2O (lOmM NH4HCO3); B: ACN]; B%: 40.00%-75.00%,8.00 min; flow rate:60.00ml/min), And the collected fraction underwent lyophilization to get the desired product. The title compound (22.68 mg) was obtained as a solid (13. 2 mg). ES-MS m/z 671 (M+H).
Example 65: (RS)-2-(3'-((5R,7S)-2-(6-butoxy-2-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo- 1, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-2, 4', 6-trimethyl-[l,l'-biphenyl]-4-yl)-2-hydroxy acetamide
[0399] A mixture of rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (85 mg, 0.28 mmol), (5R,7S)-2-(6-butoxy-2- (trifluoromethyl)pyridin-3-yl)-8-(5-chloro-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec- l-en-4-one (94 mg, 0.18 mmol), (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l, l'-biphenyl]-2-yl)-15- phosphaneyl)(2'-(methylamino)-[l,r-biphenyl]-2-yl)palladium(III) methanesulfonate (24 mg, 28 pmol) and potassium carbonate (77 mg, 0.55 mmol) in methanol (2 mL) and water (0.5 mL) was heated at 85 °C in a microwave for 2.5 h. The reaction was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted IX EtOAc. The combined organic layers later were extracted lx brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (12 g) using 0-100% (10%MeOH/ETOAc)ZDCM to give a tan foam. Submitted to high pH reverse phase chromatography, (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 5 to 95% ACN and the collected fractions underwent lyophilization to get the title compound, a solid (32 mg). ES-MS m/z 652 (M+H).
Example 66: (RS)-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(6-propoxy-2-
(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r-biphenyl]-4-
[0400] A degassed (nitrogen and vacuum 3x) mixture of rac-(R)-2-(3, 5 -dimethyl -4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (121 mg, 396 pmol), (5R,7S)- 8-(5-chloro-2-methylphenyl)-7-methyl-2-(6-propoxy-2-(trifluoromethyl)pyridin-3-yl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (97 mg, 0.20 mmol), (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l,T- biphenyl]-2-yl)-15-phosphaneyl)(2'-(methylamino)-[l,T-biphenyl]-2-yl)palladium(III) methanesulfonate (28 mg, 33 pmol) and potassium carbonate (101 mg, 731 pmol) in methanol (5 mL) and water (0.250 pL) was heated at 85°C in a microwave for 2.5 h. Allowed to stand at RT. The reaction was diluted with EtOAc and water and the layers separated. The organic phase was extracted IX brine, dried Na2SO4, filtered and concentrated. Crude was dissolved in MeOH and loaded on a prewashed SCX column (1 g, MeOH). The column was washed w excess MeOH and then eluted the product from the column using 2X 5 mL 7N
NHi/MeOH. Concentration gave a solid. Submitted to high pH reverse phase chromatography, (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 5 to 95% ACN and the collected fractions underwent lyophilization to get the title compound, a solid (44 mg). ES-MS m/'z 638 (M+H).
Example 67: (RS)-2-hydroxy-2-(3'-((5R,7S)-2-(6-isopropoxy-2-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,T-biphenyl]-4- yl)acetamide
[0401] A degassed (nitrogen and vacuum 3x) mixture of rac-(R)-2-(3, 5 -dimethyl -4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (156 mg, 511 pmol), (5R,7S)- 8-(5-chloro-2-methylphenyl)-2-(6-isopropoxy-2-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one (170 mg, 343 pmol), (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l,T- biphenyl]-2-yl)-15-phosphaneyl)(2'-(methylamino)-[l,r-biphenyl]-2-yl)palladium(III) methanesulfonate (49 mg, 57 pmol) and potassium carbonate (149 mg, 1.08 mmol) in methanol (6 mL) and water (0.5 m ) was heated at 85 °C in a microwave for 2.5 h. Allowed to stand.
The reaction was diluted with EtOAc and water and the layers separated. The organic phase was extracted IX brine, dried over lSfeSCE, filtered and concentrated. Purified by silica gel chromatography (12 g) using 0-100% (10%MeOH/EtOAc)/DCM to give a foam. Submitted to high pH reverse phase chromatography, (lOmM ammonium bicarbonate with 5% MeOH in water and ACN) 5 to 95% ACN and the collected fractions underwent lyophilization to get the title compound, a solid (120 mg). ES-MS m/z 638 (M+H).
Example 68: Racemic-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-((SR)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)acetamide
[0402] Mixed rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (110 mg, 360 pmol) with (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2- (2-((RS)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one (131 mg, 258 pmol) and dissolved in MeOH (4 mL).
Added K2CO3 (108 mg, 781 pmol) followed by water (0.80 mL). Bubbled N2 through the reaction for 10 min. Added Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r- biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (31 mg, 36 pmol). Sealed the reaction and heated via microwave irradiation to 80°C for 1.5 h. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH, 1 : 1 MeOH/DCM then again with MeOH and collected as fraction SCX1. Then elute with 7M NH3 in MeOH and collect as fraction SCX2. Concentrated the SCX2 fraction containing the desired product. Dissolved in minimal 1 : 1 DCM:THF then loaded onto a 5 g silica gel loading column and purified using a 12 g silica gel column that was eluted with a 0-100% (B/A) gradient of: Solvent A: 10% THF in DCM and Solvent B: 10% MeOH in THF. Collected fractions, but there were still some impurities also present, so repeated purification 5g loading column/12g purification column with a 0-100% (10% MeOH in EtOAc)/cyclohexanes. Collected fractions containing the pure desired product and concentrated to provide the title compound (85 mg) as a solid. 1H NMR (400.13 MHz, CDC13): 10.36-10.34 (m, 1H), 8.56-8.51 (m, 1H), 7.72 (d, J= 7.9 Hz, 1H), 7.31 (s, 1H), 7.16 (d, J= 8.1 Hz, 2H), 7.06-7.02 (m, 1H), 6.84 (d, J= 5.1 Hz, 1H), 6.31-6.17 (m, 1H), 5.68 (s, 1H), 5.19 (d, J= 6.0 Hz, 1H), 5.04 (d, J= 5.0 Hz, 1H), 4.00 (dd, J= 5.1, 6.1 Hz, 2H), 3.61-3.53 (m, 2H), 3.30-3.27 (m, 1H), 3.08-3.00 (m, 1H), 2.99-2.90 (m, 1H), 2.43-2.35 (m, 4H), 2.32-2.22 (m, 1H), 2.07-2.04 (m, 7H), 1.97-1.94 (m, OH), 1.66-1.60 (m, 4H), 0.96-0.91 (m, 3H). ES-MS 650 m/z (M+H). ES/MS (m/z): 650 (M+H).
[0403] Dissolution of 67 mg of Racemmic-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl- 4-oxo-2-(2-((SR)-tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-yl)acetamide was achieved using 4.5mL MeOH, 0.5mL DCM. The 5mL feed solution was filtered and then processed using the following parameters:
Instrument Name: Teledyne ISCO ACCQPrep SFC
Column Used: S,S Whelk-01, 21x250mm, 10pm
Mobile Phase: 25% IPA(0.5%DMEA): 75%CO2
Flow Rate: 80mL/min
BPR Set Point: lOObar
BPR Temperature: 25°C
Column Temperature: 40°C
Detection: 214, 254nm
Loading: Increased to optimal loading at ImL (appx. 13.4mg)
Total Elution Time: 16min
Example 68a: Isomer l-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-((S*)- tetrahydrofuran-2-yl)-6-(trifhjoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)acetamide
Example 68b: Isomer 2-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-((S*)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)acetamide Example 68c: Isomer 3-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-((S*)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)acetamide
Example 68d: Isomer 4-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-((S*)- tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,r- biphenyl]-4-yl)acetamide
Example 69: (RS)-2-(3'-((5R,7S)-2-(2,2-difluoro-4-((RS)-tetrahydrofuran-2- yl)benzo[d][l,3]dioxol-5-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6- trimethyl-[ 1 , 1 ’-biphenyl] -4-yl)-2-hydroxy acetamide
[0404] Into a microwave vial was added (5R,7S)-8-(5-chloro-2-methylphenyl)-2-(2,2-difluoro-4- ((RS)-tetrahydrofuran-2-yl)benzo[d][l,3]dioxol-5-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4- one (100 mg, 193 pmol) and rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2-hydroxyacetamide (90 mg, 0.29 mmol). The materials were then dissolved in Methanol (3 mL). Next, potassium carbonate (80.0 mg, 579 pmol) and water (0.6 mL) were added with stirring, and the reaction degassed with a stream of N2 gas for lOmins. Finally, Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,r-biphenyl-2-yl)palladium(II) (16 mg, 0.19 pmol) was added and the reaction vessel was capped. The reaction was subjected to microwave irradiation with heating to 80 °C and stirring for 1.5 h. The reaction was cooled to RT and poured directly onto an SCX column. The material was rinsed with CH2C12 (50mL), 1 : 1 CFtC^/MeOH (50mL) and MeOH (50mL) successively. The product was then eluted with 2M NHs-MeOH. The basic filtrate was concentrated under reduced pressure to yield 119 mg of a residue that was then submitted to high pH reverse phase chromatography, (lOmM Ammonium Bicarbonate with 5% MeOH in water and ACN) 40 to 70% ACN and the collected fractions underwent lyophilization to get the title compound, a solid (95.8 mg). ES-MS m/z 661 (M+H).
Example 70: 2-(3'-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-4'-methoxy-2,6-dimethyl-[l,r-biphenyl]-4-yl)acetamide
[0405] Dissolved 8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (84 mg, 0.17 mmol) in 1,4- dioxane (2 mL) then added water (0.4 mL). Added 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)acetamide (71 mg, 0.25 mmol). Began bubbling N2 through the reaction.
[0406] Added K2CO3 (69 mg, 3.0 Eq, 0.50 mmol). Continued to bubble N2 through the reaction for 15 min total. Added (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)-15- phosphaneyl)(2'-(methylamino)-[l,l'-biphenyl]-2-yl)palladium(III) methanesulfonate (17 mg, 20 pmol). Sealed the reaction and heated via microwave irradiation to 85 °C for 2 h. The reaction vial was opened and started bubbling N2 through the solution. Added more boronate
(36mg). After ~5 min, added (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l,T-biphenyl]-2-yl)-15- phosphaneyl)(2'-(methylamino)-[l '-biphenyl]-2-yl)palladium(III) methanesulfonate (17 mg, 20 pmol) then sealed and heated via microwave to 85 °C for 2 h. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction, which was concentrated to a residue that was purified using prep-HPLC s purified by high pH on Flash 90 utilizing a 50 g column and a 40-70% gradient over 10 CV. Fractions A15-19 were pooled to afford the title compound as a solid (56.9 mg). ES-MS m z 624 (M+H).
Example 71 : (RS)-2-(3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fhioro-4'-methoxy-2,6-dimethyl-[l,r-biphenyl]-4- yl)-2-hydroxy acetamide
[0407] Dissolved (5R,7S)-8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (69 mg, 0.14 mmol) in 1,4-Dioxane (2 mb) then added MeOH (0.3 mL) and water (0.3 mb). Began bubbling N2 through the reaction. Added rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (54 mg, 0.18 mmol), then added K2CO3 (64 mg, 0.46 mmol). Continued to bubble N2 through the reaction for 15 min total. Added (s)- (dicyclohexyl(2',4',6'-triisopropyl-[l,r-biphenyl]-2-yl)-15-phosphaneyl)(2'-(methylamino)-[l,r- biphenyl]-2-yl)palladium(III) methanesulfonate (11 mg, 13 pmol). Sealed the reaction and heated via microwave irradiation to 85 °C for 3 h. Removed cap and started bubbling N2 through the reaction mixture. Added additional rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (54 mg, 0.18 mmol). After 10 min of total N2 bubbling through the reaction, added (s)-(dicyclohexyl(2',4',6'-triisopropyl-[l,r-biphenyl]-2- yl)-15-phosphaneyl)(2'-(methylamino)-[l,r-biphenyl]-2-yl)palladium(III) methanesulfonate (11 mg, 13 pmol) then sealed the vial and heated via microwave to 90°C for 2 h. Since vial has remained sealed, heated again via microwave, this time to 100 for 13 h. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction SCX2, concentrated to a residue that was purified using prep-HPLC, low pH utilizing a 50 g column and a 20-45% gradient (A) 0.1% FA in water and (B) ACN over 10 CV. Fractions were pooled to afford the title compound as a solid (16.8 mg). ES-MS m/z 654 (M+H).
Example 72: (RS)-2-(3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-4'-methoxy-2,6-dimethyl-[l,r-biphenyl]-4-yl)-2- hydroxyacetamide
[0408] Dissolved (5R,7S)-8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (54 mg, 0.11 mmol) in 1,4-dioxane (2 mL) then added MeOH (0.3 mL) and water (0.3 mL). Began bubbling N2 through the reaction. Added rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxy acetamide (55 mg, 0. 18 mmol). Added K2CO3 (45 mg, 0.33 mmol). Continued to bubble N2 through the reaction for 15 min total. Added (s)- (dicyclohexyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)-15-phosphaneyl)(2'-(methylamino)-[l,l'- biphenyl]-2-yl)palladium(III) methanesulfonate (12 mg, 14 pmol). Sealed the reaction and heated via microwave irradiation to 90 °C for 3 h. The reaction was loaded directly onto a 10 g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction SCX2, which was concentrated to a residue that was further purified using prep-HPLC using high pH, a 20-75% B gradient over 10 CV, a Redisep gold Cl 8 50 g column and a 60 mL/min flow rate. Pooled A88-91 to provide the title compound as a solid (34.7 mg). ES-MS m/z 653 (M+H). Example 73 : (RS)-2-(5'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2',3'-difluoro-4'-methoxy-2,6-dimethyl-[l,l'-biphenyl]-4-yl)- 2-hydroxy acetamide
[0409] Dissolved (5R,7S)-8-(5-chloro-3,4-difluoro-2-methoxyphenyl)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (29 mg, 55 pmol) in 1,4- dioxane (2 mL) then added water (0.4 mL). Began bubbling N2 through the reaction.
Added rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (28 mg, 92 pmol), then added K2CO3 (31 mg, 0.22 mmol). Continued to bubble N2 through the reaction for 15 min total. Added (s)-(dicyclohexyl(2',4',6'-triisopropyl- [l,r-biphenyl]-2-yl)-15-phosphaneyl)(2'-(methylamino)-[l,r-biphenyl]-2-yl)palladium(III) methanesulfonate (10 mg, 12 pmol). Sealed the reaction and heated via microwave irradiation to 85 °C for 3 h. The reaction was loaded directly onto a 10g SCX column. Eluted with MeOH (2x, approx 2CV each) and collected as fraction SCX1. Then eluted with 7M NH3 in MeOH and collected as fraction SCX2. Product was observed only in the SCX2 fraction which was concentrated to a residue that was further purified using prep-HPLC by high pH on Accqprep 4 utilizing a 40-70% gradient over 10 min. Fractions A7-9 were pooled to provide the title compound as a solid (10.4 mg). ES-MS m/z 671 (M+H).
Example 74: rac-(R)-2-(4'-cyano-3'-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-yl)-2- hydroxy acetamide
[0410] A solution of rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (34 mg, 1.0 Eq, 0.11 mmol)4-bromo-2-(2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzonitrile (60 mg, 0.11 mmol), K2CO3 (15 mg, 0.11 mmol), XPhos Pd G4 (96 mg, 0.11 mmol), 1,4- dioxane (1 mL) and water (.1 mL) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar). The reaction was concentrated under reduced pressure. Then diluted with MeOH and a metal scavenger was added and reaction stirred for 10 min before being filtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep- HPLC using a gradient of 40 to 95% ACN in 0.1% aq. FA to give the title compound (0.018 g) as a solid. ES-MS m/z 634 (M+H).
Example 75: 2-(4'-cyano-3'-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-yl)acetamide
[0411] A solution of 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetamide (39 mg, 0.13 mmol)4-bromo-2-(2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzonitrile (60 mg, 0.11 mmol), K2CO3 (50 mg, 0.36 mmol), XPhos Pd G4 (20 mg, 23 pmol), 1,4-dioxane (1 mL) and water (.1 mL) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar).
After 12 h, additional XPhos Pd G4 (20 mg, 23 p ol) was added and the reaction was sparged again then continued to stir at 50 C. After another 24 h, the reaction was concentrated under reduced pressure. Diluted with MeOH and a metal scavenger was added and reaction stirred for 10 min before being fdtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep- HPLC using a gradient of 5 to 95% ACN in 0.1% aq. FA to give the title compound (0.012 g) as a solid. ES-MS m/z 619 (M+H).
Example 76: (R)-2-(4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-yl)-2- hydroxy acetamide
[0412] In a 5 mL MRV with magnetic stir bar was combined with 4-bromo-2-((5R,7S)-2-(2- cyclopropyl-6-ethoxypyri din-3-yl)-7-methyl -4-oxo- 1,3, 8-triazaspiro[4.5]dec-l-en-8-yl)-6- fluorobenzonitrile (56.2 mg, 107 pmol) in 1,4-di oxane (2 mL) the solvent was purged with nitrogen while adding sequentially, (R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (37.1 mg, 122 pmol), potassium phosphate, tribasic (78.0 mg, 367 pmol) and water (0.4 mL). Continued to purge and heating began. After reaching 50 °C, added methanesulfonato(2-dicyclohexylphosphino-2',4',6l-tri-i-propyl-l,r- biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (10.40 mg, 12.07 pmol), capped the vessel and continued the reaction at 100 °C for 1 h in a microwave reactor, then allowed to sit at RT overnight. The reaction was poured onto a prepared SCX column with ~2 g celite on top and washed with DCM, 2X 25 mL followed by 50% MeOH/DCM 2X25 mL washes and then 2 X 25 mL washes of 30% 7N NH3 MeOH/DCM to elute the desired product. Fractions were analyzed by TLC and the fractions containing pure desired product were combined and CIV to provide a residue that was further purified using RP-HPLC purification on high pH, EVO 30x100 mm column. 10 nM Ammonium acetate in ACN gradient of 3min 20%, lOmin 20-54%, Imin 54%, 3.2min 54-65%. Isolated the title compound as a solid (10.4 mg) ES-MS 625 m/z (M+H).
Example 77: 2-(4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,T-biphenyl]-4- yl)acetamide
[0413] In a 5 mL MRV with magnetic stir bar was combined 4-bromo-2-((5R,7S)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)-6-fluorobenzonitrile (50.012 mg, 90.871 pmol) in 1,4-dioxane (3 mL) the solvent was purged with nitrogen while adding sequentially, 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)acetamide (36.162 mg, 125.05 pmol), potassium phosphate, tribasic (97.865 mg, 38.17 pL, 461.06 pmol) and water (0.6 mL). Continued to purge and heating began. After reaching ~50 °C, added methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (17.8285 mg, 20.695 pmol), capped the vessel and continued the reaction at 100 °C for 1 h in a microwave reactor, then allowed to sit at RT overnight. The next day the reaction was continued at 50 °C for 4 h, then the reaction was poured onto a prepared SCX column with ~2 g celite on top and washed with DCM, 2X 25 mL followed by 50% MeOH/DCM 2X25 mL washes and then 2 X 25 mL washes of 30% 7N NH3 MeOH/DCM to elute the desired product. Fractions were analyzed by TLC and the fractions containing pure desired product were combined and CIV to provide a solid. The solid was purified using reverse phase HPLC using HIGH pH (10 mM ammonium bicarbonate in ACN), a 20-80% B gradient over 10 min, an EVO 30X 100 mm column was used. Isolated the title compound as a solid (10.2 mg). ES-MS m/z 633 (M+H). Example 78: (RS)-2-(4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2-
[0414] In a 5 mL MRV with magnetic stir bar was combined 4-bromo-2-((5R,7S)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8- yl)-6-fluorobenzonitrile (49.7 mg, 90.3 mol) in 1,4-di oxane (3 mL) the solvent was purged with nitrogen while adding sequentially, rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (45.8 mg, 150 umol), potassium phosphate, tribasic (97.5 mg, 459 pmol) and water (0.6 mL). Continued to purge and heating began. After reaching ~50 °C, added methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T- biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (17.78 mg, 20.64 pmol), capped the vessel and continued the reaction at 100°C for 1 h in a microwave reactor, then allowed to sit at RT. The reaction was poured onto a prepared SCX column with ~2 g celite on top and washed with DCM, 2X 25 mL followed by 50% MeOH/DCM 2X25 mL washes and then 2 X 25 mL washes of 30% 7N NH3 MeOH/DCM to elute the desired product. Fractions were analyzed by TLC and the fractions containing pure desired product were combined and CIV to provide a solid. The solid was purified using reverse phase HPLC using high pH (lOmM ammonium bicarbonate in ACN), a 20-75% B gradient over 10 min, an EVO 30 X 100 mm column was used. Isolated the title compound as a solid (14.0 mg). ES-MS m 'z 649 (M+H).
Example 79: 3-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-4'-((R)-l,2-dihydroxyethyl)-5-fluoro-2',6'-dimethyl-[l,T- biphenyl]-4-carbonitrile
[0415] A solution of (R)-l-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethane-l,2-diol (40 mg, 0.14 mmol) 4-bromo-2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6- fluorobenzonitrile (60 mg, 0.11 mmol), K2CO3 (45 mg, 3.0 Eq, 0.33 mmol), XPhos Pd G4 (20 mg, 23 pmol), MeOH (.3 m ) and water (.1 m ) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar). The reaction was concentrated under reduced pressure, then diluted with MeOH and a metal scavenger was added and reaction stirred for 10 min before being filtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPEC using a gradient of 40 to 95% ACN in 0.1% aq. FA to give the title compound (0.023 g) as a solid. ES-MS m/z 635 (M+H).
Example 80: 2-(4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,l'-biphenyl]-4-yl)acetamide
[0416] A solution of 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetamide (41 mg, 1.3 Eq, 0.14 mmol)4-bromo-2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6- fluorobenzonitrile (60 mg, 1 Eq, 0.11 mmol), K2CO3 (45 mg, 0.33 mmol), XPhos Pd G4 (19 mg, 22 pmol), MeOH (.3 mL) and water (.1 mL) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar). The reaction was concentrated under reduced pressure, then diluted with MeOH and a metal scavenger was added and reaction stirred for 10 min before being filtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep- HPLC using a gradient of 40 to 95% ACN in 0.1% aq. FA to give the title compound (0.014 g) as a solid. ES-MS m/z 632 (M+H).
Example 81 : (RS)-2-(4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0417] A solution of rac-(R)-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (44 mg, 0.14 mmol)4-bromo-2-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6- fluorobenzonitrile (58 mg, 0.11 mmol), K2CO3 (45 mg, 0.33 mmol), XPhos Pd G4 (18 mg, 0.20 Eq, 21 pmol), MeOH (1 mL) and water (.2 mL) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred over the weekend (use of stir bar). A metal scavenger was added and reaction stirred for 10 min before being filtered over celite. Crude material was concentrated under reduced pressure then diluted with MeOH and filtered through PTFE 0.45 pm filter before submission to achiral purification. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 5 to 95% ACN in 10 nM ammonium acetate to give the title compound (0.022 g) as a solid. ES-MS m/z 648 (M+H).
Example 82: 4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-carboxamide
[0418] A solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (36 mg, 1.2 Eq, 0.13 mmol)4-bromo-2-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzonitrile (60 mg, 0.11 mmol), K2CO3 (45 mg, 0.33 mmol), XPhos Pd G4 (20 mg, 23 pmol), MeOH (.3 mb) and water (.1 m ) in a scintillation vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar). The reaction was concentrated under reduced pressure. Then diluted with MeOH and a metal scavenger was added and reaction stirred for 10 min before being filtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 40 to 95% ACN in 0.1% aq. FA to give the title compound (0.016 g) as a solid. ES-MS m/z 618 (M+H).
Example 83 : 4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-sulfonamide
[0419] A solution of 4-bromo-3,5-dimethylbenzene-l-sulfonamide (40 mg, 0.15 mmol)2- ((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec- l-en-8-yl)-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (76 mg, 0.13 mmol), K2CO3 (53 mg, 0.38 mmol), XPhos Pd G4 (22 mg, 26 pmol), and water (.2 mb) in a dram vial were sparged with nitrogen for 30 seconds then placed into a preheated alumina block heated to 50 °C (controlled via external probe) and stirred overnight (use of stir bar). The reaction was concentrated under reduced pressure. Then diluted with MeOH and a metal scavenger (silicycle siliametS thiol) was added and reaction stirred for 10 min before being filtered through PTFE 0.45 pm filter. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 0 to 95% ACN in 0.1% aq. FA to give the title compound (0.019 g) as a solid. ES-MS m/z 654 (M+H).
Example 84: (RS)-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(2-(thiophen-2- yl)-4-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-8-yl)-[l,l'-biphenyl]-4-
[0420] (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(2-(thiophen-2-yl)-4- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.508 g, 0.79 mmol), rac-2- (3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.258 g, 0.837 mmol) and K3PO4 (0.435 g, 1.95 mmol) were charged into a 20 ml microwave tube, then 1,4-dioxane (5 m ) and H2O (2.5 m ) were added. The mixture was purged with N2 for 1 min before and after adding methanesulfonato(2-dicyclohexylphosphino- 2' ,4', 6' -tri -i -propyl - 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.043 g, 0.047 mmol). Then the sealed tube was irradiated in microwave at 125 °C for 2 h, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1 : 1 petroleum ether: EtOAc, Rf = 0.6, UV), then the SiO2 powder was soaked with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 40 to 70% ACN in 0.2% aq. FA to give the title compound (0.054 g) as a solid. ES-MS m/z 677 (M+H). Example 85: (RS)-2-(3'-((5R,7S)-2-(2-(l-fluorocyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,4',6-trimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0421] To an 8 mL vial with a magnetic stir bar was charged with MeOH (3.6 mL) and water (0.36 mL), followed by the addition of (5R,7S)-2-(2-(l-fluorocyclopropyl)-6- (trifluoromethyl)pyridin-3-yl)-8-(5-iodo-2-methylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l- en-4-one (0.104 g, 0.177 mmol), rac-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.066 g, 0.21 mmol) and K2CO3 (0.052 g , 0.37 mmol). The mixture was purged with N2 for 30 seconds, then methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.018 g, 0.021 mmol) was added. Then the mixture was stirred at 80 °C for 1 h, cooled down to ambient temperature, concentrated under reduced pressure to give a residue, which was poured into water (2 mL) and then extracted with EtOAc (1 mL x 3). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 5: 1 DCM : MeOH, Rf = 0.4, UV), then the SiO2 powder was soaked with MeOH (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 35 to 75% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.026 g) as solid. ESMS m/z 638 (M+H).
Example 86: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(4'-(2-hydroxyethyl)-
2',4,6'-trimethyl-[l,r-biphenyl]-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one
[0422] To a 40 ml vial with a magnetic stir bar was charged with 1,4-dioxane (10 mL) and H2O (2 mL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-8-(2-methyl-5-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (0.20 g, 69.7 wt% purity, 0.24 mmol), 2-(4-bromo-3,5- dimethylphenyl)ethan- 1 -ol (0.090 g, 0.32 mmol) and K3PO4 (0.16 g, 0.73 mmol). The mixture was purged with N2 for 2 min before and after adding methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.02 g, 0.02 mmol), then stirred at 100 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure. ACN (10 mL) was added to the residue at 15 °C, stirred for 2 min and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1 : 1 EtOAc: n-hexane, Rf = 0.6, UV), then the SiO2 powder was soaked with MeOH (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC using a gradient of 50 to 80% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.073 g) as solid. ES-MS m/z 591 (M+H).
Example 87: (RS)-2-(3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-ethyl-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0423] To an 8 mL vial with a magnetic stir bar was charged with MeOH (0.4 mL) and water (0.04 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-ethylphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.060 g, 0.11 mmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (racemic mixture, 0.049 g, 0.16 mmol) and K2CO3 (0.064g, 0.46 mmol). Then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.01g, 0.011 mmol) was added to the mixture. The mixture was purged with N2 for 30 seconds, then stirred at 80 °C for 1 h, cooled down to ambient temperature and directly concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, 1 : 1 DCM : MeOH, Rf = 0.4, UV), then the SiO2 powder was soaked with EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 45 to 85% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.022 g) as solid. ES-MS m/z 634 (M+H).
Example 88: (RS)-2-(3'-((5R,7S)-2-(2-cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,4',6-trimethyl-[l,T-biphenyl]-4-yl)-2- hy droxy acetami de
[0424] To an 8 mL vial with a magnetic stir bar was charged with 1,4-di oxane (1 mL) and water (0.1 mL), followed by the addition of (5R,7S)-8-(5-chloro-3-fluoro-2-methylphenyl)-2-(2- cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.070 g, 0.12 mmol), rac-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- hydroxyacetamide (racemic mixture, 0.070 g, 78 wt% purity, 0.22 mmol), K3PO4 (0.10 g, 0.46 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l, l'-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.015 g, 0.017 mmol) at 27 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 100 °C for 2 h, then cooled down to ambient temperature, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 20: 1 DCM : MeOH, Rf = 0.3, UV), then the SiO2 powder was soaked with a mixed solvent DCM/MeOH (20 mL, DCM: MeOH = 10: 1) and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep-HPLC using a gradient of 30 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.047 g) as solid. ES-MS m/z 600 (M+H).
Example 89: (RS)-2-(4'-cyclopropyl-3'-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0425] To an 8 mL vial with a magnetic stir bar was charged with MeOH (0.4 mL) and H2O (0.04 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-cyclopropylphenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.040 g, 0.072 mmol), 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 2-hydroxyacetamide (racemic mixture, 0.034 g, 0.11 mmol) and K2CO3 (0.042 g, 0.30 mmol). Then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.008 g, 0.009 mmol) was added to the mixture. The mixture was purged with N2 for 30 seconds then stirred at 80 °C for 1 h under N2, then cooled down to ambient temperature and fdtered through a pad of celite under reduced pressure. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1 : 1 DCM : MeOH, Rf = 0.6, UV), then the SiO2 powder was soaked with EtOAc (10 mL) and then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 50 to 80% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.017 g) as solid. ES-MS m/z 646 (M+H). Example 90: (RS)-2-hydroxy-2-(2,4',6-trimethyl-3'-((5R,7S)-7-methyl-4-oxo-2-(3-((RS)- tetrahydrofuran-2-yl)-2-(trifluoromethyl)pyridin-4-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T- biphenyl]-4-yl)acetamide
[0426] To an 8 mL vial with a magnetic stir bar was charged with MeOH (1 m ) and water (0.1 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(3-((RS)- tetrahydrofuran-2-yl)-2-(trifluoromethyl)pyridin-4-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 0.021 g, 0.041 mmol), rac-2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.018 g, 0.058 mmol), K2CO3 (0.017 g, 0.12 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T- biphenyl)(2'-methylamino-l,T-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.007 g, 0.008 mmol) at 28 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 80 °C for 1 h, then filtrated and diluted with water (3 mL), extracted with EtOAc (3 mL x 3) and the combined organic layer was washed with brine (5 mL), dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1 : 1 petroleum ether: EtOAc, Rf = 0.5, UV), then the SiO2 powder was soaked with MeOH (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase prep- HPLC using a gradient of 30 to 65% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.009 g) as solid. ES-MS m/z 650 (M+H).
Example 91 : 4'-cyano-3'-fluoro-2,6-dimethyl-5'-((5R,7S)-7-methyl-2-(2-((RS)-oxetan-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[l,T-biphenyl]-4- carboxamide
[0427] To a 40 mL vial with a magnetic stir bar was charged with THF (5 mL) and water (1 mL), followed by the addition of 4-bromo-2-fluoro-6-((5R,7S)-7-methyl-2-(2-(oxetan-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)benzonitrile (mixture of isomers, 0.13 g, 0.23 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (0.089 g, 0.32 mmol), K2CO3 (0.095 g, 0.68 mmol) and Pd(Ph3P)4 (O.O53g, 0.045 mmol) at 20 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 80 °C for 24 h, cooled down to RT, poured into water (10 mL) at 25 °C, and then extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and filtered. The obtained filtrate was concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiO2, pure EtOAc, Rf = 0.35, UV), then the SiO2 powder was soaked with DCM/MeOH (10/1, 50 mL) and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase prep-HPLC using a gradient of 25 to 55% ACN in 10 mM NH4HCO3 to give a crude product, which was further purified by prep-HPLC using a gradient of 40 to 70% ACN in 10 mM NH4HCO3 to give the title compound (0.022 g) as solid. ES-MS m/z 635 (M+H).
Example 92: 3'-((5R, 7S)-2-(6-butoxy-2-cyclopropylpyridin-3-yl)-7-methyl-4-oxo- 1,3,8- triazaspiro[4.5]dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,T-biphenyl]-4-carboxylic acid
[0428] To a 40 mb vial with a magnetic stir bar was charged with MeOH (3 mL), followed by the addition of methyl 3'-((5R,7S)-2-(6-butoxy-2-cyclopropylpyridin-3-yl)-7-methyl-4-oxo- 1,3,8-triazaspiro [4.5] dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,l'-biphenyl]-4-carboxylate (0.31 g, 87.3 wt% purity, 0.437 mmol) and LiOH (4.0 M in H2O, 4.0 mL, 4.0 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was adjusted to pH = 6 ~ 7 with HC1 (1.0 M in water, 6 mL) at 0 °C, then the mixture was poured into water (10 mL), and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 40 to 80% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.019 g) as solid. ES-MS m/z 606 (M+H).
Example 93 : 4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-6-isopropoxypyridin-3-yl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,l'-biphenyl]-4-carboxylic acid
[0429] To a 40 mL vial with a magnetic stir bar was charged with MeOH (2 mL), water (0.2 mL), methyl 4'-cyano-3'-((5R, 7S)-2-(2-cy cl opropyl-6-isopropoxypyri din-3 -yl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,T-biphenyl]-4-carboxylate (0.22 g, 76 wt% purity, 0.276 mmol) and LiOH (1.0 M in H2O, 2 mL, 2 mmol). The mixture was purged with N2 for 1 min, then stirred at 50 °C for 16 h. The reaction mixture was adjusted to pH = 6~7 with AcOH (1 mL), then concentrated under reduced pressure to give a residue, which was further purified by reverse phase prep-HPLC using a gradient of 40 to 80% ACN in 10 mM aq.
NH4HCO3 to give the title compound (0.16 g) as solid. ES-MS m/z 592 (M+H).
Example 94: 3'-((5R,7S)-2-(2-butyl-4-(trifluoromethyl)thiazol-5-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,l'-biphenyl]-4-carboxylic acid [0430] To a 40 mL vial with a magnetic stir bar was charged with THF (15 mL) and water (5 mL), followed by the addition of methyl 3'-((5R,7S)-2-(2-butyl-4-(trifluoromethyl) thiazol-5-yl)- 7-methyl-4-oxo-l,3,8-triazaspiro [4.5] dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,l'-biphenyl]-4- carboxylate (0.36 g, 63.2 wt% purity, 0.36 mmol) and LiOH monohydrate (0.080 g, 1.9 mmol) at 16 °C. Then the reaction mixture was stirred vigorously at 50 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The aqueous phase was adjusted to pH = 3~4 with HC1 (2.0 M in water) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by reverse phase prep-HPLC using a gradient of 40 to 80% ACN in aq. 0.2% FA to give the title compound (0.075 g) as solid. ES-MS m/z 624 (M+H).
Example 95: 3'-((5R,7S)-2-(l-butyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,l'-biphenyl]-4-carboxylic acid
[0431] To a 40 mL vial with a magnetic stir bar was charged with MeOH (5 mL), followed by addition of methyl 3'-((5R,7S)-2-(l-butyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-4'-cyano-2,6-dimethyl-[l,T-biphenyl]-4-carboxylate (0.41 g, 49.6 wt% purity, 0.328 mmol) and LiOH (1.0 M in H2O, 2.1 mL, 2.1 mmol) at 20 °C. The mixture was vigorously stirring at 20 °C for 4 h, then concentrated under reduced pressure to give a residue. The residue was dissolved in water (10 mL), adjusted to pH = 5 ~ 6 with HC1 (1,0 M in H2O) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SCU, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 15 to 50% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.13 g) as solid. ES-MS m/z 607 (M+H). Example 96: 4'-cyano-3'-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6-dimethyl-[l,l'-biphenyl]-4-carboxylic acid
[0432] To a 10 mL one-neck round bottom flask with a magnetic stir bar was charged with MeOH (2 mL) and water (2 mL), followed by the addition of methyl 4'-cyano-3'-((5R,7S)-2-(2- cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-2,6- dimethyl-[l,l'-biphenyl]-4-carboxylate (0.15 g, 0.231 mmol) and LiOH monohydrate (0.052 g, 1.2 mmol) at 12 °C. Then the reaction mixture was stirred vigorously at 12 °C for 16 h, cooled to ambient temperature and concentrated under reduced pressure to move MeOH. The residue was poured into water (10 mL) and washed with MTBE (20 mL * 2). The aqueous phase was adjusted pH = 3 with HC1 (1.0 M in water) and then fdtered. The filter cake was dried under reduced pressure to give a product, which was further purified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.105 g) as solid. ES-MS m/z 601 (M+H).
Example 97: rac-(R)-2-(3'-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-4'-methoxy-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxy acetamide
[0433] To a 40 ml vial with a magnetic stir bar was charged with THF (2 mL) and water (0.4 mL), followed by the addition of 8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.090 g, 0.166 mmol), rac- 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.112 g, 0.347 mmol) and K3PO4 (0.116 g, 0. 541 mmol). The mixture was purged with N2 for 2 min before and after adding chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,T-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) (XPhos Palladacycle Gen. 2, CAS# 1310584-14-5, 0.027 g, 0.034 mmol), then stirred at 80 °C for 4 h, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, 1 : 1 EtOAc : n- hexane, R = 0.5, UV), then the SiCL powder was soaked with MeOH (5 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 35 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.028 g) as solid. ES-MS m/z 640 (M+H).
Example 98: rac-(R)-2-(3'-(2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-5'-fhioro-4'-(hydroxymethyl)-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxyacetamide
[0434] To an 8 mL vial with a magnetic stir bar was charged with DCM (1 mL), rac-2-(3'-(2-(2- cyclopropyl-6-ethoxypyridin-3-yl)-3-(4-methoxybenzyl)-4-oxo-l,3,8-triazaspiro [4.5] dec-l-en- 8-yl)-4'-((difhjoromethoxy)methyl)-5'-fluoro-2,6-dimethyl-[l,l'-biphenyl]-4-yl)-2- hydroxyacetamide (racemic mixture, 0.050 g, 38.7 wt% purity, 0.025 mmol) and TFA (0.015 g, 0.13 mmol). Then the reaction mixture was stirred at 40 °C for 6 h under N2, concentrated under reduced pressure to give the crude product, which was purified by reverse phase prep-HPLC using a gradient of 30 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.012 g) as solid. ES-MS m/z 616 (M+H). Example 99: 2-(4'-cyano-3'-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-5'-fluoro-2,6-dimethyl-[l,r-biphenyl]-4-yl)-2-hydroxy acetamide
[0435] To a 40 mL vial with a magnetic stir bar was charged with THF (3 mL) and H2O (0.5 mL), followed by the addition of 4-chloro-2-(2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-fluorobenzonitrile (0.20 g, 0.39 mmol), rac-2-(3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-hydroxyacetamide (racemic mixture, 0.14 g, 0.46 mmol), K2CO3 (0.20 g, 1.53 mmol) and Pd(PhsP)4 (0.10 g, 0.89 mmol) at 20 °C. The mixture was purged with N2 and stirred at 80 °C for 16 h, cooled down to room temperature, poured into H2O (10 mL) and then extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (15 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, 1: 1 n-hexane: EtOAc, Ry = 0.4, UV) to give the crude product. The crude product was purified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 10 mM NH4HCO3 to give the title compound (0.10 g) as solid. ES-MS m/z 634 (M+H).
Functional Activity Assay I and Data
[0436] Functional activity was determined using cAMP formation in human GCGR-expressing HEK-293 clonal cell lines. Each receptor cell line was treated with compound or peptide (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 IX GlutaMAX™ (Gibco Cat# 35050061), 0.1% bovine casein (Sigma Cat# C4765-10ML), 250 pM IB MX (Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630080) in a 20 pl assay volume.
[0437] 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 60 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.
[0438] The amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with human Glucagon(l-29) {GCG(l-29)}. 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.
[0439] Data for the exemplified compounds and hGCG(l-29) which is used as a reference are shown in the table below.
Table. In Vitro Functional Assay I and Data a. % Stimulation at 10000 nM
In Vitro Functional Assay II and Data
[0440] Functional activity was determined by measuring cAMP formation in HEK293 freestyle cell that was transiently transfected with human glucagon receptor (hGCGR) in which a phenylalanine residue at the position 345 was substituted with cysteine (hereafter F345C). The activity of ligands on hGCGR F345C cells can be potentiated by the positive allosteric modulator, 4-(3 -(benzyloxy )phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP, see Willard, F.S. et al. Adv. Pharmacol. 2020, 88, 173-191). The hGCGR F345C cells were treated with a compound or peptide (20-point concentration response curves with 2-fold direct dilutions prepared with a Labcyte™ Echo Acoustic Liquid Handler) in Dulbecco’s Modified Eagle’s Medium (DMEM, Gibco® Cat# 31053) supplemented with IX GlutaMAX™ (Gibco® Cat# 35050061), 0.1% bovine casein (Sigma® Cat# C4765-10ML), 250 pM isobutylmethylxanthin (IBMX, Acros Cat# 228420010) and 20 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES, Gibco® Cat# 15630080) in a 20 pL assay volume in the presence of 1 pM BETP. [0441] After a 30 min of incubation at 37 °C, the intracellular cAMP was quantitatively determined using a 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 60 minutes 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 665 nm/620 nm* 10,000) were inversely proportional to the amount of cAMP present and were converted to cAMP (nM) per well using a cAMP standard curve. [0442] The amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with human Glucagon (2-29) [hGCG(2-29)] in the presence of 1 pM BETP. A relative ECso (Rel ECso) and Emax value were derived by non-linear regression analysis using the percent maximal response versus the concentration of compound added, fitted to a four-parameter logistic equation.
[0443] Data for exemplary analogs, human Glucagon(l-29) [hGCG(l-29)], and hGCG(2-29) are shown in the table below.
Table. In Vitro Functional Assay II and Data

Claims

1. A compound of formula (I): wherein: each of RA1, RA2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,
(3) halogen,
(4) -Ci-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-10 cycloalkyl and (d) -C1-10 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -C1-10 alkyl, and (c) -C(0)Ci-io alkyl,
(6) -CN,
(7) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,
(8) oxo,
(9) -C(O)NH2,
(10) -C3-10 cycloalkyl, and
(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
R1 is selected from:
(1) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NRcRf, wherein:
Re is selected from:
(a) H,
(b) -Ci-io alkyl, and
(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; and
Rf is selected from:
(a) H,
(b) -Cuio alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Cuio alkyl;
(4) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Cuio alkyl, and
(iii) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Cuio alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rg is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with -OH,
(5) -SO2NH2, optionally substituted with 1 to 2 Cuio alkyl,
(6) -C(O)NH2, optionally substituted with 1 to 2 Ci-10 alkyl,
(7) -C(O)OH,
(8) H, and (9) C i-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) Ci-io alkyl, and (c) -OH; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -0-C(0)Ci-io alkyl, and
(b) oxo; each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -O-Re, wherein Rc is selected from (a) H and (b) -Ci-io alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
(5) halogen; each of R4, R4 , R5, and R? is independently selected from:
(1) H,
(2) -C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,
(3) -C3 -io cycloalkyl, and
(4) halogen;
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens,
(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-io alkoxy,
(f) -S-C MO alkyl, optionally substituted with 1 to 3 halogens,
(g) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) -Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -Ci-io alkyl and (ii) halogen,
(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci -io alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) - Ci-io alkoxy,
(k) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, optionally substituted 1-3 halogens, and
(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is selected from:
(1) H, (2) -Ci-io alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (la):
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (lb):
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ic): wherein: each of R6a, R6b, R6c and R6d is independently selected from:
(1) halogen,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(4) -O-aryl, optionally substituted with 1 to 3 halogens,
(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(6) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(7) -NR6eR6f, wherein each of R6e and R6f is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(8) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, and (c) -OH,
(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(11) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(12) H.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Id):
wherein: each of R6a, R6b, R6c and R6d is independently selected from:
(1) halogen,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(4) -O-aryl, optionally substituted with 1 to 3 halogens,
(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(6) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(7) -NR6eR6f, wherein each of R6e and R6f is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(8) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, and (c) -OH,
(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(11) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(12) H.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (If): wherein: each of R6a, R6b, R6c and R6d is independently selected from:
(1) halogen,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,
(3) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(4) -O-aryl, optionally substituted with 1 to 3 halogens,
(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(6) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(7) -NR6eR6f, wherein each of R6e and R6f is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(8) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, and (c) -OH,
(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
(11) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and (12) H.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,
(3) halogen,
(4) -Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-6 cycloalkyl and (d) -C1-6 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
(6) -CN,
(7) -O-C3.6 cycloalkyl, optionally substituted with 1 to 3 halogens,
(8) oxo,
(9) -C(O)NH2,
(10) -C3-6 cycloalkyl, and
(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NReRf, wherein:
Re is selected from:
(a) H,
(b) -C1-6 alkyl, and
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; and Rf is selected from:
(a) H,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -Ci-6 alkyl;
(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Ci-6 alkyl, and
(iii) 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 halogen and Ci-6 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rg is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with Ci-6 alkyl optionally substituted with -OH,
(5) -SO2NH2,
(6) -C(O)NH2,
(7) -C(O)OH,
(8) H, and
(9) C 1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo; each of R2 and R3 is independently selected from: (1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -Ci-6 alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
(d) -NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
(5) halogen; each of R4, R4 , R5, and R5 is independently selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(3) -C3-6 cycloalkyl, and
(4) halogen, wherein at least one of R4, R4 , R5, and R5 is not H;
R6 is selected from:
(1) an aryl,
(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and
(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,
(d) -O-aryl, optionally substituted with 1 to 3 halogens, (e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy,
(f) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(g) -NR6eR6f, wherein each of R6e and R6f is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(h) a 4-6 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) -Ci-6 alkyl and (ii) halogen,
(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, and (iii) -OH,
(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci- 6 alkoxy,
(k) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(l) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is selected from:
(1) H,
(2) -Ci-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and
(3) halogen.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each of RA1, R^2, RA3, and RA4 is independently selected from:
(1) H,
(2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -O-C(O)CH3 and (c) -CN, (3) halogen,
(4) -Ci-4 alkoxy,
(5) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) methyl, (c) ethyl and (d) -C(O)CH3,
(6) -CN,
(7) -C(O)NH2,
(8) -C3-6 cycloalkyl, and
(9) a 5 to 6 membered heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1.4 alkyl and (b) halogen;
R1 is selected from:
(1) a 5 to 10 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) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo;
(2) -NRCR', wherein:
Re is selected from:
(a) H, and
(b) -Ci-4 alkyl, and
R1 is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -C1-4 alkyl;
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from: (i) H,
(ii) -Ci-4 alkyl, and
(iii) 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 halogen and Ci-4 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)RS, wherein Rs is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with C 1-4 alkyl optionally substituted with -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH,
(7) H, and
(8) C 1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; each of R2 and R3 is independently selected from:
(1) H,
(2) halogen, and
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH; each of R4, R4 , R5, and R5 is independently selected from:
(1) H,
(2) halogen,
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen, and
(4) -C3-6 cycloalkyl, wherein at least one of R4, R4 , R5, and R5 is not H; and R6 is selected from:
(1) a phenyl
(2) a naphthyl,
(3) a pyridyl, and
(4) 1,3-benzodioxolyl, wherein each of the phenyl of (1), naphthyl of (2), pyridyl of (3) and 1,3-benzodioxolyl of (4) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,
(d) a 4 or 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) -CH3 and (ii) halogen,
(e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -C1-4 alkoxy,
(f) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(g) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens.
9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each of RA1, R42, R \ and RA4 is independently selected from:
(1) H,
(2) -C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,
(3) halogen,
(4) -C 1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-4 cycloalkyl and (d) -Ci -6 alkoxy,
(5) -NRaRb, wherein each of Ra and Rb is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
(6) -CN, (7) -C(O)NH2,
(8) -C3-6 cycloalkyl, and
(9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl and (b) halogen.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each of RA1, RA2, RA3, and R44 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -O-C(O)CH3 and (c) -CN,
(3) ethyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -O-C(O)CH3 and (c) -CN,
(4) halogen,
(5) methoxy,
(6) ethoxy,
(7) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) methyl, (c) ethyl and (d) -C(O)CH3,
(8) -CN,
(9) -C(O)NH2,
(10) -C3-4 cycloalkyl, and
(11) a 5 to 6 membered heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) methyl, (b) ethyl and (c) halogen.
11. The compound of any one of claims 1-7 and 9-10, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:
(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,
(3) -NRcRf, wherein:
Re is selected from:
(a) H, and
(b) -Ci-6 alkyl; and
R1 is selected from:
(a) H,
(b) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(O)NH2, optionally substituted with 1 to 2 -Ci-6 alkyl;
(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Ci-6 alkyl, and
(iii) 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 halogen and Ci-6 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)RS, wherein Rg is 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 halogen and Ci-6 alkyl optionally substituted with -OH,
(5) -SO2NH2,
(6) -C(O)NH2,
(7) -C(O)OH,
(8) H, and
(9) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and
(b) oxo.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:
(1) a 5 to 10 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) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and
(b) oxo;
(2) -NReRf, wherein:
Re is selected from:
(a) H, and
(b) -Ci-4 alkyl, and
Rf is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -C1-4 alkyl;
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(0)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -C1.4 alkyl, and
(iii) 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 halogen and C1-4 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)Rg, wherein Rg is 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 halogen and Ci-4 alkyl optionally substituted with -OH,
(4) -SO2NH2,
(5) -C(0)NH2,
(6) -C(0)0H,
(7) H, and
(8) C1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:
(1) a 5 to 10 membered heterocyclyl selected from: wherein the heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from:
(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo,
(2) -NReRf, wherein:
Re is selected from (a) H and (b) -Ci-4 alkyl; and
R1 is selected from: (a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(0)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -Ci-4 alkyl; and
(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from:
(i) H,
(ii) -Ci-4 alkyl, and
(iii) 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 halogen and Ci-4 alkyl optionally substituted with -OH, and
(c) -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH,
(7) H, and
(8) C1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH.
14. The compound of any one of claims 1-7 and 9-13, or a pharmaceutically acceptable salt thereof, wherein: each of R2 and R3 is independently selected from:
(1) H,
(2) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH,
(3) -O-Rc, wherein Rc is selected from (a) H and (b) -C1-4 alkyl,
(4) -C(O)-Rd, wherein Rd is selected from (a) -C1.4 alkyl; (b) -C1-4 alkoxy, and (c) - NR2eR2f, wherein each of R2e and R2f is independently selected from (i) H and (ii) -Ci- 4 alkyl, and (5) halogen.
15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1-3 halogens,
(3) ethyl, optionally substituted with 1-3 halogens, and
(4) halogen.
16. The compound of any one of claims 1-7 and 9-15, or a pharmaceutically acceptable salt thereof, wherein each of R4, R4 , R5, and R5 , when present, is independently selected from:
(1) H,
(2) -C i-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(3) -C3-4 cycloalkyl, and
(4) halogen, wherein at least one of R4, R4 , R5, and R5 is not H.
17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from:
(1) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(2) -C3-4 cycloalkyl, and
(3) halogen; and each of R4 , R5, and R5 , when present, is H.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein:
R2 is selected from (1) H, (2) -CH3, optionally substituted with 1-3 halogens, and (3) halogen;
R3 is selected from (1) H, (2) -CH3, optionally substituted with 1-3 halogens, and (3) halogen; R4 is -CH3, optionally substituted with 1-3 halogens, and each of R4 , R5, and R5 , when present, is H.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is selected from:
(1) a phenyl
(2) a naphthyl,
(3) a pyridyl, and
(4) 1,3-benzodioxolyl, wherein each of the phenyl of (1), naphthyl of (2), pyridyl of (3) and 1,3-benzodioxolyl of (4) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(c) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,
(d) a 4 or 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) -CH3 and (ii) halogen,
(e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -C1-3 alkoxy,
(f) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(g) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from:
(1) a phenyl,
(2) pyridyl, and
(3) 1,3-benzodioxolyl, wherein each of the phenyl of (1), pyridyl of (2), and 1,3-benzodioxolyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen,
(b) methyl, optionally substituted with 1 to 3 halogens,
(c) ethyl, optionally substituted with 1 to 3 halogens,
(d) methoxy, optionally substituted with 1 to 3 halogens,
(e) ethoxy, optionally substituted with 1 to 3 halogens,
(f) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
(g) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,
(h) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(i) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens.
21. The compound of any one of claims 4-6 and 9-18, or a pharmaceutically acceptable salt thereof, wherein each of R6a, R6b, R6c and R6d, when present, is independently selected from:
(1) halogen,
(2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,
(3) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens,
(4) a 4 or 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) -CH3 and (ii) halogen,
(5) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1.4 alkyl, (ii) halogen, and (iii) -C1.4 alkoxy,
(6) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,
(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(8) H.
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein each of R6a, R6b, R6c and R6d, when present, is independently selected from:
(1) halogen,
(2) methyl, optionally substituted with 1 to 3 halogens,
(3) ethyl, optionally substituted with 1 to 3 halogens,
(4) methoxy, optionally substituted with 1 to 3 halogens,
(5) ethoxy, optionally substituted with 1 to 3 halogens,
(6) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl,
(iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
(7) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl,
(v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3.,
(8) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens,
(9) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(10) H.
23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each of RA1, A2, RA3, and RA4 is independently selected from:
(1) H,
(2) methyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -O-C(O)CH3 and (c) -CN,
(3) ethyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -O-C(O)CH3 and (c) -CN,
(4) halogen,
(5) methoxy,
(6) ethoxy,
(7) -NRaRb, wherein Ra and Rb is independently selected from (a) H, (b) methyl, (c) ethyl and (d) -C(O)CH3, (8) -CN,
(9) -C(O)NH2,
(10) -C3-4 cycloalkyl, and
(11) a 5 to 6 membered heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) methyl, (b) ethyl and (c) halogen;
R1 is selected from: wherein the heterocyclyl is optionally substituted 1 to 3 substituents independently selected from:
(a) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and
(b) oxo,
(2) -NReRf, wherein:
Re is selected from (a) H and (b) -C1.4 alkyl; and
Rf is selected from:
(a) H,
(b) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,
(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and
(d) -C(0)NH2, optionally substituted with 1 to 2 -C1-4 alkyl; and
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) -C(O)NRa Rb , wherein each of Ra and Rb is independently selected from: (i) H,
(ii) -Ci-4 alkyl, and
(iii) 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 halogen and Ci-4 alkyl optionally substituted with -OH,
(c) -OH, and
(d) -C(O)RS, wherein Rs is a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with C 1-4 alkyl optionally substituted with -OH,
(4) -SO2NH2,
(5) -C(O)NH2,
(6) -C(O)OH,
(7) H, and
(8) C 1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; each of R2 and R3 is independently selected from:
(1) H,
(2) halogen, and
(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH;
R4 is selected from:
(1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from
(a) -OH and (b) halogen,
(2) -C3-4 cycloalkyl, and
(3) halogen; and each of R4 , R5, and Ry is H; R6 is selected from:
(1) a phenyl,
(2) pyridyl, and
(3) 1,3-benzodioxolyl, wherein each of the phenyl of (1), pyridyl of (2), and 1,3-benzodioxolyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen,
(b) methyl, optionally substituted with 1 to 3 halogens,
(c) ethyl, optionally substituted with 1 to 3 halogens,
(d) methoxy, optionally substituted with 1 to 3 halogens,
(e) ethoxy, optionally substituted with 1 to 3 halogens,
(f) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
(g) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,
(h) -C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and
(i) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens; and
R7 is H.
24. The compound of claim 1 selected from Examples 1-99, or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
26. A method for treating a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease comprising administering an effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
27. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, for use in therapy.
28. A compound of any one of claims 1-24, 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 selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart, disease.
29. A compound or a pharmaceutically acceptable salt thereof, for use of claim 28, in the treatment of a type 2 diabetes.
30. A compound or a pharmaceutically acceptable salt thereof, for use of claim 28, in the treatment of obesity.
31. A compound or a pharmaceutically acceptable salt thereof, for use of claim 28, 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.
32. A compound of any one of claims 1-24, 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 glucosedependent insulinotropic polypeptide (GLP) 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/US2025/025163 2024-04-19 2025-04-17 Substituted 1,1'-biphenyl compounds as glucagon receptor agonists Pending WO2025222000A1 (en)

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