EP4669646A1 - MC2R MODULATOR CONNECTIONS - Google Patents

MC2R MODULATOR CONNECTIONS

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Publication number
EP4669646A1
EP4669646A1 EP24710165.2A EP24710165A EP4669646A1 EP 4669646 A1 EP4669646 A1 EP 4669646A1 EP 24710165 A EP24710165 A EP 24710165A EP 4669646 A1 EP4669646 A1 EP 4669646A1
Authority
EP
European Patent Office
Prior art keywords
piperidine
spiro
mmol
ethoxypyridin
naphthyridine
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
EP24710165.2A
Other languages
German (de)
French (fr)
Inventor
Giles Albert Brown
Laia MALET SANZ
Benjamin Gerald TEHAN
Maria MUSGAARD
Jonathan Richard Anthony Roffey
Adam Jan Sanderson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Omass Therapeutics Ltd
Original Assignee
Omass Therapeutics Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB2302630.5A external-priority patent/GB202302630D0/en
Priority claimed from GBGB2308196.1A external-priority patent/GB202308196D0/en
Priority claimed from GBGB2313601.3A external-priority patent/GB202313601D0/en
Priority claimed from GBGB2319945.8A external-priority patent/GB202319945D0/en
Application filed by Omass Therapeutics Ltd filed Critical Omass Therapeutics Ltd
Publication of EP4669646A1 publication Critical patent/EP4669646A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • MC2R MODULATOR COMPOUNDS This application relates to novel compounds and their use as melanocortin subtype-2 receptor (MC2R) antagonists. Compounds described herein may be useful in the treatment or prevention of diseases in which MC2R is involved. This application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases in which MC2R is involved.
  • Adenocorticotropic hormone is a 39-amino acid peptide implicated in the regulation of adrenal glucocorticoid synthesis and secretion within the hypothalamic-pituitary-adrenal (HPA) axis, and as such, plays a primary role in regulation of stress responses.
  • ACTH is synthesized by corticotropic cells in the anterior pituitary via proteolytic cleavage of proopiomelanocortin (POMC). Upon stressful stimuli, ACTH is secreted and acts at the melanocortin 2 receptor (MC2R) in adrenal glands to regulate synthesis and secretion of glucocorticoids and androgens.
  • M2R melanocortin 2 receptor
  • the secretion of glucocorticoids provides negative feedback to both hypothalamus and anterior pituitary to reduce production and secretion of corticotropic releasing hormone (CRH) and ACTH respectively – thereby providing a fine balance in regulating stress responses.
  • CHL corticotropic releasing hormone
  • ACTH corticotropic releasing hormone
  • Diseases linked to ACTH dysfunction range from Cushing’s disease to congenital adrenal hyperplasia and polycystic ovarian syndrome (PCOS) (Microsc. Res. Tech.61, 275–287 (2003)).
  • the MC2R belongs to the melanocortin family of G protein-coupled receptors (GPCRs), of which there are five subtypes - MC1R, MC2R, MC3R, MC4R and MC5R.
  • GPCRs G protein-coupled receptors
  • MC1R is associated with pigmentation regulation, MC2R with glucocorticoid synthesis, MC3R and MC4R with energy homeostasis and MC5R with exocrine gland physiology.
  • MC2R is selectively activated by ACTH, while the remaining receptor subtypes also bind the melanocortin peptides ⁇ -, ⁇ -, and ⁇ - melanocyte-stimulating hormone ( ⁇ -MSH, ⁇ -MSH, and ⁇ -MSH) (Am. J. Physiol. Endocrinol. Metab.284, E468-74 (2003); Life Sci.59, 797–801 (1996)).
  • MRAP melanocortin 2 receptor protein
  • MRAP is a single transmembrane protein which forms an antiparallel homodimer with MC2R to allow trafficking of the receptor to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP – 20249 (2007))
  • Binding of ACTH to the MC2R/MRAP complex in adrenal cortical cells activates cAMP production via the G s signalling pathway. Increases in intracellular cAMP in turn stimulates cortisol synthesis and secretion (Microsc. Res.
  • CAH Congenital adrenal hyperplasia
  • CYP21A2 the most common form
  • HSD3B2 3 ⁇ -hydroxysteroid dehydrogenase
  • CYP11B1 11 ⁇ - hydroxylase
  • PCOS polycystic ovary syndrome
  • inhibitors with longer residence times offer the advantage of insurmountable antagonism, whereby receptor inhibition remains in the face of high ACTH concentrations.
  • a means of achieving these favourable drug properties involves developing a compound with slow dissociation (k off ) kinetics (Neurochemistry international 2007, 51(5), 254–260). This has been demonstrated at various targets, ranging from fevipiprant at the DP2 receptor to NK 1 neurokinin receptor antagonists (Mol Pharmacol 2016, 89(5), 593-605; The Journal of pharmacology and experimental therapeutics 2007, 322(3), 1286–1293).
  • the present invention provides compounds having activity as melanocortin subtype-2 receptor (MC2R) antagonists.
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH
  • Compounds of the present invention may be used as melanocortin subtype-2 receptor (MC2R) modulators.
  • Compounds of the present invention may be used as MC2R inhibitors.
  • Compounds of the present invention may be used as MC2R antagonists.
  • Compounds of the present invention may be used as MC2R antagonists with a long residence time at the receptor.
  • Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R.
  • Compounds of the present invention may be used in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity.
  • Compounds of the present invention may be used in the manufacture of medicaments.
  • the compounds or medicaments may be for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders in which MC2R is involved.
  • Compounds of the present invention may be for use as a single agent or in combination with one or more additional pharmaceutical agents.
  • Compounds of the present invention may be useful in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome (or ectopic Cushing’s syndrome), polycystic ovary syndrome (PCOS), depressive illness, septic shock, and disorders or symptoms related thereto.
  • CAH congenital adrenal hyperplasia
  • PCOS polycystic ovary syndrome
  • depressive illness septic shock
  • disorders or symptoms related thereto DETAILED DESCRIPTION OF THE INVENTION
  • the invention relates to novel compounds.
  • the invention also relates to the use of novel compounds as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as MC2R antagonists.
  • M2R melanocortin subtype-2 receptor
  • the invention further relates to novel compounds as MC2R anatagonists which have a long residence time at the receptor.
  • the invention further relates to the use of novel compounds in the manufacture of medicaments for use as MC2R antagonists.
  • the invention further relates to compounds, compositions and medicaments that may be useful in the treatment of a disease or disorder characterised by activation of the MC2R receptor.
  • a compound of formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH2- or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH2- or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a
  • a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a 3-6
  • J can be N or CH. J can be N. J can be CH.
  • X can be -CO-, -CH 2 - or -CH 2 CH 2 -. X can be -CO- or -CH 2 -. X can be - CO-. X can be -CH 2 -. X can be -CH 2 CH 2 -.
  • Z can be a bond, -CH 2 - or -CO-. Z can be -CH 2 - or -CO-. Z can be - CH 2 -. Z can be -CO-. Z can be a bond.
  • R 1 can be C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3- 4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms.
  • R 1 can be C 1-4 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 1 can be C 1-4 alkyl.
  • R 1 can be methyl or ethyl.
  • R 1 can be methyl.
  • R 1 can be ethyl.
  • R 1 can be perdeuteroethyl.
  • R 1 can be -CD 2 CD 3 .
  • R 1 can be trideuteromethyl.
  • R 1 can be -CD 3 .
  • L 1 can be -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or - CO(CH 2 ) n -, where n is 0-5.
  • L 1 can be a bond, -CH 2 CH 2 CONH-, -COO-, -CH 2 CH 2 COO-, - CH 2 CH 2 CO-, -COCH 2 NH-, -COCH 2 CH 2 NH-, -CO-, -COCH 2 -, -CH 2 CH 2 - or -CH 2 -.
  • L 1 can be a bond.
  • R 2 can be H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R 10 , R 11 and R 12 , or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R 10 , R 11 and R 12 .
  • R 2 can be H, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R 10 , R 11 and R 12 , or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R 10 , R 11 and R 12 .
  • R 2 can be H, a piperidine ring which is optionally substituted with R 10 , R 11 and R 12 , a pyrrolidine ring which is optionally substituted with R 10 , R 11 and R 12 , an azetidine ring which is optionally substituted with R 10 , R 11 and R 12 , a hexahydro-1H- pyrrolizine ring system which is optionally substituted with R 10 , R 11 and R 12 , a 2-pyrrolidone ring which is optionally substituted with R 10 , R 11 and R 12 , a 1-azabicyclo[2.2.2]octane ring system which is optionally substituted with R 10 , R 11 and R 12 , a tetrahydrofuran ring which is optionally substituted with R 10 , R 11 and R 12 or a morpholine ring which is optionally substituted with R 10 , R 11 and R 12 .
  • R 2a and R 2b can independently be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 2a and R 2b can independently be H or C 1-3 alkyl.
  • R 2a and R 2b can independently be H or methyl.
  • R 2a and R 2b can both be H.
  • R 2a can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 2a can be H or C 1-3 alkyl.
  • R 2a can be H or methyl.
  • R 2a can be H.
  • R 2b can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 2b can be H or C 1-3 alkyl.
  • R 2b can be H or methyl.
  • R 2b can be H.
  • R 10 , R 11 and R 12 can be independently selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
  • R 10 , R 11 and R 12 can be independently selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 10 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH2)gCO2R 13 and -(CH2)gCONR 13 R 14 , where g is 0-3 and y is 1-3.
  • R 10 can be selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 10 can be H.
  • R 10 can be OH.
  • R 10 can be CH 2 CH 2 OH.
  • R 10 can be CH 2 NH 2 .
  • R 10 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 11 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
  • R 11 can be selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 11 can be H.
  • R 11 can be OH.
  • R 11 can be CH 2 CH 2 OH.
  • R 11 can be CH 2 NH 2 .
  • R 11 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 12 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
  • R 12 can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3.
  • R 12 can be H.
  • R 12 can be OH.
  • R 12 can be CH 2 CH 2 OH.
  • R 12 can be CH 2 NH 2 .
  • R 12 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 13 and R 14 can independently be H or methyl.
  • R 13 can be H or methyl.
  • R 14 can be H or methyl.
  • R 13 can be H.
  • R 13 can be methyl.
  • R 14 can be H. R 14 can be methyl.
  • R 2 can be selected from:
  • the moiety -L 1 -R 2 can be selected from:
  • R 3 can be H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3- 4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3 can be joined to R 3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
  • R 3 can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 3 can be H or C 1-3 alkyl.
  • R 3 can be H, methyl or ethyl.
  • R 3a can be H or can be joined to R 3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
  • R 3b can be H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3b can be joined to R 3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
  • R 3b can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
  • R 3b can be H or C 1-3 alkyl.
  • R 3b can be H, methyl or ethyl.
  • R 3c can be H or can be joined to R 3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
  • one or both of R 3 and R 3b is H.
  • the structure of Formula (1) as defined herein can be effectively viewed as the scope of Formula (1’) and (1’’) taken together: All of R 3 , R 3a , R 3b and R 3c can be H.
  • R 3 and R 3b can be C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3- 4cycloalkyl optionally substituted with 1-3 fluorine atoms and the other H.
  • One of R 3 and R 3b can be methyl or ethyl and the other H.
  • One of R 3 and R 3b can be methyl and the other H.
  • One of R 3 and R 3b can be ethyl and the other H.
  • L 2 can be a bond or -CO- and R 4 can be a group: Q 5 Q 9 ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one, two or none of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N; or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
  • L 2 can be a bond or -CO- and R 4 can be a group selected from: or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
  • L 2 can be a bond or -CO- and R 4 can be a group selected from: ; ; and ; or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
  • L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one, two or none of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N.
  • L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N.
  • L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where two of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 are N.
  • L 2 can be a bond or -CO- and R 4 can be a group: L 2 can be a bond or -CO- and R 4 can be a group selected from: L 2 can be a bond or -CO- and R 4 can be a group selected from: L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
  • R 5 , R 6 , R 7 , R 8 , and R 9 can be independently selected from H, halo, CN, NR 15 R 16 , C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OC 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OCH 2 cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH 2 CN and SO 2 Me.
  • R 15 and R 16 can independently be H or C 1-3 alkyl.
  • R 15 and R 16 can independently be H, methyl, ethyl, n-propyl or isopropyl.
  • R 5 , R 6 , R 7 , R 8 , and R 9 can be independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, - OEt, -O n Pr, -N(CH 3 )(CH 2 CH 2 CH 3 ), -N(CH 3 ) 2 , -OCH 2 CN, -OCH 2 cyclopropyl, -CO 2 H and -SO 2 Me.
  • L 2 can be a bond or -CO- and R 4 can be a group selected from: .
  • L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
  • L 2 can be -CO- and R 4 can be selected from: ; NH2 .
  • R 4 can be a group selected from: C
  • L 1 and L 2 are provided without limitation to a particular orientation with respect to the rest of the molecule. As such L 1 and L 2 definitions provided include all possible orientations unless stated otherwise.
  • L 1 is defined as -CONH- both of the following may be included: .
  • the compound can be a compound of Formula (1’) or (1’’): 1’); (1’’); or a salt thereof, wherein J, X, Z, L 1 , L 2 , R 1 , R 2 , R 3 , R 3a , R 3b , R 3c and R 4 are as defined herein.
  • the compound can be a compound of Formula (1’’’), (1’’’’), (1’’’’’), (1’’’’’), (1’’’’’’), (1’’’’’’) or (1’’’’’’): or a salt thereof, wherein J, X, Z, L 1 , L 2 , R 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (2a) or (2b): (2b); or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (2aD) or (2bD): 4 D (2bD); or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula or a salt thereof, wherein X, Z, L 1 , R 2 and R 4 are as defined herein.
  • the compound can be a compound of Formula (2aii), (2aiii), (2aiv), (2bii), (2biii) or (2biiv): or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (2av), (2avi), (2avii), (2bv), (2bvi) or (2bvii): or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (3a), (3b), (3c), (3d), (3e) or (3f):
  • the compound can be a compound of Formula (3ai), (3bi), (3ci), (3di), (3ei) or (3fi): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (3aii), (3bii), (3cii), (3dii), (3eii) or (3fii): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (3aiii), (3biii), (3ciii), (3diii), (3eiii) or (3fiii): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (3aiv), (3biv), (3civ), (3div), (3eiv) or (3fiv): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
  • the compound can be a compound of Formula (3av), (3bv), (3cv), (3dv), (3ev) or (3fv):
  • the compound can be a compound of Formula (5a) or (5b): or a salt thereof, wherein L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein.
  • the compound can be a compound of Formula (6a), (6b), (6c), (6d), (6e), (6f), (6g) or (6h):
  • the compound can be a compound of Formula (9a), (9b), (9c), (9d), (9e) or (9f):
  • the compound can be selected from any one of Examples 1 to 218 as shown in Table 1a or a salt thereof.
  • the compound can be selected from the group consisting of: 1 '-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- n aphthyridine-5,4'-piperidine]-8-one; 1 '-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- n aphthyridine-5,4'-piperidine]-8-one; 1 '-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-
  • the salt thereof can be a pharmaceutically acceptable salt.
  • the salt thereof can be a formate salt, a trifluoroacetic acid (TFA) salt, a mesylate salt or a hydrochloride (HCl) salt.
  • the salt thereof can be a formate salt or a trifluoroacetic acid (TFA) salt.
  • the compound can be a salt selected from the group consisting of: 1 '-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H- 1 ,7-naphthyridine-5,4'-piperidine]-8-one formate salt; ( S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- d ihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one formate salt; ( R)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-
  • Further embodiments of the invention include the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) in medicine. Also included is the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) as a melanocortin subtype-2 receptor (MC2R) modulator.
  • M2R melanocortin subtype-2 receptor
  • Compounds of the present invention may be used as MC2R receptor modulators.
  • Compounds of the present invention may be used as MC2R receptor inhibitors or antagonists.
  • Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of MC2R.
  • Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R or in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity.
  • Compounds of the present invention may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto.
  • CAH congenital adrenal hyperplasia
  • PCOS polycystic ovary syndrome
  • compounds and compositions detailed herein are used as modulators of MC2R.
  • Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (1) or any embodiment, variation or aspect thereof.
  • MC2R modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for MC2R associated diseases.
  • a compound or salt thereof described herein or a composition described herein may be used in a method of treating Cushing’s disease in an individual.
  • combinations comprising a compound of the present invention and a Corticotropin-releasing factor receptor-1 (CRF 1 ) antagonist.
  • CRF 1 Corticotropin-releasing factor receptor-1
  • the CRF 1 antagonist may be selected from the group consisting of tildacerfont, crinecerfont, NBI-27914, CP-316,311, NBI-462000, DMP696, pexacerfont, NBI-35965, ONO-2333Ms, antalarmin, NBI- 34041, DMP904, NBI-30775, SSR125543, NBI-77860, GSK876008, CRA5626/JNJ19567470/R317573, NBI-76169, verucerfont, and CP-154,526.
  • the CRF 1 antagonist may be selected from: .
  • combinations comprising a compound of the present invention and an ACTH antibody.
  • the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8).
  • the combinations may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto.
  • CAH congenital adrenal hyperplasia
  • PCOS polycystic ovary syndrome
  • septic shock and disorders or symptoms related thereto are also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament.
  • the manufacture of a medicament is for the treatment of a disorder or disease described herein.
  • the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by MC2R.
  • a compound or salt thereof described herein or a composition described herein may be used in a method as either a stand-alone therapy, or as a conjunctive therapy with other agents that are either palliative (e.g., agents that relieve the symptoms of the disorder to be treated), and/or agents that target the etiology of the disorder.
  • Compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes or less.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes.
  • M2R modulator refers to any compound which binds to and modulates the function of MC2 receptors.
  • modulator should be interpreted to include modulation by modalities including, but not limited to antagonists.
  • treatment in relation to the uses of any of the compounds described herein, including those of Formula (1) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question.
  • treatment covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed.
  • effective therapeutic amount refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief.
  • the desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain.
  • Chemical terms are all used in their conventional sense (e.g. as defined in the IUPAC Gold Book), unless indicated otherwise.
  • alkyl as used herein, means straight or branched chain, saturated alkyl groups.
  • cycloalkyl as used herein, means a saturated carbocyclic group containing the indicated number of carbon atoms.
  • carbocyclic ring as used herein, means a saturated or unsaturated carbocyclic group containing the indicated number of carbon atoms.
  • heterocyclic ring refers to a saturated or unsaturated ring containing the indicated number of total ring member atoms in which one or more of the ring members is a heteroatom selected from O, S and N, and oxidised forms thereof and the remaining atoms are C.
  • bicyclic as used herein, means a saturated or unsaturated ring system comprising two joined rings and containing the indicated number of atoms in total. All possible modes of ring junction are included (including spirocyclic, fused and bridged).
  • heterocyclic as used herein, means a saturated or unsaturated heterocyclic ring system comprising two joined rings and containing the indicated number of atoms in total.
  • C n1-n2 The number of carbon atoms that are possible in the referenced groups herein may be indicated by subscript "C n1-n2 ”.
  • C 1-3 alkyl represents an alkyl group having 1, 2 or 3 carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl.
  • optionally substituted as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different.
  • the term “optionally substituted with 1-6 fluorine atoms” as applied to a group means that the said group may if desired be substituted with 1, 2, 3, 4, 5 or 6 fluorine atoms.
  • the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers.
  • the invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared.
  • any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.
  • Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze- drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium.
  • Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5- disulfonic and p-toluenesulfonic), ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • ⁇ - oxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic
  • lactic e.g. (+)-L- lactic and ( ⁇ )-DL-lactic
  • lactobionic maleic, malic (e.g.
  • Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • a non-toxic pharmaceutically acceptable solvent referred to below as the solvating solvent.
  • solvents include water, alcohols (such as ethanol, isopropanol and butanol) and DMSO.
  • Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.
  • the compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
  • a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise.
  • a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group).
  • the daily dose range may be from about 10 ⁇ g to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 ⁇ g to about 1 mg per kg of body weight of a human and non-human animal.
  • PHARMACEUTICAL FORMULATIONS While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). Accordingly, in some embodiments of the invention, there is provided a pharmaceutical composition comprising at least one compound of Formula (1) as defined above together with at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g.
  • a solid, liquid or semi-solid carrier e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents
  • diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents
  • granulating agents binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.
  • diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents
  • pharmaceutically acceptable means compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Pharmaceutical compositions containing compounds of the Formula (1) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.
  • the composition may be a tablet composition or a capsule composition.
  • Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
  • Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract.
  • the pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95%, preferably% (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients.
  • a pharmaceutically acceptable excipient for example as defined above
  • the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre- filled syringes, dragées, powders, tablets or capsules.
  • Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments.
  • Slow release tablets would in addition typically contain 0-99% (w/w) release-controlling (e.g.
  • the film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.
  • the composition may be a parenteral composition.
  • Parenteral formulations typically contain 0- 20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried).
  • WFI Water for Injection
  • Formulations for intramuscular depots may also contain 0-99% (w/w) oils.
  • the pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.
  • the compounds of the Formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity.
  • a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient.
  • particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g.0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount).
  • the precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures.
  • compounds of formula [X3] may be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic or substituted phenyl-compound of formula [X2] in a transition metal catalysed cross-coupling reaction such as a Buchwald– Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene.
  • a transition metal catalysed cross-coupling reaction such as a Buchwald– Hartwig amination
  • a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3
  • a phosphine ligand
  • compounds of formula [X3] may also be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic-compound of formula [X2] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF.
  • SNAr nucleophilic aromatic substitution
  • compounds of formula [X3] can be prepared via reaction with a carboxylic acid of formula [X2] in an amide coupling reaction with a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA.
  • the reaction is usually conducted at RT.
  • reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.
  • Compounds of formula [X4] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3].
  • PG protecting group
  • a method such as hydrogenation under an atmosphere of hydrogen in the presence of palladium on activated carbon in a polar solvent such as ethanol or methanol.
  • a method using strong base such as KOH in a solvent such as ethanol suitably conducted at elevated temperature.
  • reaction product After reaction work up, typically filtration and/or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.
  • Compounds of formula [X6] may be prepared by the reaction of a compound of formula [X4] with an aldehyde or ketone derivative of general formula [X5] by a reductive amination reaction with reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
  • reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • a polar solvent such as DCM, DCE or methanol.
  • alkyl halides [X5’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO.
  • they can be prepared with carboxylic acids of formula [X5’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT.
  • the compounds of formula [X6] contain an amino group that is protected by nitrogen protecting group such as a tert-butyloxycarbonyl protecting group.
  • compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of a compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re- crystallisation.
  • an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid.
  • compounds of formula [X3’] may be prepared by the reaction of compound of formula [X1’] with an aldehyde of formula [X2] by reductive amination reaction with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
  • alkyl halides [X2’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO.
  • they can be prepared with carboxylic acids of formula [X2’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT.
  • Compounds of formula [X4’] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3’].
  • Compounds of formula [X6] may be prepared with compounds of formula [X4’] by the reaction of a hetero-aromatic or substituted phenyl-compound of formula [X5] in a transition metal catalysed cross-coupling reaction such as a Buchwald–Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene.
  • a transition metal catalysed cross-coupling reaction such as a Buchwald–Hartwig amination
  • a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3
  • compounds of formula [X6] may also be prepared by the reaction of compounds of formula [X4’] with a hetero-aromatic- compound of formula [X5] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF, the reaction is suitably conducted at elevated temperature.
  • the compounds of formula [X6] contains an amino group that is protected by a nitrogen protecting group such as a tert-butyloxycarbonyl protecting group.
  • compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation.
  • General Scheme 3 Compounds of formula [X1] and [X1’] can be obtained via different methodologies (General Scheme 3).
  • compounds of formula [X1’] may be prepared by the reaction- cyclisation of a compound of formula [X1’_3] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent such as THF or toluene at a suitable temperature.
  • a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent such as THF or toluene at a suitable temperature.
  • they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water.
  • Compounds of formula [X1’_3] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature.
  • compounds of formula [X1’] may be prepared by reduction of a compound of formula [X1’_5] using a suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature.
  • compounds of formula [X1’_5] may be prepared via the cyclisation reaction of compounds of formula [X1’_4] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent like THF or toluene at a suitable temperature.
  • a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent like THF or toluene at a suitable temperature.
  • they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water.
  • Compounds of formula [X1’_4] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2’] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature.
  • compounds of formula [X1’] can be prepared from compounds of formula [X1’_8] via standard deprotection conditions, depending on the nature of PG.
  • Compounds of formula [X1] may be prepared with compounds of formula [X1_8] via typical benzyl deprotection conditions such as NaOH in solvents such as ethanol and water at high temperatures.
  • they can also be prepared via a reduction reaction in a hydrogen atmosphere with a suitable catalyst such as Pd(OH)2 in a suitable solvent such as MeTHF, MeOH or IPA..
  • Compounds of formula [X1_8] can be prepared by a reduction reaction of compounds of formula [X1_7] with suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature.
  • suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP
  • suitable solvent generally alcoholic, and at a suitable temperature.
  • Compounds of formula [X1_7] can be prepared via reaction of compounds of formula [X1_6] with NaNO2/CuCl/HCl in an alcoholic solvent such as methanol or water, typically at room temperature. This is followed by treatment with aqueous HCl in a suitable solvent such as
  • the reaction mixture was heated to 100 °C and stirred at 100 °C for 16 hr. One additional vial was set up as described above. After cooling to RT, all two reaction mixtures were combined. The mixture was removed ethanol and acidified to pH 4 with hydrochloric acid (4 N). The suspension was filtered and the filtrate cake was dried under reduced pressure to get 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (8 g) as a white solid, which was used to next step directly without further purification.
  • reaction mixture was stirred at 25 °C for 12 hr.
  • One additional vial was set up as described above. All of two reaction mixtures were combined, quenched by saturation sodium sulfite (200 mL) at 0 °C and extracted with DCM (3 ⁇ 100 mL). The combined organic phase was washed with saturation sodium carbonate (200 mL), brine (100 mL) and dried over sodium sulfate.
  • reaction mixture After heating to 60 °C, the reaction mixture was stirred at 60 °C for 12 hr. After cooling to RT, the reaction mixture was quenched by water (20 mL) at 0 °C and extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and filtered.
  • reaction mixture was filtered through celite and washed with 20% MeOH in DCM (2 x 20 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography using MeOH/DCM (0 to 10%) to afford 38 mg of the product.18 mg of the compound was further purified by prep-HPLC. The fractions were lyophilized.
  • reaction mixture was filtered through celite, and the celite washed with 10% MeOH in DCM (50 mL). The combined filtrate was concentrated to get crude purified by prep-HPLC. The pure fractions were concentrated, and the residue was neutralized with 10% NaHCO 3 solution (20 mL) and extracted with (30 mL).
  • reaction mixture was stirred at 25 °C for 2 h. Four additional vials were set up as described above. All five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL ⁇ 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate and filtered.
  • reaction mixture was heated at 120 °C for 16 h.
  • the reaction mixture filtered through celite bed, filtrate was evaporated, and crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 20%) to afford (3S)- 3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (400 mg, 1.417 mmol, 65%) as a yellow liquid.
  • reaction mixture was basified with 10% NaHCO 3 diluted with water (10 mL) and extracted with EtOAc (2 x10 mL). The combined organic layer was, dried over anhydrous sodium sulphate, evaporated and purified by flash column chromatography using EtOAc in PET ether (0 to 30%) to afford tert-butyl 6-(2- ethoxyphenyl)-3-fluoropicolinate (6 g, 17.96 mmol, 72%) (intermediate 101) as a pale-yellow solid.
  • reaction mixture was stirred at 0 °C for 2 h. Five additional vials were set up as described above. After warming to RT, all six reaction mixtures were quenched with ice water (10 mL) and extracted with DCM (10 mL ⁇ 3). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and purified by prep-HPLC method L to obtain (R)-2-(1-benzyl-7'-(pyrrolidin-2- ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-2'-yl)phenol (1 g, 42%) as a yellow solid.
  • reaction mixture was stirred at 60 °C for 1 h under nitrogen atmosphere. Eight additional vials were set up as described above. After cooling to RT, all nine reaction mixtures were quenched by addition water (20 mL) and extracted with EtOAc (6 mL ⁇ 3).
  • reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. Four vials were set up as described above. Five reaction mixtures were quenched by addition of saturated NH 4 Cl solution (300 mL) at 0 °C and adjusted to pH 4 - 6 with formic acid, then extracted with EtOAc (200 mL ⁇ 3).
  • reaction mixture was stirred at 60 °C for 30 min. Five additional vials were set up as described above. After cooling to 0 °C, the reaction mixture was quenched with MeOH (1 mL). All six mixtures were combined and stirred at 60 °C for 1 h.
  • the structure was solved using SHELXT (Sheldrick, G. M.2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F2) (Sheldrick, G. M.2015. Acta Cryst. C71, 3-8).
  • the total number of refined parameters was 389, compared with 5552 data. All reflections were included in the refinement.
  • the largest differential peak and hole were 0.27 and -0.20 ⁇ -3.
  • reaction mixture was stirred for 10 min and then added 4-chloro-2-(trifluoromethyl)benzoic acid (80 mg, 0.22 mmol).
  • the reaction mixture was stirred at 25-30°C for 16h.
  • the reaction was quenched with ice- cold water (10 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over Na 2 SO 4 and concentrated to get crude (100 mg) as brown sticky compound which shows 20% of desired product.
  • Example 1 The crude product was further purified by prep HPLC, followed by lyophilization to afford 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (10 mg, 8%) (Example 1) as light pink solid.
  • Analytical data for Example 1 is in Table 2.
  • Example 21 2-amino-1-(7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)ethan-1-one (4.25 mg, 7.51 ⁇ mol, 25%) (Example 21) as white solid. Analytical data for Example 21 is in Table 9.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude.
  • the crude compound was purified by Biotage-Isolera using 25g silica gel cartridge and eluted with 0 to10% MeOH in DCM.
  • Example 22 1-(4-chloro-3-iodopyridin-2- yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one) (4.2 mg) (Example 22) as off white solid.
  • Analytical data for Example 22 is in Table 10.
  • reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). Combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude.
  • reaction mixture was precipitated using ACN (20 mL) and precipitate filtered off. Solid was washed with ACN (20 mL) and combined filtrate was collected and concentrated to get tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)nicotinoyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (50 mg, 0.030 mmol, 32%) as brown gum.
  • reaction mixture was quenched with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated.
  • the crude product was purified by prep HPLC. The fractions were lyophilized. The residue was basified with 10% NaHCO 3 solution and extracted with DCM (3 x 5 mL).
  • Route M Typical procedure for the preparation of lactams as exemplified by the preparation of (S)- 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (Example 34).
  • Example 36 Analytical data for Example 36 and Example 42 is in Table 15.
  • Example 52 The DCM layer was dried over anhydrous sodium sulfate and concentrated to get white solid which was re-dissolved in ACN:water 1:3 and lyophilized to afford 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3- yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]ethanone (3.94 mg, 0.076 mmol, 9%) (Example 52) as an off white solid. Analytical data for Example 52 is in Table 17.
  • the reaction mixture was stirred at RT for 1 h.
  • the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL).
  • the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and evaporated.
  • the crude product was purified by prep-HPLC.
  • reaction mixture was heated to 100 °C and stirred at 100 °C for 2 hr. Seven additional vials were set up as described above. After cooling to RT, all eight reaction mixtures were combined, diluted with water (20 mL) and extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and filtered.
  • Example 59 Analytical data for Example 59 is in Table 20.
  • the reaction mixture was stirred at 70 °C for 16 h.
  • the reaction mixture was filtered and evaporated.
  • the crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%). The pure fractions were evaporated, and the product was further purified by prep-HPLC. The fractions were lyophilized.
  • reaction mixture was concentrated, neutralized with 10% NaHCO 3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated afforded crude compound, which was purified by prep-HPLC.
  • Example 97 Analytical data for Example 97 is in Table 23.
  • reaction mixture was stirred at RT for 30 min.
  • Tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1- carboxylate (128 mg, 0.484 mmol) was added at RT.
  • the reaction mixture was stirred at 60 °C for 16 h.
  • the reaction mixture was quenched cautiously with saturated ammonium chloride solution (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated.
  • reaction mixture was stirred at 25 °C for 12 h.
  • Example 117 3-(2'-(2-ethoxypyridin-3-yl)-1-(3- methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3- oxopropanoic acid (9.7 mg, 35%) (Example 117) as white solid.
  • Analytical data for Example 117 is in Table 26.
  • reaction mixture was basified to pH 9 by Et 3 N, then added 2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (50 mg, 100.29 ⁇ mol) (intermediate 61) and NaCNBH 3 (31.51 mg, 501.47 ⁇ mol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 12 h. Three additional vials were set up as described above.
  • the reaction mixture was basified cautiously with 10% NaHCO 3 solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over sodium sulphate. The resulting residue was purified by prep-HPLC (Method B). The pure prep fractions were lyophilized.
  • the reaction was concentrated and the resulting residue neutralized with aqueous 10% NaHCO 3 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and purified by Prep. HPLC. The prep fractions were concentrated, and the residue was neutralized with 10% NaHCO 3 solution (10 mL) and extracted with DCM (10 mL).
  • the reaction mixture was stirred at 100 o C for 42 h.
  • the reaction mixture was cooled to RT and diluted with 10% MeOH in DCM (2 x 20 mL). pH of the reaction mixture was adjusted to ⁇ 8 by using 10% sodium hydroxide solution (50 mL) and separated the layers. The aq. layer was extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum to afford crude compound (100 mg; HPLC purity: 56.0%).
  • Crystal growth Crystallization by slow evaporation of the solvent was adopted for growing crystals suitable for single-crystal X-ray diffraction studies. Crystals were obtained from Methyl tert-Butyl Ether (MTBE) solvent. About 20 mg of the compound (B.No. OMA-SYN-C37s-E1- R-004) was dissolved in Methyl tert-Butyl Ether (3ml) solvent under hot conditions and the solution was filtered into a clean beaker and kept for crystallization at room temperature. Crystals were obtained on the walls of the beaker after 10 days.
  • MTBE Methyl tert-Butyl Ether
  • the raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite programs (Bruker (2016). APEX3, SAINT and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA).
  • the structure was solved using intrinsic phasing method [2] and further refined with the SHELXL (Sheldrick G. M. (2015). Acta Crystallogr C71: 3-8) program and expanded using Fourier techniques. Anisotropic displacement parameters were included for all non-hydrogen atoms.
  • Atom C1 of molecule A was disordered over two positions and its site occupational factors were refined to 0.6(5) and 0.4(5) respectively.
  • the atoms C17/C18/C19/C20/C21/N3 of molecule B were disordered over two positions and their site occupational factors were refined to 0.755(6) and 0.245(6) respectively.
  • the N-H and O-H atoms were located in the difference Fourier map and their positions and isotropic displacement parameters were refined. Hydrogen atoms could not be located on the partial occupy water O2W.
  • BIOLOGICAL ACTIVITY Terbium labelling and preparation of SNAP-tagged MC2 membranes Cells were labelled with 100 nM of SNAP-Lumi4-Tb and incubated for 1 h at 37 °C under 5% CO 2 prior to harvesting, and pelleting by centrifugation at 3 min at 1200 rpm. Cell pellets were homogenized using an FastPrep-245G homogeniser (MP Biomedicals) and subsequently centrifuged and resuspended twice at 22,000 ⁇ g at 4 °C (Eppendorf Centrifuge) for 30 min.
  • MP Biomedicals FastPrep-245G homogeniser
  • TR-FRET Competitive Binding Kinetic Assay To determine the association (k on ) and dissociation (k off ) rates of unlabelled compounds, a competitive kinetic binding assay was performed which involved the simultaneous addition of 100nM fluorescent tracer and increasing concentrations of competing ligand to MC2 membranes (2 ⁇ g per well). The degree of bound fluorescent tracer at MC2 was determined at multiple timepoints by HTRF. In parallel, the association (k on ) and dissociation (k off ) rates for the fluorescent tracer were determined through incubation of increasing concentrations of fluorescent tracer with MC2 membranes in the absence and presence of 1 ⁇ M unlabelled MC2 antagonist. The degree of bound fluorescent tracer was calculated at multiple timepoints by HTRF detection and association kinetic curves were generated.
  • EXAMPLE A pKi Group A >9, Group B 7.5 to 9, Group C 6 to 7.5 Koff: Group A ⁇ 0.02, Group B 0.02 to 0.07, Group C >0.07 cAMP accumulation assay
  • Chinese hamster ovary (CHO) cells stably expressing human or rat MC2 with MRAP, were maintained in DMEM/F12 cell culture medium supplemented with 10% fetal bovine serum and 1% l-glutamine.

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Abstract

The disclosures herein relate to novel compounds of Formula (1): or a salt thereof, wherein J, X, Z, L1, L2, R1, R2, R3, R3a, R3b, R3c and R4 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with the melanocortin subtype-2 receptor (MC2R).

Description

MC2R MODULATOR COMPOUNDS This application relates to novel compounds and their use as melanocortin subtype-2 receptor (MC2R) antagonists. Compounds described herein may be useful in the treatment or prevention of diseases in which MC2R is involved. This application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases in which MC2R is involved. BACKGROUND OF THE INVENTION Adenocorticotropic hormone (ACTH) is a 39-amino acid peptide implicated in the regulation of adrenal glucocorticoid synthesis and secretion within the hypothalamic-pituitary-adrenal (HPA) axis, and as such, plays a primary role in regulation of stress responses. ACTH is synthesized by corticotropic cells in the anterior pituitary via proteolytic cleavage of proopiomelanocortin (POMC). Upon stressful stimuli, ACTH is secreted and acts at the melanocortin 2 receptor (MC2R) in adrenal glands to regulate synthesis and secretion of glucocorticoids and androgens. The secretion of glucocorticoids provides negative feedback to both hypothalamus and anterior pituitary to reduce production and secretion of corticotropic releasing hormone (CRH) and ACTH respectively – thereby providing a fine balance in regulating stress responses. Diseases linked to ACTH dysfunction range from Cushing’s disease to congenital adrenal hyperplasia and polycystic ovarian syndrome (PCOS) (Microsc. Res. Tech.61, 275–287 (2003)). The MC2R belongs to the melanocortin family of G protein-coupled receptors (GPCRs), of which there are five subtypes - MC1R, MC2R, MC3R, MC4R and MC5R. MC1R is associated with pigmentation regulation, MC2R with glucocorticoid synthesis, MC3R and MC4R with energy homeostasis and MC5R with exocrine gland physiology. MC2R is selectively activated by ACTH, while the remaining receptor subtypes also bind the melanocortin peptides α-, β-, and γ- melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH) (Am. J. Physiol. Endocrinol. Metab.284, E468-74 (2003); Life Sci.59, 797–801 (1996)). Another unique aspect of the MC2R relative to the other melanocortin receptors is that the accessory protein, MRAP (melanocortin 2 receptor protein), is required for MC2R expression and function. MRAP is a single transmembrane protein which forms an antiparallel homodimer with MC2R to allow trafficking of the receptor to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP – 20249 (2007)) Binding of ACTH to the MC2R/MRAP complex in adrenal cortical cells activates cAMP production via the Gs signalling pathway. Increases in intracellular cAMP in turn stimulates cortisol synthesis and secretion (Microsc. Res. Tech.61, 275–287 (2003)). Congenital adrenal hyperplasia (CAH) is a disorder characterised by disruption in adrenal steroidogenesis linked to excessive ACTH and CRH production. Three enzyme deficiencies arising from specific gene mutations are implicated: 21-hydroxylase deficiency from mutations in CYP21A2 (the most common form), 3β-hydroxysteroid dehydrogenase (HSD3B2) and 11β- hydroxylase (CYP11B1). In CAH, these enzyme deficiencies impair cortisol synthesis, resulting in a loss of cortisol negative feedback on CRH and ACTH. Excess ACTH results in steroidogenesis proximal to the deficient enzyme, leading to the hyperandrogenic pathophysiology associated with the disorder. CAH patients can present with hirsutism, acne, alopecia oligomenorrhea and infertility associated with virilization. Glucocorticoid and mineralocorticoid hormone replacement therapies are mainstay treatments, however require close monitoring to balance overtreatment and undertreatment. Further, ‘stress dosing’ is required at times of significant stress, illness or surgery (J. Pediatr. Adolesc. Gynecol.30, 520–534 (2017)). Importantly, high doses of glucocorticoid replacement are required to inhibit ACTH production and thereby reduce adrenal androgen levels. This often means that in order to control adrenal androgen levels, patients will suffer from corticosteroid-associated side effects or Cushing’s-like symptoms. Thus, there remains a need for better treatments of CAH. As ACTH is elevated in CAH, inhibition of its activity, through antagonism of MC2R, provides an attractive means of modulating the steroidogenesis pathway. Cushing’s disease is another rare disease associated with excess secretion of ACTH caused by adenomas of pituitary corticotropic cells. Clinical presentations include obesity, hirsutism, muscle weakness as well as cardiovascular and metabolic complications associated with hypercortisolism. Treatments for Cushing’s disease involve removal of either the ACTH-secreting tumour in the pituitary, or removal of the adrenal glands, however drug treatment is often used in addition to, or before surgery to alleviate symptoms. Current drug therapies aim to inhibit adrenal steroidogenesis, however, are not without adverse effects such as hypothyroidism and hypogonadism (J. Med. Life 9, 12–18 (2016)). Inhibition of ACTH activity via MC2R antagonism provides a potential therapeutic option in management of this disease. In addition to CAH and Cushing’s disease, polycystic ovary syndrome (PCOS) may be amenable to MC2 modulation. PCOS is associated with abnormal regulation of steroidogenesis and excess androgen levels. In a subset of patients the androgen excess results from functional adrenal hyperandrogenism (Endocr. Rev. 37, 467–520 (2016)). Modulation of ACTH activity in these patients offers another therapeutic avenue for this multisystem disorder. Thus, antagonism of MC2R presents an important therapeutic modality for treatment of diseases associated with ACTH dysfunction. WO2019/23669, WO2021/091788, WO2021/126693 and WO2021/133563 disclose MC2R antagonist compounds. Long duration of action is a widely sought after feature in drug design, enabling prolonged efficacy and simplified dosing regimes (British Journal of Pharmacology 2010, 161(3), 488–508). In the treatment of diseases associated with ACTH dysfunction, in particular diseases with excess ACTH, inhibitors with longer residence times offer the advantage of insurmountable antagonism, whereby receptor inhibition remains in the face of high ACTH concentrations. A means of achieving these favourable drug properties involves developing a compound with slow dissociation (koff) kinetics (Neurochemistry international 2007, 51(5), 254–260). This has been demonstrated at various targets, ranging from fevipiprant at the DP2 receptor to NK1 neurokinin receptor antagonists (Mol Pharmacol 2016, 89(5), 593-605; The Journal of pharmacology and experimental therapeutics 2007, 322(3), 1286–1293). THE INVENTION The present invention provides compounds having activity as melanocortin subtype-2 receptor (MC2R) antagonists. Provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group: ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N; or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN, CO2H and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. Compounds of the present invention may be used as melanocortin subtype-2 receptor (MC2R) modulators. Compounds of the present invention may be used as MC2R inhibitors. Compounds of the present invention may be used as MC2R antagonists. Compounds of the present invention may be used as MC2R antagonists with a long residence time at the receptor. Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R. Compounds of the present invention may be used in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity. Compounds of the present invention may be used in the manufacture of medicaments. The compounds or medicaments may be for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders in which MC2R is involved. Compounds of the present invention may be for use as a single agent or in combination with one or more additional pharmaceutical agents. Compounds of the present invention may be useful in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome (or ectopic Cushing’s syndrome), polycystic ovary syndrome (PCOS), depressive illness, septic shock, and disorders or symptoms related thereto. DETAILED DESCRIPTION OF THE INVENTION The invention relates to novel compounds. The invention also relates to the use of novel compounds as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as MC2R antagonists. The invention further relates to novel compounds as MC2R anatagonists which have a long residence time at the receptor. The invention further relates to the use of novel compounds in the manufacture of medicaments for use as MC2R antagonists. The invention further relates to compounds, compositions and medicaments that may be useful in the treatment of a disease or disorder characterised by activation of the MC2R receptor. Provided is a compound of formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group: ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N; or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN, CO2H and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. Also provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group: wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N; or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. Also provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group: wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. Also provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl.
Also provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group selected from: ; ; and ; or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. Also provided is a compound of Formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group selected from: ; ; and ; or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, - CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. In the compounds herein, J can be N or CH. J can be N. J can be CH. In the compounds herein, X can be -CO-, -CH2- or -CH2CH2-. X can be -CO- or -CH2-. X can be - CO-. X can be -CH2-. X can be -CH2CH2-. In the compounds herein, Z can be a bond, -CH2- or -CO-. Z can be -CH2- or -CO-. Z can be - CH2-. Z can be -CO-. Z can be a bond. In the compounds herein, R1 can be C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3- 4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms. R1 can be C1-4alkyl optionally substituted with 1-3 fluorine atoms. R1 can be C1-4alkyl. R1 can be methyl or ethyl. R1 can be methyl. R1 can be ethyl. R1 can be perdeuteroethyl. R1 can be -CD2CD3. R1 can be trideuteromethyl. R1 can be -CD3. In the compounds herein, L1 can be -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or - CO(CH2)n-, where n is 0-5. L1 can be a bond, -CH2CH2CONH-, -COO-, -CH2CH2COO-, - CH2CH2CO-, -COCH2NH-, -COCH2CH2NH-, -CO-, -COCH2-, -CH2CH2- or -CH2-. L1 can be a bond. In the compounds herein, R2 can be H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12. R2 can be H, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12. R2 can be H, a piperidine ring which is optionally substituted with R10, R11 and R12, a pyrrolidine ring which is optionally substituted with R10, R11 and R12, an azetidine ring which is optionally substituted with R10, R11 and R12, a hexahydro-1H- pyrrolizine ring system which is optionally substituted with R10, R11 and R12, a 2-pyrrolidone ring which is optionally substituted with R10, R11 and R12, a 1-azabicyclo[2.2.2]octane ring system which is optionally substituted with R10, R11 and R12, a tetrahydrofuran ring which is optionally substituted with R10, R11 and R12 or a morpholine ring which is optionally substituted with R10, R11 and R12. In the compounds herein, R2a and R2b can independently be H or C1-3alkyl optionally substituted with 1-3 fluorine atoms. R2a and R2b can independently be H or C1-3alkyl. R2a and R2b can independently be H or methyl. R2a and R2b can both be H. R2a can be H or C1-3alkyl optionally substituted with 1-3 fluorine atoms. R2a can be H or C1-3alkyl. R2a can be H or methyl. R2a can be H. R2b can be H or C1-3alkyl optionally substituted with 1-3 fluorine atoms. R2b can be H or C1-3alkyl. R2b can be H or methyl. R2b can be H. In the compounds herein, R10, R11 and R12 can be independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, -CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3. R10, R11 and R12 can be independently selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. R10 can be selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, -CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3. R10 can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. R10 can be H. R10 can be OH. R10 can be CH2CH2OH. R10 can be CH2NH2. R10 can be CH2CH2OCH2CH2OCH3. R11 can be selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, -CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3. R11 can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. R11 can be H. R11 can be OH. R11 can be CH2CH2OH. R11 can be CH2NH2. R11 can be CH2CH2OCH2CH2OCH3. R12 can be selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2)gNR13R14, -CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3. R12 can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. R12 can be H. R12 can be OH. R12 can be CH2CH2OH. R12 can be CH2NH2. R12 can be CH2CH2OCH2CH2OCH3. R13 and R14 can independently be H or methyl. R13 can be H or methyl. R14 can be H or methyl. R13 can be H. R13 can be methyl. R14 can be H. R14 can be methyl. In the compounds herein, R2 can be selected from: In the compounds herein, The moiety -L1-R2 can be selected from:
In the compounds herein, R3 can be H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3- 4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 can be joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms. R3 can be H or C1-3alkyl optionally substituted with 1-3 fluorine atoms. R3 can be H or C1-3alkyl. R3 can be H, methyl or ethyl. In the compounds herein, R3a can be H or can be joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms. In the compounds herein, R3b can be H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b can be joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms. R3b can be H or C1-3alkyl optionally substituted with 1-3 fluorine atoms. R3b can be H or C1-3alkyl. R3b can be H, methyl or ethyl. In the compounds herein, R3c can be H or can be joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms. In the compounds herein, one or both of R3 and R3b is H. Thus, for example, the structure of Formula (1) as defined herein can be effectively viewed as the scope of Formula (1’) and (1’’) taken together: All of R3, R3a, R3b and R3c can be H. One of R3 and R3b can be C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3- 4cycloalkyl optionally substituted with 1-3 fluorine atoms and the other H. One of R3 and R3b can be methyl or ethyl and the other H. One of R3 and R3b can be methyl and the other H. One of R3 and R3b can be ethyl and the other H. In the compounds herein, L2 can be a bond or -CO- and R4 can be a group: Q5 Q9 ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N; or L2 can be -CO- and R4 can be -(CH2)qNH2, where q is 0-3. L2 can be a bond or -CO- and R4 can be a group selected from: or L2 can be -CO- and R4 can be -(CH2)qNH2, where q is 0-3. L2 can be a bond or -CO- and R4 can be a group selected from: ; ; and ; or L2 can be -CO- and R4 can be -(CH2)qNH2, where q is 0-3. L2 can be a bond or -CO- and R4 can be a group: ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one, two or none of Q5, Q6, Q7, Q8 and Q9 is N. L2 can be a bond or -CO- and R4 can be a group: ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where one of Q5, Q6, Q7, Q8 and Q9 is N. L2 can be a bond or -CO- and R4 can be a group: ; wherein Q5 is CR5 or N; Q6 is CR6 or N; Q7 is CR7 or N; Q8 is CR8 or N; and Q9 is CR9 or N; where two of Q5, Q6, Q7, Q8 and Q9 are N. L2 can be a bond or -CO- and R4 can be a group: L2 can be a bond or -CO- and R4 can be a group selected from: L2 can be a bond or -CO- and R4 can be a group selected from: L2 can be -CO- and R4 can be -(CH2)qNH2, where q is 0-3. In the compounds herein, R5, R6, R7, R8, and R9 can be independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me. In the compounds herein, R15 and R16 can independently be H or C1-3alkyl. R15 and R16 can independently be H, methyl, ethyl, n-propyl or isopropyl. R5, R6, R7, R8, and R9 can be independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, - OEt, -OnPr, -N(CH3)(CH2CH2CH3), -N(CH3)2, -OCH2CN, -OCH2cyclopropyl, -CO2H and -SO2Me. L2 can be a bond or -CO- and R4 can be a group selected from: . L2 can be -CO- and R4 can be -(CH2)qNH2, where q is 0-3. L2 can be -CO- and R4 can be selected from: ; NH2 . R4 can be a group selected from: C
Definitions of L1 and L2 herein are provided without limitation to a particular orientation with respect to the rest of the molecule. As such L1 and L2 definitions provided include all possible orientations unless stated otherwise. For example, in compounds where L1 is defined as -CONH- both of the following may be included: . The compound can be a compound of Formula (1’) or (1’’): 1’); (1’’); or a salt thereof, wherein J, X, Z, L1, L2, R1, R2, R3, R3a, R3b, R3c and R4 are as defined herein. The compound can be a compound of Formula (1’’’), (1’’’’), (1’’’’’), (1’’’’’’), (1’’’’’’’) or (1’’’’’’’’): or a salt thereof, wherein J, X, Z, L1, L2, R1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (2a) or (2b): (2b); or a salt thereof, wherein X, Z, L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (2aD) or (2bD): 4 D (2bD); or a salt thereof, wherein X, Z, L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula or a salt thereof, wherein X, Z, L1, R2 and R4 are as defined herein. The compound can be a compound of Formula (2aii), (2aiii), (2aiv), (2bii), (2biii) or (2biiv): or a salt thereof, wherein X, Z, L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (2av), (2avi), (2avii), (2bv), (2bvi) or (2bvii): or a salt thereof, wherein X, Z, L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (3a), (3b), (3c), (3d), (3e) or (3f):
or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (3ai), (3bi), (3ci), (3di), (3ei) or (3fi): or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein.
The compound can be a compound of Formula (3aii), (3bii), (3cii), (3dii), (3eii) or (3fii): or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (3aiii), (3biii), (3ciii), (3diii), (3eiii) or (3fiii): or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (3aiv), (3biv), (3civ), (3div), (3eiv) or (3fiv): or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (3av), (3bv), (3cv), (3dv), (3ev) or (3fv):
or a salt thereof, wherein L1, R2, R3 and R4 are as defined herein. The compound can be a compound of Formula (5a) or (5b): or a salt thereof, wherein L1, R2, R3, R5, R6, R7, R8 and R9 are as defined herein. The compound can be a compound of Formula (6a), (6b), (6c), (6d), (6e), (6f), (6g) or (6h):
or a salt thereof, wherein L1, R2, R3, R5, R6, R7, R8 and R9 are as defined herein. The compound can be a compound of Formula (9a), (9b), (9c), (9d), (9e) or (9f):
or a salt thereof, wherein R3 and R4 are as defined herein. The compound can be selected from any one of Examples 1 to 218 as shown in Table 1a or a salt thereof. The compound can be selected from the group consisting of: 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 3-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-8-oxospiro[6H-1,7- naphthyridine-5,4'-piperidine]-7-yl]propanamide; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-6-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7- naphthyridine-5,4'-piperidine]; 2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 3-[1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-8-oxospiro[6H-1,7- naphthyridine-5,4'-piperidine]-7-yl]propanamide; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin- 3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 3-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propanamide; 3-[2-(2-ethoxypyridin-3-yl)-1'-[2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]propanamide; 2-(2-ethoxypyridin-3-yl)-1'-[3-ethoxy-2-(trifluoromethyl)phenyl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro- 1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7- naphthyridine-5,4'-piperidine]; 2-(2-ethoxypyridin-3-yl)-1'-[3-ethoxy-2-(trifluoromethyl)phenyl]-7-pyrrolidin-3-ylspiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-amino-1-[7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]ethanone; 1'-(4-chloro-3-iodopyridin-2-yl)-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthyridine- 5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; [2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthyridine-5,4'-piperidine]-1'-yl]-[6- propoxy-2-(trifluoromethyl)pyridin-3-yl]methanone; 3-amino-1-[7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]propan-1-one; [6-(cyclopropylmethoxy)-2-(trifluoromethyl)pyridin-3-yl]-[2-(2-ethoxypyridin-3-yl)spiro[7,8- dihydro-6H-1,7-naphthyridine-5,4'-piperidine]-1'-yl]methanone; 1'-(4-chloropyridin-2-yl)-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H-1,7-naphthyridine- 5,4'-piperidine]-8-one; 1'-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; [2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'- yl]-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methanone; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[7,8-dihydro-6H-1,7- naphthyridine-5,4'-piperidine]; 1'-[6-(cyclopropylmethoxy)-2-(trifluoromethyl)pyridine-3-carbonyl]-2-(2-ethoxypyridin-3-yl)-7- pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 3-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-6-oxospiro[8H-1,7- naphthyridine-5,4'-piperidine]-7-yl]propanamide; 2-(2-ethoxypyridin-3-yl)-1'-[6-propoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; (S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one; (R)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-3'-ethylspiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazetidin-3- yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-pyrrolidin-3-ylspiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[4-propoxy-3-(trifluoromethyl)pyridin-2-yl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[5-[methyl(propyl)amino]-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin- 3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[2-(trifluoromethyl)phenyl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazetidin- 3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazetidin-3-yl)methyl]-1'-[5-propoxy-4- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[4-propoxy-3-(trifluoromethyl)pyridin-2-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazetidin-3-yl)methyl]-1'-[5-propoxy-4- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 7-(azetidin-3-yl)-1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3- hydroxyazetidin-3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-propoxy-2-(trifluoromethyl)phenyl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]ethanone; 3-amino-1-[1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin-3- yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)pyrrolidin- 3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-propoxy-2-(trifluoromethyl)phenyl]-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one; 7-(2-aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one; [1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2S)-pyrrolidin-2-yl]methanone; [1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2R)-pyrrolidin-2-yl]methanone; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(2S)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1- methylazetidin-3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-propoxy-3-(trifluoromethyl)pyridin-2-yl]-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-propoxy-3-(trifluoromethyl)pyridin-2-yl]spiro[6,7-dihydro- 1,7-naphthyridine-5,4'-piperidine]-8-one; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 3-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-[2-(2- methoxyethoxy)ethyl]pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-7-[[(2S)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-3'-ethylspiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-pyrrolidin-3-yl-1'-[2-(trifluoromethyl)phenyl]spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-propoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[7,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-6-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-[(3R)-pyrrolidin-3- yl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-[(3S)-pyrrolidin-3- yl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one; [2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(3R)-pyrrolidin-3-yl]methanone; [2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-piperidin-4-ylmethanone; [2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-(1-methylazetidin-3-yl)methanone; azetidin-3-yl-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-7-yl]methanone; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 2-(2-ethoxypyridin-3-yl)-1'-[5-ethoxy-4-(trifluoromethyl)pyridin-3-yl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin-3-yl]-1'-[5-propoxy-4- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[5-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(3R)-pyrrolidin-3- yl]methyl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(3S)-pyrrolidin-3- yl]methyl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; rac-(3'S,5S)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7- pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-(pyrrolidin-3-yl)-6,7- dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[2-propoxy-3-(trifluoromethyl)pyridin-4-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one; 7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7- pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7-(pyrrolidin-3- yl)-6,7-dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; (S)-2'-(2-ethoxypyridin-3-yl)-1-(3-propoxy-2-(trifluoromethyl)phenyl)-7'-(pyrrolidin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one; 2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin-3-yl]-1'-[4-propoxy-3- (trifluoromethyl)pyridin-2-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[6-propoxy-2-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 7-(azetidin-3-yl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one; 2-(2-ethoxypyridin-3-yl)-7-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethyl)-1'-[3-methoxy-2- (trifluoromethyl)phenyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; azetidin-3-yl 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-carboxylate; 2-[3-[2-(2-ethoxypyridin-3-yl)-8-oxo-7-[(3S)-pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-2-(trifluoromethyl)phenoxy]acetonitrile; 2-(2-ethoxypyridin-3-yl)-1'-[6-[methyl(propyl)amino]-2-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin- 3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-[2-(2-ethoxypyridin-3-yl)-8-oxo-7-pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-1'- yl]-6-methoxybenzonitrile; 1'-[5-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 3-amino-1-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3- yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-6H- spiro[1,7-naphthyridine-5,4'-piperidin]-7(8H)-yl]propan-1-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7- pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-(pyrrolidin-3-yl)-6,7- dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; (3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-[(3S)- pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-[(3S)-pyrrolidin-3-yl]- 6,7-dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; ‘ 2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-(pyrrolidin-3-yl)-6,7- dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[(3S)-pyrrolidin-3-yl]-1'-[2- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[(3S)-pyrrolidin-3-yl]-1'-[2-(trifluoromethyl)pyridin-3-yl]-6,7- dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; ‘ 2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-(pyrrolidin-3-yl)-1'-[2-(trifluoromethyl)pyridin-3-yl]-6,7- dihydro-8H-spiro[1,7-naphthyridine-5,4'-piperidin]-8-one; [2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2R)-pyrrolidin-2-yl]methanone; [2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2S)-pyrrolidin-2-yl]methanone; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 2-[7-(3-aminopropanoyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-6-methoxybenzonitrile; 3-amino-1-[1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; 3-amino-1-[1'-(2,4-dichloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[(3S)-pyrrolidin-3-yl]-1'-[3- (trifluoromethyl)pyridin-2-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; rac-(3'S,5S)-1'-[5-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7- pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-[(3R)- pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[(3R)-pyrrolidin-3-yl]-1'-[3- (trifluoromethyl)pyridin-2-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 3-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-3-oxopropanoic acid; 3-[2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]pyrrolidin-2-one; 1'-[6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 7-(1-azabicyclo[2.2.2]octan-3-yl)-2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2- (trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-fluoro-2-(trifluoromethyl)phenyl]-7-[(3S)- pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-3-amino-1-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; rac-(3'S,5S)-1'-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7- [(3S)-pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7- [(3S)-pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]-[(2S)-pyrrolidin-2-yl]methanone; rac-(3'S,5S)-7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; enant1-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethyl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'- piperidine]-8-one; rac-(3'S,5S)-7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[2-methoxy-3- (trifluoromethyl)pyridin-4-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[2-methoxy-3-(trifluoromethyl)pyridin-4-yl]-7-(1- methylazetidin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-1-azabicyclo[2.2.2]octan-3-yl-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]methanone; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7-(1- methylazetidin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 3-amino-1-[1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]propan-1-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-(1- methylazetidin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rel-[(2R,4S)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]oxolan-2-yl]methanamine; rel-[(2R,4R)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]oxolan-2-yl]methanamine; 2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; rac-(3'S,5S)-7-(azetidin-3-yl)-1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-3'- ethylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-3-amino-1-[rac-(3'S,5S)-1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethylspiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; [2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2R)-pyrrolidin-2-yl]methanone; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-(1- methylazetidin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7- [[(2R)-pyrrolidin-2-yl]methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; rac-3-amino-1-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-methoxy-3- (trifluoromethyl)pyridin-2-yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1- one; 2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one; 2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[3-(trifluoromethyl)pyridin-2- yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 3-amino-1-[2-(2-ethoxyphenyl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2- (trifluoromethyl)phenyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one; 1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 5-chloro-2-[2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 2-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]-5-fluorobenzonitrile; 2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2-chloro-4-fluoro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 3-[2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-1'-yl]-2-(trifluoromethyl)benzonitrile; (3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'R,5R)-2-(2-ethoxy-3-pyridinyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxy-3-pyridinyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-[2-(difluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxyphenyl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxy-3-pyridinyl)-3'-ethyl-1'-[4-methoxy-3-(trifluoromethyl)-2-pyridinyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2-chlorophenyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxy-3-pyridinyl)-1'-[6-methoxy-2-(trifluoromethyl)-3-pyridinyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 5-chloro-2-[(3'S,5S)-2-(2-ethoxy-3-pyridinyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 3-chloro-4-[2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[3-(trifluoromethyl)pyrazin-2- yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxyphenyl)-1'-[4-methoxy-3-(trifluoromethyl)-2-pyridinyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2,3-dichlorophenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-1'-[4-methoxy-3-(trifluoromethyl)-2-pyridinyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 2 5-chloro-2-[(3'R,5R)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(3-chloro-4-methoxy-2-pyridinyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 5-chloro-2-[2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 2-(2-ethoxyphenyl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2S)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 3-[[2-(2-ethoxy-3-pyridinyl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]methyl]morpholine; (3'S,5S)-1'-(2-chlorophenyl)-2-(2-ethoxy-3-pyridinyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxyphenyl)-1'-[6-methoxy-2-(trifluoromethyl)-3-pyridinyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-1'-[6-methoxy-2-(trifluoromethyl)-3-pyridinyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-(2-ethoxy-3-pyridinyl)-1'-[5-fluoro-3-(trifluoromethyl)-2-pyridinyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S)-1'-(2,3-dichlorophenyl)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S)-1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 1'-(2-chlorophenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]; 2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'- piperidine]-1'-yl]benzonitrile; 1 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 2 5-chloro-2-[(3'R,5R)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2S)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 1'-[4-chloro-2-(difluoromethyl)phenyl]-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; (3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[3- (trifluoromethyl)pyrazin-2-yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]-5-fluorobenzonitrile; (3'S,5S)-1'-(2-chlorophenyl)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 1'-(4-chloro-2-methylsulfonylphenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]; 5-chloro-2-[2-[2-(1,1,2,2,2-pentadeuterioethoxy)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R,4S)-4-hydroxypyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R,4S)-4-hydroxypyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R,4S)-4-hydroxypyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R,4S)-4-hydroxypyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 5-chloro-2-[(3'S,5S)-3'-ethyl-2-[2-(1,1,2,2,2-pentadeuterioethoxy)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile; (3S,5R)-5-[[1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxyphenyl)spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]methyl]pyrrolidin-3-ol; (3S,5R)-5-[[1'-(2,4-dichlorophenyl)-2-(2-ethoxyphenyl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'- piperidine]-7-yl]methyl]pyrrolidin-3-ol; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2S)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzoic acid; 2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-5-(trifluoromethoxy)benzonitrile; 5-(difluoromethoxy)-2-[2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile; or a salt thereof. The salt thereof can be a pharmaceutically acceptable salt. The salt thereof can be a formate salt, a trifluoroacetic acid (TFA) salt, a mesylate salt or a hydrochloride (HCl) salt. The salt thereof can be a formate salt or a trifluoroacetic acid (TFA) salt. The compound can be a salt selected from the group consisting of: 1'-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one formate salt; (S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one formate salt; (R)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one formate salt; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one formate salt; 7-(azetidin-3-yl)-1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one TFA salt; 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3- hydroxyazetidin-3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one TFA salt; 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin-3- yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one TFA salt; 2-(2-ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; 7-(2-aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-[(3R)-pyrrolidin-3- yl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-7-[(3S)-pyrrolidin-3- yl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; [2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-(1-methylazetidin-3-yl)methanone TFA salt; azetidin-3-yl-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-7-yl]methanone TFA salt; 1'-[5-chloro-4-(trifluoromethyl)pyridin-3-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(3R)-pyrrolidin-3- yl]methyl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one TFA salt; 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(3S)-pyrrolidin-3- yl]methyl]spiro[8H-1,7-naphthyridine-5,4'-piperidine]-6-one formate salt; 7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one TFA salt; 7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one TFA salt; 7-(azetidin-3-yl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one formate salt; 2-[3-[2-(2-ethoxypyridin-3-yl)-8-oxo-7-[(3S)-pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-2-(trifluoromethyl)phenoxy]acetonitrile formate salt; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; 2-[7-(3-aminopropanoyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-6-methoxybenzonitrile formate salt; 3-amino-1-[1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; 3-amino-1-[1'-(2,4-dichloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; rac-(3'S,5S)-7-(azetidin-3-yl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[6-methoxy-2- (trifluoromethyl)pyridin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one TFA salt; 3-amino-1-[2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; rac-1-azabicyclo[2.2.2]octan-3-yl-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2- (trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]methanone formate salt; rac-(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[5-methoxy-4-(trifluoromethyl)pyridin-3-yl]-7- (1-methylazetidin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one formate salt; 3-amino-1-[1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]propan-1-one formate salt; rel-[(2R,4S)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]oxolan-2-yl]methanamine formate salt; rel-[(2R,4R)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]oxolan-2-yl]methanamine formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; rac-3-amino-1-[rac-(3'S,5S)-1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethylspiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; [2-(2-ethoxypyridin-3-yl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]-[(2R)-pyrrolidin-2-yl]methanone formate salt; rac-3-amino-1-[(3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[4-methoxy-3- (trifluoromethyl)pyridin-2-yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]propan-1- one formate salt; 3-amino-1-[2-(2-ethoxyphenyl)-1'-[4-fluoro-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]propan-1-one formate salt; 1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 5-chloro-2-[2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile formate salt; 2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] HCl salt; 2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]-1'-[2-(trifluoromethyl)phenyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] mesylate salt; (3'S,5S)-1'-(2,4-dichlorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; (3'S,5S)-1'-(2-chloro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; (3'S,5S)-1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 1'-(2-chloro-4-fluoro-3-methoxyphenyl)-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 2-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 1'-[2-(difluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; (3'S,5S)-2-(2-ethoxypyridin-3-yl)-3'-ethyl-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)- pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 2-(2-ethoxyphenyl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 3-chloro-4-[2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile formate salt; 1'-(3-chloro-4-methoxy-2-pyridinyl)-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 5-chloro-2-[2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile formate salt; 3-[[2-(2-ethoxy-3-pyridinyl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]methyl]morpholine formate salt; 1'-(2-chloro-4-fluorophenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8- dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 2-(2-ethoxy-3-pyridinyl)-1'-[5-fluoro-3-(trifluoromethyl)-2-pyridinyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 1'-[4-chloro-2-(difluoromethyl)phenyl]-2-(2-ethoxy-3-pyridinyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] TFA salt; 1'-(4-chloro-2-methylsulfonylphenyl)-2-(2-ethoxyphenyl)-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine] formate salt; 5-chloro-2-[2-[2-(1,1,2,2,2-pentadeuterioethoxy)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile formate salt; 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R,4S)-4-hydroxypyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile TFA salt; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R,4S)-4-hydroxypyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile TFA salt; 5-chloro-2-[2-(2-ethoxyphenyl)-7-[[(2R,4S)-4-hydroxypyrrolidin-2-yl]methyl]spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile TFA salt; 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R,4S)-4-hydroxypyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]benzonitrile TFA salt; 5-chloro-2-[(3'S,5S)-3'-ethyl-2-[2-(1,1,2,2,2-pentadeuterioethoxy)phenyl]-7-[[(2R)-pyrrolidin-2- yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'-yl]pyridine-3-carbonitrile formate salt; (3S,5R)-5-[[1'-(3,5-dichloro-2-pyridinyl)-2-(2-ethoxyphenyl)spiro[6,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-7-yl]methyl]pyrrolidin-3-ol formate salt; (3S,5R)-5-[[1'-(2,4-dichlorophenyl)-2-(2-ethoxyphenyl)spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]methyl]pyrrolidin-3-ol TFA salt. Further embodiments of the invention include the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) in medicine. Also included is the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) as a melanocortin subtype-2 receptor (MC2R) modulator. Compounds of the present invention may be used as MC2R receptor modulators. Compounds of the present invention may be used as MC2R receptor inhibitors or antagonists. Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of MC2R. Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R or in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity. Compounds of the present invention may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto. In some embodiments, compounds and compositions detailed herein are used as modulators of MC2R. Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (1) or any embodiment, variation or aspect thereof. Compounds as MC2R modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for MC2R associated diseases. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating Cushing’s disease in an individual. Also provided are combinations comprising a compound of the present invention and a Corticotropin-releasing factor receptor-1 (CRF1) antagonist. In the combinations the CRF1 antagonist may be selected from the group consisting of tildacerfont, crinecerfont, NBI-27914, CP-316,311, NBI-462000, DMP696, pexacerfont, NBI-35965, ONO-2333Ms, antalarmin, NBI- 34041, DMP904, NBI-30775, SSR125543, NBI-77860, GSK876008, CRA5626/JNJ19567470/R317573, NBI-76169, verucerfont, and CP-154,526. In the combinations the CRF1 antagonist may be selected from: . Also provided are combinations comprising a compound of the present invention and an ACTH antibody. In the combinations the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8). The combinations may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto. Also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a disorder or disease described herein. In some embodiments, the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by MC2R. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method as either a stand-alone therapy, or as a conjunctive therapy with other agents that are either palliative (e.g., agents that relieve the symptoms of the disorder to be treated), and/or agents that target the etiology of the disorder. Compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent. In some embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes or less. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes. Either (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent may be administered first. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered simultaneously. DEFINITIONS In this application, the following definitions apply, unless indicated otherwise. The term “MC2R modulator” as used herein refers to any compound which binds to and modulates the function of MC2 receptors. The term “modulator” should be interpreted to include modulation by modalities including, but not limited to antagonists. The term “treatment”, in relation to the uses of any of the compounds described herein, including those of Formula (1) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term “treatment” covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed. The term “effective therapeutic amount” (for example in relation to methods of treatment of a disease or condition) refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain. Chemical terms are all used in their conventional sense (e.g. as defined in the IUPAC Gold Book), unless indicated otherwise. The term "alkyl" as used herein, means straight or branched chain, saturated alkyl groups. The terms “cycloalkyl” as used herein, means a saturated carbocyclic group containing the indicated number of carbon atoms. The term “carbocyclic ring” as used herein, means a saturated or unsaturated carbocyclic group containing the indicated number of carbon atoms. The term “heterocyclic ring” as used herein, refers to a saturated or unsaturated ring containing the indicated number of total ring member atoms in which one or more of the ring members is a heteroatom selected from O, S and N, and oxidised forms thereof and the remaining atoms are C. The term “bicyclic” as used herein, means a saturated or unsaturated ring system comprising two joined rings and containing the indicated number of atoms in total. All possible modes of ring junction are included (including spirocyclic, fused and bridged). The term “heterobicyclic” as used herein, means a saturated or unsaturated heterocyclic ring system comprising two joined rings and containing the indicated number of atoms in total. All possible modes of ring junction are included (including spirocyclic, fused and bridged). The number of carbon atoms that are possible in the referenced groups herein may be indicated by subscript "Cn1-n2”. Thus, for example, the term "C1-3 alkyl” represents an alkyl group having 1, 2 or 3 carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl. The term “optionally substituted” as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different. Thus, for example, the term “optionally substituted with 1-6 fluorine atoms” as applied to a group means that the said group may if desired be substituted with 1, 2, 3, 4, 5 or 6 fluorine atoms. To the extent that any of the compounds described have chiral centres, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt. Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze- drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5- disulfonic and p-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α- oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L- lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, undecylenic and valeric acids. Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and DMSO. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3. The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O. In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). The isotopes may be radioactive or non- radioactive. Therapeutic dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. In general, the daily dose range may be from about 10 μg to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 μg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 μg to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 μg to about 1 mg per kg of body weight of a human and non-human animal. PHARMACEUTICAL FORMULATIONS While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). Accordingly, in some embodiments of the invention, there is provided a pharmaceutical composition comprising at least one compound of Formula (1) as defined above together with at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing compounds of the Formula (1) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches. The composition may be a tablet composition or a capsule composition. Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract. The pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95%, preferably% (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre- filled syringes, dragées, powders, tablets or capsules. Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition typically contain 0-99% (w/w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers. The composition may be a parenteral composition. Parenteral formulations typically contain 0- 20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w/w) oils. The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. The compounds of the Formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g.0.1 milligrams to 2 milligrams of active ingredient). For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound. The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures. EXAMPLES The invention will now be illustrated, but not limited, by reference to the following examples shown in Table 1a. Table 1a – Examples PREPARATION OF THE COMPOUNDS OF THE INVENTION Compounds of Formula (1) and derivatives or synthetic intermediates thereof may be prepared in accordance with synthetic methods known to the skilled person. In some embodiments, the invention provides a process for the preparation of a compound as defined in Formula (1) above. Several methods for the chemical synthesis of spiro[piperidine-4,5'-[1,7]naphthyridine] compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. Compounds of Formula (1) and derivatives or synthetic intermediates thereof may be prepared in accordance with General Scheme 1. General Scheme 1: In one approach (General Scheme 1), compounds of formula [X3] may be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic or substituted phenyl-compound of formula [X2] in a transition metal catalysed cross-coupling reaction such as a Buchwald– Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene. The reaction is suitably conducted at elevated temperature. Alternatively, compounds of formula [X3] may also be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic-compound of formula [X2] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF. The reaction is suitably conducted at elevated temperature. Alternatively, compounds of formula [X3] can be prepared via reaction with a carboxylic acid of formula [X2] in an amide coupling reaction with a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT. In all cases, after reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of formula [X4] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3]. In the case of benzyloxycarbonyl (Cbz), a method such as hydrogenation under an atmosphere of hydrogen in the presence of palladium on activated carbon in a polar solvent such as ethanol or methanol. Alternatively, a method using strong base such as KOH in a solvent such as ethanol, suitably conducted at elevated temperature. After reaction work up, typically filtration and/or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of formula [X6] may be prepared by the reaction of a compound of formula [X4] with an aldehyde or ketone derivative of general formula [X5] by a reductive amination reaction with reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Alternatively, they can be prepared with alkyl halides [X5’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO. Alternatively, they can be prepared with carboxylic acids of formula [X5’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT. In some examples the compounds of formula [X6] contain an amino group that is protected by nitrogen protecting group such as a tert-butyloxycarbonyl protecting group. In these examples, compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of a compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re- crystallisation. General Scheme 2:
In another approach (General Scheme 2), compounds of formula [X3’] may be prepared by the reaction of compound of formula [X1’] with an aldehyde of formula [X2] by reductive amination reaction with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol. After reaction work up, typically by liquid- liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Alternatively, they can be prepared with alkyl halides [X2’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO. Alternatively, they can be prepared with carboxylic acids of formula [X2’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT. Compounds of formula [X4’] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3’]. Compounds of formula [X6] may be prepared with compounds of formula [X4’] by the reaction of a hetero-aromatic or substituted phenyl-compound of formula [X5] in a transition metal catalysed cross-coupling reaction such as a Buchwald–Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene. The reaction is suitably conducted at elevated temperature. Alternatively, compounds of formula [X6] may also be prepared by the reaction of compounds of formula [X4’] with a hetero-aromatic- compound of formula [X5] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF, the reaction is suitably conducted at elevated temperature. In some examples the compounds of formula [X6] contains an amino group that is protected by a nitrogen protecting group such as a tert-butyloxycarbonyl protecting group. In these examples, compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. General Scheme 3: Compounds of formula [X1] and [X1’] can be obtained via different methodologies (General Scheme 3). In one approach, compounds of formula [X1’] may be prepared by the reaction- cyclisation of a compound of formula [X1’_3] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH4 or RedAl in an anhydrous solvent such as THF or toluene at a suitable temperature. Alternatively, they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water. Compounds of formula [X1’_3] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature. Alternatively, compounds of formula [X1’] may be prepared by reduction of a compound of formula [X1’_5] using a suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature. In turn, compounds of formula [X1’_5] may be prepared via the cyclisation reaction of compounds of formula [X1’_4] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH4 or RedAl in an anhydrous solvent like THF or toluene at a suitable temperature. Alternatively, they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water. Compounds of formula [X1’_4] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2’] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature. Alternatively, compounds of formula [X1’] can be prepared from compounds of formula [X1’_8] via standard deprotection conditions, depending on the nature of PG. Compounds of formula [X1] may be prepared with compounds of formula [X1_8] via typical benzyl deprotection conditions such as NaOH in solvents such as ethanol and water at high temperatures. Alternatively, they can also be prepared via a reduction reaction in a hydrogen atmosphere with a suitable catalyst such as Pd(OH)2 in a suitable solvent such as MeTHF, MeOH or IPA.. Compounds of formula [X1_8] can be prepared by a reduction reaction of compounds of formula [X1_7] with suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature.Compounds of formula [X1_7] can be prepared via reaction of compounds of formula [X1_6] with NaNO2/CuCl/HCl in an alcoholic solvent such as methanol or water, typically at room temperature. This is followed by treatment with aqueous HCl in a suitable solvent such as THF, typically conducted at room temperature. Compounds of formula [X1_7] can also be prepared using compounds of formula [X1’5] via standard protecting group addition reaction conditions. Compounds of the invention may be prepared according to the methods described below. Note that all the reported yields are based on weight of starting material and product and not their purity. LCMS methods
HPLC purification methods for Examples
Abbreviations & Acroynms
Synthesis of Intermediates: Procedure for the preparation of benzyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (Intermediate 4)
To a stirred solution of 6-chloro-3-fluoropicolinic acid (10 g, 57.0 mmol) in 1,4-dioxane:H2O (80:20 mL) were added (2-ethoxypyridin-3-yl)boronic acid (11.4 g, 68.4 mmol) followed by K2CO3 (15.8 g, 114 mmol) at RT and solution was purged by nitrogen for 5 minutes. Pd(amphos)Cl2 (0.605 g, 0.854 mmol) was added in reaction mixture and heated at 100 °C for 16 h. The mixture was filtered through celite bed and bed was washed with EtOAc (100 mL). Combined filtrate was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The aqueous layer was acidified with Citric acid (10%) (solid precipitated). The precipitated solid was filtered off to afford 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (12 g, 44.8 mmol, 79%) as white solid. LCMS: 2.04 min, 263.1 (M+H)+, Method B To a stirred solution of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (12 g, 45.8 mmol) in DMF (80 mL) was added K2CO3 (12.65 g, 92 mmol) followed by ethyl iodide (4.44 mL, 54.9 mmol) and reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched by water (200 mL) and extracted with EtOAc (200 mL x 2). Combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude. The crude was purified by flash column chromatography. The pure fractions were concentrated under reduced pressure to afford ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6- carboxylate (10 g, 34.1 mmol, 75 %) (Intermediate 1) as off white solid. To a mixture of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (2.5 g, 8.61 mmol) (Intermediate 1) and tert-butyl4-cyanopiperidine-1-carboxylate (1.81 g, 8.61 mmol) in toluene (25 mL) was added 1M KHMDS in THF (8.61 mL, 8.61 mmol) and reaction mixture was stirred at rt for 30 min. The reaction mixture was quenched with Saturated NH4Cl (20 mL) and extracted with EtOAc (2 x 50 mL). Combined organic extracts were dried over sodium sulfate and concentrated to afford crude. The crude was purified by flash column chromatography using EtOAc-PET ether (0 to 10%) to afford ethyl 5-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-2'-ethoxy-[2,3'- bipyridine]-6-carboxylate (1.2 g, 2.472 mmol, 29%) as a colourless gum. LCMS: 2.99 min, 481.0 (M+H)+, Method B To a stirred solution of ethyl 5-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-2'-ethoxy-[2,3'- bipyridine]-6-carboxylate (2.5 g, 5.20 mmol) in EtOH:H2O (20:5 mL) was added Raney nickel (5.47 g, 62.4 mmol) at rt and reaction mixture was stirred under hydrogen gas at 70 psi pressure at 65 °C for 16 h. The reaction mixture was filtered through celite bed, bed was washed with MeOH (20 mL). Combined filtrate was concentrated under reduced pressure to afford crude. The crude was purified by using flash column chromatography to afford tert-butyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (1.5 g, 3.25 mmol, 63 %) (Intermediate 2) as white solid. To a stirred solution of tert-butyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridine]-1-carboxylate (1.5 g, 3.42 mmol) (Intermediate 2) in THF (5 mL) was added NaH (0.274 g, 6.84 mmol) at 0 °C and stirred for 20 min. Cbz-Cl (2.29 mL, 6.84 mmol) was added to the reaction mixture and slowly allowed to stir the reaction mixture at RT for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). Combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by using flash column chromatography to afford 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (700 mg, 1.198 mmol, 35%) (Intermediate 3) as off white solid. To a stirred solution of 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (700 mg, 1.22 mmol) (Intermediate 3) in DCM (5 mL) was added TFA (0.471 mL, 6.11 mmol) at 0 °C and reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was concentrated to get crude. The crude was quenched by 1.5 N HCl (5 mL) and extracted with DCM (2 x 10mL). Combined organic extract was washed with water (10 mL) and brine (10 mL). Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude benzyl 2'-(2-ethoxypyridin-3-yl)- 8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate 2,2,2-trifluoroacetate (600 mg, 1.002 mmol, 82%) (Intermediate 4) as gummy solid. The analytical data for Intermediate 1, 2, 3 and 4 is in Table 1. Procedure for the preparation of 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (Intermediate 5) To a stirred solution of 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (600 mg, 1.048 mmol) (intermediate 3) in THF (10 mL) was added BH3.THF (4.19 mL, 4.19 mmol) at 0 °C and reaction mixture was stirred at rt for 2 h. After 2 h, excess of BH3.THF (4.19 mL, 4.19 mmol) was added at 0 °C and reaction mixture was further stirred at rt for 14 h. The reaction was quenched by MeOH (10 mL) at 0 °C and concentrated the reaction mixture to afford crude 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxypyridin-3-yl)- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (400 mg, 0.716 mmol, 68.3%) as gummy solid. Crude was as such used for next step. To a stirred solution of 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (400 mg, 0.716 mmol) in DCM (10 mL) was added TFA (82 mg, 0.716 mmol) at 0 °C and reaction mixture was allowed to stir at rt for 3 h. The reaction mixture was directly concentrated and resulted residue was basified by saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (2 x 50 mL). Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to afford 2'-(2-ethoxypyridin-3- yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (700 mg, 1.480 mmol, 207%) (Intermediate 5) as a pale yellow gummy solid. The analytical data for Intermediate 5 is in Table 1. Procedure for the preparation of nitriles as exemplified with the preparation of 1-(4-chloro- 2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (Intermediate 6) To a stirred solution of piperidine-4-carbonitrile (250 mg, 2.269 mmol) in toluene (2 mL) at RT were added 1-bromo-4-chloro-2-(trifluoromethyl)benzene (883 mg, 3.40 mmol) and Cs2CO3 (1.48 g, 4.54 mmol). The reaction mixture was purged with nitrogen for 5 min. BINAP (283 mg, 0.454 mmol) and Pd(OAc)2 (51 mg, 0.227 mmol) were added, and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was filtered through celite and washed with EtOAc (10 mL). The filtrate was evaporated, and the crude product was purified via flash column chromatography to afford 1-(4-chloro-2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (550 mg, 1.87 mmol, 83%) (Intermediate 6) as a yellow gum. The analytical data for Intermediate 6 is in Table 1. Procedure for the preparation of lactams as exemplified with the preparation of 2'-(2- ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (Intermediate 8)
To a solution of 2-(6-chloropyridin-3-yl)acetonitrile (10 g, 65.54 mmol) in DMSO (200 mL) were added potassium hydroxide (11.03 g, 196.62 mmol) in portions and N-benzyl-2-chloro-N-(2- chloroethyl)ethan-1-amine hydrochloride (17.60 g, 65.54 mmol) at 25 °C. The reaction mixture was stirred at 30 °C for 2.5 hr. After cooling to RT, the reaction mixture was poured into ice-water (600 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with brine (500 mL) and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to get a crude, which was purified by column on silica gel (eluted with PET ether/EtOAc= 100/1 to 20/1) to get 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carbonitrile (11 g, 53.8%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.57 - 8.54 (m, 1H), 7.80 (dd, J = 2.7, 8.3 Hz, 1H), 7.43 - 7.28 (m, 6H), 3.62 (br s, 2H), 3.10 - 3.00 (m, 2H), 2.54 (br dd, J = 5.7, 12.0 Hz, 2H), 2.12 (br s, 4H) To a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carbonitrile (5.5 g, 17.64 mmol) in a mixture solvents of ethanol (55 mL) and water (55 mL) was added potassium hydroxide (7.13 g, 127.00 mmol) at 25 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 16 hr. One additional vial was set up as described above. After cooling to RT, all two reaction mixtures were combined. The mixture was removed ethanol and acidified to pH 4 with hydrochloric acid (4 N). The suspension was filtered and the filtrate cake was dried under reduced pressure to get 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (8 g) as a white solid, which was used to next step directly without further purification. LCMS: 0.72 min, 331.1 (M+H)+, Method O To a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (9.4 g, 28.42 mmol) in a mixture solvents of MeOH (100 mL) and toluene (200 mL) was added (trimethylsilyl)diazomethane in hexane (2 M, 42.62 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with acetic acid (1 mL) and neutralized with saturation sodium bicarbonate (200 mL) to pH 8 and extracted with EtOAc (3 × 100 mL). The combined organic phase was concentrated under reduced pressure to get a crude, which was purified by flash column chromatography (eluted with PET ether/ EtOAc= 100/5 to 100/20) to afford methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (6 g, 61%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.70 - 7.64 (m, 1H), 7.37 - 7.22 (m, 6H), 3.69 (s, 3H), 3.49 (s, 2H), 2.83 (br d, J = 10.4 Hz, 2H), 2.58 (br d, J = 12.8 Hz, 2H), 2.21 (br t, J = 11.2 Hz, 2H), 2.05 - 1.93 (m, 2H) To a solution of methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (1 g, 2.90 mmol) in chloroform (20 mL) was added hydrogen peroxide urea (545 mg, 5.80 mmol) and trifluoroacetic anhydride (1.22 g, 5.80 mmol, 806.7 uL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hr. One additional vial was set up as described above. All of two reaction mixtures were combined, quenched by saturation sodium sulfite (200 mL) at 0 °C and extracted with DCM (3 × 100 mL). The combined organic phase was washed with saturation sodium carbonate (200 mL), brine (100 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to get a crude, which was purified by flash column chromatography (eluted with EtOAc/MeOH= 100 to 100/10) to get 5-(1-benzyl-4- (methoxycarbonyl)piperidin-4-yl)-2-chloropyridine 1-oxide (1 g, 48%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.35 - 7.28 (m, 5H), 7.22 (dd, J = 2.1, 8.7 Hz, 1H), 3.69 (s, 3H), 3.47 (s, 2H), 2.79 (br d, J = 11.4 Hz, 2H), 2.57 - 2.45 (m, 2H), 2.18 (br t, J = 11.0 Hz, 2H), 1.99 - 1.87 (m, 2H). To a solution of 5-(1-benzyl-4-(methoxycarbonyl)piperidin-4-yl)-2-chloropyridine 1-oxide (1 g, 2.77 mmol) in 1, 2-dichloroethane (15 mL) was added trimethylsilylformonitrile (824.81 mg, 8.31 mmol, 1.04 mL) and N, N-dimethylcarbamoyl chloride (894.1 mg, 8.3 mmol, 764.2 uL) at 25 °C. The reaction mixture was heated to 70 °C and stirred for 12 hr. Two additional vials were set up as described above. After cooling to RT, all of three reaction mixtures were combined, diluted with the solution of sodium hydroxide (1 N in water, 200 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 mL × 2), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with PET ether/ EtOAc= 10/1 to 0/1) to get methyl 1-benzyl-4-(6-chloro-2-cyanopyridin-3-yl)piperidine-4-carboxylate (1.5 g, 49%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.35 - 7.30 (m, 4H), 7.28 (br d, J = 2.4 Hz, 1H), 3.76 (s, 3H), 3.51 (s, 2H), 2.74 - 2.61 (m, 4H), 2.56 - 2.46 (m, 2H), 2.22 - 2.11 (m, 2H) To a solution of methyl 1-benzyl-4-(6-chloro-2-cyanopyridin-3-yl)piperidine-4-carboxylate (1.3 g, 3.7 mmol) in a mixture solvents of dioxane (20 mL) and water (2 mL) was added (2-ethoxypyridin- 3-yl)boronic acid (921.3 mg, 5.6 mmol), K2CO3 (1.53 g, 11.04 mmol) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (269.2 mg, 367.9 μmol) at 25 °C under nitrogen. The reaction mixture was heated to 80 °C and stirred at 80 °C for 1 h. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get a crude, which was purified by prep-TLC (EtOAc, Rf = 0.29) to get methyl 1-benzyl-4-(6-cyano- 2'-ethoxy-[2,3'-bipyridin]-5-yl)piperidine-4-carboxylate (1.5 g, 3.3 mmol, 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 1.9, 7.6 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.24 (dd, J = 2.0, 4.9 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 4.3 Hz, 4H), 7.05 (dd, J = 4.9, 7.5 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.53 (s, 2H), 2.79 - 2.65 (m, 4H), 2.51 (br t, J = 10.1 Hz, 2H), 2.29 - 2.20 (m, 2H), 1.46 (t, J = 7.1 Hz, 3H) To a solution of methyl 1-benzyl-4-(6-cyano-2'-ethoxy-[2,3'-bipyridin]-5-yl)piperidine-4- carboxylate (700 mg, 1.53 mmol) in THF (14 mL) was added borane THF complex (1 M, 7.67 mL) at 0 °C dropwise under nitrogen. The reaction mixture was heated to 40 °C and stirred at 40 °C for 2 hr. One additional vial was set up as described above. After cooling to 0 °C, all of two reaction mixtures were combined and quenched with MeOH (10 mL). The mixture was heated to 80 °C and stirred at 80 °C for 30 min. After cooling to 25 °C, the resulting mixture was concentrated under reduced pressure to get a residue, which was purified by flash column chromatography (eluted with PET ether/EtOAc to EtOAc/MeOH= 20/80 to 90/10) to get 1-benzyl- 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (700 mg, 53%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 1.8, 7.4 Hz, 1H), 8.20 (dd, J = 1.9, 4.9 Hz, 1H), 8.00 (s, 1H), 7.84 (br d, J = 8.5 Hz, 1H), 7.39 - 7.30 (m, 4H), 7.30 - 7.28 (m, 1H), 7.02 (dd, J = 4.9, 7.4 Hz, 1H), 6.09 (br s, 1H), 4.65 (d, J = 3.0 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.60 (br s, 2H), 2.79 (br s, 4H), 2.22 (br d, J = 13.5 Hz, 2H), 2.11 - 2.01 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H) To a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-6'-one (100 mg, 233.4 μmol) in MeOH (5 mL) were added Pd(OH)2 (100 mg, 142.4 μmol, 20% purity) and di-tert-butyldicarbonate (101.9 mg, 466.7μmol, 107.2 uL) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred under hydrogen balloon (15 Psi) at 20 °C for 5 hr. Two additional vials were set up ad described above. All of three reaction mixtures were combined, filtered and the filtrate was concentrated under reduced pressure to get a residue, which was purified by prep- TLC to get tert-butyl 2'-(2-ethoxypyridin-3-yl)-6'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1-carboxylate (200 mg, 65%) (Intermediate 7) as a colourless oil. To a solution of tert-butyl 2'-(2-ethoxypyridin-3-yl)-6'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1-carboxylate (100 mg, 228.0 μmol) in DCM (1 mL) was added 2,2,2-TFA (154.0 mg, 1.35 mmol, 0.1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hr. One additional vial was set up as described above. All of two reaction mixtures were combined and concentrated under reduced pressure to get a residue, which was purified by prep-HPLC to get 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (50 mg, 34%) (Intermediate 8) as a yellow oil. The analytical data for Intermediate 7 and 8 is in Table 1. Procedure for the preparation of lactams as exemplified with the preparation of 2'-(2- ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Intermediate 10)
To a stirred solution of tert-butyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridine]-1-carboxylate (200 mg, 0.456 mmol) (Intermediate 2) in DCM (5 mL) at 0 °C were added TFA (0.04 mL, 0.456 mmol) and the reaction mixture was stirred at RT for 16 h. Reaction mixture was evaporated and dried under high vacuum to afford 2'-(2-ethoxypyridin-3- yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one trifluoroacetate (150 mg, 0.400 mmol, 88%) (Intermediate 10) as a brown gum. The analytical data for Intermediate 10 is in Table 1. Procedure for the preparation of nitriles as exemplified with the preparation of 1-(4-chloro- 3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (Intermediate 14) Intermediate 14 To a stirred solution of piperidine-4-carbonitrile (300 mg, 2.72 mmol) in DMSO (3 mL) were added 4-chloro-2-fluoro-3-iodopyridine (690 mg, 2.68 mmol) followed by DIPEA (1.1 mL, 6.30 mmol) and reaction was heated at 70 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, evaporated, and the crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 50%) to afford 1-(4-chloro-3-iodopyridin-2-yl) piperidine-4- carbonitrile (580 mg, 1.6 mmol, 61%) as a white solid. LCMS: 3.21 min, 348.1 (M+H)+ , Method B To a stirred solution of 1-(4-chloro-3-iodopyridin-2-yl)piperidine-4-carbonitrile (580 mg, 1.669 mmol) in DMF (1 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (390 mg, 2.030 mmol) followed by copper(I) iodide (390 mg, 2.048 mmol) and reaction mixture was heated at 85 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, evaporated, and the crude product was purified by flash column chromatography. The pure fractions were evaporated and dried under a high vacuum to afford 1-(4-chloro-3- (trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (500 mg, 1.6 mmol, 97%) (Intermediate 14) as a yellow liquid. The analytical data for Intermediate 14 is in Table 1. Procedure for the preparation of amines as exemplified with the preparation of 7'-(4-chloro- 2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (Intermediate 15) A stirred solution of benzyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (500 mg, 1.058 mmol) (Intermediate 4) and 1-bromo-4- chloro-2-(trifluoromethyl)benzene (412 mg, 1.587 mmol) in toluene (1 mL) was purged with N2 for 5 min. Cs2CO3 (1034 mg, 3.17 mmol), Pd2(dba)3 (48.4 mg, 0.053 mmol) followed by xantphos (42.9 mg, 0.074 mmol) were added and reaction mixture was stitted at 110 °C for 16 h. The reaction mixture was concentrated to afford crude. The crude was purified by using flash chromatography in 0 to 70% EtOAc in PET ether to afford benzyl 7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1-carboxylate (400 mg, 0.608 mmol, 58%) as an off white solid. Note that migration of the Cbz group was observed. LCMS: 2.89 min, 650.9 (M+H)+, Method B To a stirred solution of benzyl 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'- oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (30 mg, 0.046 mmol) in THF (2 mL) was added BH3.THF (0.184 ml, 0.184 mmol) at 0 °C and reaction mixture was stirred at rt for 4 h. The reaction was quenched by MeOH (10 mL) at 0 °C and concentrated the reaction mixture to afford crude benzyl 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin- 3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (20 mg, 0.031 mmol, 68%) as gummy solid. Crude was as such used for next step. LCMS: 2.56 min, 637.0 (M+H)+, Method A To a stirred solution of benzyl 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (100 mg, 0.157 mmol) in EtOH (1 mL) was added 20% KOH in water (1 mL, 0.157 mmol) and reaction mixture was striired at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM:MeOH (9:1) (20 mL x 2). Combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (50 mg, 0.089 mmol, 57%) (Intermediate 15) as gummy solid. The analytical data for Intermediate 15 is in Table 1. Procedure for the preparation of acids as exemplified with the preparation of 6-propoxy-2- (trifluoromethyl)nicotinic acid (Intermediate 17) To a stirred solution of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (3 g, 12.76 mmol) in DMF (30 mL) were added K2CO3 (2.292 g, 16.58 mmol) followed by 1- bromopropane (1.84 mL, 20.28 mmol) and reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and evaporated to afford crude product. The crude product was purified by flash column chromatography using EtOAc-PET ether (0 to 30%) to afford ethyl 6-propoxy-2-(trifluoromethyl)nicotinate (3.51 g, 12.54 mmol, 98 ) as a colourless. LCMS: 2.0 min, 278.1 (M+H)+, Method B A solution of ethyl 6-propoxy-2-(trifluoromethyl)nicotinate (3.5 g, 12.62 mmol) in THF:MeOH:H2O (15:7.5:0.5 mL) was added LiOH (1.51 g, 63.1 mmol) and reaction mixture was stirred at rt for 16h. The reaction mixture was concentrated and diluted with water (2 mL). The aqueous layer was acidified with 1.5N HCl (1 mL ) and extracted with DCM (5 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford 6-propoxy-2- (trifluoromethyl)nicotinic acid (2.8 g, 11.12 mmol, 88%) (Intermediate 17) as white solid. The analytical data for Intermediate 17 is in Table 1. Procedure for the preparation of lactams as exemplified with the preparation of (Intermediate 20) To a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (300 mg, 0.886 mmol) (Intermediate 10) in DMF (2 ml) were added DIPEA (0.310 ml, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol) and reaction mixture was stirred at 70 °C for 16h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude compound was purified by flash column chromatography to afford 1-(4-chloro- 3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (250 mg, 0.373 mmol, 42 %) (Intermediate 19). To a stirred solution of 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (100 mg, 0.174 mmol) (Intermediate 19) in DMF (3 ml) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (40.0 mg, 0.208 mmol) and copper(I) iodide (39.7 mg, 0.208 mmol) and the reaction mixture was stirred at 60 °C for 16h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). Combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered, and concentrated to afford crude. The crude was purified using prep HPLC. The pure fraction were collected and lyophilized to obtain desired product 1-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)-2'-(2- ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (22 mg, 0.041 mmol, 23%) (Intermediate 20) as off white solid. LCMS: 2.33 min, 518.1 (M+H)+, Method A The analytical data for Intermediate 19 and 20 is in Table 1. Procedure for the preparation of lactams as exemplified with the preparation of tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)- yl)pyrrolidine-1-carboxylate (Intermediate 26) To a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-6'-one (530 mg, 1.24 mmol) (Intermediate 7) in THF (20 mL) was added tert- butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1.31 g, 4.95 mmol) and NaH (247.34 mg, 6.18 mmol, 60% purity) at 25 °C. After heating to 60 °C, the reaction mixture was stirred at 60 °C for 12 hr. After cooling to RT, the reaction mixture was quenched by water (20 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (eluted with PET ether/EtOAc=15/85 to EtOAc/MeOH=95/5, Rf = 0.4) to get tert-butyl 3-(1-benzyl-2'-(2- ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (420 mg, 57%) as a yellow oil. LCMS: 0.69 min, 598.3 (M+H)+, Method O To a solution of tert-butyl 3-(1-benzyl-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (420 mg, 702.64 μmol) in EtOAc (50 mL) was added Pd(OH)2 (400 mg, 569.66 μmol, 20% purity) at 25 °C under hydrogen (15 Psi). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred at 25 °C under hydrogen (15 Psi) for 12 hr, then the mixture was heated to 40 °C and stirred at 40 °C for 2 hr. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue to get tert-butyl 3-(2'-(2- ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (320 mg) (Intermediate 26) as a grey oil, which was used for next step without further purification. The analytical data for Intermediate 26 is in Table 1. Procedure for the preparation of pyridines as exemplified with the preparation of 3,5- dichloro-4-(trifluoromethyl)pyridine (Intermediate 27) To a solution of 3,5-dichloro-4-(trifluoromethyl)pyridine (0.1 g, 463 μmol) in mixture solvents DMSO (0.5 mL) and propyl alcohol (0.5 mL) was added K2CO3 (192 mg, 1.39 mmol) at 25 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 hr. One additional vial was set up as described above. After cooling to RT, all two reaction mixtures were combined, diluted with brine (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC to give 3-chloro-5-propoxy-4-(trifluoromethyl)pyridine (100 mg, 45%) (Intermediate 27) as colourless oil. The analytical data for Intermediate 27 is in Table 1. Procedure for the preparation of nitriles as exemplified with the preparation of 1-(4- propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (Intermediate 29)
To a stirred suspension of NaH (139 mg, 3.47 mmol) in DMF (2 mL) at 0 °C was added propan- 1-ol (153 mg, 2.55 mmol) in DMF (2 mL) and the reaction mixture was stirred at 0 °C for 30 min. 2,4-dichloro-3-(trifluoromethyl)pyridine (500 mg, 2.315 mmol) in DMF (1 mL) was added and the reaction mixture was stirred at RT for 2.5 h. The reaction mixture was quenched cautiously with ice-cold water (20 mL) and extracted with 10% EtOAc in PET ether (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 15%) to afford 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (500 mg, 2.044 mmol, 88%) as a colourless liquid. LCMS: 2.67 min, 239.8 (M+H)+, Method B To a stirred solution of 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (400 mg, 1.669 mmol) in DMSO (4 mL) at RT were added piperidine-4-carbonitrile (221 mg, 2.003 mmol) and K2CO3 (461 mg, 3.34 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography to afford 1-(4-propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidine-4- carbonitrile (310 mg, 0.987 mmol, 59%) (Intermediate 29) as a colourless gum. The analytical data for Intermediate 29 is in Table 1. Procedure for the preparation of nitriles as exemplified with the preparation of 1-(5- (methyl(propyl)amino)-4-(trifluoromethyl)pyridin-3-yl)piperidine-4-carbonitrile (Intermediate 31)
A stirred solution of 3,5-dichloro-4-(trifluoromethyl)pyridine (300 mg, 1.389 mmol) and N- methylpropan-1-amine (508 mg, 6.94 mmol) in NMP (3 mL) was irradiated with MW at 140 °C for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with 20% EtOAc in PET ether (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to afford 5-chloro-N-methyl-N-propyl-4- (trifluoromethyl)pyridin-3-amine (280 mg, 0.499 mmol, 36%) as a yellow gum. LCMS: 2.91 min, 252.9 (M+H)+, Method B A solution of 5-chloro-N-methyl-N-propyl-4-(trifluoromethyl)pyridin-3-amine (350 mg, 1.385 mmol) and piperidine-4-carbonitrile (229 mg, 2.078 mmol) in toluene (8 mL) was degassed with nitrogen for 5 min. Cs2CO3 (903 mg, 2.77 mmol), BINAP (173 mg, 0.277 mmol), and Pd(OAc)2 (31.1 mg, 0.139 mmol) were added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography to afford 1-(5-(methyl(propyl)amino)-4-(trifluoromethyl)pyridin-3-yl)piperidine-4-carbonitrile (270 mg, 0.780 mmol, 56%) (Intermediate 31) as a pale yellow gum. The analytical data for Intermediate 31 is in Table 1. Procedure for the preparation of bromides as exemplified with the preparation of 1-bromo- 3-propoxy-2-(trifluoromethyl)benzene (Intermediate 36) To a stirred solution of 3-bromo-2-(trifluoromethyl)phenol (500 mg, 2.075 mmol) in DMF (10 mL) were added 1-iodopropane (423 mg, 2.490 mmol) and K2CO3 (430 mg, 3.11 mmol). The reaction was heated at 80 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with 20% EtOAc in PET ether (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography to afford 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (380 mg, 1.342 mmol, 65%) (Intermediate 36) as a colourless liquid. The analytical data for Intermediate 36 is in Table 1. Procedure for the preparation of chlorides as exemplified with the preparation of 4-chloro- 2-propoxy-3-(trifluoromethyl) pyridine (Intermediate 40) To a stirred suspension of NaH (222 mg, 5.55 mmol) in THF (2 mL) at 0 °C was added propan-1- ol (364 mg, 6.06 mmol) in THF (1 mL) and the reaction mixture was stirred at RT for 30 min.4- chloro-2-fluoro-3-iodopyridine (1.3 g, 5.05 mmol) in THF (3 mL) was added to the reaction at 0 °C and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched cautiously with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate and purified by flash column chromatography using EtOAc in PET ether (0 to 10%) to afford 4-chloro-3-iodo-2-propoxypyridine (1.49 g, 5.01 mmol, 99%) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 5.6 Hz, 1H), 7.20 (d, J = 5.6 Hz, 1H), 4.26 (t, J = 6.4 Hz, 2H), 1.77 − 1.71 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). To a stirred solution of 4-chloro-3-iodo-2-propoxypyridine (750 mg, 2.52 mmol) in DMF (8 mL) at RT were added copper(I) iodide (720 mg, 3.78 mmol) and Methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (0.48 mL, 3.78 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and purified by flash column chromatography to afford 4-chloro-2-propoxy-3- (trifluoromethyl)pyridine (625 mg, 2.294 mmol, 91%) (Intermediate 40) as a yellow liquid. The analytical data for Intermediate 40 is in Table 1. Procedure for the preparation of chlorides as exemplified with the preparation of rac- (3S,4S)-1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Intermediate 42) To a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (1.28 g, 4.41 mmol) (Intermediate 1) and tert-butyl 4-cyano-3-ethylpiperidine-1-carboxylate (700 mg, 2.94 mmol) in Toluene (5 mL) at RT under nitrogen atmosphere was added KHMDS (1M in THF) (3.52 mL, 3.52 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched cautiously with sat NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). Combined organic extracts were dried over sodium sulfate and purified by flash column chromatography using EtOAc in PET ether (0 to 30%) to afford rac-ethyl 5-((3S,4S)-1-(tert-butoxycarbonyl)-4-cyano-3- ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (2.2 g, 1.644 mmol, 56%) as a brown gum. LCMS: 3.19 min, 509.0 (M+H)+, Method B To a stirred solution of rac-ethyl 5-((3S,4S)-1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)- 2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (2 g, 1.573 mmol) in EtOH (10 mL) and water (2 mL) at RT was added Raney nickel (1.38 g, 15.73 mmol). The reaction mixture was stirred at 65 °C for 24 h under 5 atm of hydrogen atmosphere. Another lot of Raney nickel (1.38 g, 15.73 mmol) was added, and the reaction was stirred at 65 °C for 24 h under 5 atm of hydrogen atmosphere. The reaction mixture was filtered through celite and washed with 10% MeOH in DCM (200 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography using MeOH in DCM (0 to 20%) to afford rac-tert-butyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (650 mg, 1.393 mmol, 89%) as a pale brown gum. LCMS: 2.55 min, 467.1 (M+H)+, Method B To a stirred solution of rac-tert-butyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (650 mg, 1.393 mmol) in DCM (10 mL) at 0 °C was added TFA (1.1 mL, 13.93 mmol). The reaction mixture was stirred at RT for 2 h, then quenched cautiously with 10% NaHCO3 (10 mL) and extracted with 10% MeOH in DCM (3 x 10 mL). Combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, evaporated, and dried under a high vacuum to afford rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl- 6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (500 mg, 1.364 mmol, 98%) (Intermediate 41) as a yellow solid. To a stirred solution of rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (600 mg, 1.637 mmol) in NMP (3 mL) at RT was added 3,5-dichloro-4-(trifluoromethyl)pyridine (884 mg, 4.09 mmol). The reaction mixture was heated in the MW at 140 °C for 1 h. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 100%). The pure fractions were evaporated and dried under a high vacuum to afford 1-(5-chloro-4- (trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-8'-one (310 mg, 0.568 mmol, 35) as a yellow solid. 30 mg of the sample was further purified by prep HPLC (Method B). The prep fractions were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (3 mL), water (3 mL), dried over sodium sulfate, evaporated and lyophilized to afford rac-(3S,4S)-1-(5-chloro-4- (trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-8'-one (8.8 mg) (Intermediate 42) as a white solid. The analytical data for Intermediate 41 and 42 is in Table 1. Procedure for the preparation of anhydrides as exemplified with the preparation of tert- butyl 3-hydroxyazetidine-1-carboxylate (Intermediate 49) To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg, 1.155 mmol) in acetonitrile (6 mL) were added TEA (0.472 ml, 3.46 mmol) followed by bis(2,5-dioxopyrrolidin-1- yl) carbonate (355 mg, 1.386 mmol) at rt and reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduce pressure. The crude was diluted by EtOAc (30 mL) and washed with 10% NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, concentrated and dried under high vacuum to afford tert- butyl 3-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)azetidine-1-carboxylate (300 mg, 0.955 mmol, 83%) (Intermediate 49) as a gum. The analytical data for Intermediate 49 is in Table 1. Procedure for the preparation of amides as exemplified with the preparation of 1-(3- (benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Intermediate 50) A solution of 1-(benzyloxy)-3-bromo-2-(trifluoromethyl) benzene (537 mg, 1.622 mmol) and piperidine-4-carbonitrile (214 mg, 1.946 mmol) in toluene (10 mL) was degassed with nitrogen for 5 min. Cs2CO3 (1.06 g, 3.24 mmol), BINAP (202 mg, 0.324 mmol), and Pd(OAc)2 (37 mg, 0.162 mmol) were added, and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 40%) to afford 1-(3-(benzyloxy)-2-(trifluoromethyl) phenyl) piperidine-4- carbonitrile (483 mg, 1.315 mmol, 81%) as a pale yellow gum. LCMS: 2.85 min, 361.1 (M+H) +, Method B To a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (322 mg, 1.109 mmol) and 1-(3-(benzyloxy)-2-(trifluoromethyl) phenyl) piperidine-4-carbonitrile (480 mg, 1.331 mmol) in toluene (5 mL) at RT was added KHMDS (1M in THF) (1.22 mL, 1.220 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with sat NH4Cl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 10%) to afford ethyl 5-(1-(3-(benzyloxy)-2- (trifluoromethyl) phenyl)-4-cyanopiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (236 mg, 0.374 mmol, 34%) as a pale-yellow gum. LCMS: 3.39 min, 631.2 (M+H) +, Method B To a stirred solution of ethyl 5-(1-(3-(benzyloxy)-2-(trifluoromethyl) phenyl)-4-cyanopiperidin-4- yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (150 mg, 0.238 mmol) in EtOH (6 mL) and THF (1.50 mL) at RT was added cobalt (II) chloride hexahydrate (566 mg, 2.378 mmol). NaBH4 (135 mg, 3.57 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered through celite and washed with 20% MeOH in DCM (2 x 20 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography using MeOH/DCM (0 to 10%) to afford 38 mg of the product.18 mg of the compound was further purified by prep-HPLC. The fractions were lyophilized. The residue was dissolved in DCM (5 mL), washed with 10% NaHCO3 solution (3 mL) and dried over sodium sulfate, evaporated, and lyophilized to afford 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (4.51 mg, 7.64 µmol, 3%) (intermediate 50) as a white solid. The analytical data for Intermediate 50 is in Table 1. Procedure for the preparation of bromides as exemplified with the preparation of 5-bromo- N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (Intermediate 53) To a stirred solution of 2-chloro-6-(trifluoromethyl)pyridine (2.5 g, 13.77 mmol) in DMSO (15 mL) were added N-methylpropan-1-amine (1.511 g, 20.66 mmol) followed by K2CO3 (3.81 g, 27.5 mmol) and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). Combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (2.5 g, 11.46 mmol, 83%) which was used for next step without further purification. LCMS: 2.89 min, 219.2 (M+H)+, Method B To a stirred solution of N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (6 g, 27.5 mmol) in MeOH (50 mL) was added NBS (4.40 g, 24.75 mmol) at 0 °C and reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with pet ether (2 x 10 mL), dried over sodium sulfate and concentrated to get crude product. The crude was purified by flash column chromatography to afford 5-bromo-N-methyl-N-propyl-6- (trifluoromethyl)pyridin-2-amine (5.5 g, 18.51 mmol, 67%) (Intermediate 53) as a colourless liquid. The analytical data for Intermediate 53 is in Table 1. Procedure for the preparation of amines as exemplified with the preparation of 2'-(2- ethoxypyridin-3-yl)-3-ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 57) To stirred solution of tert-butyl rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (1.2 g, 2.57 mmol) (see Intermediate 41 synthesis-Step 2) in THF (8 mL) was added NaH (0.206 g, 5.14 mmol) at 0 °C and reaction was stirred at 0 °C for 20 min followed by 50% Cbz-Cl in toluene (0.439 g, 2.57 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to get the crude purified by flash column chromatography to afford rac-7'-benzyl 1-(tert-butyl) (3S,4S)-2'-(2-ethoxypyridin- 3-yl)-3-ethyl-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (1.3 g, 2.164 mmol, 84%) (Intermediate 55) as a off white solid. To a stirred solution of rac-7'-benzyl 1-(tert-butyl) (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (1.3 g, 2.164 mmol) in THF (10 mL) was added BH3.THF (8.66 mL, 8.66 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. The mixture was quench with MeOH (40 mL) and concentrated under reduced pressure to afford crude, which was purified by flash column chromatography in 0 to 50% EtOAc in PET ether to afford rac-7'-benzyl 1-(tert-butyl) (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (750 mg, 1.278 mmol, 59%) as an off white solid. LCMS: 3.41 min, 587.5 (M+H)+, Method B To a stirred solution of rac-7'-benzyl 1-(tert-butyl) (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (600 mg, 1.023 mmol) in DCM (10 mL) at 0 °C was added TFA (0.079 mL, 1.023 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure, and crude was neutralized with 10% NaHCO3 solution (50 mL x 1) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate and concentrated to get crude rac-benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (300 mg, 0.617 mmol, 60%) (Intermediate 56) as a brown solid. A degassed solution (purged with nitrogen gas for 10 min) of rac-benzyl (3S,4S)-2'-(2- ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (220 mg, 0.452 mmol) and 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (347 mg, 1.356 mmol) in toluene (3 mL) were added sodium tert-butoxide (130 mg, 1.356 mmol), Xanthphos (26.2 mg, 0.045 mmol) followed by Pd2(dba)3 (83 mg, 0.090 mmol) and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was filtered through a celite bed, and bed was washed with EtOAc. The combined filtrate was concentrated and purified by flash column chromatography using 0 to 20% EtOAc in PET ether to afford rac-benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl- 1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)- carboxylate (160 mg, 0.242 mmol, 54%) as an off white solid. LCMS: 8.09 min, 662.3 (M+H)+, Method B To a stirred solution of rac-benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(6-methoxy-2- (trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (30 mg, 0.045 mmol) in DCM (9 ml) was added Et3SiH (0.029 mL, 0.181 mmol), Et3N (0.00338 mL, 0.024 mmol) followed by PdCl2 (4.82 mg, 0.045 mmol) and the reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered through celite, and the celite washed with 10% MeOH in DCM (50 mL). The combined filtrate was concentrated to get crude purified by prep-HPLC. The pure fractions were concentrated, and the residue was neutralized with 10% NaHCO3 solution (20 mL) and extracted with (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and lyophilized to afford rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl- 1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (2.83 mg, 5.36 µmol, 12%) (Intermediate 57) as an off white solid. The analytical data for Intermediate 55, 56 and 57 is in Table 1. Procedure for the preparation of amines as exemplified with the preparation of tert-butyl (3-(2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3- oxopropyl)carbamate (Intermediate 62 and 90) To a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-6'-one (Intermediate 7) (150 mg, 350.04 μmol) in THF (4 mL) was added BH3.THF (1 M, 1.75 mL) at 0 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 2 h. Four additional vials were set up as described above. After cooling to RT, all five reaction mixture were quenched by addition MeOH (4 mL) at 0 °C and the mixture was refluxed at 80 °C for 2 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (EtOAc, Rf = 0) to obtain 1-benzyl-2'-(2- ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (480 mg, 66%) (intermediate 90) as yellow oil. The analytical data for Intermediate 90 is in Table 1. To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (36.51 mg, 192.98 μmol) and bis(2- oxo-3-oxazolidinyl)phosphinic chloride (98.25 mg, 385.97 μmol) in DMF (1 mL) was added N- ethyl-N-isopropylpropan-2-amine (74.83 mg, 578.95 μmol, 100.84 uL) and 1-benzyl-2'-(2- ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (80 mg, 192.98 μmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. Four additional vials were set up as described above. All five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give residue, which was purified by flash column chromatography (eluted with PET ether/ EtOAc=1/0 to 0/1 to EtOAc/MeOH=10/1, Rf = 0.3) to obtain tert-butyl (3-(1-benzyl-2'-(2- ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropyl)carbamate (530 mg, 94%) as yellow oil. LCMS: 0.44 min, 586.4 [M+H]+, Method O’ A mixture of tert-butyl (3-(1-benzyl-2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropyl)carbamate (520 mg, 887.77 μmol) and Pd(OH)2 (520 mg, 3.7 mmol) in EtOAc (10 mL) was degassed and purged with H2 (15 Psi) for 3 times at 25 °C. The reaction mixture was heated to 40 °C and stirred at 40 °C for 12 hrs under H2 (15 Psi). After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (3-(2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)-3-oxopropyl)carbamate (450 mg) (Intermediate 64) as yellow oil, which was used for next step without purification. The analytical data for Intermediate 62 is in Table 1. Procedure for the preparation of 4-chloro-2-fluoro-3-(trifluoromethyl)pyridine (Intermediate 70) To a stirred solution of 2’-(2-ethoxypyridin-3-yl)-3-ethyl-6’,7’-dihydro-8’H-spiro[piperidine-4,5’- [1,7]naphthyridine]-8’-one (150 mg, 0.409 mmol) (Intermediate 41) in 1,4 dioxane (2 mL) at RT were added 4-chloro-2-fluoro-3-(trifluoromethyl)pyridine (98 mg, 0.491 mmol) followed by AcOH (50 mg, 0.819 mmol) and reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, evaporated and purified by flash column chromatography using MeOH in DCM (0 to 10%) to afford 1-(4-chloro-3- (trifluoromethyl)naphthyr-2-yl)-2’-(2-ethoxypyridin-3-yl)-3-ethyl-6’,7’-dihydro-8’H-spiro[piperidine- 4,5’-[1,7]naphthyridine]-8’-one (70 mg).20 mg of the crude product was further purified by Prep HPLC (Method B). The prep fractions were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (3 mL), water (5 mL), dried over sodium sulfate, evaporated and lyophilized to afford 1-(4-chloro-3-(trifluoromethyl)naphthyr-2-yl)-2’-(2- ethoxypyridin-3-yl)-3-ethyl-6’,7’-dihydro-8’H-spiro[piperidine-4,5’-[1,7]naphthyridine]-8’-one (3.90 mg, 7.14 µmol, 2%) (Intermediate 70) as a white solid. The analytical data for 70 is in Table 1. Procedure for the preparation of rac-(3S,4S)-’'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(5-methoxy- 4-(trifluoromethylnaphthyrn-3-yl)-’',’'-dihydro-’'H-spiro[piperidine-4,’'-[1,7naphthyridinen]- ’'-one (Intermediate 71) To a stirred solution of rac-(3S,4S)-1-(5-chloro-4-(trifluoromethylnaphthyrn-3-yl)-’'-(2- ethoxypyridin-3-yl)-3-ethyl-’',’'-dihydro-’'H-spiro[piperidine-4,’'-[1,7naphthyridinen]-’'-one (200 mg, 0.366 mmol) (Intermediate 42) in MeOH (5 mL) was added NaOMe (5 mL, 4.50 mmol) and reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was evaporated and crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%) to afford rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(5-methoxy-4-(trifluoromethyl)pyridin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (180 mg, 0.366 mmol, 54%) (Intermediate 71) as a white solid. The analytical data for Intermediate 71 is in Table 1. Procedure for the preparation of 3-ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3- yl)piperidine-4-carbonitrile (Intermediate 72) The solution of rac-3-ethylpiperidine-4-carbonitrile (0.540 g, 3.91 mmol) in toluene (10 mL) was purged under nitrogen for 10 min and were added BINAP (0.122 g, 0.195 mmol), Pd(OAc)2 (0.088 g, 0.391 mmol), 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (1.0 g, 3.91 mmol) followed by Cs2CO3 (2.55 g, 7.81 mmol) and reaction mixture was stirred at 120 °C for 16 h. Reaction mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate and purified by flash column chromatography using EtOAc in PET-ether (0 to 30%) to afford rac-3-ethyl-1-(6-methoxy- 2-(trifluoromethyl)pyridin-3-yl)piperidine-4-carbonitrile (900 mg, 2.124 mmol, 54%) (Intermediate 72) as a colourless liquid. The analytical data for Intermediate 72 is in Table 1. Procedure for the preparation of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl methanesulfonate (intermediate 74) To a stirred solution of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)MeOH (500 mg, 3.54 mmol) in DCM (5 mL) was added TEA (537 mg, 5.31 mmol) followed by MsCl (527 mg, 4.60 mmol) and reaction mixture was stirred at RT for 5 h. Reaction mixture was diluted with DCM (50 mL) and washed with 10% NaHCO3 (20 mL) followed by water (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methyl methanesulfonate (270 mg) (Intermediate 74) as yellow gum which was used for next step without further purification. The analytical data for Intermediate 74 is in Table 1. Procedure for the preparation of rac-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 79) To a solution of 1-benzyl-3-ethylpiperidine-4-carbonitrile (1 g, 4.38 mmol) and ethyl 2'-ethoxy-5- fluoro-[2,3'-bipyridine]-6-carboxylate (1.15 g, 4.38 mmol) (Intermediate 1) in toluene (20 mL) was added KHMDS (1 M, 13.14 mL) at RT and reaction mixture was stirred at RT for 2 h under N2 atmosphere. Six vials were set up as described above. All seven reaction mixtures were quenched with saturated solution of ammonium chloride (300 mL) at 0 °C and adjusted pH around 5 with formic acid, then extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulphate and purified by flash column chromatography (PET ether/EtOAc= 7:3) to afford rac-ethyl 5-((3S,4S)-1-benzyl-4-cyano-3- ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (3 g, 22%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.33 (dd, J = 1.9, 7.5 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.12 (dd, J = 1.9, 4.8 Hz, 1H), 7.92 - 7.79 (m, 1H), 7.27 - 7.25 (m, 3H), 7.25 - 7.16 (m, 2H), 6.94 (dd, J = 4.9, 7.5 Hz, 1H), 4.51 - 4.39 (m, 4H), 3.64 - 3.56 (m, 1H), 3.52 - 3.44 (m, 1H), 3.14 - 3.05 (m, 1H), 2.84 (br d, J = 12.0 Hz, 1H), 2.45 - 2.26 (m, 3H), 2.21 - 2.14 (m, 1H), 1.62 - 1.41 (m, 1H), 1.37 (dt, J = 1.6, 7.1 Hz, 6H), 1.29 - 1.17 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H) To a solution of rac-ethyl 5-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'- bipyridine]-6-carboxylate (200 mg, 401.11 μmol) in THF (2 mL) was added BH3.THF (1 M, 2.01 mL) at 0 °C under N2 atmosphere and reaction mixture was stirred at 60 °C for 12 h. Fourteen vials were set up as described above. After cooling to RT, fifteen reaction mixtures were quenched by addition MeOH (40 mL) at 0 °C and the reaction mixture was refluxed at 80 °C for 12 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (EtOAc:MeOH (9:1)) to obtain rac-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (650 mg, 24%) (Intermediate 64) as yellow oil. To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (42.75 mg, 225.94 μmol) in DMF (2 mL) was added DIPEA (87.60 mg, 677.82 μmol, 118.06 μL) and bis(2-oxooxazolidin-3- yl)phosphinic chloride (115.04 mg, 451.88 μmol) and stirred at 25 °C for 10 min, the reaction mixture was added rac-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (100 mg, 225.94 μmol) (Intermediate 64) and stirred at 25 °C for 2 h. Five additional vials were set up as described above. All six reaction mixtures were quenched with water (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulphate and purified by prep-TLC (EtOAc/MeOH= 9/1, Rf = 0.60) to get rac-tert-butyl (3-((3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)- 3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropyl)carbamate (500 mg, 60%) as a yellow solid. LCMS: 0.75 min, 614.6 [M+H]+, Method O To a solution of Pd(OH)2 (290.00 mg, 2.07 mmol) in EtOAc (50 mL) was added rac-tert-butyl (3- ((3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)-3-oxopropyl)carbamate (290 mg, 472.48 μmol). After purging with hydrogen for three times, the reaction mixture was stirred at 25 °C for 12 h under hydrogen atmosphere (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get rac-tert-butyl (3-((3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropyl)carbamate (220 mg, crude) (Intermediate 79) as a grey solid, which was used for next step without further purification. The analytical data for Intermediate 64 and intermediate 79 is in Table 1 Procedure for the preparation of tert-butyl (R)-2-(((3RS,4RS)-2'-(2-ethoxypyridin-3-yl)-3- ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1- carboxylate (intermediate 89) A solution of (3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridine] (intermediate 64) (300 mg, 677.82 μmol) and tert-butyl (R)-2- formylpyrrolidine-1-carboxylate (202.58 mg, 1.02 mmol) in MeOH (8 mL) was stirred at RT for 30 mins and NaCNBH3 (170.38 mg, 2.71 mmol) was added at RT and stirred for 12 h. Nine additional vials were set up as described above. All ten reaction mixtures were filtered, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (PET ether/EtOAc= 1/0 to 3/1, Rf = 0.40) to get tert-butyl (R)-2-(((3SR,4SR)-1-benzyl-2'-(2- ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)- yl)methyl)pyrrolidine-1-carboxylate (1.8 g, 42%) as a white solid. LCMS: 1.57 min, 626.3 [M-H]+, Method R’ To a solution of Pd(OH)2 (1.80 g, 2.56 mmol, 20% purity) in EtOAc (180 mL) was added tert-butyl (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.8 g, 2.88 mmol) at RT. After purging with hydrogen (15 Psi) for three times, the reaction mixture was heated to 40 °C and stirred at 40 °C for 12 h under hydrogen gas pressure (15 Psi). After cooling to RT, the reaction mixture was filtered, concentrated under reduced pressure and purified by prep-TLC (EtOAc/MeOH= 1/1, Rf = 0.11) to get tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxypyridin-3-yl)-3- ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.2 g, 78%) (intermediate 89) as a white solid. The analytical data for Intermediate 89 is in Table 1. Procedure for the preparation of rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(5- methoxy-4-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (Intermediate 122) In 10 ml Microwave vial, under nitrogen atmosphere, rac-benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)- 3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (600 mg, 1.23 mmol) (Intermediate 56) and 3,5-dichloro-4-(trifluoromethyl)pyridine (666 mg, 3.08 mmol) in NMP (5 mL) was added DBU (563 mg, 3.70 mmol) and reaction mixture was heated to 140 °C under microwave for 3 h. Reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, concentrated and purified by flash column chromatography using 10-20% of EtOAc in PET ether to afford rac- benzyl (3S,4S)-1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (360 mg, 0.495 mmol, 40%) as a light yellow solid. LCMS: 2.86 min, 666.2 [M+H]+, Method G In 50 ml seal tube, under nitrogen atmosphere, rac-benzyl (3S,4S)-1-(5-chloro-4- (trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (340 mg, 0.510 mmol) in MeOH (10 mL) was added NaOMe (25% in MeOH) (10 mL, 0.510 mmol) under N2 at RT. The reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was evaporated to dryness. The crude product was dissolved in water (30 mL), washed with DCM (2 x 25 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulphate and evaporated to get crude (3S,4S)-2'-(2-ethoxypyridin- 3-yl)-3-ethyl-1-(5-methoxy-4-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (300 mg, 0.081 mmol, 16%) (Intermediate 122) as a light yellow gum which was used for next step without further purification. The analytical data for Intermediate 122 is in Table 1. Procedure for the preparation of (3S,4R)-3-ethylpiperidine-4-carbonitrile (intermediate 94- 1)
A mixture of 1-benzyl-3-ethylpiperidin-4-one (20 g, 92.04 mmol) and (2S,3S)-2,3-bis[(4- methylbenzoyl)oxy]butanedioic acid (36.63 g, 94.80 mmol) in ACN (400 mL) was degassed and purged with nitrogen for 3 times. The reaction mixture was stirred at 40 °C for 5 days under nitrogen atmosphere. After cooling to RT, the reaction mixture was filtered, and the filter cake was dried under reduced pressure to give a residue. A 50 mg sample of the material was crystallised and X-Ray analysis performed. The absolute R configuration of (R)-1-benzyl-3-ethylpiperidin-4- one was confirmed. Details can be found after intermediate Table 1 The resulting residue was diluted with water (200 mL). The reaction mixture was adjusted to pH 10 with NH4OH (30% in water) at 0 °C and extracted with EtOAc (200 mL × 3). The combined organics was washed with brine (300 mL), dried over anhydrous sodium sulphate, filtered, and concentrated to give (R)-1-benzyl-3-ethylpiperidin-4-one (16.5 g) as yellow oil. SFC Method: Rt=1.347 min, 12.71% purity, Rt=1.523 min, 87.29% purity; Column Name: Chiralpak AD-3,150×4.6mm I.D.,3um,; Co-Solvent: 10%; Co-Solvent Name: 0.1% Isopropamide in MeOH; Injected Volume: 3.5 μL; Run time: 5 min. A mixture of (R)-1-benzyl-3-ethylpiperidin-4- one (6.5 g, 29.91 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (7.59 g, 38.89 mmol) in glycol dimethyl ether (130 mL) was added KOtBu (8.39 g, 74.78 mmol) at -20 °C under nitrogen. The reaction mixture was stirred at 25 °C for 12 h, then quenched by addition water (50 mL) at 0 °C, and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulphate and purified by flash column chromatography (PET ether/EtOAc = 9/1, Rf = 0.29 and Rf = 0.41) to get (3S,4R)-1-benzyl-3-ethylpiperidine-4- carbonitrile (2.3 g, 34%) as yellow oil and (3S,4S)-1-benzyl-3-ethylpiperidine-4-carbonitrile (3.8 g, 56%) as yellow solid. (3S,4R)-1-benzyl-3-ethylpiperidine-4-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 7.27 (br s, 5H), 3.53 - 3.44 (m, 1H), 3.41 - 3.31 (m, 1H), 2.89 (br d, J = 9.4 Hz, 1H), 2.76 (br d, J = 10.5 Hz, 1H), 2.10 (dt, J = 3.6, 10.2 Hz, 1H), 1.99 - 1.76 (m, 3H), 1.74 - 1.57 (m, 3H), 1.32 - 1.15 (m, 1H), 0.90 - 0.78 (m, 3H) SFC Method: Rt= 1.312 min, 12.48% purity, Rt=1.426 min, 87.52% purity; Column Name: Chiralpak AD-3, 150×4.6mm I.D., 3um, Co-Solvent: 10%; Co-Solvent Name: 0.1% isopropamide in MeOH; Injected Volume: 1.5 μL; Run time: 5 min (3S,4S)-1-benzyl-3-ethylpiperidine-4-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.15 (m, 5H), 3.58 - 3.33 (m, 2H), 2.88 (br d, J = 2.6 Hz, 1H), 2.79 - 2.56 (m, 2H), 2.22 (br t, J = 10.8 Hz, 1H), 1.96 (br t, J = 9.9 Hz, 1H), 1.91 - 1.83 (m, 1H), 1.82 - 1.71 (m, 1H), 1.64 (br s, 1H), 1.45 - 1.29 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H) SFC Method: Rt = 1.600 min, 15.65% purity, Rt=1.802 min, 84.35% purity; Column Name: Chiralcel OD-3,150×4.6mm I.D., 3um, Co-Solvent: 10%; Co-Solvent Name: isopropanol [0.2% ammonia gas (7M in MeOH)]; Injected Volume: 5.5 μL; Run time: 5 min. A mixture of (3S,4R)-1-benzyl-3-ethylpiperidine-4-carbonitrile (2.3 g, 10.07 mmol) and Pd/C (7.5 g, 10% purity) in EtOAc (200 mL) was degassed and purged with hydrogen for 3 times. The reaction mixture was stirred at 40 °C for 12 h under hydrogen atmosphere (15 Psi). After cooling to RT, the reaction mixture was filtered and filtrate concentrated under reduced pressure to get (3S,4R)-3-ethylpiperidine-4-carbonitrile (800 mg) as yellow oil. The analytical data for Intermediate 94-1 is in Table 1. Procedure for the preparation of tert-butyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6- carboxylate (intermediate 95) To a stirred solution of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (14.5 g, 55.3 mmol) in t-BuOH (200 mL) were added Boc-anhydride (30.2 g, 138 mmol) followed by DMAP (0.676 g, 5.53 mmol) at RT and reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was basified with 10% NaHCO3 followed by water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was, dried over anhydrous sodium sulphate and purified by flash column chromatography using EtOAc in PET ether (0 to 30%) to afford tert-butyl 2'-ethoxy-5- fluoro-[2,3'-bipyridine]-6-carboxylate (14.5 g, 44.6 mmol, 81%) (intermediate 95) as a pale-yellow solid. The analytical data for Intermediate 95 is in Table 1. Procedure for the preparation of (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (intermediate 98) A solution of (3S, 4R)-3-ethylpiperidine-4-carbonitrile (intermediate 98-1) (300 mg, 2.171 mmol) and 1-bromo-2-(trifluoromethyl)benzene (1465 mg, 6.51 mmol) in toluene (20 mL) was degassed with nitrogen for 5 min and BINAP (135 mg, 0.217 mmol), Cs2CO3 (1414 mg, 4.34 mmol) followed by Pd(OAc)2 (48.7 mg, 0.217 mmol) were added. The reaction mixture was heated at 120 °C for 16 h. The reaction mixture filtered through celite bed, filtrate was evaporated, and crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 20%) to afford (3S)- 3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (400 mg, 1.417 mmol, 65%) as a yellow liquid. LCMS: 2.28 min, 283.1 [M+H]+, Method W To a stirred solution of KHMDS (1.612 mL, 1.612 mmol) in THF (20 mL) were added a mixture of (3S)-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (350 mg, 1.240 mmol) and tert- butyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (474 mg, 1.488 mmol) (Intermediate 99) in THF (20 mL) at RT and reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, concentrated and purified by flash column chromatography using EtOAc in PET ether (0 to 90%) to afford tert-butyl 5-((3S,4S)-4- cyano-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (580 mg, 0.861 mmol, 79%) as a yellow gum. LCMS: 2.84 min, 581.3 [M+H]+, Method W To a solution of tert-butyl 5-((3S,4S)-4-cyano-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)- 2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (580 mg, 0.999 mmol) in EtOH (20 mL) was added Raney Ni (876 mg, 9.99 mmol) and reaction mixture was stirred under 5 kg of hydrogen gas pressure at 65 °C for 48 h. Reaction mixture was filtered through celite bed and washed with 10% MeOH in DCM (100 mL). The filtrate was evaporated and purified by flash column chromatography using MeOH in DCM (0 to 4%) as an eluent. The pure fractions were evaporated and dried under high vacuum to afford (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (170 mg, 0.333 mmol, 33%) as a white solid. LCMS: 2.31 min, 511.2 [M+H]+, Method W To a stirred solution of (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (150 mg, 0.294 mmol) in THF (10 mL) was added KOtBu (0.588 mL, 0.588 mmol) at 0 °C and stirred at 0 °C for 15 min. Cbz-Cl (0.063 mL, 0.441 mmol) was added and reaction mixture was stirred at rt for 15 h. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography using EtOAc in PET ether (0 to 50%) to afford get benzyl (3S,4S)- 2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (100 mg, 0.155 mmol, 53%) as a yellow gum. LCMS: 2.71 min, 645.2 [M+H]+, Method W To a stirred solution of benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-1-(2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (100 mg, 0.155 mmol) in THF (5 mL) was added BH3.THF (0.233 mL, 0.233 mmol) at 0°C and stirred at RT for 15 h. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate and purified by flash column chromatography using EtOAc in PET ether (0 to 50%) as to afford get benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl) phenyl)-6'H- spiro[piperidine-4,5'-[1,7] naphthyridine]-7'(8'H)-carboxylate (85 mg, 0.135 mmol, 87%) as a yellow gum. LCMS: 2.91 min, 631.2 [M+H]+, Method W To a solution of benzyl (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (60 mg, 0.095 mmol) in EtOAc (10 mL) was added 10% Pd-C (10.12 mg, 0.095 mmol) and the mixture was stirred under 5 kg of hydrogen gas pressure at 25 °C for 15 h. Reaction mixture was filtered through celite bed and washed with 10% MeOH in DCM (100 mL). The filtrate was evaporated, and purified by flash column chromatography using MeOH in DCM (0 to 4%) to afford (3S,4S)-2'-(2-ethoxypyridin-3- yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 98) (45 mg, 0.091 mmol, 95%) as a white solid. The analytical data for Intermediate 98 is in Table 1. Procedure for the preparation of rac-benzyl (3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (Intermediate 100) To a stirred solution of ethyl 6-(2-ethoxyphenyl)-3-fluoropicolinate (2.91 g, 10.07 mmol) (Intermediate 84) and tert-butyl 4-cyano-3-ethylpiperidine-1-carboxylate (2 g, 8.39 mmol) in toluene (40 mL) was added KHMDS (1.0 M in THF) (8.39 mL, 8.39 mmol) at RT and mixture was stirred at rt for 30 min. Reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and purified by flash column chromatography using 10-20% EtOAc in PET ether to afford cis-racemic ethyl 3-(1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (2.5 g, 4.92 mmol, 59%) as yellow solid. LCMS: 3.15 min, 508.2 [M+H]+, Method B To a stirred solution of cis-racemic tert-butyl-4-cyano-4-(2-(ethoxycarbonyl)-4-(2-ethoxypyridin-3- yl)phenyl)-3-ethylpiperidine-1-carboxylate (2 g, 3.94 mmol) in EtOH (50 mL) and Water (5 mL) was added Raney Ni (4.88 g, 47.3 mmol) at RT and reaction mixture was stirred under 5 Kg of H2 gas pressure at 65 °C for 16 h. Reaction mixture was filtered through celite bed and bed was washed with MeOH (20 mL). Filtrate was concentrated and purified by flash column chromatography in 0 to10% MeOH in DCM to afford cis-racemic of tert-butyl-7-(2-ethoxypyridin- 3-yl)-3'-ethyl-1-oxo-2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidine]-1'-carboxylate (1.3 g, 2.79 mmol, 71%) as a white solid. LCMS: 2.55 min, 466.3 [M+H]+, Method B To a stirred solution of tert-butyl-2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (2 g, 4.30 mmol) in THF (3 mL) was added NaH (0.344 g, 8.59 mmol) at 0 °C and stirred at 0 °C for 30 min. Cbz-Cl (4.40 g, 12.89 mmol) was added and the mixture was stirred at RT for 16 h. Reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 2). Combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and purified by flash column chromatography in 10- 30% EtOAc in PET ether to afford 7'-benzyl 1-(tert-butyl)-2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (2.1 g, 3.50 mmol, 82%) as gummy solid. LCMS: 3.05 min, 600.3 [M+H]+, Method B To a stirred solution of 7'-benzyl 1-(tert-butyl)-2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (2 g, 3.33 mmol) in THF (20 mL) was added BH3.THF (13.34 mL, 13.34 mmol) at 0 °C and mixture stirred at RT for 16 h. Reaction mixture was quenched with MeOH (10 mL) and concentrated under reduced pressure and purified by flash column chromatography using 0 to 50% EtOAc in PET-ether to afford 7'-benzyl 1-(tert- butyl)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)- dicarboxylate (1.2 g, 2.049 mmol, 61%) as an off white solid. LCMS: 3.28 min, 586.3 [M+H]+, Method B To stirred solution of 7'-benzyl 1-(tert-butyl)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (1.2 g, 2.049 mmol) in DCM (10 mL) was added TFA (0.676 mL, 8.77 mmol) at 0 °C and reaction mixture was stirred at RT for 2 h. Reaction mixture was concentrated, was quench with 10% NaHCO3 (20 mL) and extracted with DCM (30 mL x 2). Combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford rac-benzyl (3S,4S)-2'-(2- ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (900 mg, 1.853 mmol, 90%) (intermediate 100) as an off white solid. The analytical data for intermediate 100 is in Table 1. Procedure for the preparation of benzyl 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (Intermediate 102) To a stirred solution of 6-(2-ethoxyphenyl)-3-fluoropicolinic acid (6.5 g, 24.88 mmol) (Intermediate 83) n t-BuOH were added Boc-anhydride (14.44 mL, 62.2 mmol) followed by DMAP (0.304 g, 2.488 mmol) and reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was basified with 10% NaHCO3 diluted with water (10 mL) and extracted with EtOAc (2 x10 mL). The combined organic layer was, dried over anhydrous sodium sulphate, evaporated and purified by flash column chromatography using EtOAc in PET ether (0 to 30%) to afford tert-butyl 6-(2- ethoxyphenyl)-3-fluoropicolinate (6 g, 17.96 mmol, 72%) (intermediate 101) as a pale-yellow solid. To the stirred solution of the KHMDS (16.39 mL, 16.39 mmol were added mixture of tert-butyl 6- (2-ethoxyphenyl)-3-fluoropicolinate (4 g, 12.60 mmol) and tert-butyl 4-cyanopiperidine-1- carboxylate (2.65 g, 12.60 mmol) in THF (30 mL) at RT and stirred at RT for 3 h. The reaction mixture was quenched cautiously with sat. NH4Cl at RT and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulphate and purified by flash column chromatography using EtOAc-PET ether (20 to 50%) to afford tert-butyl 3-(1-(tert- butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (5 g, 9.85 mmol, 52%) as an off white solid. LCMS: 2.55 min, 508.3 [M+H]+, Method G To the stirred solution of the tert-butyl 3-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (7.5 g, 14.77 mmol) in EtOH:water (230:40 mL) was added Raney Ni (12.96 g, 148 mmol) and reaction mixture was stirred at 65 °C and under 6 kg of hydrogen gas pressure for 48 h. The reaction mixture was filtered through celite bed and bed was washed with 10% MeOH and DCM. Filtrate was concentrated under reduced pressure (bath temperature: 42 oC) to afford crude gum which was purified by flash column chromatography using 10% MeOH:DCM to obtain tert-butyl 2'-(2-ethoxyphenyl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1-carboxylate (5.0 g, 10.74 mmol, 73%) as a white solid. LCMS: 1.84 min, 438.2 [M+H]+, Method G To the stirred solution of the tert-butyl 2'-(2-ethoxyphenyl)-8'-oxo-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-1-carboxylate (8 g, 18.28 mmol) in THF (30 mL) at 0 °C were added t-BuOK (4.10 g, 36.6 mmol) followed by benzyl chloroformate (7.77 g, 45.7 mmol) and reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched cautiously with aq. NH4Cl solution (100 mL) at 0 °C and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and purified by flash column chromatography using 15% EtOAc in PET ether to obtain 7'-benzyl 1-(tert-butyl) 2'-(2- ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (8 g, 13.55 mmol, 74%) as a white solid. LCMS: 2.37 min, 572.3 [M+H]+, Method W To a stirred solution of 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (5 g, 8.75 mmol) in THF (25 mL) was added BH3 in THF (30.6 ml, 30.6 mmol) at 0 °C and reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched cautiously with MeOH at 0 °C and evaporated to dryness and purified by flash column chromatography using EtOAc in PET ether (30%) to afford 7'-benzyl 1-(tert-butyl) 2'- (2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (4.2 g, 7.20 mmol, 82%) as an off white solid. LCMS: 2.53 min, 558.3 [M+H]+, Method G To the stirred solution of 7'-benzyl 1-(tert-butyl) 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-1,7'(8'H)-dicarboxylate (6.6 g, 11.83 mmol) in DCM (15 mL) was added TFA (13.49 g, 118 mmol) and reaction mixture was stirred at RT for 16 h. The reaction mixture was concentred, basified with 10% aq. NaHCO3 (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate to afford benzyl 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (4.2 g, 8.70 mmol, 74%) (intermediate 102) as a white solid. The analytical data for intermediate 101 and 102 is in Table 1. Procedure for the preparation rac-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 105) To a degassed solution (purged with nitrogen gas for 10 min) of rac-benzyl (3S,4S)-2'-(2- ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (500 mg, 1.03 mmol) (Intermediate 100) and 1-bromo-3-methoxy-2-(trifluoromethyl)benzene (787.7 mg, 3.09 mmol) in toluene (50 mL) were added NaOtBu (297 mg, 3.09 mmol), Xantphos (119 mg, 0.206 mmol) followed by Pd2(dba)3 (94 mg, 0.103 mmol) and reaction mixture was heated at 120 °C for 16 h. The reaction was filtered through celite bed and filtrate was washed with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, and purified by flash column chromatography in 30-35% of EtOAc in PET ether to afford rac-benzyl (3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (220 mg, 0.333 mmol, 32%) as a white solid. LCMS: 1.99 min, 660.3 [M+H]+, Method G. To a stirred solution of rac-benzyl (3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (220 mg, 0.333 mmol) in DCM (10 mL) were added PdCl2 (59.1 mg, 0.333 mmol), Et3SiH (116 mg, 1.000 mmol) followed by Et3N (67.5 mg, 0.667 mmol) and reaction mixture was stirred at RT for 16 h. The reaction was filtered through celite bed and filtrate was washed with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4and purified by flash column chromatography using 10% MeOH in DCM to afford rac- (3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (60 mg, 0.116 mmol, 34%) (intermediate 105) as a white solid. The analytical data for intermediate 105 is in Table 1. Procedure for the preparation 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 106) A solution of benzyl 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)- carboxylate (2.2 g, 3.94 mmol) and 1-bromo-2-(trifluoromethyl)benzene (1.331 g, 5.91 mmol) in Toluene (20 mL) at RT was degassed under nitrogen atmosphere for 10 min. BINAP (491 mg, 0.789 mmol), Cs2CO3 (2.6 g, 7.89 mmol), followed by Pd(OAc)2 (0.089 g, 0.394 mmol) were added and the reaction mixture was heated at 120 °C for 16 h. The reaction mixture was filtered through celite, washed with EtOAC (2 x 10 mL) and the filtrate was evaporated. The crude product was purified by flash column chromatography using EtOAc in PET ether (0 - 20%) to afford benzyl 2'- (2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]- 7'(8'H)-carboxylate (1.75 g, 2.85 mmol, 72%) as a pale yellow solid. LCMS: 3.43 min, 602.3 [M+H]+, Method B To a stirred solution of benzyl 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (1.7 g, 2.77 mmol) in EtOAc (18 mL) at RT was added 10% Pd/C (2.95 g, 27.7 mmol). The reaction mixture was stirred at RT under 1 atm of hydrogen for 16 h. The reaction mixture was filtered through celite and washed with EtOAc (2 x 10 mL). The filtrate was evaporated to afford 2'-(2-ethoxyphenyl)-1-(2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (1 g, 1.925 mmol, 70%) (intermediate 106) as a pale yellow solid. The analytical data for intermediate 106 is in Table 1. Procedure for the preparation tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 121) To a solution of 1-benzylpiperidine-4-carbonitrile (7.67 g, 38.28 mmol) in toluene (200 mL) was added KHMDS (1 M, 74.90 mL) and 6-(2-ethoxyphenyl)-3-fluoropicolinic acid (intermediate 87) (10 g, 38.28 mmol) at -78 °C under N2. The reaction mixture was warmed to RT and stirred at RT for 2 h under N2. One additional vial was set up as described above. All of two reaction mixtures were quenched by addition saturated solution of ammonium chloride (200 mL) at 0 °C and adjusted pH 4 - 6 with formic acid. The mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 3-(1-benzyl- 4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinic acid (40 g, crude) as a yellow solid, which was used to next step without further purification. LCMS: 0.39 min, 442.3 [M+H]+/ 440.2 [M-H]+, Method N To a solution of 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinic acid (20 g, 45.30 mmol) in DMF (150 mL) was added K2CO3 (18.78 g, 135.89 mmol) and EtI (8.48 g, 54.36 mmol, 4.35 mL) at 0 °C under N2. The reaction mixture was heated to 80 °C for 2 h under N2. One additional vial was set up as described above. After cooling to RT, two reaction mixtures were diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulphate, and purified by flash column chromatography (PET ether/EtOAc=1/0 to 0/1, Rf =0.5) to obtain ethyl 3-(1-benzyl-4- cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (22 g, 52%) as white solid. LCMS: 1.70 min, 470.2 [M+H]+, Method M To a solution of ethyl 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (9 g, 19.17 mmol) in THF (180 mL) was added BH3.THF (1 M, 95.83 mL) at 0 °C under N2. The reaction mixture was stirred at 60 °C for 12 h under N2. One additional vial was set up as described above. After cooling to RT, two reaction mixtures were quenched by addition MeOH (100 mL × 2) at 0 °C. The combined mixture was stirred at 80 °C for 12 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give a residue (18 g as mixture of 1-benzyl-2'-(2- ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] and precursor amide). To reduce the amide in parallel 2 reactions, the residue (9 g) in THF (180 mL) was added BH3.THF (1 M, 105.25 mL) at 0 °C under N2. The reaction mixture was stirred at 60 °C for 2 h under N2. After cooling to RT, two reaction mixtures were quenched by addition MeOH (100 mL × 2) at 0 °C. The combined mixture was stirred at 80 °C for 12 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc/MeOH= 1/0 to 0/1, Rf =0.5) to obtain 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (intermediate 130) (4.2 g, 24%) as white solid. To a solution of 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (200 mg, 483.61 μmol) and tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (192.72 mg, 967.23 μmol) in MeOH (3 mL) was added NaCNBH3 (91.17 mg, 1.45 mmol) at RT. The reaction mixture was stirred at RT for 12. Four additional vials were set up as described above. Five reaction mixtures were concentrated under reduced pressure, and then diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and purified by flash column chromatography (PET ether/EtOAc= 1/0 to 0/1, Rf =0.5) to obtain tert-butyl (R)-2-((1-benzyl-2'- (2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1- carboxylate (Intermediate 134) (1 g, 69%) as a colourless oil. A mixture of tert-butyl (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (300 mg, 502.68 μmol) (Intermediate 138) and 10% Pd/C (1.5 g, 1.41 mmol, 10% purity) in EtOAc (50 mL) was degassed and purged with H2 (15 Psi) for 3 times at RT. The reaction mixture was stirred at 50 °C for 12 h under H2 (15 Psi). One additional vial was set up as described above. After cooling to RT, two reaction mixtures were filtered and purified by prep-TLC (EtOAc/MeOH=1/1, Rf =0.2) to obtain tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)- yl)methyl)pyrrolidine-1-carboxylate (Intermediate 121) (220 mg, 43%) as white solid. The analytical data for intermediate 130, 134 and 121 is in Table 1. Procedure for the preparation tert-butyl (R)-2-((2'-(2-(ethoxy-d5)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 135) To a solution of tert-butyl (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 138) (500 mg, 837.80 μmol) in DCM (10 mL) was added BBr3 (2 M in DCM, 2.09 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Five additional vials were set up as described above. After warming to RT, all six reaction mixtures were quenched with ice water (10 mL) and extracted with DCM (10 mL × 3). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and purified by prep-HPLC method L to obtain (R)-2-(1-benzyl-7'-(pyrrolidin-2- ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-2'-yl)phenol (1 g, 42%) as a yellow solid. LCMS: 1.91 min, 469.2 [M+H]+, Method O To a solution of (R)-2-(1-benzyl-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-2'-yl)phenol (200 mg, 426.77 μmol) in DCM (5 mL) was added Et3N(129.56 mg, 1.28 mmol) and Boc2O (93.14 mg, 426.77 μmol) at 25 °C under nitrogen. The reaction mixture was stirred at 25 °C for 12 h. Four additional vials were set up as described above. All five reaction mixtures were quenched by addition ice water (40 mL) and then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and purified by prep TLC (PET ether/EtOAc=1/1, Rf = 0.75) to obtain tert-butyl (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)- yl)methyl)pyrrolidine-1-carboxylate ((950 mg, 78%) as a yellow solid. LCMS: 0.41 min, 569.3 [M+H]+, Method C To a solution of tert-butyl (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 175.83 μmol) in THF (1.5 mL) was added potassium 2-methylpropan-2-olate (39.46 mg, 351.65 μmol), 1,4,7,10,13,16- hexaoxacyclooctadecane (92.95 mg, 351.65 μmol), and 1-iodoethane-1,1,2,2,2-d5 (33.97 mg, 210.99 μmol) at 25 °C under nitrogen. The reaction mixture was stirred at 60 °C for 1 h under nitrogen atmosphere. Eight additional vials were set up as described above. After cooling to RT, all nine reaction mixtures were quenched by addition water (20 mL) and extracted with EtOAc (6 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulphate and purified by flash column chromatography (PET ether/EtOAc =99/11 to 70/30, Rf = 0.5) to obtain tert-butyl (R)-2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (800 mg, 84%) as a white solid. LCMS: 0.41 min, 602.5 [M+H]+, Method C To a solution of tert-butyl (R)-2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (200 mg, 332.32 μmol) in EtOAc (120 mL) was added Pd(OH)2 (700.04 mg, 20% purity) at 25 °C under nitrogen atmosphere. The reaction mixture was degassed and purged with hydrogen three times. The reaction mixture was stirred at 50 °C for 2 h under hydrogen atmosphere (15 psi). Three additional vials were set up as described above. After cooling to RT, all four reaction mixtures were filtered and concentrated under reduced pressure to give tert-butyl (R)-2-((2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (360 mg, 53%) as a white solid. The analytical data for intermediate 135 is in Table 1. Procedure for the preparation tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 138) To a solution of 1-benzyl-3-ethylpiperidine-4-carbonitrile (5g, 21.90 mmol) and 6-(2- ethoxyphenyl)-3-fluoropicolinic acid (intermediate 87) (5.72 g, 21.90 mmol) in toluene (150 mL) was added KHMDS (1 M, 65.69 mL) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. Four vials were set up as described above. Five reaction mixtures were quenched by addition of saturated NH4Cl solution (300 mL) at 0 °C and adjusted to pH 4 - 6 with formic acid, then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain rac-3-((3S,4S)-1-benzyl-4-cyano-3- ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)picolinic acid (50 g) as a yellow oil, which was used to next step without further purification. LCMS: 0.76 min, 468.1 [M-H]+, Method R’ To a solution of rac-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinic acid (10 g, 21.30 mmol) in DMF (200 mL) was added K2CO3 (8.83 g, 63.89 mmol) and EtI (3.99 g, 25.56 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. Four vials were set up as described above. After cooling to RT, five reaction mixtures were quenched by addition water (500 mL) at 0 °C and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulphate, filtered and purified by flash column chromatography (PET ether/EtOAc= 1/0 to 8/1, Rf = 0.55) to afford rac-ethyl 3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (32 g, 60%) as yellow oil. LCMS: 1.78 min, 498.3 [M+H]+, Method C To a solution of rac-ethyl 3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (5 g, 10.05 mmol) in THF (150 mL) was added BH3.THF (1 M, 50.24 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 12 h. After cooling to RT, reaction mixture was quenched with MeOH (100 mL) at 0 °C and stirred at 80 °C for further 12 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (PET ether/EtOAc= 1/0 to EtOAc/MeOH= 8/1, Rf = 0.40) to obtain rac-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (1.2 g, 12%) (intermediate 136) as a white solid. To a solution of rac-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (230 mg, 520.83 μmol) in MeOH (5 mL) was added tert- butyl (R)-2-formylpyrrolidine-1-carboxylate (207.55 mg, 1.04 mmol) and NaCNBH3 (130.92 mg, 2.08 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. Four vials were set up as described above. All five reaction mixtures were filtered and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (PET ether/EtOAc =1/0 to 5/1, Rf = 0.40) to obtain tert-butyl (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (intermediate 137) (800 mg, 49%) as yellow oil. A mixture of tert-butyl (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (intermediate 141) (800 mg, 1.28 mmol) and Pd(OH)2 (800 mg, 5.70 mmol) in EtOAc (20 mL) was degassed and purged with hydrogen (15 Psi) for 3 times at 25 °C. The reaction mixture was stirred at 50 °C for 12 h under hydrogen (15 psi). After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash column chromatography (eluted with PET ether/EtOAc= 1/0 to EtOAc/MeOHMeOH= 4/1, Rf = 0.20) to obtain tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)- 3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (600 mg, yield 88%) (intermediate 138) as white solid. The analytical data for intermediate 136, 137 and 138 is in Table 1. Procedure for the preparation tert-butyl (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1- carboxylate (intermediate 139) To a solution of (2R,4S)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (178.04 mg, 769.92 μmol) in DMF (7 mL) were added HATU (439.12 mg, 1.15 mmol), DIPEA (298.52 mg, 2.31 mmol) followed by rac-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (340 mg, 769.92 μmol) (Intermediate 136) at RT and reaction mixture was stirred at RT for 1 h. Four additional vials were set up as described above. All five reaction mixtures were combined, diluted with water (120 mL) and extracted with DCM (3 × 30 mL). The combined organics were washed with brine (120 mL) and dried over sodium sulfate and purified by flash column chromatography (PET ether/EtOAc = 50/50 to 10/90, Rf = 0.3) to get tert-butyl (2R,4S)-2-((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (2.2 g, 87%) as a yellow oil. LCMS: 0.44 min, 655.3 (M+H)+, Method C To a solution of tert-butyl (2R,4S)-2-((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'-carbonyl)-4-hydroxypyrrolidine-1- carboxylate (200 mg, 305.42 μmol) in THF (4 mL) was added a solution of BH3.THF (1 M, 3.05 mL) dropwise at 0 °C. After warming to RT, the reaction mixture was stirred at 60 °C for 30 min. Five additional vials were set up as described above. After cooling to 0 °C, the reaction mixture was quenched with MeOH (1 mL). All six mixtures were combined and stirred at 60 °C for 1 h. After cooling to RT, the mixture was concentrated under reduced pressure and purified by flash column chromatography (PET ether/EtOAc= 50/50 to 0 /100, Rf = 0.29) to get tert-butyl (2R,4S)- 2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (1.2 g, 100%) as a yellow oil. LCMS: 0.40 min, 641.6 (M+H)+, Method C To a suspension of Pd (OH)2/C (1.02 g, 1.46 mmol, 20% purity) in EtOAc (20 mL) was added a solution of tert-butyl (2R,4S)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (550 mg, 858.23 μmol) in EtOAc (200 mL) at 25 °C under nitrogen. The suspension was degassed and purged with hydrogen for 3 times. The reaction mixture was stirred at 50 °C for 3 h under hydrogen (15 Psi). One additional vial was set up as described above. After cooling to 25 °C, all two reaction mixtures were combined and filtered, the filtrate was concentrated under reduced pressure to get tert-butyl (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (600 mg, crude) (Intermediate 139) as a yellow solid, which was used to next step without further purification. The analytical data for intermediate 139 is in Table 1.
X-ray crystallographic analysis of (R)-1-benzyl-3-ethylpiperidin-4-one complex with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid X-ray crystal analysis was performed to determine the absolute configuration of (R)-1-benzyl-3- ethylpiperidin-4-one as described below. Summary of Results: The crystal was a colourless block with the following dimensions: 0.20 × 0.20 × 0.03 mm3. The symmetry of the crystal structure was assigned the triclinic space group P1 with the following parameters: a = 7.45200(10) Å, b = 8.45670(10) Å, c = 12.9162(2) Å, α = 85.7960(10)°, β = 89.6090(10)°, γ = 84.8360(10)°, V = 808.485(19) Å3 , Z = 1, Dc = 1.240 g/cm3 , F(000) = 320.0, μ(CuKα) = 0.741 mm-1 , and T = 300.15 K. The absolute configuration structure and ORTEP structure are as follows: Description of Equipment and Data Collection: Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector Cryogenic system: Oxford Cryostream 800 Cu: λ=1.54184 Å, 50W Distance from the crystal to the CCD detector: d = 35 mm Tube Voltage: 50 kV; Tube Current: 1 mA A total of 45334 reflections were collected in the 2θ range from 6.862 to 133.164. The limiting indices were: -8 ≤ h ≤ 8, -10 ≤ k ≤ 9, -15 ≤ l ≤ 15; which yielded 5552 unique reflections (Rint = 0.0506). The structure was solved using SHELXT (Sheldrick, G. M.2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F²) (Sheldrick, G. M.2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 389, compared with 5552 data. All reflections were included in the refinement. The goodness of fit on F² was 1.051 with a final R value for [I >= 2σ (I)] R1 = 0.0458 and wR2 = 0.1282. The largest differential peak and hole were 0.27 and -0.20 Å-3. Description of Crystal Preparation: 50mg (R)-1-benzyl-3-ethylpiperidin-4-one complex with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid complex was dissolved in 1mL MeOH and kept in a 4mL vial. The solution evaporates slowly at room temperature. Crystals were observed on the second day. Synthesis of Examples: Route A Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- [4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (Example 1) To a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (50 mg, 0.26 mmol) (Intermediate 10) in DMF (5 mL) under nitrogen at 0°C was added DIPEA (0.1 mL, 0.66 mmol) and HATU (127 mg, 0.33 mmol). The reaction mixture was stirred for 10 min and then added 4-chloro-2-(trifluoromethyl)benzoic acid (80 mg, 0.22 mmol). The reaction mixture was stirred at 25-30°C for 16h. The reaction was quenched with ice- cold water (10 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over Na2SO4 and concentrated to get crude (100 mg) as brown sticky compound which shows 20% of desired product. The crude product was further purified by prep HPLC, followed by lyophilization to afford 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (10 mg, 8%) (Example 1) as light pink solid. Analytical data for Example 1 is in Table 2. Route B Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- [4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (Example 2) To a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (100 mg, 0.344 mmol) (Intermediate 1) and 1-(4-chloro-2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (149 mg, 0.517 mmol) (Intermediate 6) in Toluene (5 mL) at RT was added KHMDS (1M in THF) (0.5 mL, 0.500 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched cautiously with Sat NH4Cl (2 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography using EtOAc-PET ether (0 to 10%) to afford ethyl 5-(1-(4-chloro- 2-(trifluoromethyl)phenyl)-4-cyanopiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (20 mg, 0.031 mmol, 8.9%) as a colourless gum. LCMS: 2.94 min, 559.2 (M+H)+, Method A To a stirred solution of ethyl 5-(1-(4-chloro-2-(trifluoromethyl)phenyl)-4-cyanopiperidin-4-yl)-2'- ethoxy-[2,3'-bipyridine]-6-carboxylate (100 mg, 0.179 mmol) in Ethanol (1 mL) and Water (0.2 mL) at RT was added Raney nickel (188 mg, 2.147 mmol). The reaction mixture was stirred at 65 °C under 75 psi of hydrogen pressure for 24 h. The reaction mixture was filtered through celite and washed with MeOH (20 mL). The filtrate was evaporated, and the crude was purified by prep HPLC. The pure fractions were lyophilized. The residue was dissolved in DCM (20 mL), washed with 10% NaHCO3 (3 mL), brine (3 mL), dried over sodium sulfate, evaporated and lyophilized to afford 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (40 mg, 0.077 mmol, 43%) (Example 2) as a white solid. Analytical data for Example 2 is in Table 3. Route C Typical procedure for the preparation of lactams as exemplified by the preparation of 3-[1'- [4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-8-oxospiro[6H-1,7- naphthyridine-5,4'-piperidine]-7-yl]propenamide (Example 4) To a stirred solution of 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (20 mg, 0.039 mmol) (Example 2) in DMF (1 mL) at 0 °C was added NaH (2.3 mg, 0.058 mmol) and stirred at RT for 30 min. 3- chloropropanamide (4.99 mg, 0.046 mmol) in DMF (1 mL) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was diluted with ice water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by prep HPLC and the fractions were lyophilized. The residue was dissolved in DCM (20 mL), washed with 10% NaHCO3 (5 mL), water (5 mL), brine (5 mL), dried over sodium sulfate, evaporated and lyophilized to afford 3-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)propanamide as a white solid (8.3 mg, 0.014 mmol, 36%) (Example 4). Analytical data for Example 4 is in Table 4. Route D Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- [4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-6-one (Example 5)
To a solution of 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 6'-one (5 mg, 14.78 μmol) (Intermediate 8) and 1-bromo-4-chloro-2-(trifluoromethyl)benzene (4.60 mg, 17.74 μmol, 2.61 uL) in dioxane (0.2 mL) was added sodiumtert-butoxide (7.10 mg, 73.90 μmol), methanesulfonato[2,2-bis(diphenylphosphino)-1,1-binaphthyl](2-amino-1,1- biphenyl-2-yl) palladium(II) (2.93 mg, 2.96 μmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′- binaphthalene (1.84 mg, 2.96 μmol) at 25 °C under nitrogen. The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 hr. Three additional vials were set up as described above. After cooling to RT, all of four reaction mixtures were combined, filtered and the filtrate was concentrated under reduced pressure to get a crude, which was purity by prep-TLC (EtOAc/MeOH= 10/1, Rf = 0.57, Rf = 0.00) to get two peaks. Two peaks were purified by prep- HPLC to get 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7- naphthyridine-5,4'-piperidine]-6-one (2.7 mg, 12%) (Example 5) as a white solid. Analytical data for Example 5 is in Table 5. Route E Typical procedure for the preparation of amines as exemplified with the preparation of 1'- [4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7- naphthyridine-5,4'-piperidine] (Example 6) To a stirred solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7- dihydro-1,7-naphthyridine-5,4'-piperidine]-8-one (20 mg, 0.039 mmol) (Example 2) in THF (1 mL) was added borane THF complex (0.077 mL, 0.077 mmol) at 0 °C and stirred reaction mixture for 3 h at RT. The reaction mixture was quenched with MeOH (10 mL), stirred for 16 h at RT and concentrated under reduced pressure to afford crude. The crude was purified by prep HPLC and the fractions were lyophilized to afford 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin- 3-yl)spiro[7,8-dihydro-6H-1,7-naphthyridine-5,4'-piperidine] (2.1 mg, 0.004 mmol, 11%) (Example 6) as white solid. Analytical data for Example 6 is in Table 6. Route F Typical procedure for the preparation of lactams as exemplified with the preparation of 1'- [3-chloro-2-(trifluoromethyl)phenyl]-7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2- ethoxypyridin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (Example 9) A solution of 1-bromo-4-chloro-2-(trifluoromethyl)benzene (115 mg, 0.443 mmol) and 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (100 mg, 0.295 mmol) (Intermediate 10) in toluene (2 mL) was degassed with nitrogen for 5 min. Cs2CO3 (193 mg, 0.591 mmol), xantphos (11.97 mg, 0.021 mmol) and Pd2(dba)3 (13.53 mg, 0.015 mmol) were added and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated and the crude product was purified by prep HPLC (Method B). The fractions were lyophilized. The residue was basified with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized to afford 7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (20 mg, 0.04 mmol, 14%) as a white solid. LCMS: 1.51 min, 517.2 (M+H)+, Method A A solution of 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (20 mg, 0.039 mmol) and 1-bromo-3-chloro-2- (trifluoromethyl)benzene (15.1 mg, 0.058 mmol) in toluene (2 mL) was degassed with nitrogen for 5 min. Cs2CO3 (25.2 mg, 0.077 mmol), xantphos (1.6 mg, 2.71 µmol) and Pd2(dba)3 (1.8 mg, 1.934 µmol) were added and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated and the crude product was purified by prep HPLC. The fractions were lyophilized. The residue was basified with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized to afford 1'-[3-chloro-2- (trifluoromethyl)phenyl]-7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H- 1,7-naphthyridine-5,4'-piperidine]-8-one (4.86 mg, 6.92 µmol, 18%) (Example 9) as an off white solid. Analytical data for Example 9 is in Table 7. Route G Typical procedure for the preparation of amines as exemplified with the preparation of 1'- [3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one (Example 15) To a stirred solution of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (20 mg, 0.039 mmol) (Example 3) in DMSO (1 ml) were added NaH (3.09 mg, 0.077 mmol) at rt and tert-butyl 3-iodopyrrolidine-1- carboxylate (22.99 mg, 0.077 mmol). The reaction mixture was stirred at RT for 16 h, quenched with ice cold water (20 mL) and extracted with EtOAc (3 x 20 mL). Combined organic extracts were washed with brine solution (10 mL), dried over sodium sulfate and evaporated to afford crude product tert-butyl 3-(1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate as red gummy liquid (24 mg, 0.035 mmol, 35%). LCMS: 3.90 min, 686.3 (M+H)+, Method B To a stirred solution of tert-butyl 3-(1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3- yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (20 mg, 0.029 mmol) in DCM (3 ml). Then added phosphoric acid (14.28 mg, 0.146 mmol) at rt. Reaction mixture was stirred at rt for 16h. The DCM layer was decanted, and the residue was washed with DCM (2 x 10 mL). The crude residue was added 10% NaHCO3 solution and adjusted to pH ~ 8. The aqueous layer was decanted, triturated with water (2 x 10 mL), decanted and lyophilized to afford as yellow solid. Crude reaction mass was purified by prep HPLC. Sample was lyophilized to afford product 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3- ylspiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (1.03 mg, 0.0017 mmol) (Example 15) as a white solid. Analytical data for Example 15 is in Table 8. Route H Typical procedure for the preparation of amines as exemplified by the preparation of 2- amino-1-[7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-1'-yl]ethenone (Example 21) To a stirred solution of 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (20 mg, 0.040 mmol) (Example 15) in DMF (1 mL) was added DIPEA (0.01042 mL, 0.060 mmol) followed by 2,5-dioxopyrrolidin-1-yl (tert- butoxycarbonyl)glycinate (16.24 mg, 0.060 mmol) at rt and reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 2/3). Combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude tert-butyl (2-(7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)-2-oxoethyl)carbamate (20 mg, 0.029 mmol, 74%) as gummy solid which was used for next step without further purification. LCMS: 3.25 min, 660.0 (M+H)+, Method B To stirred solution of tert-butyl (2-(7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)-2-oxoethyl)carbamate (20 mg, 0.030 mmol) in DCM (1 mL) was added TFA (0.117 mL, 1.515 mmol) at 0 °C and reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under vacuum and purified by prep HPLC. The pure fractions were lyophilized to afford 2-amino-1-(7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)ethan-1-one (4.25 mg, 7.51 µmol, 25%) (Example 21) as white solid. Analytical data for Example 21 is in Table 9. Route I Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- (4-chloro-3-iodopyridin-2-yl)-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthyridine- 5,4'-piperidine]-8-one (Example 22) To a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (300 mg, 0.886 mmol) (Intermediate 10) in DMF (2 ml) were added DIPEA (0.310 ml, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol) and reaction mixture was stirred at 70 °C for 16h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude compound was purified by Biotage-Isolera using 25g silica gel cartridge and eluted with 0 to10% MeOH in DCM. Pure fractions were concentrated under reduced pressure to afford 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine- 4,5'-[1,7]naphthyridin]-8'-one (250 mg, 0.373 mmol, 42%). The pure product (15 mg) was purified by prep HPLC. The fraction was collected and lyophilized to obtain 1-(4-chloro-3-iodopyridin-2- yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one) (4.2 mg) (Example 22) as off white solid. Analytical data for Example 22 is in Table 10. Route J Typical procedure for the preparation of amides as exemplified by the preparation of [2-(2- ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthyridine-5,4'-piperidine]-1'-yl]-[6- propoxy-2-(trifluoromethyl)pyridin-3-yl]methanone (Example 24) To a stirred solution of benzyl 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine]-7'(8'H)-carboxylate (200 mg, 0.436 mmol) (Intermediate 5) in DMF (5 mL) were added DIPEA (282 mg, 2.181 mmol), 6-propoxy-2-(trifluoromethyl)nicotinic acid (130 mg, 0.523 mmol) (Intermediate 17) followed by HATU (249 mg, 0.654 mmol) at RT and reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). Combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by flash silica column chromatography in 40 to 60% EtOAc in PET ether to afford benzyl 2'-(2-ethoxypyridin-3-yl)-1-(6-propoxy-2-(trifluoromethyl)nicotinoyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (140 mg, 0.151 mmol, 35%) as a brown color gummy. LCMS: 3.97 min, 690.3 (M+H)+, Method B To a stirred solution of benzyl 2'-(2-ethoxypyridin-3-yl)-1-(6-propoxy-2-(trifluoromethyl)nicotinoyl)- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (50 mg, 0.072 mmol) in EtOH (2 mL) was added 20% KOH in H2O (40.7 mg, 0.145 mmol) and reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to get crude. The crude was purified by prep HPLC. Fractions were collected and lyophilized to obtain (2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)(6-propoxy-2-(trifluoromethyl)pyridin-3- yl)methanone (20 mg, 0.035 mmol, 49%) (Example 24) as an off white solid. Analytical data for Example 24 is in Table 11. Route K Typical procedure for the preparation of amides as exemplified by the preparation of [2-(2- ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'- yl]-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methanone (Example 29) To a stirred solution of (2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)methanone (50 mg, 0.095 mmol) (Intermediate 21) in ethanol (5 mL) were added tert-butyl 3-oxopyrrolidine-1-carboxylate (35.1 mg, 0.190 mmol), titanium(IV) isopropoxide (26.9 mg, 0.095 mmol) followed by sodium cyanoborohydride (11.91 mg, 0.190 mmol) at 0 °C and reaction was allowed stir at rt for 16 h. The reaction mixture was precipitated using ACN (20 mL) and precipitate filtered off. Solid was washed with ACN (20 mL) and combined filtrate was collected and concentrated to get tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)nicotinoyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (50 mg, 0.030 mmol, 32%) as brown gum. LCMS: 3.16 min, 697.1 (M+H)+, Method B To a stirred solution of tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2- (trifluoromethyl)nicotinoyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (50 mg, 0.072 mmol) in DCM (2 mL) was added TFA (8.18 mg, 0.072 mmol) at 0 °C and reaction was allowed to stir at rt for 3 h. The reaction mixture was concentrated to get crude. Crude product was purified by prep HPLC. Fractions were collected and lyophilized. The resulting gum was dissolved in DCM (5 mL) and washed with 10% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to get colourless gum which was re-dissolve in ACN:water (1:3) and lyophilized to obtain rac-(2'-(2-ethoxypyridin-3-yl)- 7'-(pyrrolidin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)(6-methoxy-2- (trifluoromethyl)pyridin-3-yl)methanone (1.34 mg, 2.100 µmol, 3%) (Example 29) as an off white solid. Analytical data for Example 29 is in Table 12. Route L Typical procedure for the preparation of amines as exemplified by the preparation of 2-(2- ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[7,8-dihydro-6H-1,7- naphthyridine-5,4'-piperidine] (Example 30) A solution of benzyl 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)- carboxylate (100 mg, 0.218 mmol) (Intermediate 5) in toluene (2 mL) was purged with N2 gas for 5 min. 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (223 mg, 0.872 mmol), Cs2CO3 (142 mg, 0.436 mmol), xantphos (12.6 mg, 0.022 mmol) and Pd2(dba)3 (20 mg, 0.022 mmol) were added to the reaction mixture and heated at 100 °C for 16 h. The reaction mixture was evaporated and the crude product was purified by silica flash column chromatography using EtOAc in PET ether (0 to 35%) to afford benzyl 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (145 mg, 0.151 mmol, 69%) as a orange gum. LCMS: 3.72 min, 634.0 (M+H)+, Method B To a stirred solution of benzyl 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3- yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (120 mg, 0.189 mmol) in MeOH (2 mL) at RT was added 20% KOH in water (0.05 mL, 0.379 mmol) and the reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by prep HPLC. The fractions were lyophilized. The residue was basified with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized to afford 2'-(2-ethoxypyridin-3-yl)-1- (6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (16.93 mg, 0.031 mmol, 16%) (Example 30) as a white solid. Analytical data for Example 30 is in Table 13. Route M Typical procedure for the preparation of lactams as exemplified by the preparation of (S)- 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (Example 34). To a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-6-one (35 mg, 67.71 μmol) (Example 5) and tert-butyl (R)-3- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (71.86 mg, 270.82 μmol) in THF (2 mL) was added NaH (13.54 mg, 338.53 μmol, 60% purity) at 0 °C under nitrogen. The reaction mixture was heated to 60 °C and stirred at 60 °C for 5 hr. After cooling to 0 °C, the reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure to get a crude, which was purified by prep-TLC (PET ether/EtOAc= 2/1, Rf = 0.2) to get tert-butyl (S)-3-(1-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (25 mg, 53%) as a yellow oil. LCMS: 1.16 min, 686.3 (M+H)+, Method O A solution of tert-butyl (S)-3-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'- oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (22.00 mg, 32.06 μmol) in formic acid (0.5 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to get a crude, which was purified by prep-HPLC to get (S)- 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (9.3 mg, 49%) (Example 34) as a yellow oil. Analytical data for Example 34 is in Table 14. Route N Typical procedure for the preparation of lactams as exemplified by the preparation of rac- (3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Example 36) and rac-(3S,4S)- 2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Example 42) A solution of 1-bromo-4-chloro-2-(trifluoromethyl)benzene (500 mg, 1.927 mmol) and 3- ethylpiperidine-4-carbonitrile (400 mg, 2.89 mmol) in toluene (8 mL) was degassed with nitrogen for 5 min. Cs2CO3 (1.3 g, 3.85 mmol), BINAP (240 mg, 0.385 mmol), and Pd(OAc)2 (44 mg, 0.194 mmol) were added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 10%) to afford 1-(4-chloro-2-(trifluoromethyl)phenyl)-3-ethylpiperidine-4- carbonitrile (510 mg, 1.608 mmol, 83%) as a colourless gum. LCMS: 3.11 min, 317.0 (M+H)+, Method B To a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (470 mg, 1.619 mmol) (Intermediate 1) and 1-(4-chloro-2-(trifluoromethyl)phenyl)-3-ethylpiperidine-4-carbonitrile (513 mg, 1.619 mmol) in toluene (8 mL) at RT was added KHMDS (0.5 M in Toluene) (3.24 mL, 1.619 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with sat NH4Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 10%) to afford rac-ethyl 5-((3S,4S)-1-(4- chloro-2-(trifluoromethyl)phenyl)-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6- carboxylate (400 mg, 0.326 mmol, 20%) as a pale yellow gum. LCMS: 3.70 min, 587.0 (M+H)+, Method B To a stirred solution of rac-ethyl 5-((3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-4-cyano-3- ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (400 mg, 0.681 mmol) in EtOH (9 mL) and water (1 mL) was added Raney nickel (1 g, 11.40 mmol). The reaction mixture was stirred under 5 atm of H2 atmosphere at 65 °C for 16 h. As per LCMS, two compounds were observed. The reaction mixture was filtered through celite and washed with EtOAc (200 mL). The filtrate was evaporated, and the crude product was purified by preparative purification to yield two products. The pure fractions corresponding to rac-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2- (trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, evaporated and lyophilized to afford rac- (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (40 mg, 0.076 mmol, 37%) (Example 42) as a white solid. The pure fractions corresponding to rac-(3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2- ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (Example 36) were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, evaporated and lyophilized to afford rac-(3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-3- ethyl-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (3.24 mg, 5.79 µmol, 1%) (Example 36) as a white solid. Analytical data for Example 36 and Example 42 is in Table 15. Route O Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- [3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazetidin-3- yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (Example 38) and 1'-[3-chloro- 2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazetidin-3- yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (Example 43) To a stirred solution of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (50 mg, 0.097 mmol) (Example 3) in DMF (1 mL) was added NaH (7.74 mg, 0.193 mmol) at 0 °C and reaction mixture was stirred for 30 min. tert-butyl 3-(bromomethyl)-3-hydroxyazetidine-1-carboxylate (38.6 mg, 0.145 mmol) in DMF (1 mL) was added to reaction and reaction mixture was slowly allowed to stir at RT for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL X 2). Combined organic extract was washed with brine (10 x 2 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude tert-butyl 3-((1-(3- chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)-3-hydroxyazetidine-1-carboxylate (100 mg, 0.074 mmol, 77 %) as gummy solid which was used for next step without further purification. LCMS: 3.14 min, 702.0 (M+H)+, Method B To a stirred solution of tert-butyl 3-((1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3- yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-3-hydroxyazetidine-1- carboxylate (50 mg, 0.071 mmol) in DCM (1 mL) was added TFA at 0 °C (0.027 mL, 0.356 mmol) and reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was concentrated to get crude. Crude was purified by prep HPLC. Fractions were concentrated, obtained solid was basified with 10% NaHCO3 (10 mL), product was extracted with DCM (10 mL x 2). Combined organic extract was dried over sodium sulphate, concentrated and lyophilized to afford 1'-[3- chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazetidin-3- yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (7.91 mg, 0.013 mmol, 18%) (Example 38) as white solid. A stirred solution of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-((3- hydroxyazetidin-3-yl)methyl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (40 mg, 0.066 mmol) (Example 38) and formaldehyde (2.394 mg, 0.080 mmol) in DCE (2 mL) was added sodium cyanoborohydride (8.35 mg, 0.133 mmol) at 0 °C and reaction mixture was slowly allowed to stir at rt for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 2). Combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by prep HPLC purification in TFA method. The collected fractions were concentrated and obtained solid was dissolved in DCM (10 mL). The organic layer was washed with 10% NaHCO3 solution and dried over anhydrous sodium sulphate, filtered and concentrated and lyophilized to afford 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3- hydroxy-1-methylazetidin-3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (2.49 mg, 3.84 µmol, 6%) (Example 43) as white solid. Analytical data for Example 38 and Example 43 is in Table 16. Route P Typical procedure for the preparation of amines as exemplified by the preparation of 2- amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-7-yl]ethanone (Example 52) To a stirred solution of 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (25mg, 0.050 mmol) (Example 6) in DMF (8 mL) were added (tert-butoxycarbonyl)glycine (8.71 mg, 0.050 mmol), DIPEA (0.018 ml, 0.099 mmol) followed by HATU (22.68 mg, 0.060 mmol) and reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). Combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude tert-butyl (2-(1-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)-2-oxoethyl)carbamate (50 mg, 0.076 mmol) as colourless thick liquid. LCMS: 4.01 min, 661.3 (M+H )+, Method B To a stirred solution of tert-butyl (2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3- yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-2-oxoethyl)carbamate (50 mg, 0.076 mmol) in DCM (1 mL) was added TFA (5.84 µl, 0.076 mmol) and reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and neutralized with 10% NaHCO3 and extracted with EtOAc (20 mL x 2). Combined organic extract was washed with water (20 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude. Crude product was purified by Prep-HPLC. Pure fractions were collected and concentrated under reduce pressure to get white solid which was neutralized with aqueous 10% NaHCO3 (10 mL) and extracted with DCM (20 mL). The DCM layer was dried over anhydrous sodium sulfate and concentrated to get white solid which was re-dissolved in ACN:water 1:3 and lyophilized to afford 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3- yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]ethanone (3.94 mg, 0.076 mmol, 9%) (Example 52) as an off white solid. Analytical data for Example 52 is in Table 17. Route Q Typical route for the preparation of aminoalcohol as exemplified by the preparation of 1'- [3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin- 3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one trifluoroacetate (Example 54) To a stirred solution of 7-(azetidin-3-yl)-1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin- 3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (40 mg, 0.070 mmol) (Example 48) and 2- ((tert-butyldimethylsilyl)oxy)acetaldehyde (18.28 mg, 0.105 mmol) in DCM (3 mL) at RT were added TEA (0.05 mL, 0.350 mmol), Na(OAc)3BH (17.8 mg, 0.084 mmol) and acetic acid (0.400 µl, 6.99 µmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated to afford 7'-(1-(2-((tert- butyldimethylsilyl)oxy)ethyl)azetidin-3-yl)-1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2- ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (50 mg, 0.068 mmol, 98%) LCMS: 3.20 min, 730.4 (M+H)+, Method B To a stirred solution of 7'-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azetidin-3-yl)-1-(3-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-8'-one (40 mg, 0.055 mmol) in THF (3 mL) at 0 °C was added TBAF (0.082 mL, 0.082 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and evaporated. The crude product was purified by prep-HPLC. The prep fractions were lyophilized to afford 1'-[3-chloro-2- (trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azetidin-3-yl]spiro[6H-1,7- naphthyridine-5,4'-piperidine]-8-one trifluroacetate (2.08 mg, 6%) (Example 54) as a white solid. Analytical data for Example 54 is in Table 18. Route R Typical procedure for the preparation of lactams as exemplified by the preparation of 2-(2- ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H- 1,7-naphthyridine-5,4'-piperidine]-6-one (Example 58) To a solution of tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (16.95 mg, 33.39 μmol) (Intermediate 26), 3-chloro-5-propoxy-4-(trifluoromethyl)pyridine (10 mg, 41.73 μmol) (Intermediate 27) and sodium tert-butoxide (12.03 mg, 125.20 μmol) in dioxane (1 mL) was added bis(diphenylphosphino)-1,1'- binaphthyl (5.20 mg, 8.35 μmol) and methanesulfonato[2,2-bis(diphenylphosphino)-1,1- binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (8.28 mg, 8.35 μmol) under argon. Then the reaction mixture was heated to 100 °C and stirred at 100 °C for 2 hr. Seven additional vials were set up as described above. After cooling to RT, all eight reaction mixtures were combined, diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (eluted with PET ether/EtOAc= 1/2, Rf = 0.49) to give tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-1-(5-propoxy-4- (trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (21 mg, 9%) as white solid. 1H NMR (400 MHz, CD3OD) δ 8.27 - 8.16 (m, 4H), 8.08 - 7.98 (m, 2H), 7.12 – 7.05 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.20 – 4.10 (m, 2H), 3.70 - 3.47 (m, 5H), 3.44 - 3.33 (m, 4H), 3.27 - 3.21 (m, 2H), 2.40 - 2.31 (m, 2H), 2.24 - 2.13 (m, 4H), 1.87 - 1.81 (m, 2H), 1.46 (s, 12H), 1.42 (t, J = 7.1 Hz, 3H) A solution of tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-1-(5-propoxy-4-(trifluoromethyl)pyridin- 3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (10 mg, 14.07 μmol) in formic acid (0.3 mL) was stirred at 25 °C for 1 hr. One additional vial was set up as described above. All two reaction mixtures were combined and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give 2-(2-ethoxypyridin-3-yl)-1'- [5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidin-3-ylspiro[8H-1,7-naphthyridine-5,4'- piperidine]-6-one (8.2 mg, 47%) (Example 58) as white solid. Analytical data for Example 58 is in Table 19. Route S Typical procedure for the preparation of lactams as exemplified by the preparation of 7-(2- aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7- naphthyridine-5,4'-piperidine]-6-one (Example 59)
To a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro- 1,7-naphthyridine-5,4'-piperidine]-6-one (50 mg, 96.72 μmol) (Example 5) and 2- bromoacetonitrile (11.60 mg, 96.72 μmol, 6.45 uL) in THF (2 mL) was added NaH (19.34 mg, 483.60 μmol, 60% purity) at 0 °C under nitrogen. The reaction mixture was stirred at 25 °C for 12 hr. TLC (PET ether/EtOAc= 2/1, Rf = 0.23) showed starting material was consumed and desired spot was formed. The reaction mixture was quenched with ice-water (2 mL) and extracted with EtOAc (1 mL × 3). The combine organic phase was concentrated under reduced pressure to get a residue, which was purified by prep-TLC (PET ether/EtOAc= 2/1, Rf = 0.23) to get 2-(1-(4- chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)acetonitrile (20 mg, 31%) as a yellow oil. LCMS: 1.04 min, 556.2 (M+H)+, Method O To a solution of 2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)acetonitrile (3 mg, 5.40 μmol) in MeOH (5 mL) was added Rh/C (3 mg, 1.27 μmol, 5% purity) and a drop of TFA under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at 25 °C for 20 min under hydrogen balloon. Four additional vials were set up as described as above. All five reaction mixtures were combined and filtered, the filtrate was concentrated under reduced pressure to get a residue, which was purified by prep-HPLC to get 7-(2-aminoethyl)-1'- [4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7-naphthyridine-5,4'- piperidine]-6-one g (2.6 mg,17%) (Example 59) as a white solid. Analytical data for Example 59 is in Table 20. Route T Typical procedure for the preparation of lactams as exemplified by the preparation of 1'- [3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-[2-(2- methoxyethoxy)ethyl]pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'-piperidine]-8-one (Example 68) To a stirred solution of 1-(3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin- 3-yl)-7'-(pyrrolidin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (40 mg, 0.046 mmol) (Example 18) in ACN (1 mL) at 0 °C were added 1-bromo-2-(2- methoxyethoxy)ethane (16.96 mg, 0.093 mmol) and K2CO3 (9.60 mg, 0.069 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and evaporated. The crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%). The pure fractions were evaporated, and the product was further purified by prep-HPLC. The fractions were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL), dried over sodium sulfate, evaporated and lyophilized to afford 1-(3-(cyclopropylmethoxy)- 2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3- yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (14.15 mg, 0.019 mmol, 42%) as a white solid. Analytical data for Example 68 is in Table 21. Route U Typical procedure for the preparation of lactams as exemplified by the preparation of 2-(2- ethoxypyridin-3-yl)-1'-[5-ethoxy-4-(trifluoromethyl)pyridin-3-yl]spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (Example 80)
To a stirred solution of 1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'- dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (50 mg, 0.097 mmol) (Intermediate 37) in DMSO (0.5 mL) at 0 °C was added sodium ethoxide (33 mg, 0.487 mmol). The reaction mixture was heated at 60 °C for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and evaporated. The crude product was purified by prep-HPLC and the fractions were lyophilized. The residue was dissolved in DCM (15 mL), basified with 10% NaHCO3 solution (5 mL), washed with water (5mL), dried over sodium sulfate, evaporated and lyophilized to afford 1-(5-ethoxy-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (6.31 mg, 0.012 mmol, 12%) (Example 80) as a white solid. Analytical data for Example 80 is in Table 22. Route V Typical procedure for the preparation of carbamates as exemplified by the preparation of azetidin-3-yl 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3- yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-carboxylate (Example 97) To stirred solution of 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3- yl]spiro[7,8-dihydro-6H-1,7-naphthyridine-5,4'-piperidine] (100 mg, 0.200 mmol) (Example 30) in DMF (2.0 mL) were added DIPEA (0.070 ml, 0.400 mmol) followed by tert-butyl 3-((((2,5- dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)azetidine-1-carboxylate (94 mg, 0.300 mmol) (Intermediate 50) at 0 °C and reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to get the 1-(tert-butoxycarbonyl)azetidin-3-yl 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2- (trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (50 mg , 0.072 mmol, 36%) as an brown gum. LCMS: 3.49 min, 699.3 (M+H)+, Method B To stirred solution of 1-(tert-butoxycarbonyl)azetidin-3-yl 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy- 2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate (50 mg, 0.072 mmol) in DCM (2.0 mL), was added phosphoric acid (85% in water) (7.01 mg, 0.072 mmol) at 0 °C and reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated, neutralized with 10% NaHCO3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated afforded crude compound, which was purified by prep-HPLC. The pure fractions were collected and lyophilized to afford azetidin-3-yl 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2- (trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate formate salt (5.88 mg, 9.82 µmol, 14%) (Example 97) as a white solid. Analytical data for Example 97 is in Table 23. Route W Typical procedure for the preparation of nitriles as exemplified by the preparation of 2-[3- [2-(2-ethoxypyridin-3-yl)-8-oxo-7-[(3S)-pyrrolidin-3-yl]spiro[6H-1,7-naphthyridine-5,4'- piperidine]-1'-yl]-2-(trifluoromethyl)phenoxy]acetonitrile (Example 98) To a stirred suspension of 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)- 6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (57 mg, 0.097 mmol) (Intermediate 50) in THF (5 mL) at 0 °C was added NaH (20 mg, 0.484 mmol). The reaction mixture was stirred at RT for 30 min. Tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1- carboxylate (128 mg, 0.484 mmol) was added at RT. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched cautiously with saturated ammonium chloride solution (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%) to afford tert-butyl (S)-3-(1-(3-(benzyloxy)-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (57 mg, 0.062 mmol, 64%) as a yellow gum. LCMS: 3.32 min, 758.4 (M+H)+, Method B To a stirred solution of tert-butyl (S)-3-(1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2- ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (57 mg, 0.075 mmol) in MeOH (5 mL) at RT was added 10% Pd/C (50 mg, 0.047 mmol) and stirred at RT under 1atm of H2 pressure for 16h. The reaction mixture was filtered through celite and washed with 20% MeOH-in DCM (20 mL). The filtrate was evaporated and dried under high vacuum to afford tert-butyl (S)-3-(2'-(2-ethoxypyridin-3-yl)-1-(3-hydroxy-2- (trifluoromethyl)phenyl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (38 mg, 0.044 mmol, 59%) as a yellow gum. LCMS: 2.76 min, 668.3 (M+H)+, Method B. To a stirred solution of tert-butyl (S)-3-(2'-(2-ethoxypyridin-3-yl)-1-(3-hydroxy-2- (trifluoromethyl)phenyl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (35 mg, 0.052 mmol) in DMF (1 mL) at RT were added 2-bromoacetonitrile (13 mg, 0.105 mmol) and K2CO3 (11 mg, 0.079 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated to afford tert-butyl (S)- 3-(1-(3-(cyanomethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (27 mg, 0.029 mmol, 55%) as a yellow gum. LCMS: 2.88 min, 707.3 (M+H)+, Method B To a stirred solution of tert-butyl (S)-3-(1-(3-(cyanomethoxy)-2-(trifluoromethyl)phenyl)-2'-(2- ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1- carboxylate (25 mg, 0.035 mmol) in DCM (1 mL) at 0 °C was added phosphoric acid (25 mg, 0.255 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was basified with 10% NaHCO3 solution (5 mL) and extracted with DCM (2 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by prep- HPLC. The prep fractions were lyophilized to afford (S)-2-(3-(2'-(2-ethoxypyridin-3-yl)-8'-oxo-7'- (pyrrolidin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)-2- (trifluoromethyl)phenoxy)acetonitrile formate (1.25 mg, 1.968 µmol, 6%) (Example 98) as a white solid. Analytical data for Example 98 is in Table 24. Route X Typical procedure for the preparation of methyl pyrrolidine as exemplified (R)-2'-(2- ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'-(pyrrolidin-2-ylmethyl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 113) To a solution of 2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (intermediate 61) (20 mg, 40.12 μmol) in MeOH (1 mL) was added tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (15.99 mg, 80.23 μmol) and NaCNBH3 (10.08 mg, 160.47 μmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. One additional vial was set up as described above. All two reaction mixtures were diluted with water (10 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by prep-TLC (PET ether/EtOAc= 1/3, Rf = 0.43) to obtain tert-butyl (R)-2-((2'-(2- ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (25 mg, 46%) as a white solid. LCMS: 0.59 min, 682.4 [M+H]+, Method R’ A solution of tert-butyl (R)-2-((2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)- 6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (70 mg, 102.67 μmol) in DCM (1 mL) was added TFA (0.2 mL) at 25 °C. The reaction mixture stirred at 25 °C for 2 h and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give (R)-2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'- (pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (23 mg, 39%) as white solid (Example 113). Analytical data for Example 113 is in Table 25. Route Y Typical procedure for the preparation of oxo propionic acid as exemplified by 3-(2'-(2- ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropanoic acid (Example 117) To a solution of 3-methoxy-3-oxopropanoic acid (5.68 mg, 48.14 μmol) and 2'-(2-ethoxypyridin- 3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (intermediate 61) (20 mg, 40.12 μmol) in DMF (0.5 mL) were added HATU (30.51 mg, 80.23 μmol) followed by DIPEA (15.55 mg, 120.35 mmol, 20.96 uL) at 25 °C and reaction mixture was stirred at 25 °C for 2 h. One additional vial was set up as described above. All two reaction mixtures were diluted with water (2 mL) and extracted with EtOAc (3 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and filtratered. The filtrate was concentrated under reduced pressure and purified by prep-TLC (EtOAc, Rf = 0.6) to obtain methyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropanoate (30 mg, 62%) as white solid. LCMS: 2.23 min, 599.2 [M+H]+, Method R’ To a solution of methyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3-oxopropanoate (14 mg, 23.39 μmol) in MeOH (0.4 mL) and water (0.2 mL) was added LiOH (2.80 mg, 116.94 μmol) was stirred at 25 °C for 4 h. One additional vial was set up as described above. All two reaction mixtures were concentrated under reduced pressure and purified by prep-HPLC to obtain 3-(2'-(2-ethoxypyridin-3-yl)-1-(3- methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3- oxopropanoic acid (9.7 mg, 35%) (Example 117) as white solid. Analytical data for Example 117 is in Table 26. Route Z Typical procedure for the preparation of rac-((2R,4S)-4-(2'-(2-ethoxypyridin-3-yl)-1-(3- methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)- yl)tetrahydrofuran-2-yl)methanamine (Example 136) To a solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (19.03 mg, 120.35 μmol) in MeOH (5 mL) was acidified to pH 4 by acetic acid and stirred at 20 °C for 30 min. The reaction mixture was basified to pH 9 by Et3N, then added 2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (50 mg, 100.29 μmol) (intermediate 61) and NaCNBH3 (31.51 mg, 501.47 μmol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 12 h. Three additional vials were set up as described above. After cooling to RT, all four reaction mixtures were combined, quenched with water (0.3 mL), concentrated under reduced pressure and was purified by prep-TLC (PET ether/EtOAc= 1/1, peak 1, Rf = 0.36, peak 2, Rf = 0.29) to get ethyl 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)tetrahydrofuran-2- carboxylate_peak-1 (30 mg, 12%) and ethyl 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)tetrahydrofuran-2- carboxylate_peak 2 (70 mg, 27%) as colourless oil. Peak 1: LCMS: 0.549 min, 641.4(M+H)+, Method L Peak 2: LCMS: 0.547 min, 641.4(M+H)+, Method L A solution of ethyl 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)tetrahydrofuran-2-carboxylate-Peak-1 (15 mg, 23.41 μmol, 1) in a solution of ammonia in MeOH (0.5 mL, 7 N) was heated to 80 °C and stirred at 80 °C for 5 h. One additional vial was set up as described above. After cooling to RT, all two reaction mixtures were combined and concentrated under reduced pressure to get 4-(2'-(2- ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)tetrahydrofuran-2-carboxamide (25 mg, crude) as a yellow oil, which was used to next step directly without further purification. LCMS: 0.47 min, 612.3(M+H)+, Method L To a solution of 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)tetrahydrofuran-2-carboxamide (15 mg, 24.52 μmol) in THF (1 mL) was added LAH in THF (2.5 M, 49.05 μL) at 0 °C dropwise. The reaction mixture was stirred at 20 °C for 12 h. One additional vial was set up as described above. After cooling to 0 °C, all two reaction mixtures were combined and quenched with Na2SO4 (15 mg) and stirred at 20 °C for 2 h. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to get rel-[(2R,4S)-4-[2-(2- ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine- 5,4'-piperidine]-7-yl]oxolan-2-yl]methanamine_peak-1 (5 mg, 13%) (Example 136) as a white solid. Analytical data for Example 136 is in Table 27. Route Aa Typical procedure for the preparation of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)- 1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 153, 153.HCl/MSA) To a stirred solution of 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl) phenyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (1 g, 1.925 mmol) (Intermediate 106) and tert-butyl (R)-2- formylpyrrolidine-1-carboxylate (460 mg, 2.310 mmol) in DCE (10 mL) at 0 °C was added Na(OAc)3BH (816 mg, 3.85 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulphate, evaporated, and purified by flash column chromatography using EtOAc in PET ether (0 to 100%) as an eluent to afford tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.1 g, 1.521 mmol, 79%) as a pale white solid. LCMS: 3.08 min, 651.3 [M+H]+, Method B To a stirred solution of tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1 g, 1.383 mmol) in DCM (10 mL) at 0 °C was added TFA (1.6 g, 13.83 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was basified cautiously with 10% NaHCO3 solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over sodium sulphate. The resulting residue was purified by prep-HPLC (Method B). The pure prep fractions were lyophilized. The residue was dissolved in DCM (15 mL), washed with 10% NaHCO3 solution (5 mL), water (5 mL), dried over sodium sulphate, evaporated and lyophilized to afford (R)-2'-(2- ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (410 mg, 0.730 mmol, 53%) (Example 153) as an off white solid. To a stirred solution of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-1-(2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 153) (20 mg, 0.036 mmol) in iPrOAc (1 mL) at 0 °C was added HCl (2M in iPrOAc) (0.02 mL, 0.036 mmol). The reaction mixture was stirred at RT for 10 min. The solid obtained was triturated with MTBE (2 x 1 mL). The residue was lyophilised to afford (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2- ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] hydrochloride (5.50 mg, 0.00901 mmol, 25%) (Example 153.HCl) as a white solid. To a stirred solution of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-1-(2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 153) (10 mg, 0.018 mmol) in iPrOAc (1 mL) at 0 °C was added MSA (0.2M in iPrOAc) (0.01 mL, 0.018 mmol). The reaction mixture was stirred at RT for 10 min. The reaction mixture was stirred at RT for 10 min. The solid obtained was triturated with MTBE (2 x 1 mL). The residue was was purified by prep-HPLC in method I. The prep fractions were lyophilized to afford (R)-2'-(2-ethoxyphenyl)- 7'-(pyrrolidin-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] methanesulfonate (7.31 mg, 0.011 mmol, 62%) (Example 153.MSA) as a white solid. Analytical data for Example 153, 153.HCl and 153.MSA is in Table 28. Route Ab Typical procedure for the preparation of (3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3- methoxy-2-(trifluoromethyl)phenyl)-7'-(((R)-pyrrolidin-2-yl)methyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 176) To a stirred solution of rac-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 105) (55 mg, 0.105 mmol) and tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (20.85 mg, 0.105 mmol) in DCE (10 mL) was added Na(OAc)3BH (44.35 mg, 0.210 mmol) and reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, and the resulting residue purified by flash column chromatography using EtOAc in PET ether (0 to40%) to afford [tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine- 1-carboxylate (65 mg, 0.091 mmol, 88%) as a white solid. LCMS: 2.22 min, 709.3 [M+H]+, Method G. To a stirred solution of tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2- (trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine- 1-carboxylate (65 mg, 0.091 mmol) in DCM (10 mL) was added TFA (0.3 mL) and reaction mixture was stirred at RT for 16 h. The reaction was concentrated and the resulting residue neutralized with aqueous 10% NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4 and purified by Prep. HPLC. The prep fractions were concentrated, and the residue was neutralized with 10% NaHCO3 solution (10 mL) and extracted with DCM (10 mL). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulphate and lyophilized to afford (3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3- methoxy-2-(trifluoromethyl)phenyl)-7'-(((R)-pyrrolidin-2-yl)methyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (22 mg, 0.036 mmol, 39%) (Example 176) as a colourless liquid. Analytical data for Example 176 is in Table 29 Route Ac Typical procedure for the preparation of (R)-1-(2-chloro-4-fluorophenyl)-2'-(2- ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (Example 189): To a solution of tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 197.36 μmol) (intermediate 121) and 2- chloro-4-fluoro-1-iodobenzene (50.61 mg, 197.36 μmol) in toluene (2 mL) was added Cs2CO3 (192.91 mg, 592.09 mmol), Xantphos (22.84 mg, 39.47 μmol) and Pd2(dba)3 (36.15 mg, 39.47 μmol) at RT and reaction mixture was stirred at 100 °C for 12 h. Four vials were set up as described above. After cooling to RT, all five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulphate and purified by prep-TLC (PET ether/EtOAc=3/1, Rf = 0.4) to obtain tert-butyl (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (280 mg, 56%) as white solid. LCMS: 2.42 min, 635.2(M+H)+, Method M A solution of tert-butyl (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (70 mg, 110.20 μmol) in HCOOH (1 mL) was heated to 40 °C and stirred at 40 °C for 8 h. Three vials were set up as described above. After cooling to RT, all four reaction mixtures were concentrated under reduced pressure and purified by prep-HPLC to obtain (R)-1-(2-chloro-4-fluorophenyl)-2'-(2- ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (83.7 mg, 36%) (Example 189) as white solid. Analytical data for Example 189 is in Table 30 Route Ad Typical procedure for the preparation of (R)-1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2- ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridine] (Example 206): To a solution of tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]- 7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (intermediate 121) (50 mg, 98.68 μmol) and 2-bromo- 4-chloro-1-iodobenzene (31.32 mg, 98.68 μmol) in toluene (1 mL) were added Cs2CO3 (96.46 mg, 296.05 μmol), Xantphos (11.42 mg, 19.74 μmol) followed by Pd2(dba)3 (18.07 mg, 19.74 μmol) and reaction mixture was stirred at 100 °C for 12 h under nitrogen. Five additional vials were set up as described above. After cooling to RT, six reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organics were washed with brine (10 mL), dried over anhydrous sodium sulphate and purified by prep-TLC (PET ether/EtOAc=2/1, Rf = 0.5) to obtain tert-butyl (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (200 mg, 49%) as a white solid. LCMS: 2.49 min, 697.1 [M+H]+ Method R’ To a solution of tert-butyl (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (50 mg, 71.83 μmol) and sodium methane sulfinate (9.53 mg, 93.38 μmol) in DMSO (1 mL) were added K3PO4 (15.25 mg, 71.83 μmol) followed by CuI (13.68 mg, 71.83 μmol) and reaction mixture was stirred at 110 °C for 12 h under nitrogen. Four additional vials were set up as described above. After cooling to RT, all five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organics were washed with brine (10 mL), dried over anhydrous sodium sulphate and purified by prep-TLC (PET ether/EtOAc= 4/3, Rf = 0.6) to obtain tert-butyl (R)-2-((1- (4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (70 mg, 28%) as a yellow solid. LCMS: 2.16 min, 695.1 [M+H]+ Method R’ A solution of (R)-2-((1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (30 mg, 43.15 μmol) in HCOOH (1 mL) was stirred at 40 °C for 8 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain (R)-1-(4-chloro- 2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1,7]naphthyridine] (Example 206) (25.5 mg, 50%) as a white solid. Analytical data for Example 206 is in Table 31 Route Ae Typical procedure for the preparation of 5-chloro-2-((3SR,4SR)-2'-(2-ethoxyphenyl)-3- ethyl-7'-(((2R,4S)-4-hydroxypyrrolidin-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)nicotinonitrile (Example 208): To a solution of tert-butyl (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H- spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (50 mg, 90.79 μmol) (Intermediate 139) in THF (1 mL) were added 2,5 -dichloropyridine-3-carbonitrile (20.42 mg, 118.03 μmol) followed by Et3N (27.56 mg, 272.37 μmol) and reaction mixture was stirred at 70 °C for 4 h. Two additional vials were set up as described above. After cooling to RT, all three mixtures were combined, concentrated and purified by prep-TLC (PET ether/EtOAc= 1/2, Rf = 0.3) to get tert-butyl (2R,4S)-2-(((3SR,4SR)-1-(5-chloro-3-cyanopyridin-2-yl)-2'-(2- ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4- hydroxypyrrolidine-1-carboxylate (94 mg, 50%) as a white solid. LCMS: 0.62 min, 687.5 (M+H)+, Method L To a solution of tert-butyl (2R,4S)-2-(((3SR,4SR)-1-(5-chloro-3-cyanopyridin-2-yl)-2'-(2- ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)methyl)-4- hydroxypyrrolidine-1-carboxylate (22.5 mg, 32.74 μmol) in DCM (1 mL) was added TFA (153.50 mg, 1.35 mmol) and reaction mixture was stirred at RT for 2 h. Three additional vials were set up as described. All four reaction mixtures were combined, concentrated and purified by prep-HPLC to get 5-chloro-2-((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-7'-(((2R,4S)-4-hydroxypyrrolidin-2- yl)methyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)nicotinonitrile (39.1 mg, 51%) (Example 208) as a white solid. Analytical data for Example 208 is in Table 32 Route Af Typical procedure for the preparation of (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin- 2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)benzoic acid (Example 216) tert-butyl (R)-2-((1-(4-chloro-2-cyanophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Example 173) (500 mg, 0.779 mmol) was added 10 N HCl (30 mL, 300 mmol) at 25 °C. The reaction mixture was stirred at 100 oC for 42 h. The reaction mixture was cooled to RT and diluted with 10% MeOH in DCM (2 x 20 mL). pH of the reaction mixture was adjusted to ~8 by using 10% sodium hydroxide solution (50 mL) and separated the layers. The aq. layer was extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated under vacuum to afford crude compound (100 mg; HPLC purity: 56.0%). The crude was purified by prep- HPLC (Method AP) to afford (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'- (pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)benzoic acid (12 mg, 0.021 mmol, 2.75% yield) (Example 216) as an off-white solid. Analytical data for Example 216 is in Table 33
Table 18 –NMR and LCMS properties and the methods used to prepare and purify compounds represented by Examples
Table 19 –NMR and LCMS properties and the methods used to prepare and purify compounds represented by Examples
X-ray crystallographic analysis of 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7- [[(2R)-pyrrolidin-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-1'- yl]benzonitrile (Example 181-1) Crystal Data: Empirical formula 3(C34H40ClN5O), H2O, 0.4(O) Formula weight 1734.89 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P21 Unit cell dimensions a = 11.2353(9) Å a= 90°. b = 33.454(3) Å b= 103.094(4) °. c = 12.4819(10) Å g = 90°. Volume 4569.6(6) Å3 Z 2 Density (calculated) 1.261 Mg/m3 Absorption coefficient 0.163 mm-1 F (000) 1850 Crystal size 0.200 x 0.160 x 0.100 mm3 q range for data collection 1.861 to 30.891°. Index ranges -15<=h<=15, -46<=k<=47, -17<=l<=16 Reflections collected 87455 Independent reflections 25243 [R(int) = 0.0891] Completeness to q = 25.242° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7461 and 0.6603. Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 25243 / 201 / 1203 Goodness-of-fit on F20.967 Final R indices [I>2s(I)] R1 = 0.0548, wR2 = 0.1056 R indices (all data) R1 = 0.1665, wR2 = 0.1377 Absolute structure parameter 0.01(2) Largest diff. peak and hole 0.401 and -0.358 e.Å-3 Measurement Bruker D8 QUEST PHOTON-III Detector Software Used SHELXTL-PLUS. Crystal growth: Crystallization by slow evaporation of the solvent was adopted for growing crystals suitable for single-crystal X-ray diffraction studies. Crystals were obtained from Methyl tert-Butyl Ether (MTBE) solvent. About 20 mg of the compound (B.No. OMA-SYN-C37s-E1- R-004) was dissolved in Methyl tert-Butyl Ether (3ml) solvent under hot conditions and the solution was filtered into a clean beaker and kept for crystallization at room temperature. Crystals were obtained on the walls of the beaker after 10 days. Refinement: X-ray data was collected at low temperature on a Bruker D8 QUEST instrument with an IμS Mo microsource (λ = 0.7107 A) and a PHOTON-III detector. The raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite programs (Bruker (2016). APEX3, SAINT and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA). The structure was solved using intrinsic phasing method [2] and further refined with the SHELXL (Sheldrick G. M. (2015). Acta Crystallogr C71: 3-8) program and expanded using Fourier techniques. Anisotropic displacement parameters were included for all non-hydrogen atoms. Atom C1 of molecule A was disordered over two positions and its site occupational factors were refined to 0.6(5) and 0.4(5) respectively. The atoms C17/C18/C19/C20/C21/N3 of molecule B were disordered over two positions and their site occupational factors were refined to 0.755(6) and 0.245(6) respectively. The N-H and O-H atoms were located in the difference Fourier map and their positions and isotropic displacement parameters were refined. Hydrogen atoms could not be located on the partial occupy water O2W. All C bound H atoms were positioned geometrically and treated as riding on their parent C atoms [C-H = 0.93-0.97 Å, and Uiso(H) = 1.5Ueq(C) for methyl H or 1.2Ueq(C) for other H atoms]. The absolute configuration has confirmed by unambiguous refinement of the absolute structure parameter (Flack, H. D. & Bernardinelli, G. (2000). J. Appl. Cryst.33, 1143–1148). BIOLOGICAL ACTIVITY Terbium labelling and preparation of SNAP-tagged MC2 membranes Cells were labelled with 100 nM of SNAP-Lumi4-Tb and incubated for 1 h at 37 °C under 5% CO2 prior to harvesting, and pelleting by centrifugation at 3 min at 1200 rpm. Cell pellets were homogenized using an FastPrep-245G homogeniser (MP Biomedicals) and subsequently centrifuged and resuspended twice at 22,000×g at 4 °C (Eppendorf Centrifuge) for 30 min. The final pellet was resuspended in 10 mM HEPES and 0.1 mM EDTA, pH 7.4, at a concentration of 5–10 mg ml-1 and stored at -20oC for later use. Fluorescent Ligand Binding Assays All fluorescent ligand binding experiments were performed with a Cy5-labelled small molecule MC2 antagonist in 384-well Optiplate plates in 1x Tag-lite buffer (PerkinElmer), with 2% DMSO, 0.04% pluronic acid and 100µg/ml saponin. In all cases, non-specific binding was determined in the presence of 1µM unlabelled MC2 antagonist. Signal detection was performed on a Pherastar FSX (BMG Labtech, Germany) using standard HTRF settings and the HTRF ratios were calculated by dividing the acceptor signal (665nm) by the donor signal (620nm), and multiplying the value by 10,000. TR-FRET Competitive Equilibrium Binding Assay To determine the equilibrium dissociation constant (Ki) of competing test compounds, MC2 membranes (2µg per well) were incubated with a range of concentrations of test compounds in the presence of 100nM fluorescent tracer. HTRF ratios were obtained after overnight incubation at 25°C to ensure equilibrium had been reached. TR-FRET Competitive Binding Kinetic Assay To determine the association (kon) and dissociation (koff) rates of unlabelled compounds, a competitive kinetic binding assay was performed which involved the simultaneous addition of 100nM fluorescent tracer and increasing concentrations of competing ligand to MC2 membranes (2µg per well). The degree of bound fluorescent tracer at MC2 was determined at multiple timepoints by HTRF. In parallel, the association (kon) and dissociation (koff) rates for the fluorescent tracer were determined through incubation of increasing concentrations of fluorescent tracer with MC2 membranes in the absence and presence of 1µM unlabelled MC2 antagonist. The degree of bound fluorescent tracer was calculated at multiple timepoints by HTRF detection and association kinetic curves were generated. The resulting data were globally fitted to the association kinetic model (Prism 8.0, GraphPad, San Diego, USA) to derive a best-fit estimate for kon and koff as described under data analysis. From these data an estimate for the equilibrium dissociation constant (Kd) could be calculated. Competition kinetic data and fluorescent tracer kinetic parameters were fit globally to the equation first described by Motulsky and Mahan (Mol. Pharmacol., 1984, 25, 1-9) to determine unlabelled compound kon and koff. EXAMPLE A pKi: Group A >9, Group B 7.5 to 9, Group C 6 to 7.5 Koff: Group A <0.02, Group B 0.02 to 0.07, Group C >0.07 cAMP accumulation assay Chinese hamster ovary (CHO) cells, stably expressing human or rat MC2 with MRAP, were maintained in DMEM/F12 cell culture medium supplemented with 10% fetal bovine serum and 1% l-glutamine. On the day of experimentation, cells were plated at 5000 cells/well in white low-volume 384-well plates in assay buffer (Hank’s balanced salt solution (HBSS) containing 5 mM HEPES (pH 7.4) with 0.1% w/v BSA and 500 mM 3-isobutyl-1-methylxanthine) before being incubated with a range of concentrations of MC2 compounds for 2h at 37C, 5% CO2. After 2h, increasing concentrations of ACTH1-24 were added to the cells for a set duration, before lysis and cAMP detection using the homogeneous time resolved fluorescence (HTRF) cAMP Gs HiRange kit (CisBio) according to the manufacturer’s instructions. Fluorescence resonance energy transfer (FRET) levels were detected on a PHERAstar plate reader (BMG), and data interpolated from a cAMP standard curve, and analysed using GraphPad Prism 8 (GraphPad). Results for the compounds Example 113, Example 134 and Example 135 are shown in Figure 1. Brief Description of the Figures Figure 1: Inhibition of ACTH1-24-mediated cAMP responses at human MC2 by the compounds Example 113, Example 134 and Example 135. MC2-expressing cells were incubated with compounds for 2h, before stimulation with ACTH1-24 for 15min, followed by lysis and cAMP detection. Slower dissociating compounds with lower Koff showed a greater degree of insurmountability. Data represents n=1, in duplicates.

Claims

CLAIMS 1. A compound of formula (1): or a salt thereof, wherein; J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L1 is -(CH2)n-, -(CH2)nCONH-, -(CH2)nCOO-, -CO(CH2)nNH- or -CO(CH2)n-, where n is 0-5; R1 is C1-4alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R2 is H, CO2H, OH, NR2aR2b, CONR2aR2b, SO2NR2aR2b, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R10, R11 and R12, or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R10, R11 and R12; R2a and R2b are independently H or C1-3alkyl optionally substituted with 1-3 fluorine atoms; R3 is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3 is joined to R3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3a is H or is joined to R3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3b is H, C1-3alkyl optionally substituted with 1-3 fluorine atoms, C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; or R3b is joined to R3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; R3c is H or is joined to R3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms; wherein one or both of R3 and R3b is H; L2 is a bond or -CO- and R4 is a group: or L2 is -CO- and R4 is -(CH2)qNH2, where q is 0-3; R5, R6, R7, R8, and R9 are independently selected from H, halo, CN, NR15R16, C1-3alkyl optionally substituted with 1-3 fluorine atoms, OC1-3alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH2CN, CO2H and SO2Me; R10, R11 and R12 are independently selected from H, OH, oxo, halo, C1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, - (CH2)gNR13R14, -CH2(CH2)g(OCH2CH2O)yR13, -(CH2)gCO2R13 and -(CH2)gCONR13R14, where g is 0-3 and y is 1-3; R13 and R14 are independently H or methyl; and R15 and R16 are independently H or C1-3alkyl. 2. The compound according to claim 1, wherein R4 is a group selected from: 3. The compound according to claim 1 or claim 2, wherein L2 is a bond. 4. The compound according to any one of claims 1 to 3, wherein R1 is ethyl or perdeuteroethyl. 5. The compound according to claim 1 or claim 2, which is a compound of Formula (2a) or (2b): or a salt thereof. 6. The compound according to any one of claims 1 to 5, wherein J is N. 7. The compound according to any one of claims 1 to 5, wherein J is CH. 8. The compound according to claim 1 or claim 2, which is a compound of Formula (3a) or (3ai): or a salt thereof. 9. The compound according to any one of claims 1 to 8, wherein R3 is H, methyl or ethyl. 10. The compound according to any one of claims 1 to 9, wherein R3 is ethyl. 11. The compound according to any one of claims 1 to 10, wherein R5, R6, R7, R8, and R9 are independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, -OEt, -OnPr, - N(CH3)(CH2CH2CH3), -N(CH3)2, -OCH2CN, -OCH2cyclopropyl, -CO2H and -SO2Me. 12. The compound according to any one of claims 1 to 11, wherein R4 is selected from:
. 13. The compound according to any one of claims 1 to 12, wherein L1 is a bond, - CH2CH2CONH-, -COO-, -CH2CH2COO-, -CH2CH2CO-, -COCH2NH-, -COCH2CH2NH-, -CO-, - CH2CH2- or -CH2-. 15. The compound according to any one of claims 1 to 13, wherein R2 is H. 16. The compound according to any one of claims 1 to 12, wherein the moiety -L1-R2 is selected from:
17. The compound according to claim 1, which is selected from: Cl Example 10 Example 11 Example 12 O O Cl N
xampe xampe xampe
Example 46 Example 47 Example 48
Example 58 Example 59 Example 60
Example 70 Example 71 Example 72
Example 82 Example 83 Example 84
Example 92 Example 93 Example 94
Example 103 Example 103’ Example 104 F F
or a salt thereof. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient. 19. A combination comprising a compound according to any one of claims 1 to 17 and a CRF1 antagonist. 20. A combination comprising a compound according to any one of claims 1 to 17 and an ACTH antibody. 21. The compound, composition or combination according to any one of claims 1 to 20 for use in medicine. 22. The compound, composition or combination according to any one of claims 1 to 20 for use in the treatment of a disorder associated with MC2R or that would benefit from the modulation of MC2R activity. 23. The compound, composition or combination according to any one of claims 1 to 20 for use in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto.
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GBGB2313601.3A GB202313601D0 (en) 2023-09-06 2023-09-06 MC2R modulator compounds
GBGB2319945.8A GB202319945D0 (en) 2023-12-22 2023-12-22 MC2R modulator compounds
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