MC2R-modulating compounds

Abstract

The disclosure herein provides a compound of formula (1): JPEG2026507093000332.jpg3670 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 The present invention relates to their use in the treatment, prevention, amelioration, suppression, or reduction of the risk of disorders associated with the melanocortin subtype-2 receptor (MC2R) (as defined herein) and the melanocortin subtype-2 receptor (MC2R).

Description

[Technical Field]

[0001] This application relates to novel compounds and their use as melanocortin subtype-2 receptor (MC2R) antagonists. The compounds described herein may be useful in the treatment or prevention of diseases involving MC2R. This application is also directed to pharmaceutical compositions comprising these compounds, as well as the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases involving MC2R. [Background technology]

[0002] Background of the Invention Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide involved in regulating the synthesis and secretion of adrenal glucocorticoids in the hypothalamic-pituitary-adrenal (HPA) axis and therefore plays a major role in regulating stress responses. ACTH is synthesized by adrenocorticotrophic cells in the anterior pituitary gland via proteolytic cleavage of proopiomelanocortin (POMC). Upon stressful stimuli, ACTH is secreted and acts on the adrenal melanocortin 2 receptor (MC2R) to regulate the synthesis and secretion of glucocorticoids and androgens. Glucocorticoid secretion exerts negative feedback on both the hypothalamus and anterior pituitary gland, decreasing the production and secretion of corticotropin-releasing hormone (CRH) and ACTH, respectively, thereby achieving a delicate balance in regulating stress responses. Diseases associated with ACTH dysfunction range from Cushing's disease to congenital adrenal hyperplasia and polycystic ovary syndrome (PCOS) (Microsc. Res. Tech. 61, 275-287 (2003)).

[0003] MC2R belongs to the melanocortin family of G protein-coupled receptors (GPCRs) and has five subtypes: MC1R, MC2R, MC3R, MC4R, and MC5R. MC1R is involved in pigment regulation, MC2R in glucocorticoid synthesis, MC3R and MC4R in energy homeostasis, and MC5R in 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)).

[0004] Another unique aspect of MC2R compared to other melanocortin receptors is that the accessory protein MRAP (melanocortin 2 receptor protein) is required for MC2R expression and function. MRAP is a single-pass transmembrane protein that forms an antiparallel homodimer with MC2R, enabling receptor transport to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP - 20249 (2007)). In adrenocortical cells, ACTH binding to the MC2R / MRAP complex activates cAMP production via the Gs signaling pathway. Increased intracellular cAMP then stimulates cortisol synthesis and secretion (Microsc. Res. Tech. 61, 275-287 (2003)).

[0005] Congenital adrenal hyperplasia (CAH) is a disorder characterized by impaired adrenal steroidogenesis associated with excessive ACTH and CRH production. Three enzyme deficiencies resulting from specific genetic mutations are involved: 21-hydroxylase deficiency due to 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 the loss of cortisol's negative feedback loop on CRH and ACTH. Excess ACTH leads to steroidogenesis proximal to the defective enzymes, contributing to the hyperandrogenism pathophysiology associated with this disorder. Patients with CAH may present with hirsutism, acne, alopecia, oligomenorrhea, and infertility related to virilization. Glucocorticoid and mineralocorticoid hormone replacement therapy is the primary treatment, but close monitoring is required to balance overtreatment and undertreatment. Furthermore, "stress dosing" is necessary during times of major stress, illness, or surgery (J. Pediatr. Adolesc. Gynecol. 30, 520-534 (2017)). Importantly, high-dose glucocorticoid replacement is required to inhibit ACTH production and thereby reduce adrenal androgen levels. This often means that patients suffer from corticosteroid-related side effects or Cushingoid symptoms in order to control adrenal androgen levels. Therefore, better treatments for CAH are needed. Because ACTH is elevated in CAH, inhibiting its activity via MC2R antagonism represents an attractive means of modulating the steroidogenic pathway.

[0006] Cushing's disease is another rare disorder associated with excessive ACTH secretion caused by pituitary corticotropin adenomas. Clinical symptoms include obesity, hirsutism, muscle weakness, and cardiovascular and metabolic complications associated with hypercortisolism. Treatment for Cushing's disease involves removal of the ACTH-secreting tumor in the pituitary gland or removal of the adrenal gland, but drug therapy is often used in addition to or before surgery to alleviate symptoms. Current drug therapies aim to inhibit adrenal steroidogenesis but are not without side effects, including hypothyroidism and hypogonadism (J. Med. Life 9, 12-18 (2016)). Inhibition of ACTH activity via MC2R antagonism offers a potential therapeutic option in the management of this disease.

[0007] In addition to CAH and Cushing's disease, polycystic ovary syndrome (PCOS) may also be amenable to MC2 modulation. PCOS is associated with dysregulated steroidogenesis and excessive androgen levels. In some patients, androgen excess results from functional adrenal hyperandrogenism (Endocr. Rev. 37, 467-520 (2016)). Modulation of ACTH activity in such patients offers an alternative treatment for this multisystem disorder.

[0008] Thus, MC2R antagonism represents an important therapeutic modality for the treatment of diseases associated with ACTH dysfunction. WO2019 / 23669, WO2021 / 091788, WO2021 / 126693, and WO2021 / 133563 disclose MC2R antagonistic compounds.

[0009] A long duration of action is an important feature in drug design, allowing for prolonged efficacy and simplified dosing regimens (British Journal of Pharmacology 2010, 161(3), 488-508). In the treatment of diseases associated with ACTH dysfunction, especially those with ACTH excess, long-acting inhibitors offer the advantage of insurmountable antagonism, since receptor inhibition is maintained even at high ACTH concentrations. One way to achieve these advantageous drug properties is through the use of dissociation (k off ) involves the development of compounds with slower rates of action (Neurochemistry international 2007, 51(5), 254-260). This has been demonstrated for a variety of targets, 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). Summary of the Invention

[0010] The present invention The present invention provides compounds that have activity as melanocortin subtype-2 receptor (MC2R) antagonists.

[0011] Compounds of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) nNH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, optionally substituted with 1 to 3 fluorine atoms, C 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 is the base: [ka] and; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N; Or L 2 is -CO- and R 4Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, CO2H, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R 16 are independently H or C 1-3 alkyl] is provided.

[0012] The compounds of the present invention can be used as melanocortin subtype-2 receptor (MC2R) modulators. The compounds of the present invention can be used as MC2R inhibitors. The compounds of the present invention can be used as MC2R antagonists. The compounds of the present invention can be used as MC2R antagonists with long receptor retention times. The compounds of the present invention can be used in the treatment of diseases or disorders associated with MC2R. The compounds of the present invention can be used in the treatment of diseases or disorders that benefit from modulation of MC2R activity. The compounds of the present invention can be used in the manufacture of a medicament. The compound or medicament can be for use in the treatment, prevention, amelioration, suppression, or reduction of the risk of a disease or disorder involving MC2R. The compounds of the present invention can be for use as a single medicament or in combination with one or more additional medicaments.

[0013] The 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 disorders, septic shock, and disorders or conditions related thereto.

[0014] Detailed Description of the Invention The present invention relates to novel compounds. The present invention also relates to the use of novel compounds as modulators of the melanocortin subtype-2 receptor (MC2R), particularly as MC2R antagonists. The present invention further relates to novel compounds as MC2R antagonists that have a long residence time at the receptor. The present invention further relates to the use of novel compounds in the manufacture of medicaments for use as MC2R antagonists. The present invention further relates to compounds, compositions, and medicaments that may be useful in the treatment of diseases or disorders characterized by activation of the MC2R receptor.

[0015] Compounds of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, optionally substituted with 1 to 3 fluorine atoms, C 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 is the base: [ka] and; Here, 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;Q9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N; Or L 2 is -CO- and R 4 Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, CO2H, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R16 are independently H or C 1-3 alkyl] is provided.

[0016] Also, the compound of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2bare independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, optionally substituted with 1 to 3 fluorine atoms, C 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 is the base: [ka] and; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N; Or L 2 is -CO- and R 4 Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R 16 are independently H or C 1-3 alkyl] is provided.

[0017] Also, the compound of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, optionally substituted with 1 to 3 fluorine atoms, C 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 is the base: [ka] and; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2)g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R 16 are independently H or C 1-3 alkyl] is provided.

[0018] Also, the compound of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, optionally substituted with 1 to 3 fluorine atoms, C 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3cis H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is -CO- and R 4 Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R16 are independently H or C 1-3 alkyl] is provided.

[0019] Also, the compound of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2bare independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 teeth, [ka] or L 2 is -CO- and R 4 Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R 16 are independently H or C 1-3 alkyl] is provided.

[0020] Also, the compound of formula (1): [ka] ; or its salts [In the formula, J is N or CH; X is -CO-, -CH2- or -CH2CH2-; Z is a bond, -CH2- or -CO-; L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -wherein n is 0 to 5; R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; R 2 H, OH, NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted by R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 is alkyl; R 3 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 is cycloalkyl; or R 3 is R 3a and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3a is H or R 3 and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 cycloalkyl; or R 3b is R 3c and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R 3c is H or R 3b and linking to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; where R 3 and R 3b one or both of are H; L 2 is a bond or -CO-, and R 4 teeth, [ka] or L 2 is -CO- and R 4 Ha-(CH2) q NH2, where q is 0 to 3; R 5 , R6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 independently selected from alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN, and SO2Me; R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3; R 13 and R 14 are independently H or methyl; R 15 and R 16 are independently H or C 1-3 alkyl] is provided.

[0021] In the compounds herein, J can be N or CH. J can be N. J can be CH.

[0022] 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-.

[0023] 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.

[0024] In the compounds herein, R 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 R can be cycloalkyl. 1 is C optionally substituted with 1 to 3 fluorine atoms 1-4 R can be alkyl. 1 is C 1-4 R can be alkyl. 1 R can be methyl or ethyl. 1 R can be methyl. 1 R can be ethyl. 1 R can be perdeuteroethyl. 1 can be -CD2CD3. R 1 R can be trideuteromethyl. 1 can be -CD3.

[0025] In the compounds herein, L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0 to 5. 1can be a bond, -CH2CH2CONH-, -COO-, -CH2CH2COO-, -CH2CH2CO-, -COCH2NH-, -COCH2CH2NH-, -CO-, -COCH2-, -CH2CH2- or -CH2-. 1 can be a bond.

[0026] In the compounds herein, R 2 are H, CO2H, OH, and NR 2a R 2b ,CONR 2a R 2b , SO2NR 2a R 2b , possibly R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 R may be a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted with 2 is H, sometimes R 10 , R 11 and R 12 a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with, or optionally R 10 , R 11 and R 12 R may be a 7- to 10-membered bicyclic or heterobicyclic ring system optionally substituted with 2 is H, sometimes R 10 , R 11 and R 12 a piperidine ring optionally substituted with R 10 , R 11 and R 12 a pyrrolidine ring optionally substituted with R 10 , R 11 and R 12 an azetidine ring optionally substituted with R 10 , R 11 and R 12 a hexahydro-1H-pyrrolidine ring system optionally substituted with R 10 , R11 and R 12 a 2-pyrrolidone ring optionally substituted with R 10 , R 11 and R 12 a 1-azabicyclo[2.2.2]octane ring system optionally substituted with R 10 , R 11 and R 12 a tetrahydrofuran ring optionally substituted with R 10 , R 11 and R 12 It may be a morpholine ring optionally substituted with

[0027] In the compounds herein, R 2a and R 2b are independently H or C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 2a and R 2b are independently H or C 1-3 R can be alkyl. 2a and R 2b can independently be H or methyl. 2a and R 2b can both be H.

[0028] R 2a is H or C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 2a is H or C 1-3 R can be alkyl. 2a can be H or methyl. 2a can be H.

[0029] R 2b is H or C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 2b is H or C 1-3 R can be alkyl. 2b can be H or methyl. 2b can be H.

[0030] In the compounds herein, R 10 , R 11 and R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3. 10 , R 11 and R 12 can be independently selected from H, OH, CH2CH2OH, CH2NH2, and CH2CH2OCH2CH2OCH3.

[0031] R 10 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3. 10 R can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. 10 can be H. R10 can be OH. 10 can be CH2CH2OH. R 10 can be CH2NH2. R 10 can be CH2CH2OCH2CH2OCH3.

[0032] R 11 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13 and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3. 11 R can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. 11 can be H. R 11 can be OH. 11 can be CH2CH2OH. R 11 can be CH2NH2. R 11 can be CH2CH2OCH2CH2OCH3.

[0033] R 12 is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms 1-3 Alkyl, SO2NH2, OSO2OH, OSO2F, B(OH)2, Bpin, -(CH2) g NR 13 R 14 , -CH2(CH2) g (OCH2CH2O) y R 13 , -(CH2) g CO2R 13and -(CH2) g CONR 13 R 14 where g is 0 to 3 and y is 1 to 3. 12 R can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3. 12 can be H. R 12 can be OH. 12 can be CH2CH2OH. R 12 can be CH2NH2. R 12 can be CH2CH2OCH2CH2OCH3.

[0034] R 13 and R 14 can independently be H or methyl. 13 can be H or methyl. 14 can be H or methyl. 13 can be H. R 13 R can be methyl. 14 can be H. R 14 can be methyl.

[0035] In the compounds herein, R 2 teeth, [ka] [ka] You can choose from:

[0036] In the compounds herein, the moiety -L 1 -R 2 teeth, [ka] [ka] [ka] You can choose from:

[0037] In the compounds herein, R 3 is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 or R 3 is R 3a and R can be linked to form a cyclopropyl ring or a cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms. 3 is H or C optionally substituted with 1 to 3 fluorine atoms 1-3 R can be alkyl. 3 is H or C 1-3 R can be alkyl. 3 can be H, methyl or ethyl.

[0038] In the compounds herein, R 3a can be H or R 3 can be linked to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms.

[0039] In the compounds herein, R 3b is H, C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 or R 3b is R 3c and R can be linked to form a cyclopropyl ring or a cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms. 3b is H or C optionally substituted with 1 to 3 fluorine atoms1-3 R can be alkyl. 3b is H or C 1-3 R can be alkyl. 3b can be H, methyl or ethyl.

[0040] In the compounds herein, R 3c can be H or R 3b can be linked to form a cyclopropyl ring or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms.

[0041] In the compounds herein, R 3 and R 3b is H. Thus, for example, the structure of formula (1) as defined herein can be effectively depicted as the scope of formulas (1′) and (1″) taken together. [ka]

[0042] R 3 , R 3a , R 3b and R 3c can all be H. R 3 and R 3b one of which is C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, optionally substituted with 1 to 3 fluorine atoms; 3-4 Cycloalkyl or CH2C optionally substituted with 1 to 3 fluorine atoms 3-4 One can be cycloalkyl and the other can be H. 3 and R 3b One of R can be methyl or ethyl, the other H. 3 and R 3b One of R can be methyl and the other can be H. 3 and R 3b One of them can be ethyl and the other can be H.

[0043] In the compounds herein, L2 can be a bond or -CO-, and R 4 is the base: [ka] It can be; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N; Or L 2 can be -CO-, and R 4 Ha-(CH2) q NH2, where q is 0-3.

[0044] L 2 can be a bond or -CO-, and R 4 teeth, [ka] may be a group selected from: or L 2 can be -CO-, and R 4 Ha-(CH2) q NH2, where q is 0-3.

[0045] L 2 can be a bond or -CO-, and R 4 teeth, [ka] may be a group selected from: or L 2 can be -CO-, and R4 Ha-(CH2) q NH2, where q is 0-3.

[0046] L 2 can be a bond or -CO-, and R 4 teeth, [ka] may be a group selected from: Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One, two, or none of the above are N.

[0047] L 2 can be a bond or -CO-, and R 4 is the base: [ka] It can be; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 One of them is N.

[0048] L 2 can be a bond or -CO-, and R 4 is the base: [ka] It can be; Here, 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;Q 9 is CR 9 or N; where Q 5 , Q 6 , Q 7 , Q 8 and Q 9 Two of them are N.

[0049] L 2 can be a bond or -CO-, and R 4 is the base: [ka] It could be.

[0050] L 2 can be a bond or -CO-, and R 4 teeth, [ka] It may be a group selected from:

[0051] L 2 can be a bond or -CO-, and R 4 teeth, [ka] It may be a group selected from:

[0052] L 2 can be -CO-, and R4 -(CH2) q NH2, where q is 0-3.

[0053] In the compounds herein, R 5 , R 6 , R 7 , R 8 , and R 9 H, halo, CN, NR 15 R 16 C optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OC optionally substituted with 1 to 3 fluorine atoms 1-3 alkyl, OCH2cyclopropyl optionally substituted with 1 to 3 fluorine atoms, OCH2CN and SO2Me.

[0054] In the compounds herein, R 15 and R 16 are independently H or C 1-3 R can be alkyl. 15 and R 16 may independently be H, methyl, ethyl, n-propyl, or isopropyl.

[0055] R 5 , R 6 , R 7 , R 8 , and R 9 is H, Cl, F, I, CN, CF3, CF2H, -OMe, -OEt, -O n It can be independently selected from Pr, -N(CH3)(CH2CH2CH3), -N(CH3)2, -OCH2CN, -OCH2cyclopropyl, -CO2H and -SO2Me.

[0056] L 2 can be a bond or -CO-, and R 4 teeth, [ka] [ka] [ka] It may be a group selected from:

[0057] L 2 can be -CO-, and R 4 Ha-(CH2) q NH2, where q is 0-3.

[0058] L 2 can be -CO-, and R 4 teeth, [ka] You can choose from:

[0059] R 4 teeth, [ka] [ka] [ka] It may be a group selected from:

[0060] In this specification, L 1 and L 2 The definition of L is given without limitation to a particular orientation relative to the rest of the molecule. 1 and L 2 The definition of L includes all possible orientations unless otherwise specified. 1 In compounds where is defined as -CONH-, both of the following may be included: [ka]

[0061] The compound is a compound of formula (1') or (1''): [ka] 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 is as defined herein.

[0062] The compound has the formula (1'''), (1''''), (1'''''), (1''''''), (1'''''''), or (1''''''''): [ka] or a salt thereof, wherein J, X, Z, L 1 , L 2 , R 1 , R 2 , R 3 and R 4 is as defined herein.

[0063] The compound is a compound of formula (2a) or (2b): [ka] or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 is as defined herein.

[0064] The compound is a compound of formula (2aD) or (2bD): [ka] or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 is as defined herein.

[0065] The compound is a compound of formula (2ai), (2bi), (2ai') or (2bi'): [ka] or a salt thereof, wherein X, Z, L 1 , R 2 and R 4 is as defined herein.

[0066] The compound is a compound of formula (2aii), (2aiii), (2aiv), (2bii), (2biii) or (2biiv): [ka] or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 is as defined herein.

[0067] The compound is a compound of formula (2av), (2avi), (2avii), (2bv), (2bvi) or (2bvii): [ka] or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 is as defined herein.

[0068] The compound is a compound of formula (3a), (3b), (3c), (3d), (3e) or (3f): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0069] The compound is a compound of formula (3ai), (3bi), (3ci), (3di), (3ei) or (3fi): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0070] The compound is a compound of formula (3aii), (3bii), (3cii), (3dii), (3eii) or (3fii): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0071] The compound is a compound of formula (3aiii), (3biii), (3ciii), (3diii), (3eiii) or (3fiii): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0072] The compound is a compound of formula (3aiv), (3biv), (3civ), (3div), (3eiv) or (3fiv): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0073] The compound is a compound of formula (3av), (3bv), (3cv), (3dv), (3ev) or (3fv): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 is as defined herein.

[0074] The compound is a compound of formula (5a) or (5b): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined herein.

[0075] The compound is a compound of formula (6a), (6b), (6c), (6d), (6e), (6f), (6g) or (6h): [ka] or a salt thereof, wherein L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined herein.

[0076] The compound is a compound of formula (9a), (9b), (9c), (9d), (9e) or (9f): [ka] or a salt thereof, wherein R 3 and R 4 is as defined herein.

[0077] The compound can be selected from any one of Examples 1-218, or a salt thereof, as shown in Table 1a.

[0078] The compound is

[0079] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] or a salt thereof.

[0080] These salts may be pharmaceutically acceptable salts. These salts may be formate, trifluoroacetic acid (TFA) salt, mesylate or hydrochloric acid (HCl) salt. These salts may be formate or trifluoroacetic acid (TFA) salt.

[0081] The compound is

[0082] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] The salt may be selected from the group consisting of:

[0083] Further embodiments of the present 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. The compounds of the present invention can be used as MC2R receptor modulators. The compounds of the present invention can be used as MC2R receptor inhibitors or antagonists. The compounds of the present invention can be used in the treatment of diseases or disorders characterized by MC2R activation. The compounds of the present invention can be used in the treatment of diseases or disorders associated with MC2R or diseases or disorders that would benefit from modulation of MC2R activity.

[0084] The compounds of the present invention can be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depression, septic shock and disorders or conditions related thereto.

[0085] In some embodiments, the compounds and compositions detailed herein are used as modulators of MC2R. Provided herein are methods 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.

[0086] The compounds disclosed herein as MC2R modulators may be useful as prophylactic or therapeutic agents for MC2R-related diseases. In some embodiments, the compounds or salts thereof described herein or the compositions described herein may be used in methods for treating Cushing's disease in individuals.

[0087] Also provided is a combination comprising a compound of the invention and a corticotropin-releasing factor receptor-1 (CRF1) antagonist. In these 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.

[0088] In these combinations, the CRF1 antagonist [ka] may be selected from:

[0089] Also provided are combinations comprising a compound of the present invention and an ACTH antibody, in which the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8).

[0090] These combinations can be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depression, septic shock and related disorders or conditions.

[0091] Also provided herein is the use 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 the medicament is for the treatment of a disorder or disease described herein. In some embodiments, the manufacture of the medicament is for the prevention and / or treatment of a disorder or disease mediated by MC2R.

[0092] In some embodiments, the compounds or salts thereof described herein or the compositions described herein can be used in the methods as a monotherapy or as a combination therapy with other agents that are either palliatives (e.g., agents that alleviate the symptoms of the disorder being treated) and / or agents that target the etiology of the disorder. The compounds or compositions of the invention can be used or administered in combination with a second therapeutic agent.

[0093] 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 administered sequentially, concomitantly, or simultaneously. 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 within about 15 minutes, e.g., within about 10, 5, or 1 minute. 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 within about 15 minutes or more, e.g., about 20, 30, 40, 50, 60 minutes or more. Either (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, or (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.

[0094] definition In this application, the following definitions apply unless otherwise specified.

[0095] The term "MC2R modulator," as used herein, refers to any compound that binds to the MC2 receptor and modulates its function. The term "modulator" should be interpreted to include modulation by modes including, but not limited to, antagonists.

[0096] In connection with any use of the compounds described herein, including compounds of Formula (1), the term "treatment" is used to refer to any form of intervention in which a compound is administered to a subject suffering from, at risk of suffering from, or potentially at risk of suffering from the disease or disorder of interest. Thus, the term "treatment" includes both prophylactic treatment and treatment when measurable or detectable symptoms of the disease or disorder are manifest.

[0097] The term "therapeutically effective amount" refers to an amount of a compound effective to produce a desired therapeutic effect (e.g., in the context of a method for treating a disease or condition). For example, if the condition is pain, an effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain.

[0098] All chemical terms are used with their conventional meaning (eg, as defined in the IUPAC Gold Book) unless otherwise noted.

[0099] The term "alkyl," as used herein, means a saturated alkyl group of either a straight or branched chain.

[0100] The term "cycloalkyl," as used herein, means a saturated carbocyclic group containing the specified number of carbon atoms.

[0101] The term "carbocycle," as used herein, means a saturated or unsaturated carbocyclic group containing the specified number of carbon atoms.

[0102] The term "heterocyclic ring," as used herein, refers to a saturated or unsaturated ring containing a specified number of total ring member atoms, one or more of which are heteroatoms selected from O, S and N, and oxidized forms thereof, and the remaining atoms are C.

[0103] The term "bicyclic," as used herein, means a saturated or unsaturated ring system comprising two connected rings and containing the specified number of total atoms. All possible ring linkage modes are included (including spirocyclic, fused, and bridged).

[0104] The term "heterobicyclic," as used herein, means a saturated or unsaturated heterocyclic ring comprising two connected rings and containing the specified number of total atoms. All possible ring linkage modes are included (including spirocyclic, fused, and bridged).

[0105] The number of carbon atoms possible in a group referred to herein is indicated by the subscript "C n1-n2 ". Therefore, for example, "C 1-3 The term "alkyl" refers to alkyl groups having 1, 2 or 3 carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl.

[0106] The term "optionally substituted" applied to any group means that the group may be optionally substituted with one or more substituents, which may be the same or different. Thus, for example, the term "optionally substituted with 1 to 6 fluorine atoms" applied to a group means that the group may be optionally substituted with 1, 2, 3, 4, 5, or 6 fluorine atoms.

[0107] To the extent that any of the compounds described contain chiral centers, the present invention extends to all optical isomers of such compounds, whether in racemic or resolved enantiomer form. The invention described herein relates to all crystalline forms, solvates, and hydrates of the disclosed compounds, provided that they are so prepared. To the extent that any of the compounds disclosed herein contain an acidic or basic center, such as a carboxylate or amino group, all salt forms of said compounds are included herein. For pharmaceutical purposes, the salts should be considered pharmaceutically acceptable salts.

[0108] Salt or pharmaceutically acceptable salt that can be mentioned includes acid addition salt and base addition salt.Such salt can be formed by conventional means, for example, by reacting the free acid or free base form of compound with one or more equivalents of suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or the medium using standard techniques (for example, by vacuum, freeze-drying or filtration).Salt can also be prepared by exchanging the counterion of the compound in the form of salt with another counterion, for example, by using a suitable ion exchange resin.

[0109] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, and salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0110] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphoric acid, and the like. -sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D -glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1-hydroxybenzoic ... These include acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0111] Also included are any solvates of the present compounds and their salts. Preferred solvates are those formed by incorporating molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, butanol, etc.), and DMSO. Solvates can be prepared by recrystallizing the compounds of the present invention using a solvent or solvent mixture containing a solvating solvent. Whether a solvate has been formed can be determined by analyzing the crystals of the compound using well-known standard techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0112] Solvate can be stoichiometric or non-stoichiometric solvate.Particular solvate can be hydrate, and the example of hydrate includes hemihydrate, monohydrate, dihydrate.For more detailed discussion of solvate and the method used for its preparation and characterization, 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.

[0113] In the context of the present invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and one or more pharmaceutically acceptable carriers. Depending on the mode of administration and the nature of the dosage form, this composition may further comprise components selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersing agents. These compositions may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, troches, emulsions, solutions, cachets, granules, capsules, and suppositories, as well as injectable liquid preparations including liposomal preparations.

[0114] The compounds of the present invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope all isotopes of that element. 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include the ranges, respectively. 12 C. 13 C and 14 C and 16 O and 18 O. Similarly, when a particular functional group is referred to, isotopic variations are included within its scope 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 includes variations in which one or more of the hydrogen atoms in the group are isotopic forms of deuterium or tritium, such as an ethyl group in which all five hydrogen atoms are isotopic forms of deuterium (perdeuteroethyl), or a methoxy group in which all three hydrogen atoms are isotopic forms of deuterium (trideuteromethoxy). Isotopes may be radioactive or non-radioactive.

[0115] Treatment dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used.Determining the appropriate dosage for specific circumstances is within the skill of the art.Generally, treatment is started with a small dosage that is less than the optimal dosage of the compound.Then, the dosage is gradually increased until the optimal effect is achieved under the circumstances.For convenience, if desired, the total daily dosage can be divided into portions and administered in small amounts throughout the day.

[0116] The magnitude of an effective dose of a compound will, of course, vary depending on the nature and severity of the condition being treated, the particular compound, and its route of administration. Selecting an appropriate dose is within the capabilities of one skilled in the art without undue burden. Generally, the daily dose ranges from about 10 μg to about 30 mg per kg of body weight for humans and non-human animals, preferably about 50 μg to about 30 mg per kg of body weight for humans and non-human animals, e.g., about 50 μg to about 10 mg per kg of body weight for humans and non-human animals, e.g., about 100 μg to about 30 mg per kg of body weight for humans and non-human animals, e.g., about 100 μg to about 10 mg per kg of body weight for humans and non-human animals, most preferably about 100 μg to about 1 mg per kg of body weight for humans and non-human animals.

[0117] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, a formulation).

[0118] Thus, in some embodiments of the present 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.

[0119] Pharmaceutically acceptable excipients can be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), 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-suppressing or -retarding polymers or waxes), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, isotonicity agents, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste-masking agents, stabilizers, or any other excipient conventionally used in pharmaceutical compositions.

[0120] The term "pharmaceutically acceptable," as used herein, means a compound, material, composition, and / or dosage form that is, 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.

[0121] Pharmaceutical compositions containing compounds of formula (1) can be formulated according to known techniques, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical composition can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, vaginal, or transdermal administration.

[0122] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft coated), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0123] The composition can be a tablet composition or a capsule composition.The tablet composition can contain a unit dose of the active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, for example, lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents, for example, sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, for example, microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, for example, corn starch.The tablet can also contain standard ingredients, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures, as binders and granulating agents.Such excipients are well known and need not be described in detail here.

[0124] Tablets may be designed to release the drug upon contact with gastric fluids (immediate-release tablets) or may be designed to release the drug in a controlled manner over an extended period of time or in specific areas of the gastrointestinal tract (controlled-release tablets).

[0125] Pharmaceutical compositions generally comprise approximately 1% (w / w) to approximately 95%, preferably % (w / w), of the active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises approximately 20% (w / w) to approximately 90% (w / w) of the active ingredient and 80% (w / w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. Pharmaceutical compositions comprise approximately 1% to approximately 95%, preferably approximately 20% to approximately 90%, of the active ingredient. Pharmaceutical compositions according to the present invention may be in unit dosage form, for example, in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets, or capsules.

[0126] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) bulking agent and / or filler (depending on drug dose). Tablets and capsules may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, and 0-5% (w / w) pigment. Slow-release tablets also typically contain 0-99% (w / w) release-controlling (e.g., retarding) polymer (depending on drug dose). The film coat of a tablet or capsule typically contains 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0127] The composition may be a parenteral composition. Parenteral formulations generally contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether lyophilized). Intramuscular depot formulations may also contain 0-99% (w / w) oil.

[0128] Pharmaceutical formulations may be provided to the patient in "patient packs" containing an entire course of treatment in a single package, usually a blister pack.

[0129] The compounds of Formula (1) are generally provided in unit dosage form and, therefore, generally contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, subranges for particular compounds are 0.1 milligrams to 2 grams of active ingredient (more usually 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 milligram to 20 milligrams (e.g., 1 milligram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0130] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more usually 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram, of active compound.

[0131] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of compound to be administered can be determined by a supervising physician according to standard procedures. [Example]

[0132] The present invention will now be illustrated with reference to the non-limiting examples shown in Table 1a.

[0133] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20]

[0134] Preparation of Compounds of the Invention The compounds of formula (1) and derivatives or their synthetic intermediates can be prepared according to synthetic methods known to those skilled in the art. In some embodiments, the present invention provides methods for preparing the compounds defined by formula (1) above.

[0135] Several methods for the chemical synthesis of the spiro[piperidine-4,5'-[1,7]naphthyridine] compounds of the present application are described herein. These and / or other well-known methods can 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 their derivatives or synthetic intermediates can be prepared according to general scheme 1.

[0136] General Scheme 1: [ka] In one approach (General Scheme 1), compounds of formula [X3] can be prepared by reacting compounds of formula [X1] with heteroaromatic or substituted phenyl compounds of formula [X2] in a transition metal-catalyzed cross-coupling reaction, such as the Buchwald-Hartwig amination, using catalysts such as Pd(dba)2, Pd(OAc)2, or Pd(o-tolyl)3, phosphine ligands such as BINAP, DPPF, Xantphos, or JohnPhos, and bases such as NaOtBu, K2CO3, or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane, or toluene. This reaction is suitably carried out at elevated temperatures. Alternatively, compounds of formula [X3] can also be prepared by reacting compounds of formula [X1] with heteroaromatic or substituted phenyl compounds of formula [X2] in a nucleophilic aromatic substitution (SNAr)-related reaction using bases such as DIPEA, K2CO3, Cs2CO3, or KOH in a polar solvent such as DMF or THF. This reaction is suitably carried out at elevated temperatures. Alternatively, compounds of formula [X3] can be prepared by reacting them with carboxylic acids of formula [X2] in an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF, and a base such as DIPEA. This reaction is typically carried out at room temperature. In all cases, after workup, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization. Compounds of formula [X4] can be prepared by standard methods for removing protecting groups (PG) using compounds of formula [X3]. In the case of benzyloxycarbonyl (Cbz), methods include hydrogenation under a hydrogen atmosphere in the presence of palladium on activated carbon in a polar solvent such as ethanol or methanol. Alternatively, methods using a strong base such as KOH in a solvent such as ethanol, suitably carried out at elevated temperatures. After workup, typically by filtration and / or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization.Compounds of formula [X6] can be prepared by reacting compounds of formula [X4] with aldehyde or ketone derivatives of general formula [X5] via reductive amination using a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE, or methanol. After workup, typically liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, chiral preparative SFC, or recrystallization. Alternatively, they can be prepared by a displacement reaction using an alkyl halide [X5'] or an alkyl methanesulfonate with a strong base such as NaH and a solvent such as DMSO. Alternatively, they can be prepared by an amide coupling reaction using a carboxylic acid of formula [X5''] with a coupling agent such as HATU, a solvent such as DCM or DMF, and a base such as DIPEA. This reaction is typically performed at room temperature. In some instances, compounds of formula [X6] contain an amino group, which is protected by a nitrogen protecting group such as the tert-butyloxycarbonyl protecting group. In these examples, compounds of formula [X7] are prepared by standard removal of the tert-butyloxycarbonyl protecting group by reacting compounds of formula [X6] with an acid such as trifluoroacetic acid or phosphoric acid in DCM, or HCl or formic acid in dioxane. After workup of the reaction, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, chiral preparative SFC, or recrystallization.

[0137] General Scheme 2: [ka] In another approach (General Scheme 2), compounds of formula [X3'] can be prepared by reacting compounds of formula [X1'] with aldehydes of formula [X2] via reductive amination using a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE, or methanol. After workup of the reaction, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, chiral preparative SFC, or recrystallization. Alternatively, they can be prepared using alkyl halides [X2'] or alkyl methanesulfonates via a displacement reaction using a strong base such as NaH and a solvent such as DMSO. Alternatively, they can be prepared by an amide coupling reaction using a carboxylic acid of formula [X2''] with a coupling agent such as HATU, a solvent such as DCM or DMF, and a base such as DIPEA. This reaction is typically performed at room temperature. Compounds of formula [X4'] can be prepared using compounds of formula [X3'] via standard methods for the removal of protecting groups (PG). Compounds of formula [X6] can be prepared by reacting a compound of formula [X4'] with a heteroaromatic or substituted phenyl compound of formula [X5] in a transition metal-catalyzed cross-coupling reaction, such as the Buchwald-Hartwig amination, using a catalyst such as Pd(dba)2, Pd(OAc)2, or Pd(o-tolyl)3, a phosphine ligand such as BINAP, DPPF, Xantphos, or JohnPhos, and a base such as NaOtBu, K2CO3, or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane, or toluene. This reaction is suitably carried out at elevated temperatures. Alternatively, compounds of formula [X6] can also be prepared by reacting a compound of formula [X4'] with a heteroaromatic compound of formula [X5] in a nucleophilic aromatic substitution (SNAr)-related reaction using a base such as DIPEA, K2CO3, Cs2CO3, or KOH in a polar solvent such as DMF or THF, suitably carried out at elevated temperatures. In some examples, compounds of formula [X6] contain an amino group, which is protected by a nitrogen protecting group, such as a tert-butyloxycarbonyl protecting group.In these examples, compounds of formula [X7] are prepared by standard removal of the tert-butyloxycarbonyl protecting group by reacting compounds of formula [X6] with an acid such as trifluoroacetic acid or phosphoric acid in DCM, or HCl or formic acid in dioxane. After workup of the reaction, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, chiral preparative SFC, or recrystallization.

[0138] General Scheme 3: [ka] Compounds of formula [X1] and [X1'] can be obtained by various methodologies (General Scheme 3). In one approach, compounds of formula [X1'] can be prepared by reaction-cyclization of compounds of formula [X1'_3] in one or two steps by reacting 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 with a suitable solvent such as ethanol and water under a hydrogen atmosphere. Compounds of formula [X1'_3] can be prepared by reacting 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 at a suitable low temperature. Alternatively, compounds of formula [X1'] can be prepared by reducing compounds of formula [X1'_5] with a suitable reducing agent, such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd / C, ammonium formate or Mn(dpm)3, PhSiH3, TBHP, etc., in a suitable solvent, typically an alcoholic solvent, at a suitable temperature. Compounds of formula [X1'_5] can then be prepared by a one- or two-step cyclization reaction of compounds of formula [X1'_4] 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 using a suitable solvent, such as ethanol and water. Compounds of formula [X1'_4] can also be prepared by reacting 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 at a suitable low temperature. Alternatively, compounds of formula [X1'] can be prepared from compounds of formula [X1'_8] using standard deprotection conditions, depending on the nature of the PG. Compounds of formula [X1] can be prepared from compounds of formula [X1_8] using typical benzyl deprotection conditions such as NaOH in solvents such as ethanol and water at elevated temperatures.Alternatively, they can also be prepared by reduction under a hydrogen atmosphere using a suitable catalyst such as Pd(OH) in a suitable solvent such as MeTHF, MeOH, or IPA. Compounds of formula [X1_8] can be prepared by reduction of compounds of formula [X1_7] using a suitable reducing agent such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd / C, ammonium formate or Mn(dpm)3, PhSiH3, or TBHP in a suitable solvent, typically an alcoholic solvent, at a suitable temperature. Compounds of formula [X1_7] can be prepared by reacting 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 at room temperature. Compounds of formula [X1_7] can also be prepared using compounds of formula [X1'5] using standard protecting group addition reaction conditions.

[0139] The compounds of the present invention can be prepared according to the following methods: Note that all reported yields are based on the weight of starting materials and products, not their purity.

[0140] [Table 4]

[0141] [Table 5-1] [Table 5-2] [Table 5-3]

[0142] [Table 6]

[0143] [Table 7-1] [Table 7-2]

[0144] 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) [ka]

[0145] To a stirred solution of 6-chloro-3-fluoropicolinic acid (10 g, 57.0 mmol) in 1,4-dioxane:HO (80:20 mL), (2-ethoxypyridin-3-yl)boronic acid (11.4 g, 68.4 mmol) was added followed by KCO (15.8 g, 114 mmol) at room temperature, and the solution was purged with nitrogen for 5 minutes. Pd(amphos)Cl (0.605 g, 0.854 mmol) was added to the reaction mixture, which was then heated at 100 °C for 16 hours. The mixture was filtered through a Celite bed, and the bed was washed with EtOAc (100 mL). The combined filtrate was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The aqueous layer was acidified with citric acid (10%) (a solid precipitated). The precipitated solid was filtered off to give 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (12 g, 44.8 mmol, 79%) as a white solid. LCMS: 2.04 min, 263.1(M+H) + , method B

[0146] 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 the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. This crude material was purified by flash column chromatography. Pure fractions were concentrated under reduced pressure to give ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (10 g, 34.1 mmol, 75%) (Intermediate 1) as an off-white solid.

[0147] To a mixture of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (2.5 g, 8.61 mmol) (Intermediate 1) and tert-butyl 4-cyanopiperidine-1-carboxylate (1.81 g, 8.61 mmol) in toluene (25 mL) was added 1 M KHMDS in THF (8.61 mL, 8.61 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude material. The crude material was purified by flash column chromatography using EtOAc-PET ether (0-10%) to give 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 colorless gum. LCMS: 2.99min, 481.0(M+H) + , method B

[0148] 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:HO (20:5 mL) was added Raney nickel (5.47 g, 62.4 mmol) at room temperature, and the reaction mixture was stirred under hydrogen gas at 70 psi pressure at 65 °C for 16 h. The reaction mixture was filtered through a bed of Celite, and the bed was washed with MeOH (20 mL). The combined filtrate was concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography to give 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 a white solid.

[0149] 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) and stirred at 0 °C for 20 minutes. Cbz-Cl (2.29 mL, 6.84 mmol) was added to the reaction mixture, and the reaction mixture was stirred slowly at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography to give 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 an off-white solid.

[0150] 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 the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude material. The crude material was quenched with 1.5 N HCl (5 mL) and extracted with DCM (2 x 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-carboxylate benzyl 2,2,2-trifluoroacetate (600 mg, 1.002 mmol, 82%) (Intermediate 4) as a sticky solid. The analytical data for intermediates 1, 2, 3 and 4 are shown in Table 1.

[0151] 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) [ka]

[0152] 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 the reaction mixture was stirred at room temperature for 2 h. After 2 h, excess BH3.THF (4.19 mL, 4.19 mmol) was added at 0° C., and the reaction mixture was further stirred at room temperature for 14 h. The reaction was quenched with MeOH (10 mL) at 0° C., and the reaction mixture was concentrated to give 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 a sticky solid. The crude material was used directly in the next step.

[0153] 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 the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated, and the resulting residue was basified with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 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 are shown in Table 1.

[0154] Procedure for the preparation of nitriles exemplified by the preparation of 1-(4-chloro-2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (Intermediate 6) [ka]

[0155] To a stirred solution of piperidine-4-carbonitrile (250 mg, 2.269 mmol) in toluene (2 mL) at room temperature, 1-bromo-4-chloro-2-(trifluoromethyl)benzene (883 mg, 3.40 mmol) and CsCO (1.48 g, 4.54 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes. BINAP (283 mg, 0.454 mmol) and Pd(OAc) (51 mg, 0.227 mmol) were added, and the reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was filtered through Celite and washed with EtOAc (10 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography to give 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 are shown in Table 1.

[0156] Procedure for the preparation of lactams exemplified by the preparation of 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (intermediate 8) [ka]

[0157] To a solution of 2-(6-chloropyridin-3-yl)acetonitrile (10 g, 65.54 mmol) in DMSO (200 mL), potassium hydroxide (11.03 g, 196.62 mmol) was added portionwise, and N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (17.60 g, 65.54 mmol) was added at 25° C. The reaction mixture was stirred at 30° C. for 2.5 hours. After cooling to room temperature, 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), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column (eluted with PET ether / Et0Ac=100 / 1 to 20 / 1) to give 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carbonitrile (11 g, 53.8%) as an orange solid. 1 H 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)

[0158] To a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carbonitrile (5.5 g, 17.64 mmol) in a mixture 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 hours. An additional vial was prepared as described above. After cooling to room temperature, the two reaction mixtures were combined. The mixture was stripped of ethanol and acidified to pH 4 with hydrochloric acid (4 N). The suspension was filtered, and the filter cake was dried under reduced pressure to give 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (8 g) as a white solid, which was used directly in the next step without further purification. LCMS: 0.72 min, 331.1(M+H) + , method O

[0159] To a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (9.4 g, 28.42 mmol) in a mixture 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), neutralized to pH 8 with saturated sodium bicarbonate (200 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phases were concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography (eluting with PET ether / EtOAc = 100 / 5 to 100 / 20) to give methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (6 g, 61%) as a yellow solid. 1 H 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)

[0160] 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 urea hydrogen peroxide (545 mg, 5.80 mmol) and trifluoroacetic anhydride (1.22 g, 5.80 mmol, 806.7 μL) at 25° C. The reaction mixture was stirred at 25° C. for 12 hours. An additional vial was prepared as above. The two reaction mixtures were combined, quenched with saturated sodium sulfite (200 mL) at 0° C., and extracted with DCM (3×100 mL). The combined organic phase was washed with saturated 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 give a crude material, which was purified by flash column chromatography (eluted with EtOAc / MeOH = 100 to 100 / 10) to give 5-(1-benzyl-4-(methoxycarbonyl)piperidin-4-yl)-2-chloropyridine 1-oxide (1 g, 48%) as a yellow solid. 1 H 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).

[0161] 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 μL) at 25 °C. The reaction mixture was heated to 70 °C and stirred for 12 h. Two more vials were prepared as above. After cooling to room temperature, all three reaction mixtures were combined, diluted with sodium hydroxide solution (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 give 1-benzyl-4-(6-chloro-2-cyanopyridin-3-yl)piperidine-4-carboxylic acid methyl salt (1.5 g, 49%) as a yellow oil. 1 H 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)

[0162] 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 of dioxane (20 mL) and water (2 mL) was added (2-ethoxypyridin-3-yl)boronic acid (921.3 mg, 5.6 mmol), KCO (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 room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude material, which was purified by prep-TLC (EtOAc, R f =0.29) to give 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. 1 H 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)

[0163] 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) dropwise at 0°C under nitrogen. The reaction mixture was heated to 40°C and stirred at 40°C for 2 h. An additional vial was prepared as above. After cooling to 0°C, the 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 give a residue, which was purified by flash column chromatography (eluting with PET ether / EtOAc to EtOAc / MeOH = 20 / 80 to 90 / 10) to give 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. 1 H 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)

[0164] 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) was added Pd(OH) (100 mg, 142.4 μmol, 20% purity) and di-tert-butyl dicarbonate (101.9 mg, 466.7 μmol, 107.2 μL) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred under a hydrogen balloon (15 Psi) at 20 °C for 5 h. Two additional vials were prepared as above. All three reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by prep-TLC to give 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 colorless oil.

[0165] 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 h. An additional vial was prepared as above. The two reaction mixtures were combined and concentrated under reduced pressure to give a residue that was purified by prep-HPLC to give 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 intermediates 7 and 8 are shown in Table 1.

[0166] Procedure for the preparation of lactams exemplified by the preparation of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (intermediate 10) [ka]

[0167] 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., TFA (0.04 mL, 0.456 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and dried under high vacuum to give 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-8'-one trifluoroacetate (150 mg, 0.400 mmol, 88%) (Intermediate 10) as a brown gum. The analytical data for Intermediate 10 are shown in Table 1.

[0168] Procedure for the preparation of nitriles exemplified by the preparation of 1-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (Intermediate 14) [ka]

[0169] To a stirred solution of piperidine-4-carbonitrile (300 mg, 2.72 mmol) in DMSO (3 mL) was added 4-chloro-2-fluoro-3-iodopyridine (690 mg, 2.68 mmol), followed by DIPEA (1.1 mL, 6.30 mmol), and the reaction was heated at 70° C. for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×10 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 0-50% EtOAc in PET ether to give 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

[0170] To a stirred solution of 1-(4-chloro-3-iodopyridin-2-yl)piperidine-4-carbonitrile (580 mg, 1.669 mmol) in DMF (1 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (390 mg, 2.030 mmol), followed by copper(I) iodide (390 mg, 2.048 mmol), and the reaction mixture was heated at 85° C. for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×10 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. Pure fractions were evaporated and dried under high vacuum to give 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 of intermediate 14 are shown in Table 1.

[0171] Procedure for the preparation of amines exemplified by 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) [ka]

[0172] 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 N for 5 min. CsCO 3(Pd(dba) (48.4 mg, 0.053 mmol), followed by Xantphos (42.9 mg, 0.074 mmol) were added, and the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated to give the crude material. The crude material was purified by flash chromatography in 0-70% EtOAc in PET ether to give 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 the observed migration of the Cbz group. LCMS: 2.89 min, 650.9(M+H) + , method B

[0173] 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 the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with MeOH (10 mL) at 0° C., and the reaction mixture was concentrated to give 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 a sticky solid. The crude material was used directly in the next step. LCMS: 2.56 min, 637.0(M+H) + , method A

[0174] 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), 20% KOH in water (1 mL, 0.157 mmol) was added, and the reaction mixture was stirred for 16 h at 80° C. The reaction mixture was diluted with water (20 mL) and extracted with DCM:MeOH (9:1) (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 a sticky solid. The analytical data of Intermediate 15 are shown in Table 1.

[0175] Preparative procedure exemplified by the preparation of 6-propoxy-2-(trifluoromethyl)nicotinic acid (intermediate 17) [ka]

[0176] To a stirred solution of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (3 g, 12.76 mmol) in DMF (30 mL) was added KCO (2.292 g, 16.58 mmol), followed by 1-bromopropane (1.84 mL, 20.28 mmol), and the reaction mixture was stirred at room temperature 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 give the crude product. The crude product was purified by flash column chromatography using EtOAc-PET ether (0–30%) to give ethyl 6-propoxy-2-(trifluoromethyl)nicotinate (3.51 g, 12.54 mmol, 98%) as a colorless HCl. LCMS: 2.0 min, 278.1(M+H) +, method B

[0177] To a solution of ethyl 6-propoxy-2-(trifluoromethyl)nicotinate (3.5 g, 12.62 mmol) in THF:MeOH:HO (15:7.5:0.5 mL) was added LiOH (1.51 g, 63.1 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with water (2 mL). The aqueous layer was acidified with 1.5 N HCl (1 mL) and extracted with DCM (5 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-propoxy-2-(trifluoromethyl)nicotinic acid (2.8 g, 11.12 mmol, 88%) (Intermediate 17) as a white solid. The analytical data of intermediate 17 are shown in Table 1.

[0178] Procedure for the preparation of lactams exemplified by the preparation of (Intermediate 20) [ka]

[0179] 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), DIPEA (0.310 ml, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol) were added, and the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude compound was purified by flash column chromatography to give 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).

[0180] 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), 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (40.0 mg, 0.208 mmol) and copper(I) iodide (39.7 mg, 0.208 mmol) were added, and the reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude material. The crude material was purified using prep HPLC. Pure fractions were collected and lyophilized to give the 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 an off-white solid. LCMS: 2.33 min, 518.1(M+H) + , method A The analytical data for intermediates 19 and 20 are shown in Table 1.

[0181] Procedure for the preparation of lactams exemplified by 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) [ka]

[0182] 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 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layer was 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 (eluting with PET ether / EtOAc = 15 / 85 to EtOAc / MeOH = 95 / 5, R f =0.4) to give tert-butyl 3-(1-benzyl-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)pyrrolidine-1-carboxylate (420 mg, 57%) as a yellow oil. LCMS: 0.69 min, 598.3(M+H) + , method O

[0183] 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) (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 h, after which the mixture was heated to 40°C and stirred at 40°C for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which afforded tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)pyrrolidine-1-carboxylate (320 mg) (Intermediate 26) as a grey oil, which was used in the next step without further purification. The analytical data of intermediate 26 are shown in Table 1.

[0184] Procedure for the preparation of pyridines exemplified by the preparation of 3,5-dichloro-4-(trifluoromethyl)pyridine (intermediate 27) [ka] To a solution of 3,5-dichloro-4-(trifluoromethyl)pyridine (0.1 g, 463 μmol) in a mixed solvent of 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 h. An additional vial was prepared as described above. After cooling to room temperature, the two reaction mixtures were combined, diluted with brine (15 mL), and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by prep-TLC to give 3-chloro-5-propoxy-4-(trifluoromethyl)pyridine (100 mg, 45%) (Intermediate 27) as a colorless oil. The analytical data of intermediate 27 are shown in Table 1.

[0185] Procedure for the preparation of nitriles exemplified by the preparation of 1-(4-propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (Intermediate 29) [ka] To a stirred suspension of NaH (139 mg, 3.47 mmol) in DMF (2 mL) at 0 °C, propan-1-ol (153 mg, 2.55 mmol) in DMF (2 mL) was added, 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 room temperature for 2.5 h. The reaction mixture was carefully quenched with ice-cold water (20 mL) and extracted with 10% EtOAc in PET ether (3 × 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 0–15% EtOAc in PET ether to give 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (500 mg, 2.044 mmol, 88%) as a colorless liquid. LCMS: 2.67 min, 239.8(M+H) + , method B

[0186] To a stirred solution of 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (400 mg, 1.669 mmol) in DMSO (4 mL) at room temperature, piperidine-4-carbonitrile (221 mg, 2.003 mmol) and K2CO3 (461 mg, 3.34 mmol) were added. 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 × 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography to give 1-(4-propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carbonitrile (310 mg, 0.987 mmol, 59%) (Intermediate 29) as a colorless gum. The analytical data of intermediate 29 are shown in Table 1.

[0187] Procedure for the preparation of nitriles exemplified by the preparation of 1-(5-(methyl(propyl)amino)-4-(trifluoromethyl)pyridin-3-yl)piperidine-4-carbonitrile (Intermediate 31) [ka]

[0188] 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 light at 140 °C for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with 20% EtOAc in PET ether (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to give 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

[0189] 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 minutes. CsCO (903 mg, 2.77 mmol), BINAP (173 mg, 0.277 mmol), and Pd(OAc) (31.1 mg, 0.139 mmol) were added. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography to give 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 of Intermediate 31 are shown in Table 1.

[0190] Procedure for the preparation of bromides exemplified by the preparation of 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (intermediate 36) [ka]

[0191] To a stirred solution of 3-bromo-2-(trifluoromethyl)phenol (500 mg, 2.075 mmol) in DMF (10 mL) was added 1-iodopropane (423 mg, 2.490 mmol) and KCO. 3( To the resulting solution was added 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (430 mg, 3.11 mmol). The reaction was heated at 80° C. for 16 hours. The reaction was diluted with water (20 mL) and extracted with 20% EtOAc in PET ether (3×10 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 give 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (380 mg, 1.342 mmol, 65%) (Intermediate 36) as a colorless liquid. The analytical data for Intermediate 36 are shown in Table 1.

[0192] Procedure for the preparation of chlorides exemplified by the preparation of 4-chloro-2-propoxy-3-(trifluoromethyl)pyridine (Intermediate 40) [ka]

[0193] To a stirred suspension of NaH (222 mg, 5.55 mmol) in THF (2 mL) at 0 °C, propan-1-ol (364 mg, 6.06 mmol) in THF (1 mL) was added, and the reaction mixture was stirred at room temperature 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 room temperature for 1 h. The reaction mixture was carefully quenched with water (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over sodium sulfate and purified by flash column chromatography using 0–10% EtOAc in PET ether to give 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).

[0194] To a stirred solution of 4-chloro-3-iodo-2-propoxypyridine (750 mg, 2.52 mmol) in DMF (8 mL) at room temperature, copper(I) iodide (720 mg, 3.78 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.48 mL, 3.78 mmol) were added. The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography to give 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 are shown in Table 1.

[0195] Procedure for the preparation of chlorides exemplified by 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) [ka]

[0196] To a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (1.28 g, 4.41 mmol) (Intermediate 1) and butyl tert-4-cyano-3-ethylpiperidine-1-carboxylate (700 mg, 2.94 mmol) in toluene (5 mL) at room temperature under a nitrogen atmosphere, KHMDS (1 M in THF) (3.52 mL, 3.52 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with saturated NH4Cl (10 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 (0-30%) to give ethyl rac-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 minutes, 509.0 (M+H) + , method B

[0197] To a stirred solution of ethyl rac-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 room temperature was added Raney nickel (1.38 g, 15.73 mmol). The reaction mixture was stirred at 65°C for 24 hours under a hydrogen atmosphere at 5 atmospheres. An additional lot of Raney nickel (1.38 g, 15.73 mmol) was added and the reaction was stirred at 65°C for 24 hours under a hydrogen atmosphere at 5 atmospheres. 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 (0-20%) in DCM to give 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 (650 mg, 1.393 mmol, 89%) as a light brown gum. LCMS: 2.55 min, 467.1(M+H) + , method B

[0198] To a 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 (650 mg, 1.393 mmol) in DCM (10 mL) was added TFA (1.1 mL, 13.93 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h, then carefully quenched with 10% NaHCO3 (10 mL) and extracted with 10% MeOH in DCM (3 × 10 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, evaporated, and dried under high vacuum to give 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.

[0199] 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 room temperature was added 3,5-dichloro-4-(trifluoromethyl)pyridine (884 mg, 4.09 mmol). The reaction mixture was heated at 140°C for 1 h in a microwave oven. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using 0-100% EtOAc in PET ether. Pure fractions were evaporated and dried under high vacuum to give 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. A 30 mg sample was further purified by prep HPLC (Method B). The preparative 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 give 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 of intermediates 41 and 42 are shown in Table 1.

[0200] Procedure for the preparation of anhydrides exemplified by the preparation of tert-butyl 3-hydroxyazetidine-1-carboxylate (intermediate 49) [ka]

[0201] To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg, 1.155 mmol) in acetonitrile (6 mL) was added TEA (0.472 ml, 3.46 mmol) followed by bis(2,5-dioxopyrrolidin-1-yl)carbonate (355 mg, 1.386 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The crude material was diluted with EtOAc (30 mL) and washed with 10% NaHCO solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and dried under high vacuum to give 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 of intermediate 49 are shown in Table 1.

[0202] Procedure for the preparation of amides exemplified by 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) [ka]

[0203] 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 minutes. CsCO (1.06 g, 3.24 mmol), BINAP (202 mg, 0.324 mmol), and Pd(OAc) (37 mg, 0.162 mmol) were added, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using 0-40% EtOAc in PET ether to give 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

[0204] 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 room temperature, KHMDS (1 M in THF) (1.22 mL, 1.220 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated 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 (0-10%) to give 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: 3.39min, 631.2(M+H) + , method B

[0205] 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 room temperature, cobalt(II) chloride hexahydrate (566 mg, 2.378 mmol) was added. NaBH4 (135 mg, 3.57 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through Celite and washed with 20% MeOH in DCM (2 × 20 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography using MeOH / DCM (0–10%) to give 38 mg of product. 18 mg of compound was further purified by prep-HPLC. These fractions were lyophilized. The residue was dissolved in DCM (5 mL), washed with 10% NaHCO solution (3 mL), dried over sodium sulfate, evaporated and lyophilized to give 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 are shown in Table 1.

[0206] Procedure for the preparation of bromides exemplified by the preparation of 5-bromo-N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (Intermediate 53) [ka]

[0207] To a stirred solution of 2-chloro-6-(trifluoromethyl)pyridine (2.5 g, 13.77 mmol) in DMSO (15 mL) was added N-methylpropan-1-amine (1.511 g, 20.66 mmol), followed by KCO (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 × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (2.5 g, 11.46 mmol, 83%), which was used in the next step without further purification. LCMS: 2.89 min, 219.2(M+H) + , method B

[0208] 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 the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL), extracted with PET ether (2 × 10 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude material was purified by flash column chromatography to give 5-bromo-N-methyl-N-propyl-6-(trifluoromethyl)pyridin-2-amine (5.5 g, 18.51 mmol, 67%) (Intermediate 53) as a colorless liquid. The analytical data of intermediate 53 are shown in Table 1.

[0209] Procedure for the preparation of amines exemplified by 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) [ka] To a 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 step 2 of the synthesis of Intermediate 41) in THF (8 mL) was added NaH (0.206 g, 5.14 mmol) at 0°C, and the reaction was stirred at 0°C for 20 minutes. Then 50% Cbz-Cl in toluene (0.439 g, 2.57 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude material, which was purified by flash column chromatography to give 7'-benzyl rac-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 an off-white solid.

[0210] To a stirred solution of 7'-benzyl rac-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 room temperature for 16 h. The mixture was quenched with MeOH (40 mL) and concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography with 0-50% EtOAc in PET ether to give 7'-benzyl rac-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

[0211] To a stirred solution of 7'-benzyl rac-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, TFA (0.079 mL, 1.023 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was neutralized with 10% NaHCO3 solution (50 mL x 1) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give crude benzyl rac-(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.

[0212] To a degassed solution (purged with nitrogen for 10 minutes) of benzyl rac-(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), sodium tert-butoxide (130 mg, 1.356 mmol), Xantphos (26.2 mg, 0.045 mmol), and then Pd(dba) (83 mg, 0.090 mmol) were added, and the reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was filtered through a bed of Celite, and the bed was washed with EtOAc. The combined filtrate was concentrated and purified by flash column chromatography using 0-20% EtOAc in PET ether to afford benzyl rac-(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

[0213] To a stirred solution of benzyl rac-(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 EtSiH (0.029 mL, 0.181 mmol), EtN (0.00338 mL, 0.024 mmol), followed by PdCl (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 was washed with 10% MeOH in DCM (50 mL). The combined filtrates were concentrated to give the crude material, which was purified by prep-HPLC. The pure fractions were concentrated, and the residue was neutralized with 10% NaHCO 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 give 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 intermediates 55, 56 and 57 are shown in Table 1.

[0214] Procedures for the preparation of amines exemplified by 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 (Intermediates 62 and 90) [ka] 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 more vials were prepared as above. After cooling to room temperature, all five reaction mixtures were quenched with additional MeOH (4 mL) at 0 °C, and the mixtures were refluxed at 80 °C for 2 h. After cooling to room temperature, the reaction mixtures were concentrated under reduced pressure to give a residue which was identified by prep-TLC (EtOAc, R f =0) to give 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 a yellow oil. The analytical data for Intermediate 90 are shown in Table 1.

[0215] 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) at 25 °C was added N-ethyl-N-isopropylpropan-2-amine (74.83 mg, 578.95 μmol, 100.84 μL) 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). The reaction mixture was stirred at 25 °C for 2 h. Four more vials were prepared 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 a residue, which was purified by flash column chromatography (eluting with PET ether / EtOAc = 1 / 0 to 0 / 1 to EtOAc / MeOH = 10 / 1, R f=0.3), 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%) was obtained as a yellow oil. LCMS: 0.44 min, 586.4 [M+H] + , method O'

[0216] 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) (520 mg, 3.7 mmol) in EtOAc (10 mL) was degassed and purged three times with H (15 Psi) at 25° C. The reaction mixture was heated to 40° C. and stirred under H (15 Psi) at 40° C. for 12 h. After cooling to room temperature, 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 a yellow oil, which was used in the next step without purification. The analytical data for Intermediate 62 are shown in Table 1.

[0217] Procedure for the preparation of 4-chloro-2-fluoro-3-(trifluoromethyl)pyridine (Intermediate 70) [ka] To a stirred solution of 2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (150 mg, 0.409 mmol) (Intermediate 41) in 1,4 dioxane (2 mL) at room temperature, 4-chloro-2-fluoro-3-(trifluoromethyl)pyridine (98 mg, 0.491 mmol) was added followed by AcOH (50 mg, 0.819 mmol), and the reaction mixture was stirred for 16 hours at 100° C. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, evaporated, and purified by flash column chromatography using MeOH (0-10%) in DCM to give 1-(4-chloro-3-(trifluoromethyl)naphthyl-2-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (70 mg). 20 mg of the crude product was further purified by Prep HPLC (Method B). The preparative 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 give 1-(4-chloro-3-(trifluoromethyl)naphthyl-2-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one (3.90 mg, 7.14 μmol, 2%) (Intermediate 70) as a white solid. The analytical data for 70 are shown in Table 1.

[0218] 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,''-[1,7-naphthyridin]-''-one (Intermediate 71) [ka] 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,''-[1,7-naphthyridin]''-one (200 mg, 0.366 mmol) (Intermediate 42) in MeOH (5 mL), NaOMe (5 mL, 4.50 mmol) was added and the reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was evaporated and the crude product was purified by flash column chromatography using MeOH (0-10%) in DCM to give 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 of Intermediate 71 are shown in Table 1.

[0219] 3-Ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)pyridin Procedure for the preparation of peridine-4-carbonitrile (Intermediate 72) [ka] A solution of rac-3-ethylpiperidine-4-carbonitrile (0.540 g, 3.91 mmol) in toluene (10 mL) was purged under nitrogen for 10 min, BINAP (0.122 g, 0.195 mmol), Pd(OAc) (0.088 g, 0.391 mmol), 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (1.0 g, 3.91 mmol), followed by CsCO (2.55 g, 7.81 mmol) were added, and the reaction mixture was stirred for 16 h at 120° C. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography using EtOAc in PET-ether (0-30%) to give rac-3-ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)piperidine-4-carbonitrile (900 mg, 2.124 mmol, 54%) (Intermediate 72) as a colorless liquid. The analytical data for Intermediate 72 are shown in Table 1.

[0220] Procedure for the preparation of (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl methanesulfonate (intermediate 74) [ka] To a stirred solution of (tetrahydro-1H-pyrrolidin-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 the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with DCM (50 mL) and washed with 10% NaHCO (20 mL) followed by water (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl methanesulfonate (270 mg) (Intermediate 74) as a yellow gum, which was used in the next step without further purification. The analytical data for Intermediate 74 are shown in Table 1.

[0221] 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) [ka] 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 room temperature, and the reaction mixture was stirred at room temperature under a N2 atmosphere for 2 hours. Six vials were prepared as described above. All six reaction mixtures were quenched with saturated ammonium chloride solution (300 mL) at 0 °C, the pH was adjusted to around 5 with formic acid, and then extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography (PET ether / Et0Ac=7:3) to give ethyl rac-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. 1 H 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)

[0222] To a solution of ethyl rac-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 a N2 atmosphere, and the reaction mixture was stirred at 60 °C for 12 h. 14 vials were prepared as described above. After cooling to room temperature, the reaction mixture of 14 was quenched with additional MeOH (40 mL) at 0 °C, and the reaction mixture was refluxed at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (EtOAc:MeOH (9:1)) to give 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 a yellow oil.

[0223] 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 minutes. To this 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 hours. Five more vials were prepared as above. All six reaction mixtures were quenched with water (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and analyzed by prep-TLC (EtOAc / MeOH = 9 / 1, R f=0.60) to give tert-butyl rac-(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

[0224] To a solution of Pd(OH) (290.00 mg, 2.07 mmol) in EtOAc (50 mL) was added tert-butyl rac-(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 three times, the reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at 25°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl rac-(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 in the next step without further purification. The analytical data for Intermediate 64 and Intermediate 79 are shown in Table 1.

[0225] Procedure for the preparation of (R)-2-(((3RS,4RS)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 89) [ka]

[0226] 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 (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (202.58 mg, 1.02 mmol) in MeOH (8 mL) was stirred at room temperature for 30 min, and NaCNBH3 (170.38 mg, 2.71 mmol) was added at room temperature and stirred for 12 h. Nine more vials were prepared as above. All 10 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, R f =0.40), (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.8 g, 42%) was obtained as a white solid. LCMS: 1.57 min, 626.3 [MH] + , method R'

[0227] To a solution of Pd(OH) (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 room temperature. After purging with hydrogen (15 Psi) three times, the reaction mixture was heated to 40°C and stirred under hydrogen gas pressure (15 Psi) at 40°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered, concentrated under reduced pressure, and analyzed by prep-TLC (EtOAc / MeOH = 1 / 1, R f=0.11) to give tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.2 g, 78%) (Intermediate 89) as a white solid. The analytical data for Intermediate 89 are shown in Table 1.

[0228] 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) [ka] To benzyl rac-(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) under nitrogen atmosphere in a 10 mL microwave vial was added DBU (563 mg, 3.70 mmol), and the reaction mixture was heated to 140°C for 3 hours in a microwave. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography using 10-20% EtOAc in PET ether to afford benzyl rac-(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 pale yellow solid. LCMS: 2.86 min, 666.2 [M+H] + , method G

[0229] To benzyl rac-(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) under nitrogen atmosphere in a 50 mL sealed tube was added NaOMe (25% in MeOH) (10 mL, 0.510 mmol) at room temperature under N2. 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) and washed with DCM (2 x 25 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and evaporated to give 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 pale yellow gum, which was used in the next step without further purification. The analytical data for Intermediate 122 are shown in Table 1.

[0230] Preparation procedure for (3S,4R)-3-ethylpiperidine-4-carbonitrile (Intermediate 94-1) [ka] 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 three times. The reaction mixture was stirred under a nitrogen atmosphere at 40° C. for 5 days. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain a residue. A 50 mg sample of this material was crystallized and subjected to X-ray analysis. The absolute R configuration of (R)-1-benzyl-3-ethylpiperidin-4-one was confirmed. Details are provided after Intermediate Table 1.

[0231] 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 x 3). The combined organic solution was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-1-benzyl-3-ethylpiperidin-4-one (16.5 g) as a yellow oil.

[0232] SFC method: R t =1.347 min, purity 12.71%, R t = 1.523 min, purity 87.29%; Column: Chiralpak AD-3, 150 × 4.6 mm ID, 3 μm; Cosolvent: 10%; Cosolvent: 0.1% isopropamide in MeOH; Injection volume: 3.5 μL; Run time: 5 min. To 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 at 0 °C with the addition of water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography (PET ether / EtOAc = 9 / 1, R f = 0.29 and R f =0.41), (3S,4R)-1-benzyl-3-ethylpiperidine-4-carbonitrile (2.3 g, 34%) as a yellow oil and (3S,4S)-1-benzyl-3-ethylpiperidine-4-carbonitrile (3.8 g, 56%) as a yellow solid.

[0233] (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: R t =1.312 points, purity 12.48%, R t =1.426 points, purity 87.52%; color name: Chiralpak AD-3, 150×4.6mm ID, 3um, auxiliary solvent: 10%; auxiliary solvent name: 0.1% eosin ampoules in MeOH; injection volume: 1.5μL; measurement time: 5 minutes (3S,4S)-1-benzyl-3-ethylpiperidine-4-carbonitrile: 1 H 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: R t =1.600 points, purity 15.65%, R t =1.802 points, purity 84.35%; color name: Chiralcel OD-3, 150×4.6mm ID, 3um; auxiliary solvent: 10%; auxiliary solvent name: Isopropanol [0.2% Ammoniagas (7M in MeOH)]; injection volume: 5.5μL; measurement time: 5 minutes

[0234] 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 three times. The reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at 40° C. for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (3S,4R)-3-ethylpiperidine-4-carbonitrile (800 mg) as a yellow oil. The analytical data of Intermediate 94-1 are shown in Table 1.

[0235] Procedure for the preparation of tert-butyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (Intermediate 95) [ka] 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) was added Boc anhydride (30.2 g, 138 mmol) followed by DMAP (0.676 g, 5.53 mmol) at room temperature, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was basified with 10% NaHCO and then water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified by flash column chromatography using 0-30% EtOAc in PET ether to give 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 are shown in Table 1.

[0236] 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) [ka]

[0237] 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 added BINAP (135 mg, 0.217 mmol), CsCO (1414 mg, 4.34 mmol), and then Pd(OAc). 2( (48.7 mg, 0.217 mmol) was added. The reaction mixture was heated at 120° C. for 16 h. The reaction mixture was filtered through a Celite bed, the filtrate was evaporated, and the crude product was purified by flash column chromatography using EtOAc in PET ether (0-20%) to give (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

[0238] To a stirred solution of KHMDS (1.612 mL, 1.612 mmol) in THF (20 mL) was 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 room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography using EtOAc in PET ether (0-90%) 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

[0239] 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 the reaction mixture was stirred at 65°C under 5 kg of hydrogen gas pressure for 48 h. The reaction mixture was filtered through a bed of Celite and washed with 10% MeOH in DCM (100 mL). The filtrate was evaporated and purified by flash column chromatography using MeOH (0-4%) in DCM as eluent. Pure fractions were evaporated and dried under high vacuum to give (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

[0240] 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 for 15 min at 0 °C. Cbz-Cl (0.063 mL, 0.441 mmol) was added and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography using EtOAc in PET ether (0-50%) to afford 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

[0241] 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 room temperature for 15 h. The reaction mixture was quenched with saturated NH4Cl (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified by flash column chromatography using EtOAc in PET ether (0-50%) to afford 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

[0242] 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. The reaction mixture was filtered through a bed of Celite and washed with 10% MeOH in DCM (100 mL). The filtrate was evaporated and purified by flash column chromatography using MeOH (0-4%) in DCM to give (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 are shown in Table 1.

[0243] Procedure for the preparation of rac-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-benzyl carboxylate (Intermediate 100) [ka]

[0244] 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 room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified by flash column chromatography using 10-20% EtOAc in PET ether to give cis-racemic 3-(1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)ethyl picolinate (2.5 g, 4.92 mmol, 59%) as a yellow solid. LCMS: 3.15 min, 508.2 [M+H] + , method B

[0245] 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), Raney Ni (4.88 g, 47.3 mmol) was added at room temperature, and the reaction mixture was stirred at 65° C. under 5 Kg of H gas pressure for 16 h. The reaction mixture was filtered through a Celite bed, and the bed was washed with MeOH (20 mL). The filtrate was concentrated and purified by flash column chromatography with 0–10% MeOH in DCM to give the cis-racemic 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

[0246] 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), NaH (0.344 g, 8.59 mmol) was added 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 room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography with 10–30% EtOAc in PET ether to give 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 a sticky solid. LCMS: 3.05 min, 600.3 [M+H] + , method B

[0247] 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 the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with MeOH (10 mL), concentrated under reduced pressure, and purified by flash column chromatography using 0–50% 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

[0248] To a 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 the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, quenched with 10% NaHCO3 (20 mL), and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-rac-benzyl carboxylate (900 mg, 1.853 mmol, 90%) (Intermediate 100) as an off-white solid. The analytical data for Intermediate 100 are shown in Table 1.

[0249] Procedure for the preparation of 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-benzyl carboxylate (Intermediate 102) [ka] To a stirred solution of 6-(2-ethoxyphenyl)-3-fluoropicolinic acid (6.5 g, 24.88 mmol) (Intermediate 83) in t-BuOH, Boc anhydride (14.44 mL, 62.2 mmol) was added, followed by DMAP (0.304 g, 2.488 mmol), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was basified with 10% NaHCO, diluted with water (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, evaporated, and purified by flash column chromatography using 0–30% EtOAc in PET ether to give tert-butyl 6-(2-ethoxyphenyl)-3-fluoropicolinate (6 g, 17.96 mmol, 72%) (Intermediate 101) as a pale yellow solid.

[0250] To a stirred solution of KHMDS (16.39 mL, 16.39 mmol) was added a 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 room temperature and stirred for 3 hours. The reaction mixture was carefully quenched with saturated NH4Cl at room temperature and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and purified by flash column chromatography using EtOAc-PET ether (20-50%) to give 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

[0251] To a stirred solution of 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 the reaction mixture was stirred at 65° C. under 6 kg hydrogen gas pressure for 48 h. The reaction mixture was filtered through a bed of Celite and the bed was washed with 10% MeOH and DCM. The filtrate was concentrated under reduced pressure (bath temperature: 42 °C) to give a crude gum, which was purified by flash column chromatography using 10% MeOH:DCM to give 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

[0252] To a stirred solution of 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., t-BuOK (4.10 g, 36.6 mmol) was added, followed by benzyl chloroformate (7.77 g, 45.7 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was carefully quenched with aqueous NH4Cl (100 mL) at 0° C. and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and purified by flash column chromatography using 15% EtOAc in PET ether to give 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

[0253] 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 (30.6 ml, 30.6 mmol) in THF at 0°C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was carefully quenched with MeOH at 0°C, evaporated to dryness, and purified by flash column chromatography using EtOAc in PET ether (30%) to give 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

[0254] To a 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 the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, basified with 10% aqueous NaHCO3 (100 mL), and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate to give 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 intermediates 101 and 102 are shown in Table 1.

[0255] Procedure for the preparation 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) [ka]

[0256] To a degassed solution (purged with nitrogen for 10 minutes) of benzyl rac-(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), NaOtBu (297 mg, 3.09 mmol), Xantphos (119 mg, 0.206 mmol), followed by Pd(dba) (94 mg, 0.103 mmol) were added, and the reaction mixture was heated at 120 °C for 16 hours. The reaction was filtered through a Celite bed, and the filtrate was washed with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and purified by flash column chromatography with 30–35% EtOAc in PET ether to give benzyl rac-(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.

[0257] To a stirred solution of benzyl rac-(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) was added PdCl (59.1 mg, 0.333 mmol), EtSiH (116 mg, 1.000 mmol), and then EtN (67.5 mg, 0.667 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction was filtered through a bed of Celite, and the filtrate was washed with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous NaSO and purified by flash column chromatography using 10% MeOH in DCM to give 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 are shown in Table 1.

[0258] Process for preparing 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 106) [ka]

[0259] 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 room temperature was degassed under a nitrogen atmosphere for 10 minutes. BINAP (491 mg, 0.789 mmol), Cs2CO3 (2.6 g, 7.89 mmol), and Pd(OAc)2 (0.089 g, 0.394 mmol) were added, and the reaction mixture was heated at 120 °C for 16 hours. The reaction mixture was filtered through Celite, washed with EtOAc (2 × 10 mL), and the filtrate was evaporated. The crude product was purified by flash column chromatography using EtOAc in PET ether (0-20%) to give 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

[0260] 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 room temperature was added 10% Pd / C (2.95 g, 27.7 mmol). The reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through Celite and washed with EtOAc (2 x 10 mL). The filtrate was evaporated to give 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 are shown in Table 1.

[0261] Process for preparing (R)-tert-butyl 2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 121) [ka]

[0262] 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 room temperature and stirred at room temperature for 2 h under N2. An additional vial was prepared as above. Both reaction mixtures were quenched at 0 °C with the addition of saturated ammonium chloride solution (200 mL) and adjusted to 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 sulfate 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 in the next step without further purification.

[0263] LCMS: 0.39 min, 442.3 [M+H]+ / 440.2 [MH]+, Method N

[0264] 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 under N2 for 2 h. One more vial was prepared as above. After cooling to room temperature, the two reaction mixtures were diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography (PET ether / EtOAc = 1 / 0 to 0 / 1, R f=0.5), ethyl 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (22 g, 52%) was obtained as a white solid. LCMS: 1.70 min, 470.2 [M+H] + , method M

[0265] 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. An additional vial was prepared as above. After cooling to room temperature, the two reaction mixtures were quenched with additional MeOH (100 mL × 2) at 0 °C. The combined mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue (18 g as a 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 two parallel reactions, BH3.THF (1 M, 105.25 mL) was added to the residue (9 g) in THF (180 mL) at 0 °C under N2. The reaction mixture was stirred at 60 °C for 2 h under N2. After cooling to room temperature, the two reaction mixtures were quenched by adding MeOH (100 mL × 2) at 0 °C. The combined mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc / MeOH = 1 / 0 to 0 / 1, R f= Purification by HPLC / MS / MS / MS / MS / MS / MS gave 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (Intermediate 130) (4.2 g, 24%) as a white solid.

[0266] 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 (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (192.72 mg, 967.23 μmol) in MeOH (3 mL) was added NaCNBH3 (91.17 mg, 1.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. Four more vials were prepared as above. The five reaction mixtures were concentrated under reduced pressure, 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, R f= 0.5) to give tert-butyl (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 134) (1 g, 69%) as a colorless oil.

[0267] A mixture of (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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 50 mL of EtOAc was degassed and purged three times with H2 (15 Psi) at room temperature. The reaction mixture was stirred at 50 °C for 12 h under H2 (15 Psi). One more vial was prepared as above. After cooling to room temperature, the two reaction mixtures were filtered and analyzed by prep-TLC (1 / 1 EtOAc / MeOH, R f=0.2) to give (R)-tert-butyl 2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 121) (220 mg, 43%) as a white solid. The analytical data for intermediates 130, 134 and 121 are shown in Table 1.

[0268] Process for preparing (R)-tert-butyl 2-((2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 135) [ka] To a solution of tert-butyl (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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 more vials were prepared as above. After warming to room temperature, all six reaction mixtures were quenched with ice water (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, and purified by prep-HPLC method L to give (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

[0269] 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 EtN (129.56 mg, 1.28 mmol) and BocO (93.14 mg, 426.77 μmol) at 25 °C under nitrogen. The reaction mixture was stirred at 25 °C for 12 h. Four more vials were prepared as above. All five reaction mixtures were quenched by adding ice water (40 mL) and then extracted with DCM (20 mL × 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and analyzed by prep TLC (PET ether / EtOAc = 1 / 1, R f =0.75) to give tert-butyl (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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

[0270] To a solution of tert-butyl (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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. Eight additional vials were prepared as above. After cooling to room temperature, all nine reaction mixtures were quenched by adding water (20 mL) and extracted with EtOAc (6 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography (PET ether / EtOAc = 99 / 11 to 70 / 30, R f =0.5) to give tert-butyl (R)-2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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

[0271] To a solution of (R)-tert-butyl 2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (200 mg, 332.32 μmol) in EtOAc (120 mL) was added Pd(OH) 2(To the reaction mixture was added 700.04 mg (20% purity) of tert-butyl (R)-2-((2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (360 mg, 53%) as a white solid. The reaction mixture was degassed and purged with hydrogen three times. The reaction mixture was stirred at 50°C for 2 hours under a hydrogen atmosphere (15 psi). Three more vials were prepared as above. After cooling to room temperature, 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]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (360 mg, 53%) as a white solid. The analytical data for Intermediate 135 are shown in Table 1.

[0272] Method for the preparation of (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 138) [ka] To a solution of 1-benzyl-3-ethylpiperidine-4-carbonitrile (5 g, 21.90 mmol) and 6-(2-ethoxyphenyl)-3-fluoropicolinic acid (Intermediate 87) (5.72 g, 21.90 mmol) in toluene (150 mL), KHMDS (1 M, 65.69 mL) was added at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. Four vials were prepared as described above. Five reaction mixtures were quenched at 0 °C by the addition of saturated NH4Cl solution (300 mL), adjusted to pH 4-6 with formic acid, and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 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 in the next step without further purification. LCMS: 0.76 min, 468.1 [MH] + , method R'

[0273] 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 KCO 3( At 25 °C, the resulting mixture was stirred at 80 °C for 2 h. Four vials were prepared as described above. After cooling to room temperature, the five reaction mixtures were quenched by adding water (500 mL) at 0 °C, followed by extraction with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and purified by flash column chromatography (PET ether / EtOAc = 1 / 0 to 8 / 1, R f= 0.55) to give ethyl rac-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (32 g, 60%) as a yellow oil. LCMS: 1.78 min, 498.3 [M+H] + , method C

[0274] To a solution of ethyl rac-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 a nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 12 h. After cooling to room temperature, the reaction mixture was quenched with MeOH (100 mL) at 0° C. and stirred at 80° C. for an additional 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (PET ether / EtOAc=1 / 0 to EtOAc / MeOH=8 / 1, R f= 0.40), 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.

[0275] 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 (R)-tert-butyl 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 prepared as described above. All five reaction mixtures were filtered, and the filtrates were concentrated under reduced pressure and purified by flash column chromatography (PET ether / EtOAc = 1 / 0 to 5 / 1, R f= 0.40) to afford tert-butyl (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 137) (800 mg, 49%) as a yellow oil.

[0276] A mixture of (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 141) (800 mg, 1.28 mmol) and Pd(OH) (800 mg, 5.70 mmol) in EtOAc (20 mL) was degassed and purged three times with hydrogen (15 psi) at 25 °C. The reaction mixture was stirred under hydrogen (15 psi) at 50 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by flash column chromatography (PET ether / EtOAc = 1 / 0 to EtOAc / MeOH = 4 / 1, eluting with R f=0.20) to give tert-butyl (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (600 mg, 88% yield) (Intermediate 138) as a white solid. The analytical data for intermediates 136, 137 and 138 are shown in Table 1.

[0277] Process for the preparation of (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester (Intermediate 139) [ka] 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) was added HATU (439.12 mg, 1.15 mmol), DIPEA (298.52 mg, 2.31 mmol), and then 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 room temperature, and the reaction mixture was stirred at room temperature for 1 h. Four more vials were prepared as above. All five reaction mixtures were combined, diluted with water (120 mL), and extracted with DCM (3 × 30 mL). The combined organic solution was washed with brine (120 mL), dried over sodium sulfate, and purified by flash column chromatography (PET ether / EtOAc = 50 / 50 to 10 / 90, R f =0.3) to give 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

[0278] 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 BH3.THF solution (1 M, 3.05 mL) dropwise at 0 °C. After warming to room temperature, the reaction mixture was stirred at 60 °C for 30 min. Five more vials were prepared as 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 room temperature, the mixture was concentrated under reduced pressure and purified by flash column chromatography (PET ether / Et0Ac=50 / 50 to 0 / 100, R f =0.29) to give tert-butyl (2R,4S)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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

[0279] To a suspension of Pd(OH)2 / C (1.02 g, 1.46 mmol, 20% purity) in 20 mL of EtOAc 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]naphthyridine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (550 mg, 858.23 μmol) in 200 mL of EtOAc at 25 °C under nitrogen. The suspension was degassed and purged with hydrogen three times. The reaction mixture was stirred at 50 °C for 3 h under hydrogen (15 Psi). An additional vial was prepared as above. After cooling to 25°C, the two reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (600 mg, crude) (Intermediate 139) as a yellow solid, which was used in the next step without further purification.

[0280] The analytical data for Intermediate 139 are shown in Table 1.

[0281] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13] [Table 8-14] [Table 8-15] [Table 8-16] [Table 8-17]

[0282] X-ray crystallographic analysis of the complex between (R)-1-benzyl-3-ethylpiperidin-4-one and (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid X-ray crystallography was carried out to determine the absolute configuration of (R)-1-benzyl-3-ethylpiperidin-4-one as shown below.

[0283] Summary of Results: The crystal was a colorless block measuring 0.20 × 0.20 × 0.03 mm. The symmetry of the crystal structure was assigned to 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) Å, Z = 1, Dc = 1.240 g / cm, F(000) = 320.0, μ(CuKα) = 0.741 mm, and T = 300.15 K. The absolute configuration and ORTEP structure are as follows: [ka]

[0284] Equipment and Data Collection Description: Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector cryogenic system: Oxford Cryostream 800 Cu: λ = 1.54184 Å, 50 W. Crystal-to-CCD detector distance: d = 35 mm; tube voltage: 50 kV; tube current: 1 mA. A total of 45,334 reflections were collected over the 2θ range of 6.862 to 133.164. Limiting indices were -8 ≤ h ≤ 8, -10 ≤ k ≤ 9, -15 ≤ l ≤ 15; resulting in 5,552 unique reflections (Rint = 0.0506). The structure was solved using SHELXT (Sheldrick, GM 2015. Acta Cryst. A71, 3-8) and SHELXL (F 2 (Sheldrick, GM 2015. Acta Cryst. C71, 3-8) was used for refinement. The total number of refined parameters was 389, and 5552 data were compared. All reflections were included in the refinement. F 2 The goodness of fit was 1.051, with a final R value of [I>=2σ(I)]R1=0.0458, wR2=0.1282. The largest differential peaks and holes were 0.27 and -0.20 Å-3.

[0285] Description of crystal preparation: 50 mg of (R)-1-benzyl-3-ethylpiperidin-4-one complex and (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid (complex) were dissolved in 1 mL of MeOH and kept in a 4 mL vial. The solution was allowed to evaporate slowly at room temperature. Crystals were observed on the second day.

[0286] Example Synthesis: Route A Typical procedure for the preparation of lactams, 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'-piperidin]-8-one (Example 1) [ka]

[0287] 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) at 0 °C under nitrogen, DIPEA (0.1 mL, 0.66 mmol) and HATU (127 mg, 0.33 mmol) were added. The reaction mixture was stirred for 10 min, after which 4-chloro-2-(trifluoromethyl)benzoic acid (80 mg, 0.22 mmol) was added. The reaction mixture was stirred at 25-30 °C for 16 h. The reaction was quenched with ice-cold water (10 mL) and extracted with DCM (2 × 20 mL). The organic layer was dried over NaSO and concentrated to give the crude material (100 mg) as a brown sticky compound, representing 20% ​​of the desired product. The crude product was further purified by prep HPLC and then lyophilized to give 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthyridine-5,4'-piperidin]-8-one (10 mg, 8%) (Example 1) as a pale pink solid. The analytical data for Example 1 are shown in Table 2.

[0288] Route B Typical procedure for the preparation of lactams, 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'-piperidin]-8-one (Example 2) [ka]

[0289] 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 room temperature was added KHMDS (1 M in THF) (0.5 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with saturated 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 (0-10%) to give 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 colorless gum. LCMS: 2.94 min, 559.2(M+H) + , method A

[0290] 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 room temperature was added Raney nickel (188 mg, 2.147 mmol). The reaction mixture was stirred at 65°C under 75 psi hydrogen pressure for 24 hours. The reaction mixture was filtered through Celite and washed with MeOH (20 mL). The filtrate was evaporated and the crude material 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 give 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthyridine-5,4'-piperidin]-8-one (40 mg, 0.077 mmol, 43%) (Example 2) as a white solid. The analytical data for Example 2 are shown in Table 3.

[0291] Route C Typical procedure for the preparation of lactams, 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'-piperidin]-7-yl]propanamide (Example 4) [ka]

[0292] 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) was added NaH (2.3 mg, 0.058 mmol) and stirred at room temperature for 30 minutes. 3-Chloropropanamide (4.99 mg, 0.046 mmol) in DMF (1 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. 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 these fractions were lyophilized. The residue was dissolved in DCM (20 mL), washed with 10% NaHCO (5 mL), water (5 mL), brine (5 mL), dried over sodium sulfate, evaporated, and lyophilized to give 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). The analytical data for Example 4 are shown in Table 4.

[0293] Route D Typical procedure for the preparation of lactams, 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'-piperidin]-6-one (Example 5) [ka]

[0294] 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 μL) in dioxane (0.2 mL) was added sodium tert-bromine. To the mixture, methylthiazol-3-yl methylthiazol-3 (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) were added at 25°C under nitrogen. The reaction mixture was heated to 100°C and stirred at 100°C for 12 h. Three more vials were prepared as above. After cooling to room temperature, all four reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to give the crude material, which was purified by prep-TLC (EtOAc / MeOH=10 / 1, Rf=0.57, Rf=0.00) to give two peaks. The two peaks were purified by prep-HPLC to give 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-6-one (2.7 mg, 12%) (Example 5) as a white solid. The analytical data for Example 5 are shown in Table 5.

[0295] Route E Typical procedure for the preparation of amines, exemplified by 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) [ka]

[0296] 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'-piperidin]-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 the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with MeOH (10 mL), stirred at room temperature for 16 hours, and concentrated under reduced pressure to give the crude material. The crude material was purified by prep HPLC and the fractions were lyophilized to give 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 a white solid. The analytical data for Example 6 are shown in Table 6.

[0297] Route F Typical procedure for the preparation of lactams exemplified by 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'-piperidin]-8-one (Example 9) [ka]

[0298] 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. CsCO (193 mg, 0.591 mmol), Xantphos (11.97 mg, 0.021 mmol), and Pd(dba) (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). These fractions were lyophilized. The residue was made basic with 10% NaHCO3 solution and extracted with DCM (3 × 5 mL). The combined organic extracts were evaporated and lyophilized to give 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

[0299] 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 minutes. CsCO (25.2 mg, 0.077 mmol), Xantphos (1.6 mg, 2.71 μmol), and Pd(dba) (1.8 mg, 1.934 μmol) were added, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was evaporated, and the crude product was purified by prep HPLC. These fractions were lyophilized. The residue was made basic with 10% NaHCO solution and extracted with DCM (3 × 5 mL). The combined organic extracts were evaporated and lyophilized to give 1'-[3-chloro-2-(trifluoromethyl)phenyl]-7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H-1,7-naphthyridine-5,4'-piperidin]-8-one (4.86 mg, 6.92 μmol, 18%) (Example 9) as an off-white solid. The analytical data for Example 9 are shown in Table 7.

[0300] Route G Typical procedure for the preparation of amines, exemplified by the preparation of 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidin]-8-one (Example 15) [ka] 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) was added NaH (3.09 mg, 0.077 mmol) and tert-butyl 3-iodopyrrolidine-1-carboxylate (22.99 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, quenched with ice-cold water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine solution (10 mL), dried over sodium sulfate and evaporated to give 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 a red gummy liquid (24 mg, 0.035 mmol, 35%). LCMS: 3.90min, 686.3(M+H) + , method B

[0301] 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) was added phosphoric acid (14.28 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The DCM layer was decanted and the residue was washed with DCM (2 x 10 mL). To this crude residue was added 10% NaHCO3 solution to adjust the pH to about 8. The aqueous layer was decanted, triturated with water (2 x 10 mL), decanted, and lyophilized to give a yellow solid. The crude reaction mass was purified by prep HPLC. The sample was lyophilized to give the product 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H-1,7-naphthyridine-5,4'-piperidin]-8-one (1.03 mg, 0.0017 mmol) (Example 15) as a white solid. The analytical data for Example 15 are shown in Table 8.

[0302] Route H Typical procedure for the preparation of amines, 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'-piperidin]-1'-yl]ethenone (Example 21) [ka]

[0303] 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), DIPEA (0.01042 mL, 0.060 mmol) was added, followed by 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)glycinate (16.24 mg, 0.060 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2 / 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 a sticky solid, which was used in the next step without further purification. LCMS: 3.25 minutes, 660.0(M+H) + , method B

[0304] To a 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 the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and purified by prep HPLC. The pure fractions were lyophilized to give 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 a white solid. The analytical data for Example 21 are shown in Table 9.

[0305] Route I Typical procedure for the preparation of lactams, 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'-piperidin]-8-one (Example 22) [ka] 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) was added DIPEA (0.310 mL, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude compound was purified by Biotage-Isolera using a 25 g silica gel cartridge and eluted with 0-10% MeOH in DCM. The pure fractions were concentrated under reduced pressure to give 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 fractions were collected and lyophilized to give 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 an off-white solid. The analytical data for Example 22 are shown in Table 10.

[0306] Route J Typical procedure for the preparation of amides, exemplified by the preparation of [2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthyridine-5,4'-piperidin]-1'-yl]-[6-propoxy-2-(trifluoromethyl)pyridin-3-yl]methanone (Example 24) [ka]

[0307] 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), DIPEA (282 mg, 2.181 mmol), 6-propoxy-2-(trifluoromethyl)nicotinic acid (130 mg, 0.523 mmol) (Intermediate 17), and then HATU (249 mg, 0.654 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash silica column chromatography with 40-60% EtOAc in PET ether to give 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 gum. LCMS: 3.97 min, 690.3(M+H) + , method B

[0308] 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 HO (40.7 mg, 0.145 mmol) and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated to give the crude material. The crude material was purified by prep HPLC. Fractions were collected and lyophilized to give (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. The analytical data for Example 24 are shown in Table 11.

[0309] Route K Typical procedure for the preparation of amides, exemplified by the preparation of [2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-1'-yl]-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methanone (Example 29) [ka]

[0310] 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) was 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 the reaction was stirred at room temperature for 16 hours. The reaction mixture was precipitated with ACN (20 mL), and the precipitate was filtered off. The solid was washed with ACN (20 mL) and the combined filtrate was collected and concentrated to give 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 a brown gum. LCMS: 3.16 min, 697.1(M+H) + , method B

[0311] To a stirred solution of 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-carboxylic acid tert-butyl salt (50 mg, 0.072 mmol) in DCM (2 mL) was added TFA (8.18 mg, 0.072 mmol) at 0°C and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give the crude material. The 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 give a colorless gum, which was redissolved in ACN:water (1:3) and lyophilized to give 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.

[0312] The analytical data for Example 29 are shown in Table 12.

[0313] Route L Typical procedure for the preparation of amines, 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) [ka]

[0314] 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 N gas for 5 min. 3-Bromo-6-methoxy-2-(trifluoromethyl)pyridine (223 mg, 0.872 mmol), CsCO (142 mg, 0.436 mmol), Xantphos (12.6 mg, 0.022 mmol), and Pd(dba) (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 (0-35%) to give 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 an orange gum. LCMS: 3.72 minutes, 634.0(M+H) + , method B

[0315] 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 room temperature, 20% KOH in water (0.05 mL, 0.379 mmol) was added, 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 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by prep HPLC. These fractions were lyophilized. The residue was basified with 10% NaHCO3 solution and extracted with DCM (3 × 5 mL). The combined organic extracts were evaporated and lyophilized to give 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.

[0316] The analytical data for Example 30 are shown in Table 13.

[0317] Route M Typical procedure for the preparation of lactams, 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) [ka]

[0318] To a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-6-one (35 mg, 67.71 μmol) (Example 5) and (R)-tert-butyl 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 hours. After cooling to 0° C., the reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure to give the crude material, which was identified by prep-TLC (PET ether / EtOAc = 2 / 1, R f =0.2) to give 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]naphthyridine]-7'(8'H)-yl)pyrrolidine-1-carboxylate (25 mg, 53%) as a yellow oil. LCMS: 1.16 min, 686.3(M+H) + , method O

[0319] 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 minutes. The reaction mixture was concentrated under reduced pressure to give a crude material, which was purified by prep-HPLC to give (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. The analytical data for Example 34 are shown in Table 14.

[0320] Route N Typical procedures for the preparation of lactams, 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) [ka]

[0321] 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 minutes. CsCO (1.3 g, 3.85 mmol), BINAP (240 mg, 0.385 mmol), and Pd(OAc) (44 mg, 0.194 mmol) were added. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was evaporated, and the crude product was purified by flash column chromatography using 0-10% EtOAc in PET ether to give 1-(4-chloro-2-(trifluoromethyl)phenyl)-3-ethylpiperidine-4-carbonitrile (510 mg, 1.608 mmol, 83%) as a colorless gum. LCMS: 3.11 min, 317.0(M+H) + , method B

[0322] 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 room temperature, KHMDS (0.5 M in toluene) (3.24 mL, 1.619 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated 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 (0-10%) in PET ether to give ethyl rac-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: 3.70min, 587.0(M+H) + , method B

[0323] To a stirred solution of ethyl rac-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 at 65 °C under 5 atmospheres of H for 16 hours. LCMS showed two compounds. 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 give 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 give 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.

[0324] 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% NaHCO solution (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, evaporated, and lyophilized to give 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. The analytical data for Examples 36 and 42 are shown in Table 15.

[0325] Route O Typical Procedure for the Preparation of Lactams, Illustrated 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'-piperidin]-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'-piperidin]-8-one (Example 43) [ka]

[0326] 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 the reaction mixture was stirred for 30 minutes. tert-Butyl 3-(bromomethyl)-3-hydroxyazetidine-1-carboxylate (38.6 mg, 0.145 mmol) in DMF (1 mL) was added to the reaction, and the reaction mixture was stirred slowly at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic extracts were washed with brine (10 × 2 mL), dried over anhydrous sodium sulfate, 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 a sticky solid, which was used in the next step without further purification. LCMS: 3.14 minutes, 702.0(M+H) + , method B

[0327] 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 (0.027 mL, 0.356 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give the crude material. The crude material was purified by prep HPLC. The fractions were concentrated, and the resulting solid was basified with 10% NaHCO3 (10 mL), and the product was extracted with DCM (10 mL x 2). The combined organic extracts were dried over sodium sulfate, concentrated, and lyophilized to give 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazetidin-3-yl)methyl]spiro[6H-1,7-naphthyridine-5,4'-piperidin]-8-one (7.91 mg, 0.013 mmol, 18%) (Example 38) as a white solid.

[0328] To 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 the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by prep HPLC purification using the TFA method. The collected fractions were concentrated, and the resulting solid was dissolved in DCM (10 mL). The organic layer was washed with 10% NaHCO solution, dried over anhydrous sodium sulfate, filtered, concentrated, and lyophilized to give 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'-piperidin]-8-one (2.49 mg, 3.84 μmol, 6%) (Example 43) as a white solid.

[0329] The analytical data for Examples 38 and 43 are shown in Table 16.

[0330] Route P Typical procedure for the preparation of amines, 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'-piperidin]-7-yl]ethanone (Example 52) [ka] 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] (25 mg, 0.050 mmol) (Example 6) in DMF (8 mL), (tert-butoxycarbonyl)glycine (8.71 mg, 0.050 mmol), DIPEA (0.018 mL, 0.099 mmol), and then HATU (22.68 mg, 0.060 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 a colorless viscous liquid. LCMS: 4.01 min, 661.3(M+H) + , method B

[0331] 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 the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, neutralized with 10% NaHCO3, and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude material. The crude product was purified by Prep-HPLC. The pure fractions were collected and concentrated under reduced pressure to give a white solid, which was neutralized with 10% aqueous NaHCO (10 mL) and extracted with DCM (20 mL). The DCM layer was dried over anhydrous sodium sulfate and concentrated to give a white solid, which was redissolved in ACN:water 1:3 and lyophilized to give 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-7-yl]ethanone (3.94 mg, 0.076 mmol, 9%) (Example 52) as an off-white solid. The analytical data for Example 52 are shown in Table 17.

[0332] Route Q Typical route for the preparation of amino alcohols, 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'-piperidin]-8-one trifluoroacetate (Example 54) [ka]

[0333] 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'-piperidin]-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 room temperature, TEA (0.05 mL, 0.350 mmol), Na(OAc)BH (17.8 mg, 0.084 mmol), and acetic acid (0.400 μL, 6.99 μmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and evaporated to give 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

[0334] 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 room temperature for 1 hour. 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 fractions were lyophilized to give 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'-piperidin]-8-one trifluoroacetate (2.08 mg, 6%) (Example 54) as a white solid. The analytical data for Example 54 are shown in Table 18.

[0335] Route R Typical procedure for the preparation of lactams, 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'-piperidin]-6-one (Example 58) [ka]

[0336] 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 2 To a solution of 7) and sodium tert-butoxide (12.03 mg, 125.20 μmol) under argon, 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) were added. The reaction mixture was then heated to 100 °C and stirred at 100 °C for 2 h. Seven more vials were prepared as above. After cooling to room temperature, 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 eluted by prep-TLC (PET ether / EtOAc = 1 / 2, R f= 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 a 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)

[0337] 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 for 1 hour at 25° C. An additional vial was prepared as above. The two reaction mixtures were combined and concentrated under reduced pressure to give a residue that 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'-piperidin]-6-one (8.2 mg, 47%) (Example 58) as a white solid.

[0338] The analytical data for Example 58 are shown in Table 19.

[0339] Route S Typical procedure for the preparation of lactams, 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'-piperidin]-6-one (Example 59) [ka] To a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-6-one (50 mg, 96.72 μmol) (Example 5) and 2-bromoacetonitrile (11.60 mg, 96.72 μmol, 6.45 μL) 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 hours. TLC (PET ether / EtOAc = 2 / 1, R f =0.23) indicated that the starting material had been consumed and the desired spot had formed. The reaction mixture was quenched with ice water (2 mL) and extracted with EtOAc (1 mL × 3). The combined organic phase was concentrated under reduced pressure to give a residue, which was analyzed by prep-TLC (PET ether / EtOAc = 2 / 1, R f =0.23) to give 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

[0340] 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 one 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 a hydrogen balloon. Four more vials were prepared as above. All five reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by prep-HPLC to give 7-(2-aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7-naphthyridine-5,4'-piperidin]-6-one g (2.6 mg, 17%) (Example 59) as a white solid. The analytical data for Example 59 are shown in Table 20.

[0341] Route T Typical procedure for the preparation of lactams, 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'-piperidin]-8-one (Example 68) [ka]

[0342] 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, 1-bromo-2-(2-methoxyethoxy)ethane (16.96 mg, 0.093 mmol) and K2CO3 (9.60 mg, 0.069 mmol) were added. 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 (0-10%) in DCM. Pure fractions were evaporated and the product was purified by prep-HPLC. These fractions were lyophilized. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO solution (5 mL), dried over sodium sulfate, evaporated, and lyophilized to give 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. The analytical data for Example 68 are shown in Table 21.

[0343] Route U Typical procedure for the preparation of lactams, 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'-piperidin]-8-one (Example 80) [ka]

[0344] 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 (5 mL), dried over sodium sulfate, evaporated, and lyophilized to give 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. The analytical data for Example 80 are shown in Table 22.

[0345] Route V Typical procedure for the preparation of carbamates, exemplified by the preparation of 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-azetidin-3-yl carboxylate (Example 97) [ka]

[0346] To a 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) was 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 the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 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 a brown gum. LCMS: 3.49 min, 699.3(M+H) + , method B

[0347] To a 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 the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, neutralized with 10% NaHCO (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound, which was purified by prep-HPLC. Pure fractions were collected and lyophilized to give 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)-carboxylic acid azetidin-3-yl formate (5.88 mg, 9.82 μmol, 14%) (Example 97) as a white solid. The analytical data for Example 97 are shown in Table 23.

[0348] Route W Typical procedures for the preparation of nitriles, 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'-piperidin]-1'-yl]-2-(trifluoromethyl)phenoxy]acetonitrile (Example 98) [ka]

[0349] 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, NaH (20 mg, 0.484 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. (R)-tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (128 mg, 0.484 mmol) was added at room temperature. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was carefully quenched 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 (0-10%) in DCM to give 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]naphthyridine]-7'(8'H)-yl)pyrrolidine-1-carboxylate (57 mg, 0.062 mmol, 64%) as a yellow gum. LCMS: 3.32 minutes, 758.4(M+H) + , method B

[0350] To a stirred solution of (S)-tert-butyl 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 room temperature, 10% Pd / C (50 mg, 0.047 mmol) was added and stirred at room temperature under 1 atm H pressure for 16 h. 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 give 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

[0351] 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 room temperature, 2-bromoacetonitrile (13 mg, 0.105 mmol) and K2CO3 (11 mg, 0.079 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. 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 give 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]naphthyridine]-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

[0352] To a stirred solution of (S)-tert-butyl 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 room temperature 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 fractions were lyophilized to give (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. The analytical data for Example 98 are shown in Table 24.

[0353] Route X Typical procedure for the preparation of methylpyrrolidines, exemplified by (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) [ka]

[0354] 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 (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (15.99 mg, 80.23 μmol) and NaCNBH (10.08 mg, 160.47 μmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. An additional vial was prepared as above. Both 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 / Et0Ac=1 / 3, R f= 0.43) to give tert-butyl (R)-2-((2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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'

[0355] To 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]naphthyridine]-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 was stirred at 25° C. for 2 hours and concentrated under reduced pressure to give a residue that 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 a white solid (Example 113). The analytical data for Example 113 are shown in Table 25.

[0356] Route Y Typical procedure for the preparation of oxopropionic acids, exemplified by the preparation of 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) [ka]

[0357] 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) was added HATU (30.51 mg, 80.23 μmol) followed by DIPEA (15.55 mg, 120.35 mmol, 20.96 μL) at 25 °C, and the reaction mixture was stirred at 25 °C for 2 h. An additional vial was prepared as above. Both reaction mixtures were diluted with water (2 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and analyzed by prep-TLC (EtOAc, R f=0.6) to give methyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)-3-oxopropanoate (30 mg, 62%) as a white solid. LCMS: 2.23 min, 599.2 [M+H] + , method R'

[0358] 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) and stirred for 4 h at 25° C. An additional vial was prepared as above. All two reaction mixtures were concentrated under reduced pressure and purified by prep-HPLC to give 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 a white solid. The analytical data for Example 117 are shown in Table 26.

[0359] 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) [ka]

[0360] A solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (19.03 mg, 120.35 μmol) in MeOH (5 mL) was acidified to pH 4 with acetic acid and stirred at 20° C. for 30 minutes. The reaction mixture was basified to pH 9 with EtN, after which 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 NaCNBH (31.51 mg, 501.47 μmol) were added. The reaction mixture was heated to 60° C. and stirred at 60° C. for 12 hours. Three more vials were prepared as above. After cooling to room temperature, all four reaction mixtures were combined, quenched with water (0.3 mL), concentrated under reduced pressure, and analyzed by prep-TLC (PET ether / EtOAc = 1 / 1, peak 1, R f =0.36, Peak 2, R f =0.29) to give ethyl 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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]naphthyridine]-7'(8'H)-yl)tetrahydrofuran-2-carboxylate_peak-2 (70 mg, 27%) as colorless oils. Peak 1: LCMS: 0.549 min, 641.4 (M+H) + , method L Peak 2: LCMS: 0.547 min, 641.4 (M+H) + , method L

[0361] 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, 7N) was heated to 80° C. and stirred at 80° C. for 5 hours. An additional vial was prepared as above. After cooling to room temperature, the two reaction mixtures were combined and concentrated under reduced pressure to give 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 directly in the next step without further purification. LCMS: 0.47 min, 612.3(M+H) + , method L

[0362] 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 dropwise LAH in THF (2.5 M, 49.05 μL) at 0°C. The reaction mixture was stirred at 20°C for 12 h. An additional vial was prepared as above. After cooling to 0°C, the two reaction mixtures were combined, quenched with NaSO (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 give rel-[(2R,4S)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidin]-7-yl]oxolan-2-yl]methanamine_Peak-1 (5 mg, 13%) (Example 136) as a white solid. Analytical data 36 for Example 1 are shown in Table 27.

[0363] Route Aa Typical Procedure for 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) [ka]

[0364] 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 (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (460 mg, 2.310 mmol) in DCE (10 mL) at 0 °C, Na(OAc)BH (816 mg, 3.85 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, evaporated, and purified by flash column chromatography using EtOAc in PET ether (0-100%) as eluent to give tert-butyl (R)-2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (1.1 g, 1.521 mmol, 79%) as an off-white solid. LCMS: 3.08 min, 651.3 [M+H] + , method B

[0365] To a stirred solution of (R)-tert-butyl 2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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 room temperature for 2 h. The reaction mixture was carefully basified with 10% NaHCO3 solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over sodium sulfate. The resulting residue was purified by prep-HPLC (Method B). The pure preparative fractions were lyophilized. The residue was dissolved in DCM (15 mL), washed with 10% NaHCO solution (5 mL), water (5 mL), dried over sodium sulfate, evaporated, and lyophilized to give (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.

[0366] 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, HCl (2 M in iPrOAc) (0.02 mL, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. The resulting solid was triturated with MTBE (2 x 1 mL). The residue was lyophilized to give (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.

[0367] 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, MSA (0.2 M in iPrOAc) (0.01 mL, 0.018 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was stirred at room temperature for 10 minutes. The resulting solid was triturated with MTBE (2 x 1 mL). The residue was purified by prep-HPLC using Method I. The fractions were lyophilized to give (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.

[0368] Analytical data for Examples 153, 153.HCl and 153.MSA are shown in Table 28.

[0369] 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) [ka]

[0370] 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 (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (20.85 mg, 0.105 mmol) in DCE (10 mL) was added Na(OAc)BH (44.35 mg, 0.210 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous NaSO and the resulting residue was purified by flash column chromatography using EtOAc in PET ether (0-40%) 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]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (65 mg, 0.091 mmol, 88%) as a white solid. LCMS: 2.22 minutes, 709.3 [M+H] + , method G

[0371] 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]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (65 mg, 0.091 mmol) in DCM (10 mL) was added TFA (0.3 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated, and the resulting residue was neutralized with 10% aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and purified by prep. HPLC. The preparative fractions were concentrated, and the residue was neutralized with 10% aqueous NaHCO3 solution (10 mL) and extracted with DCM (10 mL). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and lyophilized to give (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 colorless liquid. Analytical data for Example 176 are shown in Table 29.

[0372] Route Ac Typical procedure for preparing (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): [ka]

[0373] To a solution of (R)-tert-butyl 2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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 CsCO 3(Pd2(dba)3 (192.91 mg, 592.09 mmol), Xantphos (22.84 mg, 39.47 μmol), and Pd2(dba)3 (36.15 mg, 39.47 μmol) were added at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. Four vials were prepared as described above. After cooling to room temperature, all five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and analyzed by prep-TLC (PET ether / EtOAc = 3 / 1, R f =0.4) to give tert-butyl (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (280 mg, 56%) as a white solid. LCMS: 2.42 min, 635.2(M+H) + , method M

[0374] A solution of tert-butyl (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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 prepared as above. After cooling to room temperature, all four reaction mixtures were concentrated under reduced pressure and purified by prep-HPLC to give (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 a white solid. The analytical data for Example 189 are shown in Table 30.

[0375] Route Ad Typical procedure for preparing (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): [ka]

[0376] To a solution of (R)-tert-butyl 2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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) was added CsCO (96.46 mg, 296.05 μmol), Xantphos (11.42 mg, 19.74 μmol), followed by Pd(dba) (18.07 mg, 19.74 μmol), and the reaction mixture was stirred at 100 °C for 12 h under nitrogen. Five additional vials were prepared as above. After cooling to room temperature, the six reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic solution was washed with brine (10 mL), dried over anhydrous sodium sulfate, and analyzed by prep-TLC (PET ether / EtOAc = 2 / 1, R f =0.5) to give tert-butyl (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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'

[0377] To a solution of (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl salt (50 mg, 71.83 μmol) and sodium methanesulfinate (9.53 mg, 93.38 μmol) in DMSO (1 mL), KPO (15.25 mg, 71.83 μmol) was added, followed by CuI (13.68 mg, 71.83 μmol), and the reaction mixture was stirred at 110 °C for 12 h under nitrogen. Four more vials were prepared as above. After cooling to room temperature, all five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic solution was washed with brine (10 mL), dried over anhydrous sodium sulfate, and analyzed by prep-TLC (PET ether / EtOAc = 4 / 3, R f =0.6) to give tert-butyl (R)-2-((1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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'

[0378] A solution of (R)-2-((1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid (30 mg, 43.15 μmol) in HCOOH (1 mL) was stirred at 40° C. for 8 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to afford (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. The analytical data for Example 206 are shown in Table 31.

[0379] 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): [ka]

[0380] To a solution of tert-butyl (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (50 mg, 90.79 μmol) (Intermediate 139) in THF (1 mL) was added 2,5-dichloropyridine-3-carbonitrile (20.42 mg, 118.03 μmol) followed by EtN (27.56 mg, 272.37 μmol) and the reaction mixture was stirred at 70 °C for 4 h. Two more vials were prepared as above. After cooling to room temperature, all three mixtures were combined, concentrated and analyzed by prep-TLC (PET ether / EtOAc = 1 / 2, R f= 0.3) to give 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]naphthyridine]-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

[0381] 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]naphthyridine]-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 the reaction mixture was stirred at room temperature for 2 h. Three more vials were prepared as described. All four reaction mixtures were combined, concentrated, and purified by prep-HPLC to give 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 are shown in Table 32.

[0382] 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) [ka]

[0383] To tert-butyl (R)-2-((1-(4-chloro-2-cyanophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine]-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°C for 42 hours. The reaction mixture was cooled to room temperature and diluted with 10% MeOH in DCM (2 x 20 mL). The pH of the reaction mixture was adjusted to about 8 with 10% sodium hydroxide solution (50 mL) and the layers were separated. The aqueous layer was extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over NaSO, and concentrated in vacuo to give the crude compound (100 mg; HPLC purity: 56.0%). The crude material was purified by prep-HPLC (method AP) to give (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 are shown in Table 33.

[0384] [Table 9]

[0385] [Table 10-1] [Table 10-2]

[0386] [Table 11-1] [Table 11-2]

[0387] Table 12

[0388] Table 13

[0389] Table 14

[0390] Table 15-1 Table 15-2 Table 15-3 Table 15-4 Table 15-5 Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17

[0391] Table 16

[0392] Table 17

[0393] Table 18

[0394] Table 19-1 Table 19-2

[0395] Table 20

[0396] Table 21-1 Table 21-2 Table 21-3 Table 21-4 Table 21-5 Table 21-6 Table 21-7 Table 21-8 Table 21-9 Table 21-10

[0397] Table 22-1 Table 22-2

[0398] Table 23-1 Table 23-2

[0399] Table 24-1 Table 24-2 Table 24-3 Table 24-4 Table 24-5 Table 24-6 Table 24-7

[0400] Table 25-1 Table 25-2 Table 25-3 Table 25-4

[0401] Table 26-1 Table 26-2 Table 26-3 Table 26-4 Table 26-5 Table 26-6 Table 26-7 Table 26-8 Table 26-9

[0402] Table 27

[0403] Table 28

[0404] Table 29

[0405] Table 30

[0406] Table 31

[0407] Table 32-1 Table 32-2 Table 32-3 Table 32-4 Table 32-5 Table 32-6 Table 32-7 Table 32-8

[0408] Table 33

[0409] Table 34

[0410] Table 35-1 Table 35-2 Table 35-3 Table 35-4 Table 35-5

[0411] Table 36-1 Table 36-2 Table 36-3 Table 36-4 Table 36-5 Table 36-6 Table 36-7 Table 36-8 Table 36-9

[0412] Table 37-1 Table 37-2 Table 37-3

[0413] Table 38

[0414] Table 39-1 Table 39-2 Table 39-3 Table 39-4 Table 39-5 Table 39-6

[0415] Table 40

[0416] 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'-piperidin]-1'-yl]benzonitrile (Example 181-1) [ka] Crystal Data: Empirical Formula 3(C34H40ClN5O), H2O, 0.4(O) Formula Weight 1734.89 Temperature 100(2)K Wavelength 0.71073Å 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 Z2 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 Data Collection Range q 1.861~30.891° Index Range -15<=h<=15 -46<=k<=47, -17<=l<=16 Number of collected reflections: 87455 Number of independent reflections: 25243 [R(int)=0.0891] Completeness: 99.9% for q=25.242° Semi-empirical absorption correction from equivalents Maximum and minimum transmittances: 0.7461 and 0.6603 Refinement method: Full matrix least squares on F2 Data / constraints / parameters: 25243 / 201 / 1203 Goodness of fit on F2: 0.967 Final R-index [I>2s(I)]: R1=0.0548, wR2=0.1056 R-index (all data): R1=0.1665, wR2=0.1377 Absolute structure parameters: 0.01(2) Maximum difference peak and hole: 0.401 and -0.358 e.Å-3 measured on Bruker D8 QUEST PHOTON-III detector used software SHELXTL-PLUS Crystal growth Crystallization by slow evaporation of solvent was employed to grow crystals suitable for single crystal X-ray diffraction studies. Crystals were obtained from methyl tert-butyl ether (MTBE) solvent. Approximately 20 mg of compound (B.No. OMA-SYN-C37s-E1-R-004) was dissolved in methyl tert-butyl ether (3 ml) solvent under elevated temperature, and the solution was filtered into a clean beaker and kept at room temperature for crystallization. After 10 days, crystals were observed on the beaker walls.

[0417] Precision X-ray data were collected cryogenically on a Bruker D8 QUEST instrument equipped with a 1μS Mo microsource (λ = 0.7107 A) and a PHOTON-III detector. Raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite (Bruker (2016) APEX3, SAINT, and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA). The structure was solved using the intrinsic phase method [2] and further refined using the SHELXL (Sheldrick GM (2015). Acta Crystallogr C71: 3-8) program, followed by expansion using Fourier transformations. Anisotropic displacement parameters were included for all non-hydrogen atoms. Atom C1 of molecule A is disordered at two positions, and the site occupancies were refined to 0.6(5) and 0.4(5), respectively. Atoms C17 / C18 / C19 / C20 / C21 / N3 of molecule B were disordered at two positions, and their site occupancies were refined to 0.755(6) and 0.245(6), respectively. The NH and OH atoms were located in the difference Fourier map, and their positions and isotropic displacement parameters were refined. The hydrogen atoms could not be placed on the partially occupied water O2W. All C-bonded H atoms were geometrically positioned and treated as riding on parent C atoms [CH = 0.93–0.97 Å, U iso (H) = 1.5 U for methyl H eq (C), or 1.2 U for other H atoms eq (C)]. The absolute configuration was confirmed by explicit refinement of the absolute structural parameters (Flack, HD & Bernardinelli, G. (2000). J. Appl. Cryst. 33, 1143-1148).

[0418] biological activity Preparation of terbium-labeled and SNAP-tagged MC2 membranes Cells were labeled with 100 nM SNAP-Lumi4-Tb and incubated at 37°C under 5% CO2 for 1 h, then harvested and pelleted by centrifugation at 1200 rpm for 3 min. The cell pellet was homogenized using a FastPrep-24 5G homogenizer (MP Biomedicals), followed by two 30-min centrifugations (Eppendorf Centrifuge) at 22,000 × g and 4°C for 30 min each. The final pellet was resuspended in 10 mM HEPES and 0.1 mM EDTA, pH 7.4, at 5–10 mg ml -1 and stored at -20°C for later use.

[0419] Fluorescent Ligand Binding Assay All fluorescent ligand binding experiments were performed using Cy5-labeled small molecule MC2 antagonists in 384-well Optiplate plates in 1x Tag-lite buffer (PerkinElmer) containing 2% DMSO, 0.04% pluronic acid, and 100 μg / ml saponin. In all cases, nonspecific binding was measured in the presence of 1 μM unlabeled MC2 antagonist. Signal detection was performed on a Pherastar FSX (BMG Labtech, Germany) using standard HTRF settings. HTRF ratios were calculated by dividing the acceptor signal (665 nm) by the donor signal (620 nm) and multiplying the result by 10,000.

[0420] TR-FRET competitive equilibrium binding assay The equilibrium dissociation constant (K i To determine the HTRF ratio, MC2 membranes (2 μg per well) were incubated with a range of test compounds in the presence of 100 nM fluorescent tracer. After overnight incubation at 25°C, the HTRF ratio was determined to ensure equilibrium had been reached.

[0421] TR-FRET competitive binding kinetics assay Binding of unlabeled compounds (k on ) and dissociation (k offTo determine the binding rate, we performed a competitive kinetic binding assay in which MC2 membranes (2 μg per well) were simultaneously added with 100 nM of fluorescent tracer and increasing concentrations of competing ligand. The extent of binding of the fluorescent tracer in MC2 was measured by HTRF at multiple time points.

[0422] In parallel, increasing concentrations of fluorescent tracer were incubated with MC2 membranes in the absence and presence of 1 μM unlabeled MC2 antagonist to determine the binding kinetics of the fluorescent tracer (k on ) and dissociation rate (k off The degree of binding of the fluorescent tracer was calculated by HTRF detection at multiple time points, and binding kinetic curves were generated. The obtained data were globally fitted to a binding kinetic model (Prism 8.0, GraphPad, San Diego, USA), and k was calculated as described in the data analysis section. on and k off From these data, a best-fit estimate of the equilibrium dissociation constant (K d ) could be estimated.

[0423] The competition kinetic data and fluorescent tracer kinetic parameters were globally fitted to the equation originally described by Motulsky and Mahan (Mol. Pharmacol., 1984, 25, 1-9) to obtain the k of the unlabeled compound. on and k off It was decided that:

[0424] Example A pKi: Group A>9, Group B 7.5~9, Group C 6~7.5 Koff: Group A<0.02, Group B 0.02~0.07, Group C>0.07

[0425] [Table 41-1] [Table 41-2] [Table 41-3]

[0426] cAMP accumulation assay Chinese hamster ovary (CHO) cells stably expressing human or rat MC2 in MRAP were maintained in DMEM / F12 cell culture medium supplemented with 10% fetal bovine serum and 1% l-glutamine. On the day of the experiment, cells were seeded 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) and then incubated with a range of MC2 compounds at 37°C and 5% CO2 for 2 hours. After 2 hours, increasing concentrations of ACTH1-24 were added to the cells for a set period, followed by 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 using a PHERAstar plate reader (BMG), and data were interpolated from a cAMP standard curve and analyzed using GraphPad Prism 8 (GraphPad). The results for Compound Example 113, Compound Example 134, and Compound Example 135 are shown in Figure 1. [Brief explanation of the drawings]

[0427] [Figure 1] Figure 1: Inhibition of ACTH1-24 mediated cAMP response in human MC2 cells by Compound Example 113, Compound Example 134, and Compound Example 135. MC2 expressing cells were incubated with compounds for 2 hours, then stimulated with ACTH1-24 for 15 minutes, lysed, and subjected to cAMP detection. Compounds with slower dissociation and lower Koff values ​​exhibited greater persistence. Data are for n=1 replicate.

Claims

1. Compound of formula (1): 【Chemistry 1】 or its salts [In the formula, J is N or CH; X is —CO—, —CH ２ - or -CH ２ CH ２ - and; 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 to 5; R １ is C optionally substituted with 1 to 3 fluorine atoms １－４ alkyl, C optionally substituted with 1 to 3 fluorine atoms ３－４ Cycloalkyl or CH optionally substituted with 1 to 3 fluorine atoms ２ C ３－４ is cycloalkyl; R ２ is H, CO ２ H, OH, NR ２ａ R ２ｂ , C.O.R. ２ａ R ２ｂ , S.O. ２ NR ２ａ R ２ｂ , and sometimes R １０ , R １１ and R １２ a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with １０ , R １１ and R １２ a 7-10 membered bicyclic or heterobicyclic ring system optionally substituted with R ２ａ and R ２ｂ are independently H or C optionally substituted with 1 to 3 fluorine atoms １－３ is alkyl; R ３ is H, optionally substituted with 1 to 3 fluorine atoms, C １－３ alkyl, C optionally substituted with 1 to 3 fluorine atoms ３－４ Cycloalkyl or CH optionally substituted with 1 to 3 fluorine atoms ２ C ３－４ cycloalkyl; or R ３ is R ３ａ and link to form a cyclopropyl or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R ３ａ is H or R ３ and link to form a cyclopropyl or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R ３ｂ is H, C optionally substituted with 1 to 3 fluorine atoms １－３ alkyl, C optionally substituted with 1 to 3 fluorine atoms ３－４ Cycloalkyl or CH optionally substituted with 1 to 3 fluorine atoms ２ C ３－４ cycloalkyl; or R ３ｂ is R ３ｃ and link to form a cyclopropyl or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; R ３ｃ is H or R ３ｂ and link to form a cyclopropyl or cyclobutyl ring optionally substituted with 1 to 3 fluorine atoms; Here, R ３ and R ３ｂ one or both of are H; L ２ is a bond or —CO—, and R ４ is a group: 【Chemistry 2】 and Here, 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; Q ９ is CR ９ or N; where Q ５ , Q ６ , Q ７ , Q ８ and Q ９ one, two, or none of are N; Or L ２ is —CO—, and R ４ Ha-(CH ２ ) ｑ NH ２ where q is 0 to 3; R ５ , R ６ , R ７ , R ８ , and R ９ H, halo, CN, NR １５ R １６ C optionally substituted with 1 to 3 fluorine atoms １－３ alkyl, OC optionally substituted with 1 to 3 fluorine atoms １－３ alkyl, OCH optionally substituted with 1 to 3 fluorine atoms ２ Cyclopropyl, OCH ２ C.N., C.O. ２ H and SO ２ Me independently selected from: R １０ , R １１ and R １２ is H, OH, oxo, halo, C optionally substituted with OH or 1 to 3 fluorine atoms １－３ Alkyl, 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 to 3 and y is 1 to 3; R １３ and R １４ is independently H or methyl; R １５ and R １６ are independently H or C １－３ alkyl].

2. R ４ but 【Transformation 3】 2. The compound of claim 1, wherein the group is selected from:

3. L ２ The compound of claim 1 or claim 2, wherein is a bond.

4. R １ The compound according to any one of claims 1 to 3, wherein is ethyl or perdeuteroethyl.

5. Compounds of formula (2a) or (2b): 【Chemistry 4】 3. The compound of claim 1 or claim 2, which is: or a salt thereof.

6. The compound of any one of claims 1 to 5, wherein J is N.

7. The compound of any one of claims 1 to 5, wherein J is CH.

8. Compounds of formula (3a) or (3ai): 【Transformation 5】 3. The compound of claim 1 or claim 2, which is: or a salt thereof.

9. R ３ The compound of any one of claims 1 to 8, wherein is H, methyl or ethyl.

10. R ３ The compound of any one of claims 1 to 9, wherein is ethyl.

11. R ５ , R ６ , R ７ , R ８ , and R ９ are H, Cl, F, I, CN, and CF ３ , C.F. ２ H, -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 The compound of any one of claims 1 to 10, independently selected from Me.

12. R ４ but 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 The compound according to any one of claims 1 to 11, selected from:

13. L １ is 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-, -CH ２ CH ２ - or -CH ２ The compound according to any one of claims 1 to 12, wherein

14. R ２ but 【Transformation 7】 The compound according to any one of claims 1 to 13, selected from:

15. R ２ The compound of any one of claims 1 to 13, wherein is H.

16. -L １ -R ２ but 【Transformation 8】 The compound according to any one of claims 1 to 12, selected from: 【Request Item 17】 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 【Chemistry 9-6】 【Chemistry 9-7】 【Chemistry 9-8】 【Chemistry 9-9】 [Chemistry 9-10] 【Chemistry 9-11】 【Chemistry 9-12】 【Chemistry 9-13】 [Chemistry 9-14] 【Chemistry 9-15】 【Chemistry 9-16】 【Chemistry 9-17】 【Chemistry 9-18】 【Chemistry 9-19】 【Chemistry 9-20】 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 compound according to any one of claims 1 to 17 and CRF １ and an antagonist.

20. A combination comprising a compound according to any one of claims 1 to 17 and an ACTH antibody.

21. A compound, composition or combination according to any one of claims 1 to 20 for use in medicine.

22. A 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 which would benefit from modulation of MC2R activity.

23. 21. A 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 disorders, septic shock, or disorders or conditions related thereto.

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