MC2r modulator compounds

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application relates to novel compounds and their use as melanocortin subtype-2 receptor (MC2R) antagonists. The compounds described herein can be used for the treatment or prevention of diseases in which MC2R is involved. The present application also relates to pharmaceutical compositions comprising these compounds and to the preparation of these compounds and compositions and their use in the prevention or treatment of such diseases in which MC2R is involved. BACKGROUND

[0002] Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide that is involved in the regulation of adrenocortical glucocorticoid synthesis and secretion within the hypothalamic-pituitary-adrenal (HPA) axis and thus plays a major role in the regulation of the stress response. ACTH is synthesized by the proopiomelanocortin (POMC) cells of the anterior pituitary through proteolytic cleavage of POMC. Upon stress stimuli, ACTH is secreted and acts on the melanocortin 2 receptor (MC2R) in the adrenal gland to regulate the synthesis and secretion of glucocorticoids and androgens. The secretion of glucocorticoids provides a negative feedback to the hypothalamus and anterior pituitary to decrease the production and secretion of corticotropin-releasing hormone (CRH) and ACTH, respectively, providing a good balance in the regulation of the stress response. The range of diseases associated with ACTH dysfunction goes 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) in which there are five subtypes: MC1R, MC2R, MC3R, MC4R and MC5R. MC1R is involved in the regulation of pigmentation, MC2R in the synthesis of glucocorticoids, MC3R and MC4R in energy homeostasis and MC5R in the physiology of exocrine glands. MC2R is selectively activated by ACTH, while the remaining receptor subtypes also bind to melanocortin peptides a-, b- and g-melanocyte-stimulating hormones (a-MSH, b-MSH and g-MSH) (Am. J. Physiol. Endocrinol. Metab. 284, E468-74 (2003); Life Sci. 59, 797-801 (1996)).

[0004] Another unique aspect of MC2R relative to other melanocortin receptors is that the accessory protein MRAP (Melanocortin 2 Receptor Accessory Protein) is required for MC2R expression and function. MRAP is a single-pass transmembrane protein that forms an anti-parallel homodimer with MC2R to enable trafficking of the receptor to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP -20249 (2007)). Binding of ACTH to the MC2R / MRAP complex in adrenal cortical cells leads to G s The signal transduction pathway activates cAMP production. The increase in intracellular cAMP in turn stimulates Cortisol synthesis and secretion (Microsc. Res. Tech. 61, 275-287 (2003)).

[0005] Congenital adrenal hyperplasia (CAH) is a disorder characterized by disruption in adrenal steroidogenesis that is associated with overproduction of ACTH and CRH. Three enzyme deficiencies caused by specific gene mutations are implicated: 21-hydroxylase deficiency caused by mutations in CYP21A2 (the most common form), 3 -hydroxysteroid dehydrogenase (HSD3B2), and 11 -hydroxylase (CYP11B1). In CAH, these enzyme deficiencies impair Cortisol synthesis, leading to loss of Cortisol negative feedback on CRH and ACTH. Excess ACTH leads to steroidogenesis proximal to the deficient enzyme, triggering the androgen excess pathophysiology associated with the disorder. Patients with CAH can present with hirsutism, acne, hair loss, oligomenorrhea, and infertility associated with virilization. Glucocorticoid and mineralocorticoid hormone replacement therapy is the primary treatment, but requires close monitoring to balance overtreatment and undertreatment. In addition, “stress dose treatment” is required when facing significant stress, illness, or surgery (J. Pediatr. Adolesc. Gynecol. 30, 520-534 (2017)). Importantly, high doses of glucocorticoid replacement are required to suppress ACTH production and thereby reduce adrenal androgen levels. This often means that patients will suffer from corticosteroid-related side effects or Cushing’s-like symptoms in order to control adrenal androgen levels. Thus, there remains a need for a better treatment for CAH. Since ACTH is elevated in CAH, antagonism of its activity through MC2R would provide an attractive means of modulating the steroidogenic pathway.

[0006] Cushing's disease is another rare disease associated with overproduction of ACTH due to adenomas of the pituitary corticotroph cells. Clinical manifestations include obesity, hirsutism, muscle weakness, and cardiovascular and metabolic complications associated with hypercortisolism. Treatment of Cushing's disease includes resection of the tumor in the pituitary that secretes ACTH or resection of the adrenal glands, but often drug therapy is used in addition to or prior to surgery to alleviate symptoms. Current drug therapy aims to suppress adrenal steroidogenesis, but there are also adverse effects such as hypothyroidism and hypogonadism (J. Med. Life 9, 12-18 (2016)). Inhibition of ACTH activity by MC2R antagonism offers a potential therapeutic option for the treatment of this disease.

[0007] In addition to CAH and Cushing's disease, polycystic ovary syndrome (PCOS) can also be amenable to MC2 modulation. PCOS is associated with abnormal regulation of steroidogenesis and elevated androgen levels. In a subset of patients, the excess androgens are the result of functional adrenal hyperandrogenism (Endocr. Rev. 37, 467-520 (2016)). Modulation of ACTH activity in these patients offers another therapeutic approach to this multi-system disorder.

[0008] Thus, antagonism of MC2R 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 antagonist compounds.

[0009] Long acting effects are a much sought after feature in drug design, which can extend the efficacy and simplify the dosing regimen (British Journal of Pharmacology 2010, 161(3), 488-508). In the treatment of diseases associated with ACTH dysfunction, in particular diseases with excess ACTH, inhibitors with a longer residence time have the advantage of unmatchable antagonism, i.e. the inhibition of the receptor is still present in the presence of high ACTH concentrations. One approach to achieve these good drug properties involves the development of compounds with slow dissociation (k off)kinetics (Neurochemistry international 2007, 51(5), 254-260). This has been demonstrated on a variety of targets, ranging from fevipiprant for 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).

[0010] Invention

[0011] The present invention provides compounds having melanocortin subtype-2 receptor (MC2R) antagonist activity.

[0012] Provided are compounds of Formula (1):

[0013] (1);

[0014] or salts thereof, wherein;

[0015] J is N or CH;

[0016] X is -CO-, -CH2-, or -CH2CH2-;

[0017] Z is a bond, -CH2-, or -CO-;

[0018] L 1 is -(CH2) n -, -(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH-, or -CO(CH2) n -, wherein n is 0-5;

[0019] R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms, or CH2C 3-4 cycloalkyl;

[0020] R 2 is H, CO2H, OH, NR 2a R 2b , CONR 2a R 2b , SO2NR 2a R 2b, optionally substituted with R 10 , R 11 , and R 12 ; a 3-6 membered carbocyclic or heterocyclic ring, or a 7-10 membered bicyclic or heterobicyclic ring system, optionally substituted with R 10 , R 11 , and R 12 ;

[0021] R 2a and R 2b are independently H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms;

[0022] R 3 is H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms, or CH 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3 is linked to R 3a to form a cyclopropyl or cyclobutyl ring, either of which can be optionally substituted with 1-3 fluorine atoms;

[0023] R 3a is H or linked to R 3 to form a cyclopropyl or cyclobutyl ring, either of which can be optionally substituted with 1-3 fluorine atoms;

[0024] R 3b is H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms, or CH 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3b is linked to R 3c to form a cyclopropyl or cyclobutyl ring, either of which can be optionally substituted with 1-3 fluorine atoms;

[0025] R 3c is H or linked to R 3b to form a cyclopropyl or cyclobutyl ring, either of which can be optionally substituted with 1-3 fluorine atoms;

[0026] wherein one or both of R 3 and R 3b is H;

[0027] L 2 is a bond or -CO- and R 4 is a group:

[0028] ;

[0029] wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; wherein one, two, or zero of Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are N;

[0030] or L 2 is -CO- and R 4 is -(CH2) q NH2, wherein q is 0-3;

[0031] R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H, halogen, CN, NR 15 R 16 , C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OC 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OCH2cyclopropyl, OCH2CN, CO2H, and SO2Me;

[0032] R 10 , R 11 , and R 12 are independently selected from H, OH, oxo, halogen, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, 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 , wherein g is 0-3 and y is 1-3;

[0033] R 13 and R 14 independently H or methyl; and

[0034] R 15 and R 16 independently H or C 1-3 alkyl.

[0035] The compounds of the present application can be used as modulators of the melanocortin subtype-2 receptor (MC2R). The compounds of the present application can be used as inhibitors of MC2R. The compounds of the present application can be used as antagonists of MC2R. The compounds of the present application can be used as antagonists of MC2R with long residence time at the receptor. The compounds of the present application can be used in the treatment of a disease or disorder associated with MC2R. The compounds of the present application can be used in the treatment of a disease or disorder that would benefit from modulation of MC2R activity. The compounds of the present application can be used in the manufacture of a medicament. The compounds or medicaments can be used in the treatment, prevention, amelioration, control or reduction of risk of a disease or disorder in which MC2R is involved. The compounds of the present application can be used as a sole agent or in combination with one or more additional pharmaceutical agents.

[0036] The compounds of the present application can be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome (or ectopic Cushing syndrome), polycystic ovary syndrome (PCOS), depression, septic shock, and disorders or symptoms associated therewith. DETAILED DESCRIPTION

[0038] The present application relates to novel compounds. The present application also relates to the use of novel compounds as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as antagonists of MC2R. The present application further relates to novel compounds as antagonists of MC2R with long residence time at the receptor. The present application further relates to the use of novel compounds in the manufacture of a medicament for use as an antagonist of MC2R. The present application further relates to compounds, compositions and medicaments useful in the treatment of a disease or disorder characterized by activation of the MC2R receptor.

[0039] Provided are compounds of Formula (1):

[0040] (1); or a salt thereof, wherein:

[0041] J is N or CH;

[0042] X is -CO-, -CH2- or -CH2CH2-;

[0043] Z is a bond, -CH2- or -CO-;

[0044] Z is a bond, -CH2- or -CO-;

[0045] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0046] R 1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0047] R 2 It is H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0048] R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl;

[0049] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0050] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0051] R 3bIt is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0052] R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0053] Where R 3 and R 3b One or both of them are H;

[0054] L 2 Is a bond or -CO- and R 4 It is a functional group:

[0055] ;

[0056] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them are N;

[0057] or L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3;

[0058] R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms.1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN, CO2H, and SO2Me;

[0059] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3;

[0060] R 13 and R 14 It is independently H or methyl; and

[0061] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0062] Compounds of formula (1) are also provided:

[0063] (1);

[0064] or its salt, wherein;

[0065] J is either N or CH;

[0066] X is -CO-, -CH2-, or -CH2CH2-;

[0067] Z represents a bond, -CH2-, or -CO-;

[0068] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0069] R1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0070] R 2 It is H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0071] R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl;

[0072] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0073] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0074] R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0075] R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0076] Where R 3 and R 3b One or both of them are H;

[0077] L 2 Is a bond or -CO- and R 4 It is a functional group:

[0078] ;

[0079] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them are N;

[0080] or L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3;

[0081] R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me;

[0082] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3Alkyl groups, 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 0-3 and y is 1-3;

[0083] R 13 and R 14 It is independently H or methyl; and

[0084] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0085] Compounds of formula (1) are also provided:

[0086] (1);

[0087] or its salt, wherein;

[0088] J is either N or CH;

[0089] X is -CO-, -CH2-, or -CH2CH2-;

[0090] Z represents a bond, -CH2-, or -CO-;

[0091] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0092] R 1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0093] R 2 It is H, CO2H, OH, NR 2a R2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0094] R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl;

[0095] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0096] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0097] R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0098] R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0099] Where R 3 and R 3b One or both of them are H;

[0100] L 2Is a bond or -CO- and R 4 It is a functional group:

[0101] ;

[0102] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them are N;

[0103] R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me;

[0104] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3;

[0105] R 13 and R14 It is independently H or methyl; and

[0106] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0107] Compounds of formula (1) are also provided:

[0108] (1);

[0109] or its salt, wherein;

[0110] J is either N or CH;

[0111] X is -CO-, -CH2-, or -CH2CH2-;

[0112] Z represents a bond, -CH2-, or -CO-;

[0113] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0114] R 1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0115] R 2 It is H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0116] R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms.1-3 alkyl;

[0117] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0118] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0119] R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0120] R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0121] Where R 3 and R 3b One or both of them are H;

[0122] L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3;

[0123] R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me;

[0124] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3;

[0125] R 13 and R 14 It is independently H or methyl; and

[0126] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0127] Compounds of formula (1) are also provided:

[0128] (1);

[0129] or its salt, wherein;

[0130] J is either N or CH;

[0131] X is -CO-, -CH2-, or -CH2CH2-;

[0132] Z represents a bond, -CH2-, or -CO-;

[0133] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0134] R 1It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0135] R 2 It is H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0136] R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl;

[0137] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0138] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0139] R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0140] R3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0141] Where R 3 and R 3b One or both of them are H;

[0142] L 2 Is a bond or -CO- and R 4 It is selected from the following groups:

[0143] ; ; and ;

[0144] or L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3;

[0145] R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me;

[0146] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3;

[0147] R 13 and R 14 It is independently H or methyl; and

[0148] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0149] Compounds of formula (1) are also provided:

[0150] (1);

[0151] or its salt, wherein;

[0152] J is either N or CH;

[0153] X is -CO-, -CH2-, or -CH2CH2-;

[0154] Z represents a bond, -CH2-, or -CO-;

[0155] L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5;

[0156] R 1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl;

[0157] R 2 It is H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system;

[0158] R 2a and R 2bIt is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl;

[0159] R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0160] R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0161] R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0162] R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms;

[0163] Where R 3 and R 3b One or both of them are H;

[0164] L 2 Is a bond or -CO- and R 4 It is selected from the following groups:

[0165] ; ; and ;

[0166] or L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3;

[0167] R 5 R 6R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me;

[0168] R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3;

[0169] R 13 and R 14 It is independently H or methyl; and

[0170] R 15 and R 16 Independently, it is H or C 1-3 alkyl.

[0171] In the compounds described herein, J can be N or CH. J can be N. J can be CH.

[0172] In the compounds described 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-.

[0173] In the compounds described 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.

[0174] In the compounds described in this article, R 1C can be optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 Cycloalkyl. R 1 C can be optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl group. R 1 It can be C 1-4 Alkyl group. R 1 It can be methyl or ethyl. R 1 It can be methyl. R 1 It can be ethyl. R 1 It can be all-deuterated ethyl. R 1 It can be -CD2CD3. R 1 It can be trideuteryl. R 1 It can be -CD3.

[0175] In the compounds described in this article, L 1 It could be -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n - where n is 0-5. L 1 It can be a bond, -CH2CH2CONH-, -COO-, -CH2CH2COO-, -CH2CH2CO-, -COCH2NH-, -COCH2CH2NH-, -CO-, -COCH2-, -CH2CH2-, or -CH2-. L 1 It can be a key.

[0176] In the compounds described in this article, R 2 It can be H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or hybrid two-ring system. 2 It can be H, or optionally R 10 R 11 and R 12The substituted 3-6 membered carbon rings or heterocycles or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or hybrid two-ring system. 2 It can be H, or optionally R 10 R 11 and R 12 The substituted piperidine ring, optionally R 10 R 11 and R 12 Substituted pyrrolidine ring, optionally R 10 R 11 and R 12 Substituted nitrogen-containing heterocyclic butane ring, optionally R 10 R 11 and R 12 The substituted hexahydro-1H-pyrrolizine ring system, optionally replaced by R 10 R 11 and R 12 The substituted 2-pyrrolidone ring, optionally replaced by R 10 R 11 and R 12 The substituted 1-azabicyclic [2.2.2]octane ring system, optionally R 10 R 11 and R 12 The substituted tetrahydrofuran ring or optionally R 10 R 11 and R 12 Substituted morpholine ring.

[0177] In the compounds described in this article, R 2a and R 2b It can be H independently or C optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl group. R 2a and R 2b It can be H or C independently. 1-3 Alkyl group. R 2a and R 2b It can be either H or methyl independently. R 2a and R 2b Both can be H.

[0178] R 2a It can be H or C, optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl group. R 2a It can be H or C 1-3 Alkyl group. R 2a It can be H or methyl. R 2a It can be H.

[0179] R 2bIt can be H or C, optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl group. R 2b It can be H or C 1-3 Alkyl group. R 2b It can be H or methyl. R 2b It can be H.

[0180] In the compounds described in this article, R 10 R 11 and R 12 C atoms can be independently selected from H, OH, oxo, halogen, or optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3. R 10 R 11 and R 12 It can be independently selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3.

[0181] R 10 It can be selected from H, OH, oxo, halogen, C atoms optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3. R 10 It can be selected from H, OH, CH2CH2OH, CH2NH2, and CH2CH2OCH2CH2OCH3. R 10 It can be H. R 10It can be OH. R 10 It can be CH2CH2OH. R 10 It could be CH2NH2. R 10 It can be CH2CH2OCH2CH2OCH3.

[0182] R 11 It can be selected from H, OH, oxo, halogen, C atoms optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3. R 11 It can be selected from H, OH, CH2CH2OH, CH2NH2, and CH2CH2OCH2CH2OCH3. R 11 It can be H. R 11 It can be OH. R 11 It can be CH2CH2OH. R 11 It could be CH2NH2. R 11 It can be CH2CH2OCH2CH2OCH3.

[0183] R 12 It can be selected from H, OH, oxo, halogen, C atoms optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3. R 12 It can be selected from H, OH, CH2CH2OH, CH2NH2, and CH2CH2OCH2CH2OCH3. R12 It can be H. R 12 It can be OH. R 12 It can be CH2CH2OH. R 12 It could be CH2NH2. R 12 It can be CH2CH2OCH2CH2OCH3.

[0184] R 13 and R 14 It can be either H or methyl independently. R 13 It can be H or methyl. R 14 It can be H or methyl. R 13 It can be H. R 13 It can be methyl. R 14 It can be H. R 14 It can be methyl.

[0185] In the compounds described in this article, R 2 You can choose from:

[0186] In the compounds described in this article, some -L 1 -R 2 Can be selected from:

[0187] In the compounds described in this article, R 3 It can be H, or C optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 It can be connected to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted with 1-3 fluorine atoms. R 3 It can be H or C, optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl group. R 3 It can be H or C 1-3 Alkyl group. R 3 It can be H, methyl, or ethyl.

[0188] In the compounds described in this article, R 3a It can be H or can be connected to R 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted with 1 to 3 fluorine atoms.

[0189] In the compounds described in this article, R 3bIt can be H, or C optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b It can be connected to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted with 1-3 fluorine atoms. R 3b It can be H or C, optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl group. R 3b It can be H or C 1-3 Alkyl group. R 3b It can be H, methyl, or ethyl.

[0190] In the compounds described in this article, R 3c It can be H or can be connected to R 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted with 1 to 3 fluorine atoms.

[0191] In the compounds described in this article, R 3 and R 3b One or both of them are H. Thus, for example, the structure of equation (1) as defined in this paper can be effectively regarded as the scope of equations (1') and (1'') combined:

[0192] (1'); (1'').

[0193] R 3 R 3a R 3b and R 3c Both can be H. R 3 and R 3b One of them can be a C that is optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 Cycloalkyl and the other is H. R 3 and R 3b One can be methyl or ethyl and the other is H. R 3 and R 3b One can be methyl and the other is H. R 3 and R 3b One of them can be ethyl and the other is H.

[0194] In the compounds described in this article, L 2 It can be a key or -CO- and R 4It can be a functional group:

[0195] ;

[0196] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them are N;

[0197] or L 2 It can be -CO- and R 4 It could be -(CH2) q NH2, where q is 0-3.

[0198] L 2 It can be a key or -CO- and R 4 It can be a group selected from the following:

[0199] ; ; ; and ;

[0200] or L 2 It can be -CO- and R 4 It could be -(CH2) q NH2, where q is 0-3.

[0201] L 2 It can be a key or -CO- and R 4 It can be a group selected from the following:

[0202] ; ; and ;

[0203] or L 2 It can be -CO- and R 4 It could be -(CH2) q NH2, where q is 0-3.

[0204] L 2 It can be a key or -CO- and R4 It can be a functional group:

[0205] ;

[0206] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them is N.

[0207] L 2 It can be a key or -CO- and R 4 It can be a functional group:

[0208] ;

[0209] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One of them is N.

[0210] L 2 It can be a key or -CO- and R 4 It can be a functional group:

[0211] ;

[0212] Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 The two in it are N.

[0213] L 2 It can be a key or -CO- and R 4 It can be a functional group:

[0214] .

[0215] L 2 It can be a key or -CO- and R 4 It can be a group selected from the following:

[0216] ; ; ; and .

[0217] L 2 It can be a key or -CO- and R 4 It can be a group selected from the following:

[0218] ; ; and .

[0219] L 2 It can be -CO- and R 4 It could be -(CH2) q NH2, where q is 0-3.

[0220] In the compounds described in this article, R 5 R 6 R 7 R 8 and R 9 It can be independently selected from H, halogen, CN, NR. 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN and SO2Me.

[0221] In the compounds described in this article, R 15 and R 16 It can be H or C independently. 1-3 Alkyl group. R 15and R 16 It can be H, methyl, ethyl, n-propyl or isopropyl independently.

[0222] R 5 R 6 R 7 R 8 and R 9 It can be independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, -OEt, -O n Pr, -N(CH3)(CH2CH2CH3), -N(CH3)2, -OCH2CN, -OCH2cyclopropyl, -CO2H and -SO2Me.

[0223] L 2 It can be a key or -CO- and R 4 It can be a group selected from the following:

[0224] L 2 It can be -CO- and R 4 It could be -(CH2) q NH2, where q is 0-3.

[0225] L 2 It can be -CO- and R 4 You can choose from:

[0226] ; .

[0227] R 4 It can be a group selected from the following:

[0228] The L provided in this article 1 and L 2 The definition of L does not restrict a specific direction relative to the rest of the molecule. Therefore, unless otherwise stated, the L provided is... 1 and L 2 The definition includes all possible directions. For example, in which L... 1 Compounds defined as -CONH- can include both of the following:

[0229] ;and .

[0230] The compound may be a compound of formula (1') or (1''):

[0231] (1'); (1'');

[0232] Or its salts, wherein J, X, Z, L 1 L 2 R 1 R 2 R 3 R 3a R 3b R 3c and R 4 As defined in this article.

[0233] The compound may be a compound of formula (1'''), (1''''), (1'''''), (1''''''), (1'''''') or (1''''''''):

[0234]

[0235]

[0236] Or its salts, wherein J, X, Z, L 1 L 2 R 1 R 2 R 3 and R 4 As defined in this article.

[0237] The compound may be a compound of formula (2a) or (2b):

[0238] (2a); (2b);

[0239] or its salts, wherein X, Z, L 1 R 2 R 3 and R 4 As defined in this article.

[0240] The compound may be a compound of formula (2aD) or (2bD):

[0241] (2aD); (2bD);

[0242] or its salts, wherein X, Z, L 1 R 2 R 3 and R 4 As defined in this article.

[0243] The compound may be a compound of formula (2ai), (2bi), (2ai'), or (2bi'):

[0244] (2ai); (2bi);

[0245] (2ai'); (2bi');

[0246] or its salts, wherein X, Z, L 1 R 2 and R 4 As defined in this article.

[0247] The compound may be a compound of formula (2aii), (2aiii), (2aiv), (2bii), (2biii), or (2biiv):

[0248]

[0249] or its salts, wherein X, Z, L 1 R 2 R 3 and R 4 As defined in this article.

[0250] The compound may be a compound of the formula (2av), (2avi), (2avii), (2bv), (2bvi), or (2bvii):

[0251]

[0252] or its salts, wherein X, Z, L 1 R 2 R 3 and R 4 As defined in this article.

[0253] The compound may be a compound of formula (3a), (3b), (3c), (3d), (3e), or (3f):

[0254] (3a); (3b); (3c);

[0255] (3d); (3e); (3f);

[0256] or its salt, wherein L 1 R 2 R3 and R 4 As defined in this article.

[0257] The compound may be a compound of the formula (3ai), (3bi), (3ci), (3di), (3ei), or (3fi):

[0258] (3ai); (3bi); (3ci);

[0259] (3di); (3ei); (3fi);

[0260] or its salt, wherein L 1 R 2 R 3 and R 4 As defined in this article.

[0261] The compound may be a compound of formula (3aii), (3bii), (3cii), (3dii), (3eii), or (3fii):

[0262]

[0263] or its salt, wherein L 1 R 2 R 3 and R 4 As defined in this article.

[0264] The compound may be a compound of formula (3aiii), (3biii), (3ciii), (3diii), (3eiii), or (3fiii):

[0265]

[0266] or its salt, wherein L 1 R 2 R 3 and R 4 As defined in this article.

[0267] The compound may be a compound of the formula (3aiv), (3biv), (3civ), (3div), (3eiv), or (3fiv):

[0268]

[0269] or its salt, wherein L 1 R 2 R3 and R 4 As defined in this article.

[0270] The compound may be a compound of the formula (3av), (3bv), (3cv), (3dv), (3ev), or (3fv):

[0271]

[0272]

[0273] or its salt, wherein L 1 R 2 R 3 and R 4 As defined in this article.

[0274] The compound may be a compound of formula (5a) or (5b):

[0275] (5a); (5b);

[0276] or its salt, wherein L 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 9 As defined in this article.

[0277] The compound may be a compound of formula (6a), (6b), (6c), (6d), (6e), (6f), (6g), or (6h):

[0278] (6a); (6b); (6c);

[0279] (6d); (6e); (6f);

[0280] (6g); (6h);

[0281] or its salt, wherein L 1 R 2 R 3 R 5 R 6 R 7 R 8 and R9 As defined in this article.

[0282] The compound may be a compound of formula (9a), (9b), (9c), (9d), (9e), or (9f):

[0283]

[0284]

[0285] or its salt, wherein R 3 and R 4 As defined in this article.

[0286] The compound may be selected from any one of Examples 1 to 218 shown in Table 1a or a salt thereof.

[0287] The compound may be selected from:

[0288] Or its salt.

[0289] Its salt can be a pharmaceutically acceptable salt. Its salt can be a formate, trifluoroacetic acid (TFA) salt, methanesulfonate, or hydrochloric acid (HCl) salt. Its salt can be a formate or a trifluoroacetic acid (TFA) salt.

[0290] The compound may be a salt selected from the following:

[0291] Other 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 a medicament. It also includes 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 to treat diseases or disorders characterized by MC2R activation. The compounds of the present invention can be used to treat diseases or disorders related to MC2R, or to treat diseases or disorders that would benefit from regulation of MC2R activity.

[0292] The compounds of this invention can be used to treat congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depression, septic shock, and related disorders or symptoms.

[0293] In some embodiments, the compounds and compositions detailed herein are used as MC2R modulators. This document provides a method of treating a disease in an individual, comprising administering an effective amount of a compound of formula (1) or any embodiment, variant or aspect thereof.

[0294] The compounds disclosed herein as MC2R modulators can be used as preventative or therapeutic agents for MC2R-related diseases. In some embodiments, the compounds described herein, or salts thereof, or compositions described herein, can be used in methods of treating an individual's Cushing's disease.

[0295] Also provided are combinations comprising the compounds of the present invention and a corticotropin-releasing factor receptor-1 (CRF1) antagonist. In the combination, the CRF1 antagonist may be selected from 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.

[0296] In combination, CRF1 antagonists can be selected from:

[0297] and .

[0298] Combinations comprising the compounds of the present invention and ACTH antibodies are also provided. In the combination, the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8).

[0299] The combination can be used to treat congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depression, septic shock, and related disorders or symptoms.

[0300] This document also provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, in the preparation of medicaments. In some embodiments, the preparation of the medicament is for treating the disorders or diseases described herein. In some embodiments, the preparation of the medicament is for preventing and / or treating disorders or diseases mediated by MC2R.

[0301] In some embodiments, the compounds described herein, or their salts, or the compositions described herein, may be used in a method as a standalone therapy, or as a combination therapy with other palliative agents (e.g., agents that relieve symptoms of the disorder to be treated) and / or agents that target the cause of the disorder. The compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent.

[0302] In some embodiments, (a) the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, and (b) the agent are administered sequentially, concurrently, or simultaneously. In some embodiments, (a) the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, and (b) the agent are administered at intervals of about 15 minutes or less (such as any one of about 10, 5, or 1 minute or less). In some embodiments, (a) the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, and (b) the agent are administered at intervals of about 15 minutes or longer (such as any one of about 20, 30, 40, 50, 60 minutes, or more). It is possible to administer (a) the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, and (b) the agent first. In some embodiments, (a) the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, and (b) the agent are administered simultaneously.

[0303] definition

[0304] In this application, unless otherwise specified, the following definitions apply.

[0305] As used herein, the term "MC2R modulator" refers to any compound that binds to the MC2 receptor and modulates its function. The term "modulator" should be interpreted to include modulation through means including, but not limited to, antagonists.

[0306] The term “treatment” in connection with the use of any compound described herein (including compounds of formula (1)) is used to describe any form of intervention in which a compound is administered to a subject who has the disease or disorder in question, or is at risk of having or may have the disease or disorder in question. Thus, the term “treatment” encompasses preventive (protective) treatment and treatment in which measurable or detectable symptoms of the disease or disorder are manifested.

[0307] The term "effective therapeutic amount" (as in relation to methods of treating a disease or disorder) refers to the amount of a compound that effectively produces the desired therapeutic effect. For example, if the symptom is pain, then the effective therapeutic amount is the amount sufficient to provide the desired level of pain relief. The desired level of pain relief might be, for example, complete elimination of pain or reduction of the severity of pain.

[0308] Unless otherwise specified, all chemical terms are used in their usual sense (e.g., as defined in the IUPAC Gold Book).

[0309] As used in this article, the term "alkyl" refers to a straight-chain or branched saturated alkyl group.

[0310] As used in this article, the term "cycloalkyl" refers to a saturated carbocyclic group containing a specified number of carbon atoms.

[0311] As used in this article, the term "carbocyclic" refers to a saturated or unsaturated carbocyclic group containing a specified number of carbon atoms.

[0312] As used herein, the term "heterocycle" refers to a saturated or unsaturated ring containing a specified number of total ring member atoms, wherein one or more ring members are heteroatoms selected from O, S, and N and their oxidized forms, and the remaining atoms are C.

[0313] As used herein, the term "bicyclic" refers to a saturated or unsaturated ring system comprising two linked rings and containing a specified total number of atoms. This includes all possible ring connection modes (including spirocyclic, fused, and bridged rings).

[0314] As used herein, the term "heterocyclic bicycle" refers to a saturated or unsaturated heterocyclic ring system containing two linked rings and a specified total number of atoms. This includes all possible ring connection modes (including spirocyclic, fused, and bridged rings).

[0315] The number of carbon atoms that may be present in the groups cited in this article can be indicated by the subscript "C". n1-n2 "Instruction. Therefore, for example, the term "C" 1-3 "alkyl" represents an alkyl group having 1, 2, or 3 carbon atoms, and includes methyl, ethyl, n-propyl, and isopropyl.

[0316] The term "optionally substituted" applied to any group means that the group can be substituted by one or more identical or different substituents if desired. Thus, for example, the term "optionally substituted by 1-6 fluorine atoms" applied to a group means that the group can be substituted by 1, 2, 3, 4, 5 or 6 fluorine atoms if desired.

[0317] With regard to any compound described having a chiral center, the invention extends to all optical isomers of such compounds, whether in racemic or resolved enantiomeric form. The invention described herein relates to all crystalline forms, solvates, and hydrates of any disclosed compound, regardless of their preparation. With regard to any compound disclosed herein having an acidic or basic center (such as a carboxylic ester or amino group), this invention includes all salt forms of the compound. In the case of pharmaceutical use, said salts should be considered pharmaceutically acceptable salts.

[0318] Salts that may be mentioned, or pharmaceutically acceptable salts, include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting the free acid or free base of the compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying, or by filtration). Salts can also be prepared by exchanging one counter ion of the compound in salt form with another counter ion, for example using a suitable ion exchange resin.

[0319] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0320] Examples of acid addition salts include those formed with the following acids: 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-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, gluconic acid (e.g., D-gluconic acid), glucose. Aldol acids (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic 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-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pyruvic 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), thiocyanate, undecenoic acid, and valeric acid.

[0321] This also includes any solvates of the compound and its 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-state structure (e.g., crystal structure) of the compound of the invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and DMSO. Solvates can be prepared by recrystallizing the compound of the invention with a solvent or solvent mixture containing a solvating solvent. Whether a solvate has been formed in any given case can be determined by analyzing the compound crystals using well-known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0322] The solvate may be stoichiometric or non-stoichiometric. Specific solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and their preparation and characterization methods, see Bryn et al., Solid-State Chemistry of Drugs, 2nd ed., published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0323] In the context of this invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and additionally comprising one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, excipients, carriers, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. The composition may be in the form of, for example, tablets, sugar-coated pills, powders, elixirs, syrups, liquid products (including suspensions), sprays, inhalers, tablets, lozenges, emulsions, solutions, capsules, granules, capsules, and suppositories, as well as injectable liquid products (including liposome products).

[0324] The compounds of this invention may contain one or more isotopic substitutions, and references to a particular element include all isotopes of that element within their scope. For example, references to hydrogen include... 1 H, 2 H (D) and 3 H(T). Similarly, references to carbon and oxygen within their scope include, respectively, 12 C 13 C and 14 C and 16 O and 18 O. In a similar manner, references to a particular functional group also include isotopic variants within their scope, unless the context otherwise indicates. For example, references to alkyl groups (such as ethyl groups) or alkoxy groups (such as methoxy groups) also cover variants in which one or more hydrogen atoms are in the form of deuterium or tritium isotopes, such as an ethyl group in which all five hydrogen atoms are in the form of deuterium isotopes (all-deuterium ethyl group), or a methoxy group in which all three hydrogen atoms are in the form of deuterium isotopes (trideuterium methoxy group). The isotopes may be radioactive or non-radioactive.

[0325] The therapeutic dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. Determining the appropriate dosage for a specific situation is a skill in the art. Generally, treatment begins with a small dose, less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved in the stated situation. For convenience, the total daily dose can be divided and administered in divided doses throughout the day if desired.

[0326] Of course, the effective dose of the compound will vary depending on the severity of the condition to be treated and the specific compound and its route of administration. The selection of an appropriate dose is within the capabilities of a person skilled in the art and will not impose an undue burden. Generally, the daily dose range can be from about 10 μg to about 30 mg / kg human and non-human animal body weight, preferably from about 50 μg to about 30 mg / kg human and non-human animal body weight, for example from about 50 μg to about 10 mg / kg human and non-human animal body weight, for example from about 100 μg to about 30 mg / kg human and non-human animal body weight, for example from about 100 μg to about 10 mg / kg human and non-human animal body weight, and most preferably from about 100 μg to about 1 mg / kg human and non-human animal body weight.

[0327] pharmaceutical preparations

[0328] While the active compound may be administered alone, it is preferred to present it as a pharmaceutical composition (e.g., a formulation).

[0329] Therefore, in some embodiments of the present invention, a pharmaceutical composition is provided comprising at least one compound of formula (1) as defined above and at least one pharmaceutically acceptable excipient.

[0330] The pharmaceutically acceptable excipient may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), excipients, diluents (e.g., solid diluents such as fillers or fillers; and liquid diluents such as solvents and co-solvents), granulators, binders, flow aids, coating agents, release control agents (e.g., polymers or waxes that delay or prolong release), adhesives, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, tension modifiers, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0331] As used herein, the term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is suitable, within reasonable medical judgment, for contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit / risk ratio. Each excipient must also be "acceptable," meaning compatible with the other components of the formulation.

[0332] Pharmaceutical compositions containing a compound of formula (1) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical composition may be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, sublingual, ophthalmic, otological, rectal, vaginal, or transdermal administration.

[0333] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, rice paper capsules, or patches such as buccal patches.

[0334] The composition may be a tablet composition or a capsule composition. The tablet composition may contain a unit dose of the active compound and an inert diluent or carrier such as sugars or sugar alcohols, such as lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch such as corn starch. The tablet may also contain standard ingredients such as binders and granulators (e.g., polyvinylpyrrolidone), disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethyl cellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and do not need to be discussed in detail here.

[0335] Tablets can be designed to release the drug upon contact with gastric juices (immediate-release tablets) or to release the drug in a controlled manner over a prolonged period of time or in a specific area of ​​the gastrointestinal tract (controlled-release tablets).

[0336] The pharmaceutical composition typically comprises from about 1% (w / w) to about 95%, preferably % (w / w) of the active ingredient, and from 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 from about 20% (w / w) to about 90% (w / w) of the active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. The pharmaceutical composition comprises from about 1% to about 95%, preferably about 20% to about 90% of the active ingredient. The pharmaceutical composition according to the invention may be, for example, in unit-dose form, such as ampoules, vials, suppositories, pre-filled syringes, sugar tablets, powders, tablets, or capsules.

[0337] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids, and / or 0-99% (w / w) fillers / or expanders (depending on drug dosage). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, and 0-5% (w / w) pigments. Extended-release tablets typically contain an additional 0-99% (w / w) polymer for controlled (e.g., delayed) release (depending on dosage). Film coatings of tablets or capsules typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0338] The composition may be a parenteral composition. Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dosage and whether it is lyophilized). Formulations for intramuscular reservoirs may also contain 0-99% (w / w) oil.

[0339] The pharmaceutical preparation can be provided to the patient in a "patient pack" containing the entire course of treatment in a single package (typically a blister pack).

[0340] Compounds of formula (1) are typically presented in unit dosage forms and therefore usually contain sufficient amounts of the compound to provide the desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligrams to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (such as 1 microgram to 10 milligrams, such as 0.1 milligrams to 2 milligrams of active ingredient).

[0341] For oral compositions, the unit dosage form may contain 1 mg to 2 g, more generally 10 mg to 1 g, such as 50 mg to 1 g, such as 100 mg to 1 g of active compound.

[0342] The active compound is administered to a patient (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective dose). The precise amount of compound administered can be determined by the attending physician according to standard procedures. Example

[0343] The invention will now be described with reference to the following embodiments shown in Table 1a, but the invention is not limited thereto.

[0344] Table 1a - Examples

[0345] Preparation of the compounds of the present invention

[0346] Compounds of formula (1) and their derivatives or synthetic intermediates can be prepared according to synthetic methods known to those skilled in the art. In some embodiments, the present invention provides a method for preparing compounds as defined in formula (1) above.

[0347] This document describes several chemical synthesis methods for the spiro[piperidine-4,5'-[1,7]naphthidine] compounds of this application. These and / or other well-known methods can be modified and / or adapted in various ways to facilitate the synthesis of other compounds within the scope of this application and the claims. Compounds of formula (1) and their derivatives or synthetic intermediates can be prepared according to general scheme 1.

[0348] General Solution 1:

[0349]

[0350] In one scheme (General Scheme 1), the compound of formula [X3] can be prepared by reacting a compound of formula [X1] with a heteroaromatic or substituted phenyl compound of formula [X2] in a transition metal-catalyzed cross-coupling reaction (such as Buchwald-Hartwig amination), wherein the catalyst is such as Pd(dba)2, Pd(OAc)2 or Pd(o-tolyl)3, the phosphine ligand is such as BINAP, DPPF, XantPhos or JohnPhos, the base is such as NaOtBu, K2CO3 or Cs2CO3, and a suitable solvent is such as DMF, THF, dioxane or toluene. The reaction is suitably carried out at an elevated temperature. Alternatively, compounds of formula [X3] can also be prepared by reacting a compound of formula [X1] with a heteroaromatic compound of formula [X2] 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. This reaction is suitably carried out at elevated temperatures. Alternatively, compounds of formula [X3] can be prepared by reacting with a carboxylic acid 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 post-reaction treatment (usually by liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization. Compounds of formula [X4] can be prepared by standard methods for removing the protecting group (PG) using compounds of formula [X3]. For the benzyloxycarbonyl (Cbz) group, hydrogenation is carried out in a polar solvent such as ethanol or methanol, in the presence of palladium supported on activated carbon, under a hydrogen atmosphere. Alternatively, a method using a strong base such as KOH in a solvent such as ethanol, appropriately at an elevated temperature, is employed. After post-reaction treatment (typically filtration and / or liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-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], wherein the reaction is a reduction amination reaction in a polar solvent such as DCM, DCE, or methanol using a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride. After post-reaction treatment (typically by liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, chiral preparative SFC, or recrystallization. Alternatively, they can be prepared by substitution reactions using alkyl halides [X5'] or alkyl methanesulfonates, employing strong bases such as NaH and solvents such as DMSO. Alternatively, they can be prepared by amide coupling reactions using carboxylic acids of formula [X5''], employing coupling agents such as HATU, solvents such as DCM or DMF, and bases such as DIPEA. This reaction is typically carried out at room temperature.In some embodiments, the compound of formula [X6] contains an amino group protected by a nitrogen-protected group such as a tert-butyloxycarbonyl protecting group. In these embodiments, the tert-butyloxycarbonyl protecting group is removed by standard removal of the tert-butyloxycarbonyl protecting group by reacting the compound of formula [X6] with an acid (such as trifluoroacetic acid or phosphoric acid in DCM, HCl in dioxane, or formic acid) to prepare the compound of formula [X7]. After post-reaction treatment (typically by liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, chiral preparative SFC, or recrystallization.

[0351] General Solution 2:

[0352]

[0353] In another scheme (General Scheme 2), the compound of formula [X3'] can be prepared by reductive amination of the compound of formula [X1'] with the aldehyde of formula [X2] in a polar solvent such as DCM, DCE, or methanol with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride. After post-reaction treatment (usually by liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, chiral preparative SFC, or recrystallization. Alternatively, they can be prepared by substitution reactions using strong bases such as NaH and solvents such as DMSO with alkyl halides [X2'] or alkyl methanesulfonates. Alternatively, they can be prepared by amide coupling reactions using coupling agents such as HATU, solvents such as DCM or DMF, and bases such as DIPEA with carboxylic acids of formula [X2'']. This reaction is usually carried out at room temperature. The compound of formula [X4'] can be prepared by standard methods, using the compound of formula [X3'] with the protecting group (PG) removed. Compounds of formula [X6] can be prepared from compounds of formula [X4'], wherein the heteroaromatic or substituted phenyl compound of formula [X5] is reacted in a transition metal-catalyzed cross-coupling reaction (such as Buchwald-Hartwig amination), with 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, a base such as NaOtBu, K2CO3, or Cs2CO3, and a suitable solvent such as DMF, THF, dioxane, or toluene. The reaction is suitably carried out at elevated temperatures. Alternatively, compounds of formula [X6] can also be prepared by reacting compounds of formula [X4'] with heteroaromatic compounds of formula [X5] in a nucleophilic aromatic substitution (SNAr) related reaction, said reaction being carried out in a polar solvent such as DMF or THF using a base such as DIPEA, K2CO3, Cs2CO3, or KOH, suitably at elevated temperatures. In some embodiments, compounds of formula [X6] contain an amino group protected by a nitrogen-protected group such as a tert-butyloxycarbonyl protecting group. In these embodiments, 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, HCl in dioxane, or formic acid). After post-reaction treatment (typically by liquid-liquid extraction), the reaction products are purified by rapid column chromatography, reversed-phase preparative HPLC, chiral preparative SFC, or recrystallization.

[0354] General Solution 3:

[0355]

[0356] Compounds of formula [X1] and [X1'] can be obtained by different methods (General Scheme 3). In one scheme, compounds of formula [X1'] can be prepared by reactive cyclization of compounds of formula [X1'_3] in an anhydrous solvent such as THF or toluene at a suitable temperature, wherein the reaction occurs in one or two steps with a reducing agent such as a borane-THF complex, LiAlH4, or RedAl. Alternatively, they can be prepared in a hydrogen atmosphere using Raney nickel and suitable solvents such as ethanol and water. Compounds of formula [X1'_3] can be prepared by reacting compounds of formula [X1'_1] with compounds of formula [X1'_2], wherein a strong base such as KHMDS and suitable anhydrous solvents such as toluene and THF are used, along with a suitable low temperature. Alternatively, compounds of formula [X1'] can be prepared by reducing compounds of formula [X1'_5] in a suitable solvent (usually an alcohol) and at a suitable temperature 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. Compounds of formula [X1'_5] can also be prepared by cyclization of compounds of formula [X1'_4], wherein the reaction is carried out in one or two steps with a reducing agent such as a 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 nickel and suitable solvents such as ethanol and water in a hydrogen atmosphere. Compounds of formula [X1'_4] can be prepared by reacting compounds of formula [X1'_1] with compounds of formula [X1'_2'] using a strong base such as KHMDS and a suitable anhydrous solvent such as toluene and THF, and at a suitable low temperature. Alternatively, compounds of formula [X1'] can be prepared from compounds of formula [X1'_8] under standard deprotection conditions, depending on the nature of PG. Compounds of formula [X1] can be prepared from compounds of formula [X1_8] under typical benzyl deprotection conditions (such as with NaOH in solvents such as ethanol and water at high temperature). Alternatively, they can also be prepared by reduction in a hydrogen atmosphere with a suitable catalyst such as Pd(OH)2 in a suitable solvent such as MeTHF, MeOH, or IPA. Compounds of formula [X1_8] can be prepared by reducing compounds of formula [X1_7] with suitable reducing agents such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd / C, ammonium formate or Mn(dpm)3, PhSiH3, TBHP in a suitable solvent (usually an alcohol) 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, usually at room temperature.Then, the mixture is treated with an aqueous solution of HCl in a suitable solvent such as THF, typically at room temperature. Compounds of formula [X1_7] can also be prepared from compounds of formula [X1'5] using standard protecting group addition reaction conditions.

[0357] The compounds of the present invention can be prepared according to the methods described below. It should be noted that all reported yields are based on the weight of the starting materials and products, not their purity.

[0358] LCMS method

[0359]

[0360] HPLC purification method of the examples

[0361] Abbreviations and acronyms

[0362] Synthesis of intermediates:

[0363] Procedure for preparing 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (intermediate 4)

[0364]

[0365] (2-ethoxypyridin-3-yl)boronic acid (11.4 g, 68.4 mmol) was added to a stirred solution of 6-chloro-3-fluoropyridinecarboxylic acid (10 g, 57.0 mmol) in 1,4-dioxane:H₂O (80:20 mL) at room temperature, followed by the addition of K₂CO₃ (15.8 g, 114 mmol), and the solution was purified with nitrogen for 5 min. Pd(amphos)Cl₂ (0.605 g, 0.854 mmol) was added to the reaction mixture and the mixture was heated at 100 °C for 16 h. The mixture was filtered through a diatomaceous earth bed, and the bed was washed with EtOAc (100 mL). The combined filtrates were diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The aqueous layer was acidified with citric acid (10%) (a solid precipitate was formed). The precipitated solid was filtered off to provide 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (12 g, 44.8 mmol, 79%) as a white solid.

[0366] LCMS: 2.04 min, 263.1 (M+H) + Method B

[0367] K₂CO₃ (12.65 g, 92 mmol) was added to a stirred solution of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (12 g, 45.8 mmol) in DMF (80 mL), followed by ethyl iodine (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 x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by rapid column chromatography. The purified fraction was concentrated under reduced pressure to provide ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (10 g, 34.1 mmol, 75%) (intermediate 1) as an off-white solid.

[0368] A solution of 1 MKHMDS in THF (8.61 mL, 8.61 mmol) was added 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-cyanopiperidinium-1-carboxylate (1.81 g, 8.61 mmol) in toluene (25 mL), and the reaction mixture was stirred at room temperature for 30 min. 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 provide a crude extract. The crude product was purified by rapid column chromatography using EtOAc-petroleum ether (0-10%) to provide 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 colloid.

[0369] LCMS: 2.99 min, 481.0 (M+H) + Method B

[0370] Raney nickel (5.47 g, 62.4 mmol) was added to a stirred solution of ethyl 5-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (2.5 g, 5.20 mmol) in EtOH:H2O (20:5 mL) at room temperature, and the reaction mixture was stirred at 65 °C for 16 h under hydrogen atmosphere at 70 psi. The reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with MeOH (20 mL). The combined filtrates were concentrated under reduced pressure to provide a crude product. The crude product was purified by rapid column chromatography to provide tert-butyl 2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylate (1.5 g, 3.25 mmol, 63%) as a white solid (intermediate 2).

[0371] NaH (0.274 g, 6.84 mmol) was added 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]naphthyl]-1-carboxylate (1.5 g, 3.42 mmol) (intermediate 2) in THF (5 mL) and stirred for 20 min. Cbz-Cl (2.29 mL, 6.84 mmol) was added to the reaction mixture and the mixture was slowly stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 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 provide the crude extract. The crude product was purified by rapid column chromatography to provide 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (700 mg, 1.198 mmol, 35%) as an off-white solid (intermediate 3).

[0372] TFA (0.471 mL, 6.11 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (700 mg, 1.22 mmol) (intermediate 3) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give a crude product. The crude product 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 provide crude 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester 2,2,2-trifluoroacetate (600 mg, 1.002 mmol, 82%) (intermediate 4) as a colloidal solid.

[0373] The analytical data for intermediates 1, 2, 3 and 4 are listed in Table 1.

[0374] Procedure for preparing 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-carboxylate (intermediate 5)

[0375]

[0376] BH3·THF (4.19 mL, 4.19 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (600 mg, 1.048 mmol) (intermediate 3) in THF (10 mL), 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 reactants were quenched with MeOH (10 mL) at 0 °C, and the reaction mixture was concentrated to provide crude 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (400 mg, 0.716 mmol, 68.3%) as a gel solid. The crude product was used as is in the next step.

[0377] TFA (82 mg, 0.716 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (400 mg, 0.716 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was directly concentrated and the resulting residue was alkalized with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-carboxylate (700 mg, 1.480 mmol, 207%) (intermediate 5) as a pale yellow gelatinous solid.

[0378] The analytical data for intermediate 5 are listed in Table 1.

[0379] The procedure for preparing nitriles, taking the preparation of 1-(4-chloro-2-(trifluoromethyl)phenyl)piperidine-4-carboxynitrile (intermediate 6) as an example.

[0380]

[0381] 1-Bromo-4-chloro-2-(trifluoromethyl)benzene (883 mg, 3.40 mmol) and Cs₂CO₃ (1.48 g, 4.54 mmol) were added to a stirred solution of piperidine-4-carboxynitrile (250 mg, 2.269 mmol) in toluene (2 mL) at room temperature. The reaction mixture was purified with nitrogen for 5 min. BINAP (283 mg, 0.454 mmol) and Pd(OAc)₂ (51 mg, 0.227 mmol) were added, and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc (10 mL). The filtrate was evaporated, and the crude product was purified by rapid column chromatography to provide 1-(4-chloro-2-(trifluoromethyl)phenyl)piperidine-4-carboxynitrile (550 mg, 1.87 mmol, 83%) (intermediate 6) as a yellow gel.

[0382] The analytical data for intermediate 6 are listed in Table 1.

[0383] The procedure for preparing lactams is exemplified by the preparation of 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-6'-one (intermediate 8).

[0384]

[0385] Aliquots of potassium hydroxide (11.03 g, 196.62 mmol) and N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine hydrochloride (17.60 g, 65.54 mmol) were added to a solution of 2-(6-chloropyridin-3-yl)acetonitrile (10 g, 65.54 mmol) in DMSO (200 mL) at 25 °C. The reaction mixture was stirred at 30 °C for 2.5 h. 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 phases were washed with brine (500 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 100 / 1 to 20 / 1) to give 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-carboxynitrile (11 g, 53.8%) as an orange solid.

[0386] 1H NMR (400 MHz, CDCl3) δ 8.57 - 8.54 (m, 1H), 7.80 (dd, J=2.7, 8.3Hz, 1H), 7.43 - 7.28 (m, 6H), 3.62 (br s, 2H), 3.10 - 3.00 (m, 2H), 2.54 (brdd, J=5.7, 12.0 Hz, 2H), 2.12 (br s, 4H)

[0387] Potassium hydroxide (7.13 g, 127.00 mmol) was added to a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-carboxylic acid (5.5 g, 17.64 mmol) in a mixed solvent of ethanol (55 mL) and water (55 mL) at 25 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 16 hours. Another tubular flask was prepared as described above. After cooling to room temperature, all two reaction mixtures were combined. The ethanol was removed from the mixture and it was 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)piperidin-4-carboxylic acid (8 g) as a white solid, which was used directly for the next step without further purification.

[0388] LCMS: 0.72 min, 331.1 (M+H) + Method O

[0389] At 25 °C, a solution of 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-carboxylic acid (9.4 g, 28.42 mmol) in a mixed solvent of MeOH (100 mL) and toluene (200 mL) was added to (trimethylsilyl)diazomethane (2 M, 42.62 mL) in hexane. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with acetic acid (1 mL) and 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 a crude product, which was purified by rapid column chromatography (eluting with petroleum ether / EtOAc = 100 / 5 to 100 / 20) to provide methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidin-4-carboxylic acid (6 g, 61%) as a yellow solid.

[0390] 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.70 - 7.64 (m, 1H), 7.37 -7.22 (m, 6H), 3.69 (s, 3H), 3.49 (s, 2H), 2.83 (br d, J=10.4 Hz, 2H), 2.58(br d, J=12.8 Hz, 2H), 2.21 (br t, J=11.2 Hz, 2H), 2.05 - 1.93 (m, 2H)

[0391] To a solution of methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (1 g, 2.90 mmol) in chloroform (20 mL), urea peroxide (545 mg, 5.80 mmol) and trifluoroacetic anhydride (1.22 g, 5.80 mmol, 806.7 μL) were added at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. Another tubular flask was prepared as described above. All 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 phases were 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 obtain a crude product, which was purified by rapid column chromatography (eluting 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.

[0392] 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=11.0Hz, 2H), 1.99 - 1.87 (m, 2H).

[0393] Trimethylsilylformonitrile (824.81 mg, 8.31 mmol, 1.04 mL) and N,N-dimethylcarbamoyl chloride (894.1 mg, 8.3 mmol, 764.2 μL) were added 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) at 25 °C. The reaction mixture was heated to 70 °C and stirred for 12 hours. Two more tubular flasks were prepared as described 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 produce a residue, which was purified by rapid column chromatography (eluting with petroleum ether / EtOAc = 10 / 1 to 0 / 1) to give methyl 1-benzyl-4-(6-chloro-2-cyanopyridin-3-yl)piperidine-4-carboxylate (1.5 g, 49%) as a yellow oil.

[0394] 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)

[0395] To a solution of methyl 1-benzyl-4-(6-chloro-2-cyanopyridin-3-yl)piperidin-4-carboxylate (1.3 g, 3.7 mmol) in a mixed solvent of dioxane (20 mL) and water (2 mL) at 25 °C under nitrogen, (2-ethoxypyridin-3-yl)boronic acid (921.3 mg, 5.6 mmol), K₂CO₃ (1.53 g, 11.04 mmol), and [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (269.2 mg, 367.9 μmol) were added (2.3 g, 3.7 mmol), (2.3 g, 3.7 mmol), and (2.5 g, 11.04 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. 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 obtain a crude product, which was then subjected to preparative TLC (EtOAc, R). f=0.29) Purification yielded methyl 1-benzyl-4-(6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl)piperidine-4-carboxylate (1.5 g, 3.3 mmol, 89%) as a white solid.

[0396] 1 H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=1.9, 7.6 Hz, 1H), 8.36 (d, J=8.8Hz, 1H), 8.24 (dd, J=2.0, 4.9 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.33 (d, J=4.3Hz, 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)

[0397] A borane THF complex (1 M, 7.67 mL) was added dropwise to a solution of methyl 1-benzyl-4-(6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl)piperidin-4-carboxylate (700 mg, 1.53 mmol) in THF (14 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was heated to 40 °C and stirred at 40 °C for 2 hours. Another tubular flask was prepared as described above. After cooling to 0 °C, all 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 obtain a residue, which was then purified by rapid column chromatography (eluting with petroleum 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[piperidin-4,5'-[1,7]naphthyl]-6'-one (700 mg, 53%) as a yellow oil.

[0398] 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J=1.8, 7.4 Hz, 1H), 8.20 (dd, J=1.9, 4.9 Hz, 1H), 8.00 (s, 1H), 7.84 (br d, J=8.5 Hz, 1H), 7.39 - 7.30 (m,4H), 7.30 - 7.28 (m, 1H), 7.02 (dd, J=4.9, 7.4 Hz, 1H), 6.09 (br s, 1H), 4.65(d, J=3.0 Hz, 2H), 4.50 (q, J=7.1 Hz, 2H), 3.60 (br s, 2H), 2.79 (br s, 4H), 2.22 (br d, J=13.5 Hz, 2H), 2.11 - 2.01 (m, 2H), 1.44 (t, J=7.0 Hz, 3H)

[0399] Under nitrogen atmosphere, Pd(OH)₂ (100 mg, 142.4 μmol, 20% purity) and di-tert-butyl dicarbonate (101.9 mg, 466.7 μmol, 107.2 μL) were added to a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-6'-one (100 mg, 233.4 μmol) in MeOH (5 mL). The suspension was degassed under vacuum and purified several times with hydrogen. The reaction mixture was stirred at 20°C for 5 hours under a hydrogen balloon (15 Psi). Two additional tubular flasks were prepared as described above. All three reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC to give tert-butyl 2'-(2-ethoxypyridin-3-yl)-6'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1-carboxylate (200 mg, 65%) (intermediate 7) as a colorless oil.

[0400] 2,2,2-TFA (154.0 mg, 1.35 mmol, 0.1 mL) was added to a solution of 2'-(2-ethoxypyridin-3-yl)-6'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1-carboxylic acid tert-butyl ester (100 mg, 228.0 μmol) in DCM (1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. Another tubular flask was prepared as described above. All two reaction mixtures were combined and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to give 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-6'-one (50 mg, 34%) (intermediate 8) as a yellow oil.

[0401] The analytical data for intermediates 7 and 8 are listed in Table 1.

[0402] The procedure for preparing lactams is exemplified by the preparation of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (intermediate 10).

[0403]

[0404] TFA (0.04 mL, 0.456 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1-carboxylic acid tert-butyl ester (200 mg, 0.456 mmol) (intermediate 2) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and dried under high vacuum to provide 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthidine]-8'-one trifluoroacetate (150 mg, 0.400 mmol, 88%) (intermediate 10) as a brown gel.

[0405] The analytical data for intermediate 10 are listed in Table 1.

[0406] The procedure for preparing nitriles is illustrated by the preparation of 1-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-carboxynitrile (intermediate 14).

[0407]

[0408] Add 4-chloro-2-fluoro-3-iodopyridine (690 mg, 2.68 mmol) to a stirred solution of piperidine-4-carboxynitrile (300 mg, 2.72 mmol) in DMSO (3 mL), followed by the addition of DIPEA. (1.1 mL, 6.30 mmol), and the reactants were heated at 70 °C for 16 h. The reactants were diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, evaporated, and the crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–50%) to provide 1-(4-chloro-3-iodopyridin-2-yl)piperidine-4-carboxynitrile (580 mg, 1.6 mmol, 61%) as a white solid.

[0409] LCMS: 3.21 min, 348.1 (M+H) +， Method B

[0410] To a stirred solution of 1-(4-chloro-3-iodopyridin-2-yl)piperidine-4-carboxynitrile (580 mg, 1.669 mmol) in DMF (1 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (390 mg, 2.030 mmol) was added, followed by cuprous iodide (I) (390 mg, 2.048 mmol), and the reaction mixture was heated at 85 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, evaporated, and the crude product was purified by rapid column chromatography. The pure fraction was evaporated and dried under high vacuum to provide 1-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylonitrile (500 mg, 1.6 mmol, 97%) (intermediate 14) as a yellow liquid.

[0411] The analytical data for intermediate 14 are listed in Table 1.

[0412] The procedure for preparing amines is 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]naphthidine] (intermediate 15).

[0413]

[0414] A stirred solution of 2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-7'(8'H)-formate (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 purified with N2 for 5 min. Cs2CO3 (1034 mg, 3.17 mmol), Pd2(dba)3 (48.4 mg, 0.053 mmol), followed by xantphos (42.9 mg, 0.074 mmol), was added, and the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated to provide a crude product. The crude product was purified by rapid chromatography in a solution of 0 to 70% EtOAc in petroleum ether to provide 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]naphthyl]-1-carboxylate (400 mg, 0.608 mmol, 58%) as an off-white solid. It should be noted that migration of the Cbz group was observed.

[0415] LCMS: 2.89 min, 650.9 (M+H) + Method B

[0416] BH3·THF (0.184 ml, 0.184 mmol) was added to a stirred solution of 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid benzyl ester (30 mg, 0.046 mmol) in THF (2 mL), and the reaction mixture was stirred at room temperature for 4 h. The reactants were quenched with MeOH (10 mL) at 0 °C and the reaction mixture was concentrated to provide crude 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid benzyl ester (20 mg, 0.031 mmol, 68%) as a gel solid. The crude product was used as is in the next step.

[0417] LCMS: 2.56 min, 637.0 (M+H) + Method A

[0418] A solution of 20% KOH in water (1 mL, 0.157 mmol) was added 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]naphthyl]-1-carboxylic acid benzyl ester (100 mg, 0.157 mmol) in EtOH (1 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM:MeOH (9:1) (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (50 mg, 0.089 mmol, 57%) (intermediate 15) as a colloidal solid.

[0419] The analytical data for intermediate 15 are listed in Table 1.

[0420] The procedure for preparing acids, taking the preparation of 6-propoxy-2-(trifluoromethyl)nicotinic acid (intermediate 17) as an example.

[0421]

[0422] K₂CO₃ (2.292 g, 16.58 mmol) was added to a stirred solution of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (3 g, 12.76 mmol) in DMF (30 mL), 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 provide the crude product. The crude product was purified by rapid column chromatography using EtOAc-petroleum ether (0–30%) to provide ethyl 6-propoxy-2-(trifluoromethyl)nicotinate (3.51 g, 12.54 mmol, 98%).

[0423] LCMS: 2.0 min, 278.1 (M+H) + Method B

[0424] A solution of ethyl 6-propoxy-2-(trifluoromethyl)nicotinic acid (3.5 g, 12.62 mmol) in THF:MeOH:H2O (15:7.5:0.5 mL) was added to 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 1.5N HCl (1 mL) and extracted with DCM (5 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide 6-propoxy-2-(trifluoromethyl)nicotinic acid (2.8 g, 11.12 mmol, 88%) (intermediate 17) as a white solid.

[0425] The analytical data for intermediate 17 are listed in Table 1.

[0426] The procedure for preparing lactams, taking the preparation of (intermediate 20) as an example.

[0427]

[0428] DIPEA (0.310 mL, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol) were added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (300 mg, 0.886 mmol) in DMF (2 mL), 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 x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude extract. The crude compound was purified by rapid column chromatography to provide 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (250 mg, 0.373 mmol, 42%) (intermediate 19).

[0429] To a stirred solution of 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (100 mg, 0.174 mmol) (intermediate 19) in DMF (3 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (40.0 mg, 0.208 mmol) and cuprous iodide (I) (39.7 mg, 0.208 mmol) were added, and the reaction mixture was stirred at 60 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to provide a crude extract. The crude extract was purified using preparative HPLC. The pure fractions were collected and lyophilized under low pressure to give the desired product 1-(4-chloro-3-(trifluoromethyl)pyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (22 mg, 0.041 mmol, 23%) as a grayish-white solid (intermediate 20).

[0430] LCMS: 2.33 min, 518.1 (M+H) + Method A

[0431] The analytical data for intermediates 19 and 20 are listed in Table 1.

[0432] The procedure for preparing lactams is exemplified by the preparation of tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-yl)pyrrolidine-1-carboxylate (intermediate 26).

[0433]

[0434] To a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-6'-one (530 mg, 1.24 mmol) (intermediate 7) in THF (20 mL), tert-butyl 3-((methanesulfonyl)oxy)pyrrolidine-1-carboxylate (1.31 g, 4.95 mmol) and NaH (247.34 mg, 6.18 mmol, 60% purity) were added. The reaction mixture was heated to 60 °C and 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 layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a residue, which was then purified by rapid column chromatography (eluting with petroleum ether / EtOAc = 15 / 85 to EtOAc / MeOH = 95 / 5). f =0.4) to obtain tert-butyl pyrrolidine-1-carboxylate (420 mg, 57%) as a yellow oil.

[0435] LCMS: 0.69 min, 598.3 (M+H) + Method O

[0436] Pd(OH)₂ (400 mg, 569.66 μmol, 20% purity) was added to a solution of 3-(1-benzyl-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg, 702.64 μmol) in EtOAc (50 mL) under hydrogen (15 Psi) at 25 °C. The suspension was degassed under vacuum and purified several times with hydrogen. The reaction mixture was stirred at 25 °C under hydrogen (15 Psi) for 12 hours, and then the mixture was heated to 40 °C and stirred at 40 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to produce a residue to give 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (320 mg) (intermediate 26) as a gray oil, which was used for the next step without further purification.

[0437] The analytical data for intermediate 26 are listed in Table 1.

[0438] The procedure for preparing pyridine, taking the preparation of 3,5-dichloro-4-(trifluoromethyl)pyridine (intermediate 27) as an example.

[0439]

[0440] K₂CO₃ (192 mg, 1.39 mmol) was added 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 propanol (0.5 mL) at 25 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 hours. Another tubular flask was prepared as described above. After cooling to room temperature, all two reaction mixtures were combined, diluted with brine (15 mL), and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a residue, which was purified by preparative TLC to yield 3-chloro-5-propoxy-4-(trifluoromethyl)pyridine (100 mg, 45%) (intermediate 27) as a colorless oil.

[0441] The analytical data for intermediate 27 are listed in Table 1.

[0442] The procedure for preparing nitriles is exemplified by the preparation of 1-(4-propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-carboxynitrile (intermediate 29).

[0443]

[0444] Propane-1-ol (153 mg, 2.55 mmol) in DMF (2 mL) was added to a stirred suspension of NaH (139 mg, 3.47 mmol) in DMF (2 mL) at 0 °C, 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 a solution of 10% EtOAc in petroleum ether (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-15%) to provide 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (500 mg, 2.044 mmol, 88%) as a colorless liquid.

[0445] LCMS: 2.67 min, 239.8 (M+H) + Method B

[0446] To a stirred solution of 2-chloro-4-propoxy-3-(trifluoromethyl)pyridine (400 mg, 1.669 mmol) in DMSO (4 mL), piperidine-4-carboxynitrile (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 x 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated. The crude product was purified by rapid column chromatography to provide 1-(4-propoxy-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxynitrile (310 mg, 0.987 mmol, 59%) (intermediate 29) as a colorless colloid.

[0447] The analytical data for intermediate 29 are listed in Table 1.

[0448] The procedure for preparing nitriles is exemplified by the preparation of 1-(5-(methyl(propyl)amino)-4-(trifluoromethyl)pyridin-3-yl)piperidin-4-carboxynitrile (intermediate 31).

[0449]

[0450] A stirred solution of 3,5-dichloro-4-(trifluoromethyl)pyridine (300 mg, 1.389 mmol) and N-methylpropane-1-amine (508 mg, 6.94 mmol) in NMP (3 mL) was irradiated with microwave at 140 °C for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with a solution of 20% EtOAc in petroleum ether (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to provide 5-chloro-N-methyl-N-propyl-4-(trifluoromethyl)pyridine-3-amine (280 mg, 0.499 mmol, 36%) as a yellow gel.

[0451] LCMS: 2.91 min, 252.9 (M+H) + Method B

[0452] A solution of 5-chloro-N-methyl-N-propyl-4-(trifluoromethyl)pyridin-3-amine (350 mg, 1.385 mmol) and piperidine-4-carboxylonitrile (229 mg, 2.078 mmol) in toluene (8 mL) was degassed with nitrogen for 5 min. Cs₂CO₃ (903 mg, 2.77 mmol), BINAP (173 mg, 0.277 mmol), and Pd(OAc)₂ (31.1 mg, 0.139 mmol) were added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by rapid column chromatography to provide 1-(5-(methyl(propyl)amino)-4-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylonitrile (270 mg, 0.780 mmol, 56%) (intermediate 31) as a pale yellow gel.

[0453] The analytical data for intermediate 31 are listed in Table 1.

[0454] The procedure for preparing bromides is exemplified by the preparation of 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (intermediate 36).

[0455]

[0456] To a stirred solution of 3-bromo-2-(trifluoromethyl)phenol (500 mg, 2.075 mmol) in DMF (10 mL), 1-iodopropane (423 mg, 2.490 mmol) and K₂CO₃ (430 mg, 3.11 mmol) were added. The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with a solution of 20% EtOAc in petroleum ether (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated. The crude product was purified by rapid column chromatography to provide 1-bromo-3-propoxy-2-(trifluoromethyl)benzene (380 mg, 1.342 mmol, 65%) (intermediate 36) as a colorless liquid.

[0457] The analytical data for intermediate 36 are listed in Table 1.

[0458] The procedure for preparing chlorides, taking the preparation of 4-chloro-2-propoxy-3-(trifluoromethyl)pyridine (intermediate 40) as an example.

[0459]

[0460] Propane-1-ol (364 mg, 6.06 mmol) in THF (1 mL) was added to a stirred suspension of NaH (222 mg, 5.55 mmol) in THF (2 mL) at 0 °C, 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 reactants 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 x 10 mL). The combined organic extracts were dried over sodium sulfate and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–10%) to provide 4-chloro-3-iodo-2-propoxypyridine (1.49 g, 5.01 mmol, 99%) as a yellow colloid.

[0461] 1 H 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).

[0462] Cuprous iodide (I) (720 mg, 3.78 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.48 mL, 3.78 mmol) were added to a stirred solution of 4-chloro-3-iodo-2-propoxypyridine (750 mg, 2.52 mmol) in DMF (8 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by rapid column chromatography to provide 4-chloro-2-propoxy-3-(trifluoromethyl)pyridine (625 mg, 2.294 mmol, 91%) (intermediate 40) as a yellow liquid.

[0463] The analytical data for intermediate 40 are listed in Table 1.

[0464] The procedure for preparing chlorides is exemplified by the preparation of racemic-(3S,4S)-1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (intermediate 42).

[0465]

[0466] KHMDS (1M solution in THF) (3.52 mL, 3.52 mmol) was added to a stirred solution of ethyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylate (1.28 g, 4.41 mmol) (intermediate 1) and tert-butyl 4-cyano-3-ethylpiperidin-1-carboxylate (700 mg, 2.94 mmol) in toluene (5 mL) under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 2 h. 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 rapid column chromatography using a solution of EtOAc in petroleum ether (0–30%) to provide racemic 5-((3S,4S)-1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid ethyl ester (2.2 g, 1.644 mmol, 56%) as a brown colloid.

[0467] LCMS: 3.19 min, 509.0 (M+H) + Method B

[0468] Raney nickel (1.38 g, 15.73 mmol) was added to a stirred solution of racemic ethyl 5-((3S,4S)-1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (2 g, 1.573 mmol) in EtOH (10 mL) and water (2 mL). The reaction mixture was stirred at 65 °C for 24 h under a hydrogen atmosphere at 5 atm. Another batch of Raney nickel (1.38 g, 15.73 mmol) was added, and the reaction mixture was stirred at 65 °C for 24 h under a hydrogen atmosphere at 5 atm. The reaction mixture was filtered through diatomaceous earth and washed with a solution of 10% MeOH in DCM (200 mL). The filtrate was evaporated, and the crude product was purified by rapid column chromatography using a solution of MeOH in DCM (0-20%) to provide racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid tert-butyl ester (650 mg, 1.393 mmol, 89%) as a light brown colloid.

[0469] LCMS: 2.55 min, 467.1 (M+H) + Method B

[0470] TFA (1.1 mL, 13.93 mmol) was added to a stirred solution of racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid tert-butyl ester (650 mg, 1.393 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h, then carefully quenched with 10% NaHCO3 (10 mL) and extracted with a solution of 10% MeOH in DCM (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, evaporated, and dried under high vacuum to provide racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (500 mg, 1.364 mmol, 98%) (intermediate 41) as a yellow solid.

[0471] To a stirred solution of racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (600 mg, 1.637 mmol) in NMP (3 mL), 3,5-dichloro-4-(trifluoromethyl)pyridine (884 mg, 4.09 mmol) was added. The reaction mixture was heated in a microwave at 140 °C for 1 h. The reaction mixture was evaporated, and the crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–100%). The purified fraction was evaporated and dried under high vacuum to provide 1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (310 mg, 0.568 mmol, 35) as a yellow solid. 30 mg of the sample was further purified by preparative HPLC (Method B). The preparative fraction was lyophilized under low pressure. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (3 mL) and water (3 mL), dried over sodium sulfate, evaporated and lyophilized under low pressure to provide racemic-(3S,4S)-1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (8.8 mg) as a white solid (intermediate 42).

[0472] The analytical data for intermediates 41 and 42 are listed in Table 1.

[0473] The procedure for preparing acid anhydrides is illustrated by the preparation of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (intermediate 49).

[0474]

[0475] TEA (0.472 mL, 3.46 mmol) was added to a stirred solution of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (200 mg, 1.155 mmol) in acetonitrile (6 mL), followed by the addition of bis(2,5-dioxopyrrolidone-1-yl) carbonate (355 mg, 1.386 mmol), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with EtOAc (30 mL) and washed with 10% NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and dried under high vacuum to provide tert-butyl 3-((((2,5-dioxopyrrolidone-1-yl)oxy)carbonyl)oxy)azacyclobutane-1-carboxylate (300 mg, 0.955 mmol, 83%) (intermediate 49) as a gel.

[0476] The analytical data for intermediate 49 are listed in Table 1.

[0477] The procedure for preparing amides is exemplified by the preparation of 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (intermediate 50).

[0478]

[0479] A solution of 1-(benzyloxy)-3-bromo-2-(trifluoromethyl)benzene (537 mg, 1.622 mmol) and piperidine-4-carboxylonitrile (214 mg, 1.946 mmol) in toluene (10 mL) was degassed with nitrogen for 5 min. Cs₂CO₃ (1.06 g, 3.24 mmol), BINAP (202 mg, 0.324 mmol), and Pd(OAc)₂ (37 mg, 0.162 mmol) were added, and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–40%) to provide 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylonitrile (483 mg, 1.315 mmol, 81%) as a pale yellow colloid.

[0480] LCMS: 2.85 min, 361.1 (M+H) + Method B

[0481] 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)piperidin-4-carboxynitrile (480 mg, 1.331 mmol) in toluene (5 mL), KHMDS (1 M solution in THF) (1.22 mL, 1.220 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. 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 rapid column chromatography using a solution of EtOAc in petroleum ether (0-10%) to provide 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 colloid.

[0482] LCMS: 3.39 min, 631.2 (M+H) + Method B

[0483] 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) 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 diatomaceous earth and washed with a solution of 20% MeOH in DCM (2 x 20 mL). The filtrate was evaporated, and the crude product was purified by rapid column chromatography using MeOH / DCM (0–10%) to provide 38 mg of product. 18 mg of the compound was further purified by preparative HPLC. The fraction was lyophilized under low pressure. The residue was dissolved in DCM (5 mL), washed with 10% NaHCO3 solution (3 mL) and dried over sodium sulfate, evaporated, and lyophilized under low pressure to provide 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (4.51 mg, 7.64 μmol, 3%) (intermediate 50) as a white solid.

[0484] The analytical data for intermediate 50 are listed in Table 1.

[0485] The procedure for preparing bromides is exemplified by the preparation of 5-bromo-N-methyl-N-propyl-6-(trifluoromethyl)pyridine-2-amine (intermediate 53).

[0486]

[0487] N-methylpropane-1-amine (1.511 g, 20.66 mmol) was added to a stirred solution of 2-chloro-6-(trifluoromethyl)pyridine (2.5 g, 13.77 mmol) in DMSO (15 mL), followed by the addition of K₂CO₃ (3.81 g, 27.5 mmol), and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide N-methyl-N-propyl-6-(trifluoromethyl)pyridine-2-amine (2.5 g, 11.46 mmol, 83%), which was used for the next step without further purification.

[0488] LCMS: 2.89 min, 219.2 (M+H) + Method B

[0489] NBS (4.40 g, 24.75 mmol) was added to a stirred solution of N-methyl-N-propyl-6-(trifluoromethyl)pyridine-2-amine (6 g, 27.5 mmol) in MeOH (50 mL) 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 petroleum ether (2 x 10 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by rapid column chromatography to provide 5-bromo-N-methyl-N-propyl-6-(trifluoromethyl)pyridine-2-amine (5.5 g, 18.51 mmol, 67%) (intermediate 53) as a colorless liquid.

[0490] The analytical data for intermediate 53 are listed in Table 1.

[0491] The procedure for preparing amines is 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]naphthidine] (intermediate 57).

[0492]

[0493] At 0 °C, tert-butyl racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylate (1.2 g, 2.57 mmol) (see Intermediate 41 Synthesis - Step 2) was added to a stirred solution of NaH (0.206 g, 5.14 mmol) in THF (8 mL), and the reaction mixture was stirred at 0 °C for 20 min. Then, a solution of 50% Cbz-Cl in toluene (0.439 g, 2.57 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. 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 a crude product, which was purified by rapid column chromatography to provide racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (1.3 g, 2.164 mmol, 84%) (intermediate 55) as an off-white solid.

[0494] BH3·THF (8.66 mL, 8.66 mmol) was added to a stirred solution of racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (1.3 g, 2.164 mmol) in THF (10 mL), 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 provide a crude product, which was purified by rapid column chromatography in a solution of 0-50% EtOAc in petroleum ether to provide racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (750 mg, 1.278 mmol, 59%) as an off-white solid.

[0495] LCMS: 3.41 min, 587.5 (M+H) + Method B

[0496] TFA (0.079 mL, 1.023 mmol) was added to a stirred solution of racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (600 mg, 1.023 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the crude product 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 racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-carboxylic acid benzyl ester (300 mg, 0.617 mmol, 60%) (intermediate 56) as a brown solid.

[0497] To a degassed solution of racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate (220 mg, 0.452 mmol) and 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (347 mg, 1.356 mmol) in toluene (3 mL) (purified with nitrogen for 10 min), sodium tert-butoxide (130 mg, 1.356 mmol), Xanthphos (26.2 mg, 0.045 mmol), followed by Pd2(dba)3 (83 mg, 0.090 mmol), were added, and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with EtOAc. The combined filtrates were concentrated and purified by rapid column chromatography using a solution of 0-20% EtOAc in petroleum ether to provide racemic-(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]naphthidine]-7'(8'H)-benzyl formate (160 mg, 0.242 mmol, 54%) as an off-white solid.

[0498] LCMS: 8.09 min, 662.3 (M+H) + Method B

[0499] Et3SiH (0.029 mL, 0.181 mmol) and Et3N (0.00338 mL, 0.024 mmol) were added to a stirred solution of racemic-(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]naphthidine]-7'(8'H)-formate (30 mg, 0.045 mmol) in DCM (9 mL), followed by PdCl2 (4.82 mg, 0.045 mmol), and the reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered through diatomaceous earth, and the diatomaceous earth was washed with a solution of 10% MeOH in DCM (50 mL). The combined filtrates were concentrated to give a crude product, which was purified by preparative HPLC. The pure fraction was concentrated, and the residue was neutralized with 10% NaHCO3 solution (20 mL) and extracted with (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate, and lyophilized under low pressure to provide racemic-(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]naphthidine] (2.83 mg, 5.36 μmol, 12%) (intermediate 57) as an off-white solid.

[0500] The analytical data for intermediates 55, 56, and 57 are listed in Table 1.

[0501] The procedure for preparing amines is exemplified by the preparation of (3-(2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-yl)-3-oxopropyl) tert-butyl carbamate (intermediates 62 and 90).

[0502]

[0503] BH3·THF (1 M, 1.75 mL) was added to a solution of 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-6'-one (intermediate 7) (150 mg, 350.04 μmol) in THF (4 mL) at 0 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 2 h. Four more tubular flasks were prepared as described above. After cooling to room temperature, all five reaction mixtures were quenched by adding MeOH (4 mL) at 0 °C and the mixture was refluxed at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to produce a residue, which was then subjected to preparative TLC (EtOAc, R). f =0) Purification to obtain 1-benzyl-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (480 mg, 66%) as a yellow oil (intermediate 90).

[0504] The analytical data for intermediate 90 are listed in Table 1.

[0505] At 25°C, N-ethyl-N-isopropylpropane-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]naphthidine] (80 mg, 192.98 μmol) were added to a solution of 3-((tert-butoxycarbonyl)amino) propionic acid (36.51 mg, 192.98 μmol) and bis(2-oxo-3-oxazolidinyl)phosphonyl chloride (98.25 mg, 385.97 μmol) in DMF (1 mL). The reaction mixture was stirred at 25°C for 2 h. Four more tubular flasks 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 produce a residue, which was purified by rapid column chromatography (eluting with petroleum ether / EtOAc = 1 / 0 to 0 / 1 to EtOAc / MeOH = 10 / 1, R). f =0.3) to obtain (3-(1-benzyl-2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-yl)-3-oxopropyl) tert-butyl carbamate (530 mg, 94%) as a yellow oil.

[0506] LCMS: 0.44 min, 586.4 [M+H] + Method O'

[0507] A mixture of (520 mg, 887.77 μmol) tert-butyl carbamate and Pd(OH)₂ (520 mg, 3.7 mmol) in EtOAc (10 mL) was degassed at 25 °C and purified three times with H₂ (15 Psi). The reaction mixture was heated to 40 °C and stirred at 40 °C with H₂ (15 Psi) for 12 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to produce tert-butyl (3-(2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-yl)-3-oxopropyl)carbamate (450 mg) (intermediate 64) as a yellow oil, which was used in the next step without purification.

[0508] The analytical data for intermediate 62 are listed in Table 1.

[0509] Procedure for preparing 4-chloro-2-fluoro-3-(trifluoromethyl)pyridine (intermediate 70)

[0510]

[0511] To a stirred solution of 2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (150 mg, 0.409 mmol) (intermediate 41) in 1,4-dioxane (2 mL), 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 at 100 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, evaporated, and purified by rapid column chromatography using a solution of MeOH in DCM (0–10%) to provide 1-(4-chloro-3-(trifluoromethyl)naphthyr-2-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (70 mg). 20 mg of the crude product was further purified by preparative HPLC (Method B). The preparative fraction was lyophilized under low pressure. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (3 mL) and water (5 mL), dried over sodium sulfate, evaporated and lyophilized under low pressure to provide 1-(4-chloro-3-(trifluoromethyl)naphthyr-2-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (3.90 mg, 7.14 μmol, 2%) (intermediate 70) as a white solid.

[0512] The analytical data for intermediate 70 are listed in Table 1.

[0513] Procedure for preparing racemic-(3S,4S)-''-(2-ethoxypyridin-3-yl)-3-ethyl-1-(5-methoxy-4-(trifluoromethylnaphthyrn-3-yl)-'',''-dihydro-''H-spiro[piperidin-4,''-[1,7-naphthidine]-''-one (intermediate 71)

[0514]

[0515] To a stirred solution of racemic-(3S,4S)-1-(5-chloro-4-(trifluoromethylnaphthyrn-3-yl)-''-(2-ethoxypyridin-3-yl)-3-ethyl-'',''-dihydro-''H-spiro[piperidin-4,''-[1,7-naphthidine]-''-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 minutes. h. The reaction mixture was evaporated and the crude product was purified by rapid column chromatography using a solution of MeOH in DCM (0-10%) to provide racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(5-methoxy-4-(trifluoromethyl)pyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (180 mg, 0.366 mmol, 54%) (intermediate 71) as a white solid.

[0516] The analytical data for intermediate 71 are listed in Table 1.

[0517] Procedure for preparing 3-ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxynitrile (intermediate 72)

[0518]

[0519] A solution of racemic-3-ethylpiperidine-4-carboxynitrile (0.540 g, 3.91 mmol) in toluene (10 mL) was purified under nitrogen for 10 min, and BINAP (0.122 g, 0.195 mmol), Pd(OAc)₂ (0.088 g, 0.391 mmol), and 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (1.0 g, 3.91 mmol) were added, followed by Cs₂CO₃ (2.55 g, 7.81 mmol). The reaction mixture was stirred at 120 °C for 16 h. 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 rapid column chromatography using a solution of EtOAc in petroleum ether (0–30%) to provide racemic-3-ethyl-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxynitrile (900 mg, 2.124 mmol, 54%) (intermediate 72) as a colorless liquid.

[0520] The analytical data for intermediate 72 are listed in Table 1.

[0521] Procedure for preparing (tetrahydro-1H-pyrrolazine-7a(5H)-yl) methyl methanesulfonate (intermediate 74)

[0522]

[0523] TEA (537 mg, 5.31 mmol) was added to a stirred solution of (tetrahydro-1H-pyrrolazin-7a(5H)-yl)MeOH (500 mg, 3.54 mmol) in DCM (5 mL), followed by MsCl (527 mg, 4.60 mmol), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (50 mL) and washed with 10% NaHCO3 (20 mL), followed by water (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide crude tetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl methanesulfonate (270 mg) (intermediate 74) as a yellow gum, which was used for the next step without further purification.

[0524] The analytical data for intermediate 74 are listed in Table 1.

[0525] Procedure for preparing racemic-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 79)

[0526]

[0527] KHMDS (1 M, 13.14 mL) was added to a solution of 1-benzyl-3-ethylpiperidin-4-carboxynitrile (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) at room temperature, and the reaction mixture was stirred at room temperature for 2 h under a N2 atmosphere. Six tubular flasks were prepared as described above. All seven reaction mixtures were quenched at 0 °C with a saturated ammonium chloride solution (300 mL), adjusted to pH to approximately 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 rapid column chromatography (petroleum ether / EtOAc = 7:3) to provide racemic-5-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid ethyl ester (3 g, 22%) as a yellow oil.

[0528] 1 H NMR (400 MHz, CDCl3) δ 8.33 (dd, J=1.9, 7.5 Hz, 1H), 8.16 (d, J=8.6Hz, 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)

[0529] BH3·THF (1 M, 2.01 mL) was added to a solution of racemic 5-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid ethyl ester (200 mg, 401.11 μmol) in THF (2 mL) at 0 °C under a N2 atmosphere, and the reaction mixture was stirred at 60 °C for 12 h. Fourteen tubular flasks were prepared as described above. After cooling to room temperature, fifteen reaction mixtures were quenched by adding MeOH (40 mL) at 0 °C, and the reaction mixtures were refluxed at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to produce a residue, which was purified by rapid column chromatography (EtOAc:MeOH (9:1)) to give racemic-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (650 mg, 24%) (intermediate 64) as a yellow oil.

[0530] DIPEA (87.60 mg, 677.82 μmol, 118.06 μL) and bis(2-oxooxazolidine-3-yl)phosphonyl chloride (115.04 mg, 451.88 μmol) were added to a solution of 3-((tert-butoxycarbonyl)amino)propionic acid (42.75 mg, 225.94 μmol) in DMF (2 mL), and the mixture was stirred at 25 °C for 10 min. Racemic-(3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (100 mg, 225.94 μmol) (intermediate 64) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 h. Five more tubular flasks were prepared as described above. All six reaction mixtures were quenched with water (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and analyzed by preparative TLC (EtOAc / MeOH = 9 / 1, R0). f =0.60) Purified to obtain racemic-(3-((3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)-3-oxopropyl) tert-butyl carbamate (500 mg, 60%) as a yellow solid.

[0531] LCMS: 0.75 min, 614.6 [M+H] + Method O

[0532] Racemic-(3-((3S,4S)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)-3-oxopropyl) tert-butyl carbamate (290 mg, 472.48 μmol) was added to a solution of Pd(OH)₂ (290.00 mg, 2.07 mmol) in EtOAc (50 mL). After purging three times with hydrogen, the reaction mixture was stirred at 25 °C for 12 h under a hydrogen atmosphere (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give racemic-(3-((3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)-3-oxopropyl)carbamate tert-butyl ester (220 mg, crude) (intermediate 79) as a gray solid, which was used for the next step without further purification.

[0533] The analytical data for intermediates 64 and 79 are listed in Table 1.

[0534] Procedure for preparing (R)-2-(((3RS,4RS)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 89)

[0535]

[0536] 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]naphthidine] (intermediate 64) (300 mg, 677.82 μmol) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (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 additional tubular flasks were prepared as described above. All ten reaction mixtures were filtered, and the filtrates were concentrated under reduced pressure and subjected to rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to 3 / 1, R f =0.40) Purified to give (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 42%) as a white solid.

[0537] LCMS: 1.57 min, 626.3 [MH] + Method R'

[0538] (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 2.88 mmol) was added to a solution of Pd(OH)₂ (1.80 g, 2.56 mmol, 20% purity) in EtOAc (180 mL) at room temperature. After purification three times with hydrogen (15 Psi), the reaction mixture was heated to 40 °C and stirred at 40 °C for 12 h under hydrogen pressure (15 Psi). After cooling to room temperature, the reaction mixture was filtered, concentrated under reduced pressure, and analyzed by preparative TLC (EtOAc / MeOH=1 / 1, Rf =0.11) Purification to give (R)-2-(((3SR,4SR)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 78%) (intermediate 89) as a white solid.

[0539] The analytical data for intermediate 89 are listed in Table 1.

[0540] Procedure for preparing racemic-(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]naphthidine] (intermediate 122)

[0541]

[0542] In a 10 mL microwave-safe flask under a nitrogen atmosphere, DBU (563 mg, 3.70 mmol) was added to racemic (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-7'(8'H)-formate benzyl ester (600 mg, 1.23 mmol) (intermediate 56) and 3,5-dichloro-4-(trifluoromethyl)pyridine (666 mg, 3.08 mmol). The reaction mixture was then microwaved to 140 °C and held for 3 h. 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 rapid column chromatography using a 10-20% EtOAc solution in petroleum ether to provide racemic-(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]naphthidine]-7'(8'H)-formate benzyl ester (360 mg, 0.495 mmol, 40%) as a pale yellow solid.

[0543] LCMS: 2.86 min, 666.2 [M+H] + Method G

[0544] In a sealed 50 mL test tube, under a nitrogen atmosphere and at room temperature, NaOMe (25% in MeOH) (10 mL, 0.510 mmol) was added to racemic (3S,4S)-1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-formate (340 mg, 0.510 mmol) in MeOH (10 mL). 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 obtain 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]naphthidine] (300 mg, 0.081 mmol, 16%) (intermediate 122) as a pale yellow gel, which was used in the next step without further purification.

[0545] The analytical data for intermediate 122 are listed in Table 1.

[0546] Procedure for preparing (3S,4R)-3-ethylpiperidine-4-carboxynitrile (intermediate 94-1)

[0547]

[0548] A mixture of 1-benzyl-3-ethylpiperidin-4-one (20 g, 92.04 mmol) and (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (36.63 g, 94.80 mmol) in ACN (400 mL) was degassed and purified three times with nitrogen. The reaction mixture was stirred at 40 °C for 5 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was dried under reduced pressure to produce a residue. A 50 mg sample of the material was crystallized and subjected to X-ray diffraction analysis. The absolute R configuration of (R)-1-benzyl-3-ethylpiperidin-4-one was confirmed. Details can be found later in Table 1 for intermediates.

[0549] The resulting residue was diluted with water (200 mL). The reaction mixture was adjusted to pH 10 at 0 °C with NH4OH (30% in water) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to produce (R)-1-benzyl-3-ethylpiperidin-4-one (16.5 g) as a yellow oil.

[0550] SFC method: R t =1.347 min, 12.71% purity, R t =1.523 min, 87.29% purity; Column name: Chiralpak AD-3, 150×4.6mm ID, 3um; Co-solvent: 10%; Co-solvent name: 0.1% isopropylamide solution in MeOH; Injection volume: 3.5 μL; Run time: 5 min. KOtBu (8.39 g, 74.78 mmol) was added 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 ethylene glycol dimethyl ether (130 mL) at -20 °C under nitrogen. The reaction mixture was stirred at 25 °C for 12 h, then quenched by adding water (50 mL) at 0 °C and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and subjected to rapid column chromatography (petroleum ether / EtOAc = 9 / 1, R...). f =0.29 and R f =0.41) Purification was performed to obtain (3S,4R)-1-benzyl-3-ethylpiperidine-4-carboxynitrile (2.3 g, 34%) as a yellow oil and (3S,4S)-1-benzyl-3-ethylpiperidine-4-carboxynitrile (3.8 g, 56%) as a yellow solid.

[0551] (3S,4R)-1-benzyl-3-ethylpiperidine-4-carboxynitrile:

[0552] 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)

[0553] SFC method: R t =1.312 min, 12.48% purity, R t =1.426 min, 87.52% purity; Column name: Chiralpak AD-3, 150×4.6mm ID, 3µm; Co-solvent: 10%; Co-solvent name: 0.1% isopropylamide solution in MeOH; Injection volume: 1.5 μL; Run time: 5 min

[0554] (3S,4S)-1-benzyl-3-ethylpiperidine-4-carboxynitrile:

[0555] 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 (brs, 1H), 1.45 - 1.29 (m, 2H), 0.84 (t, J=7.4 Hz, 3H)

[0556] SFC method: R t =1.600 min, 15.65% purity, R t=1.802 min, 84.35% purity; Column name: Chiralcel OD-3, 150×4.6mm ID, 3um; Co-solvent: 10%; Co-solvent name: Isopropanol [0.2% ammonia (7M solution in MeOH)]; Injection volume: 5.5 μL; Run time: 5 min.

[0557] The mixture of (3S,4R)-1-benzyl-3-ethylpiperidine-4-carboxynitrile (2.3 g, 10.07 mmol) and Pd / C (7.5 g, 10% purity) in EtOAc (200 mL) was degassed and purified three times with hydrogen. The reaction mixture was stirred at 40 °C for 12 h under a hydrogen atmosphere (15 Psi). 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-carboxynitrile (800 mg) as a yellow oil.

[0558] The analytical data for intermediate 94-1 are listed in Table 1.

[0559] Procedure for preparing tert-butyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (intermediate 95)

[0560]

[0561] Boc anhydride (30.2 g, 138 mmol) was added 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) at room temperature, followed by the addition of DMAP (0.676 g, 5.53 mmol), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was alkalized with 10% NaHCO3, followed by the addition of water (100 mL) and extraction with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–30%) to provide tert-butyl 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carboxylic acid (14.5 g, 44.6 mmol, 81%) (intermediate 95) as a pale yellow solid.

[0562] The analytical data for intermediate 95 are listed in Table 1.

[0563] Procedure for preparing (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 98)

[0564]

[0565] A solution of (3S, 4R)-3-ethylpiperidin-4-carboxynitrile (intermediate 98-1) (300 mg, 2.171 mmol) and 1-bromo-2-(trifluoromethyl)benzene (1465 mg, 6.51 mmol) in toluene (20 mL) was degassed with nitrogen for 5 min, and BINAP (135 mg, 0.217 mmol) and Cs₂CO₃ (1414 mg, 4.34 mmol) were added, followed by Pd(OAc)₂ (48.7 mg, 0.217 mmol). The reaction mixture was heated at 120 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth bed, the filtrate was evaporated, and the crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-20%) to provide (3S)-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidine-4-carboxynitrile (400 mg, 1.417 mmol, 65%) as a yellow liquid.

[0566] LCMS: 2.28 min, 283.1 [M+H] + Method W

[0567] A mixture of (3S)-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidin-4-carboxynitrile (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) was added to a stirred solution of KHMDS (1.612 mL, 1.612 mmol) in THF (20 mL), and the reaction mixture was stirred at room temperature for 16 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, concentrated, and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-90%) to provide 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 colloid.

[0568] LCMS: 2.84 min, 581.3 [M+H] + Method W

[0569] To a solution of 5-((3S,4S)-4-cyano-3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid tert-butyl ester (580 mg, 0.999 mmol) in EtOH (20 mL), Raney nickel (876 mg, 9.99 mmol) was added, and the reaction mixture was stirred at 65 °C for 48 h under 5 kg hydrogen pressure. The reaction mixture was filtered through a diatomaceous earth bed and washed with 10% MeOH in DCM (100 mL). The filtrate was evaporated and purified by rapid column chromatography using MeOH in DCM (0–4%) as the eluent. The pure fraction was evaporated and dried under high vacuum to provide (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (170 mg, 0.333 mmol, 33%) as a white solid.

[0570] LCMS: 2.31 min, 511.2 [M+H] + Method W

[0571] KOtBu (0.588 mL, 0.588 mmol) was added to a stirred solution of (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (150 mg, 0.294 mmol) in THF (10 mL) at 0 °C and stirred at 0 °C for 15 min. 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 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-50%) to provide (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-formate benzyl ester (100 mg, 0.155 mmol, 53%) as a yellow colloid.

[0572] LCMS: 2.71 min, 645.2 [M+H] + Method W

[0573] BH3·THF (0.233 mL, 0.233 mmol) was added to a stirred solution of (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-8'-oxo-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-formate (100 mg, 0.155 mmol) in THF (5 mL) 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 rapid column chromatography using a solution of EtOAc in petroleum ether (0-50%) to provide (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (85 mg, 0.135 mmol, 87%) as a yellow colloid.

[0574] LCMS: 2.91 min, 631.2 [M+H] + Method W

[0575] 10% Pd-C (10.12 mg, 0.095 mmol) was added to a solution of (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-carboxylic acid benzyl ester (60 mg, 0.095 mmol) in EtOAc (10 mL), and the mixture was stirred at 25 °C for 15 h under 5 kg hydrogen pressure. The reaction mixture was filtered through a diatomaceous earth bed and washed with a solution of 10% MeOH in DCM (100 mL). The filtrate was evaporated and purified by rapid column chromatography using a solution of MeOH in DCM (0–4%) to provide (3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 98) as a white solid (45 mg, 0.091 mmol, 95%).

[0576] The analytical data for intermediate 98 are listed in Table 1.

[0577] Procedure for preparing racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (intermediate 100)

[0578]

[0579] KHMDS (1.0 M solution in THF) (8.39 mL, 8.39 mmol) was added to a stirred solution of ethyl 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylate (2.91 g, 10.07 mmol) (intermediate 84) and tert-butyl 4-cyano-3-ethylpiperidin-1-carboxylate (2 g, 8.39 mmol) in toluene (40 mL), and the mixture was stirred at room temperature for 30 min. 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 rapid column chromatography using a solution of 10-20% EtOAc in petroleum ether to provide cis-racemic ethyl 3-(1-(tert-butoxycarbonyl)-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (2.5 g, 4.92 mmol, 59%) as a yellow solid.

[0580] LCMS: 3.15 min, 508.2 [M+H] + Method B

[0581] Raney nickel (4.88 g, 47.3 mmol) was added to a stirred solution of cis-racemic 4-cyano-4-(2-(ethoxycarbonyl)-4-(2-ethoxypyridin-3-yl)phenyl)-3-ethylpiperidin-1-carboxylic acid tert-butyl ester (2 g, 3.94 mmol) in EtOH (50 mL) and water (5 mL), and the reaction mixture was stirred at 65 °C for 16 h under 5 kg H2 pressure. The reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with MeOH (20 mL). The filtrate was concentrated and purified by rapid column chromatography in a solution of 0-10% MeOH in DCM to provide cis-racemic tert-butyl 7-(2-ethoxypyridin-3-yl)-3'-ethyl-1-oxo-2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidine]-1'-carboxylic acid (1.3 g, 2.79 mmol, 71%) as a white solid.

[0582] LCMS: 2.55 min, 466.3 [M+H] + Method B

[0583] NaH (0.344 g, 8.59 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid tert-butyl ester (2 g, 4.30 mmol) in THF (3 mL) 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 x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by rapid column chromatography in a solution of 10–30% EtOAc in petroleum ether to provide 2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (2.1 g, 3.50 mmol, 82%) as a colloidal solid.

[0584] LCMS: 3.05 min, 600.3 [M+H] + Method B

[0585] BH3·THF (13.34 mL, 13.34 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-3-ethyl-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (2 g, 3.33 mmol) in THF (20 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with MeOH (10 mL) and concentrated under reduced pressure, and purified by rapid column chromatography using a solution of 0-50% EtOAc in petroleum ether to provide 2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (1.2 g, 2.049 mmol, 61%) as an off-white solid.

[0586] LCMS: 3.28 min, 586.3 [M+H] + Method B

[0587] TFA (0.676 mL, 8.77 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (1.2 g, 2.049 mmol) in DCM (10 mL), 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 provide racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (900 mg, 1.853 mmol, 90%) as an off-white solid (intermediate 100).

[0588] The analytical data for intermediate 100 are listed in Table 1.

[0589] Procedure for preparing 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-benzyl formate (intermediate 102)

[0590]

[0591] Boc-anhydride (14.44 mL, 62.2 mmol) was added to a stirred solution of 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylic acid (6.5 g, 24.88 mmol) (intermediate 83) in t-BuOH, 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 alkalized with 10% NaHCO3, diluted with water (10 mL), and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, evaporated, and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–30%) to provide tert-butyl 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylic acid (6 g, 17.96 mmol, 72%) (intermediate 101) as a pale yellow solid.

[0592] A mixture of tert-butyl 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylate (4 g, 12.60 mmol) and tert-butyl 4-cyanopiperidin-1-carboxylate (2.65 g, 12.60 mmol) in THF (30 mL) was added to a stirred solution of KHMDS (16.39 mL, 16.39 mmol) at room temperature and stirred for 3 h at room temperature. 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 rapid column chromatography using EtOAc-petroleum ether (20–50%) to provide tert-butyl 3-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (5 g, 9.85 mmol, 52%) as an off-white solid.

[0593] LCMS: 2.55 min, 508.3 [M+H] + Method G

[0594] To a stirred solution of tert-butyl 3-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (7.5 g, 14.77 mmol) in EtOH:water (230:40 mL), Raney nickel (12.96 g, 148 mmol) was added, and the reaction mixture was stirred at 65 °C and 6 kg of hydrogen pressure for 48 h. The reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with 10% MeOH and DCM. The filtrate was concentrated under reduced pressure (bath temperature: 42°C) to provide a crude gel, which was purified by rapid 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]naphthylidine]-1-carboxylate (5.0 g, 10.74 mmol, 73%) as a white solid.

[0595] LCMS: 1.84 min, 438.2 [M+H] + Method G

[0596] t-BuOK (4.10 g, 36.6 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-8'-oxo-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-1-carboxylic acid tert-butyl ester (8 g, 18.28 mmol) in THF (30 mL) at 0 °C, 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 at 0 °C with 100 mL of aqueous NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and purified by rapid column chromatography using a solution of 15% EtOAc in petroleum ether to give 2'-(2-ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (8 g, 13.55 mmol, 74%) as a white solid.

[0597] LCMS: 2.37 min, 572.3 [M+H] + Method W

[0598] A solution of BH3 in THF (30.6 ml, 30.6 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (5 g, 8.75 mmol) in THF (25 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was carefully quenched with MeOH at 0 °C and evaporated to dryness, and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (30%) to provide 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (4.2 g, 7.20 mmol, 82%) as an off-white solid.

[0599] LCMS: 2.53 min, 558.3 ​​[M+H] + Method G

[0600] TFA (13.49 g, 118 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-1,7'(8'H)-dicarboxylic acid 7'-benzyl 1-(tert-butyl) ester (6.6 g, 11.83 mmol) in DCM (15 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, alkalized with 10% NaHCO3 aqueous solution (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 provide 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-carboxylic acid benzyl ester (4.2 g, 8.70 mmol, 74%) (intermediate 102) as a white solid.

[0601] The analytical data for intermediates 101 and 102 are listed in Table 1.

[0602] Procedure for preparing racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 105)

[0603]

[0604] To a degassed solution of racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate (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) (purified with nitrogen for 10 min), NaOtBu (297 mg, 3.09 mmol) and Xantphos (119 mg, 0.206 mmol) were added, followed by Pd2(dba)3 (94 mg, 0.103 mmol), and the reaction mixture was heated at 120 °C for 16 h. The reactants were filtered through a diatomaceous earth bed 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 Na2SO4 and purified by rapid column chromatography in a solution of 30–35% EtOAc in petroleum ether to provide racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (220 mg, 0.333 mmol, 32%) as a white solid.

[0605] LCMS: 1.99 min, 660.3 [M+H] + Method G.

[0606] PdCl2 (59.1 mg, 0.333 mmol), Et3SiH (116 mg, 1.000 mmol), and Et3N (67.5 mg, 0.667 mmol) were added to a stirred solution of racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate (220 mg, 0.333 mmol) in a DCM (10 mL) container with stirring. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was filtered through a diatomaceous earth bed, 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 Na2SO4 and purified by rapid column chromatography using a solution of 10% MeOH in DCM to provide racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (60 mg, 0.116 mmol, 34%) (intermediate 105) as a white solid.

[0607] The analytical data for intermediate 105 are listed in Table 1.

[0608] Procedure for preparing 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 106)

[0609]

[0610] A solution of 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate benzyl ester (2.2 g, 3.94 mmol) and 1-bromo-2-(trifluoromethyl)benzene (1.331 g, 5.91 mmol) in toluene (20 mL) was degassed for 10 min under nitrogen atmosphere at room temperature. BINAP (491 mg, 0.789 mmol), Cs₂CO₃ (2.6 g, 7.89 mmol), and then Pd(OAc)₂ (0.089 g, 0.394 mmol) were added, and the reaction mixture was heated at 120 °C for 16 h. The reaction mixture was filtered through diatomaceous earth, washed with EtOAC (2 x 10 mL), and the filtrate was evaporated. The crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-20%) to provide 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-benzyl formate (1.75 g, 2.85 mmol, 72%) as a pale yellow solid.

[0611] LCMS: 3.43 min, 602.3 [M+H] + Method B

[0612] 10% Pd / C (2.95 g, 27.7 mmol) was added to a stirred solution of 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate (1.7 g, 2.77 mmol) in EtOAc (18 mL) at room temperature. The reaction mixture was stirred at 1 atm under hydrogen for 16 h at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc (2 x 10 mL). The filtrate was evaporated to provide 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (1 g, 1.925 mmol, 70%) (intermediate 106) as a pale yellow solid.

[0613] The analytical data for intermediate 106 are listed in Table 1.

[0614] Procedure for preparing (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 121)

[0615]

[0616] KHMDS (1 M, 74.90 mL) and 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylic acid (intermediate 87) (10 g, 38.28 mmol) were added to a solution of 1-benzylpiperidin-4-carboxynitrile (7.67 g, 38.28 mmol) in toluene (200 mL) at -78 °C under N2. The reaction mixture was warmed to room temperature and stirred at room temperature under N2 for 2 h. Another tubular flask was prepared as described above. All two reaction mixtures were quenched by adding 200 mL of saturated ammonium chloride solution at 0 °C and the pH was adjusted to 4–6 with formic acid. The mixture was diluted with 100 mL of water 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 produce 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylic acid (40 g, crude product) as a yellow solid, which was used for the next step without further purification.

[0617] LCMS: 0.39 min, 442.3 [M+H]+ / 440.2 [MH]+, Method N

[0618] K₂CO₃ (18.78 g, 135.89 mmol) and EtI (8.48 g, 54.36 mmol, 4.35 mL) were added to a solution of 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylic acid (20 g, 45.30 mmol) in DMF (150 mL) at 0 °C under N₂. The reaction mixture was heated to 80 °C under N₂ and maintained for 2 h. Another tubular flask was prepared as described 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 layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and purified by rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1, R f =0.5) to obtain ethyl 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (22 g, 52%) as a white solid.

[0619] LCMS: 1.70 min, 470.2 [M+H] + Method M

[0620] BH3·THF (1 M, 95.83 mL) was added to a solution of ethyl 3-(1-benzyl-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (9 g, 19.17 mmol) in THF (180 mL) at 0 °C under N2. The reaction mixture was stirred at 60 °C under N2 for 12 h. Another tubular flask was prepared as described above. 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 to produce a residue (18 g, as a mixture of 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl] and a 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 under N2 for 2 h. 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 rapid column chromatography (EtOAc / MeOH = 1 / 0 to 0 / 1, R f =0.5) to obtain 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 130) (4.2 g, 24%) as a white solid.

[0621] To a solution of 1-benzyl-2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (200 mg, 483.61 μmol) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (192.72 mg, 967.23 μmol) in MeOH (3 mL) at room temperature, NaCNBH3 (91.17 mg, 1.45 mmol) was added. The reaction mixture was stirred at room temperature for 12 minutes. Four more tubular flasks were prepared as described above. The five reaction mixtures were concentrated under reduced pressure, 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 rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1, R f=0.5) to obtain (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 134) (1 g, 69%) as a colorless oil.

[0622] A mixture of (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 502.68 μmol) (intermediate 138) and 10% Pd / C (1.5 g, 1.41 mmol, 10% purity) in EtOAc (50 mL) was degassed and purified three times with H2 (15 Psi). The reaction mixture was stirred at 50 °C for 12 h under H2 (15 Psi). Another tubular flask was prepared as described above. After cooling to room temperature, both reaction mixtures were filtered and purified by preparative TLC (EtOAc / MeOH = 1 / 1, R f =0.2) to obtain (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 121) (220 mg, 43%) as a white solid.

[0623] The analytical data for intermediates 130, 134 and 121 are listed in Table 1.

[0624] Procedure for preparing (R)-2-((2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 135)

[0625]

[0626] BBr3 (2 M in DCM, 2.09 mL) was added to a solution of (R)-2-((1-benzyl-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 138) (500 mg, 837.80 μmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Five more tubular flasks were prepared as described 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 preparative HPLC to obtain (R)-2-(1-benzyl-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-2'-yl)phenol (1 g, 42%) as a yellow solid.

[0627] LCMS: 1.91 min, 469.2 [M+H] + Method O

[0628] Et3N (129.56 mg, 1.28 mmol) and Boc2O (93.14 mg, 426.77 μmol) were added to a solution of (R)-2-(1-benzyl-7'-(pyrrolidone-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-2'-yl)phenol (200 mg, 426.77 μmol) in DCM (5 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. Four more tubular flasks were prepared as described above. All five reaction mixtures were quenched by adding ice water (40 mL) and then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and purified by preparative TLC (petroleum ether / EtOAc = 1 / 1, R f =0.75) to obtain (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester ((950 mg, 78%)) as a yellow solid.

[0629] LCMS: 0.41 min, 569.3 [M+H] + Method C

[0630] At 25°C under nitrogen atmosphere, tert-butyl pyrrolidine-1-carboxylate (100 mg, 175.83 μmol) of (R)-2-((1-benzyl-2'-(2-hydroxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 175.83 μmol) in THF (1.5 mL) was added to potassium 2-methylpropane-2-olide (39.46 mg, 351.65 μmol), 1,4,7,10,13,16-hexaoxane (92.95 mg, 351.65 μmol), and 1-iodoethane-1,1,2,2,2-d5 (33.97 mg, 210.99 μmol). The reaction mixture was stirred at 60°C for 1 h under nitrogen atmosphere. Eight additional tubular flasks were prepared as described 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 rapid column chromatography (petroleum ether / EtOAc = 99 / 11 to 70 / 30, R...). f =0.5) to obtain (R)-2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 84%) as a white solid.

[0631] LCMS: 0.41 min, 602.5 [M+H] + Method C

[0632] Pd(OH)₂ (700.04 mg, 20% purity) was added to a solution of (R)-2-((1-benzyl-2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 332.32 μmol) in EtOAc (120 mL) under a nitrogen atmosphere at 25 °C. The reaction mixture was degassed and purified three times with hydrogen. The reaction mixture was stirred at 50 °C for 2 h under a hydrogen atmosphere (15 Psi). Three more tubular flasks were prepared as described above. After cooling to room temperature, all four reaction mixtures were filtered and concentrated under reduced pressure to produce (R)-2-((2'-(2-(ethoxy-d5)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (360 mg, 53%) as a white solid.

[0633] The analytical data for intermediate 135 are listed in Table 1.

[0634] Procedure for preparing (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 138)

[0635]

[0636] KHMDS (1 M, 65.69 mL) was added to a solution of 1-benzyl-3-ethylpiperidin-4-carboxynitrile (5 g, 21.90 mmol) and 6-(2-ethoxyphenyl)-3-fluoropyridinecarboxylic acid (intermediate 87) (5.72 g, 21.90 mmol) in toluene (150 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. Four tubular flasks were prepared as described above. Five reaction mixtures were quenched by adding 300 mL of saturated NH4Cl solution at 0 °C and adjusted to pH 4-6 with formic acid, followed by extraction 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 racemic-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylic acid (50 g) as a yellow oil, which was used for the next step without further purification.

[0637] LCMS: 0.76 min, 468.1 [MH] + Method R'

[0638] K₂CO₃ (8.83 g, 63.89 mmol) and EtI (3.99 g, 25.56 mmol) were added to a solution of racemic-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylic acid (10 g, 21.30 mmol) in DMF (200 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. Four tubular flasks were prepared as described above. After cooling to room temperature, five reaction mixtures were quenched by adding water (500 mL) at 0 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and purified by rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to 8 / 1, R f=0.55) to provide racemic-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylic acid ethyl ester (32 g, 60%) as a yellow oil.

[0639] LCMS: 1.78 min, 498.3 [M+H] + Method C

[0640] BH3·THF (1 M, 50.24 mL) was added to a solution of racemic 3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)pyridinecarboxylate (5 g, 10.05 mmol) in THF (150 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 another 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to EtOAc / MeOH = 8 / 1, R f =0.40) to obtain racemic-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (1.2 g, 12%) as a white solid (intermediate 136).

[0641] At 25 °C, (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (207.55 mg, 1.04 mmol) and NaCNBH3 (130.92 mg, 2.08 mmol) were added to a solution of racemic-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (230 mg, 520.83 μmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 12 h. Four tubular flasks were prepared as described above. All five reaction mixtures were filtered, and the filtrates were concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / EtOAc = 1 / 0 to 5 / 1, R f =0.40) to obtain (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 137) (800 mg, 49%) as a yellow oil.

[0642] A mixture of (R)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 141) (800 mg, 1.28 mmol) and Pd(OH)2 (800 mg, 5.70 mmol) in EtOAc (20 mL) was degassed and purified three times with hydrogen (15 Psi). The reaction mixture was stirred at 50 °C for 12 h under hydrogen (15 Psi). After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to produce a residue, which was purified by rapid column chromatography (eluting with petroleum ether / EtOAc = 1 / 0 to EtOAc / MeOHMeOH = 4 / 1, R f =0.20) to obtain (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, yield 88%) as a white solid (intermediate 138).

[0643] The analytical data for intermediates 136, 137, and 138 are listed in Table 1.

[0644] Procedure for preparing (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 139)

[0645]

[0646] HATU (439.12 mg, 1.15 mmol) and DIPEA (298.52 mg, 2.31 mmol) were added to a solution of (2R,4S)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (178.04 mg, 769.92 μmol) in DMF (7 mL) at room temperature, followed by racemic-(3S,4S)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (340 mg, 769.92 μmol) (intermediate 136). The reaction mixture was stirred at room temperature for 1 h. Four more tubular flasks were prepared as described above. All five reaction mixtures were combined, diluted with water (120 mL), and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (120 mL), dried over sodium sulfate, and purified by rapid column chromatography (petroleum ether / EtOAc = 50 / 50 to 10 / 90, R). f =0.3) to obtain (2R,4S)-2-((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'-carbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g, 87%) as a yellow oil.

[0647] LCMS: 0.44 min, 655.3 (M+H) + Method C

[0648] BH3·THF solution (1 M, 3.05 mL) was added dropwise to a solution of (2R,4S)-2-((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyl]-7'-carbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 305.42 μmol) in THF (4 mL) at 0 °C. After warming to room temperature, the reaction mixture was stirred at 60 °C for 30 min. Five more tubular flasks were prepared as described above. After cooling to 0 °C, the reaction mixture was quenched with MeOH (1 mL). All six mixtures were combined and stirred at 60 °C for 1 h. After cooling to room temperature, the mixtures were concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / EtOAc = 50 / 50 to 0 / 100, R f=0.29) to obtain (2R,4S)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 100%) as a yellow oil.

[0649] LCMS: 0.40 min, 641.6 (M+H)+, Method C

[0650] A solution of (2R,4S)-2-(((3SR,4SR)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (550 mg, 858.23 μmol) in EtOAc (20 mL) was added to a suspension of Pd(OH)2 / C (1.02 g, 1.46 mmol, 20% purity) in EtOAc (20 mL) under nitrogen atmosphere. The suspension was degassed and purified three times with hydrogen. The reaction mixture was stirred at 50 °C for 3 h under hydrogen (15 Psi). Another tubular flask was prepared as described above. After cooling to 25°C, all two reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to give (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, crude) (intermediate 139) as a yellow solid, which was used in the next step without further purification.

[0651] The analytical data for intermediate 139 are listed in Table 1.

[0652] Table 1

[0653] X-ray crystallization analysis of the complex of (R)-1-benzyl-3-ethylpiperidin-4-one and (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid

[0654] X-ray crystallography was performed to determine the absolute configuration of (R)-1-benzyl-3-ethylpiperidin-4-one, as described below.

[0655] Results Summary: The crystal is a colorless, bulk crystal with the following dimensions: 0.20 × 0.20 × 0.03 mm³. The symmetry of the crystal structure is 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) ų, Z = 1, Dc = 1.240 g / cm³, F(000) = 320.0, μ(CuKα) = 0.741 mm⁻¹, and T = 300.15 K. The absolute configuration and ORTEP structure are as follows:

[0656]

[0657] Equipment Description and Data Collection: Rigaku OxfordDiffraction XtaLAB Synergy-S equipped with a HyPix-6000HE zone detector cryogenic system: Oxford Cryostream 800 Cu: λ=1.54184Å, 50W. Crystal-to-CCD detector distance: d=35 mm, tube voltage: 50 kV; tube current: 1 mA. A total of 45334 reflections were collected in the 2θ range from 6.862 to 133.164. The limiting indices were: -8≤h≤8, -10≤k≤9, -15≤l≤15; which produced 5552 unique reflections (Rint=0.0506). The structure was resolved using SHELXT (Sheldrick, GM 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (for F²) (Sheldrick, GM 2015. Acta Cryst. C71, 3-8). A total of 389 refinement parameters were used, with a total of 5552 data points. All reflections were included in the refinement. The goodness of fit for F² was 1.051, and the final R-values ​​were [I>=2σ(I)] R1=0.0458 and wR2=0.1282. The maximum difference peak and porosity were 0.27 and -0.20 Å⁻³, respectively.

[0658] Description of crystal preparation: 50 mg of a complex of (R)-1-benzyl-3-ethylpiperidin-4-one with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid was dissolved in 1 mL of MeOH and kept in a 4 mL tubular flask. The solution was slowly evaporated at room temperature. Crystals were observed the next day.

[0659] Synthesis of the Implementation Examples:

[0660] Pathway A

[0661] A typical procedure for preparing lactams is illustrated by the preparation of 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (Example 1).

[0662]

[0663] Under nitrogen atmosphere at 0 °C, DIPEA (0.1 mL, 0.66 mmol) and HATU (127 mg, 0.33 mmol) were added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (50 mg, 0.26 mmol) in DMF (5 mL). The reaction mixture was stirred for 10 min, and then 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 mixture was quenched with ice-cold water (10 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over Na2SO4 and concentrated to give a crude product (100 mg) as a brown, viscous compound, showing 20% ​​of the desired product. The crude product was further purified by preparative HPLC and then lyophilized under low pressure to provide 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (10 mg, 8%) as a light pink solid (Example 1).

[0664] The analytical data for Example 1 are listed in Table 2.

[0665] Pathway B

[0666] A typical procedure for preparing lactams is illustrated by the preparation of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (Example 2).

[0667]

[0668] 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)piperidin-4-carboxynitrile (149 mg, 0.517 mmol) (intermediate 6) in toluene (5 mL), KHMDS (1 M solution in THF) (0.5 mL, 0.500 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. 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 rapid column chromatography using EtOAc-petroleum ether (0-10%) to provide 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 colloid.

[0669] LCMS: 2.94 min, 559.2 (M+H) + Method A

[0670] 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, Raney nickel (188 mg, 2.147 mmol) was added. The reaction mixture was stirred at 65 °C for 24 h at 75 psi hydrogen pressure. The reaction mixture was filtered through diatomaceous earth and washed with MeOH (20 mL). The filtrate was evaporated, and the crude product was purified by preparative HPLC. The purified fraction was lyophilized under low pressure. The residue was dissolved in DCM (20 mL), washed with 10% NaHCO3 (3 mL) and brine (3 mL), dried over sodium sulfate, evaporated and lyophilized under low pressure to provide 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (40 mg, 0.077 mmol, 43%) as a white solid (Example 2).

[0671] The analytical data for Example 2 are listed in Table 3.

[0672] Pathway C

[0673] A typical procedure for preparing lactams is illustrated by the preparation of 3-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-8-oxospiro[6H-1,7-naphthidin-5,4'-piperidin]-7-yl]acrylamide (Example 4).

[0674]

[0675] To a stirred solution of 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (20 mg, 0.039 mmol) (Example 2) in DMF (1 mL), 2.3 mg, 0.058 mmol of NaH was added and stirred at room temperature for 30 min. 3-chloropropionamide (4.99 mg, 0.046 mmol) in DMF (1 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by preparative HPLC and the fractions were lyophilized under low pressure. The residue was dissolved in DCM (20 mL), washed with 10% NaHCO3 (5 mL), water (5 mL), and brine (5 mL), dried over sodium sulfate, evaporated, and lyophilized under low pressure to provide 3-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)propionamide (8.3 mg, 0.014 mmol, 36%) as a white solid (Example 4).

[0676] The analytical data for Example 4 are listed in Table 4.

[0677] Pathway D

[0678] A typical procedure for preparing lactams is illustrated by the preparation of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthidium-5,4'-piperidin]-6-one (Example 5).

[0679]

[0680] Sodium tert-butoxide (7.10 mg, 73.90 μmol) and methanesulfonate alkyl[2,2-bis(diphenylphosphino)-1,1-binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (2.93 mg, 2.96 μmol) were added to a solution of 2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-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) at 25 °C under nitrogen atmosphere. μmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.84 mg, 2.96 μmol). The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 hours. Three more tubular flasks were prepared as described above. After cooling to room temperature, all four reaction mixtures were combined, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (EtOAc / MeOH=10 / 1, Rf=0.57, Rf=0.00) to give two peaks. The two peaks were purified by preparative HPLC to give 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthidium-5,4'-piperidin]-6-one (2.7 mg, 12%) as a white solid (Example 5).

[0681] The analytical data for Example 5 are listed in Table 5.

[0682] Pathway E

[0683] A typical procedure for preparing amines is illustrated by the preparation of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthidine-5,4'-piperidine] (Example 6).

[0684]

[0685] A borane THF complex (0.077 mL, 0.077 mmol) was added to a stirred solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (20 mg, 0.039 mmol) in THF (1 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with MeOH (10 mL), stirred at room temperature for 16 h, and concentrated under reduced pressure to provide a crude product. The crude product was purified by preparative HPLC and the fractions were lyophilized under low pressure to provide 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthidine-5,4'-piperidine] (2.1 mg, 0.004 mmol, 11%) as a white solid (Example 6).

[0686] The analytical data for Example 6 are listed in Table 6.

[0687] Pathway F

[0688] A typical procedure for preparing lactams is illustrated 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-naphthidium-5,4'-piperidin]-8-one (Example 9).

[0689]

[0690] 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[piperidin-4,5'-[1,7]naphthyl]-8'-one (100 mg, 0.295 mmol) (intermediate 10) in toluene (2 mL) was degassed with nitrogen for 5 min. Cs₂CO₃ (193 mg, 0.591 mmol), xantphos (11.97 mg, 0.021 mmol), and Pd₂(dba)₃ (13.53 mg, 0.015 mmol) were added, and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by preparative HPLC (Method B). The fraction was lyophilized under low pressure. The residue was alkalized with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized under low pressure to provide 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (20 mg, 0.04 mmol, 14%) as a white solid.

[0691] LCMS: 1.51 min, 517.2 (M+H) + Method A

[0692] A solution of 7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (20 mg, 0.039 mmol) and 1-bromo-3-chloro-2-(trifluoromethyl)benzene (15.1 mg, 0.058 mmol) in toluene (2 mL) was degassed with nitrogen for 5 min. Cs₂CO₃ (25.2 mg, 0.077 mmol), xantphos (1.6 mg, 2.71 μmol), and Pd₂(dba)₃ (1.8 mg, 1.934 μmol) were added, and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by preparative HPLC. The fractions were lyophilized under low pressure. The residue was alkalized with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized under low pressure to provide 1'-[3-chloro-2-(trifluoromethyl)phenyl]-7-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H-1,7-naphthidine-5,4'-piperidine]-8-one (4.86 mg, 6.92 μmol, 18%) as an off-white solid (Example 9).

[0693] The analytical data for Example 9 are listed in Table 7.

[0694] Pathway G

[0695] A typical procedure for preparing amines is exemplified by the preparation of 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidine-3-ylspiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one (Example 15).

[0696]

[0697] At room temperature, 20 mg, 0.039 mmol of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (Example 3) (1 mL) was added to a stirred solution of DMSO with NaH (3.09 mg, 0.077 mmol) and tert-butyl 3-iodopyrrolidine-1-carboxylate (22.99 mg, 0.077 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with ice-cold water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with a saline solution (10 mL), dried over sodium sulfate, and evaporated to provide the crude product tert-butyl 3-(1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid (24 mg, 0.035 mmol, 35%) as a red colloidal liquid.

[0698] LCMS: 3.90 min, 686.3 (M+H) + Method B

[0699] 3-(1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 0.029 mmol) was added to a stirred solution in DCM (3 mL). Phosphoric acid (14.28 mg, 0.146 mmol) was then added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The DCM layer was decanted, and the residue was washed with DCM (2 x 10 mL). The crude residue was added to 10% NaHCO3 solution and adjusted to pH ~ 8. The aqueous layer was decanted, ground with water (2 x 10 mL), decanted, and lyophilized under low pressure to provide a yellow solid. The crude reactant was purified by preparative HPLC. The sample was lyophilized under low pressure to provide the product 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidine-3-ylspiro[6H-1,7-naphthidine-5,4'-piperidine]-8-one (1.03 mg, 0.0017 mmol) as a white solid (Example 15).

[0700] The analytical data for Example 15 are listed in Table 8.

[0701] Pathway H

[0702] A typical procedure for preparing amines is 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-naphthidin-5,4'-piperidin]-1'-yl]ketene (Example 21).

[0703]

[0704] DIPEA (0.01042 mL, 0.060 mmol) was added 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]naphthidine] (20 mg, 0.040 mmol) (Example 15) in DMF (1 mL), followed by (tert-butoxycarbonyl)glycine 2,5-dioxopyrrolidine-1-yl ester (16.24 mg, 0.060 mmol), and the reaction mixture was stirred at room temperature for 3 h. 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 provide crude (2-(7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)-2-oxoethyl)carbamate tert-butyl ester (20 mg, 0.029 mmol, 74%) as a gel solid, which was used for the next step without further purification.

[0705] LCMS: 3.25 min, 660.0 (M+H) + Method B

[0706] TFA (0.117 mL, 1.515 mmol) was added to a stirred solution of (2-(7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)-2-oxoethyl)carbamate (20 mg, 0.030 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum and purified by preparative HPLC. The pure fraction was lyophilized under low pressure to provide 2-amino-1-(7'-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)ethane-1-one (4.25 mg, 7.51 μmol, 25%) as a white solid (Example 21).

[0707] The analytical data for Example 21 are listed in Table 9.

[0708] Approach I

[0709] A typical procedure for preparing lactams is exemplified by the preparation of 1'-(4-chloro-3-iodopyridin-2-yl)-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (Example 22).

[0710]

[0711] DIPEA (0.310 mL, 1.773 mmol) and 4-chloro-2-fluoro-3-iodopyridine (342 mg, 1.330 mmol) were added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (300 mg, 0.886 mmol) in DMF (2 mL), 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 x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by column chromatography using a Biotage-Isolera column with a silica gel column of 25 g and eluted with a solution of 0–10% MeOH in DCM. The purified fraction was concentrated under reduced pressure to provide 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (250 mg, 0.373 mmol, 42%). The purified product (15 mg) was purified by preparative HPLC. The fraction was collected and lyophilized under low pressure to give 1-(4-chloro-3-iodopyridin-2-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (4.2 mg) as a grayish-white solid (Example 22).

[0712] The analytical data for Example 22 are listed in Table 10.

[0713] Path J

[0714] A typical procedure for preparing amides is exemplified by the preparation of [2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-6H-1,7-naphthidin-5,4'-piperidin]-1'-yl]-[6-propoxy-2-(trifluoromethyl)pyridin-3-yl] methyl ketone (Example 24).

[0715]

[0716] DIPEA (282 mg, 2.181 mmol), 6-propoxy-2-(trifluoromethyl)nicotinic acid (130 mg, 0.523 mmol), and HATU (249 mg, 0.654 mmol) were added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formate (200 mg, 0.436 mmol) (intermediate 5) in DMF (5 mL) at room temperature, followed by the addition of HATU (249 mg, 0.654 mmol). The reaction mixture was stirred at room temperature for 16 h. 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 provide a crude extract. The crude product was purified by rapid silica gel column chromatography in a solution of 40 to 60% EtOAc in petroleum ether to provide 2'-(2-ethoxypyridin-3-yl)-1-(6-propoxy-2-(trifluoromethyl)nicotinyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-benzyl formate (140 mg, 0.151 mmol, 35%) as a brown gum.

[0717] LCMS: 3.97 min, 690.3 (M+H) + Method B

[0718] A solution of 20% KOH in H₂O (40.7 mg, 0.145 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-1-(6-propoxy-2-(trifluoromethyl)nicotinyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-formate (50 mg, 0.072 mmol) in EtOH (2 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by preparative HPLC. The fractions were collected and lyophilized under low pressure to obtain (2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)(6-propoxy-2-(trifluoromethyl)pyridin-3-yl) methyl ketone (20 mg, 0.035 mmol, 49%) as a grayish-white solid (Example 24).

[0719] The analytical data for Example 24 are listed in Table 11.

[0720] Path K

[0721] A typical procedure for preparing amides is exemplified by the preparation of [2-(2-ethoxypyridin-3-yl)-7-pyrrolidine-3-ylspiro[6,8-dihydro-1,7-naphthidin-5,4'-piperidin]-1'-yl]-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl] methyl ketone (Example 29).

[0722]

[0723] Intermediate 21 (2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)(6-methoxy-2-(trifluoromethyl)pyridin-3-yl) methyl ketone (50 mg, 0.095 mmol) was added to a stirred solution of (2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)(6-methoxy-2-(trifluoromethyl)pyridin-3-yl) ketone (50 mg, 0.095 mmol) in ethanol (5 mL). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was precipitated using ACN (20 mL) and the precipitate was filtered off. The solid was washed with ACN (20 mL) and the combined filtrates were collected and concentrated to give tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)nicotinyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid (50 mg, 0.030 mmol, 32%) as a brown gel.

[0724] LCMS: 3.16 min, 697.1 (M+H) + Method B

[0725] TFA (8.18 mg, 0.072 mmol) was added to a stirred solution of 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)nicotinyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.072 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by preparative HPLC. The fractions were collected and lyophilized under low pressure. The resulting gel 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 obtain a colorless colloid, which was then redissolved in ACN:water (1:3) and freeze-dried under low pressure to obtain racemic-(2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidine-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)(6-methoxy-2-(trifluoromethyl)pyridin-3-yl) methyl ketone (1.34 mg, 2.100 μmol, 3%) as a grayish-white solid (Example 29).

[0726] The analytical data for Example 29 are listed in Table 12.

[0727] Pathway L

[0728] A typical procedure for preparing amines is 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-naphthidine-5,4'-piperidine] (Example 30).

[0729]

[0730] The solution of 2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-benzyl formate (100 mg, 0.218 mmol) (intermediate 5) in toluene (2 mL) was purified with N2 gas for 5 min. 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (223 mg, 0.872 mmol), Cs2CO3 (142 mg, 0.436 mmol), xantphos (12.6 mg, 0.022 mmol), and Pd2(dba)3 (20 mg, 0.022 mmol) were added to the reaction mixture and heated at 100 °C for 16 h. The reaction mixture was evaporated and the crude product was purified by silica gel rapid column chromatography using a solution of EtOAc in petroleum ether (0-35%) to provide 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-benzyl formate (145 mg, 0.151 mmol, 69%) as an orange gel.

[0731] LCMS: 3.72 min, 634.0 (M+H) + Method B

[0732] A solution of 20% KOH in water (0.05 mL, 0.379 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthyl]-7'(8'H)-formate (120 mg, 0.189 mmol) in MeOH (2 mL), and the reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC. The fractions were lyophilized under low pressure. The residue was alkalized with 10% NaHCO3 solution and extracted with DCM (3 x 5 mL). The combined organic extracts were evaporated and lyophilized under low pressure to provide 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] as a white solid (16.93 mg, 0.031 mmol, 16%) (Example 30).

[0733] The analytical data for Example 30 are listed in Table 13.

[0734] Pathway M

[0735] A typical procedure for preparing lactams is exemplified by the preparation of (S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidine-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-6'-one (Example 34).

[0736]

[0737] NaH (13.54 mg, 338.53 μmol, 60% purity) was added to a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthidium-5,4'-piperidin]-6-one (35 mg, 67.71 μmol) (Example 5) and (R)-3-((methanesulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (71.86 mg, 270.82 μmol) in THF (2 mL) under nitrogen atmosphere at 0 °C. 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 a crude product, which was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1, R f =0.2) to obtain (S)-3-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (25 mg, 53%) as a yellow oil.

[0738] LCMS: 1.16 min, 686.3 (M+H) + Method O

[0739] A solution of (S)-3-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (22.00 mg, 32.06 μmol) in formic acid (0.5 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain (S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidine-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-6'-one (9.3 mg, 49%) as a yellow oil (Example 34).

[0740] The analytical data for Example 34 are listed in Table 14.

[0741] Path N

[0742] A typical procedure for preparing lactams is illustrated by the preparation of racemic-(3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (Example 36) and racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (Example 42).

[0743]

[0744] A solution of 1-bromo-4-chloro-2-(trifluoromethyl)benzene (500 mg, 1.927 mmol) and 3-ethylpiperidin-4-carboxylonitrile (400 mg, 2.89 mmol) in toluene (8 mL) was degassed with nitrogen for 5 min. Cs₂CO₃ (1.3 g, 3.85 mmol), BINAP (240 mg, 0.385 mmol), and Pd(OAc)₂ (44 mg, 0.194 mmol) were added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated, and the crude product was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–10%) to provide 1-(4-chloro-2-(trifluoromethyl)phenyl)-3-ethylpiperidin-4-carboxylonitrile (510 mg, 1.608 mmol, 83%) as a colorless colloid.

[0745] LCMS: 3.11 min, 317.0 (M+H) + Method B

[0746] 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-ethylpiperidin-4-carboxynitrile (513 mg, 1.619 mmol) in toluene (8 mL), KHMDS (0.5 M in toluene) (3.24 mL, 1.619 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. 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 rapid column chromatography using a solution of EtOAc in petroleum ether (0-10%) to provide racemic ethyl 5-((3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (400 mg, 0.326 mmol, 20%) as a pale yellow colloid.

[0747] LCMS: 3.70 min, 587.0 (M+H) + Method B

[0748] Raney nickel (1 g, 11.40 mmol) was added to a stirred solution of racemic 5-((3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-4-cyano-3-ethylpiperidin-4-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid ethyl ester (400 mg, 0.681 mmol) in EtOH (9 mL) and water (1 mL). The reaction mixture was stirred at 65 °C for 16 h under a H2 atmosphere at 5 atm. Two compounds were observed according to LCMS. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc (200 mL). The filtrate was evaporated, and the crude product was purified by preparative purification to yield two products. The pure fraction corresponding to racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one was lyophilized under low pressure. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, evaporated and lyophilized under low pressure to provide racemic-(3S,4S)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-1-(2-(trifluoromethyl)phenyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (40 mg, 0.076 mmol, 37%) as a white solid (Example 42).

[0749] The pure fraction corresponding to racemic-(3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (Example 36) was lyophilized under low pressure. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, evaporated and lyophilized under low pressure to provide racemic-(3S,4S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-3-ethyl-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (3.24 mg, 5.79 μmol, 1%) as a white solid (Example 36).

[0750] The analytical data for Examples 36 and 42 are listed in Table 15.

[0751] Pathway O

[0752] A typical procedure for preparing lactams is illustrated by the preparation of 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazacyclobutane-3-yl)methyl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one (Example 38) and 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazacyclobutane-3-yl)methyl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one (Example 43).

[0753]

[0754] NaH (7.74 mg, 0.193 mmol) was added to a stirred solution of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (50 mg, 0.097 mmol) in DMF (1 mL) at 0 °C, and the reaction mixture was stirred for 30 min. Tert-butyl 3-(bromomethyl)-3-hydroxyazacyclobutane-1-carboxylate (38.6 mg, 0.145 mmol) in DMF (1 mL) was added to the reaction mixture, and the reaction mixture was slowly stirred at room temperature for 3 h. 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 x 2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude 3-((1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)methyl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (100 mg, 0.074 mmol, 77%) as a colloidal solid, which was used for the next step without further purification.

[0755] LCMS: 3.14 min, 702.0 (M+H) + Method B

[0756] TFA (0.027 mL, 0.356 mmol) was added to a stirred solution of 3-((1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (50 mg, 0.071 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by preparative HPLC. The fraction was concentrated, the resulting solid was alkalized 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 under low pressure to provide 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxyazacyclobutane-3-yl)methyl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one (7.91 mg, 0.013 mmol, 18%) as a white solid (Example 38).

[0757] Sodium cyanoborohydride (8.35 mg, 0.133 mmol) was added to a stirred solution of 1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-((3-hydroxyazacyclobutane-3-yl)methyl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (40 mg, 0.066 mmol) (Example 38) and formaldehyde (2.394 mg, 0.080 mmol) in a DCE (2 mL), and the reaction mixture was slowly stirred at room temperature for 16 h. 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 provide a crude extract. The crude product was purified by preparative HPLC 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% NaHCO3 solution and dried over anhydrous sodium sulfate, filtered, concentrated, and lyophilized under low pressure to provide 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[(3-hydroxy-1-methylazacyclobutane-3-yl)methyl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one (2.49 mg, 3.84 μmol, 6%) as a white solid (Example 43).

[0758] The analytical data for Examples 38 and 43 are listed in Table 16.

[0759] Pathway P

[0760] A typical procedure for preparing amines is 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-naphthidium-5,4'-piperidin]-7-yl]acetone (Example 52).

[0761]

[0762] 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]naphthidine] (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), followed by HATU (22.68 mg, 0.060 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 (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 provide crude (2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)-2-oxoethyl)carbamate tert-butyl ester (50 mg, 0.076 mmol) as a colorless viscous liquid.

[0763] LCMS: 4.01 min, 661.3 (M+H) + Method B

[0764] TFA (5.84 μl, 0.076 mmol) was added to a stirred solution of (2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)-2-oxoethyl)carbamate (50 mg, 0.076 mmol) in a DCM (1 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and neutralized with 10% NaHCO3, and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude product. The crude product was purified by preparative HPLC. The pure fraction was collected and concentrated under reduced pressure to give a white solid, which was neutralized with 10% NaHCO3 aqueous solution (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 under low pressure to provide 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,8-dihydro-1,7-naphthidium-5,4'-piperidin]-7-yl]acetone (3.94 mg, 0.076 mmol, 9%) as a grayish-white solid (Example 52).

[0765] The analytical data for Example 52 are listed in Table 17.

[0766] Pathway Q

[0767] A typical route for preparing amino alcohols is exemplified by the preparation of 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azacyclobutane-3-yl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one trifluoroacetate (Example 54).

[0768]

[0769] To a stirred solution of 7-(azacyclobutan-3-yl)-1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6H-1,7-naphthidium-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 a DCM (3 mL), TEA (0.05 mL, 0.350 mmol), Na(OAc)3BH (17.8 mg, 0.084 mmol) and acetic acid (0.400 μl, 6.99 μmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and evaporated to provide 7'-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azacyclobutane-3-yl)-1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (50 mg, 0.068 mmol, 98%).

[0770] LCMS: 3.20 min, 730.4 (M+H) + Method B

[0771] TBAF (0.082 mL, 0.082 mmol) was added to a stirred solution of 7'-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azacyclobutane-3-yl)-1-(3-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (40 mg, 0.055 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and evaporated. The crude product was purified by preparative HPLC. The fractions were prepared by low-pressure freeze-drying to provide 1'-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-(2-hydroxyethyl)azacyclobutane-3-yl]spiro[6H-1,7-naphthidium-5,4'-piperidin]-8-one trifluoroacetate (2.08 mg, 6%) as a white solid (Example 54).

[0772] The analytical data for Example 54 are listed in Table 18.

[0773] Pathway R

[0774] A typical procedure for preparing lactams is illustrated by the preparation of 2-(2-ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidine-3-ylspiro[8H-1,7-naphthidin-5,4'-piperidin]-6-one (Example 58).

[0775]

[0776] Under argon atmosphere, tert-butyl pyrrolidine-1-carboxylate (16.95 mg, 33.39 μmol) (intermediate 26), 3-chloro-5-propoxy-4-(trifluoromethyl)pyridine (10 mg, 41.73 μmol) (intermediate 27), and sodium tert-butoxide (12.03 mg, 125.20 μmol) in dioxane (1 mL) were added to a solution of bis(diphenylphosphino)-1,1'-binathyl (5.20 mg, 8.35 μmol) in dioxane (1 mL). μmol) and methanesulfonate alkyl[2,2-bis(diphenylphosphino)-1,1-binaphthyl](2-amino-1,1-biphenyl-2-yl)palladium(II) (8.28 mg, 8.35 μmol). The reaction mixture was then heated to 100 °C and stirred at 100 °C for 2 hours. Seven more tubular flasks were prepared as described 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 produce a residue, which was purified by preparative TLC (eluting with petroleum ether / EtOAc = 1 / 2, R f =0.49) to produce tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-6'-oxo-1-(5-propoxy-4-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid as a white solid (21 mg, 9%).

[0777] 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)

[0778] A solution of tert-butyl pyrrolidine-1-carboxylate (10 mg, 14.07 μmol) in formic acid (0.3 mL) was stirred at 25 °C for 1 hour. Another tubular flask was prepared as described above. All two reaction mixtures were combined and concentrated under reduced pressure to produce a residue, which was purified by preparative HPLC to produce 2-(2-ethoxypyridin-3-yl)-1'-[5-propoxy-4-(trifluoromethyl)pyridin-3-yl]-7-pyrrolidine-3-ylspiro[8H-1,7-naphthidine-5,4'-piperidine]-6-one (8.2 mg, 47%) as a white solid (Example 58).

[0779] The analytical data for Example 58 are listed in Table 19.

[0780] Pathway S

[0781] A typical procedure for preparing lactams is exemplified by the preparation of 7-(2-aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7-naphthidium-5,4'-piperidin]-6-one (Example 59).

[0782]

[0783] NaH (19.34 mg, 483.60 μmol, 60% purity) was added to a solution of 1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[7,8-dihydro-1,7-naphthidium-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) under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 12 hours. TLC (petroleum ether / EtOAc = 2 / 1, R f =0.23) indicates that the starting material was depleted and the desired spot was formed. The reaction mixture was quenched with ice water (2 mL) and extracted with EtOAc (1 mL x 3). The combined organic phases were concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1, R f =0.23) to obtain 2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)acetonitrile (20 mg, 31%) as a yellow oil.

[0784] LCMS: 1.04 min, 556.2 (M+H) + Method O

[0785] Under nitrogen atmosphere, Rh / C (3 mg, 1.27 μmol, 5% purity) and one drop of TFA were added to a solution of 2-(1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)acetonitrile (3 mg, 5.40 μmol) in MeOH (5 mL). The suspension was degassed under vacuum and purified three times with hydrogen. The mixture was stirred for 20 min at 25 °C under a hydrogen balloon. Four more tubular flasks were prepared as described above. All five reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to give 7-(2-aminoethyl)-1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[8H-1,7-naphthidium-5,4'-piperidin]-6-one g (2.6 mg, 17%) as a white solid (Example 59).

[0786] The analytical data for Example 59 are listed in Table 20.

[0787] Pathway T

[0788] A typical procedure for preparing lactams is illustrated by the preparation of 1'-[3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)-7-[1-[2-(2-methoxyethoxy)ethyl]pyrrolidine-3-yl]spiro[6H-1,7-naphthidine-5,4'-piperidine]-8-one (Example 68).

[0789]

[0790] To a stirred solution of 1-(3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidine-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidium]-8'-one (40 mg, 0.046 mmol) (Example 18) in ACN (1 mL), 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 rapid column chromatography using a solution of MeOH in DCM (0–10%). The pure fraction was evaporated, and the product was further purified by preparative HPLC. The fraction was lyophilized under low pressure. The residue was dissolved in DCM (10 mL), washed with 10% NaHCO3 solution (5 mL), dried over sodium sulfate, evaporated, and lyophilized under low pressure to provide 1-(3-(cyclopropylmethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidine-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthidine]-8'-one (14.15 mg, 0.019 mmol, 42%) as a white solid.

[0791] The analytical data for Example 68 are listed in Table 21.

[0792] Path U

[0793] A typical procedure for preparing lactams is exemplified by the preparation of 2-(2-ethoxypyridin-3-yl)-1'-[5-ethoxy-4-(trifluoromethyl)pyridin-3-yl]spiro[6,7-dihydro-1,7-naphthidium-5,4'-piperidin]-8-one (Example 80).

[0794]

[0795] Sodium ethoxide (33 mg, 0.487 mmol) was added to a stirred solution of 1-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (50 mg, 0.097 mmol) (intermediate 37) in DMSO (0.5 mL). 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 preparative HPLC and the fractions were lyophilized under low pressure. The residue was dissolved in DCM (15 mL), alkalized with 10% NaHCO3 solution (5 mL), washed with water (5 mL), dried over sodium sulfate, evaporated and lyophilized under low pressure to provide 1-(5-ethoxy-4-(trifluoromethyl)pyridin-3-yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-8'-one (6.31 mg, 0.012 mmol, 12%) as a white solid (Example 80).

[0796] The analytical data for Example 80 are listed in Table 22.

[0797] Pathway V

[0798] A typical procedure for preparing carbamates is illustrated by the preparation of 2-(2-ethoxypyridin-3-yl)-1'-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]spiro[6,8-dihydro-1,7-naphthidine-5,4'-piperidine]-7-carboxylic acid aziridine-3-yl ester (Example 97).

[0799]

[0800] DIPEA (0.070 mL, 0.400 mmol) was added 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-naphthidine-5,4'-piperidine] (100 mg, 0.200 mmol) (Example 30) in DMF (2.0 mL) at 0 °C, followed by the addition of tert-butyl 3-((((2,5-dioxopyrrolidine-1-yl)oxy)carbonyl)oxy)azacyclobutane-1-carboxylate (94 mg, 0.300 mmol) (Intermediate 50), and the reaction mixture was stirred at room temperature for 5 h. 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 obtain 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-formic acid 1-(tert-butoxycarbonyl)azacyclobutane-3-yl ester (50 mg, 0.072 mmol, 36%) as a brown gel.

[0801] LCMS: 3.49 min, 699.3 (M+H) + Method B

[0802] Phosphoric acid (85% in water) (7.01 mg, 0.072 mmol) was added to a stirred solution of 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-formic acid 1-(tert-butoxycarbonyl)azacyclobutane-3-yl ester (50 mg, 0.072 mmol) in DCM (2.0 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, neutralized with 10% NaHCO3 (10 mL), and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide a crude compound, which was purified by preparative HPLC. The pure fraction was collected and lyophilized under low pressure to provide 2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-carboxylic acid aziridine-3-yl ester formate (5.88 mg, 9.82 μmol, 14%) as a white solid (Example 97).

[0803] The analytical data for Example 97 are listed in Table 23.

[0804] Pathway W

[0805] A typical procedure for preparing nitriles is illustrated by the preparation of 2-[3-[2-(2-ethoxypyridin-3-yl)-8-oxo-7-[(3S)-pyrrolidine-3-yl]spiro[6H-1,7-naphthidin-5,4'-piperidin]-1'-yl]-2-(trifluoromethyl)phenoxy]acetonitrile (Example 98).

[0806]

[0807] To a stirred suspension of 1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidin-4,5'-[1,7]naphthyl]-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 min. Tert-butyl (R)-3-((methanesulfonyl)oxy)pyrrolidine-1-carboxylate (128 mg, 0.484 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 16 h. 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 rapid column chromatography using a solution of MeOH in DCM (0–10%) to provide (S)-3-(1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (57 mg, 0.062 mmol, 64%) as a yellow colloid.

[0808] LCMS: 3.32 min, 758.4 (M+H) + Method B

[0809] To a stirred solution of (S)-3-(1-(3-(benzyloxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (57 mg, 0.075 mmol) in MeOH (5 mL), 10% Pd / C (50 mg, 0.047 mmol) was added and the mixture was stirred at room temperature for 16 h at 1 atm H2 pressure. The reaction mixture was filtered through diatomaceous earth and washed with a solution of 20% MeOH in DCM (20 mL). The filtrate was evaporated and dried under high vacuum to provide (S)-3-(2'-(2-ethoxypyridin-3-yl)-1-(3-hydroxy-2-(trifluoromethyl)phenyl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (38 mg, 0.044 mmol, 59%) as a yellow gel.

[0810] LCMS: 2.76 min, 668.3 (M+H) + Method B.

[0811] To a stirred solution of (S)-3-(2'-(2-ethoxypyridin-3-yl)-1-(3-hydroxy-2-(trifluoromethyl)phenyl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (35 mg, 0.052 mmol) in DMF (1 mL), 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 h. The reaction mixture was quenched with water (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated to provide (S)-3-(1-(3-(cyanomethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (27 mg, 0.029 mmol, 55%) as a yellow colloid.

[0812] LCMS: 2.88 min, 707.3 (M+H) + Method B

[0813] Phosphoric acid (25 mg, 0.255 mmol) was added to a stirred solution of (S)-3-(1-(3-(cyanomethoxy)-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-8'-oxo-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (25 mg, 0.035 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was alkalized 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 preparative HPLC. The fraction was prepared by low-pressure freeze-drying to provide (S)-2-(3-(2'-(2-ethoxypyridin-3-yl)-8'-oxo-7'-(pyrrolidine-3-yl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)-2-(trifluoromethyl)phenoxy)acetonitrile carbamate (1.25 mg, 1.968 μmol, 6%) as a white solid (Example 98).

[0814] The analytical data for Example 98 are listed in Table 24.

[0815] Pathway X

[0816] A typical procedure for preparing methylpyrrolidine is illustrated by (R)-2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 113).

[0817]

[0818] 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]naphthidine] (intermediate 61) (20 mg, 40.12 μmol) in MeOH (1 mL), tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (15.99 mg, 80.23 μmol) and NaCNBH3 (10.08 mg, 160.47 μmol) were added. The reaction mixture was stirred at 25 °C for 12 h. Another tubular flask was prepared as described 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 preparative TLC (petroleum ether / EtOAc = 1 / 3, R...). f =0.43) to obtain (R)-2-((2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (25 mg, 46%) as a white solid.

[0819] LCMS: 0.59 min, 682.4 [M+H] + Method R'

[0820] TFA (0.2 mL) was added to a solution of (R)-2-((2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 102.67 μmol) in DCM (1 mL) at 25 °C. The reaction mixture was stirred at 25°C for 2 h and concentrated under reduced pressure to produce a residue, which was purified by preparative HPLC to produce (R)-2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (23 mg, 39%) as a white solid (Example 113).

[0821] The analytical data for Example 113 are listed in Table 25.

[0822] Pathway Y

[0823] A typical procedure for preparing oxopropionic acid is exemplified by 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)-3-oxopropionic acid (Example 117).

[0824]

[0825] HATU (30.51 mg, 80.23 μmol) was added to a solution of 3-methoxy-3-oxopropionic 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]naphthidine] (intermediate 61) (20 mg, 40.12 μmol) in DMF (0.5 mL), followed by DIPEA (15.55 mg, 120.35 mmol, 20.96 μL), and the reaction mixture was stirred at 25 °C for 2 h. Another tubular flask was prepared as described above. All two 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 purified by preparative TLC (EtOAc, R). f =0.6) to obtain methyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)-3-oxopropionate (30 mg, 62%) as a white solid.

[0826] LCMS: 2.23 min, 599.2 [M+H] + Method R'

[0827] LiOH (2.80 mg, 116.94 μmol) was added to a solution of methyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)-3-oxopropionate (14 mg, 23.39 μmol) in MeOH (0.4 mL) and water (0.2 mL), and the mixture was stirred at 25 °C for 4 h. Another tubular flask was prepared as described above. All two reaction mixtures were concentrated under reduced pressure and purified by preparative HPLC to give 3-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)-3-oxopropionic acid (9.7 mg, 35%) as a white solid (Example 117).

[0828] The analytical data for Example 117 are listed in Table 26.

[0829] Path Z

[0830] Typical procedure for preparing racemic-((2R,4S)-4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)tetrahydrofuran-2-yl)methylamine (Example 136)

[0831]

[0832] 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 min. The reaction mixture was basified to pH 9 with Et3N, and then 2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (50 mg, 100.29 μmol) (intermediate 61) and NaCNBH3 (31.51 mg, 501.47 μmol) were added. The reaction mixture was heated to 60 °C and stirred at 60 °C for 12 h. Three more tubular flasks were prepared as described above. After cooling to room temperature, all four reaction mixtures were combined, quenched with water (0.3 mL), concentrated under reduced pressure, and purified by preparative TLC (petroleum ether / EtOAc = 1 / 1, peak 1, R). f =0.36, peak 2, R f=0.29) to obtain ethyl 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-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[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)tetrahydrofuran-2-carboxylate_peak-2 (70 mg, 27%) as colorless oil.

[0833] Peak 1: LCMS: 0.549 min, 641.4 (M+H) + Method L

[0834] Peak 2: LCMS: 0.547 min, 641.4 (M+H) + Method L

[0835] A solution of 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)tetrahydrofuran-2-carboxylate-peak-1 (15 mg, 23.41 μmol, 1) in ammonia in MeOH solution (0.5 mL, 7 N) was heated to 80 °C and stirred at 80 °C for 5 h. Another tubular flask was prepared as described above. After cooling to room temperature, all 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[piperidin-4,5'-[1,7]naphthidium]-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.

[0836] LCMS: 0.47 min, 612.3 (M+H) + Method L

[0837] A solution of LAH in THF (2.5 M, 49.05 μL) was added dropwise to a solution of 4-(2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)tetrahydrofuran-2-carboxamide (15 mg, 24.52 μmol) in THF (1 mL). The reaction mixture was stirred at 20 °C for 12 h. Another tubular flask was prepared as described above. After cooling to 0 °C, all two reaction mixtures were combined and quenched with Na2SO4 (15 mg) and stirred at 20 °C for 2 h. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain rel-[(2R,4S)-4-[2-(2-ethoxypyridin-3-yl)-1'-[3-methoxy-2-(trifluoromethyl)phenyl]spiro[6,8-dihydro-1,7-naphthidium-5,4'-piperidin]-7-yl]oxacyclopentan-2-yl]methylamine_peak-1 (5 mg, 13%) as a white solid (Example 136).

[0838] The analytical data for Example 136 are listed in Table 27.

[0839] Pathway Aa

[0840] Typical procedure for the preparation of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 153, 153.HCl / MSA)

[0841]

[0842] To a stirred solution of 2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (1 g, 1.925 mmol) (intermediate 106) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (460 mg, 2.310 mmol) in a DCE (10 mL), Na(OAc)3BH (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 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, evaporated, and purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0–100%) as the eluent to provide (R)-2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g, 1.521 mmol, 79%) as a pale white solid.

[0843] LCMS: 3.08 min, 651.3 [M+H] + Method B

[0844] TFA (1.6 g, 13.83 mmol) was added to a stirred solution of (R)-2-((2'-(2-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 1.383 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was carefully alkalized with 10% NaHCO3 solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over sodium sulfate. The resulting residue was purified by preparative HPLC (Method B). The pure preparative fraction was lyophilized under low pressure. The residue was dissolved in DCM (15 mL), washed with 10% NaHCO3 solution (5 mL) and water (5 mL), dried over sodium sulfate, evaporated and lyophilized under low pressure to provide (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (410 mg, 0.730 mmol, 53%) as an off-white solid (Example 153).

[0845] HCl (2M in iPrOAc) (0.02 mL, 0.036 mmol) was added to a stirred solution of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 153) (20 mg, 0.036 mmol) in iPrOAc (1 mL). The reaction mixture was stirred at room temperature for 10 min. The resulting solid was ground together with MTBE (2 x 1 mL). The residue was lyophilized under low pressure to provide (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] hydrochloride (5.50 mg, 0.00901 mmol, 25%) as a white solid (Example 153.HCl).

[0846] MSA (0.2 M in iPrOAc) (0.01 mL, 0.018 mmol) was added to a stirred solution of (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 153) (10 mg, 0.018 mmol) in an iPrOAc (1 mL). The reaction mixture was stirred at room temperature for 10 min. The resulting solid was ground together with MTBE (2 x 1 mL). The residue was purified by preparative HPLC according to Method I. The fraction was prepared by low-pressure lyophilization to provide (R)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-1-(2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthylidine]methanesulfonate (7.31 mg, 0.011 mmol, 62%) as a white solid (Example 153.MSA).

[0847] The analytical data for Examples 153, 153.HCl and 153.MSA are listed in Table 28.

[0848] Pathway Ab

[0849] Typical procedure for preparing (3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'-(((R)-pyrrolidine-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 176)

[0850]

[0851] To a stirred solution of racemic-(3S,4S)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (intermediate 105) (55 mg, 0.105 mmol) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (20.85 mg, 0.105 mmol) in a DCE (10 mL), Na(OAc)3BH (44.35 mg, 0.210 mmol) was added, 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 Na2SO4, and the resulting residue was purified by rapid column chromatography using a solution of EtOAc in petroleum ether (0-40%) to provide [(R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 0.091 mmol, 88%) as a white solid.

[0852] LCMS: 2.22 min, 709.3 [M+H] + Method G.

[0853] TFA (0.3 mL) was added to a stirred solution of (R)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 0.091 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the resulting residue was neutralized with 10% NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and purified by preparative HPLC. The preparative fraction was concentrated, and the residue was neutralized with 10% NaHCO3 solution (10 mL) and extracted with DCM (10 mL). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and lyophilized under low pressure to provide (3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-1-(3-methoxy-2-(trifluoromethyl)phenyl)-7'-(((R)-pyrrolidine-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (22 mg, 0.036 mmol, 39%) as a colorless liquid (Example 176).

[0854] The analytical data for Example 176 are listed in Table 29.

[0855] Path Ac

[0856] Typical procedure for preparing (R)-1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 189):

[0857]

[0858] At room temperature, tert-butyl 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) were added to Cs₂CO₃ (192.91 mg, 592.09 mmol), Xantphos (22.84 mg, 39.47 μmol), and Pd₂(dba)₃ (36.15 mg, 39.47 μmol). The reaction mixture was stirred at 100 °C for 12 h. Four tubular flasks 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 layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by preparative TLC (petroleum ether / EtOAc = 3 / 1, R...). f =0.4) to obtain (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 56%) as a white solid.

[0859] LCMS: 2.42 min, 635.2 (M+H) + Method M

[0860] A solution of (R)-2-((1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 110.20 μmol) in HCOOH (1 mL) was heated to 40 °C and stirred at 40 °C for 8 h. Three tubular flasks were prepared as described above. After cooling to room temperature, all four reaction mixtures were concentrated under reduced pressure and purified by preparative HPLC to give (R)-1-(2-chloro-4-fluorophenyl)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (83.7 mg, 36%) as a white solid (Example 189).

[0861] The analytical data for Example 189 are listed in Table 30.

[0862] Pathway Ad

[0863] Typical procedure for preparing (R)-1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-7'-(pyrrolidone-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 206):

[0864]

[0865] To a solution of (R)-2-((2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 121) (50 mg, 98.68 μmol) and 2-bromo-4-chloro-1-iodobenzene (31.32 mg, 98.68 μmol) in toluene (1 mL), Cs₂CO₃ (96.46 mg, 296.05 μmol), Xantphos (11.42 mg, 19.74 μmol), followed by Pd₂(dba)₃ (18.07 mg, 19.74 μmol), were added, and the reaction mixture was stirred at 100 °C for 12 h under nitrogen. Five additional tubular flasks were prepared as described 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 layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by preparative TLC (petroleum ether / EtOAc = 2 / 1, R...). f =0.5) to obtain (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 49%) as a white solid.

[0866] LCMS: 2.49 min, 697.1 [M+H] + Method R'

[0867] To a solution of (R)-2-((1-(2-bromo-4-chlorophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 71.83 μmol) and sodium methanesulfinate (9.53 mg, 93.38 μmol) in DMSO (1 mL), K3PO4 (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 additional tubular flasks 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 layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by preparative TLC (petroleum ether / EtOAc = 4 / 3, R...). f =0.6) to obtain (R)-2-((1-(4-chloro-2-(methylsulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 28%) as a yellow solid.

[0868] LCMS: 2.16 min, 695.1 [M+H] + Method R'

[0869] A solution of (R)-2-((1-(4-chloro-2-(methanesulfonyl)phenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (30 mg, 43.15 μmol) in HCOOH (1 mL) was stirred at 40 °C for 8 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give (R)-1-(4-chloro-2-(methanesulfonyl)phenyl)-2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthidine] (Example 206) (25.5 mg, 50%) as a white solid.

[0870] The analytical data for Example 206 are listed in Table 31.

[0871] Pathway Ae

[0872] Typical procedure for preparing 5-chloro-2-((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-7'-(((2R,4S)-4-hydroxypyrrolidine-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)nicotinonitrile (Example 208):

[0873]

[0874] To a solution of (2R,4S)-2-(((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 90.79 μmol) (intermediate 139) in THF (1 mL), 2,5-dichloropyridin-3-carboxynitrile (20.42 mg, 118.03 μmol) was added, followed by Et3N (27.56 mg, 272.37 μmol), and the reaction mixture was stirred at 70 °C for 4 h. Two additional tubular flasks were prepared as described above. After cooling to room temperature, all three mixtures were combined, concentrated, and purified by preparative TLC (petroleum ether / EtOAc = 1 / 2, R f =0.3) to obtain (2R,4S)-2-(((3SR,4SR)-1-(5-chloro-3-cyanopyridin-2-yl)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (94 mg, 50%) as a white solid.

[0875] LCMS: 0.62 min, 687.5 (M+H) + Method L

[0876] TFA (153.50 mg, 1.35 mmol) was added to a solution of (2R,4S)-2-(((3SR,4SR)-1-(5-chloro-3-cyanopyridin-2-yl)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-7'(8'H)-yl)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (22.5 mg, 32.74 μmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 2 h. Three additional tubular flasks were prepared as described above. All four reaction mixtures were combined, concentrated, and purified by preparative HPLC to give 5-chloro-2-((3SR,4SR)-2'-(2-ethoxyphenyl)-3-ethyl-7'-(((2R,4S)-4-hydroxypyrrolidine-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-1-yl)nicotinonitrile (39.1 mg, 51%) as a white solid (Example 208).

[0877] The analytical data for Example 208 are listed in Table 32.

[0878] Path Af

[0879] Typical procedure for the preparation of (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidin]-1-yl)benzoic acid (Example 216)

[0880]

[0881] (R)-2-((1-(4-chloro-2-cyanophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidin-4,5'-[1,7]naphthidine]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Example 173) (500 mg, 0.779 mmol) was added to 10 N HCl (30 mL, 300 mmol). The reaction mixture was stirred at 100 °C for 42 h. The reaction mixture was cooled to room temperature and diluted with a 10% MeOH solution in DCM (2 x 20 mL). The pH of the reaction mixture was adjusted to approximately 8 using a 10% sodium hydroxide solution (50 mL), and the layers were separated. The aqueous layer was extracted with a 10% MeOH solution in DCM (2 x 50 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to provide a crude compound (100 mg; HPLC purity: 56.0%). The crude compound was purified by preparative HPLC (method AP) to provide (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidine-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidin-4,5'-[1,7]naphthidium]-1-yl)benzoic acid (12 mg, 0.021 mmol, 2.75% yield) as an off-white solid (Example 216).

[0882] The analytical data for Example 216 are listed in Table 33.

[0883] Table 2 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0884] Table 3 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0885] Table 4 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0886] Table 5 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0887] Table 6 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0888] Table 7 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0889] Table 8 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0890] Table 9 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0891] Table 10 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0892] Table 11 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0893] Table 12 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0894] Table 13 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0895] Table 14 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0896] Table 15 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0897] Table 16 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0898] Table 17 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0899] Table 18 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0900] Table 19 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0901] Table 20 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0902] Table 21 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0903] Table 22 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0904] Table 23 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0905] Table 24 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0906] Table 25 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0907] Table 26 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0908] Table 27 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0909] Table 28 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0910] Table 29 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0911] Table 30 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0912] Table 31 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0913] Table 32 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0914] Table 33 - NMR and LCMS properties and methods for preparing and purifying the compounds represented by the examples.

[0915] X-ray crystallization analysis of 5-chloro-2-[(3'S,5S)-2-(2-ethoxyphenyl)-3'-ethyl-7-[[(2R)-pyrrolidine-2-yl]methyl]spiro[6,8-dihydro-1,7-naphthidium-5,4'-piperidinium]-1'-yl]benzyl nitrile (Example 181-1)

[0916]

[0917] Crystal data: Empirical formula 3 (C34H40ClN5O), H2O, 0.4(O) formula weight 1734.89, temperature 100(2) K, wavelength 0.71073 Å, crystal system monoclinic space group P21, cell size 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. The q range of the data collection is 1.861 to 30.891°. Index range -15<=h<=15, -46<=k<=47, -17<=l<=16. Collected reflectance 87455. Independent reflectance 25243 [R(int)=0.0891]. Completeness to q = 25.242° is 99.9%. Absorption correction semi-empirical from equivalents. Maximum and minimum transmittance 0.7461 and 0.6603, respectively. Refinement method. Full matrix least squares on F2 data / constraints / parameters 25243 / 201 / 1203. Goodness of fit on F2 is 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 structural parameters 0.01(2) Maximum difference peak and pore size 0.401 and -0.358 e. Å-3 measurements were taken using a Bruker D8 QUEST PHOTON-III detector software with SHELXTL-PLUS.

[0918] Crystal growth: Crystals suitable for single-crystal X-ray diffraction studies were grown using a slow solvent evaporation crystallization method. Crystals were obtained from methyl tert-butyl ether (MTBE) solvent. Approximately 20 mg of the compound (B.No. OMA-SYN-C37s-E1-R-004) was dissolved in 3 ml of MTBE solvent under thermal conditions, and the solution was filtered into a clean beaker and stored at room temperature for crystallization. After 10 days, crystals were obtained on the beaker wall.

[0919] Refinement: X-ray data were collected at low temperature on a Bruker D8QUEST instrument equipped with a 1 μS Mo microsource (λ = 0.7107 A) and a PHOTON-III detector. The raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite program (Bruker (2016) APEX3, SAINT and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA). The structure was resolved by the intrinsic phase method [2] and further refined using the SHELXL program (Sheldrick GM (2015) Acta Crystallogr C71: 3-8) and extended using Fourier techniques. Anisotropic shift parameters were included for all non-hydrogen atoms. Atom C1 of molecule A was disordered at two positions and its site occupancy factors were refined to 0.6 (5) and 0.4 (5), respectively. The atoms C17 / C18 / C19 / C20 / C21 / N3 of molecule B are disordered at two positions, and their site occupancy factors are refined to 0.755(6) and 0.245(6), respectively. NH and OH atoms were located in the difference Fourier plot, and their positions and isotropic shift parameters were refined. Hydrogen atoms could not be located on partially occupied water O2W. All C-bonded H atoms were located geometrically and were considered to ride on their parent C atoms [CH=0.93-0.97Å, and the U of methyl H... iso (H)=1.5U eq (C), or other H atoms, are 1.2U. eq (C)]. The absolute configuration has been confirmed by explicit refinement of the absolute structural parameters (Flack, HD and Bernardinelli, G. (2000). J. Appl. Cryst. 33, 1143-1148).

[0920] Bioactivity

[0921] Preparation of terbium-labeled and SNAP-labeled MC2 films

[0922] Cells were labeled with 100 nM SNAP-Lumi4-Tb and incubated at 37°C for 1 hour in 5% CO2 before harvest, followed by precipitation by centrifugation at 1200 rpm for 3 minutes. The cell pellet was homogenized using a FastPrep-24 5G homogenizer (MP Biomedicals) and subsequently centrifuged at 22,000 × g at 4°C (Eppendorf centrifuge) and resuspended twice, 30 minutes each time. Administered at 5–10 mg / ml. -1 The final precipitate was resuspended in 10 mM HEPES and 0.1 mM EDTA at pH 7.4 and stored at -20°C for later use.

[0923] Fluorescent ligand binding assay

[0924] All fluorescent ligand binding assays were performed using a Cy5-labeled small molecule MC2 antagonist in 384-well Optiplate plates in 1x Tag-lite buffer (PerkinElmer) containing 2% DMSO, 0.04% pluronic acid, and 100 μg / ml saponin. Nonspecific binding was determined in the presence of 1 µM of unlabeled MC2 antagonist in all cases. Signal detection was performed using a standard HTRF setup on a Pherastar FSX (BMG Labtech, Germany), and the HTRF ratio was calculated as follows: the receptor signal (665 nm) divided by the donor signal (620 nm), and then multiplied by 10,000.

[0925] TR-FRET competitive equilibrium binding assay

[0926] To determine the equilibrium dissociation constant (Ki) of the competing test compounds i The MC2 membrane (2 μg / well) was incubated with a series of concentrations of the test compound in the presence of a 100 nM fluorescent tracer. The HTRF ratio was obtained after incubation overnight at 25 °C to ensure equilibrium was reached.

[0927] TR-FRET competitive binding kinetics determination

[0928] To determine the binding (k) of unlabeled compounds on ) and dissociation (k off The binding rate was determined by competitive kinetic assays involving the simultaneous addition of 100 nM fluorescent tracer and increasing concentrations of a competing ligand (2 μg / well) to the MC2 membrane. The binding extent of the fluorescent tracer at MC2 was measured at multiple time points using HTRF.

[0929] In parallel, the binding (kb) of the fluorescent tracer was measured by incubating incremental concentrations of the fluorescent tracer with the MC2 membrane in the absence and presence of 1 μM unlabeled MC2 antagonist. on ) and dissociation (k off The binding rate was determined. The binding degree of the fluorescent tracer at multiple time points was calculated using HTRF, and binding kinetic curves were generated. The obtained data were then fitted to a binding kinetic model (Prism 8.0, GraphPad, San Diego, USA) to derive k. on and k off The best-fit estimates are as described in the data analysis section. From these data, the equilibrium dissociation constant (K0) can be calculated. d The estimated value of ).

[0930] The competitive kinetic data and fluorescent tracer kinetic parameters generally conform to the equations first described by Motulsky and Mahan (Mol. Pharmacol., 1984, 25, 1-9) for determining the unlabeled compound k. on and k off .

[0931] Example A

[0932] pKi: Group A > 9, Group B 7.5 to 9, Group C 6 to 7.5

[0933] Koff: Group A <0.02, Group B 0.02 to 0.07, Group C >0.07

[0934] cAMP accumulation assay

[0935] Chinese hamster ovary (CHO) cells stably expressing MRAP-containing human or rat MC2 were cultured in DMEM / F12 cell 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-capacity 384-well plates in assay buffer (Hank's balanced salt solution (HBSS) containing 5 mM HEPES (pH 7.4), 0.1% w / v BSA, and 500 mM 3-isobutyl-1-methylxanthine) and incubated for 2 hours at 37°C and 5% CO2 with a series of concentrations of MC2 compound. After 2 hours, incremental concentrations of ACTH1-24 were added to the cells and held for the set time. Lysis and cAMP detection were then performed using a homogeneous time-resolved fluorescence (HTRF) cAMP Gs HiRange kit (CisBio) according to the manufacturer's instructions. Fluorescence resonance energy transfer (FRET) levels were detected on a Pherastar plate reader (BMG), and data were interpolated from cAMP standard curves and analyzed using a GraphPad Prism8 (GraphPad). Results for Compound Examples 113, 134, and 135 are as follows: Figure 1 As shown. Brief description of the attached diagram

[0936] Figure 1 Compounds in Examples 113, 134, and 135 inhibited the ACTH1-24-mediated cAMP response at human MC2. Cells expressing MC2 were incubated with the compounds for 2 hours, then stimulated with ACTH1-24 for 15 minutes, followed by lysis and cAMP detection. Slower dissociation compounds with lower Koff exhibited greater insurmountability. Data represent n=1, in duplicate.

Claims

1. Compounds of formula (1): (1)； or its salt, wherein; J is either N or CH; X is -CO-, -CH2-, or -CH2CH2-; Z represents a bond, -CH2-, or -CO-; L 1 It is -(CH2) n -、-(CH2) n CONH-, -(CH2) n COO-, -CO(CH2) n NH- or -CO(CH2) n -, where n is 0-5; R 1 It is a C that is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; R 2 It is H, CO2H, OH, NR 2a R 2b CONR 2a R 2b SO2NR 2a R 2b Optionally R 10 R 11 and R 12 The substituted 3-6 membered carbon rings or heterocycles, or optionally R 10 R 11 and R 12 Replaces the 7-10 byte two-ring or mixed two-ring system; R 2a and R 2b It is independently H or C optionally substituted with 1-3 fluorine atoms. 1-3 alkyl; R 3 It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3 Connect to R 3a To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms; R 3a Is it H or connected to R? 3 To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms; R 3b It is H, or C, which is optionally replaced by 1-3 fluorine atoms. 1-3 Alkyl groups, C atoms optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl groups or CH2C groups optionally substituted with 1-3 fluorine atoms 3-4 cycloalkyl; or R 3b Connect to R 3c To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms; R 3c Is it H or connected to R? 3b To form a cyclopropyl or cyclobutyl ring, either of which may optionally be substituted by 1-3 fluorine atoms; Where R 3 and R 3b One or both of them are H; L 2 Is a bond or -CO- and R 4 It is a functional group: ； Q 5 It is CR 5 Or N; Q 6 It is CR 6 Or N; Q 7 It is CR 7 Or N; Q 8 It is CR 8 Or N; and Q 9 It is CR 9 Or N; where Q 5 Q 6 Q 7 Q 8 and Q 9 One, two, or zero of them are N; or L 2 It is -CO- and R 4 It is -(CH2) q NH2, where q is 0-3; R 5 R 6 R 7 R 8 and R 9 Independently selected from H, halogen, CN, NR 15 R 16 C atoms optionally substituted with 1-3 fluorine atoms 1-3 Alkyl groups, or OC groups optionally substituted with 1-3 fluorine atoms. 1-3 Alkyl groups, OCH2cyclopropyl groups optionally substituted with 1-3 fluorine atoms, OCH2CN, CO2H, and SO2Me; R 10 R 11 and R 12 C atoms independently selected from H, OH, oxo, halogen, optionally substituted with OH or 1-3 fluorine atoms. 1-3 Alkyl groups, 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 0-3 and y is 1-3; R 13 and R 14 It is independently H or methyl; and R 15 and R 16 Independently, it is H or C 1-3 alkyl.

2. The compound according to claim 1, wherein R 4 It is selected from the following groups: ; ; ; and .

3. The compound according to claim 1 or claim 2, wherein L 2 It is a key.

4. The compound according to any one of claims 1 to 3, wherein R 1 It is ethyl or all-deuterated ethyl.

5. The compound according to claim 1 or claim 2, wherein the compound is a compound of formula (2a) or (2b): (2a); (2b); Or its salt.

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

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

8. The compound according to claim 1 or claim 2, wherein the compound is a compound of formula (3a) or (3ai): (3a); (3ai); Or its salt.

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

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

11. The compound according to any one of claims 1 to 10, wherein R 5 R 6 R 7 R 8 and R 9 Independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, -OEt, -O n Pr, -N(CH3)(CH2CH2CH3), -N(CH3)2, -OCH2CN, -OCH2cyclopropyl, -CO2H and -SO2Me.

12. The compound according to any one of claims 1 to 11, wherein R 4 Selected from:

13. The compound according to any one of claims 1 to 12, wherein L 1 It is a bond, -CH2CH2CONH-, -COO-, -CH2CH2COO-, -CH2CH2CO-, -COCH2NH-, -COCH2CH2NH-, -CO-, -CH2CH2- or -CH2-.

14. The compound according to any one of claims 1 to 13, wherein R 2 Selected from:

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

16. The compound according to any one of claims 1 to 12, wherein the -L portion 1 -R 2 Selected from:

17. The compound according to claim 1, wherein the compound is selected from: Or its salt.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. A combination comprising a compound according to any one of claims 1 to 17 and a CRF1 antagonist.

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

21. The compound, composition, or combination according to any one of claims 1 to 20, for use in a pharmaceutical product.

22. The compound, composition, or combination according to any one of claims 1 to 20, for treating disorders related to MC2R or disorders that would benefit from regulation of MC2R activity.

23. The compound, composition, or combination according to any one of claims 1 to 20, for the treatment of congenital adrenal hyperplasia (CAH), Cushing's disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depression, septic shock, or related disorders or symptoms.

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