Melanocortin subtype-2 receptor (MC2r) antagonists and uses thereof

Abstract

SOLUTION: To provide compounds that are melanocortin subtype-2 receptor (MC2R) modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of MC2R activity.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 932,306, filed on November 7, 2019, which is hereby incorporated by reference in its entirety.

[0002] Disclosed herein are compounds that modulate the activity of one or more melanocortin receptors, methods of making such compounds, pharmaceutical compositions and formulations containing such compounds, and methods of using such compounds in the treatment of diseases, disorders, or conditions that would benefit from modulating melanocortin subtype - 2 receptor (MC2R) activity.

Background Art

[0003] Melanocortin receptors form a family of G - protein - coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by the adrenocorticotropic hormone (ACTH) of different melanocortin peptides and melanocortin peptides α -, β -, γ - melanocyte - stimulating hormones (α - MSH, β - MSH, and γ - MSH) that are proteolytically derived from the proopiomelanocortin hormone, i.e., POMC. ACTH is a major regulator of the synthesis and secretion of adrenal glucocorticoids and is a 39 - amino acid peptide that has affinity only for MC2R. ACTH plays a central role in this hypothalamic - pituitary - adrenal (HPA) axis, is secreted from the pituitary gland in response to stress stimuli, and acts on the adrenal gland to promote the synthesis and secretion of cortisol. Modulation of MC2R is attractive for the treatment of symptoms, diseases, or disorders that would benefit from modulating the activity of melanocortin receptors.

Summary of the Invention

[0004] The compounds described in this specification are melanocortin receptor modulator compounds. In some embodiments, the compounds described in this specification modulate one or more of the proteins of the melanocortin receptor subtypes. In some embodiments, the compounds described in this specification modulate two or more of the proteins of the melanocortin receptor subtypes. In some embodiments, the compounds described herein modulate MC2R.

[0005] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is described herein,

[0006]

Chemical formula

[0007] Similarly, this specification describes pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersant, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0008] In any of the foregoing embodiments, in a further embodiment, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or, (b) administered orally to a mammal, and / or, (c) administered intravenously to a mammal, and / or, (d) administered by inhalation, and / or, (e) administered by nasal administration, or, and / or, (f) administered to a mammal by infusion, and / or, (g) administered topically to a mammal, and / or, (h) administered by eye drops, and / or, (i) administered rectally to a mammal, and / or, (j) administered to a mammal non-systemically or topically.

[0009] In any of the foregoing embodiments, further embodiments comprising a single administration of an effective amount of the compound include further embodiments where the compound is administered to the mammal once a day or where the compound is administered to the mammal multiple times during a day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0010] In any of the embodiments disclosed herein, the mammal is a human.

[0011] In some embodiments, the compounds provided herein are administered orally to humans.

[0012] A product is provided that includes a packaging material, a compound of formula (I) or a pharmaceutically acceptable salt thereof within the packaging material, and a label indicating that the compound or composition, or a pharmaceutically possible salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically acceptable active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof is used for modulating a protein of one or more melanocortin receptor subtypes or for treating, preventing, or ameliorating one or more symptoms of a disease or disorder that would benefit from modulation of a protein of one or more melanocortin receptor subtypes.

[0013] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, since various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from the forms for carrying out the invention, it is to be understood that the forms for carrying out the invention and the specific examples are given by way of example only and do not represent the only embodiments.

Forms for Carrying Out the Invention

[0014] Adrenocorticotropic hormone (ACTH) is a 39 - amino acid peptide synthesized in corticotrophic cells of the anterior pituitary gland by proteolysis of proopiomelanocortin hormone (POMC). ACTH is the major regulator of adrenal glucocorticoid (GC; cortisol in humans and most other species, corticosterone in rodents) synthesis and secretion. ACTH plays a central role in this hypothalamic - pituitary - adrenal (HPA) axis, being secreted from the pituitary gland in response to stress stimuli and acting on the adrenal gland to promote cortisol synthesis and secretion. This stimulation is mediated by a highly specific G - protein - coupled receptor (GPCR) that is expressed almost exclusively in the adrenal cortex. This receptor is the melanocortin 2 receptor (MC2R), which, together with ACTH, is part of the larger melanocortin system.

[0015] The melanocortin system includes a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R); their natural agonists, the melanocortin peptides α-, β-, and γ-melanocyte stimulating hormones (α-MSH, β-MSH, and γ-MSH), and ACTH; and the endogenous melanocortin antagonists agouti and agouti-related protein (AGRP). Melanocortin receptors (MCRs) have different selectivities for endogenous agonist peptides and antagonist peptides, are expressed in diverse tissues, and there they carry out various individual physiological functions. (Gantz, I. and T.M. Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003).

[0016] It is possible to selectively modulate any one, or a combination thereof, of the MCRs. In some embodiments, selectively modulating any one, or a combination thereof, of the MCRs relative to other MCRs is useful in various clinical applications. In some embodiments, selectively modulating any one, or a combination thereof, of the MCRs relative to other MCRs reduces undesirable side effects in various clinical applications. In one aspect, the compounds described herein are antagonists of MC2R. In some embodiments, the compounds described herein are MC2R analogs or are antagonists selective for other MCRs.

[0017] MC2R is a highly selective receptor for ACTH. Although ACTH can activate all five MCRs, at physiological levels, the sensitivity of the other receptors is not high enough to be activated, and ACTH selectively activates MC2R. Importantly, the other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, have no affinity for MC2R (Gantz, I. and T. M. Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003). The main function of MC2R is to stimulate the fasciculata cells of the adrenal cortex to synthesize and secrete cortisol. MC2R requires the GPCR accessory protein MRAP (melanocortin 2 receptor accessory protein) to be successfully secreted and function on the cell surface. MRAP is a small protein with one transmembrane domain, forms a stable complex with MC2R, and is required for both the cell surface expression of MC2R and its ability to bind ACTH. MRAP can bind to any MCR and affect its activity, but is essential only for the activity of MC2R. When ACTH binds to the MC2R / MRAP complex of adrenal cortical cells, GS is activated, intracellular cAMP levels increase, and ultimately, cortisol synthesis and secretion are promoted by regulating multiple steps in the steroid production pathway.

[0018] Cushing's syndrome is a rare disease characterized by chronic excessive exposure to glucocorticoids. Clinical symptoms of Cushing's syndrome include growth of fat pads (clavicle, back of the neck, face, and trunk), excessive sweating, capillary dilation, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and various other metabolic abnormalities that lead to a high incidence of morbidity. Cushing's syndrome is associated with high mortality when severe and inadequately controlled. Glucocorticoid excess may sometimes be ACTH-independent, for example, from hyperfunctioning adrenal adenomas, carcinomas, or excessive autonomous secretion of cortisol due to steroid abuse, but approximately 60 - 80% of all cases are ACTH-dependent Cushing's syndrome, known as Cushing's disease. Cushing's disease is caused by a microadenoma of pituitary adrenocorticotropic hormone-producing cells that secrete excessive amounts of ACTH. Corticotroph adenomas are small, usually slow-growing benign tumors that typically become clinically noticeable as a result of the effects of glucocorticoid excess rather than the physical effects of tumor expansion. The first-line treatment for Cushing's disease is surgery, including removal of the ACTH-secreting tumor in the pituitary or the adrenal gland itself. Medical treatment is required for these patients because surgery is often unsuccessful, contraindicated, or delayed. Current treatment options include inhibitors of steroidogenic enzymes that can prevent cortisol production and improve symptoms, but these treatments also induce many undesirable side effects due to the accumulation of other steroid products. In one aspect, MC2R antagonists are used in the treatment of Cushing's syndrome. In some embodiments, MC2R antagonists are used in the treatment of Cushing's disease. In some embodiments, glucocorticoid excess is ACTH-independent. In some embodiments, glucocorticoid excess is ACTH-dependent.

[0019] Ectopic ACTH syndrome or ectopic Cushing's syndrome or disease is essentially the same as Cushing's disease, except that the underlying tumor expressing ACTH is outside the pituitary gland. In some embodiments, the tumor is a small carcinoid tumor that can occur anywhere in the lung or gastrointestinal tract. In some embodiments, an MC2R antagonist is used in the treatment of ectopic ACTH syndrome.

[0020] Congenital adrenal hyperplasia (CAH) is characterized by a decrease or loss of cortisol synthesis and by excessive ACTH and corticotropin-releasing hormone. CAH can be caused by various genetic defects in the adrenal steroid biosynthesis pathway. In some embodiments, CAH is caused by a mutation in 21β-hydroxylase. The lack of cortisol removes negative feedback to the pituitary gland, leading to excessive secretion of ACTH. As a result, the adrenal glands are overstimulated, causing overproduction of steroid precursors, which also have adverse effects (such as hyperandrogenemia). Administration of replacement glucocorticoids typically cannot sufficiently suppress ACTH without also causing Cushing-like symptoms. In some embodiments, an MC2R antagonist is used in the treatment of CAH.

[0021] In addition to Cushing's disease and CAH, there is also a hypothesis that an MC2R antagonist may have a role in the treatment of depression and septic shock. In some embodiments, an MC2R antagonist is used in the treatment of depression. In some embodiments, an MC2R antagonist is used in the treatment of septic shock.

[0022] In some embodiments, the compounds described herein are capable of being administered to mammals in need of treatment using an MC2R antagonist.

[0023] Compound The compounds of formula (A) or formula (I) including the pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof are melanocortin receptor modulators. In some embodiments, the compounds of formula (A) or formula (I) including the pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof are MC2R modulators. In some embodiments, the MC2R modulator is an MC2R antagonist.

[0024] In one aspect, a compound of formula (A), or a pharmaceutically acceptable salt or solvate thereof, is provided herein,

[0025]

Chemical formula

[0026] In some embodiments, at least one of L and M is -O-.

[0027] In some embodiments, X is CR 3 . In some embodiments, X is CR 3 , and R 3 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, or -OR 8 . In some embodiments, X is CR 3 , and R 3 is hydrogen, halogen, or unsubstituted or substituted C1-C6 alkyl. In some embodiments, X is CR 3 , and R 3 is hydrogen or halogen. In some embodiments, X is CR 3 , and R 3 is hydrogen or fluorine. In some embodiments, X is CH or CF. In some embodiments, X is CH. In some embodiments, X is CF.

[0028] In some embodiments, X is N.

[0029] In some embodiments, R 1is -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is -H, -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, R 1 is -H.

[0030] In some embodiments, R 1 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl, where, when R 1 is substituted, R 1 is substituted with hydrogen, -OR 6 , halogen, -N(R 5 )2, or -CN.

[0031] In some embodiments, R A is -CF3, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, where, when R A is substituted, R A is substituted with R a , R b , and R c .

[0032] In some embodiments, R Ais -CF3, unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein, R A when substituted, R A is R a R b and R c substituted.

[0033] In some embodiments, R A is -CF3, unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein, R A when substituted, R A is R a R b and R c substituted.

[0034] In some embodiments, R A is -CF3, unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, wherein, R A when substituted, R A is R a R b and R c substituted.

[0035] In some embodiments, R A is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl, wherein, R AWhen it is replaced, R A is R a , R b , and R c is replaced by

[0036] In some embodiments, R A is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl, wherein when R A is substituted, R A is R a , R b , and R c substituted, X is N, and R 1 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl, wherein when R 1 is substituted, R 1 is hydrogen, -OR 6 , halogen, -N(R 5 )2, or -CN substituted.

[0037] In some embodiments, the compound has the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0038]

Chemical formula

[0039] In some embodiments, L is -O-, -C(=O)-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 (-), or a 5-membered heterocyclic ring. In some embodiments, L is -O-, -C(=O)-, -C(=O)NR 4 (-), -S-, -SO2-, -S(=O)2NR 4 (-), a 5-membered heteroaryl, or a bond. In some embodiments, L is -O-, -C(=O)-, -C(=O)NR 4 (-), -S-, -SO2-, -S(=O)2NR 4 (-), or a 5-membered heteroaryl.

[0040] In some embodiments, L is -O-, -C(=O)-, -S-, -SO2-, a 5-membered heteroaryl, or a bond. In some embodiments, L is -O-, -C(=O)-, a 5-membered heteroaryl, or a bond. In some embodiments, L is -O- or a 5-membered heteroaryl. In some embodiments, L is -O-, -C(=O)-, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, or a bond. In some embodiments, L is -O-, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, L is -O-, -C(=O)-, imidazolyl, oxadiazolyl, or a bond. In some embodiments, L is -O-, imidazolyl, or oxadiazolyl.

[0041] In some embodiments, L is -O-, -S-, or -SO2-. In some embodiments, L is -S- or -SO2-. In some embodiments, L is -S-. In some embodiments, L is -SO2-. In some embodiments, L is -O-.

[0042] In some embodiments, L is -C(=O)-.

[0043] In some embodiments, L is -C(=O)NR 4 - or -S(=O)2NR 4 -. In some embodiments, L is -C(=O)NR 4 -. In some embodiments, L is -S(=O)2NR 4 -.

[0044] In some embodiments, L is a 5-membered heterocyclic ring. In some embodiments, L is a 5-membered heteroaryl. In some embodiments, A is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, L is imidazolyl or oxadiazolyl.

[0045] In some embodiments, L is a bond.

[0046] In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is not -C(=O)-, SO2, -C(=O)NR 4 -. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -O-, -S-, -S(=O)2NR 4 -. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -O-, -S-, -S(=O)2NR 4 -. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -O- or -S-. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -O-. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -S-. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is -S(=O)2NR 4 -. In some embodiments, when M is -C(=O)NR 4 - and Z and Y are each N, L is a 5-membered heterocyclic ring. In some embodiments, when M is -C(=O)NR 4- and when Z and Y are each N, L is a 5-membered heteroaryl.

[0047] In some embodiments, M is -O-, -C(=O)-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 -, or a 5-membered heterocycle. In some embodiments, M is -O-, -C(=O)-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond. In some embodiments, M is -O-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 -, or a 5-membered heteroaryl.

[0048] In some embodiments, M is -O-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond. In some embodiments, M is -O-, -C(=O)NR 4 -, -S-, -SO2, -S(=O)2NR 4 -, or a 5-membered heteroaryl. In some embodiments, M is -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond. In some embodiments, M is -S-, -SO2-, -S(=O)2NR 4 -, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, or a bond. In some embodiments, M is -S-, -SO2-, -S(=O)2NR 4 -, oxazolyl, imidazolyl, triazolyl, or a bond.

[0049] In some embodiments, M is -O-, -S-, or -SO2-. In some embodiments, M is -S- or -SO2-. In some embodiments, M is -S-. In some embodiments, M is -SO2-. In some embodiments, M is -O-.

[0050] In some embodiments, M is -C(=O)-.

[0051] In some embodiments, M is -C(=O)NR 4 - or -S(=O)2NR 4 -. In some embodiments, M is -C(=O)NR 4 -. In some embodiments, M is -S(=O)2NR 4 -.

[0052] In some embodiments, M is a 5-membered heterocyclic ring. In some embodiments, M is a 5-membered heteroaryl. In some embodiments, M is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, M is oxazolyl, imidazolyl, or triazolyl.

[0053] In some embodiments, M is a bond.

[0054] In some embodiments, at least one of L and M is -O-. In some embodiments, L is -O-. In some embodiments, M is -O-.

[0055] In some embodiments, L is -O-, -C(=O)-, -S-, -SO2-, a 5-membered heteroaryl, or a bond, and M is -O-, -C(=O)NR 4 -, -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond.

[0056] In some embodiments, L is -O-, -C(=O)-, a 5-membered heteroaryl, or a bond, and M is -O-. In some embodiments, L is -O-, -C(=O)-, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, or a bond, and M is -O-. In some embodiments, L is -O-, -C(=O)-, imidazolyl, oxadiazolyl, or a bond, and M is -O-.

[0057] In some embodiments, L is -C(=O)- and M is -O-. In some embodiments, L is -C(=O)-, M is -O-, Y is N, and Z is N.

[0058] In some embodiments, L is -O- or a 5-membered heteroaryl and M is -O-. In some embodiments, L is -O-, imidazolyl, or oxadiazolyl and M is -O-. In some embodiments, L is -O- or a 5-membered heteroaryl, M is -O-, Y is CR 3 and Z is N. In some embodiments, L is -O-, imidazolyl, or oxadiazolyl, M is -O-, Y is CR 3 and Z is N.

[0059] In some embodiments, L is a bond and M is -O-. In some embodiments, L is a bond, M is -O-, Y is N, and Z is CR 3 is.

[0060] In some embodiments, L is -O- and M is -C(=O)NR 4 -. In some embodiments, L is -O-, M is -C(=O)NR 4 -, Y is CR 3 and Z is N.

[0061] In some embodiments, L is -C(=O)-, and M is -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond. In some embodiments, L is -C(=O)-, and M is -S-, -SO2-, -S(=O)2NR 4 -, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, or a bond. In some embodiments, L is -C(=O)-, and M is -S-, -SO2-, -S(=O)2NR 4 -, oxazolyl, imidazolyl, triazolyl, or a bond. In some embodiments, L is -C(=O)-, M is -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond, Y is N, and Z is N. In some embodiments, L is -C(=O)-, M is -S-, -SO2-, -S(=O)2NR 4 -, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, or a bond, Y is N, and Z is N. In some embodiments, L is -C(=O)-, M is -S-, -SO2-, -S(=O)2NR 4 -, oxazolyl, imidazolyl, triazolyl, or a bond, Y is N, and Z is N.

[0062] In some embodiments, L is -S- or -SO2-, and M is -C(=O)NR 4 -. In some embodiments, L is -S- or -SO2-, M is -C(=O)NR 4 -, Y is CR 3 and Z is N.

[0063] In some embodiments, Y is N. In some embodiments, Y is CR 3 is. In some embodiments, when Y is N, L is -C(=O)-, -C(=O)NR 4 -, -SO2-, -S(=O)2NR 4 -, a 5-membered heterocyclic ring, or a bond. In some embodiments, when Y is N, L is -C(=O)-, -SO2-, a 5-membered heterocyclic ring, or a bond. In some embodiments, when Y is N, L is -C(=O)- or a bond. In some embodiments, when Y is N, L is -C(=O)-. In some embodiments, when Y is N, L is a bond.

[0064] In some embodiments, Z is N. In some embodiments, Z is CR 3 is.

[0065] In some embodiments, Y is N and Z is N. In some embodiments, Y is CR 3 is and Z is N. In some embodiments, Y is N and Z is CR 3 is. In some embodiments, Y is CR 3 is and Z is CR 3 is.

[0066] In some embodiments, R 3 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, or -OR 8 is. In some embodiments, R 3 are each independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, or -OR 8 is. In some embodiments, R 3 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C1-C6 fluoroalkyl. In some embodiments, R 3Each is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C1-C6 fluoroalkyl. In some embodiments, R 3 Each is independently hydrogen, halogen, or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 Each is independently hydrogen, or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 Each is independently hydrogen or halogen. In some embodiments, R 3 Each is independently hydrogen or fluorine. In some embodiments, R 3 Each is hydrogen.

[0067] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, where when R A is substituted, R A is substituted by R a R b and R c .

[0068] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, where when R A is substituted, R A is substituted by R a R band R c is replaced by

[0069] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, where, when R A is substituted, R A is substituted by R a R b and R c is replaced by

[0070] In some embodiments, R A is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where, when R A is substituted, R A is substituted by R a R b and R c is replaced by

[0071] In some embodiments, R A is

[0072]

Chemical formula

[0073] In some embodiments, R A is

[0074]

Chemical formula

[0075]

Chemical formula

[0076] [Chemistry] is as follows.

[0077] In some embodiments, R A is

[0078] [Chemistry] is as follows, and V is CH or N.

[0079] In some embodiments, R A is

[0080] [Chemistry] is as follows, and V is CH or N. In some embodiments, R A is

[0081] [Chemistry] is as follows. In some embodiments, R A is

[0082] [Chemistry] is as follows.

[0083] In some embodiments, the compound has the structure of formula (A2), or a pharmaceutically acceptable salt or solvate thereof,

[0084] [Chemistry] V is CH or N, and X is CR 3 or N.

[0085] In some embodiments, the compound has the structure of formula (A2a), or a pharmaceutically acceptable salt or solvate thereof,

[0086] [Chemistry] V is CH or N.

[0087] In some embodiments, the compound has the structure of formula (A2b), or a pharmaceutically acceptable salt or solvate thereof.

[0088] [Chemistry] V is CH or N.

[0089] In some embodiments, the compound has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0090] [Chemistry] V is CH or N.

[0091] In some embodiments, the compound has the structure of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

[0092] [Chemistry] V is CH or N.

[0093] In some embodiments, the compound has the structure of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0094] [Chemistry] V is CH or N.

[0095] In some embodiments, the compound has the structure of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof.

[0096] [Chemistry] V is CH or N.

[0097] In some embodiments, the compound has the structure of formula (IId), or a pharmaceutically acceptable salt or solvate thereof,

[0098] [Chemistry] V is CH or N, and L is -O- or a 5-membered heteroaryl.

[0099] In some embodiments, the compound has the structure of formula (IIe), or a pharmaceutically acceptable salt or solvate thereof,

[0100] [Chemistry] V is CH or N, and M is -S-, -SO2-, -S(=O)2NR 4 -, a 5-membered heteroaryl, or a bond.

[0101] In some embodiments, the compound has the structure of formula (IIf), or a pharmaceutically acceptable salt or solvate thereof,

[0102] [Chemistry] V is CH or N, and L is -S- or -SO2-.

[0103] In some embodiments, R B is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted polycyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bicyclic heterocycle, an unsubstituted or substituted polycyclic heterocycle, where when R B is substituted, RB is R d , R e , and R f is substituted.

[0104] In some embodiments, R B is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bridged carbocycle, an unsubstituted or substituted spirocarbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bridged heterocycle, or an unsubstituted or substituted spiroheterocycle, where when R B is substituted, R B is substituted by R d , R e , and R f .

[0105] In some embodiments, R B is an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted bicyclic heteroaryl, a monocyclic C3-C8 cycloalkyl, an unsubstituted or substituted bridged C5-C 10 cycloalkyl, an unsubstituted or substituted spiro C5-C 10 cycloalkyl, an unsubstituted or substituted monocyclic C2-C8 heterocycloalkyl, an unsubstituted or substituted bridged C5-C 10 heterocycloalkyl, or an unsubstituted or substituted spiro C5-C 10 heterocycloalkyl, where when R B is substituted, R B is substituted by R d , R e , and R f .

[0106] In some embodiments, R Bis an unsubstituted or substituted carbocyclic ring which is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted indanyl, unsubstituted or substituted indenyl, unsubstituted or substituted tetrahydronaphthyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cycloheptyl, unsubstituted or substituted cyclooctyl, unsubstituted or substituted spiro[2.2]pentyl, unsubstituted or substituted spiro[3.3]heptyl, unsubstituted or substituted spiro[3.5]nonyl, unsubstituted or substituted spiro[4.4]nonyl, unsubstituted or substituted spiro[4.5]decyl, unsubstituted or substituted norbornyl, unsubstituted or substituted norbornenyl, unsubstituted or substituted bicyclo[1.1.1]pentyl, unsubstituted or substituted adamantyl, or unsubstituted or substituted decalinyl.

[0107] In some embodiments, R Bis unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl. In some embodiments, R B is unsubstituted or substituted indolyl, wherein when R B is substituted, R B is substituted with R d , R e , and R f .

[0108] In some embodiments, R B is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted homopiperidinyl, unsubstituted or substituted oxepanyl, unsubstituted or substituted thiepanyl, unsubstituted or substituted oxazepinyl, unsubstituted or substituted diazepinyl, unsubstituted or substituted thiazepinyl, unsubstituted or substituted azaspiro[3.3]heptanyl, unsubstituted or substituted azaspiro[3.4]octanyl, unsubstituted or substituted azaspiro[3.4]octanyl, or unsubstituted or substituted azaspiro[4.4]nonyl.

[0109] In some embodiments, R B is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, where when R B is substituted, R B is substituted with R d R e and R f .

[0110] In some embodiments, R B is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, or unsubstituted or substituted cyclohexyl, where when R B is substituted, R B is substituted with R d R e and R f . In some embodiments, R Bis unsubstituted or substituted cyclobutyl, where R B when substituted, R B is R d R e and R f substituted by.

[0111] In some embodiments, R B is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl, where R B when substituted, R B is R d R e and R f substituted by. In some embodiments, R B is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl, where R B when substituted, R B is R d R e and R f substituted by. In some embodiments, R B is unsubstituted or substituted pyrrolidinyl, where R B when substituted, R B is R d R e and R f substituted by.

[0112] In some embodiments, R B is

[0113] [Chemical formula] wherein m is 0, 1, 2, or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0114] In some embodiments, R B is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, wherein when R B is substituted, R B is substituted with R d , R e , and R f .

[0115] In some embodiments, R B is

[0116] [Chemical formula] . In some embodiments, R B is

[0117] [Chemical formula] . In some embodiments, R B is

[0118] [Chemical formula] . In some embodiments, R B is

[0119] [Chemical formula] .

[0120] In some embodiments, R B is

[0121] [Chemical formula] wherein W is CH or N. In some embodiments, R B is

[0122] [Chemical formula] wherein W is CH or N.

[0123] In some embodiments, the compound has the structure of formula (A3), or a pharmaceutically acceptable salt or solvate thereof,

[0124] [Chemical formula] wherein V is CH or N, and W is CH or N.

[0125] In some embodiments, the compound has the structure of formula (A3a), or a pharmaceutically acceptable salt or solvate thereof,

[0126] [Chemical formula] wherein V is CH or N, and W is CH or N.

[0127] In some embodiments, the compound has the structure of formula (A3b), or a pharmaceutically acceptable salt or solvate thereof,

[0128] [Chemical formula] wherein V is CH or N, and W is CH or N.

[0129] In some embodiments, the compound has the structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0130]

Chem.

[0131] In some embodiments, the compound has the structure of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof,

[0132]

Chem.

[0133] In some embodiments, the compound has the structure of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof,

[0134]

Chem.

[0135] In some embodiments, the compound has the structure of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof,

[0136]

Chem.

[0137] In some embodiments, the compound has the structure of formula (IIId), or a pharmaceutically acceptable salt or solvate thereof,

[0138]

Chem.

[0139] In some embodiments, the compound has the structure of formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof,

[0140]

Chem.

[0141] In some embodiments, the compound has the structure of formula (IIIf), or a pharmaceutically acceptable salt or solvate thereof,

[0142]

Chem.

[0143] In some embodiments, the compound has the structure of formula (A4), or a pharmaceutically acceptable salt or solvate thereof,

[0144]

Chem.

[0145] In some embodiments, the compound has the structure of formula (A4a), or a pharmaceutically acceptable salt or solvate thereof,

[0146]

Chem.

[0147] In some embodiments, the compound has the structure of formula (A4b), or a pharmaceutically acceptable salt or solvate thereof,

[0148]

Chemical formula

[0149] In some embodiments, the compound has the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof,

[0150]

Chemical formula

[0151] In some embodiments, the compound has the structure of formula (IVa), or a pharmaceutically acceptable salt or solvate thereof,

[0152]

Chemical formula

[0153] In some embodiments, the compound has the structure of formula (IVb), or a pharmaceutically acceptable salt or solvate thereof,

[0154]

Chemical formula

[0155] In some embodiments, the compound has the structure of formula (IVc), or a pharmaceutically acceptable salt or solvate thereof,

[0156]

Chemical formula

[0157] In some embodiments, the compound has the structure of formula (IVd), or a pharmaceutically acceptable salt or solvate thereof,

[0158]

Chemical formula

[0159] In some embodiments, the compound has the structure of formula (IVe), or a pharmaceutically acceptable salt or solvate thereof,

[0160]

Chemical formula

[0161] In some embodiments, the compound has the structure of formula (IVf), or a pharmaceutically acceptable salt or solvate thereof,

[0162]

Chemical formula

[0163] In some embodiments, the compound has the structure of formula (A5), or a pharmaceutically acceptable salt or solvate thereof,

[0164]

Chemical formula

[0165] In some embodiments, the compound has the structure of formula (A5a), or a pharmaceutically acceptable salt or solvate thereof,

[0166]

Chemical formula

[0167] In some embodiments, the compound has the structure of formula (A5b), or a pharmaceutically acceptable salt or solvate thereof,

[0168]

Chemical formula

[0169] In some embodiments, the compound has the structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof,

[0170]

Chemical formula

[0171] In some embodiments, the compound has the structure of formula (Va), or a pharmaceutically acceptable salt or solvate thereof,

[0172]

Chemical formula

[0173] In some embodiments, the compound has the structure of formula (Vb), or a pharmaceutically acceptable salt or solvate thereof,

[0174]

Chemical formula

[0175] In some embodiments, the compound has the structure of formula (Vc), or a pharmaceutically acceptable salt or solvate thereof,

[0176]

Chemical formula

[0177] In some embodiments, the compound has the structure of formula (Vd), or a pharmaceutically acceptable salt or solvate thereof,

[0178]

Chemical formula

[0179] In some embodiments, the compound has the structure of formula (Ve), or a pharmaceutically acceptable salt or solvate thereof,

[0180]

Chemical formula

[0181] In some embodiments, the compound has the structure of formula (Vf), or a pharmaceutically acceptable salt or solvate thereof,

[0182]

Chemical formula

[0183] In some embodiments, R 1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is -CH3, -CH2CH3, or -CH2CH2CH3.

[0184] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3.

[0185] In some embodiments, R 2 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bridged carbocyclic, unsubstituted or substituted spirocyclic carbocyclic, unsubstituted or substituted monocyclic heterocyclic, unsubstituted or substituted bridged heterocyclic, unsubstituted or substituted spirocyclic heterocyclic, unsubstituted or substituted -(C1-C6 alkyl)-carbocyclic, or unsubstituted or substituted -(C1-C6 alkyl)-heterocyclic, where any substituted group of R 2 is one or more halogens, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocyclic, -N(R 5 )2, -OR 6 , -CN, -CO2R 6 , -C(=O)N(R 5 )2, -SR 6 , -S(=O)R 8, -S(=O)2R 8 , -NR 5 C(=O)R 6 , -NR 5 SO2R 8 , -SO2R 8 , or -SO2N(R 5 )2 is substituted.

[0186] In some embodiments, R 2 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, or unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, wherein any substituted group of R 2 is one or more halogens, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 5 )2, -OR 6 , -CN, -CO2R 6 , -C(=O)N(R 5 )2, -SR 6 , -S(=O)R 8 , -S(=O)2R 8 , -NR 5 C(=O)R 6 , -NR 5 SO2R 8 , -SO2R 8 , or -SO2N(R 5 )2 is substituted.

[0187] In some embodiments, R 2 contains a basic amine group.

[0188] In some embodiments, R 2 is substituted C1-C6 alkyl, unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, unsubstituted or substituted bridged heterocycle, or unsubstituted or substituted -(C1-C6 alkyl)-heterocycle, wherein R 2Any substituted group is one or more halogens, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 5 )2, -OR 6 , -CN, -CO2R 6 , -C(=O)N(R 5 )2, -SR 6 , -S(=O)R 8 , -S(=O)2R 8 , -NR 5 C(=O)R 6 , -NR 5 SO2R 8 , -SO2R 8 , or -SO2N(R 5 )2, where R 2 contains a basic amine group.

[0189] In some embodiments, R 2 is C1-C6 alkyl substituted with one -N(R 5 )2 group, further substituted with zero or more halogens, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 5 )2, -OR 6 , -CN, -CO2R 6 , -C(=O)N(R 5 )2, -SR 6 , -S(=O)R 8 , -S(=O)2R 8 , -NR 5 C(=O)R 6 , -NR 5 SO2R 8 , -SO2R 8 , or -SO2N(R 5 )2, or R 2 is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 2 is an unsubstituted or substituted bridged heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 2is -(C1-C6 alkyl)-heterocyclic ring, where the heterocyclic ring is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom.

[0190] In some embodiments, R 2 is C1-C6 alkyl substituted by -N(R 5 )2 group, or R 2 is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom, or R 2 is -(C1-C6 alkyl)-heterocyclic ring, where the heterocyclic ring is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom.

[0191] In some embodiments, R 2 is unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 2 is substituted C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl substituted by one -N(R 5 )2 group, and further substituted by 0 or more halogens, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocyclic ring, -N(R 5 )2, -OR 6 , -CN, -CO2R 6 , -C(=O)N(R 5 )2, -SR 6 , -S(=O)R 8 , -S(=O)2R 8 , -NR 5 C(=O)R 6 , -NR 5 SO2R 8 , -SO2R 8 , or -SO2N(R 5 )2. In some embodiments, R 2 is C1-C6 alkyl substituted by -N(R 5 )2 group.

[0192] In some embodiments, R 2 is an unsubstituted or substituted monocyclic heterocyclic ring, an unsubstituted or substituted bridged heterocyclic ring, or an unsubstituted or substituted spiro heterocyclic ring. In some embodiments, R 2 is an unsubstituted or substituted monocyclic heterocyclic ring. In some embodiments, R 2 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocyclic ring containing 1 - 4 N atoms and 0 or 1 O or S atom. In some embodiments, R 2 is an unsubstituted or substituted bridged heterocyclic ring. In some embodiments, R 2 is an unsubstituted or substituted bridged heterocyclic ring containing 1 - 4 N atoms and 0 or 1 O or S atom. In some embodiments, R 2 is an unsubstituted or substituted spiro heterocyclic ring.

[0193] In some embodiments, R 2 is an unsubstituted or substituted -(C1-C6 alkyl)-heterocyclic ring. In some embodiments, R 2 is a -(C1-C6 alkyl)-heterocyclic ring, wherein the heterocyclic ring is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocyclic ring containing 1 - 4 N atoms and 0 or 1 O or S atom.

[0194] In some embodiments, R 2 is hydrogen.

[0195] In some embodiments, the compound has the structure of formula (A6), or a pharmaceutically acceptable salt or solvate thereof,

[0196]

Chemical formula

[0197] In some embodiments, the compound has the structure of formula (A6a), or a pharmaceutically acceptable salt or solvate thereof,

[0198]

Chemical formula

[0199] In some embodiments, the compound has the structure of formula (A6b), or a pharmaceutically acceptable salt or solvate thereof,

[0200]

Chemical formula

[0201] In some embodiments, the compound has the structure of formula (VI), or a pharmaceutically acceptable salt or solvate thereof,

[0202]

Chemical formula

[0203] In some embodiments, the compound has the structure of formula (VIa), or a pharmaceutically acceptable salt or solvate thereof,

[0204]

Chemical formula

[0205] In some embodiments, the compound has the structure of formula (VIb), or a pharmaceutically acceptable salt or solvate thereof,

[0206]

Chemical formula

[0207] In some embodiments, the compound has the structure of formula (VIc), or a pharmaceutically acceptable salt or solvate thereof,

[0208]

Chemical formula

[0209] In some embodiments, the compound has the structure of formula (VId), or a pharmaceutically acceptable salt or solvate thereof,

[0210]

Chemical formula

[0211] In some embodiments, the compound has the structure of formula (VIe), or a pharmaceutically acceptable salt or solvate thereof,

[0212]

Chemical formula

[0213] In some embodiments, the compound has the structure of formula (VIf), or a pharmaceutically acceptable salt or solvate thereof,

[0214]

Chemical formula

[0215] In some embodiments, the compound has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof,

[0216]

Chemical formula

[0217] In some embodiments, the compound has the structure of formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof,

[0218]

Chemical formula

[0219] In some embodiments, the compound has the structure of formula (VIIb), or a pharmaceutically acceptable salt or solvate thereof,

[0220]

Chemical formula

[0221] In some embodiments, R A is

[0222]

Chemical formula

[0223] In some embodiments, R A is

[0224]

Chemical formula

[0225]

Chemical formula

[0226] In some embodiments, R a is hydrogen, halogen, -OR 6 , -CN, -N(R 5 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, and any substituted group of R a is substituted with one or more R 7 groups, and R b and R c are independently selected from the group consisting of hydrogen, halogen, -OR 6 , -CN, -N(R 5 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, and any substituted group of R b and R c is substituted with one or more R 7 groups.

[0227] In some embodiments, R ais selected from the group consisting of hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and R b and R c are independently selected from the group consisting of hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2.

[0228] In some embodiments, R d is selected from the group consisting of hydrogen, halogen, -OR 6 , -CN, -N(R 5 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted monocyclic heteroaryl, and any substituted group of R d is one or more R 7substituted with a base, and R e and R f are each independently selected from the group consisting of hydrogen, halogen, -OR 6 , -CN, -N(R 5 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl.

[0229] In some embodiments, R d is hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted monocyclic heteroaryl, and any substituted group of R d is substituted with one or more R 7 groups, and R e and R f are each independently selected from the group consisting of F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3.

[0230] In some embodiments, the compounds described herein have the following structure.

[0231] [Chemistry]

[0232] In some embodiments, R a , R b , and R 2 are as described herein.

[0233] In some embodiments, R a , R b , and R 2 are as described in Table 1.

[0234] In some embodiments, the compounds described herein have the following structure.

[0235] [Chemistry]

[0236] In some embodiments, R a , R b , R 1 , and R 2 are as described herein.

[0237] In some embodiments, R a , R b , R 1 , and R 2 are as described in Table 2.

[0238] In some embodiments, the compounds described herein have the following structure.

[0239] [Chemistry]

[0240] In some embodiments, R a , R b , R1 and R 2 Z, Y, and L are as described herein.

[0241] In some embodiments, R a and R b and R 1 and R 2 Z, Y, and L are as described in Table 3.

[0242] In some embodiments, the compounds described herein have the following structure.

[0243] [Chemical formula]

[0244] In some embodiments, R a and R b and R 2 X, and M are as described herein.

[0245] In some embodiments, R a and R b and R 2 X, and M are as described in Table 4.

[0246] In some embodiments, the compounds described herein have the following structure.

[0247] [Chemical formula]

[0248] In some embodiments, R a and R b and R 2 and L are as described herein.

[0249] In some embodiments, R a and R b and R 2 and L are as described in Table 5.

[0250] Any combination of the above bases for the various variables is contemplated herein. Throughout the specification, the bases and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0251] Typical compounds of formula (A) or formula (I) include the compounds described in the following table:

[0252] [Table 1-1]

[0253] [Table 1-2]

[0254] [Table 1-3]

[0255] The compounds in Table 1 are named as follows: 1-2: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1-3: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1-4: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1-5: 2'-Ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-6: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-7: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-8: 2'-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-9: [2-({2'-Ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-10: [2-({5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-11: [2-({2'-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-12: 2-({2'-Ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethane-1-amine, 1-13: 2-({5-[(2R)-4-[2-(Difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}oxy)ethane-1-amine, 1-14: 2-({2’-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethane-1-amine, 1-15: [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-16: 2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}oxy)ethane-1-amine, 1-17: [2-({2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl]dimethylamine, 1-18: 2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-[(3S)-pyrrolidin-3-yloxy]-2,3’-bipyridine, 1-19: (2R)-1-({2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)propane-2-amine, 1-20: (2S)-1-({2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)propane-2-amine, 1-21: (2R)-2-({2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)propan-1-amine, 1-22: (2S)-2-({2’-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)propan-1-amine, 1-23: 1-[(3R)-4-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridin]-5-yl}-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-24: 1-[(3R)-4-[6-(2-aminoethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl]-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-25: 1-[(3R)-4-[6-(2-aminoethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl]-3-ethylpiperazine-1-carbonyl]-5-chloro-2,3-dihydro-1H-indole-7-carbonitrile, 1-26: 5-chloro-1-[(3R)-4-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridin]-5-yl}-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-27: [2-({2’-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-28: [2-({5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-29: [2-({5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, and, 1-30: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine.

[0256]

Table 2-1

[0257]

Table 2-2

[0258]

Table 2-3

[0259]

Table 2-4

[0260] The compounds in Table 2 are named as follows: 2-1: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenoxy]piperidin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide, 2-2: 5-{cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridin]-6-carboxamide, 2-3: 5-{trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-4: 5-{trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-5: 5-{cis-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-6: 5-{cis-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-7: 5-{cis-4-[4-Chloro-2-(difluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-8: 5-cis-(4-{[6-Chloro-2-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-9: 5-[(2R,4R)-4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-10: 5-[(2S,4S)-4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-11: 5-[(2R,4R)-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-12: 5-[(2S,4S)-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-13: 5-(cis-2-cyclopropyl-4-{[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]oxy}piperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-14: 5-(cis-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-15: 5-(cis-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-16: 5-[cis-4-(2-cyano-4-methylphenoxy)-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-17: 5-[cis-4-(2-cyano-4-methylphenoxy)-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide, 2-18: 5-[(2R,4R)-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide, 2-19: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-(cis-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl)-2’-ethoxy-[2,3’-bipyridine]-6-carboxamide, 2-20: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-{cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl}-2’-ethoxy-[2,3’-bipyridine]-6-carboxamide, 2-21: 5-[(2R,4R)-4-(4-chloro-2-cyanophenoxy)-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide, 2-22: 5-[(2R,4R)-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide, 2-23: 3-(cis-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-methylpiperidin-1-yl)-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide, 2-24: 3-[cis-4-(4-chloro-2-cyanophenoxy)-2-methylpiperidin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide, and, 2-25: 5-[cis-4-(2-cyano-4-fluorophenoxy)-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide.

[0261]

Table 3-1

[0262]

Table 3-2

[0263] The compounds in Table 3 are named as follows: 3-1: 2-(4-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridine]-5-yl}piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 3-2: 3-(4-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridine]-5-yl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carbonitrile, 3-3: 2-{[(2R)-1-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridine]-5-yl}-2-ethylpiperidin-4-yl]oxy}-5-(trifluoromethyl)benzonitrile, 3-4: [2-({2’-ethoxy-5-[(2R)-2-ethyl-4-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl]-[2,3’-bipyridine]-6-yl}oxy)ethyl](methyl)amine, 3-5: [2-({2’-Ethoxy-5-[(2R)-2-ethyl-4-{1-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}piperidin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-6: [2-({2’-Ethoxy-5-[(2R)-2-ethyl-4-{5-[1-(trifluoromethyl)cyclobutyl]-4H-1λ 3 ,2,4-oxadiazol-3-yl}piperidin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-7: [2-({2’-Ethoxy-5-[(2R)-2-ethyl-4-{3-[1-(trifluoromethyl)cyclobutyl]-4H-1λ 3 ,2,4-oxadiazol-5-yl}piperidin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-8: 2-{[rac-(2R,4R)-1-(2’-Ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-[2,3’-bipyridin]-5-yl)-2-ethylpiperidin-4-yl]oxy}-5-(trifluoromethyl)benzonitrile, and, 3-9: 5-[rac-(2R,4R)-4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2’-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3’-bipyridine.

[0264]

Table 4-1

[0265]

Table 4-2

[0266] The compounds in Table 4 are named as follows: 4-1: 1-(2-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}-1H-imidazol-4-yl)methanamine, 4-2: 1-(5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}-4H-1,2,4-triazol-3-yl)methanamine, 4-3: 5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}-4H-1,2,4-triazol-3-amine, 4-4: 5-{5-[(2R)-4-(4-fluoro-2-trifluoromethyl-benzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}-1H-1,2,4-triazol-3-amine, 4-5: 2-(5-{3-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridin-2-yl}-1H-1,2,4-triazol-1-yl)ethan-1-amine, 4-6: 2-(2-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}-1H-imidazol-1-yl)ethan-1-amine, 4-7: 2-(5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}-1,3-oxazol-4-yl)ethan-1-amine, 4-8: N-(2-aminoethyl)-3-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-sulfonamide, 4-9: N-(2-Aminoethyl)-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridine]-6-sulfonamide, 4-10: 2-[(2R)-4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]benzene-1-sulfonamide, 4-11: 5-[(2R)-4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-sulfonamide, 4-12: [2-({5-[(2R)-4-[4-Chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-yl}sulfanyl)ethyl]dimethylamine, and, 4-13: [2-({5-[(2R)-4-[4-Chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-yl}sulfonyl)ethyl]dimethylamine.

[0267]

Table 5

[0268] The compounds in Table 5 are named as follows: 5-1: rac-2'-ethoxy-5-[(2R,4S)-2-ethyl-4-{[2-(trifluoromethyl)phenyl]sulfanyl}piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 5-2: rac-2'-Ethoxy-5-[(2R,4S)-2-ethyl-4-[2-(trifluoromethyl)benzenesulfonyl]piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, and, 5-3: 2'-Ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzenesulfonyl]piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide.

[0269] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Similarly, active metabolites of such compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist not only in the unsolvated form but also in solvated forms including pharmaceutically acceptable solvents such as water and ethanol. Solvated forms of the compounds presented herein are likewise considered to be those disclosed herein.

[0270] "Pharmaceutically acceptable" as used herein refers to a material such as a carrier or diluent which does not inhibit the biological activity or properties of the compound and is relatively non-toxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0271] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of a therapeutically active agent combined with a suitable anion, or, in an alternative embodiment, the anionic form of a therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than the non-ionized species, dissolve readily in gastric and intestinal fluids, and are therefore useful in solid dosage forms. Furthermore, because their solubility is often correlated with pH, selective dissolution in any part of the gastrointestinal tract is possible, and this ability can be manipulated as an aspect of delayed release and sustained release behavior. Additionally, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be regulated.

[0272] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (A) or formula (I) with an acid. In some embodiments, a compound of formula (A) or formula (I) (i.e., in free base form) is basic and reacts with an organic or inorganic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Examples of organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0273] In some embodiments, a compound of formula (A) or formula (I) is prepared as a chloride, sulfate, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

[0274] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (A) or formula (I) with a base. In some embodiments, the compound of formula (A) or formula (I) is acidic and is reacted with a base. In such situations, the acidic proton of the compound of formula (A) or formula (I) is replaced with a metal ion, for example, an ion of lithium, sodium, potassium, magnesium, calcium, or aluminum. In some cases, the compounds described herein cooperate with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0275] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, a solvate contains a solvent in either a stoichiometric or non-stoichiometric amount and is formed during the crystallization process with a pharmaceutically acceptable solvent such as water and ethanol. A hydrate is formed when the solvent is water and an alcoholate is formed when the solvent is an alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in both solvated and non-solvated forms.

[0276] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of formula (A) or formula (I), as well as active metabolites of these compounds having the same type of activity.

[0277] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds of formula (A) or formula (I) are susceptible to various metabolic reactions. By incorporation of suitable substituents onto the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or removing the susceptibility of an aromatic ring to metabolic reactions are, by way of example, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0278] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0279] The compounds described herein include isotopically labeled compounds, which are identical to the compounds detailed in the various formulas and structures presented herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33Examples of isotopes include those of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, such as P. In one aspect, the isotope-labeled compounds described herein, for example, 3 H and 14 compounds incorporating radioisotopes such as C are useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as an extended half-life or a reduced required dose in vivo.

[0280] In some embodiments, the compounds of formula (A) or formula (I) have one or more stereocenters, each of which independently exists in either the R or S configuration. In some embodiments, the compounds of formula (A) or formula (I) exist in the R configuration. In some embodiments, the compounds of formula (A) or formula (I) exist in the S configuration. The compounds presented herein include all diastereomers, individual enantiomers, atropisomers, and epimeric forms, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof.

[0281] Individual stereoisomers can be obtained, if necessary, by stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, or separation of diastereomers by achiral or chiral chromatography columns, or methods such as crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, a compound of formula (A) or formula (I) is prepared as its individual stereoisomer by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric isomer compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is effected by chromatography, or by forming diastereomeric salts and separating them by recrystallization or chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, the stereoisomers are obtained by stereoselective synthesis.

[0282] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because they may be easier to administer than the parent drug in some situations. For example, a prodrug may be bioavailable by oral administration while the parent drug is not. Additionally or alternatively, a prodrug may have improved solubility in a pharmaceutical composition compared to the parent drug. In some embodiments, the design of the prodrug results in increased effective water solubility. An example of a prodrug is, but is not limited to, a compound described herein that is administered as an ester ("prodrug") and is then metabolically hydrolyzed to give the active entity. A further example of a prodrug is a short peptide (polyamino acid) attached to an acidic group, which is metabolized to expose the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is metabolized by an enzyme in one or more steps or processes to become the biologically, pharmaceutically, or therapeutically active form of the compound.

[0283] Examples of prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyl-oxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38 (each of these references is incorporated herein by reference). In some embodiments, the hydroxyl groups of the compounds disclosed herein are used to form prodrugs, where the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, the hydroxyl groups in the compounds disclosed herein are prodrugs and the hydroxyls are metabolized in vivo to yield carboxylic acid groups. In some embodiments, carboxyl groups are used to provide esters or amides (i.e., prodrugs), which are then metabolized in vivo to provide carboxylic acid groups. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0284] Prodrug forms of the compounds described herein, which are metabolized in vivo to produce the compounds of formula (A) or formula (I), are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of other derivatives or active compounds.

[0285] In some embodiments, any one of a hydroxyl group, an amino group, and / or a carboxylic acid group is functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0286] In additional or further embodiments, the compounds described herein are metabolized upon administration to a living being to produce metabolites, and thereafter, the desired effects, including the desired therapeutic effect, are brought about by using these metabolites.

[0287] The "metabolites" of the compounds disclosed herein are derivatives of the above compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the above compounds formed when the compounds are metabolized. The term "metabolized" as used herein refers to the entire process by which a particular substance is changed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can bring about specific structural changes to the compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. The metabolites of the compounds disclosed herein can optionally be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0288] Synthesis of Compounds The compounds of formula (A) or formula (I) are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0289] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used.

[0290] The compounds are prepared using standard organic chemistry techniques, such as those described in March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, such as changes in solvent, reaction temperature, reaction time, and various chemical reagents, as well as other reaction conditions, may be used.

[0291] In some embodiments, the compounds described herein are prepared as described in Scheme A.

[0292]

Chemical formula

[0293] Compound I is obtained by heating 3-fluoro-2-nitropyridine with a mono-protected substituted piperazine in the presence of an organic base such as N,N-diisopropylethylamine. The S of the nitro group with the alkoxide N The 2 reaction produces a pyridinyl ether, which is then converted to chloropyridine (II) by treatment with NCS. Compound II is A subjected to an organometallic coupling reaction such as the Suzuki-Miyaura reaction with R-B(OH)2 or its corresponding ester, and then standard deprotection is performed to produce compound III. Compound III is converted to the final product (IV) via HATU-activated amide coupling. In some cases, after amide formation, to obtain compound IV, R 2A further deprotection step from the base is required.

[0294] In some embodiments, the compounds described herein are prepared as described in Scheme B.

[0295]

Chemical formula

[0296] Compound III is converted to urea V by treatment with activated carbamoyl chloride using triphosgene and NHR 4 R 5 in the presence of DIEA. Optionally, a further deprotection step of R 2 may be required to obtain compound V after urea formation.

[0297] In some embodiments, the compounds described herein are prepared as described in Scheme C.

[0298]

Chemical formula

[0299] Heating 6-bromo-3-fluoropicolinonitrile with 2-R 1 -piperidin-4-ol (cis or trans racemate) in the presence of an organic base such as N,N-diisopropylethylamine produces compound VI, which is subjected to an organometallic coupling reaction such as the Suzuki-Miyaura reaction with R A -B(OH)2 or its corresponding ester to produce compound VII. Subsequently, hydrolysis of the cyano group to an acid and then standard HATU amide coupling with R 2 -NH2 produces compound VIII. Formation of an ether by coupling the alkoxide of VIII with an electrophilic aryl halide (R B -X) produces compound IX. R 2If it contains a protecting group, an additional deprotection step is carried out to generate IX.

[0300] In some embodiments, the compounds described herein are prepared as described in Scheme D.

[0301]

Chem.

[0302] The cis-racemate VII is subjected to chiral separation by chiral preparative HPLC to produce two optically pure cis-isomers X and XI. Their absolute stereochemistry has not yet been determined. Compound X is hydrolyzed with NaOH to produce an acid intermediate, which is converted to compound XII via HATU-mediated amide coupling. The conversion to XIII is achieved in a manner similar to that described by steps e and f of Scheme C. Another stereoisomer from XI is obtained by the same route. R 2 If it contains a protecting group, an additional deprotection step is carried out to generate XIII.

[0303] In some embodiments, the compounds described herein are prepared as described in Scheme E.

[0304]

Chem.

[0305] Compound XIV is prepared by a Suzuki-Miyaura coupling reaction with N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, which reacts with an alkoxide to produce XV. Thereafter, R A -B(OH)2 or R A -SnBu3 by a Stille coupling of R AThe introduction and subsequent reduction of the tetrahydropyridine produces compound XVI. The Boc group is removed by an acid, and the final compound XVII is formed via a standard S B 2 reaction with R N -X in the presence of an organic base such as DIEA. When R 2 contains a protecting group, an additional deprotection step is performed to produce XVII.

[0306] In some embodiments, the compounds described herein are prepared as described in Scheme F.

[0307] [Chemical formula]

[0308] The HATU-mediated coupling reaction of XVIII produces an amide intermediate, which is then subjected to mesylation of the hydroxyl group with MsCl in the presence of an organic base such as TEA to produce compound XIX. The mesylate undergoes a stereochemical inversion to compound XX via an S N 2 reaction with a nucleophile. When R 2 contains a protecting group, an additional deprotection step is performed to produce XX.

[0309] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0310] Specific terms Unless otherwise defined, the following terms used in this application are defined below. The use of the term "including", as well as other forms such as "include", "includes", and "included", is not limiting. The headings of the paragraphs used herein are for organization purposes only and should not be construed as limiting the subject matter described.

[0311] As used herein, C1-C xis C1-C2, C1-C3...C1-C x including. As an example only, a group designated as "C1-C6" indicates that there are 1 to 6 carbon atoms in that moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, as an example only, "C1-C4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0312] The term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight-chain. In some embodiments, the "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10 alkyl. A range of numbers such as "1 to 10" always refers to each integer within the specified range when it appears in this specification. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to a maximum of 10 carbon atoms, but this definition also encompasses the occurrences of the term "alkyl" where no range of numbers is specified. In some embodiments, the alkyl is C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0313] The "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is C1-C6 alkylene. In other embodiments, the alkylene is C1-C4 alkylene. Exemplary alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. In some embodiments, the alkylene is -CH2-.

[0314] The "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0315] The term "alkylamine" refers to -N(alkyl) x H y group, where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0316] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by hydroxyl. In some embodiments, the hydroxyalkyl is C1-C4 hydroxyalkyl. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, etc.

[0317] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is C1-C4 aminoalkyl. Exemplary aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, etc.

[0318] The term "alkenyl" refers to a type of alkyl group in which there is at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0319] The term "alkynyl" refers to a type of alkyl group in which there is at least one carbon-carbon triple bond. In one embodiment, the alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0320] The term "heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule by a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C1-C6 heteroalkyl.

[0321] The term "aromatic" refers to a planar ring having a delocalized π - electron system containing 4n + 2π electrons (where n is an integer). The term "aromatic" includes both carbocyclic aryl ( "aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heterocyclic aromatic") groups (e.g., pyridine). The term includes monocyclic or polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) condensed ring groups.

[0322] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which all of the atoms forming the ring skeleton are carbon atoms. Thus, the above term distinguishes between "carbocyclic" and "heterocyclic" or "heterocycle" in which the ring skeleton contains at least one atom different from carbon. In some embodiments, the carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, the carbocycle is a monocyclic carbocycle. The carbocycle is non - aromatic or aromatic. The non - aromatic carbocycle is saturated or partially unsaturated. In some embodiments, the carbocycle is a bicyclic carbocycle. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. The carbocycle includes aryl and cycloalkyl.

[0323] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6 - C 10 aryl. Depending on the structure, the aryl group is a monoradical or a diradical (i.e., an arylene group).

[0324] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic aliphatic non-aromatic radical, where each of the atoms forming the ring (i.e., the backbone atoms) is a carbon atom. In some embodiments, cycloalkyl is a spirocyclic compound or a bridged compound. In some embodiments, cycloalkyl is optionally condensed with an aromatic ring, and the point of attachment is at a carbon other than an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 cyclic atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, norbornenyl, bicyclo[1.1.1]pentyl, adamantyl, norbornyl, norbornenyl, decalinyl, or 7,7-dimethyl-bicyclo[2.2.1]heptanyl. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is monocyclic cycloalkyl. Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl includes, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc.

[0325] The term "halo", or alternatively "halogen" or "halide", means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0326] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, fluoroalkyl is C1-C6 fluoroalkyl.

[0327] The terms "heterocyclic ring" or "heterocyclic" refer to aromatic heterocyclic rings (also known as heteroaryl) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom of the ring is selected from O, S, and N, and where each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O atoms or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyl) include rings having 3 to 10 atoms in their ring systems, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring systems. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, and benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The aforementioned groups are, where possible, C-bonded (or C-linked) or N-bonded. For example, groups derived from pyrrole include pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-bonded) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-bonded). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0328] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic heteroaryl and bicyclic heteroaryl. Monocyclic heteroaryl includes pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryl includes indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, heteroaryl is C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is 5- or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is C6-C9 heteroaryl.

[0329] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl is C2-C 10 heterocycloalkyl. In another aspect, the heterocycloalkyl is C4-C 10 heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atom in the ring.

[0330] The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties when the atoms joined by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a single bond, there is no reference group, thereby allowing the formation of a single bond between the remaining specified groups.

[0331] The term "moiety" refers to a particular segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded or attached to a molecule.

[0332] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some other embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl.In some embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituent is substituted with one or two of the aforementioned groups. In some embodiments, the optional substituent on an aliphatic carbon atom (acyclic or cyclic) contains oxo (=O).

[0333] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that there is no persistent adverse effect on the health of the subject being treated.

[0334] As used herein, the term "modulate" means to interact directly or indirectly with a target so as to alter the activity of the target, and altering the activity of the target includes, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, restricting the activity of the target, or expanding the activity of the target.

[0335] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0336] As used herein, terms such as "administer," "administering," "administration," etc. refer to methods that can be used to effect delivery of a compound or composition to a desired site of a biological action. These methods include, but are not limited to, oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intracascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0337] As used herein, terms such as "co-administration" are meant to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0338] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an agent or compound administered to effect some degree of reduction of one or more of the symptoms of the disease or disorder being treated. The result includes a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to clinically significantly reduce a disease symptom. The appropriate "effective" amount in an individual case can be optionally determined using techniques such as dose escalation studies.

[0339] As used herein, the terms "enhance" or "enhancing" mean increasing or prolonging a desired effect either in efficacy or duration. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong the effect of another therapeutic agent on a system, either in efficacy or duration. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0340] As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or co - administration of more than one active ingredient and includes both fixed and non - fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously both in the form of a single entity or dosage. The term "non - fixed combination" means that the active ingredients, e.g., a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient as separate entities simultaneously, concurrently, or sequentially without a specific intervening time limit, where such administration provides effective levels of the two compounds in the patient's body. The latter term also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0341] The terms "product" and "kit" are used synonymously.

[0342] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys, livestock such as cows, horses, sheep, goats, pigs, laboratory animals including rodents such as rabbits, dogs, and cats, rats, mice and guinea pigs. In one aspect, the mammal is a human.

[0343] The terms "treating", "treatment", or "treat" as used herein include alleviating, reducing, or ameliorating at least one symptom of a disorder or disease, preventing additional symptoms, inhibiting a disorder or disease, e.g., suppressing the manifestation of a disorder or disease, reducing a disorder or disease, causing regression of a disorder or disease, alleviating a condition caused by a disorder or disease, or prophylactically and / or therapeutically arresting the symptoms of a disorder or disease.

[0344] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable inert ingredients that facilitate the processing of the active compound into a pharmaceutically used preparation. The appropriate formulation depends on the route of administration selected. Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and, Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0345] In some embodiments, the compounds described herein are administered alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be accomplished by methods that enable delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (including injection or infusion such as intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, dermal, enema, ophthalmic, otic, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the recipient's disease or disorder. By way of example only, the compounds described herein can be administered locally to the area in need of treatment, for example, by intraoperative local infusion, topical application such as in creams or ointments, injection, catheter, or implantation. Administration can also be by direct injection at the site of the diseased tissue or organ.

[0346] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion in an oil. In some embodiments, the active ingredient is presented as a bolus, a lozenge, or a paste.

[0347] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may optionally be made by compression or molding, together with one or more accessory ingredients. Compressed tablets may optionally be prepared by mixing with a binder, an inert diluent, or a lubricant, surfactant, or dispersant and compressing the active ingredient in a free-flowing form such as powder or granules with a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent with a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient. All formulations for oral administration must be in amounts suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. Sugar-coated tablet cores are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets or Dragee coatings for identification or to characterize various combinations of the dosage of the active compound.

[0348] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage form, for example, in ampoules or multi-dose containers, together with an additional preservative. The composition may take the form of a suspension, solution, or emulsion, etc. in an oily or aqueous vehicle, and may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. The composition may be provided in containers for single-dose or multi-dose use, such as sealed ampoules and vials, and may be stored in powder form, or alternatively, in a lyophilized (freeze-dried) state that requires only the addition of a sterile liquid carrier, such as physiological saline or pyrogen-free distilled water, immediately prior to use. Ready-to-use injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types described above.

[0349] Pharmaceutical compositions for parenteral administration may include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes to render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0350] The pharmaceutical composition may also be formulated as a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion-exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

[0351] For buccal or sublingual administration, the composition can be in the form of tablets, lozenges, pastilles, or gels formulated by conventional methods. Such compositions can contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0352] The pharmaceutical composition can be administered topically, i.e., by non-systemic administration. This includes application of the compounds of the present invention to the skin or the exterior of the buccal cavity, and instillation of the above compounds into the ear, eye, and nose such that the compounds do not enter the bloodstream in large amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0353] Pharmaceutical compositions suitable for topical administration include gels, liniments, lotions, creams, ointments, or pastes, and liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as drops suitable for administration to the eye, ear, or nose. The active ingredient can be present in the formulation at 0.001% w / w to 10% w / w for topical administration, for example, 1% to 2% by weight.

[0354] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an inhaler, nebulizer, pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a measured amount. Alternatively, for administration by inhalation or insufflation, the formulation can be in the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition can be provided in unit dosage forms such as capsules, cartridges, gelatin, or blister packs from which the powder can be administered using an inhaler or insufflator.

[0355] For example, in addition to the components specifically described above, the compounds and compositions described herein may include other conventional agents in the art, taking into account the type of formulation in question. For example, it should be understood that agents suitable for oral administration may include flavors.

[0356] Dosage Methods and Treatment Regimens In one embodiment, a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from modulation of melanocortin receptor activity. A method for treating any of the diseases or disorders described herein in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of at least one compound of formula (A) or formula (I), or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0357] In certain embodiments, the compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or disorder. The amount effective for this use depends on the severity and course of the disease or disorder, previous treatment, the health status, weight, and response of the patient to the drug, as well as the judgment of the physician administering the treatment. A therapeutically effective amount is optionally determined by methods including, but not limited to, clinical trials of dose escalation and / or dose ranging.

[0358] For prophylactic use, a composition comprising a compound described herein is administered to a patient who is predisposed to or at risk of a particular disease, disorder, or illness. Such an amount is defined as a "prophylactically effective amount or dosage". In this use, the exact amount will also vary depending on the health status, weight, etc. of the patient. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder, or illness, previous treatment, the patient's health status and response to the drug, and the judgment of the treating physician. In one aspect, a prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, to prevent recurrence of symptoms of the disease or illness.

[0359] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, the administration of the compound is chronic, i.e., over a long period including the patient's lifetime, to relieve, or otherwise suppress or limit, the symptoms of the patient's disease or illness.

[0360] Once the patient's condition improves, a maintenance amount is administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced to a level at which the improved disease, disorder, or illness is maintained, depending on the symptoms. However, in certain embodiments, the patient will require intermittent treatment over a long period if the symptoms recur.

[0361] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the state and severity of the disease, and the idiosyncrasies (e.g., weight, gender) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0362] However, generally, the dosage used for the treatment of adult humans typically ranges from 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is preferably provided as a single dose, or as divided doses administered simultaneously or at appropriate intervals, for example, as 2, 3, 4 or more sub-doses per day.

[0363] In one embodiment, a suitable daily dosage for a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or effective amount of the active ingredient in the dosage form may be less than or greater than the ranges indicated herein, based on many variables regarding the individual treatment regimen. In various embodiments, the daily dosage and unit dosage may vary depending on many variables including, but not limited to, the activity of the compound used, the disease or disorder being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the physician.

[0364] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 50 and ED 50 The dosage ratio between toxicity and therapeutic effect is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in the formulation of therapeutically effective daily dosage ranges and / or therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of blood concentrations that include the ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dosage may vary within this range depending on the dosage form used and the route of administration utilized.

[0365] In any of the foregoing embodiments, an effective amount of a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered to a mammal by injection, and / or (e) administered topically to a mammal, and / or (f) administered to a mammal non-systemically or topically. There are further embodiments.

[0366] In any of the foregoing embodiments, there are further embodiments that include a single administration of an effective amount of a compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered to the mammal multiple times over a day.

[0367] In any of the foregoing embodiments, there are further embodiments that include multiple administrations of an effective amount of a compound, in which (i) the compound is administered continuously or intermittently, as in a single administration; (ii) the interval between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. Further or alternative embodiments include that the method includes a drug holiday period, where the administration of the compound is temporarily interrupted or the amount of the compound being administered is temporarily reduced, and at the end of the drug holiday period, the administration of the compound is resumed. In one embodiment, the length of the drug holiday period varies from 2 days to 1 year.

[0368] Combined treatment In certain examples, it is appropriate to administer at least one compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0369] In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). Alternatively, in some embodiments, the effect experienced by the patient is increased by administering one of the compounds described herein together with another agent (including therapeutic regimens) that also has a therapeutic effect.

[0370] In certain embodiments, a compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate various aspects of the disease, disorder, or condition being treated, thereby providing a greater overall effect than if either therapeutic agent were administered alone.

[0371] In all cases, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is either simply additive of the two therapeutic agents, or the patient experiences a synergistic effect.

[0372] In the case of the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the particular co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with, or sequentially to, one or more other therapeutic agents.

[0373] In combination therapies, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or simultaneously. If the administration is simultaneous, the multiple therapeutic agents are provided, by way of example only, in a single unified form or in multiple forms (e.g., as a single pill, or as two separate pills).

[0374] In combination therapy, the compound of formula (A) or formula (I), or a pharmaceutically acceptable salt thereof, is administered before, during, or after the onset of a disease or disorder, and the timing of administration of the composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as prophylactic agents to prevent the onset of a disease or disorder and are administered continuously to a subject predisposed to the disease or disorder. In another embodiment, the compounds and compositions are administered to a subject during the onset of symptoms or as soon as possible after onset. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or disorder has been detected or suspected and for the period required for the treatment of the disease. In some embodiments, the period required for treatment varies and the treatment period is adjusted according to the specific needs of each subject.

Examples

[0375] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. Abbreviations DIEA: N,N-Diisopropylethylamine, DMA: N,N-Dimethylacetamide, EtOAc: Ethyl acetate DMSO: Dimethyl sulfoxide, Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0), Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, CuI: Copper(I) iodide, PdAMphos: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), TBAF: Tetra-n-butylammonium fluoride, P(t-Bu)3: Tri-tert-butylphosphine, HBF4: Tetrafluoroboric acid, DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene, Fractional HPLC: Fractional high performance liquid chromatography, TFA: Trifluoroacetic acid, CH3CN: Acetonitrile, MeOD: Methanol-d, CDCl3: Chloroform-d DME: 1,2-Dimethoxyethane, H2O: Water, KOAc: Potassium acetate, NaOAc: Sodium acetate, Cs2CO3: Cesium carbonate P-TsOH: p-Toluenesulfonic acid, NaNO2: Sodium nitrite, THF: Tetrahydrofuran, DCM: Dichloromethane, NBS: N-Bromosuccinimide, NCS: N-Chlorosuccinimide, Br2: Bromine, AgF: Silver fluoride, LiAlH4: Lithium aluminum hydride, IBX: 2-Iodoxybenzoic acid, TEA: Trimethylamine, HOBT: Hydroxybenzotriazole, EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride, Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, PdAmphos or Pd(amphos)Cl2 or: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride, Pd(DTBPF)Cl2: [1,1'-Bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, rt: Room temperature, h: Hour, CC: Column chromatography.

[0376] Synthesis of Compounds

[0377] Example 1: 5-[(2R)-4-[4-Chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3’-bipyridine (cpd 1-2)

[0378]

Chem.

[0379] Step 1-1, Preparation of tert-butyl (3R)-3-ethyl-4-(2-nitropyridin-3-yl)piperazine-1-carboxylate: In a 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 3-fluoro-2-nitropyridine (5.0 g, 35 mmol), tert-butyl (R)-3-ethylpiperazine-1-carboxylate (9.3 g, 43 mmol), DIEA (14 g, 110 mmol), and DMA (50 mL) were added. The resulting solution was stirred at 90 °C for 16 h, cooled to room temperature, and diluted with water (100 ml). The resulting solution was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column using ethyl acetate / petroleum ether (1:3). Thereby, the title compound (7.5 g, 63%) as a yellow solid was obtained. LCMS (M+H) + = 337.2.

[0380] Preparation of tert-butyl (3R)-3-ethyl-4-(2-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-3-yl)piperazine-1-carboxylate: (R)-1-Methylpyrrolidin-3-ol (293 mg, 2.9 mmol) and DMF (4 mL) were placed in a 100 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen. The resulting solution was treated with NaH (0.15 g, 3.86 mmol) and stirred at 0 °C for 20 minutes. The reaction was treated with tert-butyl (3R)-3-ethyl-4-(2-nitropyridin-3-yl)piperazine-1-carboxylate (650 mg, 1.93 mmol) in DMF (6 mL) and then stirred at room temperature for 16 hours. The reaction was then quenched with water (20 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The filtrate was applied to a silica gel column using DCM / MeOH (10:1). This resulted in the title compound (400 mg, 53%) as a yellow oil. LCMS (M+H) + =391.3.

[0381] Preparation of tert-butyl (3R)-4-(6-chloro-2-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-3-yl)-3-ethylpiperazine-1-carboxylate: To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added tert-butyl (3R)-3-ethyl-4-(2-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-3-yl)piperazine-1-carboxylate (1.0 g, 2.6 mmol) and DMF (8 mL). The resulting solution was treated with NCS (980 mg, 7.34 mmol) in DMF (5 mL) at 17 °C and then stirred at 40 °C for 2 h. The crude product was purified by flash preparative HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% TFA) and CH3CN (from 10% to 56% CH3CN in 6 min); detector, UV 254 & 220 nm. This gave the title compound (500 mg, 46%) as a yellow oil. LCMS (M+H) + =425.2.

[0382] Preparation of tert-butyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with tert-butyl (3R)-4-(6-chloro-2-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-3-yl)-3-ethylpiperazine-1-carboxylate (500 mg, 1.18 mmol), 2-ethoxypyridin-3-yl)boronic acid (590 mg, 3.53 mmol), potassium carbonate (500 mg, 3.62 mmol), PdAMPHOS (50 mg, 0.07 mmol), and dioxane (6 mL) / H2O (0.6 mL). The resulting solution was degassed with N2 for 10 minutes and stirred at 80 °C for 8 hours. The reaction was cooled to room temperature and the inorganic solids were filtered off. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column using dichloromethane / MeOH (10:1). Thereby, the title compound (300 mg, 50%) was obtained as a yellow solid. LCMS (M+H) + =512.5.

[0383] Preparation of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine trihydrochloride: A 50 mL round-bottom flask was charged with tert-butyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (300 mg, 0.586 mmol) and DCM (2 mL). The resulting solution was treated with 4N-HCl in 1,4-dioxane (2 mL). The resulting solution was stirred at room temperature for 1 hour and concentrated. Thereby, the title compound (330 mg, 94%) was obtained as a yellow solid. LCMS (M+H) + =412.3.

[0384] Preparation of 1-6,5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3’-bipyridine formate: In a purged 50 mL round bottom flask, 4-chloro-2-(trifluoromethyl)benzoic acid (36 mg, 0.16 mmol), DMF (2 mL), HATU (70 mg, 0.18 mmol), DIEA (75 mg, 0.58 mmol), and 2’-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3’-bipyridine trihydrochloride (80 mg, 0.13 mmol) were added. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC under the following conditions (Waters I): column, SunFire Prep C18 OBD column, 5um, 19 * 150 mm; mobile phase, water (0.05% FA) and CH3CN (from 16% to 34% CH3CN in 10 minutes); detector, UV 220 & 254 nm. This gave the title compound (35 mg, 39%) as an off-white solid. LCMS (M+H) + = 618.3.

[0385] The following compounds were prepared in a similar manner to Example 1 using appropriate substitution reagents and substrates in various steps. Some examples may require further deprotection to the final product.

[0386]

Table 6

[0387] Example 2: [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2’-ethoxy-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine (cpd 1-15)

[0388] [Chemistry]

[0389] Preparation of Engineering 2-1, tert-butyl (3R)-4-(2-{2-[benzyl(methyl)amino]ethoxy}pyridin-3-yl)-3-ethylpiperazine-1-carboxylate: 2-(benzyl(methyl)aminoethan-1-ol (836 mg, 5.06 mmol) and DMF (15 mL) were placed in a 50 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen. The solution was treated with NaH (181 mg, 7.54 mmol) at 0 °C and then stirred at 0 °C for 20 minutes. The reaction was treated with tert-butyl (3R)-3-ethyl-4-(2-nitropyridin-3-yl)piperazine-1-carboxylate (850 mg, 2.53 mmol) in DMF (15 mL). The resulting solution was stirred at room temperature for 2 hours, quenched with water (50 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The filtrate was applied to a silica gel column using DCM / MeOH (10:1). This resulted in the title compound (910 mg, 79%) as a white solid. LCMS (M+H) + = 455.3.

[0390] Preparation of tert-butyl (3R)-4-(2-{2-[benzyl(methyl)amino]ethoxy}-6-chloropyridin-3-yl)-3-ethylpiperazine-1-carboxylate: To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added tert-butyl (3R)-4-(2-{2-[benzyl(methyl)amino]ethoxy}pyridin-3-yl)-3-ethylpiperazine-1-carboxylate (910 mg, 2.0 mmol) and DMF (15 mL). The solution was treated with NCS (267 mg, 2.0 mmol) at room temperature and then stirred at 60 °C for 5 h. During the reaction, additional NCS (1.0 equiv) was added to the reaction. The crude product was purified by flash preparative HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% TFA) and CH3CN (from 10% CH3CN to 56% in 6 min); detector, UV 254&220 nm. This gave the title compound (350 mg, 36%) as a yellow oil. LCMS (M+H) + =489.3.

[0391] Preparation of tert-Butyl (3R)-4-(6-{2-[Benzyl(methyl)amino]ethoxy}-2’-ethoxy-[2,3’-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added tert-butyl (3R)-4-(2-{2-[benzyl(methyl)amino]ethoxy}-6-chloropyridin-3-yl)-3-ethylpiperazine-1-carboxylate (350 mg, 0.72 mmol) and dioxane / H2O (6 mL / 0.6 mL). To the resulting solution was added (2-ethoxypyridin-3-yl)boronic acid (240 mg, 1.4 mmol), PdAMPHOS (50 mg, 0.1 equivalent), and potassium carbonate (300 mg, 2.17 mmol). The resulting solution was degassed with N2 for 5 minutes and stirred at 80 °C for 1 hour under N2. The reaction was cooled to room temperature and the inorganic solids were filtered off. The filtrate was concentrated under vacuum. The residue was purified by silica gel column eluting with dichloromethane / MeOH (10:1) to afford the title compound (320 mg, 78%) as a yellow solid. LCMS (M+H) + =576.3.

[0392] Preparation of tert-Butyl (3R)-4-{2’-Ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridin]-5-yl}-3-ethylpiperazine-1-carboxylate: To a 50 mL autoclave was added tert-butyl (3R)-4-(6-{2-[benzyl(methyl)amino]ethoxy}-2’-ethoxy-[2,3’-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (90 mg, 0.16 mmol), MeOH (2 mL), and palladium hydroxide (5 mg, 0.2 equivalent). The flask was evacuated and flushed with nitrogen three times, then flushed with hydrogen. The mixture was stirred at room temperature for 2 hours under 10 atm of hydrogen. The solids were filtered through a pad of celite. The filtrate was concentrated under vacuum to afford the title compound (77 mg, 100%). LCMS (M+H) + =486.6.

[0393] Preparation of tert-butyl (3R)-4-[6-(2-{[(benzyloxy)carbonyl](methyl)amino}ethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl]-3-ethylpiperazine-1-carboxylate: Into an 8 mL vial were placed tert-butyl (3R)-4-{2’-ethoxy-6-[2-(methylamino)ethoxy]-[2,3’-bipyridin]-5-yl}-3-ethylpiperazine-1-carboxylate (70 mg, 0.14 mmol), TEA (50 mg, 0.49 mmol), and DCM (1 mL). The resulting mixture was treated with CbzCl (50 mg, 0.29 mmol) at 0 °C and stirred at the same temperature for 2 h. The reaction mixture was diluted with water (5 mL) and then extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried, and concentrated under vacuum. This gave the title compound (90 mg, 100%) which was used in the next step without further purification. LCMS (M+H) + =620.3.

[0394] Preparation of benzyl N-[2-({2’-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl]-N-methylcarbamate: Into an 8 mL vial were placed tert-butyl (3R)-4-[6-(2-{[(benzyloxy)carbonyl](methyl)amino}ethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl]-3-ethylpiperazine-1-carboxylate (90 mg, 0.15 mmol), TFA (0.2 mL), and DCM (1 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under vacuum. The residue was dissolved in DCM (5 mL) and washed with saturated sodium bicarbonate solution (5 mL). The organic layer was washed with brine, dried, and concentrated under vacuum. This gave the title compound (70 mg, 93%) as a yellow oil. LCMS (M+H) + =520.3.

[0395] Preparation of benzyl N-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl]-N-methylcarbamate: To an 8 mL vial was added 4-chloro-2-(trifluoromethyl)benzoic acid (31 mg, 0.14 mmol), HATU (52 mg, 0.14 mmol), DIEA (55 mg, 0.43 mmol), and DMF (1 mL). After stirring at room temperature for 10 minutes, the resulting solution was treated with benzyl N-[2-({2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]-N-methylcarbamate (70 mg, 0.13 mmol). The reaction was stirred at room temperature for 1 hour, diluted with water (5 mL), and then extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried, and concentrated under vacuum. The residue was applied onto a silica gel column using ethyl acetate / petroleum ether (8:92). This gave the title compound (45 mg, 46%) as a yellow oil. LCMS (M+H) + =726.3.

[0396] Preparation of [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine formate: To an 8 mL vial was added benzyl N-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl]-N-methylcarbamate (45 mg, 0.062 mmol) and TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was purified under the following conditions (Waters I): column, SunFire Prep C18 OBD column, 5um, 19 *150 mm; mobile phase, water (0.05% FA) and CH3CN (from 16% to 34% CH3CN in 10 minutes); detector, purified by preparative HPLC at UV220&254 nm. As a result, the title compound (25 mg, 62%) was obtained as a white solid. LCMS (M+H) + = 638.2.

[0397] The following compounds were prepared in the same manner as in Example 2 using appropriate substitution reagents and substrates in various steps:

[0398]

Table 7

[0399] Example 3: [2-({2’-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3’-bipyridin]-6-yl}oxy)ethyl](methyl)amine (cpd 1-11)

[0400]

Chemical formula

[0401] Step 3-1, Preparation of (2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl chloride: In an 8 mL vial, DCM (1 mL), DIEA (60 mg, 0.6 mmol), (2S)-2-(trifluoromethyl)pyrrolidine (22 mg, 0.16 mmol), and bis(trichloromethyl) carbonate (16 mg, 0.054 mmol) were placed at 0 °C. The resulting solution was stirred at 0 °C for 3 hours, diluted with H2O (5 mL), and extracted with DCM (2×). The combined organic layers were washed with brine, dried, and concentrated under vacuum. As a result, the title compound (30 mg, 94%) was obtained as a yellow oil.

[0402] Preparation of Benzyl [2-({2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]methylamine: Into an 8 mL vial was placed tert-butyl (3R)-4-(6-{2-[benzyl(methyl)amino]ethoxy}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (220 mg, 0.38 mmol), DCM (2 mL), and TFA (0.4 mL) from Step 3 of Example 2. The resulting solution was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in DCM (5 mL) and washed with saturated - NaHCO3. The organic layer was washed with brine, dried, and concentrated to afford the title compound (180 mg, 99%). LCMS (M+H) + =476.3.

[0403] Preparation of Benzyl [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]methylamine: Into an 8 mL vial was placed benzyl [2-({2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]methylamine (50 mg, 0.11 mmol), (2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl chloride (30 mg, 0.15 mmol), K2CO3 (42 mg, 0.30 mmol), and ACN (1 mL). The resulting solution was stirred at 30 °C for 3 hours, diluted with H2O (5 mL), and extracted with DCM (2×). The combined organic layers were washed with brine, dried, and concentrated under vacuum. The residue was applied onto a silica gel column using ethyl acetate / petroleum ether (15:85). This resulted in the title compound (46 mg, 68%) as a yellow oil. LCMS (M+H) + =641.3.

[0404] Preparation of 3-4, [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine formate: In a 50 mL autoclave, benzyl [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]methylamine (46 mg, 0.072 mmol), MeOH (5 mL), and palladium hydroxide (10 mg, 0.072 mmol) were added. The flask was evacuated and flushed with nitrogen three times, and then flushed with hydrogen. The mixture was stirred at room temperature for 1 hour under 10 atm of hydrogen. The solid was filtered through a pad of celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (Preparative HPLC-013): column, SunFire Prep C18 OBD Column, 19 * 150 mm 5 um 10 nm; mobile phase, water (0.1% FA) and ACN-(from 15% B phase to 80% in 8 minutes), total flow rate 20 mL / min, detector, preparative HPLC at UV220 nm. As a result, the title compound (20 mg, 46%) was obtained as a white solid. LCMS (M+H) + =551.3.

[0405] The following compounds were prepared in the same manner as in Example 3 using appropriate substitution reagents and substrates in various steps. In some cases, further functional group exchange may be required to introduce appropriate substituents on the aryl ring. In some cases, the final deprotection step may not be required.

[0406]

Table 8

[0407] Example 4: 5-[(2R,4R) *-4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * Absolute stereochemistry is not determined](cpd 2-9)

[0408] [Chemical formula]

[0409] Step 4-1, Preparation of rac-6-bromo-3-[(2R,4R)-2-ethyl-4-hydroxypiperidin-1-yl)pyridine-2-carbonitrile: To a solution of 6-bromo-3-fluoropyridine-2-carbonitrile (500 mg, 2.49 mmol) and rac-(2R,4R)-2-ethylpiperidin-4-ol hydrochloride (495 mg, 2.99 mmol) in DMSO (2 mL) in a sealed tube, DIEA (1.08 mL, 6.22 mmol) was added. The mixture was heated at 130 °C for 3.5 hours. The mixture was purified by reverse-phase CC to obtain the title compound (429 mg, 55.6% yield) as a medium brown rubber. LCMS (M+H) + = 310.2.

[0410] Preparation of Compound 4-2, rac-2'-ethoxy-5-[(2R,4R)-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile: To a mixture of rac-6-bromo-3-[(2R,4R)-2-ethyl-4-hydroxypiperidin-1-yl]pyridine-2-carbonitrile (429 mg, 1.38 mmol), (2-ethoxypyridin-3-yl)boronic acid (346 mg, 2.07 mmol), Pd(amphos)Cl2 (97.9 mg, 0.138 mmol), and potassium carbonate (382 mg, 2.77 mmol) in a sealed tube were added 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was flushed with N2(g) and heated at 100 °C for 1 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were concentrated in vacuo, and the residue was purified by reverse-phase CC to afford the title compound (390 mg, 80.1% yield) as a brown rubber. LCMS (M+H) + =353.4.

[0411] Step 4-3, 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile and 2'-ethoxy-5-[(2R,4R) * -2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile Separation: Racemic 2'-ethoxy-5-[(2R,4R)-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (1.10 g) was purified by chiral preparative HPLC under the following conditions to afford the first enantiomer (480 mg) and the second enantiomer (470 mg). Instrument name: SHIMADZU LC-09 Column: Normal-phase Diacel Chiralpak IC column, 4.6 mm ID × 50 mm L, 3 μm particle size Column temperature: 25 °C Wavelength: 220 nm Gradient: 10% EtOH in hexane at a uniform concentration Flow rate: 20 mL / min Retention time: first enantiomer: 1.98 min; second enantiomer: 2.74 min.

[0412] Step 4-4, 2'-ethoxy-5-[(2R,4R) * - Preparation of 2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid: To a suspension of the second enantiomer, 2'-ethoxy-5-[(2R,4R) * - 2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (210 mg, 0.596 mmol) in a mixed solvent of EtOH (2 mL) and water (2 mL), potassium hydroxide (334 mg, 5.95 mmol) was added. The mixture was heated at 100 °C for 16 h. The mixture was adjusted to pH 6 - 7 with 3N HCl(aq). The resulting mixture was extracted with DCM / MeOH (10:1) (3 × 20 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (208 mg, 94.0% yield) as a yellow solid. LCMS (M+H) + = 372.2.

[0413] Step 4-5, 2'-ethoxy-5-[(2R,4R) * - Preparation of 2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 2'-ethoxy-5-[(2R,4R) * - 2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid (50 mg, 0.13 mmol) and HATU (61 mg, 0.16 mmol) in DMF (0.6 mL), DIEA (0.10 g, 0.77 mmol) was added. After stirring at room temperature for 5 min, (3R)-1-methylpyrrolidin-3-amine (16 mg, 0.16 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 1 h. The mixture was purified by reverse-phase CC to give the title compound (45 mg, 74% yield) as a yellow solid. LCMS (M+H) + = 454.3.

[0414] Steps 4-6, 5-[(2R,4R) * -4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide Preparation: To a solution of 2'-ethoxy-5-[(2R,4R) * -2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (80 mg, 0.18 mmol) in DMF (1 mL) at 0 °C was added portionwise 60% sodium hydride (25 mg, 0.63 mmol) in mineral oil. After stirring at room temperature for 10 minutes, 4-chloro-1-fluoro-2-(trifluoromethyl)benzene (42 mg, 0.21 mmol) was added. The mixture was heated at 90 °C for 2 hours. The mixture was quenched with saturated NH4Cl(aq) and extracted with DCM / MeOH (10:1) (3 × 10 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford the formate salt of the title compound as a yellow solid. LCMS (M+H) + =632.3.

[0415] The following compounds were prepared in a similar manner to Example 4 using appropriate substitution reagents and substrates in various steps. The absolute stereochemistry of each compound has not been determined.

[0416]

Table 9

[0417] Example 5: 5-[(2S,4S) * -4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide * Absolute stereochemistry not determined](cpd 2-10)

[0418]

Chem.

[0419] Step 5-1, Preparation of 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid: The first enantiomer from Step 1-3, 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (0.21 g, 0.60 mmol) in a suspension of a mixed solvent of EtOH (2 mL) and water (2 mL), potassium hydroxide (341 mg, 6.08 mmol) was added. The mixture was heated at 100 °C for 16 h. The mixture was adjusted to pH 6 with 2N HCl(aq). The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (0.20 g, 90% yield) as a yellow solid. LCMS (M+H) + = 372.1.

[0420] Step 5-2, Preparation of 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: In DMF (2 mL), 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid (0.2 g, 0.5 mmol) and HATU (0.25 g, 0.66 mmol) in solution, DIEA (0.50 mL, 2.9 mmol) was added. After stirring at room temperature for 5 min, (3R)-1-methylpyrrolidin-3-amine (0.11 g, 1.1 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 1 h. The mixture was purified by reverse-phase CC to give the title compound (0.20 g, 80% yield) as a pale yellow solid. LCMS (M+H)+ =454.3.

[0421] Project 5-3, 5-((2S,4S) * -4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide Preparation: To a solution of 2'-ethoxy-5-[(2S,4S) * -2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (80 mg, 0.20 mmol) in DMF (1 mL) at room temperature was added portionwise 60% sodium hydride in mineral oil (31 mg, 0.77 mmol). After stirring at room temperature for 10 minutes, 4-chloro-1-fluoro-2-(trifluoromethyl)benzene (54.2 mg, 0.273 mmol) was added. The mixture was heated at 90 °C for 2 hours. The mixture was quenched with saturated NH4Cl(aq) and extracted with DCM / MeOH (10:1) (3 × 10 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase CC to give the formate salt of the title compound as a pale yellow solid (31.7 mg, 30.0% yield). LCMS (M+H) + =632.3.

[0422] The following compounds were prepared in a similar manner to Example 5 using appropriate substitution reagents and substrates in various steps. The absolute stereochemistry of each compound has not been determined.

[0423]

Table 10

[0424] Example 6: 5-[(2R,4R) *-4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * Absolute stereochemistry is not determined (cpd 2-22)

[0425]

Chem.

[0426] Step 6-1, 2’-ethoxy-5-[(2R,4R) * -2-Ethyl-4-hydroxypiperidin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide Preparation: To a solution of 2’-ethoxy-5-[(2R,4R) * -2-Ethyl-4-hydroxypiperidin-1-yl]-[2,3’-bipyridine]-6-carboxylic acid (50.0 mg, 0.135 mmol) and HATU (71.7 mg, 0.188 mmol) in DMF (0.3 mL), DIEA (0.070 mL, 0.40 mmol) was added. After stirring at room temperature for 5 minutes, (3S)-1-methylpyrrolidin-3-amine (21.6 mg, 0.215 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to give the title compound (51.3 mg, 84.0% yield) as a pale yellow solid. LCMS (M+H) + =454.6.

[0427] Step 6-2, 5-[(2R,4R) * -4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2’-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide Preparation: 2’-Ethoxy-5-[(2R,4R) in DMF (0.5 mL) at 0 °C *-2-Ethyl-4-hydroxypiperidin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (25.2 mg, 0.0556 mmol) and 3-fluoro-6-(trifluoromethyl)pyridine-2-carbonitrile (52.8 mg, 0.278 mmol) in a solution, 60% sodium hydride in mineral oil (22 mg, 0.56 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice water and purified by reverse phase CC to give the title compound (24.2 mg, 69.8% yield) as a pale yellow solid. LCMS (M+H) + =624.4.

[0428] Example 7: 5-[(cis * -4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide * racemate] (cpd 2-2)

[0429]

Chemical Structure

[0430] Preparation of Step 7-1, rac-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid: To a suspension of rac-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (100 mg, 0.284 mmol) from Step 1-2 in a mixed solvent of EtOH (1 mL) and water (1 mL), potassium hydroxide (159 mg, 2.84 mmol) was added. The mixture was heated at 100 °C for 16 h. The mixture was concentrated to remove EtOH, the aqueous residue was diluted with ice water and acidified to pH 2 - 3 with 1N HCl(aq). The mixture was extracted with DCM (5×), the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound as a brown rubber (110 mg, 100% yield). LCMS (M+H) + =372.2.

[0431] Preparation of Step 7-2, 2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of rac-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid (0.11 g, 0.28 mmol) and HATU (0.16 g, 0.43 mmol) in DMF (1 mL), DIEA (0.15 mL, 0.85 mmol) was added. After stirring at room temperature for 5 min, (3R)-1-methylpyrrolidin-3-amine (51 mg, 0.51 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 min. The mixture was purified by reverse-phase CC to give the title compound as a brown rubber (83.0 mg, 64.0% yield). LCMS (M+H) + =454.4.

[0432] Preparation of [[(7S)-3,5-bis-[cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide]]: To a solution of [[(7S)-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide]] (30 mg, 0.066 mmol) and [[2-fluoro-5-(trifluoromethyl)benzonitrile]] (15 mg, 0.079 mmol) in DMF (1 mL) at 0 °C was added portionwise [[sodium hydride]] (26 mg, 0.66 mmol) in mineral oil. The mixture was stirred at 0 °C for 10 minutes. The mixture was quenched with ice and purified by reverse phase CC to afford the title compound as a white solid (29.2 mg, 70.9% yield). LCMS (M+H) + =623.3.

[0433] The following compounds were prepared in a similar manner to Example 7 using appropriate substitution reagents and substrates in various steps. The final compounds are racemates of the cis isomers.

[0434]

Table 11

[0435] Example 8: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[cis * -4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide * (racemate) (cpd 2-20)

[0436]

Chem.

[0437] Preparation of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxylic acid (50.0 mg, 0.135 mmol) and HATU (71.7 mg, 0.188 mmol) from Step 7-1 of Example 7 in DMF (0.3 mL), DIEA (0.082 mL, 0.47 mmol) was added. After stirring at room temperature for 5 minutes, (3S)-1-azabicyclo[2.2.2]octan-3-amine (42.9 mg, 0.215 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to obtain the title compound (50.0 mg, 77.4% yield) as a brown rubber. LCMS (M+H) + =480.4.

[0438] Preparation of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide: To a solution of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[cis-2-ethyl-4-hydroxypiperidin-1-yl]-[2,3'-bipyridine]-6-carboxamide (25 mg, 0.052 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (49.3 mg, 0.261 mmol) in DMF (1 mL) at 0 °C, 60% sodium hydride in mineral oil (21 mg, 0.52 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice and purified by reverse-phase CC to obtain the title compound (5.3 mg, 16% yield) as a light brown solid. LCMS (M+H) + =649.6.

[0439] The following compounds were prepared in the same manner as in Example 8 using appropriate substitution reagents and substrates in various steps. The final compounds are racemates of the cis isomers.

[0440]

Table 12

[0441] Example 9: 5-[cis * -4-{[6-chloro-2-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * racemate](cpd 2-8)

[0442]

Chemical formula

[0443] Step 9-1, Preparation of rac-6-bromo-3-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]pyridine-2-carbonitrile: To a solution of 6-bromo-3-fluoropyridine-2-carbonitrile (545 mg, 2.71 mmol) and rac-cis-2-cyclopropylpiperidin-4-ol hydrochloride (482 mg, 2.71 mmol) in DMSO (2 mL) in a sealed tube was added DIEA (1.18 mL, 6.80 mmol). The mixture was heated at 130 °C for 16 h. The mixture was purified by reverse phase CC to give the title compound (379 mg, 43.4% yield) as a medium brown rubber. LCMS (M+H) + =322.3.

[0444] Preparation of 9-2, rac-5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile: To a mixture of rac-6-bromo-3-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]pyridine-2-carbonitrile (379 mg, 1.18 mmol), (2-ethoxypyridin-3-yl)boronic acid (295 mg, 1.76 mmol), Pd(amphos)Cl2 (83.3 mg, 0.118 mmol), and potassium carbonate (325 mg, 2.35 mmol) in a sealed tube, 1,4-dioxane (0.5 mL) and water (0.5 mL) were added. The mixture was flushed with N2(g) and heated at 100 °C for 1 h. Water was added to the mixture, and the mixture was extracted with EtOAc (2×). The combined organics were concentrated to dryness, and the residue was purified by reverse-phase CC to give the title compound (429 mg, 100% yield) as a brown rubber. LCMS (M+H) + =365.2.

[0445] Preparation of 9-3, rac-5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid: To a suspension of rac-5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile (429 mg, 1.18 mmol) in a mixed solvent of EtOH (2 mL) and water (2 mL), potassium hydroxide (660 mg, 11.8 mmol) was added. The mixture was heated at 100 °C for 16 h. The mixture was concentrated to remove EtOH, the aqueous residue was diluted with ice water, and acidified to pH 2-3 with 1N HCl(aq). The mixture was extracted with DCM (5×), the combined organics were dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound (327 mg, 72.5% yield) as a yellow solid. LCMS (M+H) + =384.1.

[0446] Preparation of 9-4,5-[cis-2-Cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of rac-5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (327 mg, 0.853 mmol) and HATU (486 mg, 1.28 mmol) in DMF (1 mL) was added DIEA (0.45 mL, 2.6 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine (154 mg, 1.54 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to give the title compound (264 mg, 66.5% yield) as a brown solid. LCMS (M+H) + =466.3.

[0447] Preparation of 9-5,5-[cis-4-{[6-chloro-2-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (30.0 mg, 0.0644 mmol) and 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine (25.7 mg, 0.129 mmol) in DMF (1 mL) at 0 °C was added 60% sodium hydride in mineral oil (26 mg, 0.64 mmol) portionwise. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with ice and purified by reverse-phase CC to give the title compound (40.0 mg, 96.2% yield) as an off-white solid. LCMS (M+H) + =645.4.

[0448] The following compounds were prepared in the same manner as in Example 9 using appropriate substitution reagents and substrates in various steps. The final compounds are racemates of the cis isomers.

[0449]

Table 13

[0450] Example 10: Example 10: 5-[cis * -2-cyclopropyl-4-{[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]oxy}piperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * racemate](cpd 2-13)

[0451]

Chemical formula

[0452] Preparation of 10-1,5-[cis-2-cyclopropyl-4-{[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]oxy}piperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide: To a solution of 5-[cis-4-{[6-chloro-2-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide (39.0 mg, 0.0605 mmol) in EtOH (1 mL) at 0 °C was added sodium ethoxide (0.11 mL, 0.30 mmol) as 21 wt% in ethanol. The mixture was heated at 100 °C for 6 h. The reaction was not complete, thus more sodium ethoxide (0.11 mL) was added and the reaction was heated for an additional 16 h. The mixture was quenched with ice water and extracted with DCM (2×). The combined organics were concentrated in vacuo and the residue was purified by reverse phase CC to afford the title compound as a white solid (21.3 mg, 53.8% yield). LCMS (M+H) + =655.6.

[0453] Example 11: 5-[cis * -4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * racemate](cpd 2-5)

[0454]

Chemical Structure

[0455] Preparation of 11-1,5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (150 mg, 0.391 mmol) and HATU (223 mg, 0.587 mmol) from Step 9-3 of Example 9 in DMF (1 mL), DIEA (0.20 mL, 1.2 mmol) was added. After stirring at room temperature for 5 minutes, benzyl (3R)-3-aminopyrrolidine-1-carboxylate (155 mg, 0.704 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to obtain the title compound (164 mg, 71.7% yield) as a pale brown solid. LCMS (M+H) + =586.2.

[0456] Preparation of benzyl (3R)-3-{5-[cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate: To a solution of benzyl (3R)-3-{5-[cis-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (100 mg, 0.171 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (38.7 mg, 0.205 mmol) in DMF (1 mL) at 0 °C, 60% sodium hydride in mineral oil (55 mg, 1.4 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice and purified by reverse-phase CC to obtain the title compound (74.4 mg, 57.7% yield) as a pale yellow solid. LCMS (M+H) + =755.6.

[0457] Preparation of 11-3,5-[cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To benzyl (3R)-3-{5-[cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (74.4 mg, 0.0986 mmol) was added (methylsulfanyl)benzene (0.030 mL, 0.26 mmol) and TFA (0.15 mL, 2.0 mmol). The mixture was heated at 60 °C for 30 minutes. The mixture was purified by reverse phase CC to give the title compound (40.1 mg, 65.5% yield) as a white solid. LCMS (M+H) + =621.5.

[0458] Example 12: 5-[trans * -4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide * racemate](cpd 2-3)

[0459]

Chemical Structure

[0460] Preparation of 12-1, rac-6-bromo-3-[trans-2-cyclopropyl-4-hydroxypiperidin-1-yl]pyridine-2-carbonitrile: To a solution of 6-bromo-3-fluoropyridine-2-carbonitrile (500 mg, 2.49 mmol) and rac-trans-2-cyclopropylpiperidin-4-ol hydrochloride (530 mg, 2.99 mmol) in DMSO (2 mL) in a sealed tube, DIEA (1.08 mL, 6.22 mmol) was added. The mixture was heated at 130 °C for 16 h. The mixture was purified by reverse-phase CC to give the title compound (433 mg, 54.0% yield) as a medium brown gum. LCMS (M+H) + =322.3.

[0461] Preparation of 12-2, rac-5-[trans-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile: To a mixture of rac-6-bromo-3-[trans-2-cyclopropyl-4-hydroxypiperidin-1-yl]pyridine-2-carbonitrile (433 mg, 1.34 mmol), (2-ethoxypyridin-3-yl)boronic acid (337 mg, 2.02 mmol), Pd(amphos)Cl2 (95.2 mg, 0.134 mmol), and potassium carbonate (371 mg, 2.69 mmol) in a sealed tube, 1,4-dioxane (5 mL) and water (0.5 mL) were added. The mixture was flushed with N2(g) and heated at 100 °C for 1 h. Water was added to the mixture and it was extracted with EtOAc (2×). The combined organics were concentrated to dryness and the residue was purified by reverse-phase CC to give the title compound (386 mg, 78.8% yield) as a brown gum. LCMS (M+H) + =365.2.

[0462] Preparation of 12-3, rac-5-[trans-2-Cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid: To a suspension of rac-5-[trans-2-Cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile (386 mg, 1.06 mmol) in a mixed solvent of EtOH (5 mL) and water (5 mL) was added potassium hydroxide (594 mg, 10.6 mmol). The mixture was heated at 100 °C for 1 day. The mixture was concentrated to remove EtOH, the aqueous residue was diluted with ice water, and acidified to pH 2 - 3 with 1N HCl(aq). The mixture was extracted with DCM (5×), the combined organics were dried over anhydrous Na2SO4, and concentrated to dryness to obtain the title compound (364 mg, 89.5% yield) as a yellow solid. LCMS(M+H) + =384.2.

[0463] Preparation of 12-4, Benzyl (3R)-3-{5-[trans-2-Cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate: To a solution of rac-5-[trans-2-Cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (150 mg, 0.391 mmol) and HATU (223 mg, 0.587 mmol) in DMF (1 mL) was added DIEA (0.20 mL, 1.2 mmol). After stirring at room temperature for 5 minutes, benzyl (3R)-3-aminopyrrolidine-1-carboxylate (155 mg, 0.704 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to obtain the title compound (189 mg, 82.3% yield) as a brown solid. LCMS(M+H) + =586.2.

[0464] Preparation of Benzyl (3R)-3-{5-[trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate: To a solution of benzyl (3R)-3-{5-[trans-2-cyclopropyl-4-hydroxypiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (100 mg, 0.171 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (38.7 mg, 0.205 mmol) in DMF (1 mL) at 0 °C was added 60% sodium hydride in mineral oil (68 mg, 1.7 mmol) portionwise. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice and purified by reverse phase CC to afford the title compound as a pale brown solid (94.3 mg, 73.2% yield). LCMS (M+H) + =755.4.

[0465] Preparation of 5-[trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To benzyl (3R)-3-{5-[trans-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (94.3 mg, 0.125 mmol) was added (methylsulfanyl)benzene (0.030 mL, 0.26 mmol) and TFA (0.15 mL, 2.0 mmol). The mixture was heated at 60 °C for 30 minutes. The mixture was purified by reverse phase CC to afford the title compound as a pale yellow solid (57.1 mg, 73.6% yield). LCMS (M+H) + =621.5.

[0466] The following compounds were prepared in the same manner as in Example 12 using appropriate substitution reagents and substrates in various steps.

[0467]

Table 14

[0468] Example 13: 5-[trans * -4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide * racemate](cpd 2-4)

[0469]

Chemical Structure

[0470] Step 13-1, Preparation of 5-[trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide: To a solution of 5-[trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl]-2’-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3’-bipyridine]-6-carboxamide (42.0 mg, 0.0677 mmol) in MeOH (3 mL) were added paraformaldehyde (42.5 mg) and NaBH3CN (42.5 mg, 0.677 mmol). The mixture was stirred at room temperature for 1 h. The mixture was quenched with TFA (0.1 mL) and rebasified with saturated NaHCO3(aq). The mixture was extracted with DCM (2×), the combined organics were extracted, concentrated to dryness. The residue was purified by reverse-phase CC to give the title compound (26.7 mg, 62.2% yield) as a white solid. LCMS (M+H) + =635.2.

[0471] Example 14: 3-(cis *-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-methylpiperidin-1-yl)-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide * Racemate](cpd 2-23)

[0472]

Chemical Structure

[0473] Step 14-1, Preparation of rac-6-bromo-3-[cis-4-hydroxy-2-methylpiperidin-1-yl)pyridine-2-carbonitrile: To a solution of 6-bromo-3-fluoropyridine-2-carbonitrile (600 mg, 2.99 mmol) and rac-cis-2-methylpiperidin-4-ol hydrochloride (543 mg, 3.58 mmol) in DMSO (2 mL) in a sealed tube was added DIEA (1.30 mL, 7.46 mmol). The mixture was heated at 130 °C for 3.5 h. The mixture was purified by reverse-phase CC to give the title compound as a yellow gum (555 mg, 62.8% yield). LCMS (M+H) + =296.3.

[0474] Preparation of 14-2, rac-6-(2-ethoxyphenyl)-3-[(2R,4R)-4-hydroxy-2-methylpiperidin-1-yl]pyridine-2-carbonitrile: To a mixture of rac-6-bromo-3-[(2R,4R)-4-hydroxy-2-methylpiperidin-1-yl]pyridine-2-carbonitrile (277 mg, 0.935 mmol), (2-ethoxyphenyl)boronic acid (233 mg, 1.40 mmol), Pd(amphos)Cl2 (66.2 mg, 0.0935 mmol), and potassium carbonate (259 mg, 1.87 mmol) in a sealed tube were added 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was flushed with N2(g) and heated at 100 °C for 1 h. Water was added to the mixture, and the mixture was extracted with EtOAc (2×). The combined organics were concentrated in vacuo, and the residue was purified by reverse-phase CC to afford the title compound (316 mg, 100% yield) as a brown rubber. LCMS (M+H) + =338.2.

[0475] Preparation of 14-3, rac-6-(2-ethoxyphenyl)-3-[(2R,4R)-4-hydroxy-2-methylpiperidin-1-yl]pyridine-2-carboxylic acid: To a suspension of rac-6-(2-ethoxyphenyl)-3-[(2R,4R)-4-hydroxy-2-methylpiperidin-1-yl]pyridine-2-carbonitrile (317 mg, 0.939 mmol) in a mixed solvent of EtOH (2 mL) and water (2 mL) was added potassium hydroxide (527 mg, 9.39 mmol). The mixture was heated at 100 °C for 16 h. The mixture was concentrated to remove EtOH, the aqueous residue was diluted with ice water, and acidified to pH 2 - 3 with 1N HCl(aq). The mixture was extracted with DCM (5×), the combined organics were dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (286 mg, 85.6% yield) as a pale brown solid. LCMS (M+H) + =357.6.

[0476] Preparation of 14-4,6-(2-Ethoxyphenyl)-3-[cis-4-hydroxy-2-methylpiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide: To a solution of rac-6-(2-ethoxyphenyl)-3-[cis-4-hydroxy-2-methylpiperidin-1-yl]pyridine-2-carboxylic acid (50.0 mg, 0.140 mmol) and HATU (74.7 mg, 0.196 mmol) in DMF (0.3 mL) was added DIEA (0.073 mL, 0.42 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine (22.5 mg, 0.224 mmol) was added to the above HATU-activated solution. The mixture was stirred at room temperature for 10 minutes. The mixture was purified by reverse-phase CC to give the title compound (40.4 mg, 65.7% yield) as a brown rubber. LCMS (M+H) + =439.0.

[0477] Preparation of 14-5,3-(cis-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-methylpiperidin-1-yl)-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide: To a solution of 6-(2-ethoxyphenyl)-3-[cis-4-hydroxy-2-methylpiperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide (20.0 mg, 0.0461 mmol) and 3-fluoro-6-(trifluoromethyl)pyridine-2-carbonitrile (17 mg, 0.091 mmol) in DMF (0.5 mL) at 0 °C was added 60% sodium hydride in mineral oil (9.1 mg, 0.23 mmol) portionwise. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice and purified by reverse-phase CC to give the title compound (7.2 mg, 26% yield) as a white solid. LCMS (M+H) + =609.4.

[0478] The following compounds were prepared in the same manner as in Example 14 using appropriate substitution reagents and substrates in various steps.

[0479]

Table 15

[0480] Example 15: 2-(4-(2’-Ethoxy-6-(2-(methylamino)ethoxy)-[2,3’-bipyridin]-5-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile (cpd 3-1)

[0481]

Chem.

[0482] Step 15-1, Preparation of tert-Butyl 6-Chloro-2-Fluoro-3’,6’-Dihydro-[3,4’-Bipyridin]-1’(2’H)-Carboxylate: To a mixture of 3-Bromo-6-chloro-2-fluoropyridine (2.0 g, 9.5 mmol), potassium carbonate (3.9 g, 28 mmol), tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.2 g, 10 mmol), and Pd(dppf)Cl2 (0.31 g, 0.38 mmol) under nitrogen, 1,4-Dioxane (20 mL) and H2O (2 mL) were added. The resulting mixture was heated at 100 °C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel CC to afford the title compound (2.5 g, 84%) as a yellow solid. LCMS (M+H) + =298.1.

[0483] Preparation of tert-butyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-6-chloro-3’,6’-dihydro-[3,4’-bipyridine]-1’(2’H)-carboxylate: To a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (234 mg, 1.34 mmol) in DMF (5 mL) under nitrogen was added 60 wt% sodium hydride in mineral oil (78 mg, 2.0 mmol). The resulting solution was stirred at 0 °C for 0.5 h. To this was added tert-butyl 6-chloro-2-fluoro-3’,6’-dihydro-[3,4’-bipyridine]-1’(2’H)-carboxylate (380 mg, 1.21 mmol), and the resulting solution was stirred at room temperature for 2 h. The crude product was purified by reverse-phase CC to give the title compound (250 mg, 44.0%) as a yellow solid. LCMS (M+H) + =490.3.

[0484] Preparation of tert-butyl 6’-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-ethoxy-3’’,6’’-dihydro-[3,2’:5’,4’’-terpyridine]-1’’(2’’H)-carboxylate: To a mixture of tert-butyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-6-chloro-3’,6’-dihydro-[3,4’-bipyridine]-1’(2’H)-carboxylate (249 mg, 532 μmol), (2-ethoxypyridin-3-yl)boronic acid (133 mg, 797 μmol), Pd(amphos)Cl2 (18.8 mg, 26.6 μmol), and potassium carbonate (221 mg, 1.60 mmol) were added 1,4-dioxane (4 mL) and H2O (0.4 mL). The resulting mixture was heated at 100 °C for 1.5 h. The crude mixture was concentrated in vacuo, and the residue was purified by silica gel CC to give the title compound (210 mg, 71.2%) as a yellow solid. LCMS (M+H) + =555.4.

[0485] Preparation of tert-butyl 4-(6-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl)piperidine-1-carboxylate: To a solution of tert-butyl 6’-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-ethoxy-3’’,6’’-dihydro-[3,2’:5’,4’’-terpyridin]-1’’(2’’H)-carboxylate (210 mg, 379 μmol) in MeOH under nitrogen, 10% wet palladium on carbon (20 mg) and Pd(OH)2 (20 mg) were added. Then, hydrogen was introduced into the reaction mixture. The resulting solution was stirred at room temperature for 4 hours. The solid was filtered off and the filtrate was concentrated to dryness in vacuo to afford the title compound (190 mg, 90.1%) as a yellow solid. LCMS (M+H) + =557.4.

[0486] Preparation of 2-((2’-ethoxy-5-(piperidin-4-yl)-[2,3’-bipyridin]-6-yl)oxy)-N-methylethan-1-amine bis(2,2,2-trifluoroacetate): To a solution of tert-butyl 4-(6-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2’-ethoxy-[2,3’-bipyridin]-5-yl)piperidine-1-carboxylate (190 mg, 341 μmol) in DCM (2 mL), TFA (0.4 mL) was added. The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated to dryness to afford the title compound (190 mg, 95.2%) as a yellow oil. LCMS (M+H) + =357.2.

[0487] Preparation of 15-6,2-(4-(2’-ethoxy-6-(2-(methylamino)ethoxy)-[2,3’-bipyridin]-5-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile bis(2,2,2-trifluoroacetate): To a solution of 2-((2’-ethoxy-5-(piperidin-4-yl)-[2,3’-bipyridin]-6-yl)oxy)-N-methylethane-1-amine bis(2,2,2-trifluoroacetate) (60 mg, 0.10 mmol) in DMF (0.3 mL) were added DIEA (80 mg, 0.62 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (12 mg, 63 μmol). The resulting solution was heated at 60 °C for 19 h. The crude product was purified by reverse-phase CC to give the title compound (22 mg, 28%) as a yellow solid. LCMS (M+H) + =526.3.

[0488] The following compounds were prepared in the same manner as in Example 15 using appropriate substitution reagents and substrates in various steps.

[0489]

Table 16

[0490] Example 16: 5-[rac-(2R,4R)-4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2’-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3’-bipyridine (cpd 3-9)

[0491]

Chem.

[0492] Preparation of 16-1, rac-2-Ethyl-1-(2-nitropyridin-3-yl)piperidin-4-ol: To a solution of rac-2-ethylpiperidin-4-ol hydrochloride (700 mg, 4.23 mmol) and 3-fluoro-2-nitropyridine (1.3 g, 9.1 mmol) in DMSO (10 mL) was added DIEA (3.4 mL, 19 mmol). The mixture was heated at 90 °C for 30 h. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel CC to give the title compound (950 mg, 89.5%) as a colorless oil. LCMS (M+H) + =252.2.

[0493] Preparation of 16-2, 3-(rac-(2R,4R)-4-(4-Chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-nitropyridine: To a solution of rac-2-ethyl-1-(2-nitropyridin-3-yl)piperidin-4-ol (50 mg, 0.20 mmol) and 4-chloro-1-fluoro-2-(trifluoromethyl)benzene (50 mg, 0.25 mmol) in DMF (3 mL) at 0 °C was added 60 wt% sodium hydride in mineral oil (25 mg, 0.63 mmol). The mixture was stirred at room temperature for 1 h. The crude mixture was used in the next step. LCMS (M+H) + =430.2.

[0494] Preparation of 16-3,3-(rac-(2R,4R)-4-(4-chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridine: To a solution of (R)-1-methylpyrrolidin-3-ol (60 mg, 0.59 mmol) in DMF (2 mL) at 0 °C was added sodium hydride (25 mg, 0.63 mmol, 60 wt% in mineral oil). The mixture was stirred at 0 °C for 0.5 h, then added to the reaction solution of 3-(rac-(2R,4R)-4-(4-chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-nitropyridine (86 mg, 0.20 mmol) from Step 16-1. The mixture was stirred at room temperature for 1 h. The resulting solution was quenched with NH4Cl(aq) (20 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by reverse-phase CC to give the title compound as a yellow solid (65 mg, 67%). LCMS (M+H) + =484.2.

[0495] Preparation of 16-4,6-bromo-3-(rac-(2R,4R)-4-(4-chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridine: To a solution of 3-(rac-(2R,4R)-4-(4-chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridine (50 mg, 0.10 mmol) in DMF (2 mL) was added NBS (22 mg, 0.12 mmol). The mixture was stirred at room temperature for 1 h. The crude product was purified by reverse-phase CC to give the title compound as a yellow solid (50 mg, 86%). LCMS (M+H) + =562.1.

[0496] Preparation of 16-5,5-[rac-(2R,4R)-4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine: To a mixture of 6-bromo-3-(rac-(2R,4R)-4-(4-chloro-2-(trifluoromethyl)phenoxy)-2-ethylpiperidin-1-yl)-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridine (45 mg, 80 μmol), (2-ethoxypyridin-3-yl)boronic acid (18 mg, 0.11 mmol), K2CO3 (35 mg, 0.25 mmol), and Pd(DTBPF)Cl2 (6.0 mg, 9.2 μmol) were added 1,4-dioxane (1.5 mL) and H2O (0.15 mL). The resulting solution was heated at 70 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase CC to afford the title compound (10.3 mg, 15%) as an off-white compound. LCMS (M+H) + =605.2.

[0497] The following compounds were prepared in the same manner as in Example 16 using appropriate substitution reagents and substrates in various steps:

[0498]

Table 17

[0499] Example 17: 1-(5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-4H-1,2,4-triazol-3-yl)methanamine (cpd 4-2)

[0500]

Chemical formula

[0501] Preparation of tert-butyl (R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate: To a solution of 6-bromo-3-fluoropicolinonitrile (50 g, 0.25 mmol) and tert-butyl (R)-3-ethylpiperazine-1-carboxylate (53 g, 0.25 mol) in DMSO (500 mL) was added N-ethyl-N-isopropylpropan-2-amine (96 g, 0.74 mol). The mixture was heated at 90 °C for 24 h. The mixture was quenched with water (500 mL) and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry to afford the title compound as a yellow oil (88 g, 89% yield). LCMS (M+H) + =460.1.

[0502] Preparation of tert-butyl (R)-4-(6-cyano-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a mixture of tert-butyl (R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate (54 g, 0.14 mol), (2-ethoxypyridin-3-yl)boronic acid (46 g, 0.28 mol), K2CO3 (57 g, 0.41 mol), and Pd(DTBPF)Cl2 (8.9 g, 14 mmol) under nitrogen was added dioxane (500 mL) and water (50 mL). The resulting mixture was heated at 70 °C for 1 h. The mixture was diluted with water (500 mL) and extracted with DCM (1000 mL). The organic layer was concentrated in vacuo until dry and the residue was purified by silica gel CC to afford the title compound as a yellow oil (26 g, 43% yield). LCMS (M+H) + =438.3.

[0503] Preparation of (R)-5-(4-(tert-Butoxycarbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid: To a solution of tert-butyl (R)-4-(6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate (15 g, 34 mmol) in EtOH (80 mL) was added potassium hydroxide (19 g, 0.34 mol) and water (80 mL). The resulting mixture was heated at 100 °C for 18 h. The mixture was concentrated in vacuo to remove EtOH, the residue was diluted with water (100 mL), acidified to pH 3 with 1N HCl(aq), and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry to afford the title compound as a yellow oil (14 g, 89% yield). LCMS (M+H) + =457.3.

[0504] Preparation of methyl (R)-2'-ethoxy-5-(2-ethylpiperazin-1-yl)-[2,3'-bipyridine]-6-carboxylate: To a solution of methyl (R)-5-(4-(tert-butoxycarbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (400 mg, 850 μmol) in DCM (6 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, diluted with water (20 mL), and neutralized with saturated NaHCO3(aq). The resulting mixture was extracted with EtOAc (3×), the combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry to afford the title compound as a yellow solid (304 mg, 96.5% yield). LCMS (M+H) + =371.0.

[0505] Preparation of Methyl (R)-5-(4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate: To a solution of methyl (R)-2'-ethoxy-5-(2-ethylpiperazin-1-yl)-[2,3'-bipyridine]-6-carboxylate (304 mg, 821 μmol) in DMF (5 mL) under nitrogen, HATU (374 mg, 984 μmol), N-ethyl-N-isopropylpropan-2-amine (318 mg, 2.46 mmol), and 2-chloro-4-fluorobenzoic acid (150 mg, 859 μmol) were added. The resulting solution was stirred at room temperature for 1 hour. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry. The residue was purified by reverse-phase CC to afford the title compound (350 mg, 80.9% yield) as a yellow solid. LCMS (M+H) + =527.1.

[0506] Preparation of (R)-5-(4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carbohydrazide: To a solution of methyl (R)-5-(4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylate (200 mg, 380 μmol) in EtOH (2 mL), hydrazine hydrate (190 mg, 3.80 mmol) was added. The resulting solution was heated at 70 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry to afford the title compound (200 mg, 100% yield) as a yellow solid. LCMS (M+H) + =526.9.

[0507] Preparation of 17-7, tert-Butyl (R)-((5-(5-(4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridin]-6-yl)-4H-1,2,4-triazol-3-yl)methyl)carbamate: To a solution of (R)-5-(4-(2-Chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridin]-6-carbohydrazide (90 mg, 0.17 mmol) in toluene (1.2 mL) and DMF (0.2 mL) under nitrogen, N-ethyl-N-isopropylpropan-2-amine (0.13 g, 1.0 mmol) and methyl 2-((tert-butoxycarbonyl)amino)ethanimidothioate hydroiodide (0.11 g, 0.33 mmol) were added. The resulting solution was heated at 80 °C for 40 h. The crude mixture was purified by reverse-phase CC to afford the title compound (54 mg, 48% yield) as a yellow solid. LCMS (M+H) + =664.9.

[0508] Preparation of 17-8, Methyl 2-((tert-Butoxycarbonyl)amino)ethanimidothioate: To a solution of tert-Butyl (2-amino-2-thioxoethyl)carbamate (500 mg, 2.63 mmol) in acetone (6 mL), iodomethane (560 mg, 3.95 mmol) was added. The resulting solution was stirred at room temperature for 18 h. The mixture was diluted with ether (6 mL) and the solid was collected by vacuum filtration to afford the title compound (610 mg, 69.9% yield) as a white solid. LCMS (M+H) + =205.1.

[0509] Preparation of (R)-(4-(6-(5-(aminomethyl)-4H-1,2,4-triazol-3-yl)-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazin-1-yl)(2-chloro-4-fluorophenyl)methanone formate: To a solution of tert-butyl (R)-((5-(5-(4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[2,3'-bipyridin]-6-yl)-4H-1,2,4-triazol-3-yl)methyl)carbamate (50 mg, 75 μmol) in DCM (2 mL) was added dropwise TFA (0.4 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, the residue was diluted with water (10 mL), neutralized with saturated NaHCO3(aq), and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo until dry. The residue was purified by reverse phase CC to afford the title compound (35 mg, 76% yield) as a white solid. LCMS (M+H) + =565.2.

[0510] Example 18: (R)-(4-(6-(5-amino-4H-1,2,4-triazol-3-yl)-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazin-1-yl)(2-chloro-4-fluorophenyl)methanone (cpd 4-3)

[0511] [Chemical Structure]

[0512] Preparation of (R)-2-(5-(4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2’-ethoxy-[2,3’-bipyridine]-6-carbonyl)hydrazine-1-carboximidamide: Pyridine (2 mL) was added to a mixture of (R)-5-(4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2’-ethoxy-[2,3’-bipyridine]-6-carboxhydrazide (100 mg, 190 μmol) and methylcarbamimidothioate hydrochloride (72 mg, 0.57 mmol) from Step 17-6. The resulting mixture was heated at 80 °C for 16 hours and then concentrated in vacuo. The crude product was used in the next step without purification. LCMS (M+H) + =569.2.

[0513] Preparation of (R)-(4-(6-(5-amino-4H-1,2,4-triazol-3-yl)-2’-ethoxy-[2,3’-bipyridine]-5-yl)-3-ethylpiperazin-1-yl)(2-chloro-(4-fluorophenyl)methanone bis(2,2,2-trifluoroacetate): A solution of (R)-2-(5-(4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl)-2’-ethoxy-[2,3’-bipyridine]-6-carbonyl)hydrazine-1-carboximidamide (100 mg, 176 μmol) in DMF (1 mL) and water (1 mL) was heated at 120 °C for 16 hours. The mixture was purified by reverse phase CC to give the title compound as a white solid (25.8 mg, 18.8%). LCMS (M+H) + =551.2.

[0514] Example 19: rac-2’-ethoxy-5-((2R,4S)-2-ethyl-4-((2-(trifluoromethyl)phenyl)thio)piperidin-1-yl)-N-((R)-1-methylpyrrolidin-3-yl)-[2,3’-bipyridine]-6-carboxamide (cpd 4-2)

[0515]

Chemical Structure

[0516] Preparation of Intermediate 19-1, rac-(2R,4R)-1-(2'-ethoxy-6-(((R)-1-methylpyrrolidin-3-yl)carbamoyl)-[2,3'-bipyridin]-5-yl)-2-ethylpiperidin-4-yl methanesulfonate: To a solution of rac-2'-ethoxy-5-((2R,4R)-2-ethyl-4-hydroxypiperidin-1-yl)-N-((R)-1-methylpyrrolidin-3-yl)-[2,3'-bipyridin]-6-carboxamide (90 mg, 0.20 mmol) from Intermediate 7-2 in DCM (2 mL) was added triethylamine (60 mg, 0.59 mmol) and methanesulfonyl chloride (27 mg, 0.24 mmol). The resulting solution was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with DCM (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo until dry to afford the title compound as a yellow solid (90 mg, 85% yield). LCMS (M+H) + =532.0.

[0517] Preparation of Intermediate 19-2, rac-2'-ethoxy-5-((2R,4S)-2-ethyl-4-((2-(trifluoromethyl)phenyl)thio)piperidin-1-yl)-N-((R)-1-methylpyrrolidin-3-yl)-[2,3'-bipyridin]-6-carboxamide formate: To a solution of rac-(2R,4R)-1-(2'-ethoxy-6-(((R)-1-methylpyrrolidin-3-yl)carbamoyl)-[2,3'-bipyridin]-5-yl)-2-ethylpiperidin-4-yl methanesulfonate (60 mg, 0.11 mmol) in DMF (0.7 mL) was added 6-(trifluoromethyl)cyclohexa-2,4-dien-1-thiol (31 mg, 0.17 mmol) and potassium carbonate (47 mg, 0.34 mmol). The resulting mixture was heated at 80 °C for 5 h. The crude mixture was purified by reverse phase CC to afford the title compound as a pale yellow solid (10 mg, 13% yield). LCMS (M+H) +=614.2.

[0518] Example 20: rac-2'-ethoxy-5-((2R,4S)-2-ethyl-4-((2-(trifluoromethyl)phenyl)sulfonyl)piperidin-1-yl)-N-((R)-1-methylpyrrolidin-3-yl)-[2,3'-bipyridine]-6-carboxamide (cpd 4-3)

[0519]

Chemical formula

[0520] Example A-1: Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1 to 100 mg of a water-soluble salt of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. Appropriate buffers, and optionally an acid or base, are added optionally to adjust the pH. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0521] Example A-2: Oral Solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is added to water (together with an optional solubilizer, an optional buffer, and a taste masking excipient) to obtain a 20 mg / mL solution.

[0522] Example A-3: Oral tablets Tablets are prepared by mixing 20-50% by weight of the compound of formula (I), or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0523] Example A-4: Oral capsules To prepare a pharmaceutical composition for oral delivery, 10-500 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder mixtures. The mixture is incorporated into oral dosage units such as hard gelatin capsules suitable for oral administration.

[0524] In another embodiment, 10-500 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is placed in a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0525] Example A-5: Topical gel composition To prepare a pharmaceutical topical gel composition, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate, and purified alcohol USP. The resulting gel mixture is then incorporated into a container suitable for topical administration, such as a tube.

[0526] Example B-1: MC2R assay Membrane preparation: The crude membrane fraction is prepared from CRE-bla-CHO-K1 cells that stably express the hMC2 receptor and the hMRAP accessory protein (Thermo Fisher). Cells are grown to 85 - 100% confluence on standard tissue culture dishes in GlutaMax DMEM growth medium (Gibco) containing the following additives: 10% dialyzed FBS (Gemini), 0.1 mM NEAA (Gibco), 25 mM HEPES (Gibco), 5 μg / mL blasticidin (Goldbio), 100 μg / mL zeocin (Invitrogen), 600 μg / mL hygromycin (Goldbio). To prepare the cell membrane, cells are scraped off and collected in 1X Dulbecco's phosphate buffered saline (Corning), and then pelleted at 1000 RPM. The cell pellet is reconstituted in membrane preparation buffer (20 mM HEPES, 6 mM MgC12, and 1 mM EGTA, protease inhibitor tablets (Pierce) adjusted to pH 7.4), homogenized using a dounce homogenizer, and the resulting membrane fraction is pelleted by centrifugation at 12,000 RPM. The membrane pellet is resuspended in membrane preparation buffer, snap frozen, and stored at -80 °C for later use.

[0527] Binding assay for hMC2 antagonists: The hMC2 membrane binding assay utilizes the following components: radiolabeled 125 I]ACTH(1-39)Tyr23 (PerkinElmer), wheat germ agglutinin coated PVT SPA beads (PerkinElmer), crude hMC2R membrane, and compound. Briefly, the hMC2R membrane is incubated with SPA beads in binding assay buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA, protease inhibitor tablets (Pierce) adjusted to pH 7.4) prior to the start of the assay. Compound (final concentrations of compound are typically 0 - 10,000 nM), SPA membrane, and 0.2 nM final concentration of 125I] Plate the dose response of ACTH(1-39)Tyr23 in a 96-well assay plate and incubate at room temperature for 1.5 hours. Read the assay plate using Top Count NXT and determine the K i value of the compound using non-linear regression analysis with GraphPad Prism6.

[0528] List the exemplary binding affinities of the selective compounds in Table A. The potencies are divided into four criteria: + means that K i is from 1,000 nM to 10,000 nM, ++ means that K i is from 100 nM to 1,000 nM, +++ means that K i is from 10 nM to 100 nM, and ++++ means that K i is less than 10 nM.

[0529] [Table 18]

[0530] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of this specification and the scope of the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical 1】 in the formula,[[]]END]] R Ａ is unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic heteroaryl, where R Ａ when substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ and is substituted with R ａ 、 R ｂ 、 and R ｃ are each independently selected from the group consisting of hydrogen, halogen, -OR ５ 、 -CN, -N(R ５ ) ２ 、 unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted monocyclic heteroaryl, and any substituted group of R ａ 、 R ｂ 、 and R ｃ is substituted with one or more R ７ groups. L is —O—, —C(=O)—, —C(=O)NR ４ —, —S—, —SO ２ —, —S(=O) ２ NR ４ —, a 5-membered heterocycle, or a bond, and M is —O—, —C(=O)—, —C(=O)NR ４ —, —S—, —SO ２ —, —S(=O) ２ NR ４ —, a 5-membered heterocyclic ring, or a bond, and R Ｂ is an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, an unsubstituted or substituted C １ -C ７ -alkyl, an unsubstituted or substituted C １ -C ７ -fluoroalkyl, or an unsubstituted or substituted C １ -C ６ -heteroalkyl, where when R Ｂ is substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and Alternatively, R Ｂ and R ４ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is substituted with R ｄ R ｅ and R ｆ and is substituted with, R ｄ 、R ｅ 、and R ｆ are independently selected from the group consisting of hydrogen, halogen, -OR ５ 、-CN, -N(R ５ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted monocyclic heteroaryl, where any substituted group of R ｄ 、R ｅ 、and R ｆ is substituted with one or more R ７ groups, Y is CR ３ or N, where when Y is N, L is -C(=O)-, -C(=O)NR ４ -, -SO ２ -, -S(=O) ２ NR ４ -, a 5-membered heterocycle, or a bond, Z is CR ３ or N, and R １ is unsubstituted or substituted C １ -C ６ alkyl or unsubstituted or substituted C ３ -C ６ cycloalkyl, where when R １ is substituted, R １ is hydrogen, -OR ６ halogen, -N(R ５ ) ２ or -CN, and R ２ is hydrogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic carbocyclic ring, unsubstituted or substituted bridged carbocyclic ring, unsubstituted or substituted spiro carbocyclic ring, unsubstituted or substituted monocyclic heterocyclic ring, unsubstituted or substituted bridged heterocyclic ring, unsubstituted or substituted spiro heterocyclic ring, unsubstituted or substituted -(C １ -C ６ alkyl)-carbocyclic ring, or unsubstituted or substituted -(C １ -C ６ alkyl)-heterocyclic ring, where any substituted group of R ２ is one or more halogens, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocyclic ring, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and is substituted by R ３ each independently represents hydrogen, halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, -CN, -OR ６ -SR ６ -CO ２ R ６ -C(=O)N(R ５ ) ２ or -N(R ５ ) ２ and R ４ is hydrogen, a substituted C １ -C ６ alkyl, an unsubstituted or substituted C ３ -C ６ cycloalkyl, an unsubstituted or substituted C １ -C ６ fluoroalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl, and R ５ is each independently hydrogen, substituted C １ -C ６ -alkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, unsubstituted or substituted C １ -C ６ -fluoroalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, Alternatively, two Rs on the same nitrogen atom together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle, ５ and R ６ is each independently hydrogen, substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R ７ each independently represents hydrogen, halogen, unsubstituted or substituted C １ -C ４ alkyl, unsubstituted or substituted C １ -C ４ alkoxy, unsubstituted or substituted C １ -C ４ fluoroalkyl, unsubstituted or substituted C １ -C ４ fluoroalkoxy, unsubstituted or substituted monocyclic carbocyclic ring, unsubstituted or substituted monocyclic heterocyclic ring, -CN, -OH, -CO ２ R ６ , -CH ２ CO ２ R ６ , -C(=O)N(R ５ ) ２ , -C(=O)N(R ５ )OR ６ , -CH ２ C(=O)N(R ５ ) ２ , -N(R ５ ) ２ , -CH ２ N(R ５ ) ２ , -C(R ６ ) ２ N(R ５ ) ２ , -NR ５ C(=O)R ６ , -CH ２ NR ５ C(=O)R ６ , -NR ５ C(=O)N(R ６ ) ２ , -NR ５ C(=O)N(R ６ ) ２ , C(R ６ )=N(R ５ )-OR ６ , -SR ６ , -S(=O)R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and R ８ is each independently a substituted C １ -C ６ -alkyl, an unsubstituted or substituted C ３ -C ６ -cycloalkyl, an unsubstituted or substituted C １ -C ６ -fluoroalkyl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted heteroaryl, the compound, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

2. L is -O-, -C(=O)-, -S-, -SO ２ -, 5-membered heteroaryl, or a bond, and, M is -O-, -C(=O)NR ４ -, -S-, -SO ２ -, -S(=O) ２ NR ４ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein M is -O-, -C(=O)NR, -, -S-, -SO, -, -S(=O)NR, a 5-membered heteroaryl, or a bond.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of L and M is -O-.[[]]END]]

4. The compound according to any one of claims 1 - 3, or a pharmaceutically acceptable salt or solvate thereof, wherein M is -O-.[[]]END]]

5. L is -O-, -C(=O)-, a 5-membered heteroaryl, or a bond, and M is -O-. The compound according to any one of claims 1 - 4, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

6. L is -C(=O)-, M is -O-, Y is N, and Z is N. The compound according to any one of claims 1 - 5, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

7. L is -O- or a 5-membered heteroaryl, M is -O-, Y is CR ３ and, Z is N. The compound according to any one of claims 1 - 5, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

8. L is a bond, M is -O-, Y is N, and Z is CR ３ The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof.

9. L is -O-. The compound according to any one of claims 1 - 3, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

10. M is -C(=O)NR ４ - and Y is CR ３ and, Z is N. The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

11. L is -C(=O)-, M is -S-, -SO ２ -, -S(=O) ２ NR ４ -, a 5-membered heteroaryl, or a bond, and Y is N, and Z is N. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

12. L is -S- or -SO ２ - and M is -C(=O)NR ４ - and Y is CR ３ and, Z is N. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

13. R ３ is each independently hydrogen, unsubstituted or substituted C １ -C ６ -alkyl, or unsubstituted or substituted C １ -C ６ -fluoroalkyl, a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof.

14. R ３ is hydrogen, respectively, the compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof.

15. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein when R Ａ is substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ , a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof.

16. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein R Ａ when substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ and the compound according to any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof.

17. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein R Ａ when substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ and is a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof.

18. R Ａ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ａ when substituted, R Ａ is R ａ , R ｂ , and R ｃ substituted, a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof.

19. R Ａ is [Chemical Formula 2] The compound according to any one of claims 1 - 17, or a pharmaceutically acceptable salt or solvate thereof, wherein[[]]END]]

20. R Ａ is [Chemical Formula 3] wherein V is CH or N. The compound according to any one of claims 1 - 18, or a pharmaceutically acceptable salt or solvate thereof.[[]]END]]

21. R Ａ is 【Chemical Formula 4】 The compound according to any one of claims 1 - 20, or a pharmaceutically acceptable salt or solvate thereof, wherein[[]]END]]

22. The compound has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof, [Chemical Formula 5] The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N.

23. The compound has the structure of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, [[Chemical Formula 6]] The compound according to any one of claims 1-6 or 15-20, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N.

24. The compound has the structure of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 7】 The compound according to any one of claims 1-3, 9-10, or 13-20, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N.

25. R Ｂ is an unsubstituted or substituted monocyclic carbocyclic ring, an unsubstituted or substituted bicyclic carbocyclic ring, an unsubstituted or substituted polycyclic carbocyclic ring, an unsubstituted or substituted monocyclic heterocyclic ring, an unsubstituted or substituted bicyclic heterocyclic ring, or an unsubstituted or substituted polycyclic heterocyclic ring, where R Ｂ when substituted, R Ｂ is R ｄ , R ｅ , and R ｆ substituted, a compound according to any one of claims 1 - 24, or a pharmaceutically acceptable salt or solvate thereof.

26. R Ｂ is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bridged carbocycle, an unsubstituted or substituted spirocarbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bridged heterocycle, or an unsubstituted or substituted spiroheterocycle, where R Ｂ when substituted, R Ｂ is R ｄ , R ｅ , and R ｆ substituted, a compound according to any one of claims 1 - 24, or a pharmaceutically acceptable salt or solvate thereof.

27. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted bicyclic heteroaryl, monocyclic C ３ -C ８ -cycloalkyl, unsubstituted or substituted bridged C ５ -C １０ -cycloalkyl, unsubstituted or substituted spiro C ５ -C １０ -cycloalkyl, unsubstituted or substituted monocyclic C ２ -C ８ -heterocycloalkyl, unsubstituted or substituted bridged C ５ -C １０ -heterocycloalkyl, or unsubstituted or substituted spiro C ５ -C １０ -heterocycloalkyl, wherein when R Ｂ is substituted, R Ｂ is substituted by R ｄ 、R ｅ 、and R ｆ and the compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

28. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted indanyl, unsubstituted or substituted indenyl, unsubstituted or substituted tetrahydronaphthyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cycloheptyl, unsubstituted or substituted cyclooctyl, unsubstituted or substituted spiro[2.2]pentyl, unsubstituted or substituted spiro[3.3]heptyl, unsubstituted or substituted spiro[3.5]nonyl, unsubstituted or substituted spiro[4.4]nonyl, unsubstituted or substituted spiro[4.5]decyl, unsubstituted or substituted norbornyl, unsubstituted or substituted norbornenyl, unsubstituted or substituted bicyclo[1.1.1]pentyl, unsubstituted or substituted adamantyl, or unsubstituted or substituted decalinyl, wherein R Ｂ when substituted, R Ｂ is substituted with R ｄ , R ｅ , and R ｆ ; a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

29. R Ｂ is unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein R Ｂ when substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and the compound according to any one of claims 1 - 24, or a pharmaceutically acceptable salt or solvate thereof.

30. R Ｂ is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted homopiperidinyl, unsubstituted or substituted oxepanyl, unsubstituted or substituted thiepanyl, unsubstituted or substituted oxazepinyl, unsubstituted or substituted diazepinyl, unsubstituted or substituted thiazepinyl, unsubstituted or substituted azaspiro[3.3]heptanyl, unsubstituted or substituted azaspiro[3.4]octanyl, unsubstituted or substituted azaspiro[3.4]octanyl, or unsubstituted or substituted azaspiro[4.4]nonyl, wherein R Ｂ when substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and the compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

31. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein R Ｂ when substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and the compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

32. R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where when R Ｂ is substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and is a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

33. R Ｂ is 【Chemical Formula 8】 The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

34. R Ｂ is 【Chemical Formula 9】 The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH or N.

35. R Ｂ is 【Chemical 10】 The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

36. R Ｂ is 【Chemical Formula 11】 wherein The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3.

37. The compound has the structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 12】 The compound according to any one of claims 1-20 or 22, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N and W is CH or N.

38. The compound has the structure of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 13】 The compound according to any one of claims 1-6, 15-20, or 23, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N and W is CH or N.

39. The compound according to claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IVa). 【Chemical Formula 14】

40. The compound according to claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (Va), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical Formula 15】

41. The compound according to claim 1-3, 9-10, 13-20, or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, and 【Chemical Formula 16】 V is CH or N, and W is CH or N.

42. The compound according to claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (IVb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 17】

43. The compound according to claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (Vb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical Formula 18】

44. R １ is -CH ３ ,-CH ２ CH ３ ,-CH ２ CH ２ CH ３ ,-CH(CH ３ ) ２ ,-CH ２ CH ２ CH ２ CH ３ ,-CH ２ CH(CH ３ ) ２ ,-CH(CH ３ )(CH ２ CH ３ ),-C(CH ３ ) ３ ,-CH ２ OH,-CH ２ CN,-CH ２ F,-CHF ２ ,-CF ３ ,-CH ２ CH ２ OH,-CH ２ CH ２ CN,-CH ２ CH ２ F,-CH ２ CHF ２ ,-CH ２ CF ３ ,-CH ２ OCH ３ ,-CH ２ CH ２ OCH ３ ,-CH ２ NH ２ ,-CH ２ NHCH ３ ,-CH ２ N(CH ３ ) ２ ,-CH ２ CH ２ NH ２ ,-CH ２ CH ２ NHCH ３ ,-CH ２ CH ２ N(CH ３ ) ２ The compound according to any one of claims 1-43, which is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or a pharmaceutically acceptable salt or solvate thereof.

45. R １ is -CH ３ , -CH ２ CH ３ , or -CH ２ CH ２ CH ３ and is the compound according to any one of claims 1 - 44, or a pharmaceutically acceptable salt or solvate thereof.

46. R ４ is hydrogen or C １ -C ６ alkyl, a compound according to any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof.

47. R ４ is hydrogen, -CH ３ , -CH ２ CH ３ , or -CH ２ CH ２ CH ３ and is the compound according to claim 46, or a pharmaceutically acceptable salt or solvate thereof.

48. R ２ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bridged carbocycle, unsubstituted or substituted spirocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted bridged heterocycle, unsubstituted or substituted spirocyclic heterocycle, unsubstituted or substituted -(C １ -C ６ alkyl)-carbocycle, or unsubstituted or substituted -(C １ -C ６ alkyl)-heterocycle, wherein any substituted group of R ２ is one or more halogens, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ substituted, a compound according to any one of claims 1-47, or a pharmaceutically acceptable salt or solvate thereof.

49. R ２ is unsubstituted or substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic carbocyclic ring, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom, where any substituted group of R ２ is one or more halogens, unsubstituted or substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic heterocyclic ring, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and is substituted with, a compound according to any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof.

50. R ２ is a substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, an unsubstituted or substituted bridged heterocycle, or an unsubstituted or substituted -(C １ -C ６ alkyl)-heterocycle, wherein any substituted group of R ２ is one or more halogens, an unsubstituted or substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic heterocycle, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and is substituted with Here, R ２ is a compound according to any one of claims 1-48 containing a basic amine group, or a pharmaceutically acceptable salt or solvate thereof.

51. R ２ is a C ５ -C ２ alkyl substituted with one -N(R １ -C ６ group, and further substituted with zero or more halogens, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycles, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and Alternatively, R ２ is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, Alternatively, R ２ is an unsubstituted or substituted crosslinked heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, Alternatively, R ２ is -(C １ -C ６ -alkyl)-heterocyclic ring, The compound according to claim 50, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocycle is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom.

52. R ２ is C-substituted by an -N(R ５ ) ２ group and is C １ -C ６ alkyl, Alternatively, R ２ is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, Alternatively, R ２ is -(C １ -C ６ -alkyl)-heterocyclic ring, The compound according to claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocycle is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom.

53. The compound according to claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (VIa), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 19】

54. The compound according to claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (VIb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 20】

55. The compound according to claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof, and 【Chemical 21】 R Ａ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ａ when substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ and is substituted with L is -C(=O)-, M is -O-, Y is N, and Z is N, or L is -O-, M is -C(=O)NR ４ -, Y is CH, and Z is N, and R Ｂ is an unsubstituted or substituted carbocyclic ring or an unsubstituted or substituted heterocyclic ring, Here, when R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ substituted, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

56. The compound according to claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 22】

57. The compound according to claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (VIIb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 23】

58. R Ａ is 【Chemical 24】 The compound according to any one of claims 55 - 57, or a pharmaceutically acceptable salt or solvate thereof, which is as follows.

59. R ２ is a substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, or an unsubstituted or substituted -(C １ -C ６ alkyl)-heterocycle, wherein any substituted group of R ２ is one or more halogens, an unsubstituted or substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic heterocycle, -N(R ５ ) ２ , -OR ６ , -CN, -CO ２ R ６ , -C(=O)N(R ５ ) ２ , -SR ６ , -S(=O)R ８ , -S(=O) ２ R ８ , -NR ５ C(=O)R ６ , -NR ５ SO ２ R ８ , -SO ２ R ８ , or -SO ２ N(R ５ ) ２ and is substituted with Here, R ２ is a compound according to any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof, which contains a basic amine group.

60. R ２ is C-substituted by an -N(R ５ ) ２ group and is C １ -C ６ alkyl, the compound according to claim 59, or a pharmaceutically acceptable salt or solvate thereof.

61. R ２ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom, Alternatively, R ２ is -(C １ -C ６ -alkyl)-heterocyclic ring, and the heterocyclic ring is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, the compound according to claim 59, or a pharmaceutically acceptable salt or solvate thereof.

62. R ａ is selected from the group consisting of hydrogen, halogen, -OR ６ , -CN, -N(R ５ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl, and any substituted group of R ａ is substituted with one or more R ７ groups, and R ｂ and R ｃ each independently is hydrogen, halogen, -OR ６ , -CN, -N(R ５ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, and is selected from the group consisting of R ｂ and R ｃ Any substituted group of R ７ is substituted with one or more R groups, a compound according to any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof.

63. R ａ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NH ２ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ) ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ , -CH ２ CH ２ N(CH ３ ) ２ selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and R ｂ and R ｃ are independently hydrogen, Cl, Br, -CN, -OH, -OCH ３ -, -OCH ２ CH ３ -, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ -, -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ -, -CF ３ -, -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ -, -CH ２ CF ３ -, -CH ２ OCH ３ -, -CH ２ CH ２ OCH ３ -, -CH ２ NH ２ -, -CH ２ NHCH ３ -, -CH ２ N(CH ３ ) ２ -, -CH ２ CH ２ NH ２ -, -CH ２ CH ２ NHCH ３ and -CH ２ CH ２ N(CH ３ ) ２ The compound according to any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

64. R ｄ is selected from the group consisting of hydrogen, halogen, -OR ６ , -CN, -N(R ５ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted monocyclic heteroaryl, and any substituted group of R ｄ is substituted with one or more R ７ groups, and, R ｅ and R ｆ each independently is hydrogen, halogen, -OR ６ , -CN, -N(R ５ ), ２ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, a compound according to any one of claims 1 - 63, or a pharmaceutically acceptable salt or solvate thereof.

65. R ｄ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NH ２ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ) ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ , -CH ２ CH ２ N(CH ３ ) ２ , a non-substituted or substituted cyclopropyl, non-substituted or substituted cyclobutyl, non-substituted or substituted cyclopentyl, non-substituted or substituted cyclohexyl, non-substituted or substituted C ２ -C ７ -heterocycloalkyl, non-substituted or substituted phenyl, and non-substituted or substituted monocyclic heteroaryl, and any substituted group of R ｄ is substituted with one or more R ７ groups, and, R ｅ and R ｆ is independently selected from the group consisting of F, Cl, Br, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ), ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ), ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, -OCH ３ , and -OCH ２ CH ３ ; a compound according to any one of claims 1 - 64, or a pharmaceutically acceptable salt or solvate thereof.

66. 1 - 2: 5 - [(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1 - 3: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1 - 4: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 1 - 5: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1 - 6: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1 - 7: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-8: 2'-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-6-[(3R)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-9: [2-({2'-Ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-10: [2-({5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-11: [2-({2'-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-12: 2-({2'-Ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethan-1-amine, 1-13: 2-({5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethan-1-amine, 1-14: 2-({2'-Ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethan-1-amine, 1-15: [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-16: 2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethan-1-amine, 1-17: [2-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl]dimethylamine, 1-18: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-[(3S)-pyrrolidin-3-yloxy]-2,3'-bipyridine, 1-19: (2R)-1-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)propan-2-amine, 1-20: (2S)-1-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)propan-2-amine, 1-21: (2R)-2-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)propan-1-amine, 1-22: (2S)-2-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)propan-1-amine, 1-23: 1-[(3R)-4-{2'-ethoxy-6-[2-(methylamino)ethoxy]-[2,3'-bipyridin]-5-yl}-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-24: 1-[(3R)-4-[6-(2-aminoethoxy)-2'-ethoxy-[2,3'-bipyridin]-5-yl]-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-25: 1-[(3R)-4-[6-(2-aminoethoxy)-2'-ethoxy-[2,3'-bipyridin]-5-yl]-3-ethylpiperazine-1-carbonyl]-5-chloro-2,3-dihydro-1H-indole-7-carbonitrile, 1-26: 5-chloro-1-[(3R)-4-{2'-ethoxy-6-[2-(methylamino)ethoxy]-[2,3'-bipyridin]-5-yl}-3-ethylpiperazine-1-carbonyl]-2,3-dihydro-1H-indole-7-carbonitrile, 1-27: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-28: [2-({5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-29: [2-({5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 1-30: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 2-1: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenoxy]piperidin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide, 2-2: 5-{cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridin]-6-carboxamide, 2-3: 5-{trans-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridin]-6-carboxamide, 2-4: 5-{trans-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-5: 5-{cis-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-6: 5-{cis-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-7: 5-{cis-4-[4-Chloro-2-(difluoromethyl)phenoxy]-2-cyclopropylpiperidin-1-yl}-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-8: 5-cis-(4-{[6-Chloro-2-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-9: 5-[(2R,4R)-4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-10: 5-[(2S,4S)-4-[4-Chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-11: 5-[(2R,4R)-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-12: 5-[(2S,4S)-4-[2-Cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-13: 5-(cis-2-Cyclopropyl-4-{[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]oxy}piperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-14: 5-(cis-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-cyclopropylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-15: 5-(cis-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl)-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-16: 5-[cis-4-(2-Cyano-4-methylphenoxy)-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-17: 5-[cis-4-(2-Cyano-4-methylphenoxy)-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-18: 5-[(2R,4R)-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-19: N-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-5-(cis-4-{[2-Cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide, 2-20: N-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-5-{cis-4-[2-cyano-4-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl}-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide, 2-21: 5-[(2R,4R)-4-(4-chloro-2-cyanophenoxy)-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-22: 5-[(2R,4R)-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-ethylpiperidin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 2-23: 3-(cis-4-{[2-cyano-6-(trifluoromethyl)pyridin-3-yl]oxy}-2-methylpiperidin-1-yl)-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide, 2-24: 3-[cis-4-(4-chloro-2-cyanophenoxy)-2-methylpiperidin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide, 2-25: 5-[cis-4-(2-cyano-4-fluorophenoxy)-2-cyclopropylpiperidin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 3-1: 2-(4-(2'-ethoxy-6-(2-(methylamino)ethoxy)-[2,3'-bipyridine]-5-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 3-2: 3-(4-{2'-ethoxy-6-[2-(methylamino)ethoxy]-[2,3'-bipyridine]-5-yl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carbonitrile, 3-3: 2-{[(2R)-1-{2'-ethoxy-6-[2-(methylamino)ethoxy]-[2,3'-bipyridine]-5-yl}-2-ethylpiperidin-4-yl]oxy}-5-(trifluoromethyl)benzonitrile, 3-4: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-{1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-5: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-{1-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}piperidin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-6: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-{5-[1-(trifluoromethyl)cyclobutyl]-4H-1λ ３ ,2,4-oxadiazol-3-yl}piperidin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-7: [2-({2'-ethoxy-5-[(2R)-2-ethyl-4-{3-[1-(trifluoromethyl)cyclobutyl]-4H-1λ ３ ,2,4-oxadiazol-5-yl}piperidin-1-yl]-[2,3'-bipyridin]-6-yl}oxy)ethyl](methyl)amine, 3-8: 2-{[rac-(2R,4R)-1-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-[2,3'-bipyridin]-5-yl)-2-ethylpiperidin-4-yl]oxy}-5-(trifluoromethyl)benzonitrile, 3-9: 5-[rac-(2R,4R)-4-[4-chloro-2-(trifluoromethyl)phenoxy]-2-ethylpiperidin-1-yl]-2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2,3'-bipyridine, 4-1: 1-(2-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-1H-imidazol-4-yl)methanamine, 4-2: 1-(5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-4H-1,2,4-triazol-3-yl)methanamine, 4-3: 5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-4H-1,2,4-triazol-3-amine, 4-4: 5-{5-[(2R)-4-(4-fluoro-2-trifluoro-benzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-1H-1,2,4-triazol-3-amine, 4-5: 2-(5-{3-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridin-2-yl}-1H-1,2,4-triazol-1-yl)ethane-1-amine, 4-6: 2-(2-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}-1H-imidazol-1-yl)ethane-1-amine, 4-7: 2-(5-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}-1,3-oxazol-4-yl)ethane-1-amine, 4-8: N-(2-aminoethyl)-3-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-sulfonamide, 4-9: N-(2-aminoethyl)-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridin]-6-sulfonamide, 4-10: 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]benzene-1-sulfonamide, 4-11: 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridin]-6-sulfonamide, 4-12: [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}sulfanyl)ethyl]dimethylamine, 4-13: [2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}sulfonyl)ethyl]dimethylamine, 5-1: rac-2'-ethoxy-5-[(2R,4S)-2-ethyl-4-{[2-(trifluoromethyl)phenyl]sulfanyl}piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, 5-2: rac-2'-ethoxy-5-[(2R,4S)-2-ethyl-4-[2-(trifluoromethyl)benzenesulfonyl]piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, and, 5-3: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzenesulfonyl]piperidin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide, which is a compound, or a pharmaceutically acceptable salt or solvate thereof.

67. A pharmaceutical composition comprising a compound according to any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

68. The pharmaceutical composition according to claim 67, which is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, transdermal administration, or ophthalmic administration.

69. The pharmaceutical composition according to claim 67, which is in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersants, solutions, emulsions, ointments, or lotions.

70. A method of treating a mammalian disease or disorder that would benefit from modulation of melanocortin subtype-2 receptor (MC2R) activity, the method comprising administering to the mammal a compound according to any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

71. The disease or disorder according to claim 70, which includes growth of fat pads in the clavicle, back of the neck, face, and trunk, excessive sweating, capillary dilation, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease.

72. A method for treating Cushing's syndrome in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1 - 66, or a pharmaceutically acceptable salt or solvate thereof.

73. A method for treating ectopic Cushing's syndrome in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1 - 66, or a pharmaceutically acceptable salt or solvate thereof.

74. A method for treating congenital adrenal hyperplasia (CAH) in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1 - 66, or a pharmaceutically acceptable salt or solvate thereof.

75. A method for reducing the secretion of adrenocorticotropic hormone (ACTH) in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1 - 66, or a pharmaceutically acceptable salt or solvate thereof.

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