Gem-disubstituted piperidine melanocortin subtype-2 receptor (MC2r) antagonists and uses thereof

Abstract

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.SOLUTION: There is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein a specific example thereof is 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide.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 / 949,854, filed December 18, 2019, which is incorporated herein by reference in its entirety.

[0002] Technical Field Described 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 technology]

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

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

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

[0006] [ka] During the ceremony, R A is unsubstituted or substituted heteroaryl or unsubstituted or substituted aryl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one, two, three, or four groups selected from R a , R b , and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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 heteroaryl; R a , R b , and R c Any substituted group in may be one or more R 6 is substituted with a group, Or, one R a and one R bis R A If present on an adjacent atom of a R b and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or contains one or more R 6 is substituted with a group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R B is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, three, or four groups selected from R d , R e , and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )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 heteroaryl, wherein R d , R e , and R f Any substituted group in may be one or more R 6 is substituted with a group, where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; X 1 is CR 11 or N, X 2 is CR 12 or N, X 3 is CR 13 or N, X 4 is CR 14 or N, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, -OR 4 , -SR 4 , -CO2R 4 , -C(=O)N(R 4 )2, or -N(R 4 )2, M is -(C=O)-, -NR 3 -, -O-, -S-, -SO2-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, -NR 3 -(C=O)NR 3 -, * -NR 3(SO2)-, * -SO2NR 3 -, or a 5-membered heterocycle, wherein * is R 1 indicates the point of attachment to R 1 is 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 -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, R 3 are each independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R 4 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Or two R's 4together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle, R 5 are each independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R 6 are each independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -COR 5 , -CH2CO2R 5 , -C(=O)N(R 4 )2, -C(=O)N(R 4 ) OR 5 , -CH2C(=O)N(R 4 )2, -N(R 4 )2, -CH2N(R 4 )2, -C(R 5 )2N(R 4 )2, -NR 4 C(=O)R 5 , -CH2NR 4 C(=O)R 5 , -NR 4 C(=O)N(R 5 )2, -NR 4 C(=O)N(R 4 )2, C(R 5 )=N(R 4 )-OR 5 , -SR 5 , -S(=O)R 7 , -SO2R 7 , or -SO2N(R 4 )2, and R 7are each independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

[0007] Also described herein are 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 via intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal via oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, 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 aspects, in further embodiments, 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 intranasally, or / and / or (f) administered by injection to a mammal, 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 non-systemically or topically to a mammal.

[0009] In any of the foregoing aspects, further embodiments comprising a single administration of an effective amount of the compound include further embodiments in which the compound is administered to the mammal once daily, or in which the compound is administered to the mammal multiple times daily. 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 a human.

[0012] An article of manufacture is provided that includes 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 acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically acceptable active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used to modulate one or more melanocortin receptor subtype proteins or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that would benefit from modulation of one or more melanocortin receptor subtype proteins.

[0013] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It will be understood, however, that the detailed description and the specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF 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 primary regulator of adrenal glucocorticoid (GC) synthesis and secretion (cortisol in humans and most other species, corticosterone in rodents). As a central player in the hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted from the pituitary gland in response to stressful stimuli and acts in the adrenal gland to promote cortisol synthesis and secretion. This stimulation is mediated by a highly specific G protein-coupled receptor (GPCR) that is almost exclusively expressed in the adrenal cortex. This receptor, the melanocortin 2 receptor (MC2R), is part of the larger melanocortin system, along with ACTH.

[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 hormone (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 selectivity for endogenous agonist and antagonist peptides and are expressed in diverse tissues, where they perform a variety of distinct 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 of MCRs. In some embodiments, selectively modulating any one or a combination of MCRs relative to other MCRs is useful in various clinical applications. In some embodiments, selectively modulating any one or a combination of 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 selective antagonists of MC2R or other MCRs.

[0017] MC2R is a highly selective receptor for ACTH. Although ACTH can activate all five MCRs, at physiological levels, the sensitivity of other receptors is not high enough to activate ACTH, and ACTH selectively activates MC2R. Importantly, other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, do not have any affinity for MC2R (Gantz, I. and TM Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003). The primary function of MC2R is to stimulate fasciculata cells of the adrenal cortex to synthesize and secrete cortisol. MC2R requires the GPCR accessory protein MRAP (melanocortin 2 receptor protein) to be secreted to the cell surface and function properly. MRAP is a small protein with a single transmembrane domain that 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 and affect the activity of any MCR, but it is essential only for the activity of MC2R. ACTH binding to the MC2R / MRAP complex in adrenocortical cells activates GS, increasing intracellular cAMP levels, which in turn promotes the synthesis and secretion of cortisol by regulating multiple steps in the steroidogenic pathway.

[0018] Cushing's syndrome is a rare disorder characterized by chronic glucocorticoid overexposure. Clinical symptoms of Cushing's syndrome include growth of fat pads (on the clavicles, back of the neck, face, and trunk), excessive sweating, dilated capillaries, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and various other metabolic abnormalities that result in high morbidity. When severe and poorly controlled, Cushing's syndrome is associated with a high mortality rate. While glucocorticoid excess can often be ACTH-independent due to, for example, hyperfunctioning adrenal adenomas, cancer, or excessive autonomous secretion of cortisol caused by steroid abuse, approximately 60–80% of cases are ACTH-dependent, known as Cushing's disease. Cushing's disease is caused by microadenomas of pituitary corticotropin-producing cells that secrete excessive ACTH. Corticotroph adenomas are small, usually slow-growing, benign tumors that typically become clinically noticeable as a result of glucocorticoid excess rather than the physical effects of tumor expansion. The first-line treatment for Cushing's disease is surgery, involving removal of the ACTH-secreting tumor in the pituitary gland or the adrenal gland itself. Because surgery is often unsuccessful, contraindicated, or delayed, medical treatment is required for these patients. Current treatment options include inhibitors of steroidogenic enzymes, which can prevent cortisol production and ameliorate symptoms, but these treatments also induce many undesirable side effects due to the accumulation of other steroid products. In one aspect, an MC2R antagonist is used in the treatment of Cushing's syndrome. In some embodiments, an MC2R antagonist is used in the treatment of Cushing's disease. In some embodiments, the glucocorticoid excess is ACTH-independent. In some embodiments, the 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 occurring 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 reduced or absent cortisol synthesis and excess ACTH and corticotropin-releasing hormone. CAH can result from various genetic defects in the adrenal steroid biosynthesis pathway. In some embodiments, CAH results from a mutation in 21β-hydroxylase. Cortisol deficiency eliminates negative feedback to the pituitary gland, leading to excessive secretion of ACTH. As a result, the adrenal glands are overstimulated, causing excessive production of steroid precursors, which also have adverse effects (e.g., hyperandrogenemia). Administration of replacement glucocorticoids typically fails to adequately suppress ACTH without also causing Cushing's-like symptoms. In some embodiments, an MC2R antagonist is used in the treatment of CAH.

[0021] In addition to Cushing's disease, ectopic ACTH syndrome, and CAH, it has also been hypothesized that MC2R antagonists may have a role in the treatment of ACTH-driven adrenal tumors, functional adrenal hyperandrogenism (FAH), stress disorders, psychiatric disorders, type 2 diabetes, and septic shock. In some embodiments, MC2R antagonists are used in the treatment of ACTH-driven adrenal tumors. In some embodiments, MC2R antagonists are used in the treatment of functional adrenal hyperandrogenism. In some embodiments, MC2R antagonists are used in the treatment of stress disorders. In some embodiments, MC2R antagonists are used in the treatment of psychiatric disorders. In some embodiments, MC2R antagonists are used in the treatment of type 2 diabetes. In some embodiments, MC2R antagonists are used in the treatment of septic shock. In some embodiments, MC2R antagonists are used in the treatment of septic shock.

[0022] In some embodiments, the compounds described herein are amenable to administration to a mammal in need of treatment with an MC2R antagonist.

[0023] compound The compounds of formula (I), including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are melanocortin receptor modulators. In some embodiments, the compounds of formula (I), including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are MC2R modulators. In some embodiments, the MC2R modulators are MC2R antagonists.

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

[0025] [ka] During the ceremony, R A is unsubstituted or substituted heteroaryl or unsubstituted or substituted aryl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one, two, three, or four groups selected from R a , R b , and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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 heteroaryl; R a , R b , and R c Any substituted group in may be one or more R 6 is substituted with a group, Or, one R a and one R b is R A If present on an adjacent atom of a R b and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or contains one or more R 6 is substituted with a group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R B is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, three, or four groups selected from R d , R e , and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )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 heteroaryl, wherein R d , R e , and R f Any substituted group in may be one or more R 6 is substituted with a group, where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; X 1 is CR 11 or N, X 2 is CR 12 or N, X 3 is CR 13 or N, X 4 is CR 14 or N, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, -OR 4 , -SR 4 , -CO2R 4 , -C(=O)N(R 4 )2, or -N(R 4 )2, M is -(C=O)-, -NR 3 -, -O-, -S-, -SO2-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, -NR 3 -(C=O)NR 3 -, * -NR 3 (SO2)-, * -SO2NR 3 -, or a 5-membered heterocycle, wherein * is R 1 indicates the point of attachment to R 1is 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 -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, R 3 are each independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R 4 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Or two R's 4 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle, R 5are each independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R 6 are each independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -COR 5 , -CH2CO2R 5 , -C(=O)N(R 4 )2, -C(=O)N(R 4 ) OR 5 , -CH2C(=O)N(R 4 )2, -N(R 4 )2, -CH2N(R 4 )2, -C(R 5 )2N(R 4 )2, -NR 4 C(=O)R 5 , -CH2NR 4 C(=O)R 5 , -NR 4 C(=O)N(R 5 )2, -NR 4 C(=O)N(R 4 )2, C(R 5 )=N(R 4 )-OR 5 , -SR 5 , -S(=O)R 7 , -SO2R 7 , or -SO2N(R 4 )2, and R 7 are each independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

[0026] In some embodiments, M is —C(═O)—, —NR 3 -, -O-, -S-, -SO2-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -NR 3 SO2-, or a 5-membered heterocycle, wherein * is R 1 In some embodiments, M represents a point of attachment to -C(=O)-, -NR 3 -, -O-, -S-, -SO2-, * -(C=O)-NR 3 -, * -NR 3 -(C=O)-, * -NR 3 SO2-, or a 5-membered heteroaryl, where * is R 1 indicates the attachment point to

[0027] In some embodiments, M is —O—, * -NR 3 -C(=O)-, -S-, -SO2-, * -NR 3 SO2-, or a 5-membered heteroaryl, where * is R 1 indicates the attachment point to

[0028] In some embodiments, M is a 5-membered heterocycle. 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.

[0029] In some embodiments, M is —NR 3 -, -O-, * -NR 3 -(C=O)-, *-(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 In some embodiments, M indicates the point of attachment to * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 In some embodiments, M indicates the point of attachment to * -NR 3 -(C=O)- or * -(C=O)-NR 3 -where: * is R 1 indicates the attachment point to

[0030] In some embodiments, M is * -(C=O)-NR 3 -where: * is R 1 In some embodiments, M represents the point of attachment to * -NR 3 -(C=O)-, where * is R 1 indicates the attachment point to

[0031] In some embodiments, R 3 are each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 3are each independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, R 3 are each independently hydrogen or -CH. In some embodiments, R 3 are each -CH3. In some embodiments, R 3 are hydrogen atoms.

[0032] In some embodiments, M is —NR 3 -, -O-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 indicates the point of attachment to R 3 are each independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, M is * -NR 3 -(C=O)- or * -(C=O)-NR 3 -where: * is R 1 indicates the point of attachment to, and R 3 is hydrogen.

[0033] In some embodiments, M comprises an N atom and the N atom of M is R 1 where R 1 further comprises an N atom. In some embodiments, the N atom of M is connected to R by one carbon atom, two carbon atoms, three carbon atoms, or four carbon atoms. 1 In some embodiments, the N atom of M is connected to the N atom of R by a two carbon atom spacer. 1 In some embodiments, R1 The N atom in R is part of an unsubstituted or substituted aliphatic alkyl chain. 1 The N atom of R is part of an unsubstituted or substituted cyclic ring. 1 The N-containing cyclic ring of is an unsubstituted or substituted monocyclic C2-C7 heterocycloalkyl or an unsubstituted or substituted bicyclic C2-C7 heterocycloalkyl.

[0034] In some embodiments, the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

[0035] [ka]

[0036] In some embodiments, the compound has the structure of Formula (IIb): or a pharmaceutically acceptable salt or solvate thereof.

[0037] [ka]

[0038] In some embodiments, R A is an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is R a , R b, and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0039] In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is one R a In some embodiments, R A is replaced by one Rc.

[0040] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, 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, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, or unsubstituted or substituted phenyl, wherein R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0041] In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R AIf is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S; R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0042] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, 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 If is substituted, R Ais R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0043] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0044] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, or unsubstituted or substituted thienyl, where R A If is substituted, R A is R a , R b , and Rc In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with a group

[0045] In some embodiments, R A teeth,

[0046] [ka] or R A teeth,

[0047] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0048] In some embodiments, R A teeth,

[0049] [ka] or R A teeth,

[0050] [ka] where R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0051] In some embodiments, R A teeth,

[0052] [ka] or R A teeth,

[0053] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0054] In some embodiments, R A teeth,

[0055] [ka] In some embodiments, R A teeth,

[0056] [ka] is.

[0057] In some embodiments, R A teeth,

[0058] [ka] where R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0059] [ka] In some embodiments, R A teeth,

[0060] [ka] In some embodiments, R A teeth,

[0061] [ka] In some embodiments, R A teeth,

[0062] [ka] is.

[0063] In some embodiments, R A teeth,

[0064] [ka] or R A teeth,

[0065] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0066] In some embodiments, R A teeth,

[0067] [ka] or R A teeth,

[0068] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0069] In some embodiments, R A teeth,

[0070] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R cis hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHCHCHCHCHCH, or -CHCHCH(CH). In some embodiments, R c is hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, R c is hydrogen or -CH3. In some embodiments, R c is —CH3. In some embodiments, R c is hydrogen. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl. In some embodiments, R c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. In some embodiments, R c is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0071] In some embodiments, R A teeth,

[0072] [ka] and Y 1 is NR c , O, or S, and Y 2 and Y 3are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0073] [ka] and Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0074] [ka] and Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0075] [ka] and Y1 is NR c and Y 2 and Y 3 are CH, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0076] In some embodiments, R A teeth,

[0077] [ka] In some embodiments, R A teeth,

[0078] [ka] is.

[0079] In some embodiments, R A teeth,

[0080] [ka] and Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0081] [ka] and Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0082] [ka] and Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0083] [ka] and Y 1 is NR c and Y 2 and Y 3 are CH, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0084] In some embodiments, the compound has the structure of Formula (III):

[0085] [ka] In the formula, Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0086] In some embodiments, the compound has the structure of Formula (IIIa):

[0087] [ka] In the formula, Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0088] In some embodiments, the compound has the structure of Formula (IIIb):

[0089] [ka] In the formula, Y 1 is NR c , O, or S, and Y 2and Y 3 are independently CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0090] In some embodiments, R A is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, or unsubstituted or substituted phenyl, wherein R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0091] In some embodiments, R A is unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R cIn some embodiments, R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0092] In some embodiments, R A teeth,

[0093] [ka] is.

[0094] In some embodiments, R A teeth,

[0095] [ka] In some embodiments, R A teeth,

[0096] [ka] In some embodiments, R A teeth,

[0097] [ka] is.

[0098] In some embodiments, R A teeth,

[0099] [ka] and V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0100] In some embodiments, R A teeth,

[0101] [ka] and V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0102] In some embodiments, the compound has the structure of formula (IV):

[0103] [ka] where V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0104] In some embodiments, the compound has the structure of Formula (IVa):

[0105] [ka] where V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0106] In some embodiments, the compound has the structure of Formula (IVb):

[0107] [ka] where V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0108] In some embodiments, R A is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c R is substituted with one, two, three, or four groups selected from A is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0109] In some embodiments, R A is 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 azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaidazolyl, unsubstituted or substituted benzimidazolyl, substituted or unsubstituted azabenzyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, unsubstituted or substituted benzobenzoxazolyl, 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 A If is substituted, R Ais R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0110] In some embodiments, R A is unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0111] In some embodiments, R A is unsubstituted or substituted indazolyl or unsubstituted or substituted benzofuranyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0112] In some embodiments, R Bis unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0113] In some embodiments, R Bis phenyl, unsubstituted or substituted naphthyl, 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 benzimidazolyl 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 If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, RB is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0114] In some embodiments, R B is unsubstituted or substituted phenyl, or unsubstituted or substituted 6-membered monocyclic heteroaryl, where R B If is substituted, R B is R d , R e , and R f 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 R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0115] In some embodiments, R B is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and Rf and is substituted with one, two, or three groups selected from:

[0116] In some embodiments, R B teeth,

[0117] [ka] In some embodiments, R B teeth,

[0118] [ka] In some embodiments, R B teeth,

[0119] [ka] In some embodiments, R B teeth,

[0120] [ka] is.

[0121] In some embodiments, R B teeth,

[0122] [ka] and W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0123] In some embodiments, the compound has the structure of Formula (V):

[0124] [ka] In the formula, Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CR d , C.R. e , or N.

[0125] In some embodiments, the compound of Formula (V) has the following structure: or a pharmaceutically acceptable salt or solvate thereof:

[0126] [ka]

[0127] In some embodiments, M is * -NR 3 -(C=O)-, where * is R 1 indicates the attachment point to

[0128] In some embodiments, W is CH or N.

[0129] In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , C.R. b or N. In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b In some embodiments, Y 1 is NR cand Y 2 and Y 3 are CH respectively.

[0130] In some embodiments, the compound has the structure of Formula (Va):

[0131] [ka] In the formula, Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , C.R. b , or N and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CR d , C.R. e , or N.

[0132] In some embodiments, W is CH or N.

[0133] In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , C.R. b or N. In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b In some embodiments, Y 1 is NR c and Y 2 and Y 3 are CH respectively.

[0134] In some embodiments, the compound has the structure of Formula (Vb):

[0135] [ka] In the formula, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CR d , C.R. e , or N.

[0136] In some embodiments, W is CH or N.

[0137] In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0138] In some embodiments, the compound has the structure of Formula (Vc):

[0139] [ka] In the formula, R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CR d , C.R. e , or N.

[0140] In some embodiments, W is CH or N.

[0141] In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0142] In some embodiments, the compound has the structure of Formula (Vd):

[0143] [ka] In the formula, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CR d , C.R. e , or N.

[0144] In some embodiments, W is CH or N.

[0145] In some embodiments, R cis hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0146] In some embodiments, the compound has the structure of Formula (Ve):

[0147] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0148] In some embodiments, the compound has the structure of Formula (Vf):

[0149] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0150] In some embodiments, the compound has the structure of Formula (Vg):

[0151] [ka] W is CH, CR d , C.R. eor N. In some embodiments, W is CH or N.

[0152] In some embodiments, the compound has the structure of Formula (Vh):

[0153] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0154] In some embodiments, the compound has the structure of Formula (Vi):

[0155] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0156] In some embodiments, the compound has the structure of Formula (Vj):

[0157] [ka] During the ceremony, Y 1 is NR c , O, or S; Y 2 and Y 3 are independently CH, CR a , C.R. b , or N, R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl, and W is CH, CR d , C.R. e , or N.

[0158] In some embodiments, W is CH or N.

[0159] In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , C.R. b or N. In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b In some embodiments, Y 1 is NR c and Y 2 and Y 3 are CH respectively.

[0160] In some embodiments, the compound has the structure of Formula (Vk):

[0161] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl, and W is CH, CR d , C.R. e , or N.

[0162] In some embodiments, W is CH or N.

[0163] In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0164] In some embodiments, the compound has the structure of Formula (Vl):

[0165] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl, and W is CH, CR d , C.R. e , or N.

[0166] In some embodiments, W is CH or N.

[0167] In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. cis hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0168] In some embodiments, the compound has the structure of Formula (Vm):

[0169] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl, and W is CH, CR d , C.R. e , or N.

[0170] In some embodiments, W is CH or N.

[0171] In some embodiments, R c is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C cycloalkyl, or unsubstituted or substituted C-C heterocycloalkyl. c is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0172] In some embodiments, the compound has the structure of Formula (Ve):

[0173] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0174] In some embodiments, the compound has the structure of Formula (Vf):

[0175] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0176] In some embodiments, the compound has the structure of Formula (Vg):

[0177] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0178] In some embodiments, the compound has the structure of Formula (Vh):

[0179] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0180] In some embodiments, the compound has the structure of Formula (Vp):

[0181] [ka] W is CH, CR d , C.R. e or N. In some embodiments, W is CH or N.

[0182] In some embodiments, the compound has the structure of Formula (VI):

[0183] [ka] where V is CH, CR a , C.R. b or N, and W is CH, CR d , C.R. e , or N.

[0184] In some embodiments, the compound of formula (VI) has the following structure: or a pharmaceutically acceptable salt or solvate thereof:

[0185] [ka]

[0186] In some embodiments, M is * -NR 3 -(C=O)-, where * is R 1 In some embodiments, M represents the point of attachment to * -(C=O)-NR 3 -where: * is R 1 indicates the attachment point to

[0187] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N and W is CH or N.

[0188] In some embodiments, the compound has the structure of Formula (VIa):

[0189] [ka] where V is CH, CR a , C.R. b or N, and W is CH, CR d , C.R. e , or N.

[0190] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N and W is CH or N.

[0191] In some embodiments, the compound has the structure of Formula (VIb):

[0192] [ka] where V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0193] In some embodiments, the compound has the structure of Formula (VIc):

[0194] [ka] where V is CH, CR a , C.R. bor N, and W is CH, CR d , C.R. e , or N.

[0195] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N and W is CH or N.

[0196] In some embodiments, the compound has the structure of Formula (VId):

[0197] [ka] where V is CH, CR a , C.R. b or N. In some embodiments, V is CH or N.

[0198] In some embodiments, R B is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0199] In some embodiments, R B is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R B If is substituted, R B is R d , R e, and R f In some embodiments, R B is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R B If is substituted, R B is R d , R e , and R f In some embodiments, 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, or unsubstituted or substituted thiadiazolyl, wherein R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0200] In some embodiments, R B teeth,

[0201] [ka] or R B teeth,

[0202] [ka] where R f is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0203] In some embodiments, R 1 is 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 -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, where R 1 contains a basic amine group.

[0204] In some embodiments, R 1is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1 to 4 N atoms and 0 or 1 O or S atom, an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1 to 2 N atoms, or an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0205] In some embodiments, R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R4 )2 or R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms, or R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0206] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, or R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0207] In some embodiments, R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0208] In some embodiments, R 1 is an unsubstituted or substituted C-C heteroalkyl containing one N atom. In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0209] In some embodiments, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom.

[0210] In some embodiments, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1 to 2 N atoms.

[0211] In some embodiments, R 1is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0212] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 or R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R 1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0213] In some embodiments, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0214] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 is replaced by

[0215] In some embodiments, the compound has the structure of Formula (VIIa):

[0216] [ka] where W is CH, CR a , C.R. b or N. In some embodiments, W is CH or N.

[0217] In some embodiments, the compound has the structure of Formula (VIIb):

[0218] [ka] where V is CH, CR a , C.R. b or N, and W is CH, CR d , C.R. e , or N.

[0219] In some embodiments, the compound has the structure of Formula (VIIc):

[0220] [ka] where W is CH, CR a , C.R. b or N. In some embodiments, W is CH or N.

[0221] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N and W is CH or N.

[0222] In some embodiments, the compound has the structure of Formula (VIId):

[0223] [ka] where W is CH, CR a, C.R. b or N. In some embodiments, W is CH or N.

[0224] In some embodiments, the compound has the structure of Formula (VIIe):

[0225] [ka] where V is CH, CR a , C.R. b or N, and W is CH, CR d , C.R. e , or N.

[0226] In some embodiments, the compound has the structure of Formula (VIIf):

[0227] [ka] where W is CH, CR a , C.R. b or N. In some embodiments, W is CH or N.

[0228] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N and W is CH or N.

[0229] In some embodiments, the compound has the structure of Formula (VIII):

[0230] [ka] During the ceremony, R Ais unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, wherein R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f and M is -NR 3 -, -O-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 indicates the attachment point to

[0231] In some embodiments, X 1 is CR 11 and X 2 is CR 12 and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is N and X 2 is CR12 and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is CR 11 and X 2 is N and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is N and X 2 is CR 12 and X 3 is CR 13 and X 4 is N. In some embodiments, X 1 is N and X 2 is N and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is N and X 2 is CR 12 and X 3 is N, and X 4 is CR 14 In some embodiments, X 1 is CR 11 and X 2 is CR 12 and X 3 is CR 13 and X 4 is CR 14 is.

[0232] In some embodiments, X 1 is CR 11 or N and X 2 is CR 12 and X 3 is CR 13 and X 4 is CR 14 is.

[0233] In some embodiments, X1 is CR 11 or N and X 2 is CR 12 or N and X 3 is CR 13 and X 4 is CR 14 is.

[0234] In some embodiments, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, fluoroalkyl, unsubstituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, F, Cl, Br, -CN, -OCH, -OCHCH, -CH, -CH, -CHCH, -CHCH, -CH(CH), -CHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHF, -CHF, -CF, or cyclopropyl. 11 , R 12 , R 13 , and R 14 are each independently hydrogen or F.

[0235] In some embodiments, X 1 is CH or CF, and X 2 is CH or CF, and X 3 is CH or CF, and X 4is CH or CF. In some embodiments, X 1 is N and X 2 is CH or CF, and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is CH or CF, and X 2 is N and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is N and X 2 is CH or CF, and X 3 is CH or CF, and X 4 is N. In some embodiments, X 1 is N and X 2 is N and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is N and X 2 is CH or CF, and X 3 is N, and X 4 is CH or CF. In some embodiments, X 1 is CH or CF, and X 2 is CH or CF, and X 3 is CR 13 and X 4 is CR 14 is.

[0236] In some embodiments, X 1 is CH, CF, or N, and X 2 is CH or CF, and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is CR 11 or N and X 2 is CH and X 3 is CH, and X 4 is CH. In some embodiments, X1 is CH, CF, or N, and X 2 is CH and X 3 is CH, and X 4 is CH.

[0237] In some embodiments, X 1 is CH, CF, or N, and X 2 is CH, CF, or N, and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is CR 11 or N and X 2 is CR 12 or N and X 3 is CH, and X 4 is CH. In some embodiments, X 1 is CH, CF, or N, and X 2 is CH, CF, or N, and X 3 is CH, and X 4 is CH.

[0238] In some embodiments, X 1 is CH, CF, or N, and X 2 is CH or CF, and X 3 is CR 13 and X 4 is CH or CF. In some embodiments, X 1 is CH, CF, or N, and X 2 is CH and X 3 is CR 13 and X 4 is CH. In some embodiments, X 1 is N and X 2 is CH and X 3 is CR 13 and X 4 is CH.

[0239] In some embodiments, X 1 is CH or N, and X 2is CH or N, and X 3 is CH, CF, or N, and X 4 is CH or N. In some embodiments, X 1 is CH or N, and X 2 is CH or N, and X 3 is CH or CF, and X 4 is CH. In some embodiments, X 1 is N and X 2 is CH and X 3 is CH or CF, and X 4 is CH. In some embodiments, X 1 is N and X 2 is CH and X 3 is CH, and X 4 is CH. In some embodiments, X 1 is N and X 2 is CH and X 3 is CF, and X 4 is CH.

[0240] In some embodiments, R 13 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 13 is hydrogen, halogen, C1-C6 alkyl, fluoroalkyl, unsubstituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 13 is hydrogen, F, Cl, Br, -CN, -OCH, -OCH, -CH, -CH, -CH, -CHCH, -CH(CH), -CH, -CH, -CH(CH), -CH, -CH(CH), -CH(CH)CH, -C(CH), -CHF, -CHF, -CF, or cyclopropyl. 13 is hydrogen or F. In some embodiments, R 13is hydrogen. In some embodiments, R 13 is F.

[0241] In some embodiments, M is * -NR 3 -(C=O)- or * -(C=O)-NR 3 -where: * is R 1 indicates the attachment point to

[0242] In some embodiments, R A is unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from:

[0243] In some embodiments, R B is unsubstituted or substituted phenyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0244] In some embodiments, R a , R b , and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R a, R b , and R c Any substituted group in may be one or more R 6 group, or one R a and one R b is R A If present on an adjacent atom of a R b and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or contains one or more R 6 group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl, and R d , R e , and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein R d , R e , and R f Any substituted group in may be one or more R 6 group, where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0245] In some embodiments, R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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; R A Any substituted group in may be one or more R 6 substituted with a group, and R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group in may be one or more R 6 group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl.

[0246] In some embodiments, R ais hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH 2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF 3, -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 hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -C is selected from the group consisting of HCN, -CHF, -CHF, -CF, -CHCHOH, -CHCHCN, -CHCHF, -CHCHF, -CHCF, -CHOCH, -CHCHOCH, -CHNH, -CHNHCH, -CHN(CH), -CHCHNH, -CHCHNHCH, and -CHCHN(CH); a , R b , or R cis attached to the N atom of the heteroaryl, it is hydrogen, —C(O)CH, —C(O)CHCH, —CH, —CHCH, —CHCHCH, —CH(CH), —CHCHCHCH, —CH(CH), —CHCHCHCH, —CH(CH)(CHCH), —C(CH), —CHCHCH(CH), —CHOH, —CHCN, —CHF, —CHF, —CF, —CHCHOH, —CHCHCN, —CHCHF, —CHCHF, —CHCF, —CHOCH, —CHCHOCH, —CHNH, —CHNHCH, —CHN(CH), —CHCHNH, —CHCHNHCH, and —CHCHN(CH).

[0247] In some embodiments, R A One R on the adjacent atom of a and one R b is R a R b and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic cycloalkyl or a 5- to 6-membered monocyclic heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or contains one or more R 6 In some embodiments, R A One R on an adjacent atom of a and one R b is R a R b and together with the intervening atoms connecting them to form a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl is unsubstituted or contains one or more R 6 The group is substituted.

[0248] In some embodiments, R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4)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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group in may be one or more R 6 substituted with R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl.

[0249] In some embodiments, R dis hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C (CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2O is selected from the group consisting of CH, -CHNH, -CHNHCH, -CHN(CH), -CHCHNH, -CHCHNHCH, -CHCHN(CH), unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C-C heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; d Any substituted group in may be one or more R 6 substituted with R e and R f are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3, wherein R d , R e , or R fis attached to the N atom of the heteroaryl, it is hydrogen, —C(O)CH, —C(O)CHCH, —CH, —CHCH, —CHCHCH, —CH(CH), —CHCHCHCH, —CH(CH), —CHCHCHCH, —CH(CH)(CHCH), —C(CH), —CHCHCH(CH), —CHOH, —CHCN, —CHF, —CHF, —CF, —CHCHOH, —CHCHCN, —CHCHF, —CHCHF, —CHCF, —CHOCH, —CHCHOCH, —CHNH, —CHNHCH, —CHN(CH), —CHCHNH, —CHCHNHCH, and —CHCHN(CH).

[0250] In some embodiments, R A is an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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; R A Any substituted group in may be one or more R 6 is substituted with a group, R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group in may be one or more R 6 is substituted with a group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group in may be one or more R 6 is substituted with a group, R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; where Rd , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; X 1 is CR 11 or N, X 2 is CR 12 or N, X 3 is CR 13 or N, X 4 is CR 14 or N, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, -CN, -OR 4 , or -N(R 4 )2, M is * -NR 3 -(C=O)- or * -(C=O)-NR 3 -where: * is R 1 indicates the point of attachment to R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, Alternatively, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0251] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from X 1 is CH or N, X 2 is CH or N, X 3 is CR 13 or N, X 4 is CH or N, M is * -NR3 -(C=O)- or * -(C=O)-NR 3 -where: * is R 1 indicates the point of attachment to R 11 , R 12 , R 13 , and R 14 are each independently hydrogen, F, Cl, -CH3, CF3, -CN, or -OR 4 , or -N(R 4 )2, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 is replaced by Alternatively, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0252] In some embodiments, R A teeth,

[0253] [ka] or R A teeth,

[0254] [ka] or R A teeth,

[0255] [ka] and V is CH or N; R a is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b and R c are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl; R B teeth

[0256] [ka] and W is CH or N; R d is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R e and R f are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl; X 1 is CH, CF, or N, X 2 is CH, CF, or N, X 3 is CH, CF, or N, X 4 is CH, CF, or N, M is * —NH—(C═O)— or * -(C=O)-NH-, where * is R 1 indicates the point of attachment to R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, Alternatively, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0257] In some embodiments, R A teeth,

[0258] [ka] and V is CH or N; R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and R b and R c are independently selected from the group consisting of hydrogen, F, Cl, —CH, —CHF, —CHF, —CF, —CN, and —OCH; R B teeth

[0259] [ka] and W is CH or N; R d is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; R e and R f are independently selected from the group consisting of hydrogen, F, Cl, Br, —CH, —CHF, —CHF, —CF, —CN, —OH, and —OCH; X 1 is CH or N, X 2 is CH or N, X 3 is CH, CF, or N, X 4 is CH or N, M is * —NH—(C═O)— or * -(C=O)-NH-, where * is R 1 indicates the point of attachment to R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, Alternatively, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0260] In some embodiments, the compound has the structure of formula (IX):

[0261] [ka] During the ceremony, R Ais an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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; R A Any substituted group in may be one or more R 6 is substituted with a group, and R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group in may be one or more R 6 is substituted with a group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R B If is substituted, R B is R d , Re , and R f and is substituted with one, two, or three groups selected from R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group in may be one or more R 6 is substituted with a group, and R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; X 1 is CR 11 or N, X 2 is CR 12 or N, R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, -CN, -OR 4 , or -N(R 4 )2, M is -NR 3 -, -O-, * -NR 3-(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 indicates the point of attachment to, and R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, Alternatively, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0262] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from X 1 is CR 11 or N, X 2 is CR 12 or N, R 11 and R 12 are each independently hydrogen, F, Cl, -CH3, CF3, -CN, or -OR 4 , or -N(R 4 )2, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 is replaced by Alternatively, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0263] In some embodiments, the compound has the structure of Formula (IXa):

[0264] [ka] During the ceremony, R A is an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , 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; R A Any substituted group in may be one or more R 6 is substituted with a group, and R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group in may be one or more R 6 is substituted with a group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )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, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group in may be one or more R 6 is substituted with a group, and R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; X 1 is CR 11 or N, R 11 is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, -CN, -OR 4 , or -N(R 4 )2, M is -NR 3 -, -O-, * -NR 3 -(C=O)-, * -(C=O)-NR 3 -, * -O-(C=O)NR 3 -, * -NR 3 -(C=O)O-, or -NR 3 -(C=O)NR 3 -where: * is R 1 indicates the point of attachment to, and R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4)2, Alternatively, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0265] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from X 1 is CR 11 or N, R 11 is hydrogen, F, Cl, -CH3, CF3, -CN, -OR4 , or -N(R 4 )2, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 is replaced by Alternatively, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Alternatively, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Alternatively, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0266] In some embodiments, R A teeth,

[0267] [ka] or R A teeth,

[0268] [ka] or R A teeth,

[0269] [ka] and V is CH or N; R B teeth,

[0270] [ka] and W is CH or N.

[0271] In some embodiments, R A teeth,

[0272] [ka] or R A teeth,

[0273] [ka] and V is CH or N; R B teeth,

[0274] [ka] and W is CH or N.

[0275] In some embodiments, R A teeth,

[0276] [ka] and R B teeth,

[0277] [ka] and W is CH or N.

[0278] In some embodiments, R A teeth,

[0279] [ka] and R B teeth,

[0280] [ka] and W is CH or N.

[0281] In some embodiments, R A teeth,

[0282] [ka] and R B teeth,

[0283] [ka] and W is CH or N.

[0284] In some embodiments, the compound has the structure of Formula (X):

[0285] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0286] In some embodiments, the compound has the structure of Formula (Xa):

[0287] [ka] During the ceremony, R a and R b are independently hydrogen, halogen, -OR 4, —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0288] In some embodiments, R a and R b is independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl; R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl.

[0289] In some embodiments, the compound has the structure of Formula (Xb):

[0290] [ka] In the formula, X 1 is N and X 2 is CH or N, and R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0291] In some embodiments, X 2 is N. In some embodiments, X 2is CH.

[0292] In some embodiments, the compound has the structure of Formula (Xc):

[0293] [ka] In the formula, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0294] In some embodiments, the compound has the structure of Formula (Xd):

[0295] [ka] In the formula, R a and R b are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0296] In some embodiments, R a and R b is independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl; Rc is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl.

[0297] In some embodiments, the compound has the structure of formula (Xe):

[0298] [ka] In the formula, X 1 is N, and R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0299] In some embodiments, the compound has the structure of formula (XI):

[0300] [ka] V is CH or N.

[0301] In some embodiments, the compound has the structure of Formula (XIa):

[0302] [ka] V is CH or N, and R a is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b and R care independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0303] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; R b and R c are independently selected from the group consisting of hydrogen, F, Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, and —OCH 3 .

[0304] In some embodiments, the compound has the structure of Formula (XIb):

[0305] [ka] In the formula, V is CH or N, and X 1 is N, and X 2 is CH or N.

[0306] In some embodiments, X 2 is N. In some embodiments, X 2 is CH.

[0307] In some embodiments, the compound has the structure of Formula (XIc):

[0308] [ka] V is CH or N.

[0309] In some embodiments, the compound has the structure of Formula (XId):

[0310] [ka] V is CH or N; R a is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b and R c are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0311] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3, and R b and R c are independently selected from the group consisting of hydrogen, F, Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, and —OCH 3 .

[0312] In some embodiments, the compound has the structure of formula (XIe):

[0313] [ka] wherein V is CH or N, and X 1 is N.

[0314] In some embodiments, the compound has the structure of Formula (XII):

[0315] [ka]

[0316] In some embodiments, the compound has the structure of Formula (XIIa):

[0317] [ka] During the ceremony, R a is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0318] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3, and R b is selected from the group consisting of hydrogen, F, Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, and —OCH 3 .

[0319] In some embodiments, X 1 is N, and X 2is CH or N. In some embodiments, X 2 is N. In some embodiments, X 2 is CH.

[0320] In some embodiments, the compound has the structure of Formula (XIIb), or a pharmaceutically acceptable salt or solvate thereof:

[0321] [ka]

[0322] In some embodiments, the compound has the structure of Formula (XIIc):

[0323] [ka] During the ceremony, R a is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0324] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3, and R bis selected from the group consisting of hydrogen, F, Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, and —OCH 3 .

[0325] In some embodiments, X 1 is N, and X 2 is CH or N. In some embodiments, X 2 is N. In some embodiments, X 2 is CH.

[0326] In some embodiments, the compound has the structure of Formula (XIII):

[0327] [ka] W is CH or N.

[0328] In some embodiments, the compound has the structure of Formula (XIIIa):

[0329] [ka] During the ceremony, W is CH or N; R d is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R e and R f are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0330] In some embodiments, R dis selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; R e and R f are independently selected from the group consisting of hydrogen, F, Cl, Br, —CH3, —CH2F, —CHF2, —CF3, —CN, —OH, and —OCH3.

[0331] In some embodiments, the compound has the structure of Formula (XIIIb):

[0332] [ka] In the formula, X 1 is N and X 2 is CH or N, W is CH or N, and R d is selected from the group consisting of F, Cl, —CN, —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , and —CF 3 .

[0333] In some embodiments, X 2 is N. In some embodiments, X 2 is CH.

[0334] In some embodiments, the compound has the structure of Formula (XIIIc):

[0335] [ka] W is CH or N.

[0336] In some embodiments, the compound has the structure of Formula (XIIId):

[0337] [ka] where W is CH or N, and R d is hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R e and R f are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0338] In some embodiments, R d is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; R e and R f are independently selected from the group consisting of hydrogen, F, Cl, Br, —CH3, —CH2F, —CHF2, —CF3, —CN, —OH, and —OCH3.

[0339] In some embodiments, the compound has the structure of Formula (XIIIe):

[0340] [ka] In the formula, X 1 is N, W is CH or N, and R d is selected from the group consisting of F, Cl, —CN, —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , and —CF 3 .

[0341] In some embodiments, R1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 or R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R 1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0342] In some embodiments, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0343] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may include one or more of halogen, C1-C4 alkyl, —N(R 4 )2, or -OR 5 is replaced by

[0344] In some embodiments, the compounds described herein have the following structure:

[0345] [ka]

[0346] In some embodiments, R A , R B , X 1 , X 2 , X3, X 4 , and R 1is as described herein.

[0347] In some embodiments, R A , R B , X 1 , X 2 , X3, X 4 , and R 1 are as listed in Table 1.

[0348] In some embodiments, R A teeth,

[0349] [ka] is.

[0350] In some embodiments, R B teeth,

[0351] [ka] is.

[0352] In some embodiments, X 1 is CH or N. In some embodiments, X 2 is CH or N. In some embodiments, X 3 is CH, CF, or N. In some embodiments, X 4 is CH or N.

[0353] In some embodiments, X 1 is CH or N, and X 2 is CH or N, and X 3 is CH or CF, and X 4 is CH. In some embodiments, X 1 is CH or N, and X 2 is CH and X 3 is CH or CF, and X 4 is CH.

[0354] In some embodiments, R 1 teeth,

[0355] [ka]

[0356] [ka] is.

[0357] In some embodiments, the compounds described herein have the following structure:

[0358] [ka]

[0359] In some embodiments, R A , R B , X 1 , X 2 , X3, M, and R 1 is as described herein. In some embodiments, R A , R B , X 1 , X 2 , X3, M, and R 1 are as listed in Table 2.

[0360] In some embodiments, R A teeth,

[0361] [ka] is.

[0362] In some embodiments, R B teeth,

[0363] [ka] is.

[0364] In some embodiments, X 1 is CH or N.

[0365] In some embodiments, X 2 is CH or N.

[0366] In some embodiments, X 3 is CH or CF.

[0367] In some embodiments, M is —O—, —NH—,

[0368] [ka] where: * is R 1 indicates the attachment point to

[0369] In some embodiments, R 1 teeth,

[0370] [ka] is.

[0371] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0372] Representative compounds of formula (I) include those set forth in the table below:

[0373] [Table 1-1]

[0374] [Table 1-2]

[0375]

Table 1-3

[0376]

Table 1-4

[0377]

Table 1-5

[0378]

Table 1-6

[0379]

Table 1-7

[0380]

Table 1-8

[0381]

Table 1-9

[0382]

Table 1-10

[0383]

Table 1-11

[0384]

Table 1-12

[0385]

Table 1-13

[0386]

Table 1-14

[0387]

Table 1-15

[0388]

Table 1-16

[0389]

Table 1-17

[0390]

Table 1-18

[0391]

Table 1-19

[0392]

Table 1-20

[0393]

Table 1-21

[0394]

Table 1-22

[0395]

Table 1-23

[0396] [Table 1-24]

[0397] [Table 1-25]

[0398] [Table 1-26]

[0399] [Table 1-27]

[0400] [Table 1-28]

[0401] [Table 1-29]

[0402] [Table 1-30]

[0403] [Table 1-31]

[0404] The compounds in Table 1 are named as follows: 1-1: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-3: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-4: N-[(2R)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-5: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-6: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-7: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-8: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-9: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-10: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-11: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-12: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-13: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-14: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-15: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-16: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-17: N-[(2R)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-18: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-19: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-20: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-21: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-22: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-23: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-24: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-25: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 1-26: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-27: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3S)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 1-28: N-[(2S)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-29: 1-[2-chloro-6-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-30: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-31: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-32: 1-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-33: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-34: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-35: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide, 1-36: 1-(4-acetyl-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-37: 1-[2-cyano-4-(difluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-38: 1-[4-cyano-2-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-39: 1-[2-cyano-4-(trifluoromethoxy)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-40: 1-(2,4-dicyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-41: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S,4S) * -4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-42: 1-[3-cyano-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-43: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-44: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2R)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide, 1-45: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-46: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R,4R) * -4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-47: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide, 1-48: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-51: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-52: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-53: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-dihydro-1-benzofuran-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-54: 4-[6-(1-benzofuran-7-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-55: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(hydroxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-56: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-57: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-58: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-59: 1-[2-cyano-4-(1,1-difluoroethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-60: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-61: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-62: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-63: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-64: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-65: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-66: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-67: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-68: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-69: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-5-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-70: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[1-(3-methylbutyl)-1H-pyrazol-5-yl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-71: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}piperidine-4-carboxamide, 1-72: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-73: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indazol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-74: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-75: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)-3-fluorophenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-76: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-77: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethyl)phenyl]pyridin-3-yl}piperidine-4-carboxamide, 1-78: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyanophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-79: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(methoxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-80: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methoxythiophen-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-81: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-82: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-83: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-84: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(1,1-difluoroethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-85: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethoxy)-[2,3'-bipyridin]-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-86: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-87: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-88: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-89: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-90: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-91: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-92: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-93: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-94: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-95: 1-(2,4-dichlorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-96: 1-(2-cyano-4-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-97: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-98: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-99: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-100: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-101: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-102: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-103: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-104: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-105: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(4-methylpyrimidin-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-106: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-107: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-108: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-109: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-110: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-111: 1-(4-chloro-2-cyano-6-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-112: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-113: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-114: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethoxy)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-115: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-116: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-117: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propylphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-118: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-119: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-120: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-121: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-122: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-123: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-124: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-125: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-126: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-127: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-128: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-129: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-hydroxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-130: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxy-5-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-131: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-132: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-133: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-134: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-135: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-136: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-137: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(cyanomethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-138: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(4-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-139: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-140: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-141: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-142: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-143: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-144: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-145: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-146: 4-[6-(2-acetylthiophen-3-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-147: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylthiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-148: 4-[6-(2-cyano-3-fluorophenyl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-149: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-150: 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-151: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethyl)phenyl]pyridin-3-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-152: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-153: 4-[6-(5-cyano-1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-154: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-155: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-156: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-157: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-158: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-cyclopropyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-159: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-160: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-161: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-162: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-163: 1-(4-chloro-2-cyanophenyl)-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-164: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-165: 1-[3-chloro-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-166: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-167: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-168: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-169: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-170: 1-(4-chloro-2-cyanophenyl)-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-171: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-172: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-173: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-174: 4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-175: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-176: 4-{[2,2'-bipyridin]-5-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-177: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methyl-[2,2'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-178: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methoxy-[2,2'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-179: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-180: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-cyclopropyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-181: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-182: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-cyclopropyl-1,3-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-183: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-184: ethyl (3S)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-amide}pyrrolidine-1-carboxylate, 1-185: N-[(3S)-1-acetylpyrrolidin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-186: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-187: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-188: N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-189: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyquinolin-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-190: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-191: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-192: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-193: 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-194: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-195: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-196: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-197: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide, 1-198: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-199: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-200: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-201: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-202: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-203: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-204: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-205: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-206: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide, 1-207: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-208: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-209: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-210: 4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-211: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-212: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-213: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-214: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-215: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-216: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-217: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-218: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-219: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-220: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-221: N-{1-azabicyclo[2.2.1]heptan-4-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-222: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-223: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-224: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-225: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-226: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-227: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-228: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-229: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-230: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-231: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-232: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-233: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-aminocyclobutyl]piperidine-4-carboxamide, 1-234: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-aminocyclobutyl]piperidine-4-carboxamide, 1-235: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-236: N-{[(2R)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-237: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-238: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-239: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide, 1-240: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide, 1-241: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-242: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-243: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-244: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-245: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-246: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-247: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-248: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-249: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-250: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-251: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide, 1-252: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide, 1-253: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1,3-dimethylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-254: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-255: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-256: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-257: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-258: rac-N-[(1R,2S)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-259: rac-N-[(1R,2R)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-260: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-261: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-262: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{3-[(dimethylamino)methyl]oxetan-3-yl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-263: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[1-(dimethylamino)cyclopropyl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-264: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-(dimethylamino)oxolan-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-265: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[ethyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-266: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[cyclopropyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-267: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-268: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-269: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-270: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-271: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-272: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-273: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-274: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-275: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-276: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-277: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-278: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-279: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-280: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2R)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-281: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-282: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-283: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-284: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-285: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-286: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-287: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-288: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-289: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-290: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-291: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxamide, 1-292: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-293: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-294: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-295: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-296: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-297: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-298: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-299: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-300: N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-301: 4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-302: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-303: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-304: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-305: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-306: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-307: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-308: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-309: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-310: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-311: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-312: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-313: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-314: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-315: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-316: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-317: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-318: 1-(2,4-dichlorophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-319: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-320: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-321: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-322: 1-(2,4-dichlorophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-323: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-324: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-325: 1-(4-chloro-2-cyanophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-326: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-327: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide, 1-328: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3S)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide, 1-329: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3R)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide, 1-330: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide, 1-331: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxamide, 1-332: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-333: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-334: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-335: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide.

[0405] [Table 2-1]

[0406] [Table 2-2]

[0407] [Table 2-3]

[0408] [Table 2-4]

[0409] [Table 2-5]

[0410] [Table 2-6]

[0411] The compounds in Table 2 are named as follows: 2-1: 2-{4-[2-(dimethylamino)ethoxy]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-1-yl}-5-(trifluoromethyl)benzonitrile, 2-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl N-[2-(dimethylamino)ethyl]carbamate, 2-3: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}propanamide, 2-4: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}propanamide, 2-5: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)propanamide, 2-6: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide, 2-7: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-8: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide, 2-9: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-10: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(dimethylamino)propanamide, 2-11: (2S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide, 2-12: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate, 2-13: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate, 2-14: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-[(2-hydroxyethyl)amino]piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 2-15: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[2-(methylamino)ethyl]amino}piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 2-16: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-17: (2R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide, 2-18: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate, 2-19: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-20: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-21: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide, 2-22: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate, 2-23: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)azetidine-1-carboxamide, 2-24: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide, 2-25: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylazetidine-3-carboxamide, 2-26: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-2-(dimethylamino)acetamide, 2-27: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-28: (3S)—N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-29: (3R)—N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-30: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-3-(dimethylamino)propanamide, 2-31: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-2-(dimethylamino)acetamide, 2-32: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-33: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-34: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide, 2-35: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-36: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, 2-37: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-1-methylazetidine-3-carboxamide, 2-38: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-2-(dimethylamino)acetamide, 2-39: (3S)—N-[1-(4-chloro-2-cyanophenyl)-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-40: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-41: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-42: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-43: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-44: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}pyrrolidine-3-carboxamide, 2-45: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-46: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-47: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-48: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-49: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-50: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-51: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-52: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-53: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-54: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-55: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-56: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-57: 2-(dimethylamino)ethyl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-58: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[2-(dimethylamino)ethyl]urea, 2-59: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(1-methylazetidin-3-yl)urea, 2-60: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-61: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide, 2-62: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, 2-63: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(methylamino)propanamide, 2-64: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide.

[0412] In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included within the scope of this disclosure.In addition, the compounds described herein can exist not only in nonsolvated form, but also in solvated form, which contains pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0413] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0414] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for controlled passage through biological membranes.

[0415] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with an acid. In some embodiments, the compound of Formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. 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, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptan-1,2-disulfonic acid, methylparaben ... The following acidic acids include protonic 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.

[0416] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0417] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with a base. In some embodiments, the compound of Formula (I) is acidic and is reacted with a base. In such a situation, the acidic proton of the compound of Formula (I) is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. 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, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as arginine and 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, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0418] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric solvents, and are formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is 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 non-solvated as well as solvated forms.

[0419] 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 (I), as well as active metabolites of these compounds that possess the same type of activity.

[0420] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) portion of a compound of Formula (I) is susceptible to various metabolic reactions. By incorporating appropriate substituents into the organic radical, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, halogen, deuterium, an alkyl group, a haloalkyl group, or a deuterated alkyl group.

[0421] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0422] The compounds described herein include isotopically labeled compounds, which are identical to those detailed in the various formulas and structures presented herein except for the fact 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 normally found in nature. Examples of isotopes that can be incorporated into the present 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 33and isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium affords certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0423] In some embodiments, compounds of Formula (I) have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, compounds of Formula (I) exist in the R configuration. In some embodiments, compounds of Formula (I) exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0424] Individual stereoisomers can be obtained, as desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, compounds of Formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by separation of diastereomeric salts and separation by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0425] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. A prodrug may be, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, a prodrug has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design increases effective water solubility. An example of a prodrug is, without limitation, a compound described herein, which is administered as an ester ("prodrug") and then metabolically hydrolyzed to yield the active entity. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, which is metabolized to reveal 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 enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0426] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl 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, pp. 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, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, pp. 8, 1-38, each of which is incorporated herein by reference. In some embodiments, hydroxyl groups of the compounds disclosed herein are used to form prodrugs, and 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 group in the compounds disclosed herein is a prodrug, where the hydroxyl is metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0427] Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce a compound of formula (I) as described herein) are included within the scope of the claims. In some instances, some of the compounds described herein are prodrugs of another derivative or active compound.

[0428] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety, which in some embodiments is as described above.

[0429] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolites that are used to produce a desired effect, including a desired therapeutic effect.

[0430] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the totality of processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can cause specific structural changes to a compound. 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. Metabolites of the compounds disclosed herein are optionally identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0431] Compound synthesis The compounds of formula (I) described herein are synthesized using standard synthetic techniques, in combination with the methods described herein, or using methods known in the art.

[0432] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0433] The compounds are prepared using standard organic chemistry techniques, for example, as described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0434] In some embodiments, the compounds described herein are prepared as shown in Scheme A.

[0435] [ka]

[0436] Commercially available XVIII is R B Standard S with X N Ar reaction, or R B This is converted to compound XIX by Buchwald-Hartwig cross-coupling with X. Then, R A Suzuki-Miyaura coupling reaction using B(OH)2, or R A Stille coupling with SnBu3 affords R A The introduction of XX gives compound XX. This ester is hydrolyzed to acid XXI, which is then reacted with R via HATU. 1 Amide coupling reaction with NH2 gives the final compound XXII. 1If contains a protecting group, a further deprotection step is carried out to give XXII.

[0437] In some embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0438] [ka]

[0439] Methyl 2-(6-chloropyridin-3-yl)acetate undergoes a one-pot reaction with N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine in the presence of a strong inorganic base such as KOH to give the piperidinyl intermediate XXIII. A Suzuki-Miyaura coupling reaction using B(OH)2 yields R A and debenzylation to give compound XXIV. B is R B Standard S with X N Ar reaction, or R B The final R in XXX can be introduced by either a Buchwald-Hartwig cross-coupling reaction with X followed by hydrolysis to give the acid XXV. 1 The change in R 1 This is achieved by a HATU-mediated coupling reaction with NH. Starting from intermediate XXIII, R A (XXVI-XXVII-XXX) and various R B The introduction of various 5- and 6-membered aromatic rings into (XXVIII-XXIX-XXX) is achieved by varying the reaction sequence as described in the scheme. 1 If contains a protecting group, a further deprotection step is carried out to give XX.

[0440] In some embodiments, the compounds described herein are prepared as depicted in Scheme C.

[0441] [ka]

[0442] Cyanomethylation of 5-bromo-2-chloro-3-fluoropyridine to XXXII proceeds efficiently via Suzuki-Miyaura coupling with isoxazole-4-boronic acid pinacol ester, base-induced fragmentation, and deformylation. The nitrogen-containing heterocycle XXXIII is obtained by cyclocondensation of XXXII with N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine in a strongly alkaline medium. Starting from intermediate XXXIII, various R groups in the final XXXVI can be synthesized. B and R 1 The introduction of R is achieved via intermediates XXXIV and XXXV, respectively. The reaction conditions for each route are similar to those described in the previous schemes. 1 If contains a protecting group, a further deprotection step can be carried out to give XXXVI.

[0443] In some embodiments, the compounds described herein are prepared as depicted in Scheme D.

[0444] [ka]

[0445] Dichloropyridazine or pyrazine is converted to acetic acid XXXVII via the formation of a malonic acid adduct and removal of the tert-butyloxycarbonyl group under acidic conditions. Starting from XXXVII, intermediate XL is prepared in a similar manner as described in Scheme B. Because the acid in XL is chemically unstable, the amide bond can be cleaved by the ester and R 1 S with NH2 / LiHMDS N Direct introduction by reaction 2. R 1 If XLI contains a protecting group, a further deprotection step can be carried out to give XLI.

[0446] In some embodiments, the compounds described herein are prepared as depicted in Scheme E.

[0447] [ka]

[0448] Cyanomethyl-substituted pyrimidine XLII is obtained by a three-step sequence: Suzuki coupling, mesylation, and cyanation. Starting from XLII, the final compound XLVI is prepared in a similar manner as described in Scheme C. 1 If X contains a protecting group, a further deprotection step can be carried out to give XLVI.

[0449] In some embodiments, the compounds described herein are prepared as depicted in Scheme F.

[0450] [ka]

[0451] Curtius rearrangement of XXV with diphenylphosphoryl azide (DPPA) affords an isocyanate intermediate, which upon in situ trapping with benzyl alcohol affords XLVII. Deprotection to XLVIII, followed by R 1 HATU-mediated coupling reaction with NH2 gives the final XLIX. The isocyanate L derived from XLVIII can be converted to an alcohol (R 1 OH) and amines (R 1 R 3 NH) and various nucleophiles such as S N 2 reactions occur, giving carbamate (LI) or urea (LII) derivatives, respectively. 1 If contains protecting groups at XLIX, LI, and LII, the final product requires an additional deprotection step.

[0452] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0453] Specific Terms Unless otherwise specified, definitions of the following terms used in this application are provided below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0454] As used herein, C1-C x is C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of 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.

[0455] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight chain. In some embodiments, an "alkyl" group can contain 1 to 10 carbon atoms, i.e., C1-C 10The term "alkyl" includes alkyl. Numeric ranges such as "1 to 10," whenever they appear herein, refer to each integer within the specified range. 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, although this definition also encompasses occurrences of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 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.

[0456] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups listed above may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0457] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0458] The term "alkylamine" refers to an -N(alkyl) x H y It refers to a 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.

[0459] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with a hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0460] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with an amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0461] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, R is H or alkyl. In some embodiments, 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.

[0462] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl 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, 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, and -CH2C≡CH.

[0463] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0464] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (n ​​is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic and fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0465] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from "heterocyclic" or "heterocycle," in which the ring backbone contains at least one atom other than carbon. In some embodiments, a carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, a carbocycle is a monocyclic carbocycle. A carbocycle is non-aromatic or aromatic. A non-aromatic carbocycle is saturated or partially unsaturated. In some embodiments, a carbocycle is a bicyclic carbocycle. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0466] 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, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl is C6-C 10 Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0467] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic aliphatic, non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among 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, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0468] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0469] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with fluorine atoms. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0470] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocyclic group has 3 to 10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. 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, dithio ranyl, 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, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are 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 foregoing groups may be C-bonded (or C-linked) or N-bonded where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). 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.

[0471] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0472] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a 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, a heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0473] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one embodiment, when a group described herein is a single bond, the referenced group is absent, thereby allowing for the formation of a single bond between the remaining specified groups.

[0474] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0475] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl.In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C heterocycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0476] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0477] The term "modulate" as used herein means to interact with a target directly or indirectly so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0478] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0479] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with 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.

[0480] The term "co-administration," as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0481] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or disorder being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the quantity of a composition comprising a compound as disclosed herein that is required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0482] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0483] As used herein, the term "pharmaceutical combination" refers to 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 (I) or a pharmaceutically acceptable salt thereof, and an auxiliary agent are both administered to a patient at the same time in the form of a single entity or dosage. The term "unfixed combination" refers to the active ingredients, e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an auxiliary agent, administered to a patient simultaneously, concurrently, or sequentially as separate entities without specific intervening time restrictions, whereby such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0484] The terms "article of manufacture" and "kit" are used synonymously.

[0485] The term "subject" or "patient" includes 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 monkey species; livestock such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0486] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., suppressing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition prophylactically and / or therapeutically.

[0487] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the route of administration selected. Summary summaries of the pharmaceutical compositions described herein are found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0488] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by a method that allows 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 (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, ophthalmic, otic, intranasal, and vaginal) administration, although the most appropriate route can depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implantation. Administration may also be by direct injection at the site of the diseased tissue or organ.

[0489] 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 liquid. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0490] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in a quantity 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, stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of dosages of active compound.

[0491] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0492] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that 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 carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0493] Pharmaceutical compositions can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection.Thus, for example, compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0494] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0495] Pharmaceutical compositions can be administered locally, i.e., non-systemically. This includes applying the compounds of the present invention to the external epidermis or buccal cavity, and instilling the compounds into the ear, eye, and nose, so that the compounds do not enter the bloodstream in large amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0496] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose. The active ingredient may comprise 0.001%-10% w / w, for example 1%-2% by weight, of the formulation for topical administration.

[0497] Pharmaceutical compositions administered by inhalation are conveniently delivered from an insufflator, a nebulizer, a pressurized pack, or other conventional means for delivering an aerosol spray. The pressurized pack may 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 may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the formulation may take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in a unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0498] For example, it will be understood that, in addition to the ingredients mentioned above, among others, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0499] Dosage and treatment regimens In one embodiment, a compound of 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 of such treatment comprises administering to said mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0500] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The amount effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dosage-finding clinical trials.

[0501] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dosage." For this application, the precise amount will vary depending on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced and is in remission of at least one symptom of the disease being treated, to prevent the recurrence of the disease or condition.

[0502] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise suppress or limit the symptoms of the patient's disease or disorder.

[0503] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0504] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0505] In general, however, dosages used in adult human treatment are typically in the range of 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0506] In one embodiment, a suitable daily dosage of a compound of Formula (I) or a pharmaceutically acceptable salt thereof described herein 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 will be less than or greater than the ranges set forth herein, depending on many variables related to the particular treatment regimen. In various embodiments, the daily dosage amount and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0507] 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, determining the LD50 and ED50. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein lies within a range of circulating concentrations that includes the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dose will vary within this range depending on the dosage form used and the route of administration utilized.

[0508] In any of the foregoing aspects, in further embodiments, 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 injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0509] In any of the foregoing aspects, there are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0510] In any of the foregoing aspects, there are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments where (i) the compound is administered continuously or intermittently, such as in a single dose; (ii) the interval between multiple doses 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; or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0511] Combination therapy In certain instances, it will be appropriate to administer at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0512] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit on its own, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has a therapeutic effect.

[0513] In one particular embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall effect than administration of either therapeutic agent alone.

[0514] In all cases, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic effect.

[0515] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of 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 or sequentially with the one or more other therapeutic agents.

[0516] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0517] In conjunction with the combination therapy, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as prophylactics to prevent the onset of a disease or condition and are administered continuously to a subject prone to a disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period necessary to treat the condition. In some embodiments, the period required for treatment can vary, and the treatment period is tailored to the specific needs of each subject.

[0518] omission: DIEA: N,N-diisopropylethylamine, DMSO: dimethyl sulfoxide; CuI: copper(I) iodide; 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; Prep-HPLC: preparative high performance liquid chromatography; TFA: trifluoroacetic acid; CH3CN: acetonitrile, MeOD: deuterated methanol; CDCl3: deuterated chloroform, DME: 1,2-dimethoxyethane; H2O: water, KOAc: potassium acetate; NaOAc: sodium acetate; Cs2CO3: Cesium carbonate, P-TsOH: p-toluenesulfonic acid, NaNO2: sodium nitrate, THF: tetrahydrofuran; NBS: N-bromosuccinimide, 4Å MS: 4Å molecular sieve; DPPA: diphenylphosphoryl azide; Br2: bromine, AgF: silver fluoride; LiAlH4: lithium aluminum hydride, LiHMDS: lithium bis(trimethylsilyl)amide; IBX: 2-iodoxybenzoic acid; CDI: 1,1′-carbonyldiimidazole; TEA: Trimethylamine; HOBT: hydroxybenzotriazole; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0), Pd(OH)2: palladium hydroxide, Pd(PPh3)2Cl2: bis(triphenylphosphine)dichloride palladium(II), Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdAMphos or Pd(amphos)Cl2 or: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(DTBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), Pd2(dba)3.CHCl3: Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, RuPhos-Pd-G3: dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane palladium methanesulfonate 2-phenylaniline, XPhos-Pd-G2: chloro(2-dicyclohexynylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), rt: room temperature, h: time, CPD: Compound. [Example]

[0519] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0520] Compound synthesis

[0521] Example 1: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide (Compound 1-3)

[0522] [ka]

[0523] Step 1-1, Preparation of methyl 4-(4-bromophenyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylate: Methyl 4-(4-bromophenyl)piperidine-4-carboxylate hydrochloride (500 mg, 1.49 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (706 mg, 3.74 mmol), DIEA (772 mg, 5.98 mmol), and DMSO (5 mL) were placed in a thick-walled tube. The tube was sealed, and the resulting solution was then stirred at 125 °C for 16 hours and cooled to room temperature. The reaction was directly purified by reverse-phase C18 column chromatography to give the title compound (600 mg, 86%). LCMS (M+H) + =467.3.

[0524] Step 1-2, Preparation of methyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylate: Methyl 4-(4-bromophenyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylate (480 mg, 1.03 mmol), (2-ethoxypyridin-3-yl)boronic acid (343 mg, 2.05 mmol), PdAMphos (73 mg, 0.103 mmol), potassium carbonate (284 mg, 2.05 mmol), and dioxane / HO (5 mL / 0.5 mL) were placed in a thick-walled tube. The resulting mixture was degassed with N for 5 minutes, sealed, and stirred at 80 °C for 1 hour. The reaction was cooled to room temperature and concentrated. The residue was purified by reverse phase C18 column chromatography to give the title compound (450 mg, 86%). LCMS (M+H) + =510.3.

[0525] Step 1-3, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylic acid: To a suspension of methyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylate (450 mg, 0.883 mmol) in EtOH (8 mL) was added 2N lithium hydroxide (4 mL, 8.83 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 3 hours and cooled to room temperature. After removal of the volatile solvents, the aqueous layer was filtered to remove inorganic solids. The aqueous filtrate was acidified with 1N HCl to a pH of approximately 4 to obtain a precipitate. The solid precipitate was collected, washed with HO, and dried to give the title compound (270 mg, 62%). LCMS (M+H) + =496.1.

[0526] Step 1-4, Preparation of tert-butyl N-[2-({1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}formamido)ethyl]carbamate: To a solution of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylic acid (30 mg, 0.061 mmol) in ACN (1 mL) was added HATU (25 mg, 0.067 mmol) and TEA (12 mg, 0.12 mmol) at room temperature. After stirring at room temperature for 5 minutes, the reaction was treated with tert-butyl (2-aminoethyl)carbamate (12 mg, 0.073 mmol). The resulting solution was stirred for 30 minutes at room temperature and then directly purified by reverse phase C18 column chromatography to give the title compound (30 mg, 78%). LCMS (M+H) + =638.1.

[0527] Step 1-5, Preparation of N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide: To a solution of tert-butyl N-[2-({1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}formamido)ethyl]carbamate (30 mg, 0.047 mmol) in DCM (0.4 mL) was added TFA (0.1 mL) at room temperature. The reaction was stirred for 1 hour at room temperature and concentrated in vacuo. The residue was purified by reverse phase C18 column chromatography to give the title compound (18.5 mg, 73%). LCMS (M+H) + =538.4.

[0528] The following compounds were prepared in a similar manner to Example 1, using the appropriate substitution reagents and substrates at various steps. Some examples do not require deprotection in the final step.

[0529] [Table 3]

[0530] Example 2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[3,3′-bipyridin]-6-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-22)

[0531] [ka]

[0532] Step 2-1, Preparation of 2-(5-chloropyridin-2-yl)acetonitrile: A 250 mL round-bottom flask was charged with 5-chloro-2-(chloromethyl)pyridine (8.0 g, 49 mmol), potassium cyanide (4.5 g, 69 mmol), EtOH (80 mL), and HO (60 mL). The resulting mixture was stirred at 100 °C for 1 hour and cooled to room temperature. The reaction was quenched with water (200 mL) and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give the title compound (4.3 g, 57%) as a yellow oil. LCMS (M+H) + =153.2.

[0533] Step 2-2, Preparation of 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile: To a solution of 2-(5-chloropyridin-2-yl)acetonitrile (2.0 g, 13 mmol) and N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (5.0 g, 16 mmol) in DMSO (20 mL) was added KOH (2.0 g, 36 mmol) at room temperature. The resulting mixture was stirred at 30° C. for 1 hour and then quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This afforded the title compound (2.0 g, 49%) as a yellow oil. LCMS (M+H) + =312.0.

[0534] Step 2-3, Preparation of 1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carbonitrile: A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 1-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile (1.0 g, 3.2 mmol), (2-ethoxypyridin-3-yl)boronic acid (1.0 g, 6.0 mmol), Pd(dppf)Cl (0.3 g, 0.4 mmol), KCO (1.2 g, 8.7 mmol), and dioxane / HO (10 mL / 1 mL). The resulting solution was stirred at 80 °C under N for 1 h and cooled to room temperature. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (30:70) to give the title compound (1.0 g, 78%) as a yellow oil. LCMS (M+H) + =399.1.

[0535] Step 2-4, Preparation of 1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carboxylic acid: A 50 mL round-bottom flask was charged with 1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carbonitrile (1.0 g, 2.5 mmol), KOH (1.0 g, 17.8 mmol), EtOH (10 mL), and HO (10 mL). The resulting solution was stirred at 100 °C for 30 hours, cooled to room temperature, and concentrated in vacuo. The residue was diluted with HO, and the pH of the solution was then adjusted to approximately 4 with 4 M HCl. The solid precipitate was collected, washed with water, and dried to give the title compound as a white solid (800 mg, 80%). LCMS (M+H) + =418.3.

[0536] Step 2-5, Preparation of tert-butyl (3R)-3-(1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidin-4-amido)pyrrolidine-1-carboxylate: To a solution of 1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carboxylic acid (230 mg, 0.55 mmol) in DMF (4 mL) was added HATU (251 mg, 0.66 mmol) and DIEA (427 mg, 3.3 mmol) at room temperature. After stirring for 5 minutes at room temperature, the reaction was treated with tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (123 mg, 0.66 mmol). The resulting solution was stirred for 2 hours at room temperature and directly purified by preparative HPLC to give the title compound (230 mg, 71%) as a yellow solid. LCMS (M+H) + =586.3.

[0537] Step 2-6, Preparation of tert-butyl (3R)-3-(4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidin-4-amido)pyrrolidine-1-carboxylate: A 50 mL round-bottom flask was charged with tert-butyl (3R)-3-(1-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidin-4-amido)pyrrolidine-1-carboxylate (230 mg, 0.39 mmol), MeOH (10 mL), wet 10% Pd / C (30 mg), and Pd(OH) (30 mg, 0.21 mmol). The reaction flask was evacuated and flushed with nitrogen three times, then with hydrogen. The mixture was stirred under hydrogen (balloon) for 2 hours at room temperature. The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound (180 mg, 92%) as a yellow oil. LCMS (M+H) + =496.4.

[0538] Step 2-7, Preparation of tert-butyl (3R)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidin-4-amido}pyrrolidine-1-carboxylate: A solution of tert-butyl (3R)-3-(4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidin-4-amido)pyrrolidine-1-carboxylate (180 mg, 0.36 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (83 mg, 0.44 mmol), and DIEA (142 mg, 1.1 mmol) in DMSO (2 mL) was stirred for 2 hours at 70° C. The reaction was cooled to room temperature and purified directly by preparative HPLC to give the title compound (190 mg, 78%) as a yellow solid. LCMS (M+H) + =665.3.

[0539] Step 2-8, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide (Compound 2-21): To a solution of tert-butyl (3R)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-amide}pyrrolidine-1-carboxylate (190 mg, 0.28 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then diluted with HO. The pH of the solution was adjusted to 8-9 with saturated NaHCO. The solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (130 mg, 80%) as a yellow solid. LCMS (M+H) + =565.2.

[0540] Step 2-9, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide formate: To 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide (55 mg, 0.097 mmol) in MeOH (2 mL) was added formaldehyde (20 mg, 0.67 mmol) and AcOH (6.0 mg, 0.10 mmol), followed by sodium cyanoborohydride (sodium cyanotrihydroborate (12 mg, 0.19 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (20 mg, 33%) as a white solid. LCMS (M+H) + =579.3.

[0541] Example 3: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-51)

[0542] [ka]

[0543] Step 3-1, Preparation of 1-tert-butyl 3-ethyl 2-(5-chloropyrazin-2-yl)propanedioate: A 100 mL round-bottom flask purged and maintained under an inert atmosphere with nitrogen was charged with 2,5-dichloropyrazine (4.0 g, 27 mmol), cesium carbonate (26 g, 80 mmol), ethyl tert-butylmalonate (5.6 g, 30 mmol), and DMSO (40 mL). The resulting mixture was stirred at 100 °C for 2 hours and cooled to room temperature. The reaction was quenched with water (200 mL) and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This afforded the title compound (4.6 g, 57%) as a yellow oil. LCMS (M+H) + =301.1.

[0544] Step 3-2, Preparation of ethyl 2-(5-chloropyrazin-2-yl)acetate: To a solution of 1-tert-butyl 3-ethyl 2-(5-chloropyrazin-2-yl)propanedioate (4.6 g, 15 mmol) in DCM (40 mL) was added TFA (10 mL) in an ice bath. The reaction was stirred for 1 hour at 0 °C and quenched with water (100 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give the title compound (2.6 g, 85%) as a yellow oil. LCMS (M+H) +=201.1.

[0545] Step 3-3, Preparation of ethyl 1-benzyl-4-(5-chloropyrazin-2-yl)piperidine-4-carboxylate: A 50 mL round-bottom flask was charged with ethyl 2-(5-chloropyrazin-2-yl)acetate (1.0 g, 5.0 mmol), 18-crown-6 (300 mg, 1.13 mmol), and DMF (10 mL). The reaction mixture was cooled to 0 °C and then treated with 60% NaH (600 mg, 15 mmol). After stirring for 0.5 h at 0 °C, the reaction was treated with N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (1.8 g, 5.6 mmol). The resulting mixture was stirred at room temperature for 2 h and then quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This gave the title compound (800 mg, 45%) as a yellow oil. LCMS (M+H) + =360.2.

[0546] Step 3-4, Preparation of ethyl 1-benzyl-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate: To a 50 mL three-necked bottle purged and maintained under an inert atmosphere of nitrogen, ethyl 1-benzyl-4-(5-chloropyrazin-2-yl)piperidine-4-carboxylate (800 mg, 2.22 mmol), (2-ethoxypyridin-3-yl)boronic acid (557 mg, 3.34 mmol), Pd(DTBPF)Cl (145 mg, 0.22 mmol), KCO (922 mg, 6.67 mmol), and dioxane / HO (8 mL / 0.8 mL) were added. The resulting mixture was stirred under N at 90 °C for 2 h and cooled to room temperature. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1) to give the title compound (800 mg, 80%) as a yellow oil. LCMS (M+H) + =447.5.

[0547] Step 3-5, Preparation of ethyl 4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate: To a solution of ethyl 1-benzyl-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (800 mg, 1.79 mmol) in MeOH (20 mL) was added 10% Pd / C (191 mg) and Pd(OH) (252 mg, 1.79 mmol). The flask was evacuated and flushed with nitrogen three times, then with hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 40 minutes. The resulting solution was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound (580 mg, 91%) as a white oil. LCMS (M+H) + =357.3.

[0548] Step 3-6, Preparation of ethyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate: An 8 mL vial was charged with ethyl 4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (200 mg, 0.56 mmol), DIEA (218 mg, 1.69 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (212 mg, 1.12 mmol), and DMSO (2 mL). The resulting mixture was stirred at 60° C. for 2 hours and cooled to room temperature. The crude product was purified by preparative HPLC to give the title compound (220 mg, 74%). LCMS (M+H) + =526.5.

[0549] Step 3-7, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: In an 8 mL vial purged and maintained under an inert atmosphere of nitrogen was placed ethyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (40 mg, 0.076 mmol), (R)-1-methylpyrrolidin-3-amine (23 mg, 0.23 mmol), LHMDS (130 mg, 0.77 mmol), and THF (1.3 mL). The resulting mixture was stirred under N2 at room temperature for 1 hour, then quenched with saturated NH4Cl (20 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (13 mg, 28%). LCMS (M+H) + =580.2.

[0550] The following compounds were prepared similarly to Example 3, using the appropriate substitution reagents and substrates at the various steps.

[0551] [Table 4]

[0552] Example 4: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-56)

[0553] [ka]

[0554] Step 4-1, Preparation of ethyl 1-benzyl-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate: Starting from 3,6-dichloropyridazine, the title compound was prepared in a similar manner as described in steps 3-1 to 3-4 of Example 3. LCMS (M+H) + =447.3.

[0555] Step 4-2, 1-tert-butyl 4-ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-1,4-dicarboxylate: A 100 mL round-bottom flask was charged with ethyl 1-benzyl-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate (240 mg, 0.54 mmol), di-tert-butyl decarbonate (350 mg, 1.60 mmol), MeOH (30 mL), TEA (160 mg, 1.58 mmol), 10% Pd / C (20 mg), and Pd(OH) (20 mg, 0.14 mmol). The flask was evacuated and flushed with nitrogen three times, then with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 2 hours. The reaction was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by preparative HPLC to give the title compound (200 mg, 81%) as a pale yellow oil. LCMS (M+H)+ =457.4.

[0556] Step 4-3, Preparation of ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate trifluoroacetate: To a solution of 1-tert-butyl 4-ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-1,4-dicarboxylate (200 mg, 0.44 mmol) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. This gave the title compound (200 mg, 96%) as a yellow oil. LCMS (M+H) + =357.2.

[0557] Step 4-4, Preparation of ethyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate formate: An 8 mL vial was charged with ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate trifluoroacetate (200 mg, 0.42 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (96 mg, 51 mmol), DIEA (200 mg, 1.55 mmol), and DMSO (3 mL). The resulting solution was stirred at 60 °C for 1 hour and cooled to room temperature. The reaction was directly purified by preparative HPLC to give the title compound (145 mg, 60%) as a pale yellow oil. LCMS (M+H) + =526.3.

[0558] Step 4-5, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: Ethyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate (60 mg, 0.11 mmol), (S)-1-methylpyrrolidin-3-amine (30 mg, 0.30 mmol), and 1 M LiHMDS in THF (1.0 mL, 1.0 mmol) were placed in an 8 mL vial under N atmosphere. The resulting mixture was stirred at room temperature for 1 hour and then quenched with saturated NH Cl. The resulting solution was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (16 mg, 22%). LCMS (M+H) + =580.2.

[0559] The following compounds were prepared similarly to Example 4, using the appropriate substitution reagents and substrates at the various steps.

[0560] [Table 5]

[0561] Example 5: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-106)

[0562] [ka]

[0563] Step 5-1: Preparation of [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methanol: To a 100 mL three-necked bottle purged and maintained under an inert atmosphere with nitrogen, (2-chloropyrimidin-5-yl)methanol (3.0 g, 21 mmol), (2-ethoxypyridin-3-yl)boronic acid (4.0 g, 21 mmol), Pd(DTBPF)Cl (1.4 g, 2.1 mmol), KCO (9.0 g, 65 mmol), and dioxane (30 mL) in HO (3 mL) were added at room temperature. The resulting reaction mixture was stirred at 60 °C for 1 hour and cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (2:1) to give the title compound (4.2 g, 88%). LCMS (M+H) + =232.1.

[0564] Step 5-2: Preparation of methyl [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methanesulfonate: To a solution of [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methanol (2.0 g, 8.6 mmol) and TEA (3.0 g, 30 mmol) in DCM (20 mL) was added MsCl (1.0 g, 8.7 mmol) slowly in an ice bath. The reaction was stirred for 1 h at 0 °C, quenched with water (30 mL), and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded the title compound (2.3 g, 86%) as a yellow oil. LCMS (M+H) + =310.1.

[0565] Step 5-3, Preparation of 2-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]acetonitrile: A 50 mL round-bottom flask was charged with methyl [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methanesulfonate (2.3 g, 7.4 mmol), sodium cyanide (1.1 g, 22 mmol), and DMSO (20 mL). The resulting mixture was stirred at room temperature for 1 h, quenched with aqueous FeSO (~100 mL), and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column using DCM / MeOH (10:1) to give the title compound (1.3 g, 73%) as a yellow oil. LCMS (M+H) + =241.1.

[0566] Step 5-4, Preparation of 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carbonitrile: A 50 mL round-bottom flask was charged with 2-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]acetonitrile (600 mg, 2.5 mmol), N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (962 mg, 3.0 mmol), KOH (420 mg, 7.49 mmol), and DMSO (10 mL). The resulting mixture was stirred at room temperature for 1 hour, quenched with water (50 mL), and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:1). This gave the title compound (450 mg, 45%) as a yellow oil. LCMS (M+H) + =400.2.

[0567] Step 5-5, Preparation of 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carboxylic acid: A 50 mL round-bottom flask was charged with 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carbonitrile (450 mg, 1.13 mmol), KOH (632 mg, 11.3 mmol), and EtOH (5 mL) / HO (2.5 mL). The resulting mixture was stirred at 100 °C for 16 h and cooled to room temperature. The reaction was diluted with water (20 mL), then adjusted to pH 6-7 with 3N HCl and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded the title compound (400 mg, 85%) as a yellow oil. LCMS (M+H) + =419.2.

[0568] Step 5-6, Preparation of 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carboxylic acid (180 mg, 0.43 mmol) in DMF (2 mL) was added HATU (164 mg, 0.43 mmol) and DIEA (167 mg, 1.29 mmol) at room temperature. After stirring at room temperature for 10 minutes, the reaction was treated with (S)-1-methylpyrrolidin-3-amine (52 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 hour and directly purified by preparative HPLC to give the title compound (150 mg, 70%) as a white oil. LCMS (M+H) + =501.3.

[0569] Step 5-7, Preparation of tert-butyl 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-4-{[(3S)-1-methylpyrrolidin-3-yl]carbamoyl}piperidine-1-carboxylate: A 50 mL round-bottom flask was charged with 1-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (160 mg, 0.32 mmol), TEA (98 mg, 0.97 mmol), (Boc)O (209 mg, 0.96 mmol), wet 10% Pd / C (34 mg), Pd(OH) (45 mg 0.32 mmol), and MeOH (10 mL). The flask was evacuated and flushed with nitrogen three times, then with hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 30 minutes. The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (40 mg, 25%) as a white oil. LCMS (M+H) + =511.3.

[0570] Step 5-8, Preparation of 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate: To a solution of tert-butyl 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-4-{[(3S)-1-methylpyrrolidin-3-yl]carbamoyl}piperidine-1-carboxylate (40 mg, 0.078 mmol) in DCM (1 mL), TFA (0.3 mL) was added. The resulting solution was stirred at room temperature for 1 hour and then concentrated in vacuo. This gave the title compound (30 mg, 60%) as a yellow oil. LCMS (M+H) + =411.3.

[0571] Step 5-9, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate: In an 8 mL vial, 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate (30 mg, 0.047 mmol), DIEA (28 mg, 0.22 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (28 mg, 0.15 mmol), and DMSO (1 mL) were placed. The resulting mixture was stirred at 60 ° C. for 2 hours and cooled to room temperature. The reaction was purified by preparative HPLC to give the title compound (14 mg, 38%). LCMS (M+H) + =580.3.

[0572] The following compounds were prepared similarly to Example 5, using the appropriate substitution reagents and substrates at the various steps.

[0573] [Table 6]

[0574] Example 6: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-124)

[0575] [ka]

[0576] Step 6-1, Preparation of 2-chloro-3-fluoro-5-(1,2-oxazol-4-yl)pyridine: To a 250 mL three-necked bottle purged and maintained under an inert atmosphere of nitrogen was added 5-bromo-2-chloro-3-fluoropyridine (5.0 g, 24 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (5.6 g, 29 mmol), Pd(DTBPF)Cl (1.5 g, 2.3 mmol), KF (4.1 g, 71 mmol), and DMSO (50 mL) in HO (5 mL). The resulting mixture was stirred at 100 °C for 1 h and cooled to room temperature. The reaction was diluted with HO and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (3.5 g, 74%) as a yellow solid. LCMS (M+H) + =199.0.

[0577] Step 6-2, Preparation of 2-(6-chloro-5-fluoropyridin-3-yl)acetonitrile: To a solution of 2-chloro-3-fluoro-5-(1,2-oxazol-4-yl)pyridine (3.5 g, 18 mmol) in MeOH (35 mL) / HO (3.5 mL) was added KF (0.2 g, 3.0 mmol). The resulting solution was stirred at 90 °C for 1 hour and cooled to room temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give the title compound (2.3 g, 77%) as a yellow solid. LCMS (M+H) + =171.1.

[0578] Step 6-3, Preparation of 1-benzyl-4-(6-chloro-5-fluoropyridin-3-yl)piperidine-4-carbonitrile: A 50 mL round-bottom flask was charged with 2-(6-chloro-5-fluoropyridin-3-yl)acetonitrile (2.3 g, 13 mmol), N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (4.3 g, 13 mmol), KOH (2.3 g, 41 mmol), and DMSO (25 mL). The resulting mixture was stirred at room temperature for 1 hour, quenched with water (100 mL), and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This afforded the title compound (2.7 g, 61%) as a yellow oil. LCMS (M+H) + =330.2.

[0579] Step 6-4, Preparation of 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carbonitrile: To a 50 mL three-necked bottle purged and maintained under an inert atmosphere of nitrogen, 1-benzyl-4-(6-chloro-5-fluoropyridin-3-yl)piperidine-4-carbonitrile (500 mg, 1.52 mmol), (2-ethoxyphenyl)boronic acid (300 mg, 1.81 mmol), Pd(DTBPF)Cl (99 mg, 0.15 mmol), KCO (630 mg, 4.56 mmol), and dioxane (5 mL) in HO (0.5 mL) were added at room temperature. The resulting reaction mixture was stirred at 100 °C for 1 hour and cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1) to give the title compound (500 mg, 79%) as a pale yellow oil. LCMS (M+H) + =416.3.

[0580] Step 6-5, Preparation of 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxylic acid: A 50 mL round-bottom flask was charged with 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carbonitrile (500 mg, 1.2 mmol), KOH (675 mg, 12.0 mmol), and EtOH (10 mL) / HO (5 mL). The resulting mixture was stirred at 100 °C for 24 hours and cooled to room temperature. The reaction was diluted with water (20 ml), then adjusted to pH 6-7 with 3N HCl and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded the title compound (450 mg, 86%) as a yellow solid. LCMS (M+H) + =435.2.

[0581] Step 6-6, Preparation of 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxylic acid (140 mg, 0.32 mmol) in DMF (2 mL), HATU (123 mg, 0.32 mmol) and DIEA (125 mg, 0.97 mmol) were added. After stirring at room temperature for 10 minutes, the reaction mixture was treated with (S)-1-methylpyrrolidin-3-amine dihydrochloride (56 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 1 hour and directly purified by preparative HPLC to give the title compound (130 mg, 73%) as a white solid. LCMS (M+H) + =517.4.

[0582] Step 6-7, Preparation of 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: A 50 mL round-bottom flask was charged with 1-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (130 mg, 0.25 mmol), wet 10% Pd / C (27 mg), Pd(OH) (35 mg, 0.25 mmol), and MeOH (5 mL). The flask was evacuated and flushed with nitrogen three times, then with hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 30 minutes. The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound (90 mg, 84%) as a white oil. LCMS (M+H) + =427.5.

[0583] Step 6-8, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide formate: In an 8 mL vial, 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (45 mg, 0.11 mmol), DIEA (41 mg, 0.32 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (40 mg, 0.21 mmol), and DMSO (1 mL) were placed. The resulting mixture was stirred at 60 ° C. for 2 hours and cooled to room temperature. The reaction was purified by preparative HPLC to give the title compound (29 mg, 43%) as a white solid. LCMS (M+H) + =596.3.

[0584] The following compounds were prepared in a similar manner to Example 6, using the appropriate substitution reagents and substrates at various steps. Some examples do not require deprotection in the final step.

[0585] [Table 7]

[0586] Example 7: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-9)

[0587] [ka]

[0588] Step 7-1, Preparation of methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate: To a solution of methyl 6-chloropyridine-3-carboxylate (4.0 g, 22 mmol) and 18-crown-6 (1.1 g, 4.2 mmol) in DMF (30 mL) at 0 °C, 60% sodium hydride in mineral oil (2.2 g, 55 mmol) was added portionwise. The mixture was stirred for 2 hours at 0 °C. To this was added a solution of benzyl bis(2-bromoethyl)amine (8.3 g, 26 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EtOAc (3x). The combined organics were dried over anhydrous NaSO and concentrated to dryness to give the title compound (4.8 g, 65%) as a yellow solid. LCMS (M+H) + =345.2.

[0589] Step 7-2, Preparation of methyl 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a suspension of methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (1.8 g, 5.2 mmol) in 1,4-dioxane (20 mL) and water (2 mL) under nitrogen, potassium carbonate (2.2 g, 16 mmol), (2-ethoxypyridin-3-yl)boronic acid (1.7 g, 10 mmol), and Pd(dtbpf)Cl (0.10 g, 0.15 mmol) were added. The mixture was heated at 90 °C for 2 hours. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (1.8 g, 80%) as a pale yellow solid. LCMS (M+H) + =432.3.

[0590] Step 7-3, Preparation of methyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a solution of methyl 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.8 g, 4.2 mmol) in MeOH (25 mL), 10 wt% palladium on carbon (100 mg) and 20 wt% Pd(OH) on carbon (100 mg) were added. Hydrogen (g) was added to the mixture, which was stirred for 2 hours at room temperature. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.2 g, 60%) as a yellow oil. LCMS (M+H) + =342.2.

[0591] Step 7-4, Preparation of methyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a solution of methyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.2 g, 3.5 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (0.8 g, 4 mmol) in DMSO (15 mL) was added DIEA (1.4 g, 11 mmol). The mixture was heated at 60 °C for 2 h. The mixture was quenched with water and extracted with EtOAc (3x). The combined organics were concentrated to dryness, and the residue was purified by silica gel CC to give the title compound (1.1 g, 61%) as a white solid. LCMS (M+H) + =511.3.

[0592] Step 7-5, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid: To a suspension of methyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.4 g, 2.7 mmol) in a mixture of EtOH and water (2:1, 12 mL), lithium hydroxide (0.60 g, 25 mmol) was added. The mixture was heated at 60 °C for 2 h. The mixture was concentrated to remove the organics, and the aqueous residue was adjusted to pH 6-7 with 1 N HCl (aq). The solution was extracted with EtOAc (3X) and the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (1.2 g, 88%) as a pale yellow solid. LCMS (M+H) + =497.3.

[0593] Step 7-6, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (60 mg, 0.12 mmol) and HATU (55 mg, 0.14 mmol) in DMF (1 mL) was added DIEA (94 mg, 0.73 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine dihydrochloride (31 mg, 0.18 mmol) was added to the above HATU-activated solution. The mixture was stirred for 1 h at room temperature and purified by reverse phase CC to give the title compound (42 mg, 56%) as a white solid. LCMS (M+H) + =579.3.

[0594] The following compounds were prepared similarly to Example 7, using the appropriate substitution reagents and substrates at the various steps.

[0595] [Table 8]

[0596] Example 8: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-10)

[0597] [ka]

[0598] Step 8-1, Preparation of tert-butyl (3R)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-amido}pyrrolidine-1-carboxylate: To a solution of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (60 mg, 0.10 mmol) from Step 7-5 and HATU (58 mg, 0.15 mmol) in DMF (1 mL) was added DIEA (0.10 mL, 0.57 mmol). After stirring at room temperature for 5 minutes, tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (45 mg, 0.24 mmol) was added to the above HATU-activated solution. The mixture was stirred for 1 h at room temperature and purified by reverse phase CC to give the title compound (69 mg, 100%) as a light brown oil. LCMS (M+H) + =665.3.

[0599] Step 8-2, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of tert-butyl (3R)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-amide}pyrrolidine-1-carboxylate (69 mg, 0.10 mmol) in DCM (4 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and the residue was purified by reverse phase CC to give the title compound (32 mg, 51%) as a light brown oil. LCMS (M+H) + =565.3.

[0600] The following compounds were prepared in a similar manner to Example 8, using the appropriate substitution reagents and substrates at the various steps.

[0601] [Table 9]

[0602] Example 9: 1-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-32)

[0603] [ka]

[0604] Step 9-1, Preparation of ethyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate: To a solution of ethyl 6-chloropyridine-3-carboxylate (9.5 g, 48 mmol) in DMF (100 mL) at 0 °C, 60% sodium hydride in mineral oil (3.4 g, 0.14 mol) was added portionwise. The mixture was stirred for 0.5 h at 0 °C. To this, benzyl bis(2-bromoethyl)amine (8.3 g, 26 mmol) was added, and the mixture was stirred for 2 h at room temperature. The mixture was quenched with water and extracted with EtOAc (3x). The combined organics were dried over anhydrous NaSO and concentrated to dryness. The residue was purified by silica gel CC to give the title compound (12 g, 70%) as a yellow oil. LCMS (M+H) + =359.2.

[0605] Step 9-2, Preparation of ethyl 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a suspension of ethyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (5.0 g, 14 mmol) in 1,4-dioxane (50 mL) and water (5 mL) under nitrogen, potassium carbonate (5.8 g, 42 mmol), (2-ethoxypyridin-3-yl)boronic acid (3.5 g, 21 mmol), and Pd(dtbpf)Cl (0.91 g, 1.4 mmol) were added. The mixture was heated at 90 °C for 2 h. The mixture was quenched with water and extracted with EtOAc (3x). The combined organics were concentrated to dryness, and the residue was purified by silica gel CC to give the title compound (5.5 g, 89%) as a yellow solid. LCMS (M+H) + =446.3.

[0606] Step 9-3, Preparation of 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid: To a suspension of ethyl 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (2.0 g, 4.5 mmol) in a mixture of EtOH and water (2:1, 45 mL) was added lithium hydroxide (1.1 g, 46 mmol). The mixture was heated at 60 °C for 1 h. The mixture was diluted with water and adjusted to pH 6-7 with 3N HCl (aq). The mixture was extracted with EtOAc (3X), and the combined organics were dried over anhydrous NaSO and concentrated to dryness to give the title compound (1.5 g, 80%) as a yellow oil. LCMS (M+H) + =418.1.

[0607] Step 9-4, Preparation of 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (1.2 g, 2.9 mmol) and HATU (1.1 g, 2.9 mmol) in DMF (12 mL) was added DIEA (1.5 mL, 8.5 mmol). After stirring for 5 minutes at room temperature, (3S)-1-methylpyrrolidin-3-amine (0.30 g, 3.0 mmol) was added to the above HATU activated solution. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EtOAc (3x). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (1.1 g, 77%) as a yellow oil. LCMS (M+H) + =500.4.

[0608] Step 9-5, Preparation of 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (1.1 g, 2.2 mmol) in MeOH (20 mL), 10 wt% palladium on carbon (0.23 g) and 20 wt% Pd(OH) on carbon (0.31 g) were added. Hydrogen (g) was added to the mixture, which was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (0.70 g, 78%) as a white oil. LCMS (M+H) + =410.3.

[0609] Step 9-6, Preparation of 1-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (45 mg, 0.11 mmol) and 2-fluorobenzonitrile (40 mg, 0.33 mmol) in DMSO (1 mL) was added DIEA (28 mg, 0.22 mmol). The mixture was heated at 120°C for 1 hour. The mixture was purified by reverse phase CC to give the title compound (18 mg, 31%) as a white solid. LCMS (M+H) + =511.2.

[0610] The following compounds were prepared in a similar manner to Example 9, using the appropriate substituting reagents and substrates at the various steps.

[0611] [Table 10]

[0612] Example 10: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide (Compound 1-33)

[0613] [ka]

[0614] Step 10-1, Preparation of 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamidoformate: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine under nitrogen To a mixture of 1-4-carboxamide (40 mg, 0.098 mmol), 1-bromo-4-(trifluoromethyl)benzene (33 mg, 0.115 mmol), XPhos (17 mg, 0.020 mmol), Pd2(dba)3 (9.0 mg, 0.0098 mmol), and sodium tert-butoxide (28 mg, 0.29 mmol) was added toluene (1 mL). The mixture was heated at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by reverse phase CC to give the title compound (25 mg, 43%) as a yellow oil. LCMS (M+H) + =554.2.

[0615] The following compounds were prepared in a similar manner to Example 10, using the appropriate substituting reagents and substrates at the various steps.

[0616] [Table 11]

[0617] Example 11: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide and 3-(4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-4-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Compounds 1-24 and 1-25)

[0618] [ka]

[0619] Step 11-1, Preparation of Ethyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a solution of ethyl 1-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (2.0 g, 4.5 mmol) in MeOH (100 mL), 10 wt% palladium on carbon (100 mg) and 20 wt% Pd(OH) on carbon (100 mg) were added. The mixture was stirred under hydrogen (3 bar) for 3 hours at room temperature. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.0 g, 62%) as a pale yellow oil. LCMS (M+H) + =356.2.

[0620] Step 11-2, Preparation of ethyl 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate: To a solution of ethyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (0.2 g, 0.6 mmol) and 3-fluoro-6-(trifluoromethyl)pyridine-2-carbonitrile (0.16 g, 0.84 mmol) in DMSO (5 mL), DIEA (0.4 mL, 2 mmol) was added. The mixture was heated at 60 °C for 2 hours. The mixture was purified by reverse phase CC to give the title compound (0.21 g, 70%) as a pale yellow oil. LCMS (M+H) + =526.5.

[0621] Step 11-3, Preparation of 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid and 1-[2-carbamoyl-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid: To a suspension of ethyl 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (0.21 g, 0.40 mmol) in a mixture of EtOH and water (2:1, 6 mL), lithium hydroxide (0.10 g, 4.2 mmol) was added. The mixture was heated at 60° C. for 1 h. The mixture was adjusted to pH 6-7 with 1 N HCl(aq). The solution was extracted with EtOAc (3×) and the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give a mixture of the title compounds (0.17 g) in a 47:53 ratio as a pale yellow solid. LCMS (M+H) + =498.3 & 516.3.

[0622] Step 11-4, Preparation of 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide and 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethylpyridine-2-carboxamide): 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2 To a solution of a mixture of 1-[2-carbamoyl-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid and 1-[2-carbamoyl-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid was added DIEA (0.1 mL, 0.8 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine (64 mg, 0.64 mmol) was added to the above HATU activated solution. The mixture was stirred at room temperature for 1 hour and purified by reverse phase CC to give the first title compound (32 mg, 33% yield) as a white solid; LCMS (M+H) + = 580.3, second title compound as a white solid (44 mg, 43%); LCMS (M+H) + =598.3 was obtained.

[0623] The following compounds were prepared in a similar manner to Example 1, using the appropriate substitution reagents and substrates at the various steps.

[0624] [Table 12]

[0625] Example 12: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-88)

[0626] [ka]

[0627] Step 12-1, Preparation of methyl 4-(6-chloropyridin-3-yl)piperidine-4-carboxylate: To a solution of methyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (2.9 g, 8.4 mmol) from step 7-1 in DCM (30 mL) at 0 °C, chloroethyl chloroformate (2.3 mL, 21 mmol) was added. The mixture was stirred at room temperature for 2 hours, and then MeOH (15 mL) was added. The resulting mixture was heated at reflux for 2 hours. The mixture was concentrated to dryness, and the residue was triturated with a mixed solvent of hexane and ether (5:1, 40 mL). The solid was collected by vacuum filtration to give the title compound (1.7 g, 79%) as a white solid. LCMS (M+H) + =255.0.

[0628] Step 12-2, Preparation of methyl 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylate: To a solution of methyl 4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (1.7 g, 6.7 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (1.3 g, 7.0 mmol) in DMSO (17 mL) was added DIEA (3.6 mL, 21 mmol). The mixture was heated at 60° C. for 2 hours. The mixture was diluted with 10% citric acid (aq) (50 mL) and extracted with EtOAc (3×). The combined organics were washed with brine, dried over NaSO, and concentrated to dryness. The solid was triturated with hexanes, and the solid was collected by vacuum filtration to give the title compound (1.8 g, 64%) as a white solid. LCMS (M+H) + =424.0.

[0629] Step 12-3, Preparation of 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid: To a suspension of methyl 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylate (1.8 g, 4.2 mmol) in a mixed solvent of EtOH and water (2:1, 22.5 mL) was added lithium hydroxide (1.0 g, 42 mmol). The mixture was heated at 60° C. for 2 hours. The mixture was adjusted to pH 6-7 with 1N HCl (aq). The solution was extracted with EtOAc (3×), and the combined organics were dried over anhydrous NaSO and concentrated to dryness. The residue was purified by reverse phase CC to give the title compound (1.5 g, 83%) as an off-white solid. LCMS (M+H) + =409.9.

[0630] Step 12-4, Preparation of 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid (500 mg, 1.22 mmol) and HATU (650 mg, 1.71 mmol) in DMF (1 mL) was added DIEA (0.43 mL, 2.4 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine (183 mg, 1.83 mmol) was added to the above HATU activated solution. The mixture was stirred for 10 min at room temperature and purified by reverse phase CC to give the title compound (483 mg, 80.5%) as an off-white solid; LCMS (M+H) + =492.0.

[0631] Step 12-5, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: Add 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide to a sealed tube. To a mixture of lysine-4-carboxamide (30.0 mg, 0.0610 mmol), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (63.1 mg, 0.305 mmol), Pd(amphos)Cl (17.3 mg, 0.0244 mmol), and potassium carbonate (25.3 mg, 0.183 mmol) was added 1,4-dioxane (2 mL) and water (0.3 mL). Nitrogen (g) was bubbled through, and the resulting mixture was heated at 100 °C for 2 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness, and the residue was purified by reverse phase CC to give the title compound (9.1 mg, 28%) as an off-white solid. LCMS (M+H) + =537.5.

[0632] The following compounds were prepared in a similar manner to Example 12, using the appropriate substituting reagents and substrates at the various steps.

[0633] [Table 13]

[0634] Example 13: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-81)

[0635] [ka]

[0636] Step 13-1, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R) To a mixture of [1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (30.0 mg, 0.0610 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (51.8 mg, 0.305 mmol), Pd(dtbpf)Cl2 (15.9 mg, 0.0244 mmol), and potassium carbonate (25.3 mg, 0.183 mmol) was added 1,4-dioxane (2 mL) and water (0.3 mL). Nitrogen (g) was bubbled through and the resulting mixture was heated at 80 °C for 3 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness, and the residue was purified by reverse phase CC to give the title compound (17.2 mg, 48.5%) as a brown solid. LCMS (M+H) + =582.2.

[0637] The following compounds were prepared in a similar manner to Example 13, using the appropriate substituting reagents and substrates at the various steps.

[0638] [Table 14]

[0639] Example 14: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-100)

[0640] [ka]

[0641] Step 14-1, Preparation of 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid (1.00 g, 2.44 mmol) from Step 12-3 and HATU (1.21 g, 3.17 mmol) in DMF (1 mL) was added DIEA (0.85 mL, 4.9 mmol). After stirring at room temperature for 5 minutes, (3S)-1-methylpyrrolidin-3-amine (367 mg, 3.66 mmol) was added to the above HATU activated solution. The mixture was stirred for 10 min at room temperature and purified by reverse phase CC to give the title compound (1.14 g, 94.6%) as a light brown solid; LCMS (M+H) + =492.2.

[0642] Step 14-2, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl] in a sealed tube. To a mixture of piperidine-4-carboxamide (90.0 mg, 0.183 mmol), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (189 mg, 0.915 mmol), Pd(amphos)Cl (51.8 mg, 0.0732 mmol), and potassium carbonate (75.9 mg, 0.549 mmol) was added 1,4-dioxane (3 mL) and water (0.3 mL). Nitrogen (g) was bubbled through, and the resulting mixture was heated at 100 °C for 2 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness, and the residue was purified by reverse phase CC to give the title compound (23.5 mg, 23.9%) as an off-white solid. LCMS (M+H) + =537.6.

[0643] The following compounds were prepared in a similar manner to Example 14, using the appropriate substitution reagents and substrates at various steps. Some examples do not require deprotection in the final step.

[0644] [Table 15]

[0645] Example 15: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-102)

[0646] [ka]

[0647] Step 15-1, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: Add 4-(6-chloropyridin-3-yl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S To a mixture of )-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (60.0 mg, 0.122 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (104 mg, 0.610 mmol), Pd(dtbpf)Cl2 (31.8 mg, 0.0488 mmol), and potassium carbonate (50.6 mg, 0.366 mmol) was added 1,4-dioxane (2 mL) and water (0.3 mL). Nitrogen (g) was bubbled through and the resulting mixture was heated at 80 °C for 3 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness, and the residue was purified by reverse phase CC to give the title compound (41.9 mg, 59%) as a brown solid. LCMS (M+H) + =582.4.

[0648] The following compounds were prepared in a similar manner to Example 15, using the appropriate substituting reagents and substrates at the various steps.

[0649] [Table 16]

[0650] Example 16: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-90)

[0651] [ka]

[0652] Step 16-1, Preparation of Ethyl 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate: To a suspension of ethyl 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (4.2 g, 12 mmol) from Step 9-1 in 1,4-dioxane (50 mL) and water (5 mL) under nitrogen, potassium carbonate (3.2 g, 23 mmol), (2-ethoxyphenyl)boronic acid (2.9 g, 17 mmol), and Pd(dtbpf)Cl (0.30 g, 0.46 mmol) were added. The mixture was heated at 90 °C for 2 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness, and the residue was purified by silica gel CC to give the title compound (4.0 g, 77%) as a yellow solid. LCMS (M+H) + =445.2.

[0653] Step 16-2, Preparation of ethyl 4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate: To a solution of ethyl 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (3.5 g, 7.9 mmol) in MeOH (50 mL), 10 wt% palladium on carbon (160 mg) and 20 wt% Pd(OH) on carbon (160 mg) were added. Hydrogen (g) was added to the mixture, which was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (2.4 g, 86%) as a yellow oil. LCMS (M+H) + =355.2.

[0654] Step 16-3, Preparation of ethyl 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate: To a mixture of ethyl 4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (400 mg, 1.13 mmol), 2-bromo-5-chlorobenzonitrile (320 mg, 1.48 mmol), XPhos (33.3 mg, 0.0699 mmol), Pd(dba)CHCl (35.0 mg, 0.0338 mmol), and cesium carbonate (735 mg, 2.26 mmol) under nitrogen, toluene (5 mL) was added. The mixture was heated at 90 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel CC to give the title compound (290 mg, 52.4%) as a yellow oil. LCMS (M+H) + =490.3.

[0655] Step 16-4, Preparation of 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylic acid: To a suspension of ethyl 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (290 mg, 0.59 mmol) in a mixed solvent of EtOH and water (5:1, 6 mL) was added lithium hydroxide (72 mg, 3.0 mmol). The mixture was heated at 60° C. for 2 hours. The mixture was diluted with water and adjusted to pH 6-7 with 1N HCl (aq). The mixture was extracted with EtOAc (3×), and the combined organics were dried over anhydrous NaSO and concentrated to dryness to give the title compound (250 mg, 91.4%) as a yellow solid. LCMS (M+H) + =462.3.

[0656] Step 16-5, preparation of 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylic acid (50 mg, 0.11 mmol) and HATU (49 mg, 0.13 mmol) in DMF (0.6 mL), DIEA (84 mg, 0.65 mmol) was added. After stirring at room temperature for 5 minutes, (3S)-1-methylpyrrolidin-3-amine (14 mg, 0.14 mmol) was added to the above HATU activated solution. The mixture was stirred for 1 h at room temperature and purified by reverse phase CC to give the title compound (31 mg, 48%) as a white solid. LCMS (M+H) + =544.3.

[0657] The following compounds were prepared in a similar manner to Example 16, using the appropriate substituting reagents and substrates at the various steps.

[0658] [Table 17]

[0659] Example 17: 1-(2-cyano-4-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-96)

[0660] [ka]

[0661] Step 17-1, Preparation of 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylic acid: To a suspension of ethyl 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (500 mg, 1.12 mmol) from Step 16-1 in a mixed solvent of EtOH and water (5:1, 6 mL) was added lithium hydroxide (269 mg, 11.2 mmol). The mixture was heated at 60° C. for 1 h. The mixture was diluted with water and adjusted to pH 6-7 with 1 N HCl (aq). The mixture was extracted with EtOAc (3×), and the combined organics were dried over anhydrous NaSO and concentrated to dryness to give the title compound (450 mg, 96.1%) as a yellow oil. LCMS (M+H) + =417.3.

[0662] Step 17-2, Preparation of 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylic acid (450 mg, 1.08 mmol) and HATU (430 mg, 1.13 mmol) in DMF (5 mL) was added DIEA (450 mg, 3.48 mmol). After stirring for 5 minutes at room temperature, (3S)-1-methylpyrrolidin-3-amine (130 mg, 1.30 mmol) was added to the above HATU activated solution. The mixture was stirred for 1 hour at room temperature and purified by reverse phase CC to give the title compound (450 mg, 83.5%) as a yellow solid. LCMS (M+H) + =499.4.

[0663] Step 17-3, Preparation of 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of 1-benzyl-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (430 mg, 0.862 mmol) in MeOH (30 mL), 10 wt%...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 1】 During the ceremony, R Ａ is unsubstituted or substituted heteroaryl or unsubstituted or substituted aryl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl; R ａ , R ｂ , and R ｃ Any substituted group of may be one or more R ６ is substituted with a group, Or, one R ａ and one R ｂ is R Ａ When present on adjacent atoms of ａ R ｂ and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or contains one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ , 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, or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, R Ｂ is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, three, or four groups selected from R ｄ , R ｅ , and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , -C(=O)N(R ４ ) 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein R ｄ , R ｅ , and R ｆ Any substituted group of may be one or more R ６ is substituted with a group, Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ , 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, or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, X １ is CR １１ or N, X ２ is CR １２ or N, X ３ is CR １３ or N, X ４ is CR １４ or N, R １１ , R １２ , R １３ , and R １４ are each independently hydrogen, halogen, 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, —CN, —OR ４ , -SR ４ , -CO ２ R ４ , -C(=O)N(R ４ ) ２ , or -N(R ４ ) ２ and M is —(C═O)—, —NR ３ -, -O-, -S-, -SO ２ -, ＊ -NR ３ -(C=O)-, ＊ —(C═O)—NR ３ -, ＊ -O-(C=O)NR ３ -, ＊ -NR ３ -(C=O)O-, -NR ３ -(C=O)NR ３ -, ＊ -NR ３ (SO ２ ) -, ＊ -SO ２ NR ３ - or a 5-membered heterocycle, wherein ＊ is R １ indicates the point of attachment to R １ is 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 -(C １ -C ６ alkyl)-(C ３ -C ６ cycloalkyl), or unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by R ３ are each independently hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, R ４ are each independently hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ selected from the group consisting of fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Or, two R ４ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; R ５ are each independently hydrogen, substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ selected from the group consisting of fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ６ are each independently 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 carbocycle, unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO ２ R ５ , -CH ２ CO ２ R ５ , -C(=O)N(R ４ ) ２ , -C(=O)N(R ４ ) OR ５ , -CH ２ C(=O)N(R ４ ) ２ , -N(R ４ ) ２ , -CH ２ N (R ４ ) ２ , -C(R ５ ) ２ N (R ４ ) ２ , -NR ４ C(=O)R ５ , -CH ２ NR ４ C(=O)R ５ , -NR ４ C(=O)N(R ５ ) ２ , -NR ４ C(=O)N(R ４ ) ２ , C(R ５ ) = N(R ４ ) -OR ５ , -SR ５ , -S(=O)R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ and R ７ are each independently a substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ selected from the group consisting of fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl; The compound, or a pharmaceutically acceptable salt or solvate thereof.

2. M is -NR ３ -, -O-, ＊ -NR ３ -(C=O)-, ＊ —(C═O)—NR ３ -, ＊ -O-(C=O)NR ３ -, ＊ -NR ３ —(C═O)O—, or —NR ３ -(C=O)NR ３ -, where: ＊ is R １ indicates the point of attachment to, and R ３ are each independently hydrogen, —CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , or -CH(CH ３ ) ２ 2. The compound of claim 1, wherein:

3. M is, ＊ -NR ３ -(C=O)- or ＊ —(C═O)—NR ３ -, where: ＊ is R １ indicates the point of attachment to, and R ３ The compound of any one of claims 1-2, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

4. 10. The compound of claim 1, wherein the compound has the structure of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt or solvate thereof. 【Chemistry 2】

5. R Ａ is an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted phenyl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

6. R Ａ is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted phenyl, wherein R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

7. R Ａ is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, or unsubstituted or substituted phenyl, wherein R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

8. R Ａ is unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

9. R Ａ teeth, 【Chemistry 3】 7. The compound of any one of claims 1 to 6, wherein:

10. R Ａ teeth, 【Chemistry 4】 and V is CH, CR ａ , C.R. ｂ 7. The compound of claim 1, wherein R is 1 or N, or a pharmaceutically acceptable salt or solvate thereof.

11. The compound has the structure of formula (IV): 【Chemistry 5】 where V is CH, CR ａ , C.R. ｂ 10. The compound of claim 1, wherein:

12. M is, ＊ -NR ３ -(C=O)- or ＊ —(C═O)—NR ３ -, where: ＊ is R １ indicates the point of attachment to, and R ３ 12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein: is hydrogen.

13. the compound has the structure of formula (IVa): 【Chemistry 6】 where V is CH, CR ａ , C.R. ｂ or N, or a pharmaceutically acceptable salt or solvate thereof.

14. R Ａ is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, or three groups selected from:

15. R Ａ is unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, or unsubstituted or substituted pyrrolyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, or three groups selected from:

16. R Ａ teeth, 【Chemistry 7】 or R Ａ teeth, 【Chemistry 8】 where R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ 15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, which is heterocycloalkyl.

17. the compound has the structure of formula (III): 【Chemistry 9】 During the ceremony, Y １ is NR ｃ , O, or S; Y ２ and Y ３ are independently CH, CR ａ , C.R. ｂ , or N, and R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is heterocycloalkyl.

18. M is, ＊ -NR ３ -(C=O)- or ＊ —(C═O)—NR ３ -, where: ＊ is R １ indicates the point of attachment to, and R ３ 18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

19. The compound has the structure of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 10】 During the ceremony, Y １ is NR ｃ , O, or S; Y ２ and Y ３ are independently CH, CR ａ , C.R. ｂ , or N, and R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ 18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, which is heterocycloalkyl.

20. R Ａ is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

21. R Ａ is unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, wherein R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 21. The compound of claim 20, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

22. 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, or unsubstituted or substituted bicyclic heteroaryl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

23. R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic 6-membered heteroaryl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

24. 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 is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

25. R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two, three, or four groups selected from:

26. R Ｂ teeth, 【Chemistry 11】 24. The compound of any one of claims 1-23, wherein:

27. R Ｂ teeth 【Chemistry 12】 and W is CH, CR ｄ , C.R. ｅ or N, or a pharmaceutically acceptable salt or solvate thereof.

28. R Ｂ teeth 【Chemistry 13】 28. The compound of any one of claims 1-27, wherein:

29. The compound has the structure of formula (VI): 【Chemistry 14】 where V is CH, CR ａ , C.R. ｂ , or N, and W is CH, CR ｄ , C.R. ｅ 10. The compound of claim 1, wherein:

30. The compound has the structure of Formula (VIa) or Formula (VIc), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 15】 where V is CH, CR ａ , C.R. ｂ , or N, and W is CH, CR ｄ , C.R. ｅ 30. The compound of claim 29, wherein:

31. The compound has the structure of Formula (VIb) or Formula (VId), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 16】 where V is CH, CR ａ , C.R. ｂ , or N, and W is CH, CR ｄ , C.R. ｅ 31. The compound of claim 29 or 30, wherein:

32. 31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (VIIb) or Formula (VIIe): 【Chemistry 17】

33. The compound has the structure of formula (V): 【Chemistry 18】 During the ceremony, Y １ is NR ｃ , O, or S; Y ２ and Y ３ are independently CH, CR ａ , C.R. ｂ , or N, R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, and W is CH, CR ｄ , C.R. ｅ 10. The compound of claim 1, wherein:

34. R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ Heteroalkyl, unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom, unsubstituted or substituted bridging C containing 1-2 N atoms ２ -C ７ heterocycloalkyl, or unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ 34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

35. R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

36. R １ is an unsubstituted or substituted C containing one N atom １ -C ６ is heteroalkyl, Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 36. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

37. the compound has the structure of formula (VIII): 【Chemistry 19】 During the ceremony, R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, wherein R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and M is -NR ３ -, -O-, ＊ -NR ３ -(C=O)-, ＊ —(C═O)—NR ３ -, ＊ -O-(C=O)NR ３ -, ＊ -NR ３ —(C═O)O—, or —NR ３ -(C=O)NR ３ -, where: ＊ is R １ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, showing a point of attachment to:

38. X １ is CR １１ and X ２ is CR １２ and X ３ is CR １３ and X ４ is CR １４ and Or X １ is N and X ２ is CR １２ and X ３ is CR １３ and X ４ is CR １４ and Or X １ is CR １１ and X ２ is N and X ３ is CR １３ and X ４ is CR １４ and Or X １ is N and X ２ is CR １２ and X ３ is CR １３ and X ４ is N, Or X １ is N and X ２ is N and X ３ is CR １３ and X ４ is CR １４ and Or X １ is N and X ２ is CR １２ and X ３ is N, and X ４ is CR １４ and Or X １ is CR １１ and X ２ is CR １２ and X ３ is CR １３ and X ４ is CR １４ 38. The compound of any one of claims 1-37, wherein:

39. X １ is N and X ２ is CR １２ and X ３ is CR １３ and X ４ is CR １４ 38. The compound of any one of claims 1-37, wherein:

40. X １ is CH, CF, or N; X ２ is CH, CF, or N; X ３ is CH, CF, or N, and X ４ is CH, CF, or N, or a pharmaceutically acceptable salt or solvate thereof.

41. X １ is N, X ２ is CH, X ３ is CH or CF, and X ４ 38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or solvate thereof, wherein:

42. R ａ , R ｂ , and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ａ , R ｂ , and R ｃ Any substituted group of may be one or more R ６ is substituted with a group, Or, one R ａ and one R ｂ is R Ａ When present on adjacent atoms of ａ R ｂ and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or contains one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, and R ｄ , R ｅ , and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , -C(=O)N(R ４ ) 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein R ｄ , R ｅ , and R ｆ Any substituted group of may be one or more R ６ is substituted with a group, Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, which is heterocycloalkyl.

43. R ａ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R Ａ Any substituted group of may be one or more R ６ is substituted with a group, and R ｂ and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R ｂ and R ｃ Any substituted group of may be one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein:

44. R ａ is hydrogen, F, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -C(O)CH ３ , -C(O)CH 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 CH ２ CH(CH ３ ) ２ , -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[[ID=​​​​​​​​​​​​​​​​​​​ ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ , -CH ２ CH ２ N (CH ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and R ｂ and R ｃ are independently hydrogen, F, Cl, Br, -CN, -OH, -OCH ３ -OCH ２ CH ３ -C(O)CH ３ -C(O)CH 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 CH ２ CH(CH ３ ) ２ -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 is selected from the group consisting of R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(O)CH ３ , —C(O)CH 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 CH ２ CH (CH ３ ) ２ , -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 42. The compound of any one of claims 1-41, wherein:

45. R Ａ One R on an adjacent atom of ａ and one R ｂ is R ａ R ｂ and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic cycloalkyl or a 5- to 6-membered monocyclic heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or is substituted with one or more R ６ 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, substituted with a group.

46. R Ａ One R on an adjacent atom of ａ and one R ｂ is R ａ R ｂ and together with the intervening atoms connecting them to form a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl is unsubstituted or has one or more R ６ 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, substituted with a group.

47. R ｄ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group of may be one or more R ６ is substituted with a group, and R ｅ and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) 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; Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ 47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, wherein:

48. R ｄ is hydrogen, F, 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 CH ２ CH(CH ３ ) ２ , -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 NHCH ３ , -CH ２ CH ２ N (CH ３ ) ２ , unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C ２ -C ７ selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group of may be one or more R ６ is substituted with a group, and R ｅ and R ｆ are independently hydrogen, 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 CH ２ CH (CH ３ ) ２ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, -OCH ３ , and -OCH ２ CH ３ is selected from the group consisting of Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(O)CH ３ , —C(O)CH 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 CH ２ CH (CH ３ ) ２ , -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 47. The compound of any one of claims 1-46, wherein:

49. R Ａ is an unsubstituted or substituted 6- or 5-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R ａ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R Ａ Any substituted group of may be one or more R ６ is substituted with a group, R ｂ and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R ｂ and R ｃ Any substituted group of may be one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from R ｄ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group of may be one or more R ６ is substituted with a group, R ｅ and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) 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; Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, X １ is CR １１ or N, X ２ is CR １２ or N, X ３ is CR １３ or N, X ４ is CR １４ or N, R １１ , R １２ , R １３ , and R １４ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, or C １ -C ６ Heteroalkyl, —CN, —OR ４ , or -N(R ４ ) ２ and M is, ＊ -NR ３ -(C=O)- or ＊ —(C═O)—NR ３ -, where: ＊ is R １ indicates the point of attachment to R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharmaceutically acceptable salt or solvate thereof.

50. R Ａ is unsubstituted or substituted pyridinyl, unsubstituted or substituted phenyl, or unsubstituted or substituted pyrrolyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from X １ is CH or N, X ２ is CH or N, X ３ is CR １３ or N, X ４ is CH or N, M is, ＊ -NR ３ -(C=O)- or ＊ —(C═O)—NR ３ -, where: ＊ is R １ indicates the point of attachment to R １１ , R １２ , R １３ , and R １４ are each independently hydrogen, F, Cl, or —CH ３ , C.F. ３ , -CN, -OR ４ , or -N(R ４ ) ２ and R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ The optional substituted groups may be one or more halogens, C １ -C ４ Alkyl, —N(R ４ ) ２ , or -OR ５ is replaced by Or, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharmaceutically acceptable salt or solvate thereof.

51. R Ａ teeth 【Chemistry 20】 and Or, R Ａ teeth 【Chemical 21】 and Or, R Ａ teeth 【Chemical 22】 and V is CH or N; R ａ is hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; and R ｂ and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C １ -C ６ fluoroalkyl; R Ｂ teeth, 【Chemical 23】 and W is CH or N; R ｄ is hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; and R ｅ and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C １ -C ６ fluoroalkyl; X １ is CH, CF, or N; X ２ is CH, CF, or N; X ３ is CH, CF, or N; X ４ is CH, CF, or N; M is, ＊ —NH—(C═O)— or ＊ -(C=O)-NH-, where ＊ is R １ indicates the point of attachment to R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharmaceutically acceptable salt or solvate thereof.

52. R Ａ teeth 【Chemistry 24】 and V is CH or N; R ａ is hydrogen, F, Cl, Br, —CN, —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 F, -CHF ２ , and -CF ３ and R ｂ and R ｃ are independently hydrogen, F, Cl, —CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CN, and -OCH ３ is selected from the group consisting of R Ｂ teeth, 【Chemistry 25】 and W is CH or N; R ｄ is hydrogen, F, Cl, Br, —CN, —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 F, -CHF ２ , and -CF ３ is selected from the group consisting of R ｅ and R ｆ are independently hydrogen, F, Cl, Br, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , —CN, —OH, and —OCH ３ is selected from the group consisting of X １ is CH or N, X ２ is CH or N, X ３ is CH, CF, or N; X ４ is CH or N, M is, ＊ —NH—(C═O)— or ＊ -(C=O)-NH-, where ＊ is R １ indicates the point of attachment to R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharmaceutically acceptable salt or solvate thereof.

53. the compound has the structure of formula (IX): ​ During the ceremony, R Ａ is an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R ａ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R Ａ Any substituted group of may be one or more R ６ is substituted with a group, and R ｂ and R ｃ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , 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; R ｂ and R ｃ Any substituted group of may be one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from R ｄ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group of may be one or more R ６ is substituted with a group, and R ｅ and R ｆ are independently hydrogen, halogen, or —OR ４ , -CN, -N(R ４ ) 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; Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, X １ is CR １１ or N, X ２ is CR １２ or N, R １１ and R １２ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, or C １ -C ６ Heteroalkyl, —CN, —OR ４ , or -N(R ４ ) ２ and M is -NR ３ -, -O-, ＊ -NR ３ -(C=O)-, ＊ —(C═O)—NR ３ -, ＊ -O-(C=O)NR ３ -, ＊ -NR ３ —(C═O)O—, or —NR ３ -(C=O)NR ３ -, where: ＊ is R １ indicates the point of attachment to, and R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ Any substituted group of may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharmaceutically acceptable salt or solvate thereof.

54. R Ａ is unsubstituted or substituted pyridinyl, unsubstituted or substituted phenyl, or unsubstituted or substituted pyrrolyl, where R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is not hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from X １ is CR １１ or N, X ２ is CR １２ or N, R １１ and R １２ are each independently hydrogen, F, Cl, or —CH ３ , C.F. ３ , -CN, -OR ４ , or -N(R ４ ) ２ and R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ The optional substituted groups may be one or more halogens, C １ -C ４ Alkyl, —N(R ４ ) ２ , or -OR ５ is replaced by Or, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), and C ２ -C ７ 54. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

55. R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ The optional substituted groups may be one or more halogens, C １ -C ４ Alkyl, —N(R ４ ) ２ , or -OR ５ is replaced by Or, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), and C ２ -C ７ 55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt or solvate thereof, wherein heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

56. R １ 56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein: is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

57. R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where R １ is unsubstituted or, if substituted, it may be one or more halogens, C １ -C ４ Alkyl, —N(R ４ ) ２ , or -OR ５ 56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

58. 1-1: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-3: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-4: N-[(2R)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-5: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-6: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-7: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-8: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide, 1-9: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-10: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-11: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-12: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-13: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-14: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-15: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-16: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-17: N-[(2R)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-18: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-19: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-20: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-21: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-22: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-23: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-24: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-25: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 1-26: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-27: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3S)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 1-28: N-[(2S)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-29: 1-[2-chloro-6-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-30: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-31: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-32: 1-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-33: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-34: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-35: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide, 1-36: 1-(4-acetyl-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-37: 1-[2-cyano-4-(difluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-38: 1-[4-cyano-2-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-39: 1-[2-cyano-4-(trifluoromethoxy)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-40: 1-(2,4-dicyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-41: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S,4S) ＊ -4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-42: 1-[3-cyano-5-(trifluoromethyl)pyridin-2-yl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-43: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-44: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2R)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide, 1-45: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-46: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R,4R) ＊ -4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-47: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide, 1-48: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)-3-hydroxypropyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-51: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-52: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-53: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-dihydro-1-benzofuran-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-54: 4-[6-(1-benzofuran-7-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-55: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(hydroxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-56: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-57: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-58: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-59: 1-[2-cyano-4-(1,1-difluoroethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-60: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-61: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-62: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-63: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-64: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-65: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-66: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-67: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-68: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-69: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-5-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-70: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[1-(3-methylbutyl)-1H-pyrazol-5-yl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-71: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}piperidine-4-carboxamide, 1-72: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-73: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indazol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-74: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-75: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)-3-fluorophenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-76: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-77: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethyl)phenyl]pyridin-3-yl}piperidine-4-carboxamide, 1-78: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyanophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-79: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(methoxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-80: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methoxythiophen-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-81: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-82: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-83: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-84: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(1,1-difluoroethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-85: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2′-(difluoromethoxy)-[2,3′-bipyridin]-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-86: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-87: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-88: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-89: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-90: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-91: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-92: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-93: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-94: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-95: 1-(2,4-dichlorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-96: 1-(2-cyano-4-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-97: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-98: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-99: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-100: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-101: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-102: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-103: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-104: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-105: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(4-methylpyrimidin-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-106: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-107: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-108: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-109: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-110: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-111: 1-(4-chloro-2-cyano-6-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-112: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-113: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-114: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethoxy)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-115: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-116: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-117: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propylphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-118: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-119: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-120: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-121: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-122: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-123: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-124: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-125: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-126: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-127: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-128: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-129: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-hydroxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-130: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxy-5-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-131: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-132: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-133: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{3-fluoro-2′-methoxy-[2,3′-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-134: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-135: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-136: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-137: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(cyanomethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-138: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(4-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-139: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-140: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-141: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-142: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-143: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-144: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-145: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-146: 4-[6-(2-acetylthiophen-3-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-147: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylthiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-148: 4-[6-(2-cyano-3-fluorophenyl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-149: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-150: 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-151: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethyl)phenyl]pyridin-3-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-152: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide, 1-153: 4-[6-(5-cyano-1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-154: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-155: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-156: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-157: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-158: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-cyclopropyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-159: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-160: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-161: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-162: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-163: 1-(4-chloro-2-cyanophenyl)-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-164: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-165: 1-[3-chloro-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-166: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-167: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-168: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-169: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-170: 1-(4-chloro-2-cyanophenyl)-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-171: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-172: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-173: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-174: 4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-175: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-176: 4-{[2,2'-bipyridin]-5-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-177: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methyl-[2,2'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-178: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methoxy-[2,2'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-179: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-180: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-cyclopropyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-181: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-182: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-cyclopropyl-1,3-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-183: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-184: ethyl (3S)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-amido}pyrrolidine-1-carboxylate, 1-185: N-[(3S)-1-acetylpyrrolidin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-186: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-187: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-188: N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-189: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyquinolin-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-190: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-191: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-192: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-193: 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-194: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-195: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-196: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-197: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide, 1-198: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-199: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-200: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-201: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-202: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-203: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-204: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-205: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-206: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide, 1-207: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-208: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-209: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-210: 4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide, 1-211: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-212: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-213: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-214: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-215: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-216: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-217: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-218: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-219: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide, 1-220: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide, 1-221: N-{1-azabicyclo[2.2.1]heptan-4-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-222: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-223: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-224: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-225: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-226: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-227: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-228: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-229: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-230: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-231: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-232: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide, 1-233: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-aminocyclobutyl]piperidine-4-carboxamide, 1-234: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-aminocyclobutyl]piperidine-4-carboxamide, 1-235: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-236: N-{[(2R)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-237: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-238: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-239: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide, 1-240: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide, 1-241: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-242: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-243: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-244: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide, 1-245: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-246: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-247: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-248: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-249: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-250: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-251: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide, 1-252: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide, 1-253: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1,3-dimethylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-254: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-255: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-256: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-257: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-258: rac-N-[(1R,2S)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-259: rac-N-[(1R,2R)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-260: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-261: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-262: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{3-[(dimethylamino)methyl]oxetan-3-yl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-263: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[1-(dimethylamino)cyclopropyl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-264: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-(dimethylamino)oxolan-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-265: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[ethyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-266: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[cyclopropyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-267: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-268: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-269: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-270: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-271: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-272: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-273: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-274: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-275: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-276: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-277: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-278: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-279: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-280: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2R)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-281: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-282: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-283: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-284: N-[2-(dimethylamino)ethyl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-285: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-286: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide, 1-287: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-288: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-289: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-290: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-291: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxamide, 1-292: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-293: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-294: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-295: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2′-methoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-296: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-297: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-298: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-299: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-300: N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-301: 4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-302: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-303: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-304: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-305: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-306: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-307: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-308: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-309: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-310: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-311: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide, 1-312: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-313: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-314: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-315: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-316: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-317: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 1-318: 1-(2,4-dichlorophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-319: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-320: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-321: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-322: 1-(2,4-dichlorophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-323: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-324: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide, 1-325: 1-(4-chloro-2-cyanophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2′-ethoxy-3-fluoro-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-326: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide, 1-327: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide, 1-328: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3S)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide, 1-329: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3R)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide, 1-330: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide, 1-331: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxamide, 1-332: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)propyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidine-4-carboxamide, 1-333: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-334: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide, 1-335: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide, 2-1: 2-{4-[2-(dimethylamino)ethoxy]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-1-yl}-5-(trifluoromethyl)benzonitrile, 2-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl N-[2-(dimethylamino)ethyl]carbamate, 2-3: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}propanamide, 2-4: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}propanamide, 2-5: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)propanamide, 2-6: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide, 2-7: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-8: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide, 2-9: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-10: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(dimethylamino)propanamide, 2-11: (2S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide, 2-12: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate, 2-13: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate, 2-14: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-[(2-hydroxyethyl)amino]piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 2-15: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[2-(methylamino)ethyl]amino}piperidin-1-yl)-5-(trifluoromethyl)benzonitrile, 2-16: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-17: (2R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide, 2-18: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}carbamate, 2-19: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-20: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-21: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide, 2-22: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}carbamate, 2-23: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)azetidine-1-carboxamide, 2-24: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide, 2-25: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylazetidine-3-carboxamide, 2-26: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-2-(dimethylamino)acetamide, 2-27: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-28: (3S)-N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-29: (3R)-N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-30: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-3-(dimethylamino)propanamide, 2-31: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-2-(dimethylamino)acetamide, 2-32: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-33: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-34: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide 2-35: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-36: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, 2-37: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-1-methylazetidine-3-carboxamide, 2-38: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-2-(dimethylamino)acetamide, 2-39: (3S)-N-[1-(4-chloro-2-cyanophenyl)-4-{2′-ethoxy-[2,3′-bipyridin]-5-yl}piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide, 2-40: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-41: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-42: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-43: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-44: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}pyrrolidine-3-carboxamide, 2-45: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide, 2-46: (3S)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, and 2-47: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-48: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-49: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-50: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-51: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-52: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-53: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-54: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-55: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea, 2-56: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea, 2-57: 2-(dimethylamino)ethyl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate, 2-58: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[2-(dimethylamino)ethyl]urea, 2-59: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(1-methylazetidin-3-yl)urea, 2-60: (3R)—N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide, 2-61: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide 2-62: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, 2-63: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(methylamino)propanamide, 2-64: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, or a pharmaceutically acceptable salt or solvate thereof.

59. 60. A pharmaceutical composition comprising a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

60. 60. The pharmaceutical composition of claim 59, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ocular administration.

61. 60. The pharmaceutical composition of claim 59, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

62. 100. A method of treating a disease or disorder in a mammal that would benefit from modulation of melanocortin subtype-2 receptor (MC2R) activity, comprising administering to said mammal in need thereof a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof.

63. 63. The method of claim 62, wherein the disease or disorder comprises growth of fat pads on the collarbone, back of the neck, face, and trunk, excessive sweating, dilated capillaries, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, high blood pressure, osteoporosis, insulin resistance, hyperglycemia, and heart disease.

64. 100. A method of treating Cushing's syndrome in a mammal, said method comprising administering to said mammal in need thereof a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof.

65. 100. A method of treating ectopic Cushing's syndrome in a mammal, said method comprising administering to said mammal in need thereof a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof.

66. 100. A method of treating congenital adrenal hyperplasia (CAH) in a mammal, said method comprising administering to said mammal in need thereof a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof.

67. 100. A method for decreasing secretion of adrenocorticotropic hormone (ACTH) in a mammal, said method comprising administering to said mammal in need thereof a compound of any one of claims 1-58, or a pharmaceutically acceptable salt or solvate thereof.

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