Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof

Abstract

To provide compounds, pharmaceutical compositions, and uses in the manufacture of a medicament for methods of treating conditions, diseases, or disorders that would benefit from modulation of melanocortin subtype-2 receptor activity.SOLUTION: A compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided. (RA: substituted / unsubstituted phenyl, substituted / unsubstituted monocyclic heteroaryl, etc. L: bond, CO, CONR7, SO2. RB: substituted / unsubstituted carbocycle, substituted / unsubstituted heterocycle, etc. X1: CR6. X2, X3: N, CR6. R1-R7: substituted / unsubstituted C1-C6 alkyl, etc. n: 1, 2.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 681,011, filed June 5, 2018, and U.S. Provisional Patent Application No. 62 / 734,873, filed September 21, 2018, each of which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with United States government support under SBIR Grant No. 1R43DK115245-01 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Technical Field Described herein are compounds that modulate the activity of one or more melanocortin receptors, methods for making the compounds, pharmaceutical compositions and medicaments containing the compounds, and methods of using the compounds in the treatment of diseases, disorders, or conditions that would benefit from modulation of melanocortin subtype-2 receptor (MC2R) activity. [Background technology]

[0004] Melanocortin receptors form a family of G protein-coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by various melanocortin peptides, including adrenocorticotropic hormone (ACTH) and the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH), all of which are proteolytically derived from propiomelanocortin hormone or 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 actor in the hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary gland in response to stressful stimuli and acts in the adrenal gland to stimulate cortisol synthesis and secretion. Modulation of MC2R is attractive for the treatment of diseases, conditions, or disorders that would benefit from modulation of melanocortin receptor activity. Summary of the Invention

[0005] The compounds described herein are melanocortin receptor modulator compounds. In some embodiments, the compounds described herein modulate one or more subtype melanocortin receptor proteins. In some embodiments, the compounds described herein modulate two or more subtype melanocortin receptor proteins. In some embodiments, the compounds described herein modulate MC2R.

[0006] In one aspect, described herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0007] [ka] During the ceremony, R A is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and R A If is substituted, R A is Ra , R b , and R c is replaced by R a , R b , and R c are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )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, or unsubstituted or substituted monocyclic heteroaryl; R a , R b , and R c Any of the substituents may be one or more R 9 is substituted with a group, L is absent, -C(=O)-, or -C(=O)NR 7 -, or -SO2-, R B is an unsubstituted or substituted carbocycle, an unsubstituted or substituted heterocycle, an unsubstituted or substituted C1-C7 alkyl, an unsubstituted or substituted C1-C7 fluoroalkyl, or an unsubstituted or substituted C1-C6 heteroalkyl; R B If is substituted, R B is R d , R e , and R f is replaced by or R B and R 7 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is R d , R e , and R f is replaced by R d , R e , and R f are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7)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, or unsubstituted or substituted monocyclic heteroaryl; R d , R e , and R f Any of the substituents may be one or more R 9 is substituted with a group, X 1 is CR 6 or N, X 2 is CR 6 or N, X 3 is CR 6 or N, R 1 is unsubstituted or substituted C1-C6 alkyl or unsubstituted or substituted C3-C6 cycloalkyl, and R 1 If is substituted, R 1 is hydrogen, -OR 8 , halogen, -N(R 7 )2, or substituted with -CN, R 2 and R 3 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl; R 2 and R 3 Any of the substituents may be hydrogen, -OR 8 , -N(R 7 )2, halogen, or -CN; or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, or R 2 and R 3 together with the carbon atoms to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic carbocyclic ring, R 4 and R 5are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted -(C1-C6 alkyl)-carbocycle, or unsubstituted or substituted -(C1-C6 alkyl)-heterocycle; R 4 and R 5 Any of the substituents may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2, or R 4 and R 5 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocyclic ring, and when the 3- to 6-membered heterocyclic ring is substituted, the 3- to 6-membered heterocyclic ring may be substituted with one or more halogen atoms, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocyclic ring, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2, or R 2 and R 4 together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered N-containing heterocycle; Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OR 8 , -SR 8 , -CO2R 8 , -C(=O)N(R 7 )2, or -N(R 7 )2, Each R 7 are 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; or two R's 7 form, together with the nitrogen atom to which they are attached, an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; Each R 8 are 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; Each R 9 are 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 8 , -CH2CO2R 8 , -C(=O)N(R 7 )2, -C(=O)N(R 7 ) OR 8 , -CH2C(=O)N(R 7 )2, -N(R 7 )2, -CH2N(R 7 )2, -C(R 8 )2N(R 7 )2, -NR 7 C(=O)R 8 , -CH2NR7 C(=O)R 8 , -NR 7 C(=O)N(R 7 )2, -NR 7 C(=O)N(R 7 )2, C(R 8 )=N(R 7 )-OR 8 , -SR 8 , -S(=O)R 10 , -SO2R 10 , or -SO2N(R 7 )2, Each R 10 is 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; n is 1 or 2.

[0008] 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 by 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 by 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.

[0009] In any of the foregoing aspects, there are further embodiments, in which an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, (b) administered orally to a mammal, (c) administered intravenously to a mammal, (d) administered by inhalation, (e) administered intranasally, (f) administered by injection to a mammal, (g) administered topically to a mammal, (h) administered ophthalmically to a mammal, (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0010] In any of the above aspects, there are further embodiments comprising a single administration of an effective amount of the compound, wherein the compound is administered to the mammal once daily or administered to the mammal multiple times throughout the day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0011] In any of the embodiments disclosed herein, the mammal is a human.

[0012] In some embodiments, the compounds provided herein are administered orally to a human.

[0013] An article of manufacture is provided that includes packaging material; and within the packaging material, a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a label indicating that the compound or composition, pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically acceptable metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof is used 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 subtypes of melanocortin receptor proteins.

[0014] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that this 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 present disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0015] Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide synthesized by the corticotroph cells of the anterior pituitary gland via proteolytic cleavage of proopiomelanocortin hormone (POMC). ACTH is the primary modulator of adrenal glucocorticoid (GC) synthesis and secretion (cortisol in most species, including humans; corticosterone in rodents). As a central actor in the hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary gland in response to stressful stimuli and acts in the adrenal gland to stimulate cortisol synthesis and secretion. This stimulation is mediated through a highly specific G protein-coupled receptor (GPCR) that is almost uniquely expressed in the adrenal cortex. This receptor is the melanocortin 2 receptor (MC2R), and together with ACTH, it is part of the larger melanocortin system.

[0016] The melanocortin system includes a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R) and their natural agonists, the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH) and ACTH, as well as 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 a variety of tissues where they perform a variety of discrete physiological functions (see Gantz, I. and T. M. Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003).

[0017] Any one of the MCRs, or a combination thereof, can be selectively modulated. In some embodiments, selective modulation of any one of the MCRs relative to another MCR, or a combination thereof, is useful in various clinical applications. In some embodiments, selective modulation of any one of the MCRs relative to another MCR, or a combination thereof, reduces unwanted 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.

[0018] 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 as high, and ACTH selectively activates MC2R. Importantly, other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, lack affinity for MC2R (see Gantz, I. and T. M. 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 normally. MRAP is a small protein with a single transmembrane domain that forms an antiparallel homodimer in a stable complex with MC2R and is required for both the cell surface expression of MC2R and its ability to bind ACTH. MRAP can bind to any of the MCRs and affect their activity, but is required only for MC2R activity. Binding of ACTH to the MC2R / MRAP complex on adrenocortical cells induces G S Activation of and elevation of intracellular cAMP levels stimulates cortisol synthesis and secretion by regulating multiple steps in the steroidogenic pathway.

[0019] Cushing's syndrome is a rare disorder characterized by chronic, excessive glucocorticoid exposure. Clinical signs of Cushing's syndrome include growth of fat pads (in the clavicles, posterior neck, face, and trunk), excessive sweating, telangiectasia, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disorders resulting in significant morbidity. In its severe form, when inadequately suppressed, Cushing's syndrome is associated with a high mortality rate. Although glucocorticoid excess can sometimes be ACTH-independent, such as due to hyperfunctioning adrenal adenomas, carcinomas, or excessive autonomous secretion of cortisol caused by steroid abuse, approximately 60–80% of all cases are ACTH-dependent, also known as Cushing's disease. Cushing's disease is caused by microadenomas of the pituitary corticotrophic cells, which secrete excess ACTH. Corticotropin-secreting adenomas are small, slow-growing benign tumors that typically become apparent clinically as a result of glucocorticoid excess rather than the physical effects of expanding tumors. First-line treatment for Cushing's disease is surgery, which involves removal of either the ACTH-secreting tumor in the pituitary gland or the adrenal gland itself. Because surgery is often unsuccessful, contraindicated, or delayed, medical therapy is necessary for these patients. Current treatment options include inhibitors of steroidogenic enzymes, which can prevent cortisol production and ameliorate symptoms, but these treatments also cause a large proportion of unwanted side effects due to the accumulation of other steroid products. In one aspect, an MC2R antagonist is used to treat Cushing's syndrome. In some embodiments, an MC2R antagonist is used to treat Cushing's disease. In some embodiments, the glucocorticoid excess is ACTH-independent. In some embodiments, the glucocorticoid excess is ACTH-dependent.

[0020] Ectopic ACTH syndrome, also known as ectopic Cushing's syndrome or Cushing's disease, is similar to Cushing's disease, except that the underlying tumor expressing ACTH is located outside the pituitary gland.In some embodiments, this tumor is a small carcinoid tumor occurring anywhere in the lung or gastrointestinal tract.In some embodiments, an MC2R antagonist is used to treat ectopic ACTH syndrome.

[0021] Congenital adrenal hyperplasia (CAH) is characterized by reduced or decreased cortisol synthesis and excess ACTH and corticotropin-releasing hormone. CAH can result from various inherited defects in the adrenal steroid biosynthetic pathway. In some embodiments, CAH is due to mutations in 21β-hydroxylase. Cortisol deficiency eliminates the negative feedback on the pituitary gland that causes excessive ACTH secretion. The resulting excessive adrenal stimulation leads to the overproduction of steroid precursors, which also has negative consequences (e.g., hyperandrogenism). Administration of replacement glucocorticoids usually does not adequately suppress ACTH without also causing Cushingoid symptoms. In some embodiments, an MC2R antagonist is used to treat CAH.

[0022] In addition to Cushing's disease and CAH, it has also been hypothesized that there may be a role for MC2R antagonists in the treatment of depression and septic shock. In some embodiments, MC2R antagonists are used to treat depression. In some embodiments, MC2R antagonists are used to treat septic shock.

[0023] In some embodiments, the compounds described herein are suitable for administration to a mammal in need of treatment with an MC2R antagonist.

[0024] compound The compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are melanocortin receptor modulators. In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are MC2R modulators. In some embodiments, the MC2R modulator is an MC2R antagonist.

[0025] In one aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0026] [ka] During the ceremony, R A is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and R A If is substituted, R A is R a , R b , and R c is replaced by R a , R b , and R c are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )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, or unsubstituted or substituted monocyclic heteroaryl; R a , R b , and R c Any of the substituents may be one or more R 9 is substituted with a group, L is absent, -C(=O)-, or -C(=O)NR 7 -, or -SO2-, R Bis an unsubstituted or substituted carbocycle, an unsubstituted or substituted heterocycle, an unsubstituted or substituted C1-C7 alkyl, an unsubstituted or substituted C1-C7 fluoroalkyl, or an unsubstituted or substituted C1-C6 heteroalkyl; R B If is substituted, R B is R d , R e , and R f is replaced by or R B and R 7 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is R d , R e , and R f is replaced by R d , R e , and R f are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )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, or unsubstituted or substituted monocyclic heteroaryl; R d , R e , and R f Any of the substituents may be one or more R 9 is substituted with a group, X 1 is CR 6 or N, X 2 is CR 6 or N, X 3 is CR 6 or N, R 1 is unsubstituted or substituted C1-C6 alkyl or unsubstituted or substituted C3-C6 cycloalkyl, and R 1 If is substituted, R 1 is hydrogen, -OR8 , halogen, -N(R 7 )2, or substituted with -CN, R 2 and R 3 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl; R 2 and R 3 Any of the substituents may be hydrogen, -OR 8 , -N(R 7 )2, halogen, or -CN; or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, or R 2 and R 3 together with the carbon atoms to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic carbocyclic ring, R 4 and R 5 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted -(C1-C6 alkyl)-carbocycle, or unsubstituted or substituted -(C1-C6 alkyl)-heterocycle; R 4 and R 5 Any of the substituents may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2, or R 4 and R 5together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocyclic ring, and when the 3- to 6-membered heterocyclic ring is substituted, the 3- to 6-membered heterocyclic ring may be substituted with one or more halogen atoms, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocyclic ring, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2, or R 2 and R 4 together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered N-containing heterocycle; Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OR 8 , -SR 8 , -CO2R 8 , -C(=O)N(R 7 )2, or -N(R 7 )2, Each R 7 are 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; or two R's 7 form, together with the nitrogen atom to which they are attached, an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; Each R 8are 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; Each R 9 are 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 8 , -CH2CO2R 8 , -C(=O)N(R 7 )2, -C(=O)N(R 7 ) OR 8 , -CH2C(=O)N(R 7 )2, -N(R 7 )2, -CH2N(R 7 )2, -C(R 8 )2N(R 7 )2, -NR 7 C(=O)R 8 , -CH2NR 7 C(=O)R 8 , -NR 7 C(=O)N(R 7 )2, -NR 7 C(=O)N(R 7 )2, C(R 8 )=N(R 7 )-OR 8 , -SR 8 , -S(=O)R 10 , -SO2R 10 , or -SO2N(R 7 )2, Each R 10 is 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; n is 1 or 2.

[0027] In some embodiments, L is absent, —C(═O)—, —C(═O)NR 7 In some embodiments, L is absent, —C(═O)—, or —C(═O)NR 7 In some embodiments, L is —C(═O)—, or —C(═O)NR 7 In some embodiments, L is —C(═O)—. In some embodiments, L is —C(═O)NR 7 -It is.

[0028] In some embodiments, L is —C(═O)— and R 2 and R 3 are independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH 3、- CH2OR 8 , or -CH2NHR 7 or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-. In some embodiments, R 2 and R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-. In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-.

[0029] In some embodiments, L is —C(═O)— and R 2 and R 3 are independently hydrogen or -CH3, or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl.

[0030] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, and R A If is substituted, R A is R a , R b , and R c is replaced by

[0031] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl; R A If is substituted, R A is R a , R b , and R c is replaced by

[0032] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl; R A If is substituted, R A is R a , R b , and R c is replaced by

[0033] In some embodiments, R Ais unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, and R A If is substituted, R A is R a , R b , and R c is replaced by

[0034] In some embodiments, R A is as follows:

[0035] [ka]

[0036] In some embodiments, R A is as follows:

[0037] [ka] In some embodiments, R A is as follows:

[0038] [ka] In some embodiments, R A is as follows:

[0039] [ka]

[0040] In some embodiments, R A is

[0041] [ka] wherein V is CH or N.

[0042] In some embodiments, R A is

[0043] [ka] wherein V is CH or N. In some embodiments, R A is as follows:

[0044] [ka] In some embodiments, R A is as follows:

[0045] [ka]

[0046] In some embodiments, n is 1. In some embodiments, n is 2.

[0047] In some embodiments, the compound has the structure of Formula (II):

[0048] [ka] During the ceremony, V is CH or N.

[0049] In some embodiments, R B is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted polycyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bicyclic heterocycle, or an unsubstituted or substituted polycyclic heterocycle; R B If is substituted, R B is R d , R e , and R f is replaced by

[0050] In some embodiments, R Bis an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bridged carbocycle, an unsubstituted or substituted spirocarbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bridged heterocycle, or an unsubstituted or substituted spiroheterocycle; R B If is substituted, R B is R d , R e , and R f is replaced by

[0051] In some embodiments, R B is an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted 6-membered monocyclic heteroaryl, an unsubstituted or substituted 5-membered monocyclic heteroaryl, an unsubstituted or substituted bicyclic heteroaryl, a monocyclic C3-C8 cycloalkyl, an unsubstituted or substituted bridged C5-C 10 Cycloalkyl, unsubstituted or substituted spiro C5-C 10 Cycloalkyl, unsubstituted or substituted monocyclic C2-C8 heterocycloalkyl, unsubstituted or substituted bridged C5-C 10 Heterocycloalkyl or unsubstituted or substituted spiro C5-C 10 heterocycloalkyl, and R B If is substituted, R B is R d , R e , and R f is replaced by

[0052] In some embodiments, R Bis an unsubstituted or substituted carbocycle which is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted indanyl, unsubstituted or substituted indenyl, unsubstituted or substituted tetrahydronaphthyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cycloheptyl, unsubstituted or substituted cyclooctyl, unsubstituted or substituted spiro[2.2]pentyl, unsubstituted or substituted spiro[3.3]heptyl, unsubstituted or substituted spiro[3.5]nonyl, unsubstituted or substituted spiro[4.4]nonyl, unsubstituted or substituted spiro[4.5]decyl, unsubstituted or substituted norbornyl, unsubstituted or substituted norbornenyl, unsubstituted or substituted bicyclo[1.1.1]pentyl, unsubstituted or substituted adamantyl, or unsubstituted or substituted decalinyl.

[0053] In some embodiments, R Bis unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl. B is an unsubstituted or substituted indolyl, and R B If is substituted, R B is R d , R e and R f is replaced by

[0054] In some embodiments, RB is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted tetrahydrofuran ... or substituted piperazinyl, unsubstituted or substituted homopiperidinyl, unsubstituted or substituted oxepanyl, unsubstituted or substituted thiepanyl, unsubstituted or substituted oxazepinyl, unsubstituted or substituted diazepinyl, unsubstituted or substituted thiazepinyl, unsubstituted or substituted azaspiro[3.3]heptanyl, unsubstituted or substituted azaspiro[3.4]octanyl, unsubstituted or substituted azaspiro[3.4]octanyl, or unsubstituted or substituted azaspiro[4.4]nonyl.

[0055] 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; R B If is substituted, R B is R d , R e , and R f is replaced by

[0056] In some embodiments, R B is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, or unsubstituted or substituted cyclohexyl; R B If is substituted, R B is R d , R e , and R f In some embodiments, R B is unsubstituted or substituted cyclobutyl, and R B If is substituted, RB is R d , R e , and R f is replaced by

[0057] In some embodiments, R B is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl; R B If is substituted, R B is R d , R e , and R f In some embodiments, R B is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl; R B If is substituted, R B is R d , R e , and R f In some embodiments, R B is unsubstituted or substituted pyrrolidinyl, and R B If is substituted, R B is R d , R e and R f is replaced by

[0058] In some embodiments, R B is

[0059] [ka] wherein m is 0, 1, 2, or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0060] In some embodiments, R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, and R B If is substituted, R B is R d , R e , and R f is replaced by

[0061] In some embodiments, R B is as follows:

[0062] [ka] In some embodiments, R B is as follows:

[0063] [ka] In some embodiments, R B is as follows:

[0064] [ka] In some embodiments, R B is as follows:

[0065] [ka]

[0066] In some embodiments, R B is

[0067] [ka] wherein V is CH or N. In some embodiments, R B is

[0068] [ka] wherein Z is CH or N.

[0069] In some embodiments, the compound has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0070] [ka] During the ceremony, V is CH or N; Z is CH or N.

[0071] In some embodiments, the compound has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0072] [ka]

[0073] In some embodiments, the compound has the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof.

[0074] [ka]

[0075] In some embodiments, R 1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0076] In some embodiments, R 1 is -CH3, -CH2CH3, or -CH2CH2CH3.

[0077] In some embodiments, R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted -(C1-C6 alkyl)-carbocycle, or unsubstituted or substituted -(C1-C6 alkyl)-heterocycle; R 4 The optional substituents of may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2 and R 5 is selected from the group consisting of hydrogen and C1-C6 alkyl, or R 4 and R 5together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocyclic ring, and when the 3- to 6-membered heterocyclic ring is substituted, the 3- to 6-membered heterocyclic ring may be substituted with one or more halogen atoms, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocyclic ring, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2.

[0078] In some embodiments, R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, or unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom; R 4 The optional substituents of are one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atoms, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2 and R 5 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, and -CH2CH2CH3.

[0079] In some embodiments, R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, or unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom; R 4 The optional substituents of are one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atoms, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2 and R 5 is selected from the group consisting of hydrogen, —CH, —CHCH, and —CHCHCH. In some embodiments, R 4 is selected from the group consisting of unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atom; R 4 The optional substituents of are one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atoms, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8, -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2 and R 5 is selected from the group consisting of hydrogen, —CH, —CHCH, and —CHCHCH. In some embodiments, R 4 is selected from the group consisting of unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atom; R 4 The optional substituents of are one or more halogens, C1-C6 alkyl unsubstituted or substituted with a 1,3-dioxol-2-one group, an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2 and R 5 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, and -CH2CH2CH3.

[0080] In some embodiments, the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof.

[0081] [ka]

[0082] In some embodiments, the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:

[0083] [ka] During the ceremony, R A is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, and R A If is substituted, R A is R a , R b , and R c is replaced by L is absent, -C(=O)- or -C(=O)NR 7 - and R B is an unsubstituted or substituted carbocyclic ring or an unsubstituted or substituted heterocyclic ring, and R B If is substituted, R B is R d , R e , and R f is replaced by or R B and R 7 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is R d , R e , and R f is replaced by

[0084] In some embodiments, R A is as follows:

[0085] [ka]

[0086] In some embodiments, R A is as follows:

[0087] [ka] In some embodiments, R A is as follows:

[0088] [ka]

[0089] In some embodiments, X 1 is CR 6 and X 2 is CR 6 and X 3 is CR 6 is.

[0090] In some embodiments, X 1 is N and X 2 is CR 6 and X 3 is CR 6 is.

[0091] In some embodiments, X 1 is CR 6 and X 2 is N and X 3 is CR 6 is.

[0092] In some embodiments, X 1 is CR 6 and X 2 is CR 6 and X 3 is N.

[0093] In some embodiments, each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, and -OR 8 In some embodiments, each R 6 is independently selected from the group consisting of hydrogen, halogen, and unsubstituted or substituted C1-C6 alkyl. In some embodiments, each R 6 is independently selected from the group consisting of hydrogen and halogen. 6 is independently selected from the group consisting of hydrogen and fluorine.

[0094] In some embodiments, X 1 is CH, C, F or N, and X 2 is CH, CF, or N, and X 3 is CH, CF, or N.

[0095] In some embodiments, R 4 is an unsubstituted or substituted C1-C6 alkyl or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 2 N atoms and 0 or 1 O or S atom; R 4 The optional substituents of are one or more halogen, unsubstituted or substituted C1-C6 alkyl, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2.

[0096] In some embodiments, R 4 is unsubstituted or substituted C1-C6 alkyl, and R 4 The optional substituents of are one or more halogen, unsubstituted or substituted C1-C6 alkyl, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10, -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2.

[0097] In some embodiments, R 4 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O or S atom, R 4 The optional substituents may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2. In some embodiments, R 4 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O or S atom, and R 4 The optional substituents may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, -N(R 7 )2, -OR 8 or -CN. In some embodiments, R 4 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing one atom, and R 4 The optional substituents may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, -N(R 7 )2, -OR 8 , or substituted with -CN.

[0098] In some embodiments, Ra is hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, wherein R a Any substituent in may be one or more R 9 is replaced by R b and R c are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, 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 substituent in may be one or more R 9 The group is substituted.

[0099] In some embodiments, R a is hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R b and R care independently selected from the group consisting of hydrogen, Cl, Br, -CN, -OH, -OCH, -OCHCH, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CH(CH), -CH(CH)(CHCH), -C(CH), -CHOH, -CHCN, -CHF, -CHF, -CF, -CHCHOH, -CHCHCN, -CHCHF, -CHCHF, -CHCF, -CHOCH, -CHCHOCH, -CHNH, -CHNHCH, -CHN(CH), -CHCHNH, -CHCHNHCH, or -CHCHN(CH).

[0100] In some embodiments, R d is hydrogen, halogen, -OR 8 , -CN, -N(R 7 )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, or unsubstituted or substituted monocyclic heteroaryl; R d The optional substituents of may be one or more R 9 substituted with R e and R f are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl; R e and R f The optional substituents of may be one or more R 9 In some embodiments, R d is hydrogen, halogen, -OR 8 , -CN, -N(R 7)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R d Any substituent in may be one or more R 9 is replaced by R e and R f are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, and unsubstituted or substituted C1-C6 alkyl; R e and R f Any substituent in may be one or more R 9 The group is substituted.

[0101] In some embodiments, R d is hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3) (CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3 , -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl; R d The optional substituents of may be one or more R 9 substituted with R e and R fare independently selected from the group consisting of F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3.

[0102] In some embodiments, the compound has the structure of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof:

[0103] [ka]

[0104] In some embodiments, R A , R B , R 4 , and X 1 is as described in Table 1, Table 2, or Table 3.

[0105] In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (IX):

[0106] [ka] During the ceremony, V is CH or N.

[0107] In some embodiments, the compound has the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein: V is CH or N; R a is hydrogen, halogen, -OR 8 , -CN, -N(R 7)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; R a The optional substituents of may be one or more R 9 is substituted with a group, R b and R c are each independently hydrogen, halogen, or -OR 8 , -CN, -N(R 7 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R b and R c The optional substituents of may be one or more R 9 is substituted with a group, R B is an unsubstituted or substituted carbocycle, an unsubstituted or substituted heterocycle, an unsubstituted or substituted C1-C7 alkyl, an unsubstituted or substituted C1-C7 fluoroalkyl, or an unsubstituted or substituted C1-C6 heteroalkyl; R B If is substituted, R B is R d , R e , and R f is replaced by R d is hydrogen, halogen, -OR 8 , -CN, -N(R 7 )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, or unsubstituted or substituted monocyclic heteroaryl; R d The optional substituents of may be one or more R 9 is substituted with a group, R e and R f are each independently hydrogen, halogen, or -OR 8 , -CN, -N(R 7)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R e and R f The optional substituents of may be one or more R 9 is substituted with a group, X 1 is CR 6 or N, R 2 and R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted -(C1-C6 alkyl)-carbocycle, or unsubstituted or substituted -(C1-C6 alkyl)-heterocycle; R 4 The optional substituents of may be one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 7 )2, -OR 8 , -CN, -CO2R 8 , -C(=O)N(R 7 )2, -SR 8 , -S(=O)R 10 , -S(=O)2R 10 , -NR 7 C(=O)R 8 , -NR 7 SO2R 10 , -SO2R 10 , or -SO2N(R 7 )2, R 6 is H or F, Each R 7 are 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; or two R's 7 form, together with the nitrogen atom to which they are attached, an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; Each R 8 are 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; Each R 9 are 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 8 , -CH2CO2R 8 , -C(=O)N(R 7 )2, -C(=O)N(R 7 ) OR 8 , -CH2C(=O)N(R 7 )2, -N(R 7 )2, -CH2N(R 7 )2, -C(R 8 )2N(R 7 )2, -NR 7 C(=O)R 8 , -CH2NR 7 C(=O)R 8 , -NR 7 C(=O)N(R 7 )2, -NR 7 C(=O)N(R 7 )2, C(R 8 )=N(R 7 )-OR 8 , -SR 8 , -S(=O)R 10 , -SO2R 10 , or -SO2N(R 7 )2, and Each R 10is 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.

[0108] In some embodiments, V is CH. In some embodiments, V is N.

[0109] In some embodiments, R a is hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R a Any substituent in may be one or more R 9 is replaced by R b and R c are independently hydrogen, halogen, -OR 8 , -CN, -N(R 7 )2, and unsubstituted or substituted C1-C6 alkyl; R b and R c Any substituent in may be one or more R 9 R a is hydrogen, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R b and R cis hydrogen. In some embodiments, R a HA-OR 8 and R b and R c is hydrogen. In some embodiments, R a is -OH, -OCH3, or -OCH2CH3, and R b and R c is hydrogen.

[0110] In some embodiments, X 1 is CH, CF, or N, V ​​is CH or N, and R 2 and R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, and R a is -OCH2CH3, and R b and R c is hydrogen.

[0111] In some embodiments, X 1 is CH, CF, or N, V ​​is CH or N, and R 2 and R 3 is hydrogen, or R 2 and R 3 together with the carbon atom to which they are attached to form -C(=O)-, and R a is -OCH2CH3, and R b and R c is hydrogen and R B is as described in Table 1 and / or Table 2. R 4 is as described in Table 1 and / or Table 2.

[0112] In some embodiments, each R 7 are independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, and unsubstituted or substituted C1-C6 fluoroalkyl, or two R 7together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3-6 membered monocyclic heterocycle. 7 are independently selected from the group consisting of hydrogen and substituted C1-C6 alkyl, or two R 7 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle.

[0113] In some embodiments, each R 8 is independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, and unsubstituted or substituted C1-C6 fluoroalkyl. 8 is independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, and unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, each R 8 is independently selected from the group consisting of hydrogen and substituted C1-C6 alkyl.

[0114] In some embodiments, each R 9 are independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, unsubstituted or substituted C1-C4 fluoroalkoxy, unsubstituted or substituted C1-C4 fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -COR 8 , -CH2CO2R 8 , -C(=O)N(R 7 )2, -CH2C(=O)N(R 7 )2, -N(R 7 )2, -CH2N(R 7 )2, -NR 7 C(=O)R 8 , or -CHNR 7 C(=O)R 8 In some embodiments, each R 9are independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, unsubstituted or substituted C1-C4 fluoroalkyl, -CN, -OH, -CO2R 8 , -C(=O)N(R 7 )2, -N(R 7 )2, or -CH2N(R 7 )2.

[0115] In some embodiments, each R 10 is independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted phenyl. In some embodiments, each R 10 is independently selected from the group consisting of substituted C1-C6 alkyl and unsubstituted or substituted phenyl.

[0116] In some embodiments, the compound of Formula (IX) has the structure of Formula (IXa):

[0117] [ka] During the ceremony, V is CH or N.

[0118] In some embodiments, R B , R 4 , and X 1 is as described in Table 1 and / or Table 2.

[0119] In some embodiments, the compounds described herein have the following structure:

[0120] [ka]

[0121] In some embodiments, R A , RB , R 4 , and X 1 is as described herein.

[0122] In some embodiments, R A , R B , R 4 , and X 1 are as listed in Table 1.

[0123] In some embodiments, the compounds described herein have the following structure:

[0124] [ka]

[0125] In some embodiments, R A , R B , R 4 , and X 1 is as described herein.

[0126] In some embodiments, R A , R B , R 4 , and X 1 are as listed in Table 2.

[0127] In some embodiments, the compounds described herein have the following structure:

[0128] [ka]

[0129] In some embodiments, R A , R B , R 1 , R 4 , and X 1 , X 2 , X 3 is as described herein.

[0130] In some embodiments, R A , R B , R 1 , R 4 , and X 1 , X 2 , X 3 are as listed in Table 3.

[0131] All combinations of groups described above in various variations are contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0132] Exemplary compounds of formula (I) include those set forth in the table below.

[0133] [Table 1-1]

[0134] [Table 1-2]

[0135] [Table 1-3]

[0136] [Table 1-4]

[0137] [Table 1-5]

[0138] [Table 1-6]

[0139] [Table 1-7]

[0140] Table 1-8

[0141] Table 1-9

[0142] Table 1-10

[0143] Table 1-11

[0144] Table 1-12

[0145] Table 1-13

[0146] Table 1-14

[0147] Table 1-15

[0148] Table 1-16

[0149] Table 1-17

[0150] Table 1-18

[0151] Table 1-19

[0152] Table 1-20

[0153] Table 1-21

[0154] Table 1-22

[0155] Table 1-23

[0156] Table 1-24

[0157] Table 1-25

[0158] Table 1-26

[0159] Table 1-27

[0160] Table 1-28

[0161] Table 1-29

[0162] Table 1-30

[0163] Table 1-31

[0164] Table 1-32

[0165] Table 1-33

[0166] Table 1-34

[0167] Table 1-35

[0168] Table 1-36

[0169] Table 1-37

[0170] Table 1-38

[0171] Table 1-39

[0172] Table 1-40

[0173] Table 1-41

[0174] Table 1-42

[0175] Table 1-43

[0176] Table 1-44

[0177] Table 1-45

[0178] Table 1-46

[0179] Table 1-47

[0180] [Table 1-48]

[0181] The compounds in Table 1 are named as follows: 1-1: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'-difluoro-[1,1'-biphenyl]-3-carboxamide; 1-2: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methoxy-[1,1'-biphenyl]-3-carboxamide; 1-3: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-4: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-5: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethyl-[1,1'-biphenyl]-3-carboxamide; 1-6: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-carboxamide; 1-7: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyano-[1,1'-biphenyl]-3-carboxamide; 1-8: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methyl-[1,1'-biphenyl]-3-carboxamide; 1-9: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3'-fluoro-[1,1'-biphenyl]-3-carboxamide; 1-10: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-11: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propoxy-[1,1'-biphenyl]-3-carboxamide; 1-12: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-(propan-2-yloxy)-[1,1'-biphenyl]-3-carboxamide; 1-13: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-hydroxy-[1,1'-biphenyl]-3-carboxamide; 1-14: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyclopropoxy-[1,1'-biphenyl]-3-carboxamide; 1-15: (R)-N-(2-aminoethyl)-4-(4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-16: (R)-N-(2-aminoethyl)-4-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-2'-(methoxymethyl)-[1,1'-biphenyl]-3-carboxamide; 1-17: (R)-N-(2-aminoethyl)-4-(4-(4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-18: (R)-N-(2-aminoethyl)-4-(4-(4'-(aminomethyl)-5-methyl-[1,1'-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-19: methyl (R)-3'-((2-aminoethyl)carbamoyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-[1,1'-biphenyl]-2-carboxylate; 1-20: (R)-N3'-(2-aminoethyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2-methyl-[1,1'-biphenyl]-2,3'-dicarboxamide; 1-21: (R)-N3'-(2-aminoethyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2,N2-dimethyl-[1,1'-biphenyl]-2,3'-dicarboxamide; 1-22: N-(2-aminoethyl)-2'-(aminomethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-carboxamide; 1-23: N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-24: N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-25: N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-26: N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-3'-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-27: N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-3-fluoro-5-methyl-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 1-28: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propyl-[1,1'-biphenyl]-3-carboxamide; 1-29: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-4'-propyl-[1,1'-biphenyl]-3-carboxamide; 1-30: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-2-yl)benzamide; 1-31: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-3-yl)benzamide; 1-32: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-2-yl)benzamide; 1-33: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-4-yl)benzamide; 1-34: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-35: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4-ethoxypyridin-3-yl)benzamide; 1-36: N-(2-aminoethyl)-2-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-37: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-38: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-39: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyridin-4-yl)benzoyl]piperazin-1-yl]benzamide; 1-40: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-41: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-42: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-43: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-44: N-(2-aminoethyl)-2-[(2R)-4-[4'-(aminomethyl)-3-fluoro-5-methyl-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-45: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-46: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; 1-47: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-48: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 1-49: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 1-50: N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-51: N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-52: N-(2-aminoethyl)-2-[(2R)-4-[2-(4-aminopiperidin-1-yl)-4-chlorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-53: N-(2-aminoethyl)-2-[(2R)-4-(3,5-dichloropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-54: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methoxybenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-55: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-56: N-(2-aminoethyl)-2-[(2R)-4-{4-[3-(aminomethyl)pyrrolidin-1-yl]-2-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-57: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-58: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; 1-59: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; 1-60: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dimethylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-61: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(pyrrolidin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-62: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; 1-63: N-(2-aminoethyl)-2-[(2R)-4-(2-cyclopropylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-64: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-2-yl)methyl]benzamide; 1-65: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-3-yl)methyl]benzamide; 1-66: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-4-yl)methyl]benzamide; 1-67: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]benzamide; 1-68: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-69: N-(2-aminoethyl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-70: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(pyridin-4-yl)benzamide; 1-71: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-methoxypyridin-3-yl)benzamide; 1-72: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-73: 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-74: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(piperidin-4-yl)benzoyl]piperazin-1-yl]benzamide; 1-75: N-(2-aminoethyl)-2-[(2R)-4-[2-(6-aminopyridin-3-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-76: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-77: N-(2-aminoethyl)-2-[(2R)-4-(2,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-78: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methylbenzoyl)piperazin-1-yl]benzamide; 1-79: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methoxybenzoyl)piperazin-1-yl]benzamide; 1-80: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(2-methoxy-4-methylbenzoyl)piperazin-1-yl]benzamide; 1-81: N-(2-aminoethyl)-2-[(2R)-4-(4-tert-butylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-82: 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-83: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-5-yl)methyl]benzamide; 1-84: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-5-yl)ethyl]benzamide; 1-85: N-(2-aminoethyl)-2-[(2R)-4-[2-(2-aminopyridin-4-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-86: N-(2-aminoethyl)-2-[(2R)-4-(4,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-87: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-88: N-(2-aminoethyl)-2-[(2R)-4-(4-cyclopropyl-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-89: N-(2-aminoethyl)-2-[(2R)-4-(3-chloro-5-fluoropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-90: 2-[(2R)-4-[4-chloro-2-(piperazin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-91: 2-[(2R)-4-[4-chloro-2-(dimethylamino)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-92: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-pyrrolidin-3-yl]benzamide; 1-93: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 1-94: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-95: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-96: 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-97: N-{[(2S)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-98: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-pyrrolidin-2-yl]methyl}benzamide; 1-99: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide; 1-100: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-piperidin-3-yl]benzamide; 1-101: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-fluoro-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-102: N-{[(2R)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-103: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-fluoro-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-104: N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-105: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(morpholin-4-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; 1-106: N-(2-aminoethyl)-2-[(2R)-4-[3-(dimethylamino)-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-107: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-108: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide; 1-109: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-morpholin-2-yl]methyl}benzamide; 1-110: 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-111: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-112: N-{[(2S)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-113: 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-114: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-115: 2-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-116: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 1-117: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-118: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-fluoro-3-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]benzamide; 1-119: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(methylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; 1-120: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; 1-121: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-122: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-123: N-{[(2R)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-124: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide; 1-125: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-126: 2-[(2R)-4-[2-amino-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide; 1-127: N-(2-aminoethyl)-2-[(2R)-4-[6-(dimethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-128: 2-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; 1-129: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-imidazol-1-yl)benzoyl]piperazin-1-yl]benzamide; 1-130: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrrol-1-yl)benzoyl]piperazin-1-yl]benzamide; 1-131: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrazol-1-yl)benzoyl]piperazin-1-yl]benzamide; 1-132: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-2-yl)methyl]benzamide; 1-133: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-134: 2-[(2R)-4-[3-chloro-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-135: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-136: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-137: 2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-138: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(3S)-morpholin-3-yl]methyl}benzamide; 1-139: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]benzamide; 1-140: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 1-141: 6-[(2R)-4-(4-chloro-2-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 1-142: 2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-143: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-144: 2-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-145: 2-[(2R)-4-[6-amino-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide; 1-146: N-(2-aminoethyl)-2-[(2R)-4-[4-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-147: 2-[(2R)-4-[2-(dimethylamino)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-148: 2-[(2R)-4-[2-(3-aminoazetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-149: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide; 1-150: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-151: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-152: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-153: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-154: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-155: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-156: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-157: 6-[(2R)-4-[2-cyano-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-158: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-159: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; 1-160: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-methylpyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-161: 2-[(2R)-4-[2-(azetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-162: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyrrolidin-1-yl)benzoyl]piperazin-1-yl]benzamide; 1-163: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-(methylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-164: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-165: 6-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-166: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-167: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-168: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-169: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-170: N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-171: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-172: 5-[(2R)-4-(2-carbamoyl-4-chlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-173: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-174: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-175: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-176: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-177: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-178: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-179: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-180: 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-181: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-182: N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-183: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-184: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-185: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methyl-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-186: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-187: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-188: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-189: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-190: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-191: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-[ethyl(methyl)amino]-4-fluorobenzoyl}piperazin-1-yl]benzamide; 1-192: 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(4,6-dimethoxypyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide; 1-193: 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(6-methoxy-4-oxo-1,4-dihydropyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide; 1-194: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethyl-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-195: 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-196: 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-197: 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-198: N-(azetidin-3-yl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-199: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 1-200: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-pyrrolidin-3-yl]benzamide; 1-201: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-1-methylpyrrolidin-3-yl]benzamide; 1-202: N-(azetidin-3-yl)-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-203: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-(1-methylazetidin-3-yl)benzamide; 1-204: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide; 1-205: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethyl-[2,3'-bipyridine]-6-carboxamide; 1-206: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-207: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-208: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[2-(methylamino)ethyl]pyridine-2-carboxamide; 1-209: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-210: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-211: N-(azetidin-3-yl)-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-212: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-213: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-214: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-215: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-216: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(1-methylazetidin-3-yl)benzamide; 1-217: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(4-ethoxypyrimidin-5-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-218: 5-[(2R)-4-(2-chloro-4-cyclopropoxybenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-219: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-220: N-(azetidin-3-yl)-3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide; 1-221: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-222: N-[(azetidin-3-yl)methyl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-223: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-224: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(1H-imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-225: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-(ethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-226: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-227: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-228: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-1-methylazetidin-2-yl]methyl}benzamide; 1-229: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2S)-1-methylazetidin-2-yl]methyl}benzamide; 1-230: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-231: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-232: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-233: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-234: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(1-methyl-1H-imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-235: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-236: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-237: 3-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-238: 5-[(2R)-4-(adamantane-2-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-239: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-240: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-241: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-242: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-243: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-244: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-245: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-246: 5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2'-methoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-247: 5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2'-methoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-248: 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-249: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-250: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclobutanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-251: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-252: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[trans-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-253: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-254: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-255: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-256: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-257: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-258: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-259: 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-260: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-261: 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-262: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-263: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-264: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclopentanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-265: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-266: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-267: 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-268: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-269: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-270: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 1-271: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-272: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-273: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-274: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-275: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-276: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-277: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-278: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-279: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-280: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-281: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-282: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-283: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-284: 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-285: 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-286: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-287: 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-288: 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-289: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-290: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-291: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-292: 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-293: 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-294: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-295: 5-[(2R)-4-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-296: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-297: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-298: 5-[(2R)-4-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-299: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-300: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-301: 2'-ethoxy-5-[(2R)-2-ethyl-4-[trans-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-302: 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-303: 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-304: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-305: 3-[(2R)-4-(2-tert-butylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-306: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-307: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-308: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1,2,2,3-tetramethylcyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-309: 1,1,1-trifluoro-2-methylpropan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-310: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-311: 5-[(2R)-4-(2-cyclopropylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-312: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-313: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-314: 5-[(2R)-4-{7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl}-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-315: 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-316: 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-317: 5-[(2R)-4-(2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-318: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoroazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-319: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoro-1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-320: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-321: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-322: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-323: 5-[(2R)-4-(2,2-diethylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-324: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-325: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-pyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-326: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-methyl-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-327: N-{[(2R)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-328: 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-329: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-330: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-331: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-332: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-333: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-334: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-methoxy-1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-335: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-336: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-337: N-[2-(azetidin-1-yl)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-338: 1-(trifluoromethyl)cyclobutyl (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate; 1-339: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-340: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide; 1-341: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-342: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-343: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-344: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-345: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-phenylpyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-346: 5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-347: 5-[(2R)-4-(5-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-348: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate; 1-349: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-350: 2'-ethoxy-5-[(2R)-2-ethyl-4-(7-fluoro-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-351: (1R)-2,2,2-trifluoro-1-phenylethyl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-352: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclopentanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-353: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-354: 5-[(2R)-4-[2,2-difluoro-7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-355: 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-356: 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 1-357: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(3-fluoroazetidin-1-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-358: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-359: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-360: 2'-ethoxy-5-[(2R)-2-ethyl-4-(7-methyl-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-361: 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-362: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide; 1-363: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-364: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-365: 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-366: (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-367: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-368: 2'-ethoxy-5-[(2R)-2-ethyl-4-[5-(trifluoromethyl)thiophene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-369: 1,1,1,3,3,3-hexafluoropropan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-370: 3-(trifluoromethyl)pentan-3-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-371: 5-[(2R)-4-[1-(2,4-difluorophenyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-372: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-373: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-374: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-375: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-376: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-377: (1S)-2,2,2-trifluoro-1-phenylethyl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-378: 5-[(2R)-4-(2,5-dichlorothiophene-3-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-379: 2'-ethoxy-5-[(2R)-2-ethyl-4-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-380: 5-[(2R)-4-(3,5-dichlorothiophene-2-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-381: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(3-fluorophenyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-382: 5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indene-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-383: 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-384: 1-phenylcyclobutyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-385: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-386: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-387: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}pyridine-2-carboxamide; 1-388: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-389: 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-390: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-391: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-392: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-393: 3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-394: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-395: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-396: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-397: 1-ethylcyclopentyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-398: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-399: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-400: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-401: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-402: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-403: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-404: 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-405: N-{1-azabicyclo[2.2.1]heptan-4-yl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-406: (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-407: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-408: 2,2-dimethyl-1-phenylpropyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-409: 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-410: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide; 1-411: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-412: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-413: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-414: 3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-415: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-416: 5-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-417: 3-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-418: 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-419: 5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-420: 5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-421: 3-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-422: 5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-423: 5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-424: 3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 1-425: 5-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-426: 3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-427: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-428: 5-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-429: 5-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-430: 3-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-431: 3-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-432: 3-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-433: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-434: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-435: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-436: 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-437: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1-438: 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; and 1-439: 3-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide.

[0182] [Table 2-1]

[0183] [Table 2-2]

[0184] [Table 2-3]

[0185] [Table 2-4]

[0186] The compounds in Table 2 are named as follows: 2-1: 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}methyl)amino]ethan-1-ol; 2-2: (2S)-1-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}methyl)amino]propan-2-ol; 2-3: 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methoxy-[1,1'-biphenyl]-3-yl}methanamine; 2-4: 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl}methanamine; 2-5: 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propoxy-[1,1'-biphenyl]-3-yl}methanamine; 2-6: 2-{[3'-(aminomethyl)-4'-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-2-yl]oxy}ethan-1-ol; 2-7: 2-{[3'-(aminomethyl)-4'-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1'-biphenyl]-2-yl]oxy}ethan-1-ol; 2-8: [3'-(aminomethyl)-4'-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-2-yl]methanol; 2-9: 1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine; 2-10: 1-{2-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine; 2-11: 1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine; 2-12: 1-{3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridin-2-yl}methanamine; 2-13: 1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 2-14: 1-{5-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 2-15: 1-{5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 2-16: ({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methyl)(methyl)amine; 2-17: 1-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 2-18: 1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine; 2-19: 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-(2,3,4-trifluorobenzoyl)piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 2-20: 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 2-21: {[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]phenyl]methyl}[2-(methylamino)ethyl]amine; 2-22: 13-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N-methylpyridin-2-amine; 2-23: 3-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N,N-dimethylpyridin-2-amine; 2-24: 1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-[2-(pyrrolidin-1-yl)pyridin-3-yl]phenyl}methanamine; 2-25: 1-{2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 2-26: 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-3'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 2-27: 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1'-biphenyl]-3-yl}methanamine; 2-28: 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-4'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 2-29: 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-5'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 2-30: 1-{2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; and 2-31: 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine.

[0187] [Table 3-1]

[0188] [Table 3-2]

[0189] The compounds in Table 3 are named as follows: 3-1: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2',3'-difluoro-[1,1'-biphenyl]-3-carboxamide; 3-2: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 3-3: 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-4: (3R)-N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl}phenyl]-3-ethylpiperazine-1-carboxamide; 3-5: N-(2-aminoethyl)-2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 3-6: 2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-methylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; 3-7: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxamide; 3-8: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide; and 3-9: N-(2-aminoethyl)-5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2-(2-ethoxyphenyl)pyridine-4-carboxamide.

[0190] In one aspect, 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 in the scope of the present disclosure.In addition, the compounds described herein can exist not only in unsolvated form, but also in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0191] "Pharmaceutically acceptable," as used herein, refers to a substance, 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 adversely with any of the components of the composition in which it is included.

[0192] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting 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 more 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. Also, salt-forming molecules can be in equilibrium with neutral forms, allowing for controlled passage across biological membranes.

[0193] 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; glucohedral acid; These 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.

[0194] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0195] 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 situations, 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 coordinate 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, but not limited to, 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, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0196] It should be understood that 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 or ethanol. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein are suitably prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0197] The methods and formulations described herein 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 said compounds that possess the same type of activity.

[0198] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of a compound of Formula (I) is susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radical reduces, minimizes, or eliminates this metabolic pathway. 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, alkyl, haloalkyl, or deuteroalkyl groups.

[0199] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioisotope) or by other means, including, but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0200] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced by 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 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, and phosphorus, such as P. In one aspect, 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 aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0201] 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, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0202] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on non-chiral or chiral chromatographic columns, followed by crystallization and recrystallization in an appropriate solvent or solvent mixture. 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 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 formation of diastereomeric salts and separation by recrystallization, chromatography, or any combination thereof. See Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomars, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0203] 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 in some situations because they are easier to administer than the parent drug. For example, they may be more bioavailable by oral administration than the parent drug. Additionally or alternatively, prodrugs have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the prodrug is designed to increase effective water solubility. Non-limiting examples of prodrugs include the compounds described herein, which are administered as esters ("prodrugs") that are subsequently 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 some embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0204] 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, 8, pp. 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 subsequently metabolized in vivo to yield a carboxylic acid group. In some embodiments, the carboxyl group is used to yield an ester or amide (i.e., a prodrug), which is subsequently metabolized in vivo to yield a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0205] Prodrug forms of the compounds described herein, which are metabolized in vivo to produce compounds 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.

[0206] 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.

[0207] In additional or further embodiments, the compounds described herein are metabolized after administration to an organism to produce metabolic products that are subsequently used to provide a desired effect, including a desired therapeutic effect.

[0208] A "metabolite" of a compound disclosed herein is a derivative of that compound formed upon metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed upon metabolism of the compound. The term "metabolized," as used herein, refers to the totality of processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can effect specific structural changes to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either 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.

[0209] 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.

[0210] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0211] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0212] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0213] [ka]

[0214] Heating methyl 2-fluoro-5-nitrobenzoate or methyl 2,6-difluoro-3-nitrobenzoate with a monoprotected substituted piperazine in the presence of an organic base such as N,N-diisopropylethylamine gives compound I. Iron-catalyzed reduction of the nitro group gives the arylamine, which is then transformed to the aryl bromide (II) by preparation of the diazonium salt and subsequent copper(I)-catalyzed displacement with Br anion. Compound II can be prepared by the reaction of R ACompound IV undergoes an organometallic coupling reaction, such as the Suzuki-Miyaura reaction with B(OH) or its corresponding ester, followed by standard hydrolysis to yield compound III. Compound IV is converted to intermediate V via iron-catalyzed nitro reduction and subsequent Sandmeyer reaction of aniline. Alternatively, compound V can be obtained from standard deprotection of II.

[0215] In some embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0216] [ka]

[0217] Compound V is converted to intermediate VI by treatment with an activated carboxylic acid using HATU, triethylamine, or an acyl chloride in the presence of triethylamine or other base. A Organometallic coupling reactions such as Suzuki-Miyaura reaction with B(OH)2 or its esters, or R A Compound VII is prepared from aryl bromides (VI) by Stille coupling with SnBu. Direct conversion of carboxylic acid esters (VII) to amides (VIII) is achieved by heating the carboxylic acid ester with a diamine in a polar protic solvent. Alternatively, compound VI can be converted to the corresponding boron ester intermediate (IX), followed by reaction with R. A Conversion of the ester to an amide via a coupling reaction such as Suzuki-Miyaura reaction with an aryl halide such as -Br provides VIII.

[0218] In some embodiments, the compounds described herein are prepared as depicted in Scheme C.

[0219] [ka]

[0220] Compound III was reacted with the amine (R 4 R 5 NH) to give intermediate X. Compound X is subjected to removal of Boc with TFA or other acid to give R A CO2H or R A Amide formation with COCl gives XI. 4 or R 5 If R contains a protecting group, an additional deprotection step is performed to yield XI. Alternatively, intermediate XII, obtained by deprotection of III with TFA, can be converted to XI by cleaving a pre-activated R B Treatment with COH converts to XIII. Compound XIII can be utilized to produce the corresponding amide (XI) in a similar manner.

[0221] In some embodiments, the compounds described herein are prepared as depicted in Scheme D.

[0222] [ka]

[0223] Compound II is reacted with boronic acid R in the presence of a transition metal catalyst. B Suzuki coupling with B(OH)2 gives intermediate (XIV). The carboxylic acid ester on XIV is reduced to the alcohol using NaBH4, which is then oxidized with 2-iodoxybenzoic acid to give benzaldehyde XV. 4 R 5 Reductive amination with a reducing agent such as NaBH(OAc)3 gives XVI, followed by Boc deprotection and R B Amide formation with COH gives compound XVII. 4 If XVII contains a protecting group, an additional deprotection step takes place to afford XVII.

[0224] In some embodiments, the compounds described herein are prepared as depicted in Scheme E.

[0225] [ka]

[0226] Boronic acid R A Suzuki-Miyaura coupling reaction with B(OH)2, or R A Stille coupling with SnBu3 prepares compound XVIII, which is reacted with a monoprotected substituted piperazine in the presence of an organic base such as DIEA to give XIX. The Boc group is then removed with acid and the corresponding amide is converted to XIX via the R B Formation by standard amide formation with COH gives XX. Nickel(II)-catalyzed reduction of the carbonitrile produces the benzylamine analog (XXII-B). Hydrolysis of the -CN on XX with a strong inorganic base such as KOH gives the carboxylic acid intermediate (XXI), which can be converted to R 4 R 5 This is converted to compound XXII-A by coupling with NH. 4 If XIX contains a protecting group, an additional deprotection step is performed to yield XXII. Alternatively, XXII-A can be prepared in a four-step synthesis starting from XIX by hydrolysis of the cyano group to a carboxylic acid, followed by addition of R 4 R 5 Amide formation at NH to form XXIII, removal of the Boc group, and R B CO2H or R B COCl is used to obtain XXII-A. 4 If XIX contains a protecting group, an appropriate deprotection step is performed to remove the protecting group to yield XXII. In some embodiments, compound XXII-B is prepared from XIX via an alternative route: the cyano group is reduced with NaBH in the presence of NiCl. The newly formed amine is then protected with a Cbz group. The Boc group is then removed, and R B Amide formation is carried out with CO2H. Finally, the Cbz group is removed by stirring in hot TFA to give XXXII-B.

[0227] In some embodiments, the compounds described herein are prepared as described in Scheme F.

[0228] [ka]

[0229] Heating methyl 6-bromo-3-chloropyrazine-2-carboxylate with a monoprotected substituted piperazine gives compound XXIV. A Suzuki-Miyaura coupling with B(OH)2, hydrolysis of the ester to the acid, and standard de-Boc treatment affords XXV. B Coupling with COH affords XXVI, which is then reacted with HATU in R 4 R 5 Further reaction with NH gives XXVII. 4 or R 5 If contains a protecting group, an additional deprotection step is performed to yield XXII.

[0230] In some embodiments, the compounds described herein are prepared as depicted in Scheme G.

[0231] [ka]

[0232] The Boc group on II is removed to give XXVIII, which is then reacted with R B -Cl or R B XXIX is formed by treatment with -F and saponification of the ester. 4 R 5 Coupling reaction with NH gives XXX, which is then converted to boronic acid R A Suzuki-Miyaura reaction with B(OH)2 gives XXXI. 4 or R 5 If contains a protecting group on XXXI, the protecting group is further removed.

[0233] In some embodiments, the compounds described herein are prepared as depicted in Scheme H.

[0234] [ka]

[0235] Removal of the Boc group on X forms XXXII, which can be reacted with an arylsulfonyl chloride in the presence of an organic base to give XXXIII. Similarly, isocyanic acid (RBNCO) or reaction R B R 7 Reaction with CO2Ph, or thiophosgene and R B R 7 The urea analog (XXXIV) was prepared by either reaction of XXXII with NH. Additionally, an efficient synthesis of carbamate derivative (XXXV) was achieved by reacting XXXII with CDI-activated alcohol. 4 If contains a protecting group, R4 is removed under appropriate conditions for XXXIII, XXXIV, or XXXV.

[0236] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0237] Specific Terms Unless otherwise stated, the following terms used in this application have the definitions given below. Use of the term "including," as well as other forms such as "include," "includes," and "included," is non-limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0238] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C6" indicates that the moiety has from 1 to 4 carbon atoms, i.e., 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 from 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.

[0239] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may be branched or straight-chain. In some embodiments, an "alkyl" group may contain 1 to 10 carbon atoms, i.e., C1-C6. 10 The term "alkyl" includes alkyl. Whenever a numerical range such as "1 to 10" appears herein, it refers to each integer within the given 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 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.

[0240] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups described above may be alkylene by abstraction 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. Examples of typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0241] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0242] The term "alkylamine" refers to -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.

[0243] "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 examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0244] "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. Examples of typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0245] 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)=CR 2 and R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, 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.

[0246] 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.

[0247] 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 aspect, the heteroalkyl is a C1-C6 heteroalkyl.

[0248] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where 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 or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0249] 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. This term thus 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 of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0250] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C 10 Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0251] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic aliphatic non-aromatic radical, wherein 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 to an aromatic ring, and the point of attachment is to 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-dimethylbicyclo[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.

[0252] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0253] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0254] 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, provided that each heterocycle group has 3 to 10 atoms in its ring system, but the ring does not contain two adjacent O or S atoms. Non-aromatic heterocycle groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocycle groups include rings having 5 to 10 atoms in their ring system. Heterocycle groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups include 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, dithiolazolinyl, and the like. nyl, 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.

[0255] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Representative 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 zero to four N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0256] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyls contain 0-2 N atoms in the ring. In some embodiments, heterocycloalkyls contain 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0257] The term "single bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the single bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a single bond, the referenced group is absent, thus allowing for the formation of a single bond between the remaining specified groups.

[0258] The term "moiety" refers to a specific area or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0259] 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(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 an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0260] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject receiving the treatment.

[0261] The term "modulate" as used herein means to interact with a target directly or indirectly so as to alter the activity of the target, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to expand the activity of the target.

[0262] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. This interaction includes, but is not limited to, that of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0263] 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 of skill 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.

[0264] 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 treatment regimens in which agents are administered by the same or different routes of administration, or at the same or different times.

[0265] As used herein, the term "effective amount" or "therapeutically effective amount" refers 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. This result may include a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in a particular case is optionally determined using techniques such as a dose escalation study.

[0266] The terms "enhance" or "enhancing," as used herein, mean increasing or prolonging a desired effect either in potency or duration. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, in either potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0267] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or blending of more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the auxiliary agent are simultaneously administered to a patient in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the auxiliary agent are simultaneously, concurrently, or sequentially administered to a patient as separate entities without a specific time limit between them, such that the administration provides the patient with effective levels of the two compounds. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[0268] The terms "article of manufacture" and "kit" are used synonymously.

[0269] 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 ape and monkey species; livestock animals 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 aspect, the mammal is a human.

[0270] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the progression 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.

[0271] 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 to facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found in, for example, 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 such disclosure.

[0272] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be achieved by any 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 tube, rectal suppository, and rectal enema), 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, and the most appropriate route may depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein can 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.

[0273] 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 presented as a bolus, electuary, or paste.

[0274] Orally usable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft, sealed 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 may 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, lubricant, surfactant, or dispersing agent. Molded tablets may 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 intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may 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 may be dissolved or suspended in a 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 may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. For identification or to characterize different combinations of dosages of active compound, dyes or pigments may be added to tablets or dragee coatings.

[0275] 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 formulating 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) state 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 type described above.

[0276] 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, as well as 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.

[0277] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts.

[0278] For buccal or sublingual administration, the pharmaceutical 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.

[0279] Pharmaceutical compositions can be administered topically, i.e., non-systemically. This method includes administering the compound of the present invention to the external epidermis or buccal cavity, and instilling such a compound into the ear, eye, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0280] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations 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 from 0.001% to 10% by weight w / w of the formulation for topical administration, for example, from 1% to 2% by weight.

[0281] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, a nebulizer, a pressurized pack, or other convenient means of delivering an aerosol spray. Pressurized packs 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, pharmaceutical preparations may be in 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 unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0282] It will be understood that in addition to the ingredients particularly mentioned above, 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, formulations suitable for oral administration may include flavoring agents.

[0283] Administration and Treatment Regimen 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.

[0284] In some embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In some 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 arrest at least one symptom of the disease or condition. Amounts 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 studies and / or dose ranging clinical trials.

[0285] 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 depend, among other things, on the patient's health and weight. When used in a patient, the amount effective for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition symptoms.

[0286] In some embodiments in which the patient's disease is not improved, at the physician's discretion, the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to improve or otherwise inhibit or limit the patient's disease or symptoms of the disease.

[0287] Once improvement of the patient's disease has occurred, a maintenance dose is administered if necessary. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level at which improvement of the disease, disorder, or condition is maintained. In some embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0288] 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 (e.g., weight, sex) of the subject or host requiring treatment, 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.

[0289] In general, however, dosages employed for adult human treatment are typically in the range of 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is conveniently 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.

[0290] In one embodiment, a suitable daily dose for a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein is about 0.01 to about 50 mg / kg. In some embodiments, the daily amount of active ingredient in a dosage form is less than or greater than the ranges set forth herein, based on many variables related to the particular treatment regimen. In various embodiments, the daily dose 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 attending physician.

[0291] The toxicity and efficacy of these treatment regimens are 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD 50 and ED 50 In some embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is determined to be within the range of ED100 with minimal toxicity. 50 In certain embodiments, the daily dose range and / or unit dose varies within this range depending upon the dosage form employed and the route of administration utilized.

[0292] 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.

[0293] 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 over the course of a day to the mammal.

[0294] In any of the foregoing aspects, (i) the compound is administered continuously or intermittently as 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, in which administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and compound administration is resumed at the end of the drug holiday. In one embodiment, the duration of the drug holiday varies from 2 days to 1 year.

[0295] Combination treatment 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.

[0296] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient), or in some embodiments, the benefit received by the patient is increased by administering one of the compounds described herein with another agent (including a therapeutic regimen) that also has a therapeutic effect.

[0297] 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 benefit than administration of either therapeutic agent alone.

[0298] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the additive of the two therapeutic agents, or the patient experiences a synergistic effect.

[0299] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of drug being combined, the particular drug being utilized, 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.

[0300] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0301] 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 and are administered continuously to a subject prone to developing a disease or condition to prevent the onset of the 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 as long as necessary to treat the condition. In some embodiments, the required duration of treatment can vary, and the duration of treatment is tailored to the specific needs of each subject.

[0302] Abbreviation: DIEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0); Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; CuI: copper(I) iodide; 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, MeCN, or ACN: acetonitrile; MeOD: deuterated methanol; CDCl3: deuterated chloroform; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DCM: dichloromethane; H2O: water; KOAc: potassium acetate; NaOAc: sodium acetate; Cs2CO3: Cesium carbonate; P-TsOH: p-toluenesulfonic acid; NaNO2: sodium nitrite; THF: tetrahydrofuran; NBS: N-bromosuccinimide; Br2: Bromine; AgF: silver fluoride; LiAlH4: lithium aluminum hydride; IBX: 2-iodoxybenzoic acid; TEA: trimethylamine; DMAP: N,N-dimethylpyridin-4-amine; HOBT: hydroxybenzotriazole; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride; PdAMphos or Pd(amphos)Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(DTBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); cc: column chromatography; rt: room temperature; h: Time. [Example]

[0303] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0304] Compound synthesis Example 1: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide (Compound 1-1)

[0305] [ka]

[0306] Step 1-1, Preparation of tert-butyl (3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate: A 40 mL round-bottom flask was charged with methyl 2-fluoro-5-nitrobenzoate (2.2 g, 0.01 mmol, 1.2 equiv.), tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (2.0 g, 9.33 mmol), TEA (2.8 g, 0.03 mmol, 3.0 equiv.), and DMSO (20 mL). The resulting solution was stirred at 100 °C for 2 hours and cooled to room temperature. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to give 3.3 g (90%) of the title compound as a brown oil. LCMS (M+H) + :394.2.

[0307] Step 1-2, Preparation of methyl 2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate: A solution of tert-butyl (3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate (3.3 g, 8.39 mmol) in TFA (3 mL) / DCM (6 mL) was stirred at 30° C. for 2 hours. The resulting mixture was concentrated in vacuo. This afforded 3.3 g (97%) of the title compound as a brown oil. LCMS (M+H) + :294.1.

[0308] Step 1-3, Preparation of tert-butyl (3R)-4-[4-bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate: 2-Chloro-4-(trifluoromethyl)benzoic acid (860 mg, 3.83 mmol, 1.2 equiv.) and HATU (1.46 g, 3.83 mmol, 1.2 equiv.) were dissolved in DMF (20 mL). After stirring at room temperature for 5 minutes, the resulting solution was treated with methyl 2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate trifluoroacetate (1.3 g, 3.19 mmol) and DIEA (1.23 g, 9.57 mmol, 3.0 equiv.). The reaction was stirred at room temperature for 1 hour, diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:1). 1.8 g (83%) of the title compound was obtained as a yellow oil. LCMS (M+H) + :500.1.

[0309] Step 1-4, Preparation of 5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate: A 40 mL round-bottom flask was charged with methyl 2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-nitrobenzoate (1.8 g, 3.60 mmol), Fe (1 g, 18.00 mmol, 5.0 equiv), NHCl (963 mg, 18.00 mmol, 5.0 equiv), and EtOH (20 mL) / HO (4 mL). The resulting solution was stirred at 70 °C for 1 h and cooled to room temperature. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were dried and concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:1). 1.1 g (65%) of the title compound was isolated as a yellow oil. LCMS (M+H) + :470.1.

[0310] Step 1-5, Preparation of methyl 5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate: A 40 mL round-bottom flask was charged with CuBr (1.31 g, 5.85 mmol, 2.5 equiv.), n-butyl nitrite (482 mg, 4.68 mmol, 2.0 equiv.), and ACN (20 mL). The resulting solution was stirred at 0 °C for 5 min and then treated dropwise with a solution of methyl 5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate (1.1 g, 2.34 mmol) in ACN (5 mL) at 0 °C. The resulting solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:1). 520 mg (42%) of the title compound was isolated as a pale yellow oil. LCMS (M+H) + :533.0.

[0311] Step 1-6, Preparation of methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'-difluoro-[1,1'-biphenyl]-3-carboxylate: An 8 mL pressure tube was charged with methyl 5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate (30 mg, 0.06 mmol), 2,3-difluorophenylboronic acid (13.3 mg, 0.08 mmol), Pd(dba)CHCl (5.8 mg, 0.01 mmol), P(t-Bu)HBF (1.6 mg, 0.01 mmol), KPO (35.8 mg, 0.17 mmol), and toluene / HO (1 mL / 0.1 mL). The resulting solution was degassed with N for 5 min, sealed, and stirred in an oil bath at 70 °C for 2 h. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 20 mg (63%) of the title compound. LCMS (M+H) + :567.1.

[0312] Step 1-7, Preparation of N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'-difluoro-[1,1'-biphenyl]-3-carboxamide: An 8 mL pressure tube was charged with methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'-difluoro-[1,1'-biphenyl]-3-carboxylate (20 mg, 0.04 mmol), ethane-1,2-diamine (0.5 mL), and IPA (0.5 mL). The resulting solution was sealed and stirred at 70 °C for 16 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: SunFire Prep C18 OBD column; mobile phase, Phase A: water (0.05% TFA); Phase B: ACN (30% to 45% in 6 min); flow rate: 20 mL / min; detector, 220 & 254 nm. The resulting yield was 7.4 mg (30%) of the title compound. LCMS (M+H) + :595.2.

[0313] Using the appropriate substitution reagents and substrates at various steps, the following compounds were prepared similarly to Example 1. Some examples may require additional functional group transformations to introduce appropriate substituents onto the aryl ring.

[0314] [Table 4]

[0315] Example 2: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxamide (Compound 1-14)

[0316] [ka]

[0317] Step 2-1, Preparation of methyl 2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate: An 8 mL pressure tube vessel, purged and maintained with an inert nitrogen atmosphere, was charged with methyl 5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate (250 mg, 0.47 mmol) from Step 1-5 of Example 1, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (178 mg, 0.70 mmol), Pd(DTBPF)Cl (25 mg, 0.04 mmol), KOAc (138 mg, 1.4 mmol), and dioxane (5 mL). The resulting solution was degassed with N for 10 minutes, sealed, and stirred in an oil bath at 90 °C for 3 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:3), resulting in 120 mg (44%) of the title compound. LCMS (M+H) + :581.2.

[0318] Step 2-2, Preparation of methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxylate: An 8 mL pressure tube vessel was charged with 2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (43 mg, 0.07 mmol), 1-bromo-2-cyclopropoxybenzene (28 mg, 0.13 mmol), Pd(DTBPF)Cl (2 mg, 0.003 mmol), KCO (20 mg, 0.14 mmol), and dioxane / HO (2 mL / 0.2 mL). The resulting solution was degassed with N2 for 10 minutes, sealed, and stirred in an oil bath at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by prep-TLC eluting with ethyl acetate / petroleum ether (1:3) to give 25 mg (57%) of the title compound. LCMS (M+H) + :587.0.

[0319] Step 2-3, Preparation of N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyclopropoxy-[1,1'-biphenyl]-3-carboxamide: An 8 mL pressure tube vessel was charged with methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]2-ethylpiperazin-1-yl]-2'-cyclopropoxy-[1,1-biphenyl]-3-carboxylate (25 mg, 0.04 mmol), ethane-1,2-diamine (2 mL), and IPA (2 mL). The resulting solution was sealed and stirred at 70 °C for 16 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: SunFire Prep C18 OBD column; mobile phase, Phase A: water (0.05% TFA); Phase B: ACN (21% to 38% in 6 min); flow rate: 20 mL / min; detector, 220 & 254 nm. 10.7 mg (34%) of the title compound was obtained. LCMS (M+H)+ :615.2.

[0320] The following compounds were prepared in a similar manner to Example 2, using the appropriate substitution reagents and substrates at the various steps.

[0321] [Table 5]

[0322] Example 3: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide (Compound 1-95)

[0323] [ka]

[0324] Step 3-1, Preparation of tert-butyl (3R)-3-ethyl-4-[3-fluoro-2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate: To a solution of tert-butyl-(3R)-3-ethylpiperazine-1-carboxylate (555 mg, 2.59 mmol) and methyl 2,6-difluoro-3-nitrobenzoate (843 mg, 3.89 mmol) in DMSO (2 mL) was added DIEA (0.90 mL, 5.2 mmol). The mixture was heated at 130 °C for 1 hour. The mixture was purified by C18 reverse-phase column chromatography to give the title compound (813 mg, 76% yield) as a brownish-yellow gum. LCMS (M+H) + :412.3.

[0325] Step 3-2, Preparation of tert-butyl (3R)-4-[4-amino-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate: To a solution of tert-butyl (3R)-3-ethyl-4-[3-fluoro-2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate (813 mg, 1.98 mmol) in MeOH (30 mL) was added 10% Pd / C (213 mg, 0.0941 mmol) and NH4Cl (1.188 g, 18.83 mmol). The mixture was heated at 80°C for 20 minutes. The mixture was filtered through Celite, and the filtrate was concentrated and purified by C18 reverse-phase column chromatography to give the title compound (612 mg, 81% yield) as a reddish-brown gum. LCMS (M+H) + :382.3.

[0326] Step 3-3, Preparation of tert-butyl (3R)-4-[4-bromo-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate: To a solution of tert-butyl (3R)-4-[4-amino-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (612 mg, 1.60 mmol) in MeCN (10 mL) under nitrogen, CuBr (197 mg, 0.882 mmol) and 90% tert-butyl nitrite (0.24 mL, 1.8 mmol) were added. The mixture was heated at 70 °C for 30 min. The mixture was quenched with ice water and extracted with DCM (3x). The combined organic layers were washed with saturated NaHCO3 (aq), concentrated and purified by C18 reverse phase column chromatography to give the title compound (267 mg, 0.600 mmol, 38% yield) as a brown gum. LCMS (M+H) + :445.2.

[0327] Step 3-4, Preparation of tert-butyl (3R)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate: To a solution of tert-butyl (3R)-4-[4-bromo-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (267 mg, 0.600 mmol), (2-ethoxypyridin-3-yl)boronic acid (150 mg, 0.900 mmol), Pd[t-BuP(4-NMeCH)]Cl (42.5 mg, 0.0600 mmol), and KCO (249 mg, 1.80 mmol) in a sealed tube was added dioxane (4 mL) and HO (0.4 mL). The resulting solution was degassed with N2(g) for 10 minutes, sealed, and stirred at 100 °C for 30 minutes. The reaction was treated with additional (2-ethoxypyridin-3-yl)boronic acid (37.8 mg, 0.226 mmol), Pd[t-Bu2P(4-NMe2C6H4)]2Cl2 (13.4 mg, 0.0189 mmol), and K2CO3 (78.3 mg, 0.567 mmol) and stirred at 100 °C for an additional 30 minutes. The mixture was concentrated and purified by C18 reverse-phase column chromatography to give the title compound (255 mg, 87% yield) as a brown gum. LCMS (M+H) + :488.4.

[0328] Step 3-5, Preparation of 6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid: To a solution of tert-butyl (3R)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (255 mg, 0.523 mmol) in THF / MeOH / HO (4.5 / 1.5 / 1.5 mL) was added LiOH.HO (220 mg, 5.24 mmol). The mixture was heated at 60 °C overnight. The reaction was approximately 50% complete. After the addition of additional LiOH.HO (220 mg, 5.24 mmol), the mixture was continued to heat at 70° C. for 2 days. After removal of the volatile solvents, the aqueous residue was diluted with ice water and acidified to pH 4 with 1 N HCl (aq). The solid was collected by suction filtration and dried to give the title compound (239 mg, 97% yield) as a brown solid. LCMS (M+H) + :474.2.

[0329] Step 3-6, Preparation of 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoic acid dihydrochloride: To a solution of 6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid (100 mg, 0.211 mmol) in DCM (0.3 mL) was added 4N HCl in dioxane (0.30 mL, 1.2 mmol). The mixture was stirred at room temperature for 1 hour. The solution was decanted, and the residue was rinsed with DCM (3x) and dried under vacuum to give the title compound as a brown solid. LCMS (M+H) + :374.3.

[0330] Step 3-7, Preparation of 6-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid: To a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (94.9 mg, 0.423 mmol) and HATU (145 mg, 0.381 mmol) in DMF (0.5 mL) was added DIEA (0.073 mL, 0.42 mmol). After stirring at room temperature for 5 minutes, the resulting solution was added to a solution of 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoic acid dihydrochloride (0.211 mmol) and DIEA (0.11 mL, 0.42 mmol) in DMF (0.2 mL). The mixture was stirred at room temperature for 10 minutes. The reaction was directly purified by C18 reverse-phase column chromatography to give the title compound (69.8 mg, 57% yield) as a white solid. LCMS (M+H) + :580.3.

[0331] Step 3-8, Preparation of tert-butyl N-[2-({6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}formamido)ethyl]-N-methylcarbamate: To a solution of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-piperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid (35.0 mg, 0.06 mmol) and HATU (34.4 mg, 0.091 mmol) in DMF (0.2 mL) was added DIEA (0.021 mL, 0.12 mmol). After stirring at room temperature for 5 minutes, the reaction was treated with tert-butyl N-(2-aminoethyl)-N-methylcarbamate (21.0 mg, 0.121 mmol) and stirred at room temperature for 5 minutes. The mixture was purified by C18 reverse phase column chromatography to give the title compound (35.6 mg, 80% yield) as an off-white solid. LCMS (M+H) + :736.4.

[0332] Step 3-9, Preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide: To a solution of tert-butyl N-[2-({6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}formamido)ethyl]-N-methylcarbamate (35.6 mg, 0.0484 mmol) in DCM (0.1 mL) was added 4 N HCl in dioxane (0.10 mL, 0.40 mmol). The mixture was stirred at room temperature for 10 minutes. The solution was decanted and the residue was rinsed with DCM (3x) and dried under vacuum. The HCl salt of the product was triturated with saturated NaHCO3 (aq) and dried to give the title compound (24.6 mg, 80% yield) as an off-white solid. LCMS (M+H) + :636.3.

[0333] The following compounds were prepared similarly to Example 3, using appropriate substitution reagents and substrates at various steps. In some examples, additional functional group transformations may be required to introduce appropriate substituents onto the aryl ring. In some instances, a final deprotection step may not be required:

[0334] [Table 6]

[0335] Example 4: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide (Compound 1-173)

[0336] [ka]

[0337] Step 4-1, Preparation of tert-butyl (3R)-4-(2-{[2-(dimethylamino)ethyl]carbamoyl}-4-(2-ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1-carboxylate: To a solution of 6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid (1.000 g, 2.111 mmol) from Step 3-5 of Example 3 and HATU (963 mg, 2.53 mmol) in DMF (1 mL) was added DIEA (0.92 mL, 5.3 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with (2-aminoethyl)dimethylamine (0.35 mL, 3.1 mmol) and stirred at room temperature for 10 minutes. The reaction was purified by C18 reverse phase column chromatography to give the title compound (973.7 mg, 85% yield) as a pale yellow solid. LCMS (M+H) + :544.4.

[0338] Step 4-2, Preparation of N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzamide trihydrochloride: To a solution of tert-butyl (3R)-4-(2-{[2-(dimethylamino)ethyl]carbamoyl}-4-(2-ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1-carboxylate (973.7 mg, 1.791 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (2.3 mL, 9.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was treated with additional 4 N HCl in dioxane (2.0 mL, 8.0 mmol) and stirring was continued for 2 hours. The solution was decanted and the residue was rinsed with DCM (3x) and dried under vacuum to give the title compound as a pale yellow solid. LCMS (M+H) + :444.3.

[0339] Step 4-3, Preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide: To a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (40.6 mg, 0.181 mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0.2 mL) was added DIEA (0.047 mL, 0.27 mmol). After stirring at room temperature for 5 minutes, the resulting solution was stirred at room temperature for 5 minutes, and then cooled to 5°C. The resulting solution was cooled to 5°C. The resulting solution was stirred at room temperature for 5 minutes, and then cooled to 5°C. The resulting solution was cooled to 5°C. The resulting solution was cooled to 5°C. The resulting solution was cooled to 5°C. To a solution of [1-[(2- ...3-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(3-(2-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(3-(2-(2-(3-(2-(2-(3-(2-(2-(3-(2-(3-(2-(2-(3-(2-(3 + :650.3.

[0340] The following compounds were prepared similarly to Example 4, using appropriate substitution reagents and substrates at various steps. In some examples, additional functional group transformations may be required to introduce appropriate substituents onto the aryl ring. In some instances, additional deprotection is required in the final step:

[0341] [Table 7-1]

[0342] [Table 7-2]

[0343] Example 5: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide (Compound 1-184)

[0344] [ka]

[0345] Step 5-1, Preparation of 4-chloro-2-(difluoromethyl)benzoic acid: To a solution of 4-chloro-2-methylbenzoic acid (0.460 g, 2.70 mmol), Selectfluor (2.697 g, 7.612 mmol), and NaSO (0.365 g, 1.53 mmol) in a sealed tube was added MeCN (2 mL) and water (2 mL). After N (g) was bubbled through, the mixture was cooled to −78 °C under nitrogen, and AgNO (51.8 mg, 0.305 mmol) was added. After the addition, the mixture was warmed to room temperature under nitrogen, then heated at 80 °C for 3 h, filtered through Celite, and rinsed with EtOAc. The filtrate was washed with saturated NaHCO (aq) (3 × 25 mL). The combined basic aqueous solution was acidified with 1N HCl (aq) to pH 2-3 and extracted with EtOAc (2x). The combined organic layers were concentrated and purified by C18 reverse-phase column chromatography to give the title compound (128.8 mg, 23% yield) as an off-white solid.

[0346] Step 5-2, Preparation of 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide: To a solution of 4-chloro-2-(difluoromethyl)benzoic acid (37.3 mg, 0.181 mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0.2 mL) was added DIEA (0.047 mL, 0.27 mmol). After stirring at room temperature for 5 minutes, the resulting solution was added to a solution of N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzamide trihydrochloride (43.0 mg, 0.0778 mmol) from Step 4-2 of Example 4 and DIEA (0.110 mL, 0.631 mmol) in DMF (0.2 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was purified by C18 reverse-phase column chromatography to give the title compound (20.6 mg, 0.0326 mmol, 41.9% yield) as an off-white solid. LCMS (M+H) + :632.3.

[0347] The following compounds were prepared similarly to Example 5, using the appropriate substitution reagents and substrates at various steps. In some instances, additional deprotection was required in the final step:

[0348] [Table 8]

[0349] Example 6: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide (Compound 1-188)

[0350] [ka]

[0351] Step 6-1, Preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide: To a solution of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid (48 mg, 0.082 mmol) from Step 3-7 of Example 3 in ACN (1 mL) was added HATU (31 mg, 0.082 mmol) and EtN (17 μL, 0.12 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with (4,5-dihydro-1H-imidazol-2-yl)methylamine dihydrochloride (14 mg, 0.081 mmol) pre-neutralized with EtN (34 μL, 0.24 mmol) in ACN (1 mL). The reaction was stirred at room temperature for 20 minutes, diluted with DCM, and washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (100 / 0 to 85 / 15) to give the title compound (21 mg, 39%). LCMS (M+H) + :661.2.

[0352] The following compounds were prepared in a similar manner to Example 6, using the appropriate substitution reagents and substrates at the various steps.

[0353] [Table 9]

[0354] Example 7: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide (Compound 1-57)

[0355] [ka]

[0356] Step 7-1, Preparation of 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid: A 15 mL pressure tube vessel was charged with 4-chloro-2-fluorobenzoic acid methyl ester (80 mg, 0.42 mmol), pyrrolidin-3-yl-carbamic acid tert-butyl ester (118 mg, 0.63 mmol), and a solution of DIEA (0.11 mL, 0.63 mmol) in DMSO (2 mL). The resulting solution was stirred in an oil bath at 140 °C. The progress of the reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and purified by C18 reverse-phase column chromatography using 0.1% TFA-ACN / 0.1% TFA-HO to give 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid methyl ester (150 mg, 100%). LCMS (M+H) + :355.3.

[0357] A 25 mL round-bottom flask was charged with a solution of 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid methyl ester (150 mg, 0.42 mmol) in HO / MeOH / THF (0.6 / 0.6 / 1.8 mL). The resulting solution was treated with LiOH monohydrate (170 mg, 4.2 mmol) and stirred at 70 °C overnight. The reaction was cooled to room temperature, concentrated, and diluted with HO (~2 mL). The resulting solution was acidified with 1 N HCl and then extracted with EtOAc (2x). The combined organic layers were washed with brine, dried and concentrated to give 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid (110 mg, 82%). LCMS (M+H) + :341.1.

[0358] Step 7-2, Preparation of benzyl N-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate: A 10 mL round-bottom flask was charged with a solution of 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid (25 mg, 0.073 mmol) in ACN (1.0 mL). This solution was treated with HATU (30 mg, 0.079 mmol) and EtN (11 μL, 0.079 mmol). After stirring for 5 minutes, the resulting solution was treated with benzyl N-(2-{[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethylpiperazin-1-yl]phenyl]formamido}ethylcarbamate (40 mg, 0.073 mmol) and stirred at room temperature for 20 minutes. The resulting mixture was directly purified by C18 reverse-phase column chromatography using 0.1% TFA-ACN / 0.1% TFA-HO to give benzyl N-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate (30 mg, 48%). LCMS (M+H) + :854.5.

[0359] Step 7-3, Preparation of N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide. A solution of benzyl N-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate (28 mg, 0.032 mmol) and a catalytic amount of thioanisole (1-2 drops) in TFA (0.5 mL) was stirred at 60° C. for 30 min. The reaction was cooled to room temperature and concentrated. The residue was purified by C18 reverse-phase column chromatography using 0.1% TFA-ACN / 0.1% TFA-HO to give N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide (13 mg, 65%). LCMS (M+H) + :620.5.

[0360] The following compounds were prepared similarly to Example 7, using appropriate substitution reagents and substrates at various steps. Some examples may require additional functional group transformations to introduce appropriate substituents onto the aryl ring. In some instances, acid-catalyzed deprotection is not required in the final step:

[0361] [Table 10]

[0362] Example 8: N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide (Compound 1-17)

[0363] [ka]

[0364] Step 8-1, Preparation of benzyl N-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate: A 10 mL round-bottom flask was charged with a solution of 2-bromo-4-fluorobenzoic acid (40 mg, 0.18 mmol) in ACN (2.0 mL). This solution was treated with HATU (76 mg, 0.2 mmol) and EtN (36 μL, 0.27 mmol). After stirring for 5 minutes, the resulting solution was treated with benzyl N-[2-({2'-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate trifluoroacetate (120 mg, 0.18 mmol) and stirred at room temperature for 20 minutes. The resulting mixture was directly purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give benzyl N-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate (54 mg, 41%). LCMS (M+H) + :731.5.

[0365] Step 8-2, Preparation of benzyl N-[2-({4-[(2R)-4-[4'-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate: A 15 mL pressure tube vessel was charged with benzyl N-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate (50 mg, 0.068 mmol), [4-({[(tert-butoxy)carbonyl]amino}methylphenyl]boronic acid (35 mg, 0.14 mmol), PdCl(t-BuPPhNMe) (5 mg, 0.007 mmol), KCO (19 mg, 0.14 mmol), and dioxane / HO (2 mL / 0.2 mL). The resulting solution was degassed with N for 5 min and sealed with a cap. The reaction mixture was then cooled to room temperature. The mixture was stirred at 85° C. in an oil bath for 2 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc, and washed with 1N HCl and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give benzyl N-[2-({4-[(2R)-4-[4'-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate (43 mg, 74%). LCMS (M+H) + :858.8.

[0366] Step 8-3, Preparation of N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide: A solution of benzyl N-[2-({4-[(2R)-4-[4'-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate (43 mg, 0.050 mmol) and a catalytic amount of thioanisole (1-2 drops) in TFA (0.5 mL) was stirred at 60° C. for 30 min. The reaction was cooled to room temperature and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide (22 mg, 71%). LCMS (M+H) + :624.4.

[0367] The following compounds were prepared similarly to Example 8 using the appropriate substitution reagents and substrates at various steps. Some examples may require -CN reduction to introduce the benzylamine in the final step:

[0368] [Table 11]

[0369] Example 9. 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide (Compound 1-135)

[0370] [ka]

[0371] Step 9-1, Preparation of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carbonitrile: To a solution of a mixture of 6-bromo-3-fluoropyridine-2-carbonitrile and 6-chloro-3-fluoropyridine-2-carbonitrile (4:1 ratio, 1.0 equiv., 1.0 mmol, 200 mg) in dioxane (4 mL) was added Pd(Amphos)Cl (0.025 equiv., 0.025 mmol, 18 mg), 2-ethoxypyridin-3-ylboronic acid (2.0 equiv., 2.0 mmol, 334 mg), KCO (2.2 equiv., 2.2 mmol, 304 mg), and water (0.4 mL). The resulting solution was purged with nitrogen and heated at 100 °C for 1 h. LCMS showed complete consumption of the starting material and formation of the desired product. This reaction was repeated under similar conditions on a 5.0 mmol scale. The two batches of reaction mixture were combined, diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc / hexanes (0-50%) to afford 1.7 g (>100%) of the desired product containing an unidentified impurity. LCMS (M+H) + =244.1.

[0372] Step 9-2, Preparation of tert-butyl (3R)-4-{6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl}-3-ethylpiperazine-1-carboxylate: To a solution of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carbonitrile (1.0 equiv., 6.0 mmol, 1.7 g) in DMSO (10 mL) was added tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (1.5 equiv., 9.0 mmol, 1.9 g) and DIEA (2.0 equiv., 12 mmol, 2.0 mL). The resulting solution was purged with nitrogen and heated at 140 °C for 2 days. LCMS showed the desired product had formed, but the Boc protecting group had been partially lost. Therefore, the reaction was cooled to room temperature, and then DIPEA (2.0 equiv., 12 mmol, 2.0 mL) and di-tert-butyl dicarbonate (2.0 equiv., 12 mmol, 2.75 mmol) were added and stirred for 1 hour. The reaction solution was then diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with MeCN / water (5-100%). Pure fractions were combined, neutralized with saturated NaHCO3, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and dried under high vacuum to give 1.20 g (46%) of the desired product. LCMS (M+H) + =438.3.

[0373] Step 9-3, Preparation of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carbonitrile trifluoroacetate: To a solution of tert-butyl (3R)-4-{6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl}-3-ethylpiperazine-1-carboxylate (1.0 equiv., 0.73 mmol, 320 mg) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo to give the crude product (560 mg) as a TFA salt. This material was used in the next step without further purification. LCMS (M+H) +=338.4.

[0374] Step 9-4, Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile: To a solution of 2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitrile trifluoroacetate (560 mg crude, 0.73 mmol) in DMF (3.0 mL) was added DIEA (1.06 mL, 4.38 mmol, 6.0 equiv), HATU (570 mg, 1.5 mmol, 2.0 equiv), and 2-trifluoromethyl-4-chlorobenzoic acid (224 mg, 1.0 mmol, 1.35 equiv). The resulting mixture was stirred at room temperature for 10 minutes, at which point LCMS showed complete consumption of the starting material. The reaction solution was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / hexanes (0-50%) to give 230 mg (58%) of the desired product. LCMS (M+H) + =544.3.

[0375] Step 9-5, Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid: To a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile (27 mg, 0.05 mmol) in EtOH (0.25 mL) was added KOH (85%, 28 mg, 0.50 mmol, 10 equiv.) and water (0.25 mL). The resulting mixture was heated at 100 °C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with saturated NaHSO4 (5.0 mL) and brine, dried, and concentrated to give 26 mg of the crude title compound. This material was used in the next step without further purification. LCMS (M+H) +=563.3.

[0376] Step 9-6, Preparation of tert-butyl N-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}formamido)ethyl]-N-methylcarbamate: To a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) was added DIEA (0.10 mL, 0.55 mmol, 11 equiv.), HATU (38 mg, 0.10 mmol, 2.0 equiv.), and 1-boc-1-methylethylenediamine (19 mg, 0.10 mmol, 2.0 equiv.). The resulting mixture was stirred at ambient temperature for 0.5 h. The crude reaction solution was purified by C18 reverse-phase column chromatography eluting with MeCN / water (5–100%). Pure fractions were combined, neutralized with saturated NaHCO3 and NaCl, extracted with ethyl acetate, and dried over MgSO4. The organic layer was concentrated and dried under high vacuum to give 15 mg of the desired product (47%). LCMS (M+H) + =719.3.

[0377] Step 9-7, Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide: To a solution of tert-butyl N-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-yl}formamido)ethyl]-N-methylcarbamate (15 mg, 0.021 mmol) in DCM (0.5 mL) was added TFA (0.2 mL). The resulting mixture was stirred at ambient temperature for 0.5 hours. The reaction was concentrated and purified by C18 reverse-phase column chromatography eluting with MeCN / water (5-60%). Pure fractions were combined, neutralized with saturated NaHCO3 and NaCl, extracted with ethyl acetate, and dried over MgSO4. The organic layer was concentrated and dried under high vacuum to give 9 mg (70%) of the desired product. LCMS (M+H) + =619.4.

[0378] The following compounds were prepared similarly to Example 9, using appropriate substitution reagents and substrates at various steps. In some examples, additional functional group transformations may be required to introduce appropriate substituents onto the aryl ring. In some instances, no additional deprotection is required in the final step:

[0379] [Table 12-1]

[0380] [Table 12-2]

[0381] Example 10: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide acetate (Compound 1-150)

[0382] [ka]

[0383] Step 10-1, Preparation of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid: To a solution of tert-butyl (3R)-4-{6-cyano-2'-ethoxy-[2,3'-bipyridine]-5-yl}-3-ethylpiperazine-1-carboxylate (271 mg, 0.62 mmol) from Step 9-2 of Example 9 in EtOH (3 mL), KOH (85%, 409 mg, 6.2 mmol, 10 equiv.) and water (3.0 mL) were added. The resulting mixture was heated at 100 ° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with saturated NaHSO4 (10 mL) and brine, dried and concentrated to give 283 mg of the crude title compound. This material was used in the next step without further purification. LCMS (M+H) + =457.3.

[0384] Step 10-2, Preparation of tert-butyl (3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a solution of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (283 mg, 0.619 mmol) in DMF (5.0 mL) was added HATU (353 mg, 0.93 mmol, 1.5 equiv), DIEA (0.31 mL, 1.86 mmol, 3.0 equiv), and N,N-dimethylethylenediamine (84 mg, 353 mmol, 1.5 equiv). The resulting mixture was stirred at 50° C. for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with MeOH / DCM (0-15%) to give 396 mg of the desired product as a brown oil. LCMS (M+H) + =527.4.

[0385] Step 10-3, Preparation of N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of tert-butyl (3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (396 mg, 0.75 mmol) in DCM (4.0 mL) was added TFA (2.0 mL). The resulting mixture was stirred at ambient temperature for 0.5 hours and concentrated in vacuo. The residue was neutralized with saturated NaHCO3, extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with MeOH / DCM (0-20%) to give 201 mg (64%) of the desired product as a brown oil. LCMS (M+H) + =427.4.

[0386] Step 10-4. Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide acetate: To a solution of N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide (89 mg, 0.20 mmol) in DMF (2 mL) was added HATU (91 mg, 0.24 mmol, 1.2 equiv), DIEA (0.092 mL, 0.50 mmol, 2.5 equiv), and 2-trifluoromethyl-4-chlorobenzoic acid (45 mg, 0.20 mmol, 1.0 equiv). The resulting mixture was heated at 50 °C for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with MeOH / DCM (0–9%). The pure fractions were combined and concentrated with HOAc (0.1 mL) to give 90 mg (64%) of the desired product. LCMS (M+H) + =633.4.

[0387] The following compounds were prepared similarly to Example 10, using the appropriate substitution reagents and substrates at various steps. In some instances, additional deprotection was required in the final step:

[0388] [Table 13]

[0389] Example 11: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide (Compound 3-8)

[0390] [ka]

[0391] Step 11-1, Preparation of methyl 6-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylate: A 15 mL pressure tube vessel was charged with 6-bromo-3-chloropyrazine-2-carboxylic acid methyl ester (300 mg, 1.19 mmol), tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (370 mg, 1.72 mmol, 1.4 equiv), DIEA (0.3 mL, 1.78 mmol, 1.5 equiv), and DMSO (6 mL). The resulting solution was stirred at 140 °C for 1 h, cooled to room temperature, and diluted with EtOAc (~15 mL). The organic layer was washed with 1 N HCl (2x) and brine (1x), dried over anhydrous NaSO, and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-H2O. 140 mg (27%) of methyl 6-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylate was isolated. LCMS (M+H) + :429.3.

[0392] Step 11-2, Preparation of methyl 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate: To a 15 mL pressure tube vessel was added 66-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylate (100 mg, 0.23 mmol), 2-ethoxypyridine-3-boronic acid (78 mg, 0.46 mmol), PdCl(t-BuPPhNMe) (24 mg, 0.033 mmol), KCO (64 mg, 0.46 mmol), and dioxane / HO (2.5 mL / 0.25 mL). The resulting solution was degassed with N2 for 5 minutes and sealed with a cap. The reaction was stirred in an oil bath at 100 °C for 1 hour. The resulting mixture was cooled to room temperature, diluted with EtOAc, and washed with 1N HCl and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-H2O to give methyl 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate (85 mg, 77%). LCMS (M+H) + :472.3.

[0393] Step 11-3, Preparation of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid: To a solution of methyl 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate (85 mg, 0.18 mmol) in MeOH / HO / THF (1 / 1 / 3 mL) was added lithium hydroxide hydrate (108 mg, 15 equiv). The resulting solution was stirred at room temperature for 3 h. After removal of the volatile solvents, the aqueous residue was diluted with HO (~3 mL) and then acidified with 1 N HCl. The resulting aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid (75 mg, 91%). LCMS (M+H) + :458.3.

[0394] Step 11-4, Preparation of 6-(2-ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazine-2-carboxylic acid: A solution of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid (75 mg, 0.16 mmol) in TFA (0.2 mL) / DCM (0.6 mL) was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated in vacuo. The residue (~100%) was diluted with ACN (1 mL) and neutralized with EtN, and used in the next step without further purification. LCMS (M+H) + :358.2.

[0395] Step 11-5. Preparation of 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid: To a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (45 mg, 0.2 mmol, 1.33 equiv) in ACN (1 mL) was added HATU (75 mg, 0.2 mmol) followed by EtN (40 μL, 0.35 mmol). The resulting solution was stirred at room temperature for 5 min and treated with 6-(2-ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazine-2-carboxylic acid (∼55 mg, 0.15 mmol, 1 equiv) prepared in the previous step. The resulting solution was stirred at room temperature for 20 minutes and concentrated under vacuum. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid (55 mg, 64%). LCMS (M+H) + :564.5.

[0396] Step 11-6, Preparation of tert-butyl N-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate: A 10 mL vial was charged with 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylic acid (30 mg, 0.053 mmol, 1.00 equiv), HATU (21 mg, 0.056 mmol), EtN (11 μL, 0.08 mmol), and ACN (1 mL). The resulting solution was stirred at room temperature for 5 minutes and treated with tert-butyl N-(2-aminoethyl)-N-methylcarbamate (11 mg, 0.063 mmol, 1.2 equiv). The reaction was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give tert-butyl N-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate (18 mg, 47%). LCMS (M+H) + :720.3.

[0397] Step 11-7, Preparation of 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide: A solution of tert-butyl N-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate (18 mg, 0.025 mmol) in TFA (0.2 mL) / DCM (0.6 mL) was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated in vacuo. The residue was purified by C18 reverse-phase column chromatography eluting with 0.1% TFA-ACN / 0.1% TFA-HO to give 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide (10 mg, 67%). LCMS (M+H) + :620.4.

[0398] The following compounds were prepared similarly to Example 11 using the appropriate substitution reagents and substrates at various steps. In some instances, no additional deprotection is required in the final step:

[0399] [Table 14]

[0400] Example 12: 1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine (Compound 2-13)

[0401] [ka]

[0402] Step 12-1, Preparation of 1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-yl}methanamine: To a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile (65 mg, 0.12 mmol) from Step 9-4 of Example 9 in MeOH (1.0 mL) was added NiCl (8.0 mg, 0.06 mmol, 0.5 equiv) and NaBH (36 mg, 0.96 mmol, 8.0 equiv) at 0° C. The resulting mixture was stirred at the same temperature for 15 min, and LCMS analysis showed approximately 40% conversion to the desired product. At 0 °C, additional NiCl (0.5 equiv., 0.06 mmol, 8.0 mg) and NaBH (8.0 equiv., 0.96 mmol, 36 mg) were added, and the resulting mixture was stirred for an additional 15 min. The reaction mixture was diluted with ethyl acetate and washed with saturated NH Cl. The organic layer was dried and concentrated. The residue was purified by C18 reverse-phase column chromatography eluting with MeCN / water (5-60%). Pure fractions were combined, neutralized with saturated NaHCO and NaCl, extracted with ethyl acetate, and dried over MgSO. The organic layer was concentrated and dried under high vacuum to give 8 mg (12%) of the desired product. LCMS (M+H) + =548.3.

[0403] Using the appropriate substitution reagents and substrates at various steps, the following compounds were prepared similarly to Example 12. Some examples may require additional functional group transformations to introduce appropriate substituents onto the aryl ring.

[0404] [Table 15]

[0405] Example 13: 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-ol (Compound 2-1)

[0406] [ka]

[0407] Step 13-1, Preparation of tert-butyl (3R)-4-[2′-ethoxy-3-(methoxycarbonyl)-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate: An 8 mL pressure tube was charged with tert-butyl (3R)-4-[4-bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (80 mg, 0.19 mmol) from Step 1-3 of Example 1, (2-ethoxyphenyl)boronic acid (46.6 mg, 0.28 mmol), Pd(dba)CHCl (19.4 mg, 0.02 mmol), P(t-Bu)HBF (5.4 mg, 0.02 mmol), KPO (119.2 mg, 0.56 mmol), and toluene / HO (1 mL / 0.1 mL). The resulting solution was degassed with N for 5 minutes, sealed, and stirred in an oil bath at 70 °C for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate / petroleum ether (1:1). 80 mg (91%) of the desired product was isolated. LCMS (M+H) + =469.1.

[0408] Step 13-2, Preparation of tert-butyl (3R)-4-[2'-ethoxy-3-(hydroxymethyl)-[1,2'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate: To a heterogeneous solution of tert-butyl (3R)-4-[2'-ethoxy-3-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate (60 mg, 0.13 mmol) and NiCl (16.6 mg, 0.13 mmol) in MeOH (1.0 mL) was added NaBH (48.4 mg, 1.28 mmol, 10 equiv.) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with HO, and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give 60 mg (~100%) of the desired product. LCMS (M+H) + =441.3.

[0409] Step 13-3, Preparation of tert-butyl (3R)-4-{2'-ethoxy-3-formyl-[1,1'-biphenyl]-4-yl}-3-ethylpiperazine-1-carboxylate: A solution of tert-butyl (3R)-4-[2'-ethoxy-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate (90 mg, 0.2 mL) and IBX (171.6 mg, 0.62 mmol) in ACN (2 mL) was stirred at room temperature for 1 hour. After removing the solids by filtration, the filtrate was concentrated in vacuo to give the desired crude product (90 mg, ∼100%), which was used in the next step without further purification. LCMS (M+H) + =439.3.

[0410] Step 13-4, Preparation of tert-butyl (3R)-4-[3-({[2-(benzyloxy)ethyl]amino}methyl)-2'-ethoxy-[1,1'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate: To a solution of tert-butyl (3R)-4-{2'-ethoxy-3-formyl-[1,1'-biphenyl]-4-yl}-3-ethoxypiperazine-1-carboxylate (30 mg, 0.07 mmol) and 2-(benzyloxy)ethan-1-amine (21 mg, 0.14 mmol) in DCM (2.0 mL) was added NaBH(OAc) (44 mg, 0.21 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 30 minutes and diluted with HO (20 mL). The resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the desired product (25 mg, 64%). LCMS (M+H) + =574.4.

[0411] Step 13-5: Preparation of [2-(benzyloxy)ethyl]({2'-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-yl}methyl)amine trifluoroacetate: To a solution of tert-butyl (3R)-4-[3-({[2-(benzyloxy)ethyl]amino}methyl)-2'-ethoxy-[1,1'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate (25 mg, 0.04 mmol) in DCM (2.0 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo. This resulted in the desired product (25 mg, 98%) as a TFA salt. LCMS (M+H) + =474.3.

[0412] Step 13-6, Preparation of [2-(benzyloxy)ethyl]({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amine: To a solution of 2-chloro-4-(trifluoromethyl)benzoic acid (2 mg, 0.01 mmol, 0.3 equiv.), HATU (5.7 mg, 0.01 mmol, 0.3 equiv.), and [2-(benzyloxy)ethyl]({2'-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-yl}methyl)amine trifluoroacetate (17.5 mg, 0.03 mmol) in DMF (2 mL) was added DIEA (11.6 mg, 0.09 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 1 h and diluted with HO (20 mL). The resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the desired product (20 mg, 38%). LCMS (M+H) + =680.2.

[0413] Step 13-7, Preparation of 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-ol trifluoroacetate: A solution of [2-(benzyloxy)ethyl]({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amine (20 mg, 0.03 mmol) in TFA (1.0 mL) was stirred at 80° C. for 3 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: SunFire Prep C18 OBD column; mobile phase, Phase A: water (0.05% TFA); Phase B: ACN (31% to 45% in 6 min); flow rate: 20 mL / min; detector, 220 & 254 nm. 3.9 mg (19%) of the desired product was isolated as the TFA salt. LCMS (M+H) + =590.2.

[0414] The following compounds were prepared similarly to Example 13, using the appropriate substitution reagents and substrates at various steps. In some instances, no additional deprotection is required in the final step:

[0415] [Table 16]

[0416] Example 14: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide (Compound 3-2)

[0417] [ka]

[0418] Step 14-1, Preparation of tert-butyl 4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: To a solution of tert-butyl piperazine-1-carboxylate (1.600 g, 8.588 mmol) and methyl 4-bromo-2-fluorobenzoate (1.000 g, 4.292 mmol) in DMSO (5 mL) was added DIEA (2.20 mL, 12.6 mmol). The mixture was heated at 130° C. for 1 day. The mixture was partitioned between water and DCM, and the organic layer was separated and concentrated. The residue was purified by C18 reverse-phase column chromatography to give the title compound (0.5088 g, 30% yield) as a medium brown solid. LCMS (M+H) + :399.2. The hydrolyzed acid (0.7537 g, 46% yield) was also isolated as a light brown solid. LCMS (M+H) + =385.3.

[0419] Step 14-2, Preparation of methyl 5-bromo-2-(piperazin-1-yl)benzoate hydrochloride: To a solution of tert-butyl 4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (508.8 mg, 1.274 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2.0 mL, 8.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound as a pale yellow solid. LCMS (M+H) + =299.2.

[0420] Step 14-3, Preparation of methyl 5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoate: To a solution of methyl 5-bromo-2-(piperazin-1-yl)benzoate hydrochloride (0.4538 g, 1.352 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (353.0 mg, 1.867 mmol) in DMSO (3 mL) was added DIEA (0.81 mL, 4.7 mmol). The mixture was heated at 130 °C overnight. The mixture was purified by C18 reverse-phase column chromatography to obtain the title compound (453 mg, 72% yield) as a yellow solid. LCMS (M+H) + =468.3.

[0421] Step 14-4, Preparation of methyl 5-bromo-2-{4-[2-cyano-4-(trifluoro)phenyl]piperazin-1-yl}benzoate: To a solution of methyl 5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoate (453 mg, 0.967 mmol) in a mixture of THF:MeOH:HO (6:2:2 mL) was added LiOH.HO (406 mg, 9.67 mmol). The mixture was stirred at room temperature for 4 hours. After removal of the volatile solvents, the aqueous residue was diluted with water and acidified with 1N HCl (aq) to a pH of 2-3. The solid was collected by suction filtration, dried, washed with water, and dried to give the title compound (421 mg, 96% yield) as a yellow solid. LCMS (M+H) + =454.1.

[0422] Step 14-5, Preparation of tert-butyl N-{3-[(5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)formamido]propyl}carbamate: To a solution of 5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoic acid (201.9 mg, 0.4444 mmol) and HATU (220 mg, 0.579 mmol) in DMF (1 mL) was added DIEA (0.15 mL, 0.86 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with tert-butyl N-(3-aminopropyl)carbamate (126.5 mg, 0.7262 mmol) and stirred at room temperature for 5 minutes. The reaction was purified by C18 reverse phase column chromatography to give the title compound (198.7 mg, 73% yield) as an off-white solid. LCMS (M+H) + =610.3.

[0423] Step 14-6, Preparation of tert-butyl N-{3-[(4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-yl)formamido]propyl}carbamate: To a mixture of tert-butyl N-{3-[(5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)formamido]propyl}carbamate (20.0 mg, 0.0328 mmol), 2-ethoxyphenylboronic acid (10.9 mg, 0.0657 mmol), Pd[t-BuP(4-NMeCH)]Cl (9.2 mg, 0.013 mmol), and KCO (27.2 mg, 0.197 mmol) in a sealed tube was added dioxane (2 mL) and HO (0.2 mL). The resulting mixture was degassed with N for 10 min and stirred at 100 °C for 30 min. The mixture was concentrated and purified by C18 reverse phase column chromatography to give the title compound (18.5 mg, 87% yield) as a white solid. LCMS (M+H) + =652.5.

[0424] Step 14-7, Preparation of N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide: To a solution of tert-butyl N-{3-[(4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-yl)formamido]propyl}carbamate (18.5 mg, 0.0284 mmol) in DCM (0.1 mL) was added 4 N HCl in dioxane (0.1 mL, 0.4 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness to give the monoHCl salt, which was triturated with saturated NaHCO3(aq) to give the title compound (12.9 mg, 82% yield) as an off-white solid. LCMS (M+H) + =552.2.

[0425] The following compounds were prepared in a similar manner to Example 14, using the appropriate substituting reagents and substrates at the various steps.

[0426] [Table 17]

[0427] Example 15: 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide (Compound 3-3)

[0428] [ka]

[0429] Step 15-1, Preparation of benzyl N-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate: An 8 mL vial was charged with benzyl N-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorophenyl]formamido]ethyl)-N-methylcarbamate trifluoroacetate (30 mg, 0.027 mmol), prepared as described in Steps 1 and 2 of Example 4, TEA (8 mg, 0.079 mmol, 2.98 equiv.), 2,4-dichlorobenzene-1-sulfonyl chloride (8 mg, 0.033 mmol, 1.23 equiv.), and DCM (2 mL). The resulting solution was stirred at 25 °C for 2 h. The reaction was diluted with DCM (10 mL) and washed with HO (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 20 mg (crude) of the title compound as an off-white oil. LCMS(M+H) + =772.2.

[0430] Step 15-2, Preparation of 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide: In an 8 mL vial, benzyl N-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate (20 mg, 0.021 mmol) and trifluoroacetic acid (2 mL) were placed. The resulting solution was stirred at 60 ° C. for 3 hours, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in DMF (4 mL) and purified by reverse phase HPLC to give 7.9 mg (56%) of the title compound as the formate salt. LCMS (M+H) + =638.2.

[0431] Example 16: (3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl}phenyl]-3-ethylpiperazine-1-carboxamide (Compound 3-4)

[0432] [ka]

[0433] Step 16-1, Preparation of phenyl N-(2,4-dichlorophenyl)carbamate: An 8 mL vial was charged with 2,4-dichloroaniline (200 mg, 1.23 mmol) and THF (1 ml). The resulting solution was treated with NaH (59 mg, 1.47 mmol, 1.19 equiv., 60% purity) and stirred at 0° C. for 20 minutes. The reaction was treated with phenyl carbonochloridate (232 mg, 1.48 mmol, 1.2 equiv.), stirred at 0° C. for an additional 3 hours, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (1:5). This resulted in 120 mg (34%) of the title compound as a yellow oil. LCMS (M+H) + =282.0.

[0434] Step 16-2, Preparation of benzyl N-[2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate: An 8 mL vial was charged with benzyl N-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorophenyl]formamido]ethyl)-N-methylcarbamate trifluoroacetate (36 mg, 0.053 mmol), DCM (2 mL), TEA (16 mg, 0.158 mmol, 2.97 equiv.), and phenyl N-(2,4-dichlorophenyl)carbamate (15 mg, 0.053 mmol). The resulting solution was stirred at 25 °C for 2 h, diluted with DCM (10 mL), and washed with water (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 30 mg (crude) of the title compound as a yellow oil. LCMS (M+H) + =751.2.

[0435] Step 16-3, Preparation of (3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl]phenyl]-3-ethylpiperazine-1-carboxamide: In an 8 mL vial, benzyl N-[2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate (30 mg, 0.04 mmol) and TFA (2 mL) were placed. The resulting solution was stirred at 60° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in DMF (4 mL) and purified by Prep-HPLC under the following conditions: Column, Atlantis Prep T3 OBD Column, 19 *150 mm 5 μm; Mobile phase: water (0.1% FA) and ACN (24% to 53% Phase B in 6 min); 20 mL / min. Detector: UV 220, 254 nm. This resulted in 5.6 mg (21%) of the title compound as the formate salt. LCMS (M+H) + =617.2.

[0436] Example 17: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide (Compound 1-152)

[0437] [ka]

[0438] Step 17-1, Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (40 mg, 0.071 mmol) from Step 5 of Example 9 in ACN (0.5 mL) was added HATU (30 mg, 0.078 mmol, 1.1 equiv) and EtN (19 μL, 2.0 equiv). The resulting solution was stirred at room temperature for 5 minutes and treated with (R)-1-methylpyrrolidin-3-ylamine (10.6 mg, 0.106 mmol, 1.5 equiv). The reaction was stirred at room temperature for 0.5 hours. The crude reaction solution was purified by C18 reverse-phase column chromatography eluting with MeCN / water (5-100%). The combined pure fractions were neutralized with saturated NaHCO3, the volatile solvents were removed, and extracted with DCM (3x). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and dried under high vacuum to give 25 mg (55%) of the title compound. LCMS (M+H) +=645.5.

[0439] Example 18: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide (Compound 1-212)

[0440] [ka]

[0441] Step 18-1, Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide: Starting from 40 mg of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (0.071 mmol), the title compound was prepared as described in Example 17. 20 mg (45%) of the title compound was isolated. LCMS (M+H) + =631.4.

[0442] The following compounds were prepared in a similar manner to Example 18, using the appropriate substituting reagents and substrates at the various steps.

[0443] [Table 18]

[0444] Example 19: 1-{2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine (Compound 2-30)

[0445] [ka]

[0446] Step 19-1, Preparation of 5-[(2R)-4-[6-chloro-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile: To 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (Step 9-3, 1.0 equiv., 0.26 mmol, 87 mg) in DMF (3.0 mL) was added DIPEA (2.5 equiv., 0.65 mmol, 0.1 mL), HATU (1.2 equiv., 0.39 mmol, 118 mg), and 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid (1.0 equiv., 0.26 mmol, 61 mg). The resulting mixture was stirred at room temperature for 0.5 hours, at which point LCMS showed complete consumption of the starting material. The reaction solution was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc / hexanes (0-50%) to give 104 mg of the title compound. LCMS (M+H) + =545.3.

[0447] Step 19-2, Preparation of 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carbonitrile: To a solution of 5-[(2R)-4-[6-chloro-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carbonitrile (1.0 equiv., 0.05 mmol, 28 mg) in EtOH (0.5 mL) was added NaOEt (21% w / w in EtOH, 2.5 equiv., 0.13 mmol, 0.05 mL), and the resulting mixture was heated at 70°C for 0.5 h. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 25 mg of crude product, which was used in the next step without purification. LCMS (M+H) + =555.2.

[0448] Step 19-3, Preparation of tert-butyl N-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methyl)carbamate: To a solution of 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carbonitrile (1.0 equiv., 0.05 mmol, 25 mg) in MeOH (1.0 mL) was added NiCl (0.5 equiv., 0.025 mmol, 3.3 mg) and di-tert-butyl dicarbonate (2.0 equiv., 0.10 mmol, 0.023 mL). At 0 °C, NaBH (7.0 equiv., 0.35 mmol, 13.5 mg) was added portionwise, and the resulting mixture was stirred at the same temperature for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc / hexanes (0-50%) to give 24 mg of the title compound. LCMS (M+H) + =659.4.

[0449] Step 19-4, preparation of 1-{2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine: tert-butyl N-({2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methyl)carbamate (1.0 equivalent, 0.036 mmol, 24 mg) in DCM (0.5 mL) was added TFA (0.10 mL). The resulting mixture was stirred at ambient temperature for 0.5 hours. The reaction solution was concentrated, and the resulting residue was purified by C18 reverse-phase chromatography eluting with MeCN / water (5-50%). Pure fractions were combined, neutralized with saturated NaHCO3 and NaCl, extracted with ethyl acetate, and dried over MgSO4. The organic layer was concentrated and dried under high vacuum to give 6 mg of the title compound. LCMS (M+H) + =559.2.

[0450] The following compounds were prepared in a similar manner to Example 19, using the appropriate substituting reagents and substrates at the various steps.

[0451] [Table 19]

[0452] Example 20: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide (Compound 1-279)

[0453] [ka]

[0454] Step 20-1, Preparation of 2-(difluoromethyl)-4-fluorobenzoic acid: To a mixture of 4-fluoro-2-methylbenzoic acid (1.000 g, 6.49 mmol), Selectfluor (6.895 g, 19.46 mmol), and sodium persulfate (0.772 g, 3.24 mmol) under nitrogen, MeCN (3.2 mL) and water (3.2 mL) were added. The mixture was cooled to -78 °C under nitrogen, and silver nitrate (110.2 mg, 0.649 mmol) was added. The frozen mixture was degassed under vacuum and backfilled with nitrogen (repeated three times). The mixture was warmed to room temperature under nitrogen and then heated at 80 °C for 7 hours. The reaction was not complete, so more Selectfluor (2.298 g, 6.49 mmol), sodium persulfate (0.257 g, 1.08 mmol), and silver nitrate (36.7 mg, 0.216 mmol) were added under nitrogen, and the reaction was continued to heat at 80 °C for 6 h. The mixture was filtered through Celite, and the Celite was rinsed with EtOAc. The filtrate was washed with saturated NaHCO (aq) (5 × 25 mL). The combined basic aqueous solution was acidified with 1 N HCl (aq) to pH 2-3, forming a solid. The solid was collected by suction filtration, washed with water, and dried under vacuum to give the title compound (484.1 mg). The filtrate was extracted with EtOAc (1 ×), and the organic layer was concentrated and purified by C18 reverse-phase column chromatography to give more product (314.4 mg). The overall reaction gave the title compound (798.5 mg, 4.20 mmol, 64.7% yield) as an off-white solid.

[0455] Step 20-2, Preparation of tert-butyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a solution of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (400 mg, 0.876 mmol) from Step 10-1 in DMF (2.0 mL) were added HATU (500 mg, 1.31 mmol) and DIEA (0.46 mL, 2.63 mmol). After stirring at room temperature for 5 minutes, (3R)-1-methylpyrrolidin-3-amine (176 mg, 1.75 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to give the title compound (284.6 mg, 0.53 mmol, 60.3% yield) as a light brown solid. LCMS (M+H) + =539.5.

[0456] Step 20-3, Preparation of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide tris(2,2,2-trifluoroacetate): To a solution of tert-butyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate (268.8 mg, 0.50 mmol), TFA (0.76 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes and concentrated to dryness in vacuo to give the title compound (389.5 mg, 0.50 mmol, 100% yield) as a brown gum, which was used in the next step without further purification. LCMS (M+H) + =439.1.

[0457] Step 20-4, Preparation of 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 2-(difluoromethyl)-4-fluorobenzoic acid (142.3 mg, 0.75 mmol) in DMF (0.5 mL) was added HATU (265.6 mg, 0.70 mmol) and DIEA (0.26 mL, 1.50 mmol). After stirring at room temperature for 5 minutes, the HATU-activated solution was added to a solution of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide tris(2,2,2-trifluoroacetate) (389.5 mg, 0.50 mmol) and DIEA (0.52 mL, 3.00 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse-phase column chromatography to give the title compound (245.0 mg, 0.40 mmol, 80.4% yield) as a light brown solid. LCMS (M+H) + =611.3.

[0458] The following compounds were prepared in a similar manner to Example 20, using the appropriate substituting reagents and substrates at the various steps.

[0459] [Table 20]

[0460] Example 21: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide (Compound 1-278)

[0461] [ka]

[0462] Step 21-1, Preparation of tert-butyl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate: To a solution of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylic acid (300 mg, 0.657 mmol) from Step 10-1 in DMF (1.0 mL) were added HATU (325 mg, 0.854 mmol) and DIEA (0.23 mL, 1.3 mmol). After stirring at room temperature for 5 minutes, benzyl (3R)-3-aminopyrrolidine-1-carboxylate (217 mg, 0.986 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to give the title compound (270.8 mg, 0.411 mmol, 62.6% yield) as a brown solid. LCMS (M+H) + =659.5.

[0463] Step 21-2, Preparation of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate bis(2,2,2-trifluoroacetate): To a solution of tert-butyl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate (90.0 mg, 0.137 mmol) in DCM (0.4 mL) was added TFA (0.2 mL). The resulting mixture was stirred at room temperature for 30 minutes and concentrated to dryness in vacuo to give the title compound (107 mg, 0.137 mmol, 100% yield) as a brown gum, which was used in the next step without further purification. LCMS (M+H) + =559.4.

[0464] Step 21-3, Preparation of benzyl (3R)-3{5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate: To a solution of 2-(difluoromethyl)-4-fluorobenzoic acid (38.8 mg, 0.204 mmol) from Step 20-1 in DMF (0.2 mL) was added HATU (72.4 mg, 0.190 mmol) and DIEA (0.071 mL, 0.41 mmol). After stirring at room temperature for 5 minutes, the HATU-activated solution was added to a solution of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethoxypiperazin-1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate bis(2,2,2-trifluoroacetate) (107 mg, 0.136 mmol) and DIEA (0.14 mL, 0.80 mmol) in DMF (0.2 mL). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse-phase column chromatography to give the title compound (63.0 mg, 0.0862 mmol, 63.4% yield) as a pale yellow solid. LCMS (M+H) + =731.3.

[0465] Step 21-4, preparation of 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To benzyl (3R)-3{5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (63.0 mg, 0.0862 mmol), (methylsulfanyl)benzene (0.050 mL) and TFA (0.25 mL) were added. The resulting mixture was heated at 60 ° C for 30 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to give the title compound (39.9 mg, 0.0669 mmol, 77.6% yield) as an off-white solid. LCMS (M+H) + =597.4.

[0466] The following compounds were prepared in a similar manner to Example 21, using the appropriate substitution reagents and substrates at the various steps.

[0467] [Table 21]

[0468] Example 22: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (Compound 1-263)

[0469] [ka]

[0470] Step 22-1, Preparation of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate: To a solution of tert-butyl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate (27 mg, 0.041 mmol) from Step 1 of Example 21 in DCM (0.4 mL) was added TFA (0.1 mL). The resulting solution was stirred at room temperature for 1 hour and concentrated in vacuo to remove volatile solvents. The residue was dissolved in ACN (0.3 mL), neutralized with TEA (16 μL, ∼3 eq) and used in the next step without further purification. LCMS (M+H) + =559.3.

[0471] Step 22-2, Preparation of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate: To a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (11 mg, 0.06 mmol) in ACN (0.5 mL) was added HATU (22 mg, 0.06 mmol) and TEA (11 μL, 0.08 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate (22 mg, 0.039 mmol) from Step 1. The reaction was stirred at room temperature for 30 minutes and purified directly by C18 reverse phase column chromatography to give the title compound (21 mg, 74% yield). LCMS (M+H) + =723.8.

[0472] Step 22-3, Preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-amide}pyrrolidine-1-carboxylate (21 mg, 0.029 mmol) in TFA (0.5 mL) was added one drop of methyl(phenyl)sulfane. The resulting mixture was stirred at 60 ° C. for 1 hour and cooled to room temperature. After removal of the volatile solvents, the residue was purified by C18 reverse phase column chromatography to give the title compound (14 mg, 82% yield) as a white powder. LCMS (M+H) + =589.4.

[0473] The following compounds were prepared in a similar manner to Example 22, using the appropriate substitution reagents and substrates at the various steps.

[0474] [Table 22]

[0475] Example 23: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (Compound 1-255)

[0476] [ka]

[0477] Step 23-1. Preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (13 mg, 0.071 mmol) in ACN (0.5 mL) was added HATU (27 mg, 0.071 mmol) and TEA (19 μL, 0.14 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with neutral 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (20 mg, 0.045 mmol) from Step 3 of Example 20. The reaction was stirred at room temperature for 30 minutes and purified directly by C18 reverse phase column chromatography to give the title compound (19 mg, 70% yield). LCMS (M+H) + =603.6.

[0478] The following compounds were prepared similarly to Example 23 using the appropriate substitution reagents and substrates at various steps. Some examples may require reductive amination to introduce the tert-amine moiety in the final step:

[0479] [Table 23]

[0480] Example 24: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (Compound 1-283)

[0481] [ka]

[0482] Step 24-1. Preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (632 mg, 3.76 mmol) in DMF (5.0 mL) was added HATU (1.43 g, 3.76 mmol) and TEA (0.67 mL, 5.02 mmol). After stirring at room temperature for 5 minutes, the resulting solution was treated with 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (1.10 g, 2.51 mmol) from Step 3 of Example 20. The reaction was stirred at room temperature for 30 minutes and purified directly by C18 reverse phase column chromatography to give the title compound (0.85 g, 58% yield). LCMS (M+H) + =589.4.

[0483] The following compounds were prepared similarly to Example 24 using the appropriate substitution reagents and substrates at various steps. Some examples may require reductive amination to introduce a tert-amine moiety in the final step:

[0484] [Table 24]

[0485] Example 25: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide (Compound 1-374)

[0486] [ka]

[0487] Step 25-1, Preparation of tert-butyl (3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate: A 1000 mL round-bottom flask was charged with 6-bromo-3-fluoropicolinonitrile (50.0 g, 249 mmol), tert-butyl (R)-3-ethylpiperazine-1-carboxylate (59 g, 275 mmol), DIEA (97 g, 750 mmol), and DMSO (500 mL). The resulting reaction mixture was stirred at 90° C. for 24 hours. The reaction mixture was cooled to room temperature and quenched with water (1000 ml). The resulting solution was extracted with ethyl acetate (3×1000 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in the title compound (100 g, 66%) as a yellow oil. LCMS (M+H) + =395.1.

[0488] Step 25-2, Preparation of tert-butyl (3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3-ethylpiperazine-1-carboxylate: A 250 mL round-bottom flask purged with an inert nitrogen atmosphere was charged with tert-butyl (3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate (5.0 g, 13 mmol), (2-ethoxyphenyl)boronic acid (4.0 g, 26 mmol), potassium carbonate (5.0 g, 36 mmol), Pd(DTBPF)Cl (0.4 g, 0.62 mmol), and dioxane / water (50 mL / 5 mL). The resulting solution was stirred at 80 °C for 1 hour and cooled to room temperature. The inorganic solids were removed by filtration, and the filtrate was concentrated. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:3), to give the title compound (4.0 g, 67%) as a slightly yellow oil. LCMS (M+H) + =437.2.

[0489] Step 25-3, Preparation of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid: To a purged 250 mL round-bottom flask was added tert-butyl (3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3-ethylpiperazine-1-carboxylate (4.0 g, 9.2 mmol), EtOH (40 mL), and water (40 mL). The resulting solution was treated with KOH (5.3 g, 94 mmol) at room temperature and then stirred at 100 °C for 50 h. The reaction was cooled to room temperature and concentrated to remove EtOH. The pH of the aqueous layer was adjusted to 6-7 with 3N HCl. The resulting solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.3 g, 55%) as a yellow solid. LCMS (M+H) + =456.2.

[0490] Step 25-4, Preparation of ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylate: A 50 mL round-bottom flask was charged with 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (1.0 g, 2.2 mmol), EtOH (10 mL), and sulfuric acid (0.5 mL). The resulting reaction mixture was stirred at 80 °C for 3 h and cooled to room temperature. The reaction mixture was diluted with water (50 mL) and then adjusted to pH 6-7 with sodium bicarbonate. The resulting solution was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (400 mg, 48%) as a yellow oil. LCMS(M+H) + =384.2.

[0491] Step 25-5, Preparation of ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylate: An 8 mL vial was charged with (S)-2-(trifluoromethyl)pyrrolidine (75 mg, 0.54 mmol), DIEA (210 mg, 1.62 mmol), and DCM (1 mL). The reaction mixture was cooled to 0 °C and treated with bis(trichloromethyl)carbonate (64 mg, 0.22 mmol). The resulting mixture was stirred at 0 °C for 3 hours, quenched with water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The activated pyrrolidine was used directly in the next step without further purification. Ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylate (210 mg, 5.43 mmol), the above activated pyrrolidine, potassium carbonate (750 mg, 5.43 mmol), and ACN (2 mL) were placed in an 8 mL vial. The resulting reaction mixture was stirred at 30° C. for 2 hours and cooled to room temperature. The crude product was purified by C18 reverse-phase column chromatography to give the title compound (200 mg, 68%) as a yellow oil. LCMS (M+H) + =549.4.

[0492] Step 25-6, Preparation of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylic acid: An 8 mL vial was charged with ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylate (200 mg, 0.365 mmol), LiOH (88 mg, 3.7 mmol), EtOH (2 mL), and water (1 mL). The resulting reaction mixture was stirred at 60 °C for 1 h and cooled to room temperature. The reaction mixture was diluted with water (10 mL) and then adjusted to pH 6-7 with 3N HCl. The resulting solution was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (170 mg, 90%) as a yellow oil. LCMS (M+H) + =521.6.

[0493] Step 25-7, Preparation of 6-(2-ethoxyphenyl-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide formate: A 50 mL round-bottom flask was charged with 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylic acid (80 mg, 0.15 mmol), HATU (58 mg, 0.15 mmol), DIEA (40 mg, 0.30 mmol), and DMF (1 mL). The resulting reaction mixture was stirred at room temperature for 10 minutes and then treated with (R)-1-methylpyrrolidin-3-amine (20 mg, 0.20 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The crude product was purified by Prep-HPLC (Prep-HPLC-013) under the following conditions: Column, Atlantis Prep T3 OBD Column, 19 *150 mm 5 μm; mobile phase, water (0.1% FA) and ACN (30% to 90% phase B in 8 min); total flow rate 20 mL / min. Detector, UV 220 nm. This gave the title compound (62 mg, 62%) as a white solid. LCMS (M+H) + =603.4.

[0494] The following compounds were prepared in a similar manner to Example 25, using appropriate substitution reagents and substrates at various steps. Some examples may require chiral separation to obtain optically pure compounds, but their absolute stereochemistry was not determined. In some instances, additional deprotection is required in the final step:

[0495] [Table 25-1]

[0496] [Table 25-2]

[0497] Example 26: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (Compound 1-307)

[0498] [ka]

[0499] Step 26-1, 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a heterogeneous solution of Example 22 (50 mg, 0.085 mmol) and potassium bicarbonate (10 mg, 0.10 mmol) in DMF (1.5 mL) was slowly added 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (20 mg, 0.10 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After filtering off the inorganic solids, the filtrate was purified by C18 reverse phase column chromatography to give the title compound (18 mg, 30%). LCMS (M+H) + =701.4.

[0500] Example 27: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (Compound 1-367) [ * Absolute stereochemistry not determined]

[0501] [ka]

[0502] Process 27-1, (2S *Preparation of 1,1,1-trifluoro-3,3-dimethylbutan-2-yl 1H-imidazole-1-carboxylate: To a solution of 1,1,1-trifluoro-3,3-dimethylbutan-2-ol (100 mg, 0.640 mmol) in THF (3.0 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (156 mg, 0.961 mmol). The mixture was stirred at room temperature for 2.5 days. The mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography to give the racemic mixture of the title compounds (145 mg, 0.578 mmol, 90.3% yield) as a white solid. LCMS (M+H) + =251.1 The racemic mixture was purified by the following conditions to give the enantiomerically pure title compound (second enantiomer: temporary assignment).

[0503] Chiral resolution conditions: Column: normal phase Daicel Chiralpak ID column, 20 mm ID x 250 mm L, 5 μm particle size. Gradient: Isocratic 5% EtOH in hexane Flow rate: 20mL / min Retention times: 1st enantiomer: 1.22 min (absolute stereochemistry not determined; tentatively assigned as compound 1-366) 2nd enantiomer: 1.52 min (absolute stereochemistry not determined; tentatively assigned as compound 1-367).

[0504] Step 27-1, Preparation of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1-carboxylate: To a solution of tert-butyl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine]-5-yl)-3-ethylpiperazine-1-carboxylate (181 mg, 0.274 mmol) from Step 21-1 in DCM (0.7 mL) was added TFA (0.38 mL, 4.9 mmol). The resulting mixture was stirred at room temperature for 30 hours and concentrated to dryness in vacuo. The crude TFA salt was neutralized with saturated NaHCO3 (aq) to give the title compound (153 mg, 0.274 mmol, 100% yield) as a brown solid. LCMS (M+H) + =559.3.

[0505] Step 27-3, Benzyl (2S * Preparation of (3R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a solution of benzyl (3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3-bipyridine]-6-amido}pyrrolidine-1-carboxylate (110 mg, 0.197 mmol) in THF (5.0 mL) was added DIEA (0.270 mL, 1.55 mmol) and (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl 1H-imidazole-1-carboxylate (75 mg, 0.30 mmol) in a sealed tube. The mixture was heated at 100 °C for 24 hours. The mixture was concentrated to dryness, and the residue was purified by C18 reverse-phase column chromatography to give the title compound (120 mg, 0.162 mmol, 82.2% yield) as a yellow oil. LCMS (M+H) + =741.4.

[0506] Process 27-4, (2S * Preparation of 2-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate formate: Benzyl (2S * To )-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (120 mg, 0.162 mmol) was added TFA (2.0 mL). The resulting mixture was heated at 60°C for 2 hours. The reaction mixture was purified by C18 reverse phase column chromatography to give the title compound (72.0 mg, 0.110 mmol, 67.9% yield) as a white solid. LCMS (M+H) + =597.4.

[0507] The following compounds were prepared in a similar manner to Example 27, using the appropriate substitution reagents and substrates at various steps. The absolute stereochemistry of some examples was not determined. In some instances, no additional deprotection was required in the final step:

[0508] [Table 26]

[0509] Example 28: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (Compound 1-392) [ * Absolute stereochemistry not determined]

[0510] [ka]

[0511] Process 28-1, (2S * Preparation of (3R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: To a solution of (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate formate (40.0 mg, 0.0613 mmol) in MeOH (3.0 mL) was added paraformaldehyde (38.5 mg) and sodium cyanoborohydride (38.5 mg, 0.613 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with TFA (0.1 mL) and rebasified with saturated NaHCO3 (aq). The mixture was extracted with DCM, and the organic layer was concentrated to dryness in vacuo. The residue was purified by C18 reverse phase column chromatography to give the title compound (26.1 mg, 0.0420 mmol, 68.5% yield) as an off-white solid. LCMS (M+H) + =621.5.

[0512] The following compounds were prepared in a similar manner to Example 28, using the appropriate substitution reagents and substrates at various steps. The absolute stereochemistry of some examples was not determined:

[0513] [Table 27]

[0514] Example 29: 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide (Compound 1-438)

[0515] [ka]

[0516] Step 29-1, Preparation of 5-fluoro-1H-indole-7-carbonitrile: To a mixture of 7-bromo-5-fluoro-1H-indole (920 mg, 4.30 mmol), dicyanozinc (1.514 g, 12.89 mmol), and Pd(PPh3)4 (993 mg, 0.860 mmol) in a sealed tube, DMF (10 mL) was added. Nitrogen (g) was bubbled through the reaction mixture. The resulting mixture was heated at 120 °C for 16 h. The mixture was quenched with water and extracted with DCM (3x). The combined organics were concentrated to dryness, and the residue was purified by C18 reverse-phase column chromatography to give the title compound (676 mg, 4.22 mmol, 98% yield) as an off-white solid.

[0517] Step 29-2, Preparation of 4-nitrophenyl 7-cyano-5-fluoro-1H-indole-1-carboxylate: To a suspension of 5-fluoro-1H-indole-7-carbonitrile (306 mg, 1.91 mmol) and 4-nitrophenyl carbonochloridate (463 mg, 2.30 mmol), TEA (0.80 mL, 5.74 mmol) and DMAP (23.4 mg, 0.191 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours, but the reaction was not completed. More 4-nitrophenyl carbonochloridate (463 mg, 2.30 mmol) and triethylamine (0.80 mL, 5.73 mmol) were added, and the reaction was continued for 2 hours. The mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography to obtain the title compound (411 mg, 1.26 mmol, 66% yield) as an off-white solid.

[0518] Step 29-3, Preparation of 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide: To a solution of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (50.0 mg, 0.114 mmol) from Step 3 of Example 20 and 4-nitrophenyl 7-cyano-5-fluoro-1H-indole-1-carboxylate (44.5 mg, 0.137 mmol) in MeCN (1 mL) was added DMAP (34.8 mg, 0.285 mmol). The mixture was heated at 50°C for 1 hour. The mixture was purified by C18 reverse-phase column chromatography to give the title compound (14.5 mg, 0.023 mmol, 20% yield) as a pale yellow solid. LCMS (M+H) + =625.4.

[0519] The following compounds were prepared in a similar manner to Example 29, using the appropriate substituting reagents and substrates at the various steps.

[0520] [Table 28]

[0521] Example 30: 5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide (Compound 1-261)

[0522] [ka]

[0523] Step 30-1, Preparation of 5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: To a solution of 2-chloro-4-fluorobenzoic acid (35.9 mg, 0.206 mmol) and HATU (73.0 mg, 0.192 mmol) in DMF (0.2 mL) was added DIEA (0.072 mL, 0.41 mmol). After stirring at room temperature for 5 minutes, the HATU-activated solution was added to a solution of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ is replaced by R ａ , R ｂ , and R ｃ are independently hydrogen, halogen, or —OR ８ , -CN, -N(R ７ ) 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, or unsubstituted or substituted monocyclic heteroaryl; R ａ , R ｂ , and R ｃ Any of the substituents may be one or more R ９ is substituted with a group, L is absent, -C(=O)-, or -C(=O)NR ７ - or -SO ２ - and R Ｂ is an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, an unsubstituted or substituted C １ -C ７ Alkyl, unsubstituted or substituted C １ -C ７ Fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, and R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ is replaced by or R Ｂ and R ７ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is R ｄ , R ｅ , and R ｆ is replaced by R ｄ , R ｅ , and R ｆ are independently hydrogen, halogen, or —OR ８ , -CN, -N(R ７ ) 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, or unsubstituted or substituted monocyclic heteroaryl; R ｄ , R ｅ , and R ｆ Any of the substituents may be one or more R ９ is substituted with a group, X １ is CR ６ or N, X ２ is CR ６ or N, X ３ is CR ６ or N, R １ is unsubstituted or substituted C １ -C ６ Alkyl, or unsubstituted or substituted C ３ -C ６ is cycloalkyl, and R １ is substituted, R １ is hydrogen, -OR ８ , halogen, —N(R ７ ) ２ or -CN, R ２ and R ３ are independently hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, or unsubstituted or substituted C ３ -C ６ is cycloalkyl, and R ２ and R ３ Any of the substituents may be hydrogen, —OR ８ , -N(R ７ ) ２ , halogen, or -CN; or R ２ and R ３ together with the carbon atom to which they are attached to form -C(=O)-, or R ２ and R ３ together with the carbon atoms to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic carbocyclic ring; R ４ and R ５ are independently hydrogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic carbocyclic ring, unsubstituted or substituted monocyclic heterocyclic ring, unsubstituted or substituted -(C １ -C ６ alkyl)-carbocyclic, or unsubstituted or substituted -(C １ -C ６ alkyl)-heterocycle; R ４ and R ５ Any of the substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ is replaced by or R ４ and R ５ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocyclic ring, and when the 3- to 6-membered heterocyclic ring is substituted, the 3- to 6-membered heterocyclic ring may contain one or more halogen atoms, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ is replaced by or R ２ and R ４ together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered N-containing heterocycle; Each R ６ are independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, —CN, —OR ８ , -SR ８ , -CO ２ R ８ , -C(=O)N(R ７ ) ２ , or -N(R ７ ) ２ is selected from the group consisting of Each R ７ are 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; or two R's ７ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; Each R ８ are 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; Each R ９ are 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 ８ , -CH ２ CO ２ R ８ , -C(=O)N(R ７ ) ２ , -C(=O)N(R ７ ) OR ８ , -CH ２ C(=O)N(R ７ ) ２ , -N(R ７ ) ２ , -CH ２ N (R ７ ) ２ , -C(R ８ ) ２ N (R ７ ) ２ , -NR ７ C(=O)R ８ , -CH ２ NR ７ C(=O)R ８ , -NR ７ C(=O)N(R ７ ) ２ , -NR ７ C(=O)N(R ７ ) ２ , C(R ８ ) = N(R ７ ) -OR ８ , -SR ８ , -S(=O)R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ and Each R １０ are independently a substitution 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; n is 1 or 2 The compound, or a pharmaceutically acceptable salt or solvate thereof.

2. L is —C(═O)—; R ２ and R ３ are independently hydrogen, —CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ OR ８ , or -CH ２ NHR ７ and or R ２ and R ３ and R 1 and R 2 together with the carbon atom to which they are attached form -C(=O)-, or a pharmaceutically acceptable salt or solvate thereof.

3. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

4. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl; R Ａ When R is substituted, Ａ is R ａ , R ｂ , and R ｃ 4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

5. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl; R Ａ When R is substituted, Ａ is R ａ , R ｂ , and R ｃ 5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

6. R Ａ is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, and R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

7. R Ａ teeth 【Chemistry 2】 6. The compound of any one of claims 1 to 5, wherein:

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

9. R Ａ teeth 【Chemistry 4】 7. The compound of any one of claims 1 to 6, wherein V is CH or N, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound has the structure of formula (II) or a pharmaceutically acceptable salt or solvate thereof: 【Transformation 5】 During the ceremony, 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N.

11. R Ｂ is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted polycyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bicyclic heterocycle, or an unsubstituted or substituted polycyclic heterocycle; R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

12. R Ｂ is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bridged carbocycle, an unsubstituted or substituted spirocarbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bridged heterocycle, or an unsubstituted or substituted spiroheterocycle; R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

13. R Ｂ is an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted bicyclic heteroaryl, a monocyclic C ３ -C ８ Cycloalkyl, unsubstituted or substituted bridge C ５ -C １０ Cycloalkyl, unsubstituted or substituted spiro C ５ -C １０ Cycloalkyl, unsubstituted or substituted monocyclic C ２ -C ８ Heterocycloalkyl, unsubstituted or substituted bridge C ５ -C １０ Heterocycloalkyl, or unsubstituted or substituted spiro C ５ -C １０ heterocycloalkyl, and R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

14. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted indanyl, unsubstituted or substituted indenyl, unsubstituted or substituted tetrahydronaphthyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cycloheptyl, unsubstituted or substituted cyclooctyl, unsubstituted or substituted spiro[2.2]pentyl, unsubstituted 11. The compound of any one of claims 1 to 10, wherein the carbocycle is substituted or substituted spiro[3.3]heptyl, unsubstituted or substituted spiro[3.5]nonyl, unsubstituted or substituted spiro[4.4]nonyl, unsubstituted or substituted spiro[4.5]decyl, unsubstituted or substituted norbornyl, unsubstituted or substituted norbornenyl, unsubstituted or substituted bicyclo[1.1.1]pentyl, unsubstituted or substituted adamantyl, or unsubstituted or substituted decalinyl, or a pharmaceutically acceptable salt or solvate thereof.

15. R Ｂ is unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indole 11. The compound of claim 1, wherein the benzothiazolyl is substituted or substituted benzoindolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, or a pharmaceutically acceptable salt or solvate thereof.

16. R Ｂ is unsubstituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted oxetanyl, unsubstituted or substituted thietanyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl, unsubstituted or substituted oxazolidinonyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted homo 11. The compound of any one of claims 1 to 10, which is piperidinyl, unsubstituted or substituted oxepanyl, unsubstituted or substituted thiepanyl, unsubstituted or substituted oxazepinyl, unsubstituted or substituted diazepinyl, unsubstituted or substituted thiazepinyl, unsubstituted or substituted azaspiro[3.3]heptanyl, unsubstituted or substituted azaspiro[3.4]octanyl, unsubstituted or substituted azaspiro[3.4]octanyl, or unsubstituted or substituted azaspiro[4.4]nonyl, or a pharmaceutically acceptable salt or solvate thereof.

17. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl; R Ｂ When R is substituted, Ｂ is R ｄ , R ｅ , and R ｆ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

18. R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, and R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

19. R Ｂ teeth 【Transformation 6】 11. The compound of any one of claims 1 to 10, wherein:

20. R Ｂ teeth 【Transformation 7】 11. The compound of any one of claims 1 to 10, wherein:

21. R Ｂ teeth 【Transformation 8】 11. The compound of any one of claims 1 to 10, wherein Z is CH or N, or a pharmaceutically acceptable salt or solvate thereof.

22. The compound has the structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 9】 During the ceremony, V is CH or N; 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is CH or N.

23. 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IV): 【Chemistry 10】

24. 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (V): 【Chemistry 11】

25. R １ は、-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CH ２ CH ２ CH ２ CH ３ 、-CH ２ CH(CH ３ ) ２ 、-CH(CH ３ )(CH ２ CH ３ )、-C(CH ３ ) ３ 、-CH ２ OH、-CH ２ CN、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ CH ２ OH、-CH ２ CH ２ CN、-CH ２ CH ２ F、-CH ２ CHF ２ 、-CH ２ CF ３ 、-CH ２ OCH ３ 、-CH ２ CH ２ OCH ３ 、-CH ２ NH ２ 、-CH ２ NHCH ３ 、-CH ２ N(CH ３ ) ２ 、-CH ２ CH ２ NH ２ 、-CH ２ CH ２ NHCH ３ 、-CH ２ CH ２ N(CH ３ ) ２ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26

26. R １ is -CH ３ , -CH ２ CH ３ , or -CH ２ CH ２ CH ３ 26. The compound of any one of claims 1 to 25, wherein:

27. R ４ is hydrogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic carbocyclic ring, unsubstituted or substituted monocyclic heterocyclic ring, unsubstituted or substituted -(C １ -C ６ alkyl)-carbocyclic, or unsubstituted or substituted -(C １ -C ６ alkyl)-heterocycle; R ４ The optional substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ is replaced by R ５ is hydrogen, and C １ -C ６ is selected from the group consisting of alkyl, or R ４ and R ５ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocyclic ring, and when the 3- to 6-membered heterocyclic ring is substituted, the 3- to 6-membered heterocyclic ring may contain one or more halogen atoms, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

28. R ４ is hydrogen, unsubstituted or substituted C １ -C ６ alkyl, an unsubstituted or substituted monocyclic carbocycle, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom; R ４ The optional substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycles containing 1 to 4 N atoms and 0 or 1 O or S atom; ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ is replaced by R ５ is hydrogen, -CH ３ , -CH ２ CH ３ , and -CH ２ CH ２ CH ３ 28. The compound of any one of claims 1 to 27, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

29. 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (VI): 【Chemistry 12】

30. The compound has the structure of formula (VII) or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 13】 During the ceremony, R Ａ is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, and R Ａ is substituted, R Ａ is R ａ , R ｂ , and R ｃ is replaced by L is -C(=O)- or -C(=O)NR ７ - and R Ｂ is an unsubstituted or substituted carbocyclic ring or an unsubstituted or substituted heterocyclic ring; R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ is replaced by or R Ｂ and R ７ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring, and when the 3- to 7-membered heterocyclic ring is substituted, the 3- to 7-membered heterocyclic ring is R ｄ , R ｅ , and R ｆ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

31. R Ａ teeth 【Chemistry 14】 31. The compound of claim 30, wherein:

32. X １ is CR ６ and X ２ is CR ６ and X ３ is CR ６ 32. The compound of any one of claims 1 to 31, wherein:

33. X １ is N, X ２ is CR ６ and X ３ is CR ６ 32. The compound of any one of claims 1 to 31, wherein:

34. X １ is CR ６ and X ２ is N, X ３ is CR ６ 32. The compound of any one of claims 1 to 31, wherein:

35. X １ is CR ６ and X ２ is CR ６ and X ３ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt or solvate thereof, wherein:

36. The compound has the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 15】 During the ceremony, 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein V is CH or N.

37. R ４ is unsubstituted or substituted C １ -C ６ alkyl, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O or S atom; R ４ The optional substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, —N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

38. R ４ is unsubstituted or substituted C １ -C ６ alkyl, and R ４ The optional substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ alkyl, or an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1 to 4 N atoms and 0 or 1 O or S atom, —N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

39. R ４ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O or S atom; R ４ The optional substituents may be one or more halogen, unsubstituted or substituted C １ -C ６ Alkyl, —N(R ７ ) ２ , -OR ８ , -CN, -CO ２ R ８ , -C(=O)N(R ７ ) ２ , -SR ８ , -S(=O)R １０ , -S(=O) ２ R １０ , -NR ７ C(=O)R ８ , -NR ７ SO ２ R １０ , -SO ２ R １０ , or -SO ２ N (R ７ ) ２ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

40. R ａ is hydrogen, halogen, -OR ８ , -CN, -N(R ７ ) 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; R ａ The optional substituents of may be one or more R ９ is substituted with a group, R ｂ and R ｃ are independently hydrogen, halogen, or —OR ８ , -CN, -N(R ７ ) 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, wherein R ｂ and R ｃ The optional substituents of may be one or more R ９ 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt or solvate thereof, substituted with a group.

41. R ａ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH<~ ２ CH ２ CH ３ , -CH ２ [[ID=~34]]CH(CH ３ ) ２ ', -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NH ２ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ) ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ [[ID=1~4]], -CH ２ CH ２ N(CH It should be noted that there may be some inaccuracies in the original text, especially in the chemical formula - like expressions which seem a bit fragmented. If possible, it would be beneficial to double - check the source for a more accurate translation. ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R ｂ and R ｃ are independently hydrogen, Cl, Br, -CN, -OH, -OCH ３ -, -OCH ２ CH ３ -, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -CH(CH[[ID=四十一]] ３ (CH ２ CH ３ ), -C(CH ３ ) ３ -, -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ -, -CF ３ -, -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ -, -CH ２ CF ３ -, -CH ２ OCH ３ -, -CH ２ CH ２ OCH ３ -, -CH ２ NH ２ -, -CH ２ NHCH ３ -, -CH ２ N(CH ３ ), -CH ２ CH ２ CH ２ NH ２ -, -CH ２ CH ２ NHCH ３ or -CH ２ CH ２ N (CH ３ ) ２ 40. The compound of any one of claims 1 to 39, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

42. R ｄ is hydrogen, halogen, -OR ８ , -CN, -N(R ７ ) 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, or unsubstituted or substituted monocyclic heteroaryl; R ｄ The optional substituents of may be one or more R ９ is substituted with a group, R ｅ and R ｆ are independently hydrogen, halogen, or —OR ８ , -CN, -N(R ７ ) ２ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of heteroalkyl.

43. R ｄ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 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 is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl; R ｄ The optional substituents of may be one or more R ９ is substituted with a group, R ｅ and R ｆ are independently F, Cl, Br, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CH(CH ３ ) (CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, -OCH ３ , and -OCH ２ CH ３ 42. The compound of any one of claims 1 to 41, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

44. N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'-difluoro-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-fluoro-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethyl-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyano-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methyl-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3'-fluoro-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-(propan-2-yloxy)-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-hydroxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyclopropoxy-[1,1'-biphenyl]-3-carboxamide; (R)—N-(2-aminoethyl)-4-(4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide; (R)—N-(2-aminoethyl)-4-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-2′-(methoxymethyl)-[1,1′-biphenyl]-3-carboxamide; (R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide; (R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-methyl-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide; Methyl (R)-3'-((2-aminoethyl)carbamoyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-[1,1'-biphenyl]-2-carboxylate; (R)-N3'-(2-aminoethyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2-methyl-[1,1'-biphenyl]-2,3'-dicarboxamide; (R)-N3'-(2-aminoethyl)-4'-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2,N2-dimethyl-[1,1'-biphenyl]-2,3'-dicarboxamide; N-(2-aminoethyl)-2'-(aminomethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-carboxamide; N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-3'-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-3-fluoro-5-methyl-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propyl-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-4'-propyl-[1,1'-biphenyl]-3-carboxamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-2-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-2-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-4-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyridin-4-yl)benzoyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4'-(aminomethyl)-3-fluoro-5-methyl-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(4-aminopiperidin-1-yl)-4-chlorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(3,5-dichloropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methoxybenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-{4-[3-(aminomethyl)pyrrolidin-1-yl]-2-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2,4-dimethylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(pyrrolidin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2-cyclopropylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-2-yl)methyl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-3-yl)methyl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-4-yl)methyl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(pyridin-4-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-methoxypyridin-3-yl)benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(piperidin-4-yl)benzoyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(6-aminopyridin-3-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(2,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methylbenzoyl)piperazin-1-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methoxybenzoyl)piperazin-1-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(2-methoxy-4-methylbenzoyl)piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4-tert-butylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-5-yl)methyl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-5-yl)ethyl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(2-aminopyridin-4-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4-cyclopropyl-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-(3-chloro-5-fluoropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(piperazin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(dimethylamino)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; N-{[(2S)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-pyrrolidin-2-yl]methyl}benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-piperidin-3-yl]benzamide; 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-fluoro-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; N-{[(2R)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-fluoro-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(morpholin-4-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-[3-(dimethylamino)-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-morpholin-2-yl]methyl}benzamide; 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; N-{[(2S)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 2-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-fluoro-3-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(methylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; N-{[(2R)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[2-amino-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[6-(dimethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-imidazol-1-yl)benzoyl]piperazin-1-yl]benzamide; N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrrol-1-yl)benzoyl]piperazin-1-yl]benzamide; N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrazol-1-yl)benzoyl]piperazin-1-yl]benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-2-yl)methyl]benzamide; 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[3-chloro-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(3S)-morpholin-3-yl]methyl}benzamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]benzamide; 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 6-[(2R)-4-(4-chloro-2-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 2-[(2R)-4-[6-amino-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide; N-(2-aminoethyl)-2-[(2R)-4-[4-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[2-(dimethylamino)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[2-(3-aminoazetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-[2-cyano-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide; N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-methylpyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(2R)-4-[2-(azetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide; N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyrrolidin-1-yl)benzoyl]piperazin-1-yl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-(methylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-carbamoyl-4-chlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methyl-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-[ethyl(methyl)amino]-4-fluorobenzoyl}piperazin-1-yl]benzamide; 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(4,6-dimethoxypyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide; 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(6-methoxy-4-oxo-1,4-dihydropyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethyl-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; N-(azetidin-3-yl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-pyrrolidin-3-yl]benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-1-methylpyrrolidin-3-yl]benzamide; N-(azetidin-3-yl)-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-(1-methylazetidin-3-yl)benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethyl-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[2-(methylamino)ethyl]pyridine-2-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; N-(azetidin-3-yl)-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(1-methylazetidin-3-yl)benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(4-ethoxypyrimidin-5-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 5-[(2R)-4-(2-chloro-4-cyclopropoxybenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; N-(azetidin-3-yl)-3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; N-[(azetidin-3-yl)methyl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(1H-imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-(ethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-1-methylazetidin-2-yl]methyl}benzamide; 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2S)-1-methylazetidin-2-yl]methyl}benzamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(1-methyl-1H-imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 3-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 5-[(2R)-4-(adamantane-2-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2'-methoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2'-methoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclobutanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[trans-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; N-{[(2S)-Azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclopentanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[trans-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-(2-tert-butylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1,2,2,3-tetramethylcyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1,1,1-trifluoro-2-methylpropan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2-cyclopropylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-{7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl}-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 5-[(2R)-4-(2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoroazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoro-1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(2,2-diethylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-pyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-methyl-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; N-{[(2R)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; N-{[(2S)-Azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-methoxy-1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; N-[2-(azetidin-1-yl)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-(trifluoromethyl)cyclobutyl (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-phenylpyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(5-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(7-fluoro-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; (1R)-2,2,2-trifluoro-1-phenylethyl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclopentanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[2,2-difluoro-7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide; 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(3-fluoroazetidin-1-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-(7-methyl-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-[5-(trifluoromethyl)thiophene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1,1,1,3,3,3-hexafluoropropan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 3-(trifluoromethyl)pentan-3-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 5-[(2R)-4-[1-(2,4-difluorophenyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (1S)-2,2,2-trifluoro-1-phenylethyl (3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 5-[(2R)-4-(2,5-dichlorothiophene-3-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(3,5-dichlorothiophene-2-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(3-fluorophenyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indene-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-phenylcyclobutyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(2'-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 1-ethylcyclopentyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; N-{1-azabicyclo[2.2.1]heptan-4-yl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 2,2-dimethyl-1-phenylpropyl (3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate; 5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1-methylazetidin-3-yl)-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide; 5-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 5-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 3-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2'-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 3-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide; 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}methyl)amino]ethan-1-ol; (2S)-1-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}methyl)amino]propan-2-ol; 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methoxy-[1,1'-biphenyl]-3-yl}methanamine; 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-(2-methoxyethoxy)-[1,1'-biphenyl]-3-yl}methanamine; 1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-propoxy-[1,1'-biphenyl]-3-yl}methanamine; 2-{[3'-(aminomethyl)-4'-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-2-yl]oxy}ethan-1-ol; 2-{[3'-(aminomethyl)-4'-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1'-biphenyl]-2-yl]oxy}ethan-1-ol; [3'-(aminomethyl)-4'-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-2-yl]methanol; 1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine; 1-{2-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine; 1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine; 1-{3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridin-2-yl}methanamine; 1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 1-{5-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 1-{5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; ({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methyl)(methyl)amine; 1-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6-yl}methanamine; 1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine; 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-(2,3,4-trifluorobenzoyl)piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; {[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]phenyl]methyl}[2-(methylamino)ethyl]amine; 13-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N-methylpyridin-2-amine; 3-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N,N-dimethylpyridin-2-amine; 1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-[2-(pyrrolidin-1-yl)pyridin-3-yl]phenyl}methanamine; 1-{2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-3'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1'-biphenyl]-3-yl}methanamine; 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-4'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 1-{2'-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-5'-fluoro-[1,1'-biphenyl]-3-yl}methanamine; 1-{2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; 1-{2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3'-bipyridin]-6-yl}methanamine; N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2',3'-difluoro-[1,1'-biphenyl]-3-carboxamide; N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide; 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; (3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl}phenyl]-3-ethylpiperazine-1-carboxamide; N-(2-aminoethyl)-2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide; 2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-methylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxamide; 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide; N-(2-aminoethyl)-5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2-(2-ethoxyphenyl)pyridine-4-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

45. 45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, dermal, or ocular administration.

47. 46. ​​The pharmaceutical composition of claim 45, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

48. 45. 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 a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt or solvate thereof.

49. 49. The method of claim 48, wherein the disease or disorder comprises fat pad growth in the collarbone, back of the neck, face, and trunk, excessive sweating, telangiectasia, thinning skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease.

50. 46. ​​A method of treating Cushing's syndrome in a mammal, comprising administering to said mammal a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt or solvate thereof.

51. A method for reducing adrenocorticotropic hormone (ACTH) secretion in a mammal, comprising administering to said mammal a selective small molecule antagonist of the melanocortin subtype-2 receptor (MC2R).

52. 52. The method of claim 51, wherein the selective MC2R antagonist reduces ACTH secretion from pituitary corticotrophic cell microadenomas.

53. 53. The method of claim 51 or claim 52, wherein the selective small molecule MC2R antagonist binds to or interacts with MC2R and does not substantially bind to or interact with other melanocortin subtype receptors.

54. 54. The method of any one of claims 51 to 53, wherein the selective small molecule MC2R antagonist is at least 10-fold selective for MC2R over any other melanocortin subtype receptor.

55. 55. The method of any one of claims 51 to 54, wherein the selective small molecule MC2R antagonist is a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt or solvate thereof.

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