GEM-disubstituted piperidine melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof

Abstract

Described herein are compounds that are melanocortin subtype-2 receptor (MC2R) modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of MC2R activity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 949,854 filed on December 18, 2019, which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION

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

[0003] The melanocortin receptors form a family of G protein-coupled receptor (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by different melanocortin peptides adrenocorticotropic hormone (ACTH), and the melanocortin peptides a-, P-, and y-melanocyte-stimulating hormone (a-MSH, P-MSH, and y-MSH) that are all derived proteolytically from proopiomelanocortin hormone, or POMC. ACTH is a 39 amino acid peptide that is the primary regulator of adrenal glucocorticoid synthesis and secretion and only has affinity for MC2R . As the central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary in response to stressful stimuli and acts at the adrenal gland to stimulate the synthesis and secretion of cortisol. Modulation of MC2R is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating melanocortin receptor activity. SUMMARY OF THE INVENTION

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

[0005] In one aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof R1^M Formula (I) wherein: Ra is unsubstituted or substituted heteroaryl or unsubstituted or substituted aryl, wherein if Ra is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc; Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Ra, Rb, and Rc is substituted with one or more R6 groups; or one Ra and one Rb, when present on adjacent atoms of RA, are taken together with the intervening atoms connecting Ra to Rb to form a 5- to 6-membered monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; Rb is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein if Rb is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf; Rd, Re, and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, -C(=O)N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Rd, Re, and Rf is substituted with one or more R6 groups; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; X1isCR11orN; X2 is CR12 orN; X3 is CR13 orN; X4 is CR14 orN; R11, R12, R13, and R14 are each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-Cecycloalkyl, -CN, -OR4, -SR4, -CO2R4, -C(=O)N(R4)2, or -N(R4)2; M is -(C=O)-, -NR3-, -0-, -S-, -SO2-, *-NR3-(C=0)-, *-(C=0)-NR3-, *-0-(C=0)NR3-, *-NR3-(C=0)0-, -NR3-(C=O)NR3-, *-NR3(SO2)-, *-SO2NR3-, or 5-membered heterocycle, wherein * indicates the attachment point to R1; R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(Ci-Ce alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C7 heterocycloalkyl), wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; each R3 is independently hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; each R4is independently selected from the group consisting of hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted Ci-Cefluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; or two R4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; each R5 is independently selected from the group consisting of hydrogen, substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted Ci-Cefluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; each R6is independently hydrogen, halogen, unsubstituted or substituted Ci-C4alkyl, unsubstituted or substituted Ci-C4alkoxy, unsubstituted or substituted Ci-C4fluoroalkyl, unsubstituted or substituted Ci-C4fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -CO2R5, -CH2CO2R5, -C(=O)N(R4)2, -C(=O)N(R4)OR5, -CH2C(=O)N(R4)2, -N(R4)2, -CH2N(R4)2, -C(R5)2N(R4)2, -NR4C(=O)R5, -CH2NR4C(=O)R5, -NR4C(=O)N(R5)2, -NR4C(=O)N(R4)2, C(R5)=N(R4)-OR5, -SR5, -S(=O)R7, -SO2R7, or -SO2N(R4)2; and each R7 is independently selected from the group consisting substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted Ci-Cefluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

[0006] Also described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

[0007] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation; and / or (e) administered by nasal administration; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[0008] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one 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.

[0009] In any of the embodiments disclosed herein, the mammal is a human.

[0010] In some embodiments, compounds provided herein are orally administered to a human.

[0011] Articles of manufacture, which include packaging material, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating one or more subtype melanocortin receptor proteins, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating one or more subtype melanocortin receptor proteins, are provided.

[0012] 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 the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0013] Adrenocorticotropic hormone (ACTH) is a 39 amino acid peptide synthesized by anterior pituitary corticotrophic cells by proteolytic cleavage of the proopiomelanocortin hormone (POMC). ACTH is the primary regulator of adrenal glucocorticoid (GC; cortisol in humans and most other species; corticosterone in rodents) synthesis and secretion. As the central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary in response to stressful stimuli and acts at the adrenal gland to stimulate the synthesis and secretion of cortisol. This stimulation is mediated through a highly specific G protein-coupled receptor (GPCR) which is expressed almost uniquely in the adrenal cortex. The receptor is the melanocortin 2 receptor (MC2R), and, along with ACTH, is part of the larger melanocortin system.

[0014] The melanocortin system comprises a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R); their natural agonists, the melanocortin peptides a-, P-, and y-melanocyte-stimulating hormone (a-MSH, P-MSH, and y-MSH) and ACTH; and endogenous melanocortin antagonists agouti and agouti-related protein (AGRP). The melanocortin receptors (MCRs) have different selectivities for endogenous agonist and antagonist peptides and are expressed in diverse tissues where they serve varied and discreet physiological functions (Gantz, I. and T.M. Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003).

[0015] It is possible to selectively modulate any one of the MCRs, or combinations thereof. In some embodiments, selectively modulating any one of the MCRs relative to the other MCRs, or combinations thereof, is useful in a variety of clinical applications. In some embodiments, selectively modulating any one of the MCRs relative to the other MCRs, or combinations thereof, reduces unwanted side effects in a variety of clinical applications. In one aspect, compounds described herein are antagonists of MC2R. In some embodiments, compounds described herein are selective antagonists for MC2R relative or other MCRs.

[0016] MC2R is a highly selective receptor for ACTH. Although ACTH can activate all five MCRs, at physiological levels, the sensitivity of the other receptors is not high enough to be activated, and ACTH selectively activates MC2R. Importantly, the other naturally occurring agonists a-MSH, P-MSH, and y-MSH have no affinity for MC2R (Gantz, I. and T.M. Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003). The major function of MC2R is to stimulate the fasciculata cells of the adrenal cortex to synthesize and secret cortisol. MC2R requires the GPCR accessory protein MRAP (melanocortin 2 receptor protein) to be successfully secreted to the cell surface and as well as to function. MRAP is a small protein with a single transmembrane domain that forms an antiparallel homodimer in stable complex with MC2R and is necessary for both cell surface expression of MC2R and its ability to bind ACTH. MRAP can bind to any of the MCRs and affect their activities, but is only essential for MC2R activity. Binding of ACTH to the MC2R / MRAP complex on adrenal cortical cells activates Gs to elevate intracellular cAMP levels which in turn stimulates cortisol synthesis and secretion by regulating multiple steps in the steroidogenic pathway.

[0017] Cushing’s syndrome is a rare disorder characterized by chronic, excess glucocorticoid exposure. Clinical signs of Cushing’s syndrome include growth of fat pads (collarbone, back of neck, face and trunk), excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disturbances resulting in high morbidity. If inadequately controlled in its severe forms, Cushing's syndrome is associated with high mortality. Although glucocorticoid excess can sometimes be ACTH independent, for example from excessive autonomous secretion of cortisol from a hyperfunctioning adrenal adenoma, carcinoma, or steroid abuse, about 60-80% of all cases are ACTH dependent Cushing’s syndrome, known as Cushing’s disease. Cushing’s disease is caused by microadenomas of pituitary corticotropic cells that secrete excess ACTH. Corticotroph adenomas are small, usually slow growing, benign tumors that normally come to clinical attention as a result of the effects of glucocorticoid excess, rather than because of the physical effects of an expanding tumor. First line treatments for Cushing’s disease are surgical and involve removal of either the ACTH- secreting tumor in the pituitary or the adrenal glands themselves. As surgery is often unsuccessful, contraindicated, or delayed, medical therapy for these patients becomes necessary. Current treatment options include inhibitors of steroid synthesis enzymes that can prevent the production of cortisol and improve symptoms, but these treatments also induce a host of unwanted side effects due to the accumulation of other steroid products. In one aspect, an MC2R antagonist is used in the treatment of Cushing’s syndrome. In some embodiments, an MC2R antagonist is used in the treatment of Cushing’s disease. In some embodiments, glucocorticoid excess is ACTH independent. In some embodiments, glucocorticoid excess is ACTH dependent.

[0018] Ectopic ACTH syndrome, or ectopic Cushing’s syndrome or disease, is essentially the same as Cushing’s disease, except that the underlying tumor expressing ACTH is outside the pituitary gland. In some embodiments, the tumors are small carcinoid tumors that occur anywhere in the lungs or gastrointestinal tract. In some embodiments, an MC2R antagonist is used in the treatment of ectopic ACTH syndrome.

[0019] Congenital adrenal hyperplasia (CAH) is characterized by a reduction or loss of cortisol synthesis and excessive ACTH and corticotropin-releasing hormone. CAH can result from a variety of genetic defects in the adrenal steroidal biosynthesis pathway. In some embodiments, CAH is due to a mutation in 2ip-hydroxylase. The lack of cortisol removes the negative feedback to the pituitary which leads to excessive ACTH secretion. The resulting excessive adrenal stimulation causes overproduction of steroid precursors which also have negative consequences (e.g., hyperandrogenism). Administration of replacement glucocorticoids typically does not adequately suppress ACTH without also causing Cushing's-like symptoms. In some embodiments, an MC2R antagonist is used in the treatment of CAH.

[0020] In addition to Cushing's disease, Ectopic ACTH syndrome and CAH it has also been hypothesized that there might be a role for an MC2R antagonist in the treatment of ACTH driven adrenal tumors, Functional Adrenal Hyperandrogenism (FAH), stress disorders, psychiatric disorders, type 2 diabetes and septic shock. In some embodiments, an MC2R antagonist is used in the treatment of ACTH driven adrenal tumors. In some embodiments, an MC2R antagonist is used in the treatment of Functional Adrenal Hyperandrogenism. In some embodiments, an MC2R antagonist is used in the treatment of stress disorders. In some embodiments, an MC2R antagonist is used in the treatment of psychiatric disorders. In some embodiments, an MC2R antagonist is used in the treatment of type 2 diabetes. In some embodiments, an MC2R antagonist is used in the treatment of septic shock. In some embodiments, an MC2R antagonist is used in the treatment of septic shock.

[0021] In some embodiments, compounds described herein are amenable to administration to a mammal in need of treatment with an MC2R antagonist. Compounds

[0022] 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 modulators are MC2R antagonists.

[0023] In one aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof: Formula (I) wherein: Ra is unsubstituted or substituted heteroaryl or unsubstituted or substituted aryl, wherein if Ra is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc; Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Ra, Rb, and Rc is substituted with one or more R6 groups; or one Ra and one Rb, when present on adjacent atoms of RA, are taken together with the intervening atoms connecting Ra to Rb to form a 5- to 6-membered monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; Rb is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein if Rb is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf; Rd, Re, and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, -C(=O)N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Rd, Re, and Rf is substituted with one or more R6 groups; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; X1isCR11orN; X2 is CR12 orN; X3 is CR13 orN; X4 is CR14 orN; R11, R12, R13, and R14 are each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-Cecycloalkyl, -CN, -OR4, -SR4, -CO2R4, -C(=O)N(R4)2, or -N(R4)2; M is -(C=O)-, -NR3-, -O-, -S-, -SO2-, *-NR3-(C=0)-, *-(C=0)-NR3-, *-0-(C=0)NR3-, *-NR3-(C=0)0-, -NR3-(C=O)NR3-, *-NR3(SO2)-, *-SO2NR3-, or 5-membered heterocycle, wherein * indicates the attachment point to R1; R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(Ci-Ce alkyl)-(C3-Ce cycloalkyl), or unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C7 heterocycloalkyl), wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; each R3 is independently hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; each R4is independently selected from the group consisting of hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or WO 2021 / 126693                                                 PCT / US2020 / 064493 substituted Ci-Cefluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; or two R4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; each R5 is independently selected from the group consisting of hydrogen, substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted Ci-Cefluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; each R6is independently hydrogen, halogen, unsubstituted or substituted Ci-C4alkyl, unsubstituted or substituted Ci-C4alkoxy, unsubstituted or substituted Ci-C4fluoroalkyl, unsubstituted or substituted Ci-C4fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -CO2R5, -CH2CO2R5, -C(=O)N(R4)2, -C(=O)N(R4)OR5, -CH2C(=O)N(R4)2, -N(R4)2, -CH2N(R4)2, -C(R5)2N(R4)2, -NR4C(=O)R5, -CH2NR4C(=O)R5, -NR4C(=O)N(R5)2, -NR4C(=O)N(R4)2, C(R5)=N(R4)-OR5, -SR5, -S(=O)R7, -SO2R7, or -SO2N(R4)2; and each R7 is independently selected from the group consisting substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted Ci-Cefluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

[0024] In some embodiments, M is -C(=O)-, -NR3-, -O-, -S-, -SO2-, *-NR3-(C=0)-, *-(C=O)-NR3-, *-NR3SO2-, or 5-membered heterocycle, wherein * indicates the attachment point to R1. In some embodiments, M is -0(=0)-, -NR3-, -0-, -S-, -SO2-, *-(C=0)-NR3-, *-NR3-(C=0)-, *-NR3SO2-,or 5-membered heteroaryl, wherein * indicates the attachment point to R1.

[0025] In some embodiments, M is -0-, *-NR3-C(=0)-, -S-, -SO2-, *-NR3SO2-, or 5-membered heteroaryl, wherein * indicates the attachment point to R1.

[0026] In some embodiments, M is 5-membered heterocycle. In some embodiments, M is 5membered heteroaryl. In some embodiments, M is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, M is oxazolyl, imidazolyl, or triazolyl.

[0027] In some embodiments, M is -NR3-, -0-, *-NR3-(C=0)-, *-(C=0)-NR3-, *-O-(C=0)NR3-, *-NR3-(C=0)0-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1. In some embodiments, M is *-NR3-(C=0)-, *-(C=0)-NR3-, *-0-(C=0)NR3-, *-NR3-(C=O)O-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1. In some embodiments, M is *-NR3-(C=0)- or *-(C=0)-NR3-, wherein * indicates the attachment point to

[0028] In some embodiments, M is *-(C=O)-NR3-, wherein * indicates the attachment point to R1. In some embodiments, M is *-NR3-(C=O)-, wherein * indicates the attachment point to R1.

[0029] In some embodiments, each R3 is independently hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, each R3 is independently hydrogen or Ci-Ce alkyl. In some embodiments, each R3 is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, each R3 is independently hydrogen or -CH3. In some embodiments, each R3 is -CH3. In some embodiments, each R3 is hydrogen.

[0030] In some embodiments, M is -NR3-, -O-, *-NR3-(C=O)-, *-(C=O)-NR3-, *-O-(C=O)NR3-, *-NR3-(C=O)O-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1; and each R3 is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, M is *-NR3-(C=O)- or *-(C=O)-NR3-, wherein * indicates the attachment point to R1; and R3 is hydrogen.

[0031] In some embodiments, M comprises an N atom and the N atom of M is attached to R1, wherein R1 also comprises an N atom. In some embodiments, the N atom of M is connected to the N atom of R1 through one carbon atom, two carbon atoms, three carbon atoms, or four carbon atoms. In some embodiments, the N atom of M is connected to the N atom of R1 through a two carbon atom spacer. In some embodiments, the N atom of R1 is part of an unsubstituted or substituted aliphatic alkyl chain. In some embodiments, the N atom of R1 is part of an unsubstituted or substituted cyclic ring. In some embodiments, the N-containing cyclic ring of R1 is an unsubstituted or substituted monocyclic C2-C7 heterocycloalkyl or unsubstituted or substituted bicyclic C2-C7 heterocycloalkyl.

[0032] In some embodiments, the compound has the structure of Formula (Ila), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Ila).

[0033] In some embodiments, the compound has the structure of Formula (lib), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (lib).

[0034] In some embodiments, RA is unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic 5membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group.

[0035] In some embodiments, RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, RA is substituted with 1 group selected from Ra, Rb, and Rc. In some embodiments, RA is substituted with one Ra. In some embodiments, RA is substituted with one Rc.

[0036] In some embodiments, RA is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group.

[0037] In some embodiments, RA is unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2 or 3 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, wherein if RA is substituted then Ra is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, wherein if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group.

[0038] In some embodiments, RA is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein if Ra is substituted then RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group.

[0039] In some embodiments, RA is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, wherein if RA is substituted then RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group.

[0040] In some embodiments, RA is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, or unsubstituted or substituted thienyl, wherein if RA is substituted then RA is substituted with 1, 2, or 3 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 Ra, Rb, or Rc group. where Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0042] In some embodiments, RA is C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0045] In some embodiments, RA is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, RA is In some embodiments, RA is . In some embodiments, RA In some embodiments, RA is

[0046] In some embodiments, RA is where Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3- Ce cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. or Rc , where Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0048] In some embodiments, RA is , where Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, - C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. In some embodiments, Rc is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, Rc is hydrogen or -CH3. In some embodiments, Rc is -CH3. In some embodiments, Rc is hydrogen. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl. In some embodiments, Rc is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, - C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. In some embodiments, Rc is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, Rc is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0049] In some embodiments, RA is ; Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, RA is ; Y1 is NRC; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, RA is ; Y1 is NRC; Y2 and Y3 are independently CH, CRa, or CRb; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, RA is ; Y1 is NRC; Y2 and Y3 are each CH; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. Y2^                              y2.y3 y’J^r               y’^

[0050] In some embodiments, RA is          . In some embodiments, RA is Ra . Y2ytRa

[0051] In some embodiments, RA is ; Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 Y2ytRa heterocycloalkyl. In some embodiments, RA is        ; Y1 is NRC; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 Y2ytRa % heterocycloalkyl. In some embodiments, RA is        ; Y1 is NRC; Y2 and Y3 are independently CH, CRa, or CRb; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 Y2'yvRa heterocycloalkyl. In some embodiments, RA is        ; Y1 is NRC; Y2 and Y3 are each CH; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0052] In some embodiments, the compound has the structure of Formula (III), or a pharmaceutically acceptable salt, or solvate thereof: Y2'y>Ra ✓X                 / R1-M Formula (III) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-Ce cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0053] In some embodiments, the compound has the structure of Formula (Illa), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Illa) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-Ce cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0054] In some embodiments, the compound has the structure of Formula (Illb), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Illb) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; and Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-Ce cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0055] In some embodiments, RA is unsubstituted or substituted monocyclic 6-membered heteroaryl or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, RA is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc.

[0056] In some embodiments, RA is unsubstituted or substituted pyridinyl or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc. Rb Ra Rb Ra pb Ra pb Ra 100^71 T     b d’ t pA- R0^^ R^ R^ R^

[0057] In some embodiments, R is K , K , K , K , or In some embodiments, RAis In some embodiments, RAis

[0058] In some embodiments, RAis

[0059] In some embodiments, RA is R embodiments, V is CH orN. , where V is CH, CRa, CRb, or N. In some

[0060] In some embodiments, RA is , where V is CH, CRa, CRb, or N. In some embodiments, V is CH orN.

[0061] In some embodiments, the compound has the structure of Formula (IV), or a pharmaceutically acceptable salt, or solvate thereof: Ra R1'M Formula (IV) wherein V is CH, CRa, CRb, orN. In some embodiments, V is CH orN.

[0062] In some embodiments, the compound has the structure of Formula (IVa), or a pharmaceutically acceptable salt, or solvate thereof: Ra Formula (IVa) wherein V is CH, CRa, CRb, orN. In some embodiments, V is CH orN.

[0063] In some embodiments, the compound has the structure of Formula (IVb), or a pharmaceutically acceptable salt, or solvate thereof: Formula (IVb) wherein V is CH, CRa, CRb, or N. In some embodiments, V is CH or N.

[0064] In some embodiments, RA is unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. RA is unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and

[0065] In some embodiments, RA is unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein if Ra is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc.

[0066] In some embodiments, RA is unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc.

[0067] In some embodiments, RA is unsubstituted or substituted indazolyl or unsubstituted or substituted benzofuranyl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc. In some embodiments, if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc.

[0068] In some embodiments, RB is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf. In some embodiments, if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf.

[0069] In some embodiments, RB is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf. In some embodiments, if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf.

[0070] In some embodiments, RB is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf. In some embodiments, RB is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf. In some embodiments, if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf.

[0071] In some embodiments, RB is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf. In some embodiments, if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf. In some embodiments, RB is Rd\Re or N in some embodiments, RB In some embodiments, RBis

[0073] In some embodiments, RB is W , where W is CH, CRd, CRe, or N. In some embodiments, W is CH orN.

[0074] In some embodiments, the compound has the structure of Formula (V), or a pharmaceutically acceptable salt, or solvate thereof: R1'M Formula (V) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and WisCH, CRd, CRe, orN.

[0075] In some embodiments, the compound of Formula (V) has one of the following structures, or a pharmaceutically acceptable salt, or solvate thereof:

[0076] In some embodiments, M is *-NR3-(C=O)-, wherein * indicates the attachment point to R1.

[0077] In some embodiments, W is CH or N.

[0078] In some embodiments, Y1 is NRC; and Y2 and Y3 are independently CH, CRa, CRb, or N. In some embodiments, Y1 is NRC; Y2 and Y3 are independently CH, CRa, or CRb. In some embodiments; Y1 is NRC; Y2 and Y3 are each CH.

[0079] In some embodiments, the compound has the structure of Formula (Va), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Va) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CRd, CRe, orN.

[0080] In some embodiments, W is CH or N.

[0081] In some embodiments, Y1 is NRC; and Y2 and Y3 are independently CH, CRa, CRb, or N. In some embodiments, Y1 is NRC; Y2 and Y3 are independently CH, CRa, or CRb. In some embodiments; Y1 is NRC; Y2 and Y3 are each CH.

[0082] In some embodiments, the compound has the structure of Formula (Vb), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vb) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CRd, CRe, orN.

[0083] In some embodiments, W is CH or N.

[0084] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[0085] In some embodiments, the compound has the structure of Formula (Vc), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vc) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CRd, CRe, orN.

[0086] In some embodiments, W is CH or N.

[0087] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[0088] In some embodiments, the compound has the structure of Formula (Vd), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vd) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and W is CH, CRd, CRe, orN.

[0089] In some embodiments, W is CH or N.

[0090] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[0091] In some embodiments, the compound has the structure of Formula (Ve), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Ve) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[0092] In some embodiments, the compound has the structure of Formula (Vf), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vf) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[0093] In some embodiments, the compound has the structure of Formula (Vg), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vg) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[0094] In some embodiments, the compound has the structure of Formula (Vh), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vh) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[0095] In some embodiments, the compound has the structure of Formula (Vi), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vi) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[0096] In some embodiments, the compound has the structure of Formula (Vj), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Vj) wherein: Y1 is NRC, O, or S; Y2 and Y3 are independently CH, CRa, CRb, or N; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and WisCH, CRd, CRe, orN.

[0097] In some embodiments, W is CH or N.

[0098] In some embodiments, Y1 is NRC; and Y2 and Y3 are independently CH, CRa, CRb, or N. In some embodiments, Y1 is NRC; Y2 and Y3 are independently CH, CRa, or CRb. In some embodiments; Y1 is NRC; Y2 and Y3 are each CH.

[0099] In some embodiments, the compound has the structure of Formula (Vk), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vk) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and WisCH, CRd, CRe, orN.

[00100] In some embodiments, W is CH or N.

[00101] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[00102] In some embodiments, the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (VI) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and WisCH, CRd, CRe, orN.

[00103] In some embodiments, W is CH or N.

[00104] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[00105] In some embodiments, the compound has the structure of Formula (Vm), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vm) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and WisCH, CRd, CRe, orN.

[00106] In some embodiments, W is CH or N.

[00107] In some embodiments, Rc is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, Rc is hydrogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is hydrogen or Ci-Ce alkyl. In some embodiments, Rc is unsubstituted or substituted Ci-Ce alkyl. In some embodiments, Rc is Ci-Ce alkyl.

[00108] In some embodiments, the compound has the structure of Formula (Ve), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vn) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[00109] In some embodiments, the compound has the structure of Formula (Vf), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vn) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[00110] In some embodiments, the compound has the structure of Formula (Vg), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vo) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[00111] In some embodiments, the compound has the structure of Formula (Vh), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vo) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[00112] In some embodiments, the compound has the structure of Formula (Vp), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vp) wherein W is CH, CRd, CRe, or N. In some embodiments, W is CH or N.

[00113] In some embodiments, the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof: Ra r^M Formula (VI) wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

[00114] In some embodiments, the compound of Formula (VI) has the following structure, or a pharmaceutically acceptable salt, or solvate thereof:

[00115] In some embodiments, M is *-NR3-(C=O)-, wherein * indicates the attachment point to R1. In some embodiments, M is *-(C=O)-NR3-, wherein * indicates the attachment point to R1.

[00116] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N; and W is CH or N.

[00117] In some embodiments, the compound has the structure of Formula (Via), or a pharmaceutically acceptable salt, or solvate thereof: Ra R1 Formula (Via) wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

[00118] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N; and W is CH or N.

[00119] In some embodiments, the compound has the structure of Formula (VIb), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (VIb) wherein V is CH, CRa, CRb, or N. In some embodiments, V is CH or N.

[00120] In some embodiments, the compound has the structure of Formula (Vic), or a pharmaceutically acceptable salt, or solvate thereof: Ra R1 Formula (Vic) wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

[00121] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N; and W is CH or N.

[00122] In some embodiments, the compound has the structure of Formula (Vid), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Vid) wherein V is CH, CRa, CRb, or N. In some embodiments, V is CH or N.

[00123] In some embodiments, RB is an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf

[00124] In some embodiments, RB is unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf. In some embodiments, RB is unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1 or 2 groups selected from Rd, Re, and Rf. In some embodiments, RB is unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, wherein if RB is substituted then Rb is substituted with 1 or 2 groups selected from Rd, Re, and Rf. In some embodiments, RB is unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, wherein if RB is substituted then RB is substituted with 1 or 2 groups selected from Rd, Re, and Rf. In some embodiments, RB is unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf.

[00125] In some embodiments, RB is C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00126] In some embodiments, R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(Ci-Ce alkyl)-(C3-Ce cycloalkyl), or unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C7 heterocycloalkyl), wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; wherein R1 comprises a basic amine group.

[00127] In some embodiments, R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, unsubstituted or substituted monocyclic 4-, 5-or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms, unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms, or unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C7 heterocycloalkyl), wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2.

[00128] In some embodiments, R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

[00129] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

[00130] In some embodiments, R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2.

[00131] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom. In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom; wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2.

[00132] In some embodiments, R1 is unsubstituted or substituted monocyclic 4-, 5- or 6membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms.

[00133] In some embodiments, R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms.

[00134] In some embodiments, R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

[00135] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5; or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[00136] In some embodiments, R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[00137] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5.

[00138] In some embodiments, the compound has the structure of Formula (Vila), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Vila) wherein W is CH, CRa, CRb, or N. In some embodiments, W is CH or N.

[00139] In some embodiments, the compound has the structure of Formula (Vllb), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Vllb) wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

[00140] In some embodiments, the compound has the structure of Formula (Vile), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vile) wherein W is CH, CRa, CRb, or N. In some embodiments, W is CH or N.

[00141] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N; and W is CH or N.

[00142] In some embodiments, the compound has the structure of Formula (Vlld), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Vlld) wherein W is CH, CRa, CRb, or N. In some embodiments, W is CH or N.

[00143] In some embodiments, the compound has the structure of Formula (Vile), or a pharmaceutically acceptable salt, or solvate thereof: R1 Formula (Vile) wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

[00144] In some embodiments, the compound has the structure of Formula (Vllf), or a pharmaceutically acceptable salt, or solvate thereof: Rb R1 Formula (Vllf) wherein W is CH, CRa, CRb, or N. In some embodiments, W is CH or N.

[00145] In some embodiments, V is CH or N. In some embodiments, W is CH or N. In some embodiments, V is CH or N; and W is CH or N.

[00146] In some embodiments, the compound has the structure of Formula (VIII), or a pharmaceutically acceptable salt, or solvate thereof: R1^M Formula (VIII) wherein: RAis unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted indolyl, unsubstituted or substituted indazolyl, or unsubstituted or substituted benzofuranyl, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if Rb is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; and M is -NR3-, -O-, *-NR3-(C=O)-, *-(C=O)-NR3-, *-O-(C=O)NR3-, *-NR3-(C=O)O-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1.

[00147] In some embodiments, X1 is CR11; X2 is CR12; X3 is CR13; and X4 is CR14. In some embodiments, X1 is N; X2 is CR12; X3 is CR13; and X4 is CR14. In some embodiments, X1 is CR11; X2 is N; X3 is CR13; and X4 is CR14. In some embodiments, X1 is N; X2 is CR12; X3 is CR13; and X4 is N. In some embodiments, X1 is N; X2 is N; X3 is CR13; and X4 is CR14. In some -38- WO 2021 / 126693                                                 PCT / US2020 / 064493 embodiments, X1 is N; X2 is CR12; X3 is N; and X4 is CR14. In some embodiments, X1 is CR11; X2 is CR12; X3 is CR13; and X4 is CR14.

[00148] In some embodiments, X1 is CR11 or N; X2 is CR12; X3 is CR13; and X4 is CR14.

[00149] In some embodiments, X1 is CR11 or N; X2 is CR12 or N; X3 is CR13; and X4 is CR14.

[00150] In some embodiments, R11, R12, R13, and R14 are each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted C3-Cecycloalkyl, -CN, or -OR4. In some embodiments, R11, R12, R13, and R14 are each independently hydrogen, halogen, Ci-Ce alkyl, fluoroalkyl, unsubstituted C3-Cecycloalkyl, -CN, or -OR4. In some embodiments, R11, R12, R13, and R14 are each independently hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, or cyclopropyl. In some embodiments, R11, R12, R13, and R14 are each independently hydrogen or F.

[00151] In some embodiments, X1 is CH or CF; X2 is CH or CF; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is N; X2 is CH or CF; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is CH or CF; X2 is N; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is N; X2 is CH or CF; X3 is CH or CF; and X4 is N. In some embodiments, X1 is N; X2 is N; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is N; X2 is CH or CF; X3 is N; and X4 is CH or CF. In some embodiments, X1 is CH or CF; X2 is CH or CF; X3 is CR13; and X4 is CR14.

[00152] In some embodiments, X1 is CH, CF, or N; X2 is CH or CF; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is CR11 or N; X2 is CH; X3 is CH; and X4 is CH. In some embodiments, X1 is CH, CF, or N; X2 is CH; X3 is CH; and X4 is CH.

[00153] In some embodiments, X1 is CH, CF, or N; X2 is CH, CF, or N; X3 is CH or CF; and X4 is CH or CF. In some embodiments, X1 is CR11 or N; X2 is CR12 or N; X3 is CH; and X4 is CH. In some embodiments, X1 is CH, CF, or N; X2 is CH, CF, or N; X3 is CH; and X4 is CH.

[00154] In some embodiments, X1 is CH, CF, or N; X2 is CH or CF; X3 is CR13; and X4 is CH or CF. In some embodiments, X1 is CH, CF, orN; X2 is CH; X3 is CR13; and X4 is CH. In some embodiments, X1 is N; X2 is CH; X3 is CR13; and X4 is CH.

[00155] In some embodiments, X1 is CH or N; X2 is CH or N; X3 is CH, CF, or N; and X4 is CH or N. In some embodiments, X1 is CH or N; X2 is CH or N; X3 is CH or CF; and X4 is CH. In some embodiments, X1 is N; X2 is CH; X3 is CH or CF; and X4 is CH. In some embodiments, X1 is N; X2 is CH; X3 is CH; and X4 is CH. In some embodiments, X1 is N; X2 is CH; X3 is CF; and X4 is CH.

[00156] In some embodiments, R13 is hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted C3- Cecycloalkyl, -CN, or -OR4. In some embodiments, R13 is hydrogen, halogen, Ci-Ce alkyl, fluoroalkyl, unsubstituted C3-Cecycloalkyl, -CN, or -OR4. In some embodiments, R13 is hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, or cyclopropyl. In some embodiments, R13 is hydrogen or F. In some embodiments, R13 is hydrogen. In some embodiments, R13 is F.

[00157] In some embodiments, M is *-NR3-(C=O)- or *-(C=O)-NR3-, wherein * indicates the attachment point to R1

[00158] In some embodiments, RA is unsubstituted or substituted pyridinyl or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1 or 2 groups selected from Ra, Rb, and Rc.

[00159] In some embodiments, RB is unsubstituted or substituted phenyl, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf.

[00160] In some embodiments, Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Ra, Rb, and Rc is substituted with one or more R6 groups; or one Ra and one Rb, when present on adjacent atoms of RA, are taken together with the intervening atoms connecting Ra to Rb to form a 5- to 6-membered monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and Rd, Re, and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, -C(=O)N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd, Re, and Rf is substituted with one or more R6 groups; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00161] In some embodiments, Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, wherein any substituted group of Ra is substituted with one or more R6 groups; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl, wherein any substituted group of Rb and Rc is substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl.

[00162] In some embodiments, Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and Rb and Rc are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2.

[00163] In some embodiments, one Ra and one Rb on adjacent atoms of RA are taken together with the intervening atoms connecting Ra to Rb to form a 5- to 6-membered monocyclic cycloalkyl or 5- to 6-membered monocyclic heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more R6 groups. In some embodiments, one Ra and one Rb on adjacent atoms of RA are taken together with the intervening atoms connecting Ra to Rb to form a 5-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more R6 groups.

[00164] In some embodiments, Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl.

[00165] In some embodiments, Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; and Re and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2.

[00166] In some embodiments, Ra is unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, wherein any substituted group of Ra is substituted with one or more R6 groups; Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl, wherein any substituted group of Rb and Rc is substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; X1isCR11orN; X2 is CR12 orN; X3 is CR13 orN; X4 is CR14 orN; R11, R12, R13, and R14 are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, or Ci-Ce heteroalkyl, -CN, -OR4, or -N(R4)2; M is *-NR3-(C=O)- or *-(C=O)-NR3-, wherein * indicates the attachment point to R1; R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C? heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00167] In some embodiments, Ra is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if Rb is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; X1 is CH orN; X2isCH orN; X3 is CR13 orN; X4isCH orN; M is *-NR3-(C=O)- or *-(C=O)-NR3-, wherein * indicates the attachment point to R1; R11, R12, R13, and R14 are each independently hydrogen, F, Cl, -CH3, CF3, -CN, -OR4, or -N(R4)2; R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5; or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R1 is unsubstituted or substituted bridged C2-C? heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00168] In some embodiments, Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl; II RB is Rd W Re where W is CH or N; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl; X1 is CH, CF, orN; X2isCH, CF, orN; X3 is CH, CF, orN; X4isCH, CF, orN; M is *-NH-(C=O)- or *-(C=O)-NH-, wherein * indicates the attachment point to R1; R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C? heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00169] In some embodiments, X RA is R * , where V is CH or N; Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and Rb and Rc are independently selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3; RB is Rd W Re where W is CH or N; Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; Re and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, and -OCH3; X1 is CH orN; X2 is CH orN; X3 is CH, CF, orN; X4 is CH orN; M is *-NH-(C=O)- or *-(C=O)-NH-, wherein * indicates the attachment point to R1; R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00170] In some embodiments, the compound has the structure of Formula (IX), or a pharmaceutically acceptable salt, or solvate thereof: Formula (IX) wherein, Ra is unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, wherein any substituted group of Ra is substituted with one or more R6 groups; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl, wherein any substituted group of Rb and Rc is substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; X1isCR11orN; X2 is CR12 orN; R11 and R12 are each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, or Ci-Ce heteroalkyl, -CN, -OR4, or -N(R4)2; M is -NR3-, -O-, *-NR3-(C=0)-, *-(C=0)-NR3-, *-0-(C=0)NR3-, *-NR3-(C=0)0-, or -NR3-(C=0)NR3-, wherein * indicates the attachment point to R1; and R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00171] In some embodiments, Ra is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if Rb is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; X1isCR11orN; X2 is CR12 orN; R11 and R12 are each independently hydrogen, F, Cl, -CH3, CF3, -CN, -OR4, or -N(R4)2; R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5; or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00172] In some embodiments, the compound has the structure of Formula (IXa), or a pharmaceutically acceptable salt, or solvate thereof: Formula (IXa) wherein, Ra is unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl, wherein any substituted group of Ra is substituted with one or more R6 groups; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl, wherein any substituted group of Rb and Rc is substituted with one or more R6 groups; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted Ci-Ce heteroalkyl; wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; XHsCR^rN; R11 is hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, or Ci-Ce heteroalkyl, -CN, -OR4, or -N(R4)2; M is -NR3-, -O-, *-NR3-(C=0)-, *-(C=0)-NR3-, *-0-(C=0)NR3-, *-NR3-(C=0)0-, or -NR3-(C=0)NR3-, wherein * indicates the attachment point to R1; and R1 is unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms; or R1 is unsubstituted or substituted bridged C2-C? heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00173] In some embodiments, Ra is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc; wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted Ci-Ce alkyl; Rb is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if Rb is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf; X1isCR11orN; R11 is hydrogen, F, Cl, -CH3, CF3, -CN, -OR4, or -N(R4)2; R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5; or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycloalkyl containing 1-2 N atoms.

[00174] In some embodiments, RA is where V is CH or N; and RB is Ra Rc Re In some embodiments, RA is

[00175] Re where W is CH or N.

[00176] In some embodiments, RA is

[00177] In some embodiments, RA is

[00178] In some embodiments, RA is or Ra is Ra where W is CH or N. Ra Rc Ra Rc Ra or Ra is ; and RB is ; and RB is , where V is CH or N; Re Re where W is CH or N. where W is CH or N. , where V is CH or N; and RB is where W is CH or N.

[00179] In some embodiments, the compound has the structure of Formula (X), or a pharmaceutically acceptable salt, or solvate thereof: Formula (X) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00180] In some embodiments, the compound has the structure of Formula (Xa), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xa) wherein: Ra and Rb are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00181] In some embodiments, Ra and Rb are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl.

[00182] In some embodiments, the compound has the structure of Formula (Xb), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xb) wherein: X1 is N; X2 is CH or N; and Rc is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[00183] In some embodiments, X2 is N. In some embodiments, X2 is CH.

[00184] In some embodiments, the compound has the structure of Formula (Xc), or a pharmaceutically acceptable salt, or solvate thereof: Rb Formula (Xc) wherein: Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00185] In some embodiments, the compound has the structure of Formula (Xd), or a pharmaceutically acceptable salt, or solvate thereof: Rb Formula (Xd) wherein: Ra and Rb are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; Rc is hydrogen, - WO 2021 / 126693                                                 PCT / US2020 / 064493 C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[00186] In some embodiments, Ra and Rb are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl; Rc is hydrogen, -C(=O)R7, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C3-C6 cycloalkyl.

[00187] In some embodiments, the compound has the structure of Formula (Xe), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xe) wherein: X1 is N; and Rc is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[00188] In some embodiments, the compound has the structure of Formula (XI), or a pharmaceutically acceptable salt, or solvate thereof: Formula (XI) wherein V is CH or N.

[00189] In some embodiments, the compound has the structure of Formula (Xia), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xia) wherein V is CH or N; Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00190] In some embodiments, Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; Rb and Rc are independently selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3.

[00191] In some embodiments, the compound has the structure of Formula (Xlb), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xlb) wherein: V is CH or N; X1 is N; and X2 is CH or N.

[00192] In some embodiments, X2 is N. In some embodiments, X2 is CH.

[00193] In some embodiments, the compound has the structure of Formula (XIc), or a pharmaceutically acceptable salt, or solvate thereof: Formula (XIc) wherein V is CH or N.

[00194] In some embodiments, the compound has the structure of Formula (Xld), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xld) wherein V is CH or N; Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00195] In some embodiments, Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and Rb and Rc are independently selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3.

[00196] In some embodiments, the compound has the structure of Formula (Xie), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xie) wherein: V is CH or N; and X1 is N.

[00197] In some embodiments, the compound has the structure of Formula (XII), or a pharmaceutically acceptable salt, or solvate thereof: Formula (XII).

[00198] In some embodiments, the compound has the structure of Formula (Xlla), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xlla) wherein: Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Rb is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00199] In some embodiments, Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and Rb is selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3.

[00200] In some embodiments, X1 is N; andX2 is CH or N. In some embodiments, X2 is N. In some embodiments, X2 is CH.

[00201] In some embodiments, the compound has the structure of Formula (Xllb), or a pharmaceutically acceptable salt, or solvate thereof: Rb Formula (Xllb).

[00202] In some embodiments, the compound has the structure of Formula (XIIc), or a pharmaceutically acceptable salt, or solvate thereof: Rb Formula (XIIc) wherein: Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-Ce cycloalkyl; and Rb is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00203] In some embodiments, Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and Rb is selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3.

[00204] In some embodiments, X1 is N; andX2 is CH or N. In some embodiments, X2 is N. In some embodiments, X2 is CH.

[00205] In some embodiments, the compound has the structure of Formula (XIII), or a pharmaceutically acceptable salt, or solvate thereof: Formula (XIII) wherein W is CH or N.

[00206] In some embodiments, the compound has the structure of Formula (Xllla), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xllla) wherein: WisCH orN; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00207] In some embodiments, Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; Re and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, and -OCH3.

[00208] In some embodiments, the compound has the structure of Formula (Xlllb), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xlllb) wherein: X1 is N; X2 is CH or N; W is CH or N; and Rd is selected from the group consisting of F, Cl, -CN, -OCH3, -CH3, -CH2F, -CHF2, and -CF3.

[00209] In some embodiments, X2 is N. In some embodiments, X2 is CH.

[00210] In some embodiments, the compound has the structure of Formula (XIIIc), or a pharmaceutically acceptable salt, or solvate thereof: wherein W is CH or N.

[00211] In some embodiments, the compound has the structure of Formula (Xllld), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xllld) wherein: W is CH or N; Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and Re and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, unsubstituted or substituted Ci-Ce alkyl, and unsubstituted or substituted Ci-Ce fluoroalkyl.

[00212] In some embodiments, Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; Re and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, and -OCH3.

[00213] In some embodiments, the compound has the structure of Formula (Xllle), or a pharmaceutically acceptable salt, or solvate thereof: Formula (Xllle) wherein: X1 is N; W is CH or N; and Rd is selected from the group consisting of F, Cl, -CN, -OCH3, -CH3, -CH2F, -CHF2, and -CF3.

[00214] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5; or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R1 is unsubstituted or substituted -(Ci-Ce alkyl)-(C2-C? heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[00215] In some embodiments, R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[00216] In some embodiments, R1 is unsubstituted or substituted Ci-Ce heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5.

[00217] In some embodiments, compounds described herein have the following structure:

[00218] In some embodiments, RA, RB, X1, X2, X3, X4, and R1 are as described herein.

[00219] In some embodiments, RA, RB, X1, X2, X3, X4, and R1 are as described in Table 1.

[00222] In some embodiments, X1 is CH or N. In some embodiments, X2 is CH or N. In some embodiments, X3 is CH, CF, or N. In some embodiments, X4 is CH or N.

[00223] In some embodiments, X1 is CH or N; X2 is CH or N; X3 is CH, or CF; and X4 is CH. In some embodiments, X1 is CH or N; X2 is CH; X3 is CH, or CF; and X4 is CH.

[00226] In some embodiments, RA, RB, X1, X2, X3, M and R1 are as described herein. In some embodiments, RA, RB, X1, X2, X3, M and R1 are as described in Table 2.

[00227] In some embodiments, RA is

[00228] In some embodiments, RB is CN or CN

[00229] In some embodiments, X1 is CH or N.

[00230] In some embodiments, X2 is CH or N.

[00231] In some embodiments, X3 is CH or CF.

[00232] In some embodiments, M is -O-, -NH-,

[00234] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[00235] Exemplary compounds of Formula (I) include the compounds described in the following Tables: Table 1: Cpd No. Ra X1 X2 X3 X4 RB R1 Cpd No. Ra X1 X2 X3 X4 RB R1 1-1 ( I CH CH CH CH ^^CF3 CN 1-2 ( I CH CH CH CH Of CN hnQ- 1-3 R O CH CH CH CH _^,CF3 or CN H2N^Xx^- 1-4 L I CH CH CH CH X^OF3 or CN HjN^^ 1-5 CH CH CH CH ^^CF3 or CN 1-6 ( I CH CH CH CH ^OF3 or CN HzN^^- 1-7 ( I CH CH CH CH _^,CF3 or CN H 1-8 L I CH CH CH CH X^OF3 or CN 1 1-9 ( I Oy N CH CH CH ^^CF3 J J rY CN ~^N0 1-10 N CH CH CH ^OF3 or CN hnC-3 1-11 p <, o N CH CH CH _^XF3 or CN "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1-12 ( I N CH CH CH ^^CF3 CN hn0^ 1-13 ( I N CH CH CH Of CN HzN^^ 1-14 R O N CH CH CH _^,CF3 or CN H 1-15 L I N CH CH CH X^OF3 or CN 1 1-16 N CH CH CH ^^CF3 or CN 1-17 ( I N CH CH CH ^OF3 or CN HO^ h2nz^x / ^ 1-18 ( I N CH CH CH _^,CF3 or CN 1-19 L I N CH CH CH X^OF3 or CN / nO^ 1-20 ( I Oy N CH CH CH ^^CF3 J J rY CN 1-21 CH N CH CH ^OF3 or CN hnC-3 1-22 p <, o CH N CH CH _^XF3 or CN Cpd No. Ra X1 X2 X3 X4 RB R1 1-23 ( I CH CH CH CH ^^CF3 YyN CN 1-24 ( I N CH CH CH ^^CF3 CN -3- 1-25 R O N CH CH CH ^^CF3 yX^N conh2 ^nQ' 1-26 L I N CH CH CH _^,CF3 CN 1-27 N CH CH CH ^^CF3 conh2 1-28 ( I N CH CH CH ,^XF3 Of CN H0^_ H2N'Z^Z^ 1-29 ( I CH CH CH CH CI^^^CFa jOi CN 1-30 rx0^ N CH CH CH X^^CF3 O| CN "NCy^ 1-31 rx0^ N CH CH CH ^^CF3 J J yY CN ~^NO 1-32 ( I N CH CH CH CN 1-33 ( I N CH CH CH ,^ / CF3 Cpd No. Ra X1 X2 X3 X4 RB R1 1-34 ( I N CH CH CH CN 1-35 ( I N CH CH CH n-Vcf’ UU^ 1-36 ( I N CH CH CH ^^.COCHa OT CN 1-37 L I N CH CH CH ^^.CFzH FJ CN "NCy^ 1-38 ( I ^S5 N CH CH CH FaC^^.CN 1-39 ( I N CH CH CH ^%f3 CN 1-40 ( I N CH CH CH NC^^CN jTj 1-41 L I N CH CH CH xd^CF3 CN *trans- '-■n'F OH 1-42 ( I ^S5 N CH CH CH NC^^.CFa I J Y^n 1-43 dr rd N CH CH CH d^CF3 OT CN ^NO 1-44 L I N CH CH CH _^XF3 F^ CN HO-^ H Cpd No. Ra X1 X2 X3 X4 RB R1 1-45 ( I N CH CH CH ^^CF3 CN HO^ xnzY / ^ 1-46 ( I N CH CH CH ^^CF3 Of CN *trans- -nQ^ '"OH 1-47 R Ru O N CH CH CH _^XF3 Of CN HO-. H 1-48 ^S5 N CH CH CH _^,CF3 Of CN HO-. ^n^Y^ 1-51 N CH CH N ^^CF3 O| CN 1-52 ( X N CH CH CH ^^CF3 Of CN "N\X 1-53 X^ / ° Uy N CH CH CH _^XF3 Of CN 1-54 N CH CH CH _^,CF3 Of CN ~^NO 1-55 ^oh Uy N CH CH CH ^^CF3 O| CN ~^NO 1-56 R <, o N N CH CH ^^CF3 Of CN 1-57 & o N N CH CH ^^CF3 OT CN ^nO Cpd No. Ra X1 X2 X3 X4 RB R1 1-58 ( I N CH CH N ^^CF3 CN 1-59 ( I N CH CH CH NC\X^^CF2CH3 jrj 1-60 OO N CH CH CH _^,CF3 Or CN 1-61 F ( J N CH CH CH X^^CF3 Or CN 1-62 di z 1 N CH CH CH ^^CF3 Or CN ~^NO 1-63 Oy N CH CH CH ,^XF3 Or CN 1-64 F o ^y N CH CH CH _^,CF3 Or CN 1-65 F a N CH CH CH X^^CF3 Or CN 1-66 or N CH CH CH ^^CF3 Or CN ~^NO 1-67 4 d-o v__y । / V-O % O -n ”V>         M N CH CH CH ,^XF3 Or CN ~^NC^ 1-68 F 1 JL F^^y N CH CH CH X^^CF3 Or CN Cpd No. Ra X1 X2 X3 X4 RB R1 1-69 rr N CH CH CH ^^CF3 FJ CN 1-70 N CH CH CH ,^XF3 Of CN -3- 1-71 Pf0'CF! Uy N CH CH CH _^XF3 Of CN ^nQ' 1-72 F N CH CH CH X^^CF3 O| CN 1-73 r=N N-— f JL N CH CH CH _^,CF3 Of CN ~^N0 1-74 F ( J N CH CH CH ^^CF3 O| CN ~^N0 1-75 ft <, o CH CH CF CH ^^CF3 Of CN 1-76 N CH CH CH _^XF3 Of CN / nU" 1-77 ^^.cf3 Uy N CH CH CH _^,CF3 JO CN ~^n0 1-78 / x / CN N CH CH CH ^^CF3 JO CN ~^N0 Cpd No. Ra X1 X2 X3 X4 RB R1 1-79 Of0' Oy N CH CH CH O^CF3 CN 1-80 / O°\ ( T s^y N CH CH CH ,^XF3 Of CN 1-81 X J N CH CH CH ZM / CF3 CN ~^NCX 1-82 F ( J ^^y N CH CH CH X^OCF3 CN 1-83 <Y N CH CH CH O^CF3 O| CN ~^NO 1-84 ^^.cf2ch3 ( J ^y N CH CH CH ,^XF3 Of CN 1-85 My N CH CH CH ZM / CF3 or CN ~^NCX 1-86 u U. N CH CH CH X^OCF3 Of CN "NCX 1-87 F X J F^^y N CH CH CH O^CF3 X J yY CN ~^NO 1-88 / N CH CH CH / ^OCF3 Of CN ~^NO 1-89 N CH CH CH ^OCF3 Of CN Cpd No. ra X1 X2 X3 X4 RB R1 1-90 N CH CH CH CN -nQ^ 1-91 ( J N CH CH CH CN -nQ^ 1-92 ( X N CH CH CH jC^^01 CN ^nCX 1-93 rx0^ ^X N CH CH CH CN ^nCX 1-94 (X N CH CH CH ^^CF3 FJ CN ^nCX 1-95 fX0^ ^X N CH CH CH Cl "NCX*^ 1-96 fX°^ ^X N CH CH CH or CN 1-97 fX0^ ^x N CH CH CH _^,CF3 Of Cl ■^N^X^ 1-98 ,N^O^ (X ^X N CH CH CH ^^CF3 J X yY CN ~^N0 1-99 fY FA^y N CH CH CH ^^CF3 O| CN ~^N0 1 100 o. A N CH CH CH ^^CF3 Of CN "NCy^ Cpd No. ra X1 X2 X3 X4 RB R1 1 101 F ( JL N CH CH CH ^^CF3 JOI CN ^nQj^ 1 102 X J N CH CH CH or CN 1 103 u U. N CH CH CH _^,CF3 or CN 1 104 CQ N CH CH CH X^OF3 or CN 1 105 nV NOy N CH CH CH ^^CF3 or CN ~^N0 1 106 ( I Y^y N CH N CH ^OF3 or CN ^NCX*^ 1 107 ( I Y^y N CH N CH _^,CF3 or CN ~^NCX 1 108 R Y o N CH CF CH X^OF3 or CN "NCX 1 109 ( I Oy N CH CF CH ^^CF3 X J Of^ CN 1 110 N CH CF CH X^OF3 yXfX CN ■^nQX^ 1 111 Oy N CH CH CH F^^-CI or CN "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 112 N CH CH CH ^^CF3 CN ~^NO 1 113 Ci N CH CH CH ,^XF3 Of CN ~^NC^ 1 114 Uy N CH CH CH _^,CF3 CN 1 115 —N ] N CH CH CH X^^CF3 jO| CN 1 116 o7 ] py N CH CH CH ^^CF3 O| CN 1 117 N CH CH CH ,^XF3 Of CN ~^NC^ 1 118 ( J N CH CH CH _^XF3 or CN 1 119 p N CH CH CH X^^CF3 Of CN "NCy^ 1 120 o'] yy N CH CH CH ^^CF3 1 J Yp CN 1 121 Ci N CH CH CH X^ / CF3 Y^r CN 1 122 41 N CH CH CH X^^CF3 y^Qi CN "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 123 N CH CF CH ^^CF3 fX CN ~^N0 1 124 N CH CF CH ,^XF3 Of CN "NCX*^ 1 125 fx°^ N CH CF CH CN 1 126 ( X N CH CF CH X^^CF3 O| CN "N0 1 127 (X ^X N CH CF CH ^^CF3 O| CN ^nQX^ 1 128 ( X ^x N CH CF CH ^^CF3 4? CN "NCX*^ 1 129 F X^xoh N CH CH CH _^,CF3 CN 1 130 l X ^^X N CH CH CH X^^CF3 Of CN "NO 1 131 ,N^Cy (X ^X N CH CF CH ^^CF3 J X y^ CN ~^N0 1 132 ,N^O\ (X ^^X N CH CF CH X^ / CF3 CN ^NCX*^ 1 133 .N^Cy (X N CH CF CH X^^CF3 CN "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 134 rx0^ N N CH CH CJ CN ^NCX*^ 1 135 N N CH CH ^^.Cl CN / nZX 1 136 N N CH CH _^,CF3 OT CN ^nCX 1 137 PpCN N CH CH CH X^^CF3 FJ CN 1 138 yv N CH CH CH ^^CF3 FJ CN ~^NO 1 139 ( I N N CH CH ^^.Cl FJ CN "NCX*^ 1 140 N N CH CH _^,CF3 or CN ^nCX 1 141 (X N CH CH CH X^^CF3 Of Cl "NCy^ 1 142 p <, o / N CH CH CH ^^CF3 Of Cl 1 143 H N CH CH CH ,^XF3 OT CN ^NCX*^ 1 144 N CH CH CH _^,CF3 or Cl "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 145 N CH CH CH ^^CF3 Of F ~^N0^ 1 146 0 N CH CH CH or CN "NCX*^ 1 147 41 N CH CH CH _^,CF3 or CN 1 148 F j^cn My N CH CH CH X^^CF3 or CN 1 149 7a N CH CH CH ^^CF3 or CN ~^N0^ 1 150 ( I N CH CH CH N^^3 Xt Cl "NCX*^ 1 151 ^^,cf2h (X N CH CH CH _^,CF3 CN "NCy^ 1 152 X N CH CH CH X^^CF3 or CN hnCX*^ 1 153 z o 1 N CH CH CH _^,CF3 OT CN —N(X 1 154 IX N CH CH CH X^^CF3 y^y Cl 1 155 1 X F^^y N CH CH CH ^^CF3 yJM Cl "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 156 N CH CH CH X^^CF3 Cl -nQ^ 1 157 z N CH CH CH ,^XF3 Of CN ~~nQP*^ 1 158 A "'V N CH CH CH _^,CF3 CN 1 159 (X CH CH CH CH _^XF3 Ol OMe 1 160 X N CH CH CH ^^CF3 O| Cl 1 161 / Naz N CH CF CH ,^ / CF3 Of CN ~~nQP*^ 1 162 X N CH CF CH .^,CF3 or Cl 1 163 pv N CH CF CH 7?° CN 1 164 ( I CH CH CH CH _^,CF3 XX 1 165 ( I CH CH CH CH ^^CF3 JO Y^^oi 1 166 (X N CH CH CH _^XF3 XX CN "NCy^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 167 p o / N CH CH CH ^^CF3 Cl 1 168 o. N N CH CH FJ CN ~~nQP*^ 1 169 rv N N CH CH X^^CF3 or Cl 1 170 Vy N N CH CH 7?° CN ~~NCy^ 1 171 r* N N CH CH ^^CF3 O| F 1 172 ( I N CH CH CH ^^CF3 or Cl 1 173 Pv N CH CH CH _^XF3 Of F 1 174 N N CH CH ^^CF3 Of F "NCy^ 1 175 op" N N CH CH ^^CF3 Of Cl 1 176 rx N CH CH CH ^^CF3 or CN 1 177 —V / z N CH CH CH _^XF3 OT CN Cpd No. Ra X1 X2 X3 X4 RB R1 1 178 z— / / °x N CH CH CH ^^CF3 CN 1 179 R < o / N CH CH CH ^^CF3 rj CN 1 180 ( I N CH CH CH _^,CF3 FJ CN 1 181 n^.cf2h N CH CH CH _^XF3 FJ CN "NCy^ 1 182 N^ / N CH CH CH X^^CF3 CN 1 183 ( J N N CH CH ^^CF3 fj CN 1 184 rv N CH CH CH _^XF3 FJ CN ° Eto^'^Or** 1 185 Vy N CH CH CH ^^CF3 FJ CN ° 1 186 ( I N CH CH CH X^^CF3 FJ F 1 187 nAz N CH CH CH ^^CF3 fj CN 1 188 rv N CH CH CH _^XF3 FJ CN n^e^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 189 f! N CH CH CH ^^CF3 CN 1 190 y7 N CH CH CH ^^CF3 rj CN 1 191 Afi N CH CH CH _^,CF3 FJ CN 1 192 N CH CF CH _^XF3 FJ F "NCy^ 1 193 is- N N CH CH X^^CF3 F 1 194 is N N CH CH ^^CF3 fj Cl 1 195 FAAy N CH CF CH _^XF3 FJ CN 1 196 L 1 N CH CF CH ^^CF3 FJ CN H 1 197 ( 1 N CH CF CH X^^CF3 FJ CN H        . 1 198 ( 1 N CH CF CH ^^CF3 fj CN 1 1 199 ( 1 N CH CF CH _^XF3 FJ CN Cpd No. Ra X1 X2 X3 X4 RB R1 1 200 ar N CH CF CH ^^CF3 F 1 201 ar N CH CF CH ^^CF3 F 1 202 ar N CH CF CH _^,CF3 Cl 1 203 ar N CH CF CH _^XF3 FJ Cl ^n^f^ 1 204 N CH CF CH X^^CF3 F 1 205 N CH CH CH ^^CF3 fj CN 1 206 N CH CH CH _^XF3 FJ CN H             ., 1 207 pa N CH CH CH ^^CF3 FJ CN 1                  5 1 208 o rv N CH CH CH X^^CF3 FJ CN 1 209 y N CH CF CH ^^CF3 fj CN 1 210 N CH CF CH _^XF3 FJ F Cpd No. Ra X1 X2 X3 X4 RB R1 1 211 N CH CH CH ^^CF3 CN 1 212 N CH CH CH ^^CF3 rj CN 1 1 213 N CH CH CH _^,CF3 FJ CN hn^^A. 1 214 N CH CH CH _^XF3 FJ CN H 1 215 / N CH CH CH X^^CF3 CN ^N^^Y2?. H 1 216 <fl N CH CH CH ^^CF3 fj CN 1 1 217 N CH CH CH _^XF3 FJ CN n^sYV / 1 218 / V^°\ N CH CH CH ^^CF3 FJ CN 1 219 / N CH CH CH X^^CF3 FJ CN xnO^ 1 220 <fl N CH CH CH ^^CF3 y^Qi CN 1 221 N CH CH CH X^^CF3 Y^r CN N^^ Cpd No. Ra X1 X2 X3 X4 RB R1 1 222 N CH CH CH ^^CF3 F i 1 223 ( I N CH CH CH ^^CF3 rj F H 1 224 ft N CH CH CH _^,CF3 FJ Cl 1 1 225 fa N CH CH CH _^XF3 FJ Cl H 1 226 N CH CH CH X^^CF3 F 1 1 227 N CH CH CH ^^CF3 fj F H 1 228 rr0^ N CH CH CH _^XF3 FJ Cl 1 1 229 yfa N CH CH CH ^^CF3 FJ CN / 1 230 ^y N CH CH CH X^^CF3 FJ Cl H 1 231 nAz N CH CH CH ^^CF3 fj CN ^P^xY H 1 232 yfa N CH CH CH _^XF3 FJ CN 1 Cpd No. Ra X1 X2 X3 X4 RB R1 1 233 r* N CH CH CH ^^CF3 CN 1 234 / Naz N CH CH CH ^^CF3 rj CN h2n''’^>Z 1 235 Pv N CH CH CH _^,CF3 FJ CN hn^v-A 1 236 ( J N CH CH CH _^XF3 FJ CN hn^'-' / zA 1 237 (J N CH CH CH _^XF3 FJ CN *cis-hn^Y^ 1 238 (J N CH CH CH ^s^CF3 fj CN *trans- ''F 1 239 A N CH CH CH ^^CF3 OT CN 1 240 pv N CH CH CH .^ / CF3 FJ CN 1 241 Pv N CH CH CH _^,CF3 JI J yY CN N^sY- / 1 242 ( J N CH CH CH ^^CF3 fj CN *cis- —N / pp*^’ SF Cpd No. Ra X1 X2 X3 X4 RB R1 1 243 (Jl N CH CH CH _^xCF3 OT CN *trans-^N\JJ^ 1 244 ( JL N CH CH CH ^^CF3 CN N-'J / xA / 1 245 X^-O^ ( JL N CH CH CH ^^CF3 Of CN 1 246 ( JL N CH CH CH ,^xCF3 O| CN F hPxA H 1 247 ( JL N CH CH CH / ^ / CF3 OT CN F H 1 248 pv N CH CH CH ^^CF3 or CN 1 249 / X / Ox L JL N CH CH CH ^^CF3 Of CN F \A^A / 1 250 ( JL N CH CH CH ,^ / CF3 O| CN F ^\J^xA / 1 251 pv N CH CH CH X^^CF3 or CN * 1 252 ( JL ^S5 N CH CH CH / ^ / CF3 Of CN * aC^* Cpd No. Ra X1 X2 X3 X4 RB R1 1 253 P* N CH CH CH ^^CF3 CN 1 254 ( J N CH CH CH ^^CF3 rj F ^N^AYt 1 1 255 ( JL N CH CH CH _^,CF3 FJ Cl 1 1 256 ( J N CH CH CH _^XF3 FJ F H 1 257 ( J N CH CH CH X^^CF3 Cl ^n^^Y2?. H 1 258 nAz N CH CH CH ^s^CF3 CN *cis- ^1^ 1 259 A N CH CH CH _^XF3 OT CN * trans- nh2 1 260 A N CH CH CH ^^CF3 OT CN ^N^^Y22- 1 i 1 261 P* N CH CH CH _^XF3 FJ CN ^n^aY^ 1 i 1 262 pv N CH CH CH _^XF3 FJ CN yY o Cpd No. Ra X1 X2 X3 X4 RB R1 1 263 r* N CH CH CH ^^CF3 CN 1 1 264 / Naz N CH CH CH ^s^CF3 CN *trans- ZzN^ / 1 265 <n A N CH CH CH ^^CF3 Of CN 1 1 266 N CH CH CH ^^CF3 O| CN Y-a 1 1 267 r* N CH CH CH X^^CF3 O| CN *cis- —N J Z,o^ 1 268 o. nAz N CH CH CH ^^CF3 or CN *trans- '''O^ 1 269 o nAz N CH CH CH ^^CF3 Of CN ~~nC^^ '"OH 1 270 pv N CH CH CH _^XF3 O| CN SOH 1 271 R o / N CH CH CH X^ / CF3 OT F 1 1 272 9 < o / N CH CH CH ^s^CF3 O| F ^N^aY^ H Cpd No. Ra X1 X2 X3 X4 RB R1 1 273 R < o / N CH CH CH ^^CF3 Cl 1 1 274 N CH CH CH ^^CF3 Cl H 1 275 rv N CH CH CH _^,CF3 CN HO. 1 1 276 Vy N CH CH CH _^XF3 FJ F 1 1 277 r* N CH CH CH X^^CF3 CN F / \ N 1 1 278 / Naz N CH CH CH ^^CF3 fj CN F. 1 1 279 Pv N CH CH CH _^XF3 FJ CN N^*^ 1 1 280 pv N CH CH CH ^^CF3 FJ CN FJ N^-"^ 1 1 281 Pv N CH CH CH _^XF3 1 J yY F ^n^^Y. H 1 282 nAz N CH CH CH ^^CF3 fj Cl 1 1 283 pv N CH CH CH _^XF3 FJ Cl ^N^^Y. H Cpd No. Ra X1 X2 X3 X4 RB R1 1 284 ( I N CH CF CH _^.CF3 OT F 1 1 285 ( JL N CH CF CH or F 1 1 286 ( JL N CH CF CH Or Cl 1 1 287 R o N CH CF CH _^XF3 F H 1 288 ( I N CH CF CH ^s^CF3 O| Cl ^n^^Yv 1 1 289 rr0^ N CH CF CH X^OF3 or F 1 1 290 N CH CF CH ^^CF3 Of F H 1 291 rx0^ N CH CF CH ^s^CF3 Of Cl ^N^^Y2!-1 1 292 rx0^ Oy N CH CF CH ^^CF3 J J Vy Cl H 1 293 ( JL Oy N CH CF CH ^^CF3 JO F ^N^^Y2!-H 1 294 (J Oy N CH CF CH _^XF3 y^y Cl ^n^^Y2^ H Cpd No. Ra X1 X2 X3 X4 RB R1 1 295 N CH CH CH _^.CF3 OT F 1 i 1 296 N CH CH CH _^,CF3 OT Cl 1 1 1 297 Pv N CH CH CH ^^CF3 F 1 i 1 298 P* N CH CH CH _^XF3 OT F H i 1 299 ( I N CH CF CH ^^CF3 Cl H 1 300 ,N^O^ ( I N CH CF CH ^^CF3 or F 1 1 301 X, o / N CH CF CH ^^CF3 Of F H 1 302 H N CH CF CH ^s^CF3 Cl 1 1 303 ,N^O^ CXZ N CH CF CH ^^CF3 1 J vy ci H 1 304 pv N CH CF CH ^^CF3 O[ F ^n^^Y-1 1 305 py N CH CF CH ,^XF3 Of F H Cpd No. Ra X1 X2 X3 X4 RB R1 1 306 N CH CH CH _^.CF3 OT F H i 1 307 N CH CH CH _^,CF3 OT Cl H i 1 308 R o N CH CF CH ^^CF3 CN 1 1 309 r* N CH CF CH X^^CF3 Cl 1 1 310 N CH CF CH ^^CF3 fj Cl H 1 311 ( I N CH CF CH ^^CF3 Of CN H 1 312 R o N CH CF CH ^^CF3 ^or F 1 i 1 313 ( I N CH CH CH _^XF3 O] CN 1 i 1 314 ( I N CH CH CH ^^CF3 Of CN H i 1 315 is N CH CF CH ^^CF3 Of F H i 1 316 N CH CH CH ,^XF3 Of CN H i Cpd No. Ra X1 X2 X3 X4 RB R1 1 317 ( I N CH CH CH _^.CF3 OT F 1 i 1 318 ( I N CH CH CH Of Cl 1 1 1 319 ( I N CH CF CH ^^CF3 ^Ol CN 1 i 1 320 ( I ^y N CH CF CH _^XF3 OT CN H i 1 321 ( I N CH CH CH X^^CF3 Of F H i 1 322 is N CH CH CH / ^Cl Of Cl H i 1 323 N^o^ / (I N CH CF CH CN ^N^r^ H 1 1 324 A N CH CF CH _^XF3 O| CN 1 i 1 325 OQ N CH CF CH ^^.Cl Of CN ■.V 1 1 1 326 Pv N CH CF CH ^^CF3 Of CN H 1 1 327 ( J N CH CH CH _^XF3 O| CN f^° Cpd No. Ra X1 X2 X3 X4 RB R1 1 328 ( X N CH CH CH yO CN .cf3 "N^ 1 329 ( X N CH CH CH yO CN xCF3 1 330 (X ^X N CH CH CH yO CN xCF3 \) 1 331 (X ^X N N CH CH Xf CN .cf3 ^n^X^ 1 1 332 (X ^X N CH CH CH Xf CN xCF3 1 333 Uk / N CH CH CH vO CN .cf3 XN' - 1 334 (X N CH CF CH yO CN xCF3 ^N' .OH 1 335 (X ^X N N CH CH Q F xCF3 1 *absolute stereochemistry has not been determined. **cis- & trans- were assigned tentatively.

[00236] Compounds in Table 1 are named: 1-1: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-2: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-3: N-(2-aminoethyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide; 1-4: N-[(2R)-2-aminopropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide; 1-5: N-(3-aminopropyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide; 1-6: N-[(2S)-2-aminopropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide; 1-7: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-8: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide; 1-9: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-10: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-11: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-12: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-13: N-(2-aminoethyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-14: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-15: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-16: N-[(2S)-2-aminopropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-17: N-[(2R)-2-amino-3-hydroxypropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-18: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(l-methylazetidin-3-yl)methyl]piperidine-4-carboxamide; 1-19: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-20: N-[(3S)-l-azabicyclo[2.22]octan-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-21: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-22: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-23: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-24: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-25: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3R)-l-methylpyrrolidin-3-yl]carbamoyl}piperidin-l-yl)-6-(trifluoromethyl)pyridine-2-carboxamide; 1-26: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-27: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3S)-l-methylpyrrolidin-3-yl]carbamoyl}piperidin-l-yl)-6-(trifluoromethyl)pyridine-2-carboxamide; 1-28: N-[(2S)-2-amino-3-hydroxypropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-29: l-[2-chloro-6-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-30: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-31: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-32: l-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-33: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]-l-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-34: l-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-35: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]-l-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide; 1-36: l-(4-acetyl-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-37: l-[2-cyano-4-(difluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-38: l-[4-cyano-2-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-39: l-[2-cyano-4-(trifluoromethoxy)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-40: l-(2,4-dicyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-41: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S,4S)*-4-hydroxy-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-42: l-[3-cyano-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-43: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-44: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2R)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide; 1-45: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-46: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R,4R)*-4-hydroxy-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-47: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide; 1-48: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-51: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-52: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-53: 1 - [2-cy ano-4-(trifluoromethyl)phenyl] -4- [6-(2,3 -dihydro-1 -benzofuran-7-yl)pyri din-3 -y 1 ] -N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-54: 4-[6-(l-benzofuran-7-yl)pyridin-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-55: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(hydroxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-56: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-57: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-58: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-59: l-[2-cyano-4-(l,l-difluoroethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-60: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-61: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-difluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-62: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-ethyl-lH-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-63: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[6-(2-propoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-64: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-65: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-66: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-67: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,2-difluoro-2H-l,3-benzodioxol-4-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-68: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-69: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-5-fluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-70: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[l-(3-methylbutyl)-lH-pyrazol-5-yl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-71: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}piperidine-4-carboxamide; 1-72: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-3-fluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-73: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-indazol-7-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-74: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-fluorophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-75: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)-3-fluorophenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-76: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-77: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethyl)phenyl]pyridin-3-yl}piperidine-4-carboxamide; 1-78: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyanophenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-79: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(methoxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-80: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methoxythiophen-2-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-81: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-82: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-83: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-84: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(l,l-difluoroethyl)phenyl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-85: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethoxy)-[2,3'-bipyridin]-5-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-86: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-87: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-88: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-89: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-90: l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-91: l-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-92: l-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-93: l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-94: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-95: l-(2,4-dichlorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-96: l-(2-cyano-4-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-97: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-98: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-99: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methylphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-100: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-101: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-102: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-103: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-104: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-105: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(4-methylpyrimidin-5-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-106: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-107: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-108: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-109: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-110: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-111: 1 -(4-chloro-2-cyano-6-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3 -yl]-N-[(3 S)-1 -methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-112: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[6-(2- m ethylthi ophen-3-yl)pyri din-3-yl]piperidine-4-carboxamide; 1-113: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-114: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethoxy)phenyl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-115: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-3-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-116: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-117: l-[2-cyano-4-(trifhioromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[6-(2-propylphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-118: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-119: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-120: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-121: l-[2-cyano-4-(trifhioromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-122: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]-4-[6-(2- m ethylthi ophen-3-yl)pyri din-3-yl]piperidine-4-carboxamide; 1-123: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-124: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-125: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-126: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-127: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-128: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3- yl]-N-[(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-129: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-hydroxyphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-130: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxy-5-methylphenyl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-131: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-132: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-133: l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-134: l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-l- methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-135: l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-136: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-137: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(cyanomethyl)phenyl]pyridin-3-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-138: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]-4-[6-(4- m ethylthi ophen-3-yl)pyri din-3-yl]piperidine-4-carboxamide; 1-139: l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-l- methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-140: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-141: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-142: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-143: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]-4-[6-(lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-144: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-145: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-146: 4-[6-(2-acetylthiophen-3-yl)pyridin-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-147: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylthiophen-3-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-148: 4-[6-(2-cyano-3-fluorophenyl)pyridin-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-149: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methyl-l,2-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-150: l-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-151: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethyl)phenyl]pyridin-3-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-152: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-153: 4-[6-(5-cyano-l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-154: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-155: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-156: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-157: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-methyl-l,2-oxazol-4-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-158: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-cyclopropyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-159: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-l-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-160: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-161: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-IH-pyrrol-2-yl)pyri din-3-yl]-N-[(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-162: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-163: l-(4-chloro-2-cyanophenyl)-4-[5-fluoro-6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-164: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-l-[2-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-165: l-[3-chloro-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-166: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-167: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-168: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-169: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-170: l-(4-chloro-2-cyanophenyl)-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-171: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-172: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-173: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-174: 4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-175: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-176: 4-{[2,2'-bipyridin]-5-yl}-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-177: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methyl-[2,2'-bipyridin]-5-yl}-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-178: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methoxy-[2,2'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-179: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-180: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-cyclopropyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-181: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-182: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-cyclopropyl-l,3-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-183: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-184: ethyl (3S)-3-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-amido}pyrrolidine-l-carboxylate; 1-185: N-[(3S)-l-acetylpyrrolidin-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-186: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-187: N-[(3S)-l-azabicyclo[2.2.2]octan-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-188: N-[(3R)-l-azabicyclo[2.2.2]octan-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-189: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyquinolin-3-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-190: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-indol-7-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-191: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-indol-2-yl)pyridin-3-yl]-N-[(3R)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-192: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-193: 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-194: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-195: 1 - [2-cy ano-4-(trifluoromethyl)phenyl] -4- [5 -fluoro-6-(5 -fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-196: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-197: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide; 1-198: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-199: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-200: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-201: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-202: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-203: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-204: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-205: N-(3-aminopropyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-206: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide; 1-207: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-208: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-ethyl-lH-pyrrol-2-yl)pyridin-3-yl]-N- [(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-209: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}- N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-210: 4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide; 1-211: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(l-methylazetidin-3-yl)methyl]piperidine-4-carboxamide; 1-212: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2- methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-213: N-{[(2S)-azetidin-2-yl]methyl}-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2- methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-214: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-215: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-216: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(l-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-217: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-l-methylazetidin-2-yl]methyl}piperidine-4-carboxamide; 1-218: N-[(3S)-l-azabicyclo[2.22]octan-3-yl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-219: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-(l-methylazetidin-3-yl)piperidine-4-carboxamide; 1-220: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(l-methylazetidin-3-yl)methyl]piperidine-4-carboxamide; 1-221: N-{l-azabicyclo

[224] heptan-4-yl}-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-222: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-223: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-224: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-225: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-226: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-l-[2-fluoro-4- (trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-227: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-228: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-229: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-l-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide; 1-230: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-231: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}piperidine-4-carboxamide; 1-232: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-l-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide; 1-233: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(lS,3S)-3-aminocyclobutyl]piperidine-4-carboxamide; 1-234: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(lR,3R)-3-aminocyclobutyl]piperidine-4-carboxamide; 1-235: N-{[(2S)-azetidin-2-yl]methyl}-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-236: N-{[(2R)-azetidin-2-yl]methyl}-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-237: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-238: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-239: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(lS,3S)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide; 1-240: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(lR,3R)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide; 1-241: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-l-methylazeti din-2-yl]methyl}piperidine-4-carboxamide; 1-242: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoro-l-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-243: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoro-l-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-244: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-l-methylazetidin-2-yl]methyl}piperidine-4-carboxamide; 1-245: N-[2-(azetidin-l-yl)ethyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-246: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-247: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-248: N-[2-(azetidin-1 -yl)ethyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl- 1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-249: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-l-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-250: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-251: rac-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(lS,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide; 1-252: rac-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(lS,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide; 1-253: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-l,3-dimethylpyrrolidin-3-yl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-254: N-[2-(dimethylamino)ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-255: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2- methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-256: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-257: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-258: rac-N-[(lR,2S)-2-aminocyclopropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-259: rac-N-[(lR,2R)-2-aminocyclopropyl]-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-260: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-l-(dimethylamino)propan-2-yl]-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-261: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-262: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{3-[(dimethylamino)methyl]oxetan-3-yl}-4-[6-(1 -methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-263: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[l-(dimethylamino)cyclopropyl]methyl}-4-[6-(1 -methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-264: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-(dimethylamino)oxolan-3-yl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-265: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[ethyl(methyl)amino]ethyl}-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-266: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[cyclopropyl(methyl)amino]ethyl}-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-267: rac-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4R)-4-methoxy-l-methylpyrrolidin-3-yl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-268: rac-l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-methoxy-l-methylpyrrolidin-3-yl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-269: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-hydroxy-l-methylpyrrolidin-3-yl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-270: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-hydroxy-l-methylpyrrolidin-3-yl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-271: N-[2-(dimethylamino)ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-272: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-273: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-274: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-275: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-276: N-[2-(dimethylamino)ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-277: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-l-methylpyrrolidin-2-yl]methyl}-4-[6-(l -methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-278: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-l-methylpyrrolidin-2- yl]methyl}-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-279: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S)-4,4-difluoro-l-methylpyrrolidin-2- yl]methyl}-4-[6-(l -methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-280: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2R)-4,4-difluoro-l-methylpyrrolidin-2- yl]methyl}-4-[6-(l -methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-281: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-282: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(l-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-283: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-284: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-285: N-[2-(dimethylamino)ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-286: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2- methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide; 1-287: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-288: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-289: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-290: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-291: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2- ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxamide; 1-292: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-293: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-294: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-295: N-[(2S)-l-(dimethylamino)propan-2-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'- methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-296: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'- methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-297: N-[(2S)-l-(dimethylamino)propan-2-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-298: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-299: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-300: N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-301: 4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-302: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'- methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-303: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-304: N-[2-(dimethylamino)ethyl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-305: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-306: l-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-307: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-308: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3- fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-309: l-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(l- methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-310: l-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-311: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; 1-312: N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-313: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'- ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-314: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-315: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-316: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-317: N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide; 1-318: l-(2,4-dichlorophenyl)-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-319: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-320: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-321: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-l-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-322: l-(2,4-dichlorophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-l- (methylamino)propan-2-yl]piperidine-4-carboxamide; 1-323: l-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-324: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-[5-fluoro-6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide; 1-325: l-(4-chloro-2-cyanophenyl)-N-[(2S)-l-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-326: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(l-methyl-IH-pyrrol-2-yl)pyri din-3-yl]-N-[(2S)-l-(methylamino)propan-2-yl]piperidine-4-carboxamide; 1-327: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide; 1-328: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3S)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide; WO 2021 / 126693                                                 PCT / US2020 / 064493 1-329: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3R)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide; 1-330: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide; 1-331: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2- ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxamide; 1-332: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-333: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-334: l-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide; 1-335: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide. Cpd No. Ra X1 X2 X3 RB R1 -M- 2-1 R o CH CH CH ^CF3 CN 1 -0- 2-2 R o CH CH CH CN 1 0 AnAA * H 2-3 CH CH CH CN 0 X^A x H * 2-4 ( I N CH CH CN 0 x^A x H * Cpd No. Ra X1 X2 X3 RB R1 -M- 2-5 Il I N CH CH CN H 0 Y^A V H * 2-6 .N^O^ / ( I N CH CH ^CF3 CN hnQa 0 y^A x H * 2-7 R O N CH CH ^CF3 CN -OA 0 Y^N^ X H * 2-8 R o N CH CH CN 0 y^A x H * 2-9 N CH CH CN 0 y^A V H * 2-10 Il I N CH CH ^^ / CF3 CN 1 0 y^A x H * 2-11 R K, o CH CH CH CN 6a 0 y^A x H * 2-12 R o CH CH CH CN 0 AAA * H 2-13 R o CH CH CH CN ^■y 0 AAA * H 2-14 Il I N CH CH ^^ / CF3 CN -NH- 2-15 R K, o N CH CH CN H -NH- Cpd No. Ra X1 X2 X3 RB R1 -M- 2-16 Il I CH CH CH CN ^nCT^ 0 AA V H * 2-17 .N^O^ / ( I CH CH CH ^CF3 CN 1 s 0 \Ana x H * 2-18 R O N CH CH ^CF3 CN -Oy 0 *        H 2-19 R o N CH CH CN 0 * H H 2-20 Il I N CH CH CN -Oy 0 * H H 2-21 .N^O^ / ( I N CH CH ^CF3 CN H y\ A zNy NX 0 \Ana x H * 2-22 R K, o N CH CH ^CF3 CN —-N^k^y 0 *        H 2-23 R o N CH CH CN ^N^^ H 0 x H * 2-24 R o N CH CH CN H A / "■0 0 H * 2-25 ^S5 N CH CH / ^Cl Fj CN ^nCT^ 0 x H * 2-26 R K, o N CH CH CN 1 K / N^A 0 \Ana x H ★ Cpd No. Ra X1 X2 X3 RB R1 -M- 2-27 N CH CH CN 0 yA V H * 2-28 N CH CH / ^Cl jTj CN 0 X^A x H * 2-29 rr0^ N CH CH CN -0A 0 X^A X H * 2-30 N CH CH / ^Cl ^OT CN 1 0 X^A x H * 2-31 rr0^ N CH CH / ^ / Cl JTT CN 1 \ zNV\ 0 yA V H * 2-32 ( I N CH CH ^^ / CF3 CN 0 X^A x H * 2-33 rr0^ N CH CH CN -0A 0 X^A x H * 2-34 CT0^ ^y N CH CH CN 1 \ 0 \AA x H * 2-35 rr0^ N CH CH CN / nZT^ 0 yA H * 2-36 ^y N CH CH ^^ / CF3 CN 1 0 yA x H * 2-37 (I ^y N CH CH ^.Cl CN 0 yA x H * Cpd No. Ra X1 X2 X3 RB R1 -M- 2-38 Il I N CH CH JTT CN 1 \ / N^Y 0 Y>A V H * 2-39 .N^O^ / ( I N CH CH / ^Cl CN 0 Y^A x H * 2-40 ,N^O^ ( I N CH CH ^CF3 CN ^nZZ^ 0 P>A X H * 2-41 P* N CH CH CN -OA 0 aAn^ * H 2-42 pv N CH CH CN 0 APA^ * H 2-43 Cl A N CH CH ^F3 CN 0 ■^N^N^ * H H 2-44 P* N CH CH CN 0 P>A X H * 2-45 Cl A N CH CH CN ^nCP^ 0 pA x H * 2-46 py N CH CH CN 0 pA H * 2-47 py N CH CH ^^ / CF3 CN 'OA 0 pA x H * 2-48 py N CH CH CN 0 * H H Cpd No. Ra X1 X2 X3 RB R1 -M- 2-49 ( J N CH CF CN 0 *        H 2-50 ( JI N CH CF ^CF3 CN 'OA 0 Aq^N^ *        H 2-51 N CH CF ^CF3 CN "NvJl^ 0 * H H 2-52 ( JI N CH CF CN ~OA 0 * H H 2-53 ( JI N CH CH CN 0 Aq^N^ *        H 2-54 ( JI N CH CH ^CF3 CN 'OA 0 *        H 2-55 LAZ N CH CH ^CF3 CN "NvJl^ 0 An^N^ * H H 2-56 ( JI ^S5 N CH CH CF3 CN ~OA 0 An^nA * H H 2-57 ( JI ^S5 N CH CH ^ / Cf3 Yy CN 1 0 Aq^nA *        H 2-58 ( JI N CH CH ^CF3 CN 1 0 An^N^ * H H 2-59 ( JI N CH CH ^CF3 CN / nH"^ 0 * H H Cpd No. Ra X1 X2 X3 RB R1 -M- 2-60 ( J N CH CH CN 0 Y^A V H * 2-61 ( JI N CH CF ^CF3 CN 1 . / N^ 0 x H * 2-62 N CH CF ^CF3 CN 1 0 Y^A X H * 2-63 ( J N CH CF CN H 0 Y^A x H * 2-64 R O N N CH CN 1 0 y^A V H * * attachment point to R1

[00237] Compounds in Table 2 are named: 2-1: 2-{4-[2-(dimethylamino)ethoxy]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-l-yl}-5-(trifluoromethyl)benzonitrile; 2-2: l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl N-[2-(dimethylamino)ethyl]carbamate; 2-3: 3-amino-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3- yl)phenyl]piperidin-4-yl}propanamide; 2-4: 3-amino-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}propanamide; 2-5: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperi din-4-yl}-3-(methylamino)propanamide; 2-6: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5- yl}piperidin-4-yl}pyrrolidine-3-carboxamide; 2-7: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5- yl }piperidin-4-yl} -1 -methylpyrrolidine-3 -carboxamidev; 2-8: (3S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide; 2-9: (3S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-10: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(dimethylamino)propanamide; 2-11: (2S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl} -1 -methylpyrrolidine-2-carboxamide; 2-12: (3R)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl} carbamate; 2-13: (3S)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl} carbamate; 2-14: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-[(2-hydroxyethyl)amino]piperidin-l-yl)-5-(trifluoromethyl)benzonitrile; 2-15: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[2-(methylamino)ethyl]amino}piperidin-l-yl)-5-(trifluoromethyl)benzonitrile; 2-16: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl} -1 -methylazetidine-3 -carboxamide; 2-17: (2R)-N- {1 - [2-cyano-4-(trifluoromethyl)phenyl] -4- [4-(2-ethoxypyridin-3 -yl)phenyl]piperidin-4-yl} -1 -methylpyrrolidine-2-carboxamide; 2-18: (3S)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate; 2-19: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea; 2-20: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperi din-4- yl} -3 -[(3 S)-1 -methylpyrrolidin-3 -yl]urea; 2-21: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5- yl }piperidin-4-yl} -3 -(methylamino)pyrrolidine-1 -carboxamide; 2-22: (3R)-1-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate; 2-23: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4- yl} -3 -(methylamino)azetidine-1 -carboxamide; 2-24: (3S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5- yl }piperidin-4-yl} -3 -(methylamino)pyrrolidine-1 -carboxamide; 2-25: N-[l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-l- methylazetidine-3-carboxamide; 2-26: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-2-(dimethylamino)acetamide; 2-27: (3S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-28: (3S)-N-[l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-l-methylpyrrolidine-3-carboxamide; 2-29: (3R)-N-[l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-l-methylpyrrolidine-3-carboxamide; 2-30: N-[l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-3-(dimethylamino)propanamide; 2-31: N-[l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-2-(dimethylamino)acetamide; 2-32: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperi din-4-yl} -1 -methylazetidine-3 -carboxamide; 2-33: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-34: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide; 2-35: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl} -1 -methylazetidine-3 -carboxamide; 2-36: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide; 2-37: N-[l-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-l-methylazetidine-3-carboxamide; 2-38: N-[l-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-2-(dimethylamino)acetamide; 2-39: (3S)-N-[l-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-l-methylpyrrolidine-3-carboxamide; 2-40: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl} -1 -methylazetidine-3 -carboxamide; 2-41: (3R)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate; 2-42: (3S)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate; 2-43: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl} -3 -[(3 S)-1 -methylpyrrolidin-3 -yl]urea; 2-44: (3 S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}pyrrolidine-3-carboxamide; 2-45: N-{ l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l -methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-l-methylazetidine-3-carboxamide; 2-46: (3 S)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-IH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-47: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l-methyl-lH-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-48: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(l -methyl-IH-pyrrol -2-yl)pyridin-3- yl]piperidin-4-yl}-3-[(3R)-l-methylpyrrolidin-3-yl]urea; 2-49: (3 S)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} carbamate; 2-50: (3R)-1-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} carbamate; 2-51: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} -3 -[(3 S)-1 -methylpyrrolidin-3 -yl]urea; 2-52: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-l-methylpyrrolidin-3-yl]urea; 2-53: (3S)-l-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} carbamate; 2-54: (3R)-1-methylpyrrolidin-3-yl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} carbamate; 2-55: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} -3 -[(3 S)-1 -methylpyrrolidin-3 -yl]urea; 2-56: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea; 2-57: 2-(dimethylamino)ethyl N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} carbamate; 2-58: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[2-(dimethylamino)ethyl]urea; 2-59: l-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl} -3 -(1 -methylazeti din-3 -yl)urea; 2-60: (3R)-N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyri din-3-yl]piperidin-4-yl}-l-methylpyrrolidine-3-carboxamide; 2-61: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide; 2-62: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide; 2-63: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(methylamino)propanamide; 2-64: N-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide.

[00238] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[00239] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[00240] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an 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. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the saltforming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[00241] 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. free base form) is basic and is reacted with an organic acid or an 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; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic 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.

[00242] In some embodiments, a compound of Formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[00243] 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, an acidic proton of the compound of Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[00244] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[00245] The methods and formulations described herein include the use of A-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity.

[00246] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formula (I) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[00247] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[00248] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but 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 usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36C1, 123I, !24I, i23I, 1311,32P and 33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[00249] In some embodiments, the compounds of Formula (I) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I) exists in the R configuration. In some embodiments, the compound of Formula (I) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, 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.

[00250] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds of Formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[00251] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[00252] 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, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[00253] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I) as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.

[00254] In some embodiments, any one of the hydroxyl group(s), amino group(s) and / or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[00255] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[00256] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Synthesis of Compounds

[00257] Compounds of Formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[00258] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[00259] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[00260] In some embodiments, compounds described herein are prepared as described in Scheme A. Scheme A a) RbX, Pd(lI), or RBX, DIEA; b) RAB(OH)2, Pd(DtBPF)CI2, K2CO3, Dioxane / H2O; c) LiOH, EtOH; c) R1NH2, HATU, TEA; e) deprotection

[00261] Commercially available XVIII is converted to compound XIX by either a standard SnAt reaction with RBX or Buchwald-Hartwig cross coupling reaction with RBX. Subsequently, introduction of RA by Suzuki-Miyaura coupling reaction with RAB(OH)2 or Stille coupling with RASnBu3 yield compound XX. Hydrolysis of the ester to the acid XXI and then HATU-mediated amide coupling reaction with R1NH2 produce the final compound XXII. If R1 contains a protecting group, then an additional deprotection step takes place to produce XXII.

[00262] In some embodiments, compounds described herein are prepared as described in Scheme B. Scheme B H XXVIII                        XXIX a) W-benzyl-2-bromo-W-(2-bromoethyl)ethan-1-amine, KOH; b) RAB(OH)2, Pd(DtBPF)CI2, K2CO3, Dioxane / H2O; c) Pd(OH)2, Pd / C, H2; d) RBX, DIEA, or RBX, Pd(ll);e) LiOH, MeOH; f) R1NH2, HATU, TEA; g) deprotection

[00263] Methyl 2-(6-chloropyridin-3-yl)acetate efficiently undergoes a one-pot reaction with N-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine in the presence of a strong inorganic base such as KOH to produce the piperidinyl intermediate XXIII. Subsequently, introduction of RA by Suzuki-Miyaura coupling reaction with RAB(0H)2 and then de-benzylation yield compound XXIV. Rb is introduced by either a standard SNAr reaction with RBX or Buchwald-Hartwig cross coupling reaction with RBX and followed by hydrolysis to yield the acid XXV. Variation of R1 in the final XXX is achieved by HATU-mediated coupling reaction with R1NH2. Starting from the intermediate XXIII, introduction of various 5- and 6-membered aromatic rings for RA (XXVI-XXVII-XXX) and diverse RB (XXVIII-XXIX-XXX) is accomplished by change of the reaction sequence as described in the scheme. If R1 contains a protecting group, then an additional deprotection step takes place to produce XX.

[00264] In some embodiments, compounds described herein are prepared as described in Scheme C. Scheme C HO 0 XXXV a) Pd(DTBPF)CI2, KF, DMSO / H2O; b) KF, MeOH / H2O; c) A / -benzyl-2-bromo- / V-(2-bromoethyl) ethan-1-amine, KOH; d) RAB(OH)2, PdAMPhos, K2CO3, Dioxane / H2O; e) KOH, EtOH, H2O; f) R1NH2, HATU, TEA; g) Pd(OH)2, Pd / C, H2; h) RBX, DIEA, or RBX, Pd(ll); i) deprotection

[00265] The cyanomethylation of 5-bromo-2-chloro-3-fluoropyridine to XXXII efficiently proceeds through Suzuki-Miyaura coupling reaction with isoxazole-4-boronic acid pinacol ester, base-induced fragmentation, and deformylation. The nitrogen-containing heterocycle XXXIII is obtained from cyclocondensation of XXXII with / V-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine in a strong alkaline medium. Starting from the intermediate XXXIII, introduction of various RB and R1 in the final XXXVI is achieved through the intermediate XXXIV and XXXV, respectively. The reaction conditions for each route are similar to those described in the previous scheme. If R1 contains a protecting group, then an additional deprotection step takes place to produce XXXVI.

[00266] In some embodiments, compounds described herein are prepared as described in Scheme D. Scheme D a) Cs2CO3, DMSO; b) TFA, DCM; c) N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine, KOH; d) RAB(OH)2, PdAMPhos, K2CO3, Dioxane / H2O; e) Pd(OH)2, Pd / C, H2; f) RBX, DIEA, or RBX, Pd(ll); g) R1NH2, LiHMDS; h) deprotection

[00267] Dichloro pyridazine or pyrazine is converted to the acetate XXXVII through formation of the malonate adduct and then removal of Zc / 7-buty I oxy carbonyl group in an acidic condition. Starting from XXXVII, the intermediate XL is prepared by a similar manner as described in Scheme B. Due to chemical instability of the acid of XL, the amide bond is directly introduced by Sn2 reaction of the ester with R1NH2 / LiHMDS. If R1 contains a protecting group, then an additional deprotection step takes place to produce XLI.

[00268] In some embodiments, compounds described herein are prepared as described in Scheme E. Scheme E a) RaB(OH)2, PdAMPhos, K2CO3, Dioxane / H2O; b) MsCI, TEA; c) NaCN, DMSO; d) N-benzyl-2-bromo -N-(2-bromoethyl)ethan-1-amine, KOH; e) KOH, EtOH; f) R1NH2, HATU, TEA; g) Pd(OH)2, Pd / C, H2; h) RbX, DIEA, or RBX, Pd(ll); i) deprotection

[00269] The cyanomethyl substituted pyrimidine XLII is obtained from a three-step sequence, Suzuki coupling, mesylation, and cyanation. Starting from XLII, the final compound XLVI is prepared by a similar manner as described in Scheme C. If Rf contains a protecting group, then an additional deprotection step takes place to produce XLVI.

[00270] In some embodiments, compounds described herein are prepared as described in Scheme F. Scheme F a) DPPA, TEA, tol, BnOH, 4A MS ; b) Pd(OH)2, Pd / C, H2; c) R1NH2, HATU, TEA; d) deprotection; e) triphosgene, tol; f) R1OH, 4A MS; g) R1R3NH, TEA, toluene.

[00271] Curtius Rearrangement by the reaction of XXV with diphenylphosporyl azide (DPPA) yields the isocyanate intermediate, which is subjected to in situ trapping of benzyl alcohol to produce XLVII. Deprotection to XLVIII and then HATU-mediated coupling reaction with R1NH2 yield the final XLIX. The isocyanate L derived from XLVIII undergoes Sn2 reaction with various nucleophiles such as alcohols (R’OH) and amines (R’R'NH) to yield carbamate (LI) or urea (LII) derivatives, respectively. If Rf contains a protecting group in XLIX, LI, and LII, then an additional deprotection step is required for the final product.

[00272] In some embodiments, compounds described herein are synthesized as outlined in the Examples. Certain Terminology

[00273] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[00274] As used herein, Ci-Cx includes C1-C2, C1-C3. . . Ci-Cx. By way of example only, a group designated as "Ci-Ce" indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, / / -butyl, Ao-butyl, sec-butyl, and / -butyl.

[00275] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-135- Cioalkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Cealkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[00276] An “alkylene” group refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkelene is a Ci-Cealkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[00277] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[00278] The term “alkylamine” refers to the -N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[00279] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a Ci-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[00280] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a Ci-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[00281] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Nonlimiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[00282] 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=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -OCCH3 -OCCH2CH3, -CH2C=CH.

[00283] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ceheteroalkyl.

[00284] The term “aromatic” refers to a planar ring having a delocalized K-electron system containing 4n+2 71 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 which share adjacent pairs of carbon atoms) groups.

[00285] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, a carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, a carbocycle is a monocyclic carbocycle. Carbocycles are non-aromatic or aromatic. Non-aromatic carbocycles are 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 aryls and cycloalkyls.

[00286] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahyodronaphthyl. In some embodiments, an aryl is a Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[00287] The term “cycloalkyl” refers to a monocyclic, bicyclic or polycyclic aliphatic, nonaromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl, norbornenyl, bicycle[l.l.l]pentyl, adamantyl, norbomyl, norbomenyl, decalinyl, or 7,7-dimethyl-bicyclo[2.2.1]heptanyl. In some embodiments, a cycloalkyl is a Cs-Cecycloalkyl. In some embodiments, a 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, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[00288] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[00289] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-Cefluoroalkyl.

[00290] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. 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 are either C-attached (or C-linked) or TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) 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.

[00291] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclcic 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, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cgheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[00292] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, 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 ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[00293] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[00294] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[00295] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-Cecycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, C2-Ceheterocycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[00296] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[00297] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, 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 extend the activity of the target.

[00298] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[00299] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the 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 and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[00300] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[00301] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[00302] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[00303] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[00304] The terms “article of manufacture” and “kit” are used as synonyms.

[00305] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[00306] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. Pharmaceutical compositions

[00307] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[00308] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via 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), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[00309] 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 a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[00310] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as 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 binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. 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, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[00311] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multidose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[00312] Pharmaceutical compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[00313] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[00314] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[00315] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[00316] Pharmaceutical compositions suitable for topical administration include liquid or semiliquid 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, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[00317] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, 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 take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[00318] It should 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 those suitable for oral administration may include flavoring agents. Methods of Dosing and Treatment Regimens

[00319] In one embodiment, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of melanocortin receptor activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of Formula (I) or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[00320] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, 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, a dose escalation and / or dose ranging clinical trial.

[00321] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[00322] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[00323] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00324] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[00325] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00326] In one embodiment, the daily dosages appropriate for the compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be 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 practitioner.

[00327] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and EDso. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[00328] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[00329] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[00330] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Treatments

[00331] In certain instances, it is 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.

[00332] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[00333] In one specific 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.

[00334] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[00335] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[00336] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[00337] The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence 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 the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.

[00338] Abbreviations: DIEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; Cui: copper(I) iodide; TBAF: tetra-n-butylammonium fluoride; P(t-Bu)3: tri-tert-buytlphosphine; HBF4: tetrafluoroboric acid; DBU: l,8-diazabicyclo[5.4.0]undec-7-ene; Prep-HPLC: preparative high performance liquid chromatography; TFA: tri fluoroacetic acid; CH3CN: acetonitrile; MeOD: deuterated methanol; CDCh: deuterated chloroform; DME: 1,2-dimethoxy ethane; H2O: water; KOAc: potassium acetate; NaOAc: sodium acetate; CS2CO3: cesium carbonate; P-TsOH: p-toluenesulfonic acid; NaNO2: sodium nitrate; THF: tetrahydrofuran; NBS: N-bromosuccinimide; 4A MS: 4A molecular sieves; DPPA: diphenyl phosphoryl azide; Bn: bromine; AgF: silver fluoride; LiAlH4: lithium aluminium hydride; WO 2021 / 126693                                                 PCT / US2020 / 064493 LiHMDS: lithium bis(trimethylsilyl)amide; IBX: 2-iodoxybenzoic acid; CDI: 1J'-carbonyldiimidazole; TEA: trimethylamine; HOBT: hydroxybenzotriazole; EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0); Pd(OH)2: palladium hydroxide; Pd(PPh3)2Ch: bis(triphenylphosphine)palladium(II) dichloride; Pd(dppf)C12: [1,1' -Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdAMphos or Pd (amphos)C12 or : bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(DTBPF)C12: [1,1 '-bis(di- / c / 7-butylphosphino)ferrocene]dichloropalladium('II); Pd2(dba)3 CHCh: tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct; XPhos: 2-dicyclohexylphosphino-2 ',4', 6'-trii sopropylbiphenyl; RuPhos-Pd-G3: dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane methanesulfonic acid palladium 2-phenylaniline; XPhos-Pd-G2: chloro(2-dicyclohexnylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II); rt: room temperature; h: hour or hours; Cpd: compound. EXAMPLES

[00339] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Synthesis of Compounds Example 1: N-(2-aminoethyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin- ^xljphenxlJjiijiendine^^^mljoxmnide^^

[00340] Step 1-1, preparation of methyl 4-(4-bromophenyl)-l-[2-cyano-4-(trifluoromethyl)phenyl1piperidine-4-carboxylate: Methyl 4-(4-bromophenyl)piperidine-4-carboxylate hydrochloride (500 mg, 1.49 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (706 mg, 3.74 mmol), DIEA (772 mg, 5.98 mmol), and DMSO (5 mL) were charged into a heavy-wall tube. The tube was sealed, and then the resulting solution was stirred at 125 °C for 16 h and cooled to rt. The reaction was directly purified by reverse phase Cl8 column chromatography to afford the title compound (600 mg, 86%). LCMS (M+H)+ = 467.3.

[00341] Step 1-2, preparation of methyl l-[2-cyano-4-(trifluoromethyl)phenyl1-4-[4-(2-ethoxypyridin-3-yl)phenyl1piperidine-4-carboxylate: Methyl 4-(4-bromophenyl)-l-[2-cyano-4-(trifluoromethyl)phenyl]piperidine-4-carboxylate (480 mg, 1.03 mmol), (2-ethoxypyridin-3-yl)boronic acid (343 mg, 2.05 mmol), PdAMphos (73 mg, 0.103 mmol), potassium carbonate (284 mg, 2.05 mmol), and dioxane / H2O (5 mL / 0.5 mL) were charged into a heavy-wall tube. The resulting mixture was degassed with N2 for 5 min, sealed, and stirred at 80 °C for 1 h. The reaction was cooled to rt, and concentrated. The residue was directly purified by reverse phase Cl8 column chromatography to afford the title compound (450 mg, 86%). LCMS (M+H)+ = 510.3.

[00342] Step 1-3, preparation of l-r2-cyano-4-(trifluoromethyl)phenyl1-4-r4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylic acid: To a suspension of methyl l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylate (450 mg, 0.883 mmol) in EtOH (8 mL) was added 2N-lithium hydroxide (4 mL, 8.83 mmol) at rt. The resulting mixture was stirred at 85 °C for 3 h and cooled to rt. After removal of the volatile solvent, the aqueous layer was filtered to remove inorganic solid. The aqueous filtrate was acidified to -pH 4 with 1N-HC1 to form ppts. The solid ppts were collected, washed with H2O, and dried to afford the title compound (270 mg, 62%). LCMS (M+H)+ = 496.1.

[00343] Step 1-4, preparation of tert-butyl N-[2-(l l-[2-cyano-4-(trifluoromethyl)phenyl1-4-r4-(2-ethoxypyridin-3-yl)phenyl1piperidin-4-ynformamido)ethyl1carbamate: To a solution of l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxylic acid (30 mg, 0.061 mmol) in ACN (1 mL) was added HATU (25 mg, 0.067 mmol) and TEA (12 mg, 0.12 mmol) at rt. After stirring for 5 min at rt, the reaction was treated with tert-butyl (2-aminoethyl)carbamate (12 mg, 0.073 mmol). The resulting solution was stirred at rt for 30 min, and then directly purified by reverse phase Cl8 column chromatography to afford the title compound (30 mg, 78%). LCMS (M+H)+ = 638.1.

[00344] Step 1-5, preparation of N-(2-aminoethyl)-l-[2-cyano-4-(trifluoromethyl)phenyl1-4-r4-(2-ethoxypyridin-3-yl)phenyl1piperidine-4-carboxamide: To a solution of tert-butyl N-[2-({l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperi din-4- yl}formamido)ethyl]carbamate (30 mg, 0.047 mmol) in DCM (0.4 mL) was added TFA (0.1 mL) at rt. The reaction was stirred at rt for Ih and concentrated under vacuum. The residue was purified by reverse phase C18 column chromatography to afford the title compound (18.5 mg, 73%). LCMS (M+H)+ = 538.4.

[00345] The following compounds were prepared similarly to Example 1 with appropriate substituting reagents and substrates at different steps. Some examples do not require deprotection in the final step. Compound no. MS (M+H)+ 1-1 578.3 1-2 564.4 1-4 552.3 1-5 552.3 1-6 552.2 1-7 552.4 1-8 566.3 Compound no. MS (M+H)+ 1-23 579.4 1-29 612.3 1-75 596.4 1-159 583.6 1-164 567.4 1-165 587.2 Example 2: l-[2-cyano-4-(trifluoromethyl)Dhenyl]-4-f2,-ethoxy-[3.,3,-biDyridin]-6-yn-N-[(3R)-l-methylDyrrolidin-3-yl]DiDeridine-4-carboxamide (cpd 1-22)

[00346] Step 2-1, preparation of 2-(5-chloropvridin-2-yl)acetonitrile: Into a 250-mL roundbottom flask, were placed 5-chloro-2-(chloromethyl)pyridine (8.0 g, 49 mmol), potassium cyanide (4.5 g, 69 mmol), EtOH (80 mL) and H2O (60 mL). The resulting mixture was stirred at 100 °C for 1 h and cooled to room temperature. The reaction was quenched with water (200 mL) and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to afford the title compound (4.3 g, 57%) as a yellow oil. LCMS (M+H)+ = 153.2.

[00347] Step 2-2, preparation of l-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile: To a solution of 2-(5-chloropyridin-2-yl)acetonitrile (2.0 g, 13 mmol) and N-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine (5.0 g, 16 mmol) in DMSO (20 mL) was added KOH (2.0 g, 36 mmol) at rt. The resulting mixture was stirred at 30 °C for 1 h and then quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in the title compound (2.0 g, 49%) as a yellow oil. LCMS (M+H)+= 312.0.

[00348] Step 2-3, preparation of l-benzvl-4-f2'-ethoxv-r3,3'-bipvridin]-6-vHpiperidine-4-carbonitrile: Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed l-benzyl-4-(5-chloropyridin-2-yl)piperidine-4-carbonitrile (1.0 g, 3.2 mmol), (2-ethoxypyridin-3-yl)boronic acid (1.0 g, 6.0 mmol), Pd(dppf)C12 (0.3 g, 0.4 mmol), K2CO3 (1.2 g, 8.7 mmol), and dioxane / H2O (10 mL / lmL). The resulting solution was stirred at 80 °C for Ih under N2 and cooled to room temperature. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (30:70) to afford the title compound (1.0 g, 78%) as a yellow oil. LCMS (M+H)+ = 399.1.

[00349] Step 2-4, preparation of l-benzvl-4-f2'-ethoxv-r3,3'-bipvridin]-6-vHpiperidine-4-carboxylic acid: Into a 50-mL round-bottom flask, were placed l-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carbonitrile (1.0 g, 2.5 mmol), KOH (1.0 g, 17.8 mmol), EtOH (10 mL) and H2O (10 mL). The resulting solution was stirred at 100 °C for 30 h, cooled to rt, and concentrated under vacuum. The residue was diluted with H2O, and then pH of the solution was adjusted to ~4 with 4M-HC1. The solid ppts were collected, washed with water, and dried to afford the title compound as a white solid (800 mg, 80%). LCMS (M+H)+ = 418.3.

[00350] Step 2-5, preparation of tert-butyl (3R)-3-(l-benzyl-4-f2'-ethoxy-[3,3'-bipyridin1-6-yll piperi dine-4-amido)pyrrolidine-1 -carboxylate: To a solution of l-benzyl-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-carboxylic acid (230 mg, 0.55 mmol) in DMF (4 mL) was added HATU (251 mg, 0.66 mmol) and DIEA (427 mg, 3.3 mmol) at rt. After stirring at rt for 5 min, the reaction was treated with tert-butyl (R)-3-aminopyrrolidine-l-carboxylate (123 mg, 0.66 mmol). The resulting solution was stirred at rt for 2 h and directly purified by Prep-HPLC to afford the title compound (230 mg, 71%) as a yellow solid. LCMS (M+H)+ = 586.3.

[00351] Step 2-6, preparation of tert-butyl (3R)-3-(4-f2'-ethoxv-r3,3'-bipvridin]-6-vHpiperidine-4-amido)pyrrolidine-l-carboxylate: Into a 50-mL round-bottom flask, were placed tert-butyl (3R)-3 -(1 -benzyl-4-{2'-ethoxy-[3,3' -bipy ri din]-6-y 1 } piperi dine-4-amido)pyrrolidine-1 -carboxylate (230 mg, 0.39 mmol), MeOH (10 mL), wet 10%-Pd / C (30 mg), and Pd(OH)2 (30 mg, 0.21 mmol). The reaction flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred at rt for 2 h under hydrogen (balloon). The reaction was diluted with MeOH, and filtered through a pad of Celite. The filtrate was concentrated under vacuum to afford the title compound (180 mg, 92%) as a yellow oil. LCMS (M+H)+ = 496.4.

[00352] Step 2-7, preparation of tert-butyl (3R)-3-(l-r2-cyano-4-(trifluoromethyl)phenyl1-4-(2'-ethoxv-r3,3'-bipvridin1-6-vHpiperidine-4-amidolpvrrolidine-l-carboxvlate: A solution of tertbutyl (3R)-3-(4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-amido)pyrrolidine-l-carboxylate (180 mg, 0.36 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (83 mg, 0.44 mmol), and DIEA (142 mg, 1.1 mmol) in DMSO (2 mL) was stirred 70 °C for 2 h. The reaction was cooled to rt and directly purified by Prep-HPLC to afford the title compound (190 mg, 78%) as a yellow solid. LCMS (M+H)+ = 665.3.

[00353] Step 2-8, preparation of l-[2-cyano-4-(trifluoromethvl)phenvl1-4-(2'-ethoxv-r3,3'-bipyridin1-6-yn-N-r(3R)-pyrrolidin-3-yl1piperidine-4-carboxamide (cpd 2-21): To a solution of tert-butyl (3R)-3-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}piperidine-4-amido}pyrrolidine-l-carboxylate (190 mg, 0.28 mmol) in DCM (2 mL) was added TFA (0.4 mL) at rt. The resulting mixture was stirred at rt for 2h and then diluted with H2O. The pH of the solution was adjusted to 8-9 with sat-NaHCCh. The solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford the title compound (130 mg, 80%) as a yellow solid. LCMS (M+H)+ = 565.2.

[00354] Step 2-9, preparation of l-[2-cyano-4-(trifluoromethvl)phenvl1-4-(2'-ethoxv-r3,3'-bipyridin1-6-yn-N-r(3R)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide formate: To a solution of l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide (55 mg, 0.097 mmol) in MeOH (2 mL) was added formaldehyde (20 mg, 0.67 mmol) and AcOH (6.0 mg, 0.10 mmol), and followed by sodium cyanotrihydroborate (12 mg, 0.19 mmol) at rt. The resulting solution was stirred at rt for 2 h, and then concentrated under vacuum. The residue was purified by Prep-HPLC to afford the title compound (20 mg, 33%) as a white solid. LCMS (M+H)+ = 579.3. Example 3: l-[2-cvano-4-(trifluoromethvl)phenvl]-4-[5-(2-ethoxvpvridin-3-vl)pvrazin-2-vl]-N-[(3R)-l-methvlpyrrolidin-3-vl]piperidine-4-carboxamide (cpd 1-51)

[00355] Step 3-1, preparation of 1-tert-butyl 3-ethyl 2-(5-chloropyrazin-2-yl)propanedioate: Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,5-dichloropyrazine (4.0 g, 27 mmol), cesium carbonate (26 g, 80 mmol), tert-butyl ethyl malonate (5.6 g, 30 mmol) and DMSO (40 mL). The resulting mixture was stirred 100 °C for 2 h and cooled to room temperature. The reaction was quenched with water (200 mL) and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in the title compound (4.6 g, 57%) as a yellow oil. LCMS (M+H)+ = 301.1.

[00356] Step 3-2, preparation of ethyl 2-(5-chloropyrazin-2-vl)acetate: To a solution of 1-tert-butyl 3-ethyl 2-(5-chloropyrazin-2-yl)propanedioate (4.6 g, 15 mmol) in DCM (40 mL) was added TFA (10 mL) in an ice bath. The reaction was stirred at 0 °C for 1 h and quenched with water (100 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3) to afford the title compound (2.6 g, 85%) as yellow oil. LCMS (M+H)+ = 201.1.

[00357] Step 3-3, preparation of ethyl l-benzyl-4-(5-chloropyrazin-2-yl)piperidine-4- carb oxy late: Into a 50 mL round-bottom flask, were placed ethyl 2-(5-chloropyrazin-2-yl)acetate (1.0 g, 5.0 mmol), 18-crown-6 (300 mg, 1.13 mmol) and DMF (10 mL). The reaction mixture was cooled to 0 °C and then treated with 60%-NaH (600 mg, 15 mmol). After stirring at 0 °C for 0.5 h, the reaction was treated with N-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine (1.8 g, 5.6 mmol). The resulting mixture was stirred at rt for 2 h and then quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in the title compound (800 mg, 45%) as a yellow oil. LCMS (M+H)+ = 360.2.

[00358] Step 3-4, preparation of ethyl l-benzyl-4-r5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate: Into a 50 mL three-neck bottle, purged and maintained with an inert atmosphere of nitrogen, were added ethyl l-benzyl-4-(5-chloropyrazin-2-yl)piperidine-4-carboxylate (800 mg, 2.22 mmol), (2-ethoxypyridin-3-yl)boronic acid (557 mg, 3.34 mmol), Pd(DTBPF)C12 (145 mg, 0.22 mmol), K2CO3 (922 mg, 6.67 mmol), and dioxane / H2O (8 mL / 0.8 mL). The resulting mixture was stirred 90 °C for 2 h under N2 and then cooled to room temperature. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to afford the title compound (800 mg, 80%) as yellow oil. LCMS (M+H)+= 447.5.

[00359] Step 3-5, preparation of ethyl 4-l5-(2-ethoxypyridin-3-yl)pyrazin-2-yl1piperidine-4-carboxylate: To a solution of ethyl l-benzyl-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (800 mg, 1.79 mmol) in MeOH (20 mL) was added 10%-Pd / C (191 mg) and Pd(OH)2 (252 mg, 1.79 mmol). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred at rt 40 min under an atmosphere of hydrogen (balloon). The resulting solution was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated under vacuum to afford the title compound (580 mg, 91%) as a white oil. LCMS (M+H)+ = 357.3.

[00360] Step 3-6, preparation of ethyl l-[2-cyano-4-(trifluoromethyl)phenyl1-4-r5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate: Into a 8-mL vial, were placed ethyl 4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (200 mg, 0.56 mmol), DIEA (218 mg, 1.69 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (212 mg, 1.12 mmol) and DMSO (2 mL). The resulting mixture was stirred at 60 °C for 2 h and then cooled to room temperature. The crude product was purified by Prep-HPLC to afford the title compound (220 mg, 74%). LCMS (M+H)+= 526.5.

[00361] Step 3-7, preparation of l-[2-cvano-4-(trifluoromethvl)phenvl1-4-r5-(2-ethoxvpvridin-3-vl)pvrazin-2-vl1-N-r(3R)-l-methvlpvrrolidin-3-yl1piperidine-4-carboxamide: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, were placed ethyl l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]piperidine-4-carboxylate (40 mg, 0.076 mmol), (R)-l-methylpyrrolidine-3-amine (23 mg, 0.23 mmol), LHMDS (130 mg, 0.77 mmol), and THF (1.3 mL). The resulting mixture was stirred at rt for 1 h under N2 and then quenched with sat-NH4Cl (20 mL). The resulting solution was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC to afford the title compound (13 mg, 28%). LCMS (M+H)+ = 580.2.

[00362] The following compounds were prepared similarly to Example 3 with appropriate substituting reagents and substrates at different steps. Compound no. MS (M+H)+ 1-58 580.2 Example 4: l-[2-cvano-4-(trifluoromethvl)Dhenvl]-4-[6-(2-ethoxvDvridin-3-vl)Dvridazin-3-yl]-N-[(3S)-l-methylDyrrolidin-3-yl]DiDeridine-4-carboxamide (cpd 1-56)

[00363] Step 4-1, preparation of ethyl l-benzvl-4-r6-(2-ethoxvpvridin-3-vl)pyridazin-3-vl1piperidine-4-carboxylate: Starting from 3,6-dichloropyridazine, the title compound was prepared by a similar manner described from step 3-1 to 3-4 in Example 3. LCMS (M+H)+ = 447.3.

[00364] Step 4-2, preparation of 1-tert-butyl 4-ethyl 4-r6-(2-ethoxypyridin-3-yl)pyridazin-3-yllpiperidine-1,4-dicarboxylate: Into a 100-mL round bottom flask, was placed ethyl l-benzyl-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate (240 mg, 0.54 mmol), di-tert-butyl decarbonate (350 mg, 1.60 mmol), MeOH (30 mL), TEA (160 mg, 1.58 mmol), 10%-Pd / C (20 mg) and Pd(OH)2 (20 mg, 0.14 mmol). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The reaction mixture was stirred at rt for 2h under an atmosphere of hydrogen (balloon). The reaction was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by Prep-HPLC to afford the title compound (200 mg, 81%) as a light yellow oil. LCMS (M+H)+ = 457.4.

[00365] Step 4-3, preparation of ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carb oxy late trifluoroacetate: To a solution of 1-tert-butyl 4-ethyl 4-[6-(2-ethoxypyridin-3 -yl)pyridazin-3-yl]piperidine-l,4-dicarboxylate (200 mg, 0.44 mmol) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h and then concentrated under vacuum. This resulted in the title compound (200 mg, 96%) as yellow oil. LCMS (M+H)+ = 357.2.

[00366] Step 4-4, preparation of ethyl l-[2-cyano-4-(trifluoromethyl)phenyl1-4-r6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate formate: Into a 8-mL vial, was placed ethyl 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate trifluoroacetate (200 mg, 0.42 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (96 mg, 51 mmol), DIEA (200 mg, 1.55 mmol) and DMSO (3 mL). The resulting solution was stirred at 60 °C for 1 h and cooled to rt. The reaction was directly purified by Prep-HPLC to afford the title compound (145 mg, 60%) as a light yellow oil. LCMS (M+H)+ = 526.3.

[00367] Step 4-5, preparation of l-[2-cvano-4-(trifluoromethvl)phenvl1-4-r6-(2-ethoxvpvridin-3-yl)pyridazin-3-yl1-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide: Into a 8-mL vial, were placed ethyl l-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxylate (60 mg, 0.11 mmol), (S)-l-methylpyrrolidine-3-amine (30 mg, 0.30 mmol), and IM-LiHMDS in THF (1.0 mL, 1.0 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 1 h and then quenched with sat-NH4Cl. The resulting solution was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC to afford the title compound (16 mg, 22%). LCMS (M+H)+ = 580.2.

[00368] The following compounds were prepared similarly to Example 4 with appropriate substituting reagents and substrates at different steps. Compound no. MS (M+H)+ 1-57 580.2 1-134 545.3 1-135 531.2 1-136 565.3 1-139 546.3 1-140 566.3 1-168 538.2 Compound no. MS (M+H)+ 1-169 547.2 1-170 504.3 1-171 531.2 1-174 572.2 1-175 588.2 1-183 565.5 1-331 568.4 Example 5: l-[2-cvano-4-(trifluoromethvl)Dhenvl]-4-[2-(2-ethoxvDvridin-3-vl)Dvrimidin-5-yl]-N-[(3S)-l-methylDyrrolidin-3-yl]DiDeridine-4-carboxamide (cpd 1-106)

[00369] Step 5-1, preparation of [2-(2-ethoxvpyri din-3-yl)pvrimidin-5-yl1methanol: Into a 100 mL three-neck bottle, purged and maintained with an inert atmosphere of nitrogen, were added (2-chloropyrimidin-5-yl)methanol (3.0 g, 21 mmol), (2-ethoxypyridin-3-yl)boronic acid (4.0 g, 21 mmol), Pd(DTBPF)C12 (1.4 g, 2.1 mmol), K2CO3 (9.0g, 65 mmol) and dioxane (30 mL) / H20 (3 mL) at rt. The resulting reaction mixture was stirred at 60 °C for 1 h and cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (2:1) to afford the title compound (4.2 g, 88%). LCMS (M+H)+ = 232.1.

[00370] Step 5-2, preparation of r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methyl methanesulfonate: To a solution of [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methanol (2.0 g, 8.6 mmol) and TEA (3.0 g, 30 mmol) in DCM (20 mL) was slowly added MsCl (1.0 g, 8.7 mmol) in an ice bath. The reaction was stirred at 0 °C for Ih, quenched with water (30 mL), and extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in the title compound (2.3 g, 86%) as a yellow oil. LCMS (M+H)+ = 310.1.

[00371] Step 5-3, preparation of 2-l2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl1acetonitrile: Into a 50-mL round-bottom flask, were placed [2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]methyl methanesulfonate (2.3 g, 7.4 mmol), sodium cyanide (1.1 g, 22 mmol) and DMSO (20 mL). The resulting mixture was at rt stirred for 1 h, quenched with aq-FeS04(~100 mL), and then extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM / MeOH (10:1) to afford the title compound (1.3 g, 73%) as a yellow oil. LCMS (M+H)+= 241.1.

[00372] Step 5-4, preparation of l-benzvl-4-r2-(2-ethoxvpvridin-3-vl)pyrimidin-5-vl1piperidine-4-carbonitrile: Into a 50-mL round-bottom flask, were placed 2-[2-(2-ethoxypyridin-3 -yl)pyrimidin-5-yl]acetonitrile (600 mg, 2.5 mmol), N-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine (962 mg, 3.0 mmol), KOH (420 mg, 7.49 mmol), and DMSO (10 mL). The resulting mixture was stirred at rt for 1 h, quenched with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in the title compound (450 mg, 45%) as a yellow oil. LCMS (M+H)+ = 400.2.

[00373] Step 5-5, preparation of l-benzyl-4-r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl1piperidine-4-carboxylic acid: Into a 50-mL round-bottom flask, were placed l-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carbonitrile (450 mg, 1.13 mmol), KOH (632 mg, 11.3 mmol), and EtOH (5 mL) / H20 (2.5 mL). The resulting mixture was stirred at 100 °C for 16 h and cooled to room temperature. The reaction was diluted with water (20 ml), then adjusted to pH 6~7 with 3N-HC1 and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in the title compound (400 mg, 85%) as a yellow oil. LCMS (M+H)+ = 419.2.

[00374] Step 5-6, preparation of l-benzyl-4-r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl1-N-[(3S)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide: To a solution of l-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]piperidine-4-carboxylic acid (180 mg, 0.43 mmol) in DMF (2 mL) was added HATU (164 mg, 0.43 mmol) and DIEA (167 mg, 1.29 mmol) at rt. After stirring for 10 min at rt, the reaction was treated with (S)-l-methylpyrrolidine-3-amine (52 mg, 0.52 mmol). The resulting mixture was stirred at rt for 1 h and then directly purified by prep-HPLC to afford the title compound (150 mg, 70%) as a white oil. LCMS (M+H)+ = 501.3.

[00375] Step 5-7, preparation of tert-butyl 4-r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl1-4-ll(3S)-l-methylpyrrolidin-3-yl]carbamoyH piperi dine-1 -carboxylate: Into a 50-mL round-bottom flask, were placed l-benzyl-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide (160 mg, 0.32 mmol), TEA (98 mg, 0.97 mmol), (Boc)2O (209 mg, 0.96 mmol), wet 10%-Pd / C (34 mg), Pd(OH)2 (45 mg, 0.32 mmol) and MeOH (10 mL). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred at rt 30 min under an atmosphere of hydrogen (balloon). The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residue was purified by prep-HPLC to afford the title compound (40 mg, 25%) as a white oil. LCMS (M+H)+ = 511.3.

[00376] Step 5-8, preparation of 4-r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl1-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate: To a solution of tert-butyl 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-4-{[(3 S)-l-methylpyrrolidin-3- yl]carbamoyl (piperidine-1-carboxylate (40 mg, 0.078 mmol) in DCM (1 mL) was added TFA (0.3 mL). The resulting solution was stirred at rt for 1 h and then concentrated under vacuum. This resulted in the title compound (30 mg, 60 %) as yellow oil. LCMS (M+H)+ = 411.3.

[00377] Step 5-9, preparation of l-[2-cvano-4-(trifluoromethyl)phenyl1-4-r2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-r(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate: Into a 8-mL vial, were placed 4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide bistrifluoroacetate (30 mg, 0.047 mmol), DIEA (28 mg, 0.22 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (28 mg, 0.15 mmol), and DMSO (1 mL). The resulting mixture was stirred at 60 °C for 2 h and cooled to room temperature. The reaction was purified by Prep-HPLC to afford the title compound (14 mg, 38%). LCMS (M+H)+ = 580.3.

[00378] The following compounds were prepared similarly to Example 5 with appropriate substituting reagents and substrates at different steps: Compound no. MS (M+H)+ 1-107 580.3 Example 6: l-[2-cyano-4-(trifluoromethvl)Dhenvl]-4-[6-(2-ethoxvDhenvl)-5-fluoroDvridin-3- Yl]-N-[(3S)-l-methvlDvrrolidin-3-vl]Diperidine-4-carboxamide (cpd 1-124)

[00379] Step 6-1, preparation of 2-chloro-3-fluoro-5-(l,2-oxazol-4-vl)pvridine: Into a 250 mL three-neck bottle, purged and maintained with an inert atmosphere of nitrogen, were added 5-bromo-2-chloro-3-fluoropyridine (5.0 g, 24 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (5.6 g, 29 mmol), Pd(DTBPF)Ch (1.5 g, 2.3 mmol), KF (4.1 g, 71 mmol), and DMSO (50 mL) / H20 (5 mL). The resulting mixture was stirred at 100 °C for 1 h and cooled to room temperature. The reaction was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to afford the title compound (3.5 g, 74%) as yellow solid. LCMS (M+H)+ = 199.0.

[00380] Step 6-2, preparation of 2-(6-chloro-5-fluoropyridin-3-yl)acetonitrile: To a solution of 2-chloro-3-fluoro-5-(l,2-oxazol-4-yl)pyridine (3.5 g, 18 mmol) in MeOH (35 mL) / H20 (3.5 mL) was added KF (0.2 g, 3.0 mmol). The resulting solution was stirred at 90 °C for 1 h and cooled to room temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to afford the title compound (2.3 g, 77%) as yellow solid. LCMS (M+H)+= 171.1.

[00381] Step 6-3, preparation of l-benzvl-4-(6-chloro-5-fluoropyridin-3-vl)piperidine-4-carbonitrile: Into a 50-mL round-bottom flask, were placed 2-(6-chloro-5-fluoropyridin-3-yl)acetonitrile (2.3 g, 13 mmol), N-benzyl-2-bromo-N-(2-bromoethyl)ethan-l-amine (4.3 g, 13 mmol), KOH (2.3 g, 41 mmol), and DMSO (25 mL). The resulting mixture was stirred at rt for 1 h, quenched with water (100 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in the title compound (2.7 g, 61%) as a yellow oil. LCMS (M+H)+ = 330.2.

[00382] Step 6-4, preparation of l-benzvl-4-[6-(2-ethoxvphenvl)-5-fluoropvridin-3 -yl1piperidine-4-carbonitrile: Into a 50 mL three-neck bottle, purged and maintained with an inert atmosphere of nitrogen, were added l-benzyl-4-(6-chloro-5-fluoropyridin-3-yl)piperidine-4- carbonitrile (500 mg, 1.52 mmol), (2-ethoxyphenyl)boronic acid (300 mg, 1.81 mmol), Pd(DTBPF)Ch (99 mg, 0.15 mmol), K2CO3 (630 mg, 4.56 mmol) and dioxane (5 mL) / H2O (0.5 mL) at rt. The resulting reaction mixture was stirred at 100 °C for 1 h and cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to afford the title compound (500 mg, 79%) as light yellow oil. LCMS (M+H)+= 416.3.

[00383] Step 6-5, preparation of l-benzvl-4-16-(2-ethoxvphenvl)-5-fluoropvridin-3 -vl1piperidine-4-carboxvlic acid: Into a 50-mL round-bottom flask, were placed l-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carbonitrile (500 mg, 1.2 mmol), KOH (675 mg, 12.0 mmol), and EtOH (10 mL) / H20 (5 mL). The resulting mixture was stirred at 100 °C for 24 h and cooled to room temperature. The reaction was diluted with water (20 ml), then adjusted to pH 6~7 with 3N-HC1 and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in the title compound (450 mg, 86%) as a yellow solid. LCMS (M+H)+ = 435.2.

[00384] Step 6-6, preparation of l-benzyl-4-r6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl1-N-[(3S)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide: To a solution of l-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxylic acid (140 mg, 0.32 mmol) in DMF (2 mL) was added HATU (123 mg, 0.32 mmol) and DIEA (125 mg, 0.97 mmol). After stirring for 10 min at rt, the reaction was treated with (S)-l-methylpyrrolidine-3-amine dihydrochloride (56 mg, 0.32 mmol). The resulting mixture was stirred at rt for 1 h and then directly purified by prep-HPLC to afford the title compound (130 mg, 73%) as a white solid. LCMS (M+H)+ = 517.4.

[00385] Step 6-7, preparation of 4-r6-(2-ethoxvphenvl)-5-fluoropvridin-3-vl1-N-[(3S)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide: Into a 50-mL round-bottom flask, were placed l-benzyl-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3 S)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide (130 mg, 0.25 mmol), wet 10%-Pd / C (27 mg), Pd(OH)2 (35 mg, 0.25 mmol) and MeOH (5 mL). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred at rt 30 min under an atmosphere of hydrogen (balloon). The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated under vacuum. This resulted in the title compound (90 mg, 84%) as a white oil. LCMS (M+H)+ = 427.5.

[00386] Step 6-8, preparation of l-[2-cvano-4-(trifluoromethvl)phenvl1-4-r6-(2-ethoxvphenvl)-5-fluoropyridin-3-yl1-N-r(3S)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide formate: Into a 8-mL vial, were placed 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-l-methylpyrrolidin- WO 2021 / 126693                                                 PCT / US2020 / 064493 3-yl]piperidine-4-carboxamide (45 mg, 0.11 mmol), DIEA (41 mg, 0.32 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (40 mg, 0.21 mmol), and DMSO (1 mL). The resulting mixture was stirred at 60 °C for 2 h and cooled to room temperature. The reaction was purified by Prep-HPLC to afford the title compound (29 mg, 43%) as a white solid. LCMS (M+H)+ = 596.3.

[00387] The following compounds were prepared similarly to Example 6 with appropriate substituting reagents and substrates at different steps. Some examples require deprotection in the final step: Compound no. MS (M+H)+ 1-108 597.3 1-109 597.3 1-110 598.3 1-123 596.3 1-125 597.3 1-126 582.3 1-127 582.3 1-128 583.3 1-131 583.3 Compound no. MS (M+H)+ 1-132 583.3 1-133 584.3 1-161 555.2 1-162 564.5 1-163 522.2 1-195 600.3 1-196 556.3 1-197 570.3 1-334 615.3 Example 7: l-[2-cvano-4-(trifluoromethvl)phenvl]-4-12,-ethoxv-[2,3,-bipyridin]-5-vn-A-[(37?)-l-methvlpyrrolidin-3-vl]piperidine-4-carboxamide (cpd 1-9) CF3

[00388] Step 7-1, preparation of methyl l-benzyl-4-(6-chloropyri din-3-yl)piperidine-4-carb oxy late: To a solution of methyl 6-chloropyridine-3-carboxylate (4.0 g, 22 mmol) and 18-Crown-6 (1.1 g, 4.2 mmol) in DMF (30 mL) at 0°C was added 60 % sodium hydride in mineral oil (2.2 g, 55 mmol) in portions. The mixture was stirred at 0°C for 2 h. To this was added a solution of benzylbis(2-bromoethyl)amine (8.3 g, 26 mmol) in DMF (10 mL). The mixture was stirred at rt for 2 h. The mixture was quenched with water and extracted with EtOAc (3X). The combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (4.8 g, 65%) as a yellow solid. LCMS (M+H)+ = 345.2.

[00389] Step 7-2, preparation of methyl l-benzvl-4-12'-ethoxv-r2,3'-bipvridin]-5-vHpiperidine-4-carboxylate: To a suspension of methyl l-benzyl-4-(6-chloropyridin-3-yl)piperidine-4- carboxylate (1.8 g, 5.2 mmol) in 1,4-di oxane (20 mL) and water (2 mL) under nitrogen was added potassium carbonate (2.2 g, 16 mmol), (2-ethoxypyridin-3-yl)boronic acid (1.7 g, 10 mmol) and Pd(dtbpf)C12 (0.10 g, 0.15 mmol). The mixture was heated at 90°C for 2 h. The mixture was quenched with water and extracted with EtOAc (2X). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (1.8 g, 80%) as a light yellow solid. LCMS (M+H)+ = 432.3.

[00390] Step 7-3, preparation of methyl 4-I2'-ethoxv-r2,3'-bipvridin]-5-vHpiperidine-4-carboxylate: To a solution of methyl l-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.8 g, 4.2 mmol) in MeOH (25 mL) was added 10 wt.% of Pd on carbon (100 mg) and 20 wt.% of Pd(OH)2 on carbon (100 mg). The mixture was charged with hydrogen (g) and stirred at rt for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (1.2 g, 60%) as yellow oil. LCMS (M+H)+ = 342.2.

[00391] Step 7-4, preparation of methyl l-[2-cyano-4-(trifluoromethyl)phenyl1-4-l2'-ethoxy-r2,3'-bipyridin1-5-ynpiperidine-4-carboxylate: To a solution of methyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.2 g, 3.5 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (0.8 g, 4 mmol) in DMSO (15 mL) was added DIEA (1.4 g, 11 mmol). The mixture was heated at 60°C for 2 h. The mixture was quenched with water and extracted with EtOAc (3X). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (1.1 g, 61%) as a white solid. LCMS (M+H)+= 511.3.

[00392] Step 7-5, preparation of l-[2-cyano-4-(trifluoromethyl)phenyl1-4-l2'-ethoxy-r2,3'-bipyridin]-5-yHpiperidine-4-carboxylic acid: To a suspension of methyl l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (1.4 g, 2.7 mmol) in a mixed solvent of EtOH and water (2:1, 12 mL) was added lithium hydroxide (0.60 g, 25 mmol). The mixture was heated at 60°C for 2 h. The mixture was concentrated to remove the organics and the aqueous residue was adjusted to pH 6-7 with 1AHC1 (aq). The solution was extracted with EtOAc (3X) and the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (1.2 g, 88%) as a light yellow solid. LCMS (M+H)+= 497.3.

[00393] Step 7-6, preparation of l-[2-cyano-4-(trifluoromethyl)phenyl1-4-l2'-ethoxy-r2,3'-bipyridin1-5-yH-A-r(3A)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide: To a solution ofl-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (60 mg, 0.12 mmol) and HATU (55 mg, 0.14 mmol) in DMF (1 mL) was added DIEA (94 mg, 0.73 mmol). After stirring at rt for 5 min, (3A)-l-methylpyrrolidin-3-amine dihydrochloride (31 mg, 0.18 mmol) was added to the above HATU-activated solution. The mixture was stirred at rt for 1 h and purified by reversed-phase CC to give the title compound (42 mg, 56%) as a white solid. LCMS (M+H)+ = 579.3.

[00394] The following compounds were prepared similarly to Example 7 with appropriate substituting reagents and substrates at different steps: Compound no. MS (M+H)+ 1-11 579.3 1-15 567.4 1-18 579.3 1-19 565.3 1-20 605.3 1-41 595.3 1-45 597.2 Compound no. MS (M+H)+ 1-46 595.2 1-48 597.2 1-166 564.5 1-176 535.5 1-178 565.7 1-179 565.4 Example 8: l-[2-cyano-4-(trifluoromethyl)Dhenyl]-4-f2,-ethoxy-[2.,3,-biDyridin]-5-yn- / V-

[00395] Step 8-1, preparation of tert-butyl (3A)-3-ll-r2-cyano-4-(trifluoromethyl)phenyl1-4-l2'-ethoxy-r2,3'-bipvridin1-5-ynpiperidine-4-amidolpyrrolidine-l-carboxylate: To a solution ofl-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (60 mg, 0.10 mmol) from Step 7-5 and HATU (58 mg, 0.15 mmol) in DMF (1 mL) was added DIEA (0.10 mL, 0.57 mmol). After stirring at rt for 5 min, tert-butyl (37?)-3-aminopyrrolidine-1 -carboxylate (45 mg, 0.24 mmol) was added to the above HATU-activated solution. The mixture was stirred at rt for 1 h and purified by reversed-phase CC to give the title compound (69 mg, 100%) as light brown oil. LCMS (M+H)+ = 665.3.

[00396] Step 8-2, preparation of l-[2-cyano-4-(trifluoromethyl)phenyl1-4-l2'-ethoxy-r2,3'-bipvridin1-5-vn-A-[(3A)-pvrrolidin-3-vl1piperidine-4-carboxamide: To a solution of tert-butyl (3A)-3-{l-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-amido}pyrrolidine-l-carboxylate (69 mg, 0.10 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. The mixture was concentrated to dryness and the residue was purified by reversed-phase CC to give the title compound (32 mg, 51%) as light brown oil. LCMS (M+H)+= 565.3.

[00397] The following compounds were prepared similarly to Example 8 with appropriate substituting reagents and substrates at different steps: Compound no. MS (M+H)+ 1-12 565.3 1-13 539.3 1-14 553.3 1-16 553.3 1-17 569.3 Compound no. MS (M+H)+ 1-28 569.2 1-44 583.3 1-47 583.3 1-21 565.3 Example 9: l-(2-cvanophenvl)-4-12,-ethoxv-[2.,3,-biDvridin|-5-vn- / V-[(3ty)-l-methylDyrrolidin-3-yl]DiDeridine-4-carboxamide (cpd 1-32)

[00398] Step 9-1, preparation of ethyl l-benzyl-4-(6-chloropyri din-3-yl)piperidine-4-carb oxy late: To a solution of ethyl 6-chloropyridine-3-carboxylate (9.5 g, 48 mmol) in DMF (100 mL) at 0°C was added 60 % sodium hydride in mineral oil (3.4 g, 0.14 mol) in portions. The mixture was stirred at 0°C for 0.5 h. To this was added benzylbis(2-bromoethyl)amine (8.3 g, 26 mmol) and the mixture was stirred at rt for 2 h. The mixture was quenched with water and extracted with EtOAc (3X). The combined organics were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel CC to give the title compound (12 g, 70%) as yellow oil. LCMS (M+H)+ = 359.2.

[00399] Step 9-2, preparation of ethyl l-benzvl-4-l2'-ethoxv-[2,3'-bipvridin1-5-vnpiperidine-4-carboxylate: To a suspension of ethyl l-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (5.0 g, 14 mmol) in 1,4-di oxane (50 mL) and water (5 mL) under nitrogen was added potassium carbonate (5.8 g, 42 mmol), (2-ethoxypyridin-3-yl)boronic acid (3.5 g, 21 mmol) and Pd(dtbpf)C12 (0.91 g, 1.4 mmol). The mixture was heated at 90°C for 2 h. The mixture was quenched with water and extracted with EtOAc (3X). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (5.5 g, 89%) as a yellow solid. LCMS (M+H)+ = 446.3.

[00400] Step 9-3, preparation of l-benzvl-4-12'-ethoxv-r2,3'-bipvridin]-5-vHpiperidine-4-carboxylic acid: To a suspension of ethyl l-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxylate (2.0 g, 4.5 mmol) in a mixed solvent of EtOH and water (2:1, 45 mL) was added lithium hydroxide (1.1 g, 46 mmol). The mixture was heated at 60°C for 1 h. The mixture was diluted with water and adjusted to pH 6-7 with 3AHC1 (aq). The mixture was extracted with EtOAc (3X) and the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (1.5 g, 80%) as yellow oil. LCMS (M+H)+= 418.1.

[00401] Step 9-4, preparation of I-benzvl-4-l2'-ethoxv-l2,3'-bipvridin1-5-vl 1-5-1(35)-1-methvlpyrrolidin-3-vl1piperidine-4-carboxamide: To a solution of l-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (1.2 g, 2.9 mmol) and HATU (1.1 g, 2.9 mmol) in DMF (12 mL) was added DIEA (1.5 mL, 8.5 mmol). After stirring at rt for 5 min, (35)-1 -methylpyrrolidin-3-amine (0.30 g, 3.0 mmol) was added to the above HATU-activated solution. The mixture was stirred at rt for 2 h. The mixture was quenched with water and extracted with EtOAc (3X). The combined organics were concentrated to dryness and the residue was purified by silica gel CC to give the title compound (1.1 g, 77%) as yellow oil. LCMS (M+H)+ = 500.4.

[00402] Step 9-5, preparation of 4-l2'-ethoxy-[2,3'-bipyridin1-5-yH-A-r(35)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide: To a solution of l-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-A-[(35)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide (1.1 g, 2.2 mmol) in MeOH (20 mL) was added 10 W.% of Pd on carbon (0.23 g) and 20 W.% of Pd(OH)2 on carbon (0.31 g). The mixture was charged with hydrogen (g) and stirred at rt for 1 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (0.70 g, 78%) as white oil. LCMS (M+H)+= 410.3.

[00403] Step 9-6, preparation of l-(2-cyanophenyl)-4-l2'-ethoxy-[2,3'-bipyridin1-5-yH-A-r(35)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide: To a solution of 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-A-[(35)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide (45 mg, 0.11 mmol) and 2-fluorobenzonitrile (40 mg, 0.33 mmol) in DMSO (1 mL) was added DIEA (28 mg, 0.22 mmol). The mixture was heated at 120°C for 1 h. The mixture was purified by revered-phase CC to give the title compound (18 mg, 31%) as a white solid. LCMS (M+H)+ = 511.2.

[00404] The following compounds were prepared similarly to Example 9 with appropriate substituting reagents and substrates at different steps: Compound no. MS (M+H)+ 1-34 545.2 1-35 555.3 1-36 553.2 1-37 561.3 1-38 579.2 1-39 595.2 Compound no. MS (M+H)+ 1-40 536.2 1-42 580.3 1-59 575.3 1-150 588.4 1-308 585.3 1-311 571.3 Example 10: 4-12,-ethoxv-[2,3,-bipvridin]-5-vn-7V-[(3ty)-l-methvlpyrrolidin-3-vl]-l-[4-(trifluoromethvl)phenyl]piperidine-4-carboxamide (cpd 1-33) CF3

[00405] Step 10-1, preparation of 4-)2'-ethoxy-r2,3'-bipyridin1-5-yn-7V-[(35)-l-methylpyrrolidin-3-yl1-l-[4-(trifluoromethyl)phenyl1piperidine-4-carboxamide formate: To a mixture of 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-7V-[(35)-l-methylpyrrolidin-3-yl]piperidine-4-carboxamide (40 mg, 0.098 mmol), l-bromo-4-(trifluoromethyl)benzene (33 mg, 0.115 mmol), XPhos (17 mg, 0.020 mmol), Pd2(dba)3 (9.0 mg, 0.0098 mmol), and sodium tert-butoxide (28 mg, 0.29 mmol) under nitrogen was added toluene (1 mL). The mixture was heated at 80°C for 1 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by reversed-phase CC to give the title compound (25 mg, 43%) as yellow oil. LCMS (M+H)+ = 554.2.

[00406] The following compounds were prepared similarly to Example 10 with appropriate substituting reagents and substrates at different steps: Compound no. MS (M+H)+ 1-154 592.2 1-155 591.2 1-156 571.2 1-186 572.3 Example 11: l-[2-cvano-6-(trifluoromethvl)pyridin-3-vl]-4-12,-ethoxv-[2,3,-bipvridin]-5-vn-7V-[(31?)-l-methvlpvrrolidin-3-vl]piperidine-4-carboxamide & 3-(4-12,-ethoxv-[2,3’-bipyridin]-5-yl)-4-{[(31?)-l-methylpyrrolidin-3-yl]carbamoyl}piperidin-l-yl)-6-(trifluoromethvl)pyridine-2-carboxamide (cpd 1-24 & 1-25)

[00407] Step 11-1, preparation of ethyl 4-12'-ethoxv-r2,3'-bipvridin]-5-vHpiperidine-4-carb oxy late: To a solution of ethyl l-benzyl-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (2.0 g, 4.5 mmol) in MeOH (100 mL) was added 10 wt.% of Pd on carbon (100 mg) and 20 wt.% of Pd(OH)2 on carbon (100 mg). The mixture was stirred at rt for 3 h under hydrogen (3 bar). The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (1.0 g, 62%) as light yellow oil. LCMS (M+H)+ = 356.2.

[00408] Step 11-2, preparation of ethyl l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-12'-ethoxy-r2,3'-bipyridin]-5-yHpiperidine-4-carboxylate: To a solution of ethyl 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (0.2 g, 0.6 mmol) and 3-fluoro-6-(trifluoromethyl)pyridine-2-carbonitrile (0.16 g, 0.84 mmol) in DMSO (5 mL) was added DIEA (0.4 mL, 2 mmol). The mixture was heated at 60°C for 2 h. The mixture was purified by reversed-phase CC to give the title compound (0.21 g, 70%) as light yellow oil. LCMS (M+H)+ = 526.5.

[00409] Step 11-3, preparation of l-[2-cvano-6-(trifluoromethyl)pyridin-3-yl]-4-12'-ethoxy-r2,3'-bipyridin1-5-ynpiperidine-4-carboxylic acid & l-r2-carbamoyl-6-(trifluoromethyl)pyridin-3-yl]-4-12'-ethoxy-[2,3'-bipyridin]-5-yHpiperidine-4-carboxylic acid: To a suspension of ethyl 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylate (0.21 g, 0.40 mmol) in a mixed solvent of EtOH and water (2:1,6 mL) was added lithium hydroxide (0.10 g, 4.2 mmol). The mixture was heated at 60°C for 1 h. The mixture was adjusted to pH 6-7 with 17VHC1 (aq). The solution was extracted with EtOAc (3X) and the combined organics were dried over anhydrous Na2SO4 and concentrated to dryness to give the mixture of title compounds (0.17 g) in a ratio of 47:53 as a light yellow solid. LCMS (M+H)+ = 498.3 & 516.3.

[00410] Step 11-4, preparation ofl-[2-cyano-6-(trifluoromethyl)pyridin-3-yl1-4-l2'-ethoxy-r2,3'-bipyridin1-5-yH-A-r(3A)-l-methylpyrrolidin-3-yl1piperidine-4-carboxamide & 3-(4-{2'-ethoxv-[2,3'-bipvridin]-5-vn-4-l[(3A)-l-methvlpvrrolidin-3-vl]carbamovllpiperidin-l-yl)-6-(trifluoromethyl)pyridine-2-carboxamide: To a solution of a mixture of l-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid & -169- l-[2-carbamoyl-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxylic acid (85 mg, 0.17 mmol) and HATU (79 mg, 0.21 mmol) in DMF (1 mL) was added DIEA (0.1 mL, 0.8 mmol). After stirring at rt for 5 min, (3A)-l-methylpyrrolidin-3-amine (64 mg, 0.64 mmol) was added to the above HATU-activated solution. The mixture was stirred at rt for 1 h and purified by reversed-phase CC to give the first title compound (32 mg, 33% yield) as a white solid; LCMS (M+H)+ = 580.3 and the second title compound (44 mg, 43%) as a white solid; LCMS (M+H)+ = 598.3.

[00411] The following compounds were prepared similarly to Example 1 with appropriate substituting reagents and substrates at different steps: Example 12: l-|2-cvaiio-4-(tiiniioioiiietlivl)plieiivl|-4-|6-(l-iiietlivl-l / / -pvriol-2-vl)pviidiii- 3-yll-A-[(31?)-l-methylDyrrolidin-3-yl]DiDeridine-4-carboxamide (cpd 1-88)

[00412] Step 12-L preparation of methyl 4-(6-chloropyridin-3-vl)piperidine-4-carboxvlate: To a solution of methyl l-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylate (2.9 g, 8.4 mmol) from step 7-1 in DCM (30 mL) at 0°C was added chloroethyl chloroformate (2.3 mL, 21 mmol). The mixture was stirred at rt for 2 h and then MeOH (15 mL) was added. The resulting mixture was heated at reflux for 2 h. The mixture was concentrated to dryness and the residue was triturated with a mixed solvent of hexanes and ether (5:1, 40 mL). The solid was collected by vacuum filtration to give the title compound (1.7 g, 79%) as a white solid. LCMS (M+H)+ = 255.0.

[00413] Step 12-2, preparation of methyl 4-(6-chloropvridin-3-vl)-l-[2-cvano-4-(trifluoromethyl)phenyl1piperidine-4-carboxylate: To a solution of methyl 4-(6-chloropyridin-3 -yl)piperidine-4-carboxylate (1.7 g, 6.7 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (1.3 g, 7.0 mmol) in DMSO (17 mL) was added DIEA (3.6 mL, 21 mmol). The mixture was heated at 60°C for 2 h. The mixture was diluted with 10% citric acid (aq) (50 mL) and extracted with EtOAc (3X). The combined organ...

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I)wherein:RA is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if RA is substituted then RA is substituted with 1, 2, 3 or 4 groups selected from Ra, Rb, and Rc;Ra, Rb, and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Ra, Rb, and Rc is substituted with one or more R6 groups;or one Ra and one Rb, when present on adjacent atoms of RA, are taken together with the intervening atoms connecting Ra to Rb to form a 5- to 6-membered monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle, wherein the carbocycle or heterocycle is unsubstituted or substituted with one or more R6 groups;wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;RB is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if RB is substituted then RB is substituted with 1, 2, 3 or 4 groups selected from Rd, Re, and Rf;2020407016   15 Jul 2026Rd, Re, and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, -C(=O)N(R4)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein any substituted group of Rd, Re, and Rf is substituted with one or more R6 groups;wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;X1 is CR11 or N;X2 is CR12 or N;X3 is CR13 or N;X4 is CR14 or N;R11, R12, R13, and R14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6cycloalkyl, -CN, -OR4, -SR4, -CO2R4, -C(=O)N(R4)2, or -N(R4)2;M is -NR3-, -O-, -S-, *-NR3-(C=O)-, *-(C=O)-NR3-, *-O-(C=O)NR3-, *-NR3-(C=O)O-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1;R1 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the substituted C1-C6 alkyl is substituted with one or more unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; and the substituted C1-C6 heteroalkyl, substituted C3-C6 cycloalkyl, substituted C2-C7 heterocycloalkyl, substituted -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl) is substituted with one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic2020407016   15 Jul 2026heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2;each R3 is independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl;each R4 is independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;or two R4 are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle;each R5 is independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;each R6 is independently hydrogen, halogen, unsubstituted or substituted C1-C4alkyl, unsubstituted or substituted C1-C4alkoxy, unsubstituted or substituted C1-C4fluoroalkyl, unsubstituted or substituted C1-C4fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -CO2R5, -CH2CO2R5, -C(=O)N(R4)2, -C(=O)N(R4)OR5, -CH2C(=O)N(R4)2, -N(R4)2, -CH2N(R4)2, -C(R5)2N(R4)2, -NR4C(=O)R5, -CH2NR4C(=O)R5, -NR4C(=O)N(R5)2, -NR4C(=O)N(R4)2, C(R5)=N(R4)-OR5, -SR5, -S(=O)R7, -SO2R7, or -SO2N(R4)2; andeach R7 is independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:M is -NR3-, -O-, *-NR3-(C=O)-, *-(C=O)-NR3-, *-O-(C=O)NR3-, *-NR3-(C=O)O-, or -NR3-(C=O)NR3-, wherein * indicates the attachment point to R1; andeach R3 is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.2020407016   15 Jul 20263.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIa) or Formula (IIb), or a pharmaceuticallyacceptable salt thereof:R1Formula (IIb)Formula (IIa) wherein:RA isRB is; and,,,,4.     The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound has the structure of Formula (IVa), or a pharmaceutically acceptable salt, or solvate thereof:Formula (IVa)wherein V is CH, CRa, CRb, or N.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound has the structure of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof:2020407016   15 Jul 20266.Formula (VI)wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIa), Formula (VIc), Formula (VIb), Formula (VId), Formula (VIIb) or Formula (VIIe), or a pharmaceutically acceptablesalt, or solvate thereof:Formula (VIa)Formula (VIc)Formula (VIb)Formula (VId)Rd\ Re2020407016   15 Jul 2026Formula (VIIb)             or           Formula (VIIe);wherein V is CH, CRa, CRb, or N; and W is CH, CRd, CRe, or N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable saltthereof, wherein:R1 is substituted C1-C6 alkyl or unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, wherein the substituted C1-C6 alkyl is substituted with one or more unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; and the substituted C1-C6 heteroalkyl containing 1 N atom is substituted with one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2;or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms;or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms;or R1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein:R1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom;or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms;2020407016   15 Jul 2026or R1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atoms.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable saltthereof, wherein:X1 is CH, CF, or N;X2 is CH, CF, or N;X3 is CH, CF, or N; andX4 is CH, CF, or N;preferably wherein:X1 is N;X2 is CH;X3 is CH or CF; andX4 is CH.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein:Ra is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, 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 any substituted group of Ra is substituted with one or more R6 groups;Rb and Rc are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, -C(=O)R7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein any substituted group of Rb and Rc is substituted with one or more R6 groups;wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted C1-C6 alkyl;Rd is selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or2020407016   15 Jul 2026substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; andRe and Rf are independently selected from the group consisting of hydrogen, halogen, -OR4, -CN, -N(R4)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl;wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(=O)R7, or unsubstituted or substituted C1-C6 alkyl;preferably wherein:Ra is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;Rb and Rc are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2;wherein, if Ra, Rb, or Rc is attached to the N atom of a heteroaryl, then it is hydrogen, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2;Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -2020407016   15 Jul 2026CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of Rd is substituted with one or more R6 groups; andRe and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3;wherein, if Rd, Re, or Rf is attached to the N atom of a heteroaryl, then it is hydrogen, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: RA is unsubstituted or substituted pyridinyl, unsubstituted or substituted phenyl, or unsubstituted or substituted pyrrolyl, wherein if RA is substituted then RA is substituted with 1, or 2 groups selected from Ra, Rb, and Rc;RB is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if RB is substituted then RB is substituted with 1, 2, or 3 groups selected from Rd, Re, and Rf;X1 is CH or N;X2 is CH or N;X3 is CR13 or N;X4 is CH or N;2020407016   15 Jul 2026M is *-NR3-(C=O)- or *-(C=O)-NR3-, wherein * indicates the attachment point to R1; R11, R12, R13, and R14 are each independently hydrogen, F, Cl, -CH3, CF3, -CN, -OR4, or -N(R4)2;R1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5;or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl;or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms;or R1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6membered heterocycloalkyl containing 1-2 N atoms;preferably wherein:□ bK^ / ^RaRA is Rc     ^h where V is CH or N;Ra is selected from the group consisting ofhydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; andRb and Rc are independently selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3;? Rfnrb is Rd W Re, where W is CH or N;Rd is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3;Re and Rf are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, and -OCH3;X1 is CH or N;X2 is CH or N;2020407016   15 Jul 2026X3 is CH, CF, or N;X4 is CH or N;M is *-NH-(C=O)- or *-(C=O)-NH-, wherein * indicates the attachment point to R1;R1 is substituted C1-C6 alkyl or unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, wherein the substituted C1-C6 alkyl is substituted with one or more unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2; and the substituted C1-C6 heteroalkyl containing 1 N atom is substituted with one or more halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R4)2, -OR5, -CN, -CO2R5, -C(=O)N(R4)2, -SR5, -S(=O)R7, -S(=O)2R7, -NR4C(=O)R5, -NR4SO2R7, -SO2R7, or -SO2N(R4)2;or R1 is unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms;or R1 is unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms;or R1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5- or 6membered heterocycloalkyl containing 1-2 N atoms.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein:R1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, wherein any substituted group of R1 is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5;or R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl;or R1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), wherein the C2-C7 heterocycloalkyl is an unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl;preferably wherein:2020407016   15 Jul 2026R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl;or R1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, wherein if R1 is unsubstituted or substituted then it is substituted with one or more halogen, C1-C4 alkyl, -N(R4)2, or -OR5.

13. A compound selected from the group consisting of:1-1: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide;1-3: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide;1-4: N-[(2R)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide;1-5: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide;1-6: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide;1-7: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-8: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidine-4-carboxamide;1-9: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-10: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide;1-11: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-12: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide;1-13: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;2020407016   15 Jul 20261-14: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-15: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-16: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-17: N-[(2R)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-18: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide;1-19: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-20: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-21: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide;1-22: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[3,3'-bipyridin]-6-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-23: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-24: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-25: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide;1-26: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-27: 3-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[(3S)-1-methylpyrrolidin-3-yl]carbamoyl}piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-carboxamide;1-28: N-[(2S)-2-amino-3-hydroxypropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-29: 1-[2-chloro-6-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-30: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-31: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-32: 1-(2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-33: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-34: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-35: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide;1-36: 1-(4-acetyl-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-37: 1-[2-cyano-4-(difluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-38: 1-[4-cyano-2-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-39: 1-[2-cyano-4-(trifluoromethoxy)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-40: 1-(2,4-dicyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-41: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S,4S)*-4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-42: 1-[3-cyano-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-43: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-44: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2R)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide;1-45: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;2020407016   15 Jul 20261-46: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3R,4R)*-4-hydroxy-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-47: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-3-hydroxy-2-(methylamino)propyl]piperidine-4-carboxamide;1-48: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-51: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-52: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-53: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-dihydro-1-benzofuran-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-54: 4-[6-(1-benzofuran-7-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-55: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(hydroxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-56: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-57: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-58: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-(2-ethoxypyridin-3-yl)pyrazin-2-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-59: 1-[2-cyano-4-(1,1-difluoroethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-60: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-61: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,3-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-62: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-63: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-64: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-65: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-66: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-67: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-68: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2,5-difluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-69: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-5-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-70: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[1-(3-methylbutyl)-1H-pyrazol-5-yl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-71: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}piperidine-4-carboxamide;1-72: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxy-3-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-73: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indazol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-74: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-fluorophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-75: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)-3-fluorophenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-76: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-77: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-{6-[2-(trifluoromethyl)phenyl]pyridin-3-yl}piperidine-4-carboxamide;1-78: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyanophenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-79: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(methoxymethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-80: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methoxythiophen-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-81: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-82: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-83: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-84: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(1,1-difluoroethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-85: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethoxy)-[2,3'-bipyridin]-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-86: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-87: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3,5-difluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-88: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-89: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-90: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-91: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-92: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;2020407016   15 Jul 20261-93: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-94: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-95: 1-(2,4-dichlorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-96: 1-(2-cyano-4-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-97: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-98: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-99: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-100: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-101: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-102: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-103: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-104: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-105: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(4-methylpyrimidin-5-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-106: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-107: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2-(2-ethoxypyridin-3-yl)pyrimidin-5-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-108: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-109: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-110: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-111: 1-(4-chloro-2-cyano-6-fluorophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-112: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide;1-113: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-114: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethoxy)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-115: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-116: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-117: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(2-propylphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-118: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-119: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-120: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methylfuran-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-121: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-122: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(2-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide;1-123: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-124: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-125: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-126: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-127: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-128: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-129: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-fluoro-2-hydroxyphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-130: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxy-5-methylphenyl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-131: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-132: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-133: 1-[2-cyano-6-(trifluoromethyl)pyridin-3-yl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-134: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-135: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-136: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;2020407016   15 Jul 20261-137: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(cyanomethyl)phenyl]pyridin-3-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-138: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]-4-[6-(4-methylthiophen-3-yl)pyridin-3-yl]piperidine-4-carboxamide;1-139: 1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-140: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-141: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-142: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-143: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-144: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-145: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-146: 4-[6-(2-acetylthiophen-3-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-147: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylthiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-148: 4-[6-(2-cyano-3-fluorophenyl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-149: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(3-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-150: 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-151: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{6-[2-(difluoromethyl)phenyl]pyridin-3-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-152: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide;1-153: 4-[6-(5-cyano-1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-154: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{5'-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-155: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-156: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethylphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-157: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-methyl-1,2-oxazol-4-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-158: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-cyclopropyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-159: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-160: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-161: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-162: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-163: 1-(4-chloro-2-cyanophenyl)-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-164: 4-[4-(2-ethoxypyridin-3-yl)phenyl]-1-[2-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-165: 1-[3-chloro-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-166: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-167: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxythiophen-3-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-168: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-169: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-170: 1-(4-chloro-2-cyanophenyl)-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-171: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-172: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-173: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-174: 4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-175: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-176: 4-{[2,2'-bipyridin]-5-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-177: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methyl-[2,2'-bipyridin]-5-yl}-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-178: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3'-methoxy-[2,2'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-179: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-180: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-cyclopropyl-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-181: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[2'-(difluoromethyl)-[2,3'-bipyridin]-5-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-182: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(5-cyclopropyl-1,3-oxazol-4-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-183: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-184: ethyl (3S)-3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-amido}pyrrolidine-1-carboxylate;1-185: N-[(3S)-1-acetylpyrrolidin-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-186: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-187: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-188: N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-189: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyquinolin-3-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-190: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-7-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-191: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-indol-2-yl)pyridin-3-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-192: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-193: 4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-194: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-195: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-196: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-197: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide;1-198: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-199: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-200: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-201: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-202: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-203: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-204: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-205: N-(3-aminopropyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-206: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[3-(methylamino)propyl]piperidine-4-carboxamide;1-207: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[3-(dimethylamino)propyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-208: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-ethyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-209: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-210: 4-{3,5'-difluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide;1-211: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide;1-212: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-213: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-214: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;2020407016   15 Jul 20261-215: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-216: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-217: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide;1-218: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-219: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;1-220: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1-methylazetidin-3-yl)methyl]piperidine-4-carboxamide;1-221: N-{1-azabicyclo[2.2.1]heptan-4-yl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-222: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-223: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-224: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-225: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-226: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-227: 4-[6-(2-ethoxyphenyl)pyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-228: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-229: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide;2020407016   15 Jul 20261-230: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-231: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}piperidine-4-carboxamide;1-232: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}piperidine-4-carboxamide;1-233: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-aminocyclobutyl]piperidine-4-carboxamide;1-234: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-aminocyclobutyl]piperidine-4-carboxamide;1-235: N-{[(2S)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-236: N-{[(2R)-azetidin-2-yl]methyl}-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-237: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-238: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-239: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,3S)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide;1-240: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1R,3R)-3-(dimethylamino)cyclobutyl]piperidine-4-carboxamide;1-241: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide;1-242: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-243: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-244: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}piperidine-4-carboxamide;2020407016   15 Jul 20261-245: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-246: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-247: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-248: N-[2-(azetidin-1-yl)ethyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-249: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-250: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-251: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide;1-252: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[(1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl]piperidine-4-carboxamide;1-253: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S)-1,3-dimethylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-254: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-255: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-256: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-257: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-258: rac-N-[(1R,2S)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-259: rac-N-[(1R,2R)-2-aminocyclopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-260: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-261: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-262: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{3-[(dimethylamino)methyl]oxetan-3-yl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-263: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[1-(dimethylamino)cyclopropyl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-264: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-(dimethylamino)oxolan-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-265: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[ethyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-266: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{2-[cyclopropyl(methyl)amino]ethyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-267: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-268: rac-1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-269: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3R,4R)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-270: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-271: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-272: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-273: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-274: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-275: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-276: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-277: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-278: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-279: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-280: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-{[(2R)-4,4-difluoro-1-methylpyrrolidin-2-yl]methyl}-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-281: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-282: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-283: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-284: N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;2020407016   15 Jul 20261-285: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-286: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidine-4-carboxamide;1-287: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-288: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-289: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-290: 4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-291: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]piperidine-4-carboxamide;1-292: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)-5-fluoropyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-293: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-294: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-295: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-296: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-297: N-[(2S)-1-(dimethylamino)propan-2-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-298: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-299: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;2020407016   15 Jul 20261-300: N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-301: 4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-302: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-303: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{3-fluoro-2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-304: N-[2-(dimethylamino)ethyl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-305: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-306: 1-[2-fluoro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-307: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-308: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-309: 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-310: 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-311: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[2-(methylamino)ethyl]piperidine-4-carboxamide;1-312: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-313: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-314: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-315: 4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-316: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-317: N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;1-318: 1-(2,4-dichlorophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-319: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-320: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-321: 4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-322: 1-(2,4-dichlorophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-323: 1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-324: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidine-4-carboxamide;1-325: 1-(4-chloro-2-cyanophenyl)-N-[(2S)-1-(dimethylamino)propan-2-yl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-326: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]-N-[(2S)-1-(methylamino)propan-2-yl]piperidine-4-carboxamide;1-327: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2S)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide;1-328: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3S)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide;1-329: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(3R)-4-methylmorpholin-3-yl]methyl}piperidine-4-carboxamide;1-330: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]-N-{[(2R)-4-methylmorpholin-2-yl]methyl}piperidine-4-carboxamide;1-331: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidine-4-carboxamide;2020407016   15 Jul 20261-332: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2S)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-333: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)propyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-334: 1-[2-cyano-4-(trifluoromethyl)phenyl]-N-[(2R)-2-(dimethylamino)-3-hydroxypropyl]-4-{2'-ethoxy-3-fluoro-[2,3'-bipyridin]-5-yl}piperidine-4-carboxamide;1-335: N-[2-(dimethylamino)ethyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]-1-[2-fluoro-4-(trifluoromethyl)phenyl]piperidine-4-carboxamide;2-1: 2-{4-[2-(dimethylamino)ethoxy]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-1-yl}-5-(trifluoromethyl)benzonitrile;2-2: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl N-[2-(dimethylamino)ethyl]carbamate;2-3: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}propanamide;2-4: 3-amino-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}propanamide;2-5: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)propanamide;2-6: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide;2-7: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2-8: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}pyrrolidine-3-carboxamide;2-9: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2-10: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(dimethylamino)propanamide;2-11: (2S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide;2-12: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate;2020407016   15 Jul 20262-13: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}carbamate;2-14: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-[(2-hydroxyethyl)amino]piperidin-1-yl)-5-(trifluoromethyl)benzonitrile;2-15: 2-(4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}-4-{[2-(methylamino)ethyl]amino}piperidin-1-yl)-5-(trifluoromethyl)benzonitrile;2-16: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylazetidine-3-carboxamide;2-17: (2R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[4-(2-ethoxypyridin-3-yl)phenyl]piperidin-4-yl}-1-methylpyrrolidine-2-carboxamide;2-18: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate;2-19: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea;2-20: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea;2-21: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide;2-22: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}carbamate;2-23: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)azetidine-1-carboxamide;2-24: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-3-(methylamino)pyrrolidine-1-carboxamide;2-25: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylazetidine-3-carboxamide;2-26: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-2-(dimethylamino)acetamide;2-27: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2-28: (3S)-N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide;2020407016   15 Jul 20262-29: (3R)-N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide;2-30: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-3-(dimethylamino)propanamide;2-31: N-[1-(4-chloro-2-cyanophenyl)-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl]-2-(dimethylamino)acetamide;2-32: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide;2-33: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2-34: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide;2-35: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide;2-36: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide;2-37: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-1-methylazetidine-3-carboxamide;2-38: N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-2-(dimethylamino)acetamide;2-39: (3S)-N-[1-(4-chloro-2-cyanophenyl)-4-{2'-ethoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl]-1-methylpyrrolidine-3-carboxamide;2-40: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-methoxy-[2,3'-bipyridin]-5-yl}piperidin-4-yl}-1-methylazetidine-3-carboxamide;2-41: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate;2-42: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}carbamate;2-43: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea;2-44: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}pyrrolidine-3-carboxamide;2020407016   15 Jul 20262-45: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylazetidine-3-carboxamide;2-46: (3S)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide; and2-47: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2-48: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea;2-49: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate;2-50: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate;2-51: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea;2-52: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea;2-53: (3S)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate;2-54: (3R)-1-methylpyrrolidin-3-yl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate;2-55: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3S)-1-methylpyrrolidin-3-yl]urea;2-56: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[(3R)-1-methylpyrrolidin-3-yl]urea;2-57: 2-(dimethylamino)ethyl N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}carbamate;2-58: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-[2-(dimethylamino)ethyl]urea;2-59: 1-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(1-methylazetidin-3-yl)urea;2-60: (3R)-N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-1-methylpyrrolidine-3-carboxamide;2020407016   15 Jul 20262-61: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-2-(dimethylamino)acetamide;2-62: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide;2-63: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(methylamino)propanamide; and2-64: N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[6-(2-ethoxypyridin-3-yl)pyridazin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide;or a pharmaceutically acceptable salt thereof.

14. A compound that is N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein the compound is N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide.

16. The compound of claim 14, wherein the compound is a pharmaceutically acceptable salt of N-{1-[2-cyano-4-(trifluoromethyl)phenyl]-4-[5-fluoro-6-(2-methoxyphenyl)pyridin-3-yl]piperidin-4-yl}-3-(dimethylamino)propanamide.

17. A pharmaceutical composition comprising a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

18. Use of a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Cushing’s syndrome, ectopic Cushing's syndrome, congenital adrenal hyperplasia (CAH), or for reducing the secretion of adrenocorticotropic hormone (ACTH) in a mammal.

19. A method of treating Cushing’s syndrome, ectopic Cushing's syndrome, congenital adrenal hyperplasia (CAH), or for reducing the secretion of adrenocorticotropic2020407016   15 Jul 2026hormone (ACTH) in a mammal, comprising administering to the mammal a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof.