SPIROCYCLIC PIPERIDINE MELANOCORTIN SUBTYPE-2 RECEPTOR (MC2R) ANTAGONISTS AND USES THEREOF - Patent application

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 953,001, filed December 23, 2019, which is incorporated by reference in its entirety.

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

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

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

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

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

[0007] Also described herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, dermal, or ocular administration.In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration.In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

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

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

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

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

[0012] An article of manufacture is provided that includes packaging material, a compound of Formula (I) or a pharma- ceutically acceptable salt thereof within the packaging material, and a label indicating that the compound or composition, or a pharma- ceutically acceptable salt, tautomer, pharma- ceutically acceptable N-oxide, pharma- ceutically acceptable active metabolite, pharma- ceutically acceptable prodrug, or pharma- ceutically acceptable solvate thereof, is used for modulating one or more melanocortin receptor subtype proteins or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that would benefit from modulation of one or more melanocortin receptor subtype proteins.

[0013] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, however, it will be understood that the detailed description and specific examples, while illustrating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

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

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

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

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

[0020] Congenital adrenal hyperplasia (CAH) is characterized by reduced or lost cortisol synthesis and excess ACTH and corticotropin releasing hormone. CAH can result from various genetic defects in the adrenal steroid biosynthetic pathway. In some embodiments, CAH results from a mutation in 21β-hydroxylase. Lack of cortisol removes the negative feedback to the pituitary gland, leading to hypersecretion of ACTH. As a result, the adrenal glands are overstimulated, causing overproduction of steroid precursors, which also have adverse effects (e.g., hyperandrogenemia, etc.). Administration of replacement glucocorticoids typically cannot adequately suppress ACTH without also causing Cushing-like symptoms. In some embodiments, MC2R antagonists are used in the treatment of CAH.

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

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

[0023] compound The compound of formula (I), including its pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, is a melanocortin receptor modulator.In some embodiments, the compound of formula (I), including its pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, is an MC2R modulator.In some embodiments, the MC2R modulator is an MC2R antagonist.

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

[0025] [ka] During the ceremony, R A is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one, two, three, or four groups selected from R a , R b , and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl; R a , R b , and R c Any substituted group may be selected from one or more R 6 is substituted with a group, Here, R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R B is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, three, or four groups selected from Rd , R e , and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, wherein R d , R e , and R f Any substituted group may be selected from one or more R 6 is substituted with a group, Here, R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; X 1 is CR 11 or N, X 3 is CR 13 or N, X 4 is CR 14 or N, R 11 , R 13 , and R 14 each independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, -OR 4 , -SR 4 , -CO2R 4, -C(=O)N(R 4 )2, or -N(R 4 )2, W is absent or -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, -C(=O)-, # -C(=O)-O-, # -C(=O)-C(R 3 )2-, or # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring, Y is absent or -(C=O)-, * -O(C=O)-, * -NR 2 -(C=O)-, -(SO2)-, or * -NR 2 -(SO2)-, where * is R 1 indicates the point of attachment to R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R 1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7, or -SO2N(R 4 )2, R 2 are each independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R 3 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; R 4 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Or, two R's 4 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; R 5 are each independently selected from the group consisting of hydrogen, substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R 6 are each independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 alkoxy, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -COR 5 , -CH2CO2R 5 , -C(=O)N(R 4 )2, -C(=O)N(R 4 ) OR 5 , -CH2C(=O)N(R 4 )2, -N(R 4 )2, -CH2N(R 4 )2, -C(R5 )2N(R 4 )2, -NR 4 C(=O)R 5 , -CH2NR 4 C(=O)R 5 , -NR 4 C(=O)N(R 5 )2, -NR 4 C(=O)N(R 4 )2, C(R 5 )=N(R 4 )-OR 5 , -SR 5 , -S(=O)R 7 , -SO2R 7 , or -SO2N(R 4 ) 2, and R 7 are each independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

[0026] In some embodiments, W is -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, -C(=O)-, # -C(=O)-O-, # -C(=O)-C(R 3 )2-, or # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring. In some embodiments, W is -C(R 3 )2-, -C(R 3 )2-C(R 3 )2-, or -C(=O)-. In some embodiments, W is -C(R 3 )2- or -C(=O)-.

[0027] In some embodiments, W is -C(R 3 In some embodiments, W is -C(R 3 )2- and R 3are the same. In some embodiments, W is -C(R 3 )2- and R 3 are different. In some embodiments, W is -CH(R 3 In some embodiments, W is -C(R 3 )2- and R 3 are each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, W is -C(R 3 )2- and R 3 are each independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, W is -CH(R 3 )- and R 3 is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, W is -CH(R 3 )- and R 3 is hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, W is -CH(R 3 )- and R 3 is unsubstituted or substituted C1-C6 alkyl. In some embodiments, W is -CH(R 3 )- and R 3 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, W is -CH(CH3)-.

[0028] In some embodiments, W is -CH2-.

[0029] In some embodiments, W is -C(=O)-.

[0030] In some embodiments, W is -CH2-, -CH(CH3)-, or -C(=O)-.

[0031] In some embodiments, W is absent.

[0032] In some embodiments, W is # -C(=O)-O-, - # -C(=O)-C(R 3 )2-, or # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring. In some embodiments, W is # -C(=O)-C(R 3 )2-, or # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring.

[0033] In some embodiments, W is # -C(=O)-C(R 3 )2-, where: # indicates the point of attachment to the N atom of the ring. In some embodiments, W is # -C(=O)-C(R 3 )2-, where: # indicates the point of attachment to the N atom of the ring, and R 3 In some embodiments, W is # -C(=O)-C(R 3 )2-, where: # indicates the point of attachment to the N atom of the ring, and R 3 In some embodiments, W is # -C(=O)-C(R 3 )2-, where: # indicates the point of attachment to the N atom of the ring, and R 3 are each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, W is # -C(=O)-C(R 3 )2-, where: # indicates the point of attachment to the N atom of the ring, and R 3 is independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). #-C(=O)-CH2-, where # indicates the point of attachment to the N atom of the ring.

[0034] In some embodiments, W is # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring. In some embodiments, W is # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring, and R 2 is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, W is # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring, and R 2 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, W is # -C(=O)NR 2 -where: # indicates the point of attachment to the N atom of the ring, and R 2 is hydrogen or -CH3. In some embodiments, W is # -C(=O)NH-, where # indicates the point of attachment to the N atom of the ring.

[0035] In some embodiments, Y is absent or -(C=O)-, * -O(C=O)-, * -NR 2 -(C=O)-, -(SO2)-, or * -NR 2 -(SO2)-, where * is R 1 In some embodiments, Y is absent, -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * is R 1 The attachment points to the

[0036] In some embodiments, Y is absent.

[0037] In some embodiments, Y is -(C=O)-.

[0038] In some embodiments, Y is -(SO2)-.

[0039] In some embodiments, Y is * -NR 2 -(C=O)-, where * is R 1 In some embodiments, Y represents the point of attachment to * -NR 2 -(C=O)-, where * is R 1 indicates the point of attachment to, and R 2 is hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, Y is * -NR 2 -(C=O)-, where * is R 1 indicates the point of attachment to, and R 2 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, Y is * -NR 2 -(C=O)-, where * is R 1 indicates the point of attachment to, and R 2 is hydrogen or -CH3. In some embodiments, Y is * -NH-(C=O)-, where * is R 1 In some embodiments, Y represents the point of attachment to * -N(CH3)-(C=O)-, where * is R 1 The attachment points to the

[0040] In some embodiments, Y is absent or -(C=O)-.

[0041] In some embodiments, R 2 are each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 2 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 2 are each independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). 2 are each independently hydrogen or -CH. In some embodiments, R 2 Each is -CH3. In some embodiments, R 2 are hydrogen.

[0042] In some embodiments, R 3 are each independently hydrogen, halogen, or unsubstituted or substituted C-C alkyl. 3 are each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 3 are each independently hydrogen, -F, -Cl, -CH, -CHCH, -CHCHCH, or -CH(CH). 3 are each independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). 3 are each independently hydrogen or -CH. In some embodiments, R 3 Each is -CH3. In some embodiments, R 3 are hydrogen.

[0043] In some embodiments, W is -C(R 3 )2- or -C(=O)-, and Y is absent or -(C=O)-, * -NR 2-(C=O)-, or -(SO2)-, where * is R 1 indicates the point of attachment to R 2 are each independently hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH); and R 3 are each independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0044] In some embodiments, W is -CH2-, -CH(CH3)-, or -C(=O)-, and Y is absent, -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 The attachment points to the

[0045] In some embodiments, W is -CH2- or -C(=O)- and Y is absent or -(C=O)-.

[0046] In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R Ais an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , or R c is substituted with the group:

[0047] In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is R a , R b , and R c In some embodiments, R A is one R a In some embodiments, R A is one R c is replaced by.

[0048] In some embodiments, R Ais unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted 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, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with the group:

[0049] In some embodiments, R A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, where R A If is substituted, R A is R a , Rb , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c is substituted with one or two groups selected from:

[0050] In some embodiments, R A is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c is substituted with one or two groups selected from:

[0051] In some embodiments, R A teeth,

[0052] [ka] It is.

[0053] In some embodiments, R A teeth,

[0054] [ka] In some embodiments, R A teeth,

[0055] [ka] In some embodiments, RA teeth,

[0056] [ka] It is.

[0057] In some embodiments, R A teeth,

[0058] [ka] and V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0059] In some embodiments, R A teeth,

[0060] [ka] and V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0061] In some embodiments, the compound has the structure of formula (II):

[0062] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0063] In some embodiments, the compound has the structure of Formula (IIa), (IIb), (IIc), or (IId), or a pharma- ceutically acceptable salt or solvate thereof.

[0064] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0065] In some embodiments, the compound has the structure of Formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IId), or a pharma- ceutically acceptable salt or solvate thereof.

[0066] In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R A If is substituted, R A is R a , R b , and R cIn some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where R A If is substituted, R A is R a , R b , or R c is substituted with the group:

[0067] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with the group:

[0068] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, where R AIf is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with the group:

[0069] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, or unsubstituted or substituted thienyl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is one R a , R b , or R c is substituted with the group:

[0070] In some embodiments, R A teeth,

[0071] [ka] or R A teeth,

[0072] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0073] In some embodiments, R A teeth,

[0074] [ka] or R A teeth,

[0075] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0076] In some embodiments, R A teeth,

[0077] [ka] or R A teeth,

[0078] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0079] In some embodiments, R A teeth,

[0080] [ka] In some embodiments, R A teeth,

[0081] [ka] It is.

[0082] In some embodiments, R A teeth,

[0083] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0084] [ka] In some embodiments, R A teeth,

[0085] [ka] In some embodiments, R A teeth,

[0086] [ka] In some embodiments, R A teeth,

[0087] [ka] It is.

[0088] In some embodiments, R A teeth,

[0089] [ka] or R A teeth,

[0090] [ka] Here, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0091] In some embodiments, R A teeth,

[0092] [ka] or R A teeth,

[0093] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0094] In some embodiments, R A teeth,

[0095] [ka] where R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R c is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R c is hydrogen or unsubstituted or substituted C-C alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHCHCHCHCHCHCH, or -CHCHCH(CH). c is hydrogen, -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, R c is hydrogen or -CH3. In some embodiments, R c is -CH3. In some embodiments, R c is hydrogen. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl. In some embodiments, R c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. cis -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0096] In some embodiments, R A teeth,

[0097] [ka] and Y 1 is NR c , O, or S; and Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0098] [ka] and Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0099] [ka] and Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , or CR b and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0100] [ka] and Y 1 is NR c and Y 2 and Y 3 are CH, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0101] In some embodiments, R A teeth,

[0102] [ka] In some embodiments, R A teeth,

[0103] [ka] It is.

[0104] In some embodiments, R A teeth,

[0105] [ka] and Y 1 is NR c , O, or S; and Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0106] [ka] and Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0107] [ka] and Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , or CR b and R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R A teeth,

[0108] [ka] and Y 1 is NR c and Y 2 and Y 3 are CH, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0109] In some embodiments, the compound has the structure of formula (III):

[0110] [ka] During the ceremony, Y 1 is NR c , O, or S; Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0111] In some embodiments, the compound has the structure of Formula (IIIa), (IIIb), (IIIc), or (IIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0112] [ka] During the ceremony, Y 1 is NR c , O, or S; Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0113] In some embodiments, the compound has the structure of Formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IIIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (IIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0114] In some embodiments, R A is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c In some embodiments, R A is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R A If is substituted, R A is R a , R b , and R c is substituted with one or two groups selected from:

[0115] In some embodiments, R A is unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, substituted or unsubstituted azabenzyl, unsubstituted or substituted phenylalanine ... unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein R A If is substituted, R A is R a , R b , and R c In some embodiments, R A If is substituted, R A is R a , R b , and R c is substituted with one or two groups selected from:

[0116] In some embodiments, R Bis unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0117] In some embodiments, R Bis 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 oxazolyl, thiadiazolyl, 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 naphthyl Lysinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolyl, 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 unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, RB is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0118] In some embodiments, R B is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0119] In some embodiments, R B is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f In some embodiments, R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0120] In some embodiments, R B teeth,

[0121] [ka] In some embodiments, R B teeth,

[0122] [ka] In some embodiments, R B teeth,

[0123] [ka] In some embodiments, R B teeth,

[0124] [ka] It is.

[0125] In some embodiments, R B teeth,

[0126] [ka] and Z is CH, CR d , C.R. e or N. In some embodiments, Z is CH or N.

[0127] In some embodiments, the compound has the structure of formula (IV):

[0128] [ka] where V is CH, CR a , C.R. b or N, and Z is CH, CR d , C.R. e , or N.

[0129] In some embodiments, V is CH or N. In some embodiments, Z is CH or N. In some embodiments, V is CH or N and Z is CH or N.

[0130] In some embodiments, the compound has the structure of formula (V):

[0131] [ka] where V is CH, CR a , C.R. b or N, and Z is CH, CR d , C.R. e , or N.

[0132] In some embodiments, V is CH or N. In some embodiments, Z is CH or N. In some embodiments, V is CH or N and Z is CH or N.

[0133] In some embodiments, the compound has the structure of formula (VI):

[0134] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0135] In some embodiments, the compound has the structure of Formula (VIa) or (VIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0136] [ka] where V is CH, CR a , C.R. bIn some embodiments, V is CH or N.

[0137] In some embodiments, the compound has the structure of Formula (VIa), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of Formula (VIb), or a pharma- ceutically acceptable salt or solvate thereof.

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

[0139] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0140] In some embodiments, the compound has the structure of Formula (VId):

[0141] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0142] In some embodiments, the compound has the structure of formula (VII):

[0143] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0144] In some embodiments, the compound has the structure of Formula (VIIa) or (VIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0145] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0146] In some embodiments, the compound has the structure of Formula (VIIa), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of Formula (VIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0147] In some embodiments, the compound has the structure of formula (VIIc):

[0148] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0149] In some embodiments, the compound has the structure of formula (VIId), or a pharma- ceutically acceptable salt or solvate thereof:

[0150] [ka] where V is CH, CR a , C.R. b In some embodiments, V is CH or N.

[0151] In some embodiments, the compound has the structure of formula (VIII):

[0152] [ka] During the ceremony, Y 1 is NR c , O, or S; Y 2 and Y 3 are independent, CH, CR a , C.R. b , or N, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and Z is CH, CR d , C.R. e , or N.

[0153] In some embodiments, the compound of formula (VIII) has the following structure: or a pharma- ceutically acceptable salt or solvate thereof.

[0154] [ka]

[0155] In some embodiments, Y is absent or -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0156] In some embodiments, W is -CH-, -CH(R 3 ), or -(C=O)-. In some embodiments, W is -CH2-, or -(C=O)-.

[0157] In some embodiments, Z is CH or N.

[0158] In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , C.R. b or N. In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independent, CH, CR a , or CR b In some embodiments, Y 1 is NR c and Y 2 and Y 3 are CH, respectively.

[0159] In some embodiments, the compound has the structure of formula (IXa):

[0160] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and Z is CH, CR d , C.R. e , or N.

[0161] In some embodiments, Y is absent or -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0162] In some embodiments, W is -CH-, -CH(R3 ), or -(C=O)-. In some embodiments, W is -CH2-, or -(C=O)-.

[0163] In some embodiments, Z is CH or N.

[0164] In some embodiments, R c is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R c is hydrogen or unsubstituted or substituted C-C alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0165] In some embodiments, the compound has the structure of Formula (IXb) or (IXc), or a pharma- ceutically acceptable salt or solvate thereof.

[0166] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and Z is CH, CR d , C.R. e , or N.

[0167] In some embodiments, the compound has the structure of formula (IXb), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of formula (IXc), or a pharma- ceutically acceptable salt or solvate thereof.

[0168] In some embodiments, Y is absent or -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0169] In some embodiments, W is -CH-, -CH(R 3 ), or -(C=O)-. In some embodiments, W is -CH2-, or -(C=O)-.

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

[0171] In some embodiments, R c is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl. In some embodiments, R c is hydrogen or unsubstituted or substituted C-C alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

[0172] In some embodiments, the compound has the structure of Formula (IXd), (IXe), (IXf), or (IXg), or a pharma- ceutically acceptable salt or solvate thereof.

[0173] [ka] Z is CH, CR d , C.R. e , or N.

[0174] In some embodiments, the compound has the structure of formula (IXd), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IXe), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IXf), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IXg), or a pharma- ceutically acceptable salt or solvate thereof.

[0175] In some embodiments, Y is absent or -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0176] In some embodiments, W is -CH-, -CH(R 3 ), or -(C=O)-. In some embodiments, W is -CH2-, or -(C=O)-.

[0177] In some embodiments, Z is CH or N.

[0178] In some embodiments, the compound has the structure of formula (X):

[0179] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0180] In some embodiments, Y is absent or -(C=O)-, *-NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0181] In some embodiments, the compound has the structure of Formula (Xa) or (Xb), or a pharma- ceutically acceptable salt or solvate thereof.

[0182] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0183] In some embodiments, the compound has the structure of formula (Xa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (Xb), or a pharma- ceutically acceptable salt or solvate thereof.

[0184] In some embodiments, the compound has the structure of Formula (Xc):

[0185] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0186] In some embodiments, the compound has the structure of formula (Xd):

[0187] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0188] In some embodiments, the compound has the structure of formula (XI):

[0189] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0190] In some embodiments, Y is absent or -(C=O)-, * -NH-(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0191] In some embodiments, the compound has the structure of formula (XIa) or (XIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0192] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0193] In some embodiments, the compound has the structure of formula (XIa), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of formula (XIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0194] In some embodiments, the compound has the structure of formula (XIc):

[0195] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0196] In some embodiments, the compound has the structure of formula (XId):

[0197] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0198] In some embodiments, R Bis unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from:

[0199] In some embodiments, R B teeth,

[0200] [ka] or R B teeth,

[0201] [ka] where R f is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0202] In some embodiments, R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted -(C1-C6 alkyl)-(C3-C6 cycloalkyl), or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, where R 1 contains a basic amine group.

[0203] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1 to 4 N atoms and 0 or 1 O or S atom, an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1 to 2 N atoms, or an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where R 1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0204] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2 or R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; or R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0205] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, or R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or R 1is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0206] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0207] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom. In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2.

[0208] In some embodiments, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom.

[0209] In some embodiments, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms.

[0210] In some embodiments, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0211] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, C1-C4 alkyl, -N(R 4 )2, or -OR 5 or R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R 1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0212] In some embodiments, R1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0213] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, C1-C4 alkyl, -N(R 4 )2, or -OR 5 is replaced by.

[0214] In some embodiments, the compound has the structure of formula (XIIa), (XIIb), (XIIc), or (XIId), or a pharma- ceutically acceptable salt or solvate thereof:

[0215] [ka] where V is CH, CR a , C.R. b or N, and Z is CH, CR d , C.R. e , or N.

[0216] In some embodiments, the compound has the structure of formula (XIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0217] In some embodiments, V is CH or N. In some embodiments, Z is CH or N. In some embodiments, V is CH or N and Z is CH or N.

[0218] In some embodiments, the compound has the structure of formula (XIIIa), (XIIIb), (XIIIc), or (XIIId), or a pharma- ceutically acceptable salt or solvate thereof:

[0219] [ka] Z is CH, CR d , C.R. e , or N.

[0220] In some embodiments, the compound has the structure of formula (XIIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIIIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIIIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0221] In some embodiments, Z is CH or N.

[0222] In some embodiments, the compound has the structure of formula (XIV):

[0223] [ka] During the ceremony, R A is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where R A If is substituted, R A is R a , R b , and R c is replaced by R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R BIf is substituted, R B is R d , R e , and R f is replaced by W is -C(R 3 )2- or -C(=O)-, and Y is absent, -(C=O)-, -(C=O)NR 2 - * or -(SO2)-, where * is R 1 The attachment points to the

[0224] In some embodiments, X 1 is CR 11 and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is N and X 3 is CR 13 and X 4 is CR 14 In some embodiments, X 1 is CR 11 and X 3 is N, and X 4 is CR 14 In some embodiments, X 1 is N and X 3 is CR 13 and X 4 is N. In some embodiments, X 1 is N and X 3 is N, and X 4 is CR 14 It is.

[0225] In some embodiments, X 1 is CR 11 or N and X 3 is CR 13 and X 4 is CR 14 It is.

[0226] In some embodiments, R 11 , R 13 , and R 14 each independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 11 , R 13 , and R 14 each independently represents hydrogen, halogen, C1-C6 alkyl, fluoroalkyl, unsubstituted C3-C6 cycloalkyl, -CN, or -OR 4 In some embodiments, R 11 , R 13 , and R 14 are each independently hydrogen, F, Cl, Br, -CN, -OCH, -OCHCH, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CH(CH)CHCHCH, -C(CH), -CHF, -CHF, -CF, or cyclopropyl. 11 , R 13 , and R 14 are each independently hydrogen or F.

[0227] In some embodiments, X 1 is CH or CF, and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is N and X 3 is CH or CF, and X 4 is CH or CF. In some embodiments, X 1 is CH or CF, and X 3 is N, and X 4 is CH or CF. In some embodiments, X 1 is N and X 3 is CH or CF, and X 4is N. In some embodiments, X 1 is N and X 3 is N, and X 4 is CH or CF.

[0228] In some embodiments, X 1 is CH, CF, or N, and X 3 is CH or CF, and X 4 is CH or CF.

[0229] In some embodiments, X 1 is CH, CF, or N, and X 3 is CH, and X 4 is CH. In some embodiments, X 1 is CH or N, and X 3 is CH, and X 4 is CH.

[0230] In some embodiments, the compound has the structure of formula (XV):

[0231] [ka] During the ceremony, R A is an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; R a Any substituted group may be selected from one or more R 6 group, and R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group may be selected from one or more R 6 is substituted with a group, Here, R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; R B is an unsubstituted or substituted phenyl or an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4)2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group may be selected from one or more R 6 group, and R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; Here, R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl; X 1 is CR 11 or N, R 11 is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, -CN, -OR 4 , or -N(R 4 )2, W is -C(R 3 )2- or -C(=O)-; Y is absent or -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * is R 1 indicates the point of attachment to, and R 1 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R1 The optional substituted groups in the formula (I) are selected from the group consisting of one or more of halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R 4 )2, -OR 5 , -CN, -CO2R 5 , -C(=O)N(R 4 )2, -SR 5 , -S(=O)R 7 , -S(=O)2R 7 , -NR 4 C(=O)R 5 , -NR 4 SO2R 7 , -SO2R 7 , or -SO2N(R 4 )2, Or, R 1 is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Or, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0232] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R A If is substituted, R A is R a , R b , and R c and is substituted with one or two groups selected from Here, R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R7 or unsubstituted or substituted C1-C6 alkyl; R B is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R B If is substituted, R B is R d , R e , and R f and is substituted with one, two, or three groups selected from X 1 is CR 11 or N, R 11 is hydrogen, F, Cl, -CH3, CF3, -CN, -OR 4 , or -N(R 4 )2, and R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, C1-C4 alkyl, -N(R 4 )2, or -OR 5 is replaced by Or, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R 1 is an unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1-2 N atoms; Or, R 1 is an unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms.

[0233] In some embodiments, Y is absent or -(C=O)-.

[0234] In some embodiments, W is -CH-, -CH(R 3), or -(C=O)-. In some embodiments, W is -CH2-, or -(C=O)-.

[0235] In some embodiments, R A teeth,

[0236] [ka] or R A teeth,

[0237] [ka] V is CH or N, and R B teeth,

[0238] [ka] and Z is CH or N.

[0239] In some embodiments, R A teeth,

[0240] [ka] and R B teeth,

[0241] [ka] and Z is CH or N.

[0242] In some embodiments, R A teeth,

[0243] [ka] V is CH or N, and R B teeth,

[0244] [ka] and Z is CH or N.

[0245] In some embodiments, the compound has the structure of Formula (XVIa) or (XVIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0246] [ka]

[0247] In some embodiments, the compound has the structure of Formula (XVIa), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of Formula (XVIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0248] In some embodiments, R a is hydrogen, halogen, -OR 4 , -CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R b and R c are independently hydrogen, halogen, -OR 4 , —CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl, and V is CH or N.

[0249] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; R b and R cis independently selected from the group consisting of hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -CN, and -OCH3.

[0250] In some embodiments, the compound has the structure of formula (XVIc) or (XVId), or a pharma- ceutically acceptable salt or solvate thereof:

[0251] [ka] V is CH or N.

[0252] In some embodiments, the compound has the structure of formula (XVIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVId), or a pharma- ceutically acceptable salt or solvate thereof.

[0253] In some embodiments, X 1 is N. In some embodiments, X 1 is CH.

[0254] In some embodiments, Y is absent or -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0255] In some embodiments, the compound has the structure of formula (XVIIa) or (XVIIb), or a pharma- ceutically acceptable salt or solvate thereof:

[0256] [ka] During the ceremony, R c is hydrogen, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0257] In some embodiments, the compound has the structure of Formula (XVIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (XVIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0258] In some embodiments, R a and R b are independently hydrogen, halogen, -OR 4 , -CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl.

[0259] In some embodiments, R a and R b is independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl; R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C3-C6 cycloalkyl.

[0260] In some embodiments, the compound has the structure of formula (XVIIc) or (XVIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0261] [ka]

[0262] In some embodiments, the compound has the structure of formula (XVIIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0263] In some embodiments, R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, or unsubstituted C3-C6 cycloalkyl.

[0264] In some embodiments, X 1 is N. In some embodiments, X 1 is CH.

[0265] In some embodiments, Y is absent or -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0266] In some embodiments, the compound has the structure of formula (XVIIIa) or (XVIIIb), or a pharma- ceutically acceptable salt or solvate thereof:

[0267] [ka] Z is CH or N.

[0268] In some embodiments, the compound has the structure of Formula (XVIIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (XVIIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0269] In some embodiments, R d is hydrogen, halogen, -OR 4 , -CN, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; and R e and R f are independently hydrogen, halogen, -OR 4 , -CN, unsubstituted or substituted C1-C6 alkyl, and unsubstituted or substituted C1-C6 fluoroalkyl.

[0270] In some embodiments, R d is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, and -CF3; and R e and R f is independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, and -OCH3.

[0271] In some embodiments, the compound has the structure of formula (XVIIIc) or (XVIIId), or a pharma- ceutically acceptable salt or solvate thereof:

[0272] [ka] Z is CH or N.

[0273] In some embodiments, the compound has the structure of formula (XVIIIc), or a pharma- ceutically acceptable salt or solvate thereof.In some embodiments, the compound has the structure of formula (XVIIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0274] In some embodiments, R d is selected from the group consisting of F, Cl, -CN, -OCH3, -CH3, -CH2F, -CHF2, and -CF3.

[0275] In some embodiments, X 1 is N. In some embodiments, X 1 is CH.

[0276] In some embodiments, Y is absent or -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * is R 1 In some embodiments, Y is absent or is -(C=O)-.

[0277] In some embodiments, R 1 is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, C1-C4 alkyl, -N(R 4 )2, or -OR 5 or R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; or R 1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0278] In some embodiments, R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl.

[0279] In some embodiments, R 1is an unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where R 1 The optional substituted groups may be one or more of halogen, C1-C4 alkyl, -N(R 4 )2, or -OR 5 is replaced by.

[0280] In some embodiments, R a , R b , and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R a , R b , and R c Any substituted group may be selected from one or more R 6 group or one R a and one R b is R A If present on adjacent atoms of a R b and together with the intervening atoms to which they are attached form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is unsubstituted or is substituted with one or more R 6 group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl; and R d , R e , and Rf are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein R d , R e , and R f Any substituted group may be selected from one or more R 6 group, where R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted C2-C7 heterocycloalkyl.

[0281] In some embodiments, R a is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, and unsubstituted or substituted C3-C6 cycloalkyl; R a Any substituted group may be selected from one or more R 6 group, and R b and R c are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl; R b and R c Any substituted group may be selected from one or more R 6 group, where R a , R b , or R c When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl.

[0282] In some embodiments, R a is hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH 2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF 3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and R b and R care independently hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -C HCN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2; R a , R b , or R c When is attached to the N atom of a heteroaryl, 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.

[0283] In some embodiments, R A One R on the adjacent atom of a and one R b is R a R b and together with the intervening atoms connecting them form a 5- to 6-membered monocyclic cycloalkyl, or a 5- to 6-membered monocyclic heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is unsubstituted or has one or more R 6 In some embodiments, RA One R on the adjacent atom of a and one R b is R a R b and together with the intervening atoms connecting them to form a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl is unsubstituted or has one or more R 6 The group is substituted.

[0284] In some embodiments, R d is hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group may be selected from one or more R 6 group, and R e and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, wherein R d , R e , or R f When is attached to the N atom of a heteroaryl, it is not hydrogen, -C(=O)R 7 or unsubstituted or substituted C1-C6 alkyl.

[0285] In some embodiments, R dis hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C (CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2O is selected from the group consisting of CH, -CHNH, -CHNHCH, -CHN(CH), -CHCHNH, -CHCHNHCH, -CHCHN(CH), unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C-C heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R d Any substituted group may be selected from one or more R 6 group, and R e and R f is 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, where R d , R e , or R fWhen is attached to the N atom of a heteroaryl, 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.

[0286] In some embodiments, the compounds described herein have the structure:

[0287] [ka]

[0288] In some embodiments, R A , R B , X 1 , W, Y, and R 1 is as described herein.

[0289] In some embodiments, R A , R B , X 1 , W, Y, and R 1 is as set forth in Table 1.

[0290] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0291] Exemplary compounds of formula (I) include those set forth in the table below:

[0292] [Table 1-1]

[0293] [Table 1-2]

[0294] [Table 1-3]

[0295] [Table 1-4]

[0296] [Table 1-5]

[0297] [Table 1-6]

[0298] The compounds in Table 1 are named as follows: 1-1: 2-[1-(2-aminoacetyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-2: 2-[1-(2-aminoacetyl)-6-(2-ethoxyphenyl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-3: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-4: 2-[1-(3-aminopropanoyl)-6-(2-ethoxyphenyl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-5: 2-{1-[(3S)-3-aminobutanoyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-6: 2-{1-[(3R)-3-aminobutanoyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-7: 3-amino-1-{1'-[2-chloro-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-8: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-9: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-10: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3S)-pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-11: 2-[1-(4-aminobutanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-12: 2-[1-(2-aminoethyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-13: 2-{1-[(2R)-2-aminopropyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-14: 2-{1-[(2S)-2-aminopropyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-15: 2-{6-(2-ethoxypyridin-3-yl)-1-[2-(methylamino)ethyl]-2-oxospiro[indoline-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-16: 2-[1-(2-aminoethyl)-6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-17: 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3S)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-18: 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-19: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-6-(trifluoromethyl)pyridine-4-carbonitrile, 1-20: 3-amino-1-[6-(2-ethoxypyridin-3-yl)-1'-[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl]propan-1-one, 1-21: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-1-methylpyrrolidin-3-yl]-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-22: 3-amino-1-{1'-[4-chloro-2-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-23: 3-amino-1-{1'-[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-24: 6-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-4-(trifluoromethyl)pyridine-2-carbonitrile, 1-25: 3-amino-1-{1'-[5-ethoxy-6-(trifluoromethyl)pyridin-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-26: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-2-methyl-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-27: N-(2-aminoethyl)-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-28: 2-[1'-(3-aminopropanoyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-29: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-30: N-[(2R)-2-aminopropyl]-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-31: N-[(2S)-2-aminopropyl]-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-32: 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-33: 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-N-[(3S)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-34: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-chlorobenzonitrile, 1-35: 2-[1-(3-aminopropanoyl)-6-[2-(hydroxymethyl)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-36: 3-amino-1-[6-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-6-(trifluoromethyl)pyridin-2-yl]-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl]propan-1-one, 1-37: 2-[1-(2-aminoethanesulfonyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile, 1-38: 2-(1-{[(2R)-azetidin-2-yl]methyl}-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl)-5-(trifluoromethyl)benzonitrile, 1-39: 2-(1-{[(2S)-azetidin-2-yl]methyl}-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl)-5-(trifluoromethyl)benzonitrile, 1-40: 2-{1-[(2R)-1-aminopropan-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-41: 2-{1-[(2S)-1-aminopropan-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-42: 2-{1-[(2R)-2-aminopropyl]-6-[2-(hydroxymethyl)phenyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl}-5-(trifluoromethyl)benzonitrile, 1-43: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-6-methoxypyridine-2-carbonitrile, 1-44: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-6-ethoxypyridine-2-carbonitrile, 1-45: (2R)-1-{1'-[4-chloro-2-(difluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-2-amine, 1-46: 2-{1'-[(2R)-2-aminopropyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-47: 2-{1'-[(2R)-2-aminopropanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-48: 2-{1'-[(2S)-2-aminopropanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-49: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3R)-pyrrolidine-3-carbonyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-50: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[3-(methylamino)propanoyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-51: 2-{1'-[(2S)-2-amino-3-hydroxypropyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-52: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3R)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-53: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3S)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-54: 2-[1'-(3-aminopropyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-55: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-56: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-57: 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-58: 2-{1'-[3-(dimethylamino)propanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-59: 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-60: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-61: 2-{1'-[(2R)-2-aminopropyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-62: 2-{1'-[2-(dimethylamino)ethyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-63: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-64: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-65: 2-[7'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-66: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-67: 2-[1'-(3-aminopropyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-68: 2-{1'-[(2S)-2-aminopropyl]-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-69: 2-[7'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, and 1-70: 2-{1'-[(2R)-2-aminopropyl]-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl}-5-(trifluoromethyl)benzonitrile.

[0299] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included within the scope of this disclosure.In addition, the compounds described herein can exist not only in unsolvated form, but also in solvated form, including pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0300] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0301] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and are rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one or another part of the digestive tract, an ability that can be manipulated as an aspect of delayed and sustained release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for controlled passage across biological membranes.

[0302] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohetic acid, glyceric acid, glycerol ... The acidic acids include protonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0303] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0304] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, a compound of formula (I) is acidic and is reacted with a base. In such a situation, the acidic proton of the compound of formula (I) is replaced with a metal ion, for example, an ion of lithium, sodium, potassium, magnesium, calcium, or aluminum. In some cases, the compounds described herein cooperate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0305] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates include either stoichiometric or non-stoichiometric solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0306] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharma- ceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds that have the same type of activity.

[0307] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compound of formula (I) is susceptible to various metabolic reactions. By incorporating an appropriate substituent into the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0308] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0309] The compounds described herein include isotopically labeled compounds, which are identical to those detailed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the present compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33Isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14 Compounds incorporating a radioactive isotope such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0310] In some embodiments, the compounds of formula (I) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compounds of formula (I) exist in the R configuration. In some embodiments, the compounds of formula (I) exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0311] The individual stereoisomers can be obtained, as appropriate, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of the stereoisomers is carried out by chromatography, or by separation of diastereomeric salts and separation by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0312] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, the prodrug has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. An example of a prodrug, without limitation, is a compound described herein that is administered as an ester ("prodrug"), but is subsequently metabolically hydrolyzed to yield the active entity. A further example of a prodrug is a short peptide (polyamino acid) that is bonded to an acid group, and the peptide is metabolized to reveal the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0313] 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, e.g., 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, the hydroxyl groups of the compounds disclosed herein are used to form prodrugs, and the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, where the hydroxyl is metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0314] Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to generate a compound of formula (I) as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0315] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety, in some embodiments, the prodrug moiety is as described above.

[0316] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolites that are used to produce a desired effect, including a desired therapeutic effect.

[0317] 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 totality of processes by which a particular substance is changed by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can result in specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of a compound disclosed herein are optionally identified by either administration of the compound to a host and analysis of tissue samples from the host, or by in vitro incubation of the compound with hepatocytes and analysis of the resulting compound.

[0318] Compound synthesis The compounds of formula (I) described herein are synthesized using standard synthetic techniques in combination with the methods described herein, or using methods known in the art.

[0319] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0320] The compounds are prepared using standard organic chemistry techniques, for example, as described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0321] In some embodiments, the compounds described herein are prepared as shown in Scheme A.

[0322] [ka]

[0323] Spiro[indoline-3,4'-piperidine] I can be obtained by Fischer indole synthesis of (3-bromophenyl)hydrazine with benzyl 4-formylpiperidine-1-carboxylate in the presence of TFA and reduction of the indole intermediate. A Compound II can be prepared by subjecting the compound to an organometallic coupling reaction such as the Suzuki-Miyaura reaction with B(OH)2 or its corresponding ester, followed by standard deprotection. Compound II can be prepared by reacting the compound II with R B By reacting with X, it is converted to intermediate III. Then, R 1 HATU-activated amide coupling with COH, R 1 Triphosgene activation with NH2 to form urea, R 1Reductive amination with CHO, or R 1 Triphosgene-activated sulfonylation with SO3H gives the final compound IV. In some cases, R 1 Further deprotection of is required.

[0324] In some embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0325] [ka]

[0326] Starting from (2,6-dichloropyridin-3-yl)methanol, acetonitrile V is obtained by treating the mesyl intermediate with sodium cyanide. One-pot condensation of compound V with bis(2-bromoethyl)amine in the presence of a strong inorganic base such as KOH efficiently generates piperidinyl intermediate VI. Reduction of the cyano group to the primary amine smoothly undergoes intramolecular cyclization to afford azaspiroindoline VII, which can be further catalyzed by R A Organometallic coupling reactions such as Suzuki-Miyaura reaction with B(OH)2 or its corresponding ester followed by standard debenzylation provide compound VIII. The final compound IX can then be obtained from a similar method as described in steps e and f of Scheme A. In some cases, R can be used to obtain compound IX after urea formation. 1 Further deprotection of is required.

[0327] In some embodiments, the compounds described herein are prepared as depicted in Scheme C.

[0328] [ka]

[0329] Hydrolysis of the cyano gives the amide intermediate X, which undergoes intramolecular cyclization in the presence of a strong inorganic base such as KOH to give the azaspiroindolinone XI. A Organometallic coupling reactions such as Suzuki-Miyaura reaction with B(OH)2 or its corresponding ester followed by standard debenzylation afford compound XII, which can be converted to R in the presence of an organic base. B X is reacted with R to convert it to compound XIII. 1 N-alkylation with X gives compound XIV. 1 If contains a protecting group, a further deprotection step can be carried out to give XIV.

[0330] In some embodiments, the compounds described herein are prepared as depicted in Scheme D.

[0331] [ka]

[0332] Commercially available compound XV was A Suzuki-Miyaura coupling with B(OH)2 and deprotection gives intermediate XVI. Conversion to XVII is accomplished in a similar manner as described in steps e and f of Scheme C. 1 If contains a protecting group, a further deprotection step can be carried out to give XVII.

[0333] In some embodiments, the compounds described herein are prepared as depicted in Scheme E.

[0334] [ka]

[0335] Reduction of the starting indanone with NaBH4 gives the corresponding alcohol, which is then dehydrated in the presence of sulfuric acid to give the indene, XVIII. Spiro-piperidinyl ring formation then takes place at the benzylic position of the indene to give XIV. Alkene, XIV, can be converted to ketone, XXI by hydrobromination of the alkene, hydroxylation of the alkyl bromide, and Dess-Martin oxidation of the alcohol. AlCl3-catalyzed ring expansion of the O-mesylated indanone oxime gives dihydroquinolinone, XXIII. R B Deprotection was set up for the SNAr reaction with X. Subsequent R A Suzuki-Miyaura reaction with B(OH)2 or its corresponding ester gives XXIV. Then, in the presence of an organic base, R B X and S N Two reactions give the final compound XXV.

[0336] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0337] Specific Terms Definitions of the following terms used in this application are provided below unless otherwise specified. The use of the term "including," as well as other forms such as "include," "includes," and "included" is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0338] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C6" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0339] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may be branched or straight chain. In some embodiments, the "alkyl" group has 1-10 carbon atoms, i.e., C1-C10 alkyl. A number range, such as "1-10", whenever it occurs herein refers to each integer within the given range. For example, "1-10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no number range is specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0340] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups listed above may be an alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0341] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0342] The term "alkylamine" refers to -N(alkyl) x H y It refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0343] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0344] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Exemplary aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0345] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0346] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0347] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0348] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0349] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from "heterocyclic" or "heterocycle", in which the ring backbone contains at least one atom different from carbon. In some embodiments, the carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, the carbocycle is a monocyclic carbocycle. The carbocycle is non-aromatic or aromatic. The non-aromatic carbocycle is saturated or partially unsaturated. In some embodiments, the carbocycle is a bicyclic carbocycle. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0350] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl is C6-C 10 Depending on the structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group).

[0351] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic aliphatic non-aromatic radical, where each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, norbornenyl, bicyclo[1.1.1]pentyl, adamantyl, norbornyl, norbornenyl, decalinyl, or 7,7-dimethyl-bicyclo[2.2.1]heptanyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0352] The term "halo," or alternatively, "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0353] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0354] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing 1-4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocyclic group has 3-10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5-10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiamine ... dithiamine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-3-yl, dithiamine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, dithiamine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-3-yl, dithiamine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-3-yl, dithiamine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, dithiamine, anyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, 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 C-bonded (or C-linked) or N-bonded where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Additionally, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0355] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0356] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl is a C2-C 10 In another embodiment, the heterocycloalkyl is a C4-C 10 Heterocycloalkyl. 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.

[0357] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one embodiment, when a group described herein is a single bond, the referenced group is not present, thereby allowing for the formation of a single bond between the remaining specified groups.

[0358] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0359] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl.In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C heterocycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -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 foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0360] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the health status of the subject being treated.

[0361] The term "modulate" as used herein means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0362] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, the interaction of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0363] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0364] Terms like "co-administration," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0365] The term "effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. An appropriate "effective" amount in an individual case is optionally determined using techniques such as dose escalation studies.

[0366] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0367] The term "pharmaceutical combination" as used herein refers to a product resulting from the mixing or combination of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an auxiliary agent, both administered to a patient at the same time in the form of a single entity or dose. The term "non-fixed combination" refers to the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an auxiliary agent, both administered to a patient as separate entities, simultaneously, concurrently, or sequentially, without specific intervening time restrictions, where such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0368] The terms "article of manufacture" and "kit" are used synonymously.

[0369] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following mammalian classes: humans, non-human primates such as chimpanzees, and other apes and monkey species, farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0370] The terms "treat", "treating" or "treatment" as used herein include alleviating, relieving or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., suppressing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0371] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Appropriate formulations depend on the route of administration selected. Summaries of pharmaceutical compositions described herein can be found, for example, in: 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, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0372] In some embodiments, the compounds described herein are administered alone or in pharmaceutical compositions in combination with pharma- ceutically acceptable carriers, excipients, or diluents. Administration of the compounds and compositions described herein can be accomplished by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric, or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implantation. Administration may also be by direct injection at the site of the diseased tissue or organ.

[0373] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water emulsion or a water-in-oil emulsion in an oil liquid. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0374] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide a delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in a quantity suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compound may be dissolved or suspended in suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of dosages of active compound.

[0375] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The formulation for injection may be provided in unit dosage form, for example, in ampoules or multi-dose containers, together with additional preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The composition may be provided in unit or multi-dose 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 a sterile liquid carrier, for example, saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0376] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the desired recipient, and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0377] Pharmaceutical compositions can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.Thus, for example, compound can be formulated in suitable polymeric or hydrophobic materials (e.g., as an emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0378] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may contain the active ingredient in a flavored base, such as sucrose and acacia or tragacanth.

[0379] Pharmaceutical compositions can be administered locally, i.e., by non-systemic administration. This includes applying the compound of the present invention to the external epidermis or buccal cavity, and instilling the compound into the ear, eye, and nose, so that the compound does not enter the bloodstream in significant amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0380] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise 0.001%-10% w / w, for example 1%-2% by weight, of the formulation for topical administration.

[0381] Pharmaceutical compositions administered by inhalation are conveniently delivered from an insufflator, nebulizer, pressurized pack, or other conventional means of delivering an aerosol spray. Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for administration by inhalation or insufflation, the formulation can 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 can be presented in unit dosage form, for example capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0382] 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.

[0383] Dosage and treatment regimens In one embodiment, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from modulation of melanocortin receptor activity. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0384] In certain embodiments, compositions comprising the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dosage-finding clinical trials.

[0385] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dosage." In this application, the exact amount will vary depending on the patient's health status, weight, and the like. When used in patients, the effective amount for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition.

[0386] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise inhibit or limit the symptoms of the patient's disease or disorder.

[0387] Once improvement of the patient's condition has occurred, a maintenance dose is administered as necessary. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient will require intermittent treatment on a long-term basis upon recurrence of symptoms.

[0388] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0389] In general, however, dosages used in adult human treatment typically range from 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0390] In one embodiment, the appropriate daily dosage of the compound of formula (I) or a pharma- ceutically acceptable salt thereof described herein is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the amount of active ingredient in the daily dosage or dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0391] The toxicity and therapeutic efficacy of such treatment regimens are discussed below, including but not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In some embodiments, the data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is at least about 100 mg / kg / day with minimal toxicity, and is expressed as a ratio between ED 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0392] In any of the foregoing aspects, in further embodiments, an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal.

[0393] In any of the foregoing aspects, there are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal over the course of a day.

[0394] In any of the foregoing aspects, there are further embodiments that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently, such as in a single dose, (ii) the interval between multiple doses is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, where administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0395] Combination therapy In certain instances, it will be appropriate to administer at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0396] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a treatment regimen) that also has a therapeutic effect.

[0397] In one particular embodiment, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is co-administered with a second therapeutic agent, where the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall effect than administration of either therapeutic agent alone.

[0398] In any case, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is simply additive of the two therapeutic agents or, alternatively, the patient experiences a synergistic effect.

[0399] With respect to the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0400] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (e.g., as a single pill, or as two separate pills), by way of example only.

[0401] In conjunction with the combination therapy, the compound of formula (I) or its pharma- ceutically acceptable salt is administered before, during, or after the onset of a disease or condition, and the timing of administering the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to disease or condition to prevent the onset of disease or condition. In another embodiment, the compounds and compositions are administered to subjects during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as feasible after the onset of a disease or condition is detected or suspected, and for the period required to treat the condition. In some embodiments, the period required for treatment varies, and the treatment period is adjusted to the specific needs of each subject.

[0402] omission: DIEA: N,N-diisopropylethylamine, DMSO: dimethyl sulfoxide; CuI: copper(I) iodide; TBAF: tetra-n-butylammonium fluoride; P(t-Bu)3: tri-tert-butylphosphine, HBF4: tetrafluoroboric acid; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, Prep-HPLC: preparative high performance liquid chromatography; TFA: trifluoroacetic acid; CH3CN: acetonitrile, MeOD: deuterated methanol; CDCl3: deuterated chloroform, DME: 1,2-dimethoxyethane; H2O: water, KOAc: Potassium acetate; NaOAc: sodium acetate; Cs2CO3: Cesium carbonate, P-TsOH: p-toluenesulfonic acid, NaNO2: sodium nitrate, THF: tetrahydrofuran; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol, NBS: N-bromosuccinimide, 4Å MS: 4Å molecular sieve; DPPA: diphenylphosphoryl azide; Br2: Bromine, AgF: silver fluoride; LiAlH4: lithium aluminum hydride; LiHMDS: lithium bis(trimethylsilyl)amide; IBX: 2-iodoxybenzoic acid; CDI: 1,1'-carbonyldiimidazole; TEA: Trimethylamine; HOBT: hydroxybenzotriazole; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0), Pd(OH)2: palladium hydroxide, Pd(PPh3)2Cl2: bis(triphenylphosphine) palladium(II) dichloride, Pd(dppf)Cl2: [1',1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdAMphos or Pd(AMPhos)Cl2 or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(DtBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), Pd2(dba)3.CHCl3: Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, rt: room temperature, h: time, CPD: Compound. EXAMPLES

[0403] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0404] Compound synthesis Example 1: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-3)

[0405] [ka]

[0406] Step 1-1, Preparation of benzyl 6-bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: A purged 250 mL round bottom flask was charged with benzyl 4-formylpiperidine-1-carboxylate (2.9 g, 12 mmol) and DCM (30 mL). The resulting solution was treated with (3-bromophenyl)hydrazine (2.0 g, 11 mmol) at 0 °C followed by TFA (2.5 mL). The reaction mixture was stirred at 40 °C for 18 h and cooled to room temperature. After cooling to 0 °C, the reaction was treated with NaBH4 (0.82 g, 22 mmol) in several portions and stirred for 30 min. The resulting solution was diluted with water (20 mL) and the pH was adjusted to 8-9 by adding saturated NaHCO3. The solution was extracted with CHCl2 (2x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). This gave the title compound (1.3 g, 30%) as a yellow oil. LCMS (M+H) + =401.1.

[0407] Step 1-2, Preparation of benzyl 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed benzyl 6-bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (650 mg, 1.62 mmol) and dioxane / HO (8.0 mL / 0.8 mL). The resulting solution was added with (2-ethoxypyridin-3-yl)boronic acid (540 mg, 3.23 mmol), Pd(DtBPF)Cl2 (63 mg, 0.06 equiv.), and KCO. 3 (675 mg, 4.88 mmol) was added under N2. The reaction mixture was degassed with N2 for 5 min and stirred at 80 °C for 1 h. The reaction was cooled to room temperature and the solid precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This gave the title compound (600 mg, 84%) as a yellow oil. LCMS (M+H) + =444.2.

[0408] Step 1-3, Preparation of 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]: Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed benzyl 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (600 mg, 1.35 mmol), wet 10%-Pd / C (80 mg), EtOH (6 mL), and EtOAc (6 mL). Hydrogen was bubbled through the reaction. The resulting solution was stirred at room temperature for 4 h and then filtered through a pad of Celite. The filtrate was concentrated to give the title compound (400 mg, 95%) as a yellow solid. LCMS (M+H) + =310.2.

[0409] Step 1-4, Preparation of 2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile: Into an 8 mL vial was placed 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine] (170 mg, 0.55 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (104 mg, 0.55 mmol), DIEA (213 mg, 1.65 mmol), and DMSO (2 mL). The resulting mixture was stirred at 50° C. for 1 h and cooled to room temperature. The reaction was directly purified by preparative HPLC to give the title compound (150 mg, 57%) as a white solid. LCMS (M+H) + =479.1.

[0410] Step 1-5, Preparation of tert-butyl N-(3-{1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}-3-oxopropyl)carbamate: To a solution of 3-[(tert-butoxycarbonyl)amino]propanoic acid (28 mg, 0.15 mmol) in DMF (1 mL) was added HATU (56 mg, 0.15 mmol) and DIEA (60 mg, 0.46 mmol). The resulting mixture was stirred at room temperature for 10 min and then treated with 2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (70 mg, 0.15 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This afforded the title compound (65 mg, 68%) as a white solid. LCMS (M+H) + =650.2.

[0411] Step 1-6, Preparation of 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl N-(3-{1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}-3-oxopropyl)carbamate (65 mg, 0.1 mmol) in DCM (1 mL) was added 4M-HCl in dioxane (1 mL). The resulting solution was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (21 mg, 36%) as a white solid. LCMS (M+H) + =550.3.

[0412] The following compounds were prepared similarly to Example 1 using the appropriate substitution reagents and substrates at the various steps.

[0413] [Table 2]

[0414] Example 2: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-1-methylpyrrolidin-3-yl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-21)

[0415] [ka]

[0416] Step 2-1, Preparation of tert-butyl 6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: tert-butyl 6-bromo-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (300 mg, 0.79 mmol), (2-ethoxypyridin-3-yl)boronic acid (263 mg, 1.57 mmol), Pd(AMPhos)Cl2 (56 mg, 0.1 equiv), potassium carbonate (217 mg, 1.57 mmol), and dioxane / water (4 mL / 0.4 mL) were charged to a thick-walled tube. The resulting mixture was degassed with N2 for 5 min, sealed, and stirred at 90 °C for 1.5 h. The reaction was cooled to room temperature and concentrated. The residue was directly purified by reverse phase C18 column chromatography to give the title compound (290 mg, 87%). LCMS (M+H) + =424.3.

[0417] Step 2-2, Preparation of 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-2-one: To a solution of tert-butyl 6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (190 mg, 0.45 mmol) in DCM (0.4 mL) was added TFA (0.1 mL) at room temperature. The resulting solution was stirred at room temperature for 1.5 h and then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and neutralized with DIEA, which was used in the next step without further purification (140 mg, 96%). LCMS (M+H) + =324.4.

[0418] Step 2-3, Preparation of 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile: 6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-2-one (140 mg, 0.43 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (164 mg, 0.87 mmol), DIEA (224 mg, 1.73 mmol), and DMSO (2 mL) were charged into a thick-walled tube. The tube was sealed, and the resulting solution was then stirred at 125° C. for 16 hours. The reaction was cooled to room temperature and then directly purified by reverse phase C18 column chromatography to give the title compound (190 mg, 89%). LCMS (M+H) + =493.3.

[0419] Step 2-4, preparation of tert-butyl (3R)-3-{1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}pyrrolidine-1-carboxylate: To a solution of 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (30 mg, 0.061 mmol) and tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (40 mg, 0.15 mmol) in DMF (1 mL) was added cesium carbonate (99 mg, 0.3 mmol) at room temperature. The resulting mixture was stirred at 90° C. for 3 h. The reaction was cooled to room temperature and the inorganic solids were filtered off. The filtrate was directly purified by reverse phase C18 column chromatography to give the title compound (22 mg, 55%). LCMS (M+H) + =662.3.

[0420] Step 2-5, preparation of 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (compound 1-18): To a solution of tert-butyl (3R)-3-{1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}pyrrolidine-1-carboxylate (22 mg, 0.033 mmol) in DCM (0.4 mL), TFA (0.1 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was purified by reverse phase C18CC to give the title compound (14 mg, 75%). LCMS (M+H) + =562.4.

[0421] Step 2-6, Preparation of 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-1-methylpyrrolidin-3-yl]-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile: To a solution of 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (11 mg, 0.02 mmol) in MeOH (1 mL) was added paraformaldehyde (12 mg, 0.39 mmol) followed by sodium cyanotrihydroborate (12 mg, 0.2 mmol) at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with TFA (0.1 mL) and purified directly by reverse phase C18 column chromatography to give the title compound (6.0 mg, 53%). LCMS (M+H) + =576.5.

[0422] The following compounds were prepared similarly to Example 2 using the appropriate substituting reagents and substrates at the various steps.

[0423] [Table 3]

[0424] Example 3: N-(2-aminoethyl)-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide (compound 1-27)

[0425] [ka]

[0426] Step 3-1, Preparation of 4-nitrophenyl 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxylate: A purged 50 mL round bottom flask was charged with 2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (120 mg, 0.58 mmol) from step 1-4 of Example 1, ACN (3.0 mL), sodium bicarbonate (100 mg, 1.19 mmol), and 4-nitrophenyl carbonochloridate (120 mg, 0.60 mmol). The resulting solution was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:4). This afforded the title compound (320 mg, 85%) as a white solid. LCMS (M+H) + =644.4.

[0427] Step 3-2, Preparation of tert-butyl N-{2-[({1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}carbonyl)amino]ethyl}carbamate: To a solution of 4-nitrophenyl 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxylate (55 mg, 0.085 mmol) in DMF (0.6 mL), tert-butyl (2-aminoethyl)carbamate (27 mg, 0.169 mmol) and TEA (26 mg, 0.257 mmol) were added under N2 atmosphere. The resulting solution was stirred at 60° C. for 2 h and cooled to room temperature. The reaction was purified by flash preparative HPLC to give the title compound (40 mg, 70%) as a yellow solid. LCMS (M+H) + =665.5.

[0428] Step 3-3, Preparation of N-(2-aminoethyl)-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide formate: To a solution of tert-butyl N-{2-[({1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}carbonyl)amino]ethyl}carbamate (40 mg, 0.06 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC to give the title compound (30 mg, 82%) as a white solid. LCMS (M+H) + =565.3.

[0429] The following compounds were prepared similarly to Example 3 using the appropriate substitution reagents and substrates at the various steps.

[0430] [Table 4]

[0431] Example 4: 2-[1-(2-aminoethanesulfonyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-37)

[0432] [ka]

[0433] Step 4-1, Preparation of tetrabutylammonium 2-((tert-butoxycarbonyl)amino)ethane-1-sulfonate: Into an 8 mL vial was placed 2-aminoethane-1-sulfonic acid (100 mg, 0.799 mmol) and water (1 mL). The reaction was treated with 50% aqueous tetrabutylammonium hydroxide (207 mg, 0.799 mmol) followed by dropwise addition of di-tert-butyl dicarbonate (174 mg, 0.797 mmol) in acetone (3 mL) at room temperature. The resulting mixture was stirred for 16 h at room temperature. After removal of volatile solvents, the aqueous phase was extracted with DCM (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (300 mg, 80%) as a yellow oil.

[0434] Step 4-2, Preparation of tert-butyl N-[2-({1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}sulfonyl)ethyl]carbamate: To a solution of tetrabutylammonium 2-((tert-butoxycarbonyl)amino)ethane-1-sulfonate (50 mg, 0.11 mmol) and DMF (4.0 mg, 0.055 mmol) in DCM (2 mL) was added bis(trichloromethyl)-carbonate (12 mg, 0.040 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated in vacuo. The crude intermediate was used in the next step without further purification. 2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile (50 mg, 0.10 mmol) from step 1-4 of Example 1, the crude intermediate described above, DCM (2 mL), and TEA (33 mg, 0.33 mmol) were placed in an 8 mL vial. The resulting mixture was stirred at room temperature for 1 h, quenched with water (30 mL), and then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) to give the title compound (40 mg, 56%) as a yellow solid. LCMS (M+H) + =686.2.

[0435] Step 4-3, Preparation of 2-[1-(2-aminoethanesulfonyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl N-[2-({1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl}sulfonyl)ethyl}carbamate (40 mg, 0.058 mmol) in DCM (1 mL) was added TFA (0.2 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (17.6 mg, 48%) as a white solid. LCMS (M+H) + =586.2.

[0436] Example 5: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-29)

[0437] [ka]

[0438] Step 5-1, Preparation of methyl (2,6-dichloropyridin-3-yl)methanesulfonate: To a solution of (2,6-dichloropyridin-3-yl)methanol (3 g, 16.9 mmol) in DCM (40 mL) in a 250 mL flask, TEA (5.1 g, 50 mmol) and MsCl (3.1 g, 27 mmol) were added at 0° C. The resulting solution was stirred at room temperature for 1 h and then washed with saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gave the title compound (4.1 g, 100%), which is used in the next step without further purification. LCMS (M+H) + =255.9.

[0439] Step 5-2, Preparation of 2-(2,6-dichloropyridin-3-yl)acetonitrile: To a solution of methyl (2,6-dichloropyridin-3-yl)methanesulfonate (4.1 g, 16 mmol) in EtOH (90 mL) and water (10 mL) was added sodium cyanide (2.1 g, 43 mmol). The resulting mixture was stirred at 80° C. for 2 h, cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (EA: 0-30%) to give the title compound (1.9 g, 63%) as a yellow solid. LCMS (M+H) + =187.0.

[0440] Step 5-3, Preparation of 1-benzyl-4-(2,6-dichloropyridin-3-yl)piperidine-4-carbonitrile: A mixture of 2-(2,6-dichloropyridin-3-yl)acetonitrile (1.3 g, 7.0 mmol), KOH (1.5 g, 27 mmol), and N-benzyl-2-bromo-N-(2-bromoethyl)ethano-1-amine (3.1 g, 9.7 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (EA: 0-50%) to give the title compound (1.2 g, 50%) as a dark green oil. LCMS (M+H) + =346.0.

[0441] Step 5-4, Preparation of 1-benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]: A mixture of 1-benzyl-4-(2,6-dichloropyridin-3-yl)piperidine-4-carbonitrile (1.2 g, 3.5 mmol) and aluminum(III) lithium tris(2-methylpropan-2-oleate) hydride (3.0 g, 12 mmol) in dioxane (10 mL) was stirred at 100° C. for 15 hours. The reaction was cooled to 0° C., quenched with 1N NaOH (20 mL), diluted with EtOAc (30 mL), and then filtered. The filter cake was washed with EtOAc, and then the organic layer from the filtrate was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (EA: 0-50%) to give the title compound (0.7 g, 64%) as a pale yellow solid. LCMS (M+H) + =314.0.

[0442] Step 5-5, Preparation of 1-benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]: 1-benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] (0.4 g, 1.0 mmol), (2-ethoxypyridin-3-yl)boronic acid (0.46 g, 2.8 mmol), PdAMphos (90 mg, 0.1 equiv), potassium carbonate (0.63 g, 4.6 mmol), and dioxane (4 mL) / water (0.4 mL) were charged to a thick-walled tube. The reaction mixture was degassed with N2 for 5 min, sealed, stirred at 100 °C for 1 h, and cooled to room temperature. The reaction was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (EA: 0-55%) to give the title compound (0.27 g, 54%) as a pale yellow solid. LCMS (M+H) + =401.1.

[0443] Step 5-6, Preparation of 6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]: A mixture of 1-benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] (0.27 g, 0.67 mmol), 10%-Pd / C (50 mg), and PdOH2 (50 mg, 0.36 mmol) in MeOH (10 mL) was stirred at 30° C. for 0.5 h under H2 (3 bar). The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give the title compound (0.21 g, 100%) as a brown oil, which was used in the next step without further purification. LCMS (M+H) + =311.3.

[0444] Step 5-7, Preparation of 2-[6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile: A mixture of 6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] (0.21 g, 0.68 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (0.28 g, 1.5 mmol), and DIEA (0.3 g, 2 mmol) in DMSO (3 mL) was stirred at 50° C. for 1 h. The reaction was cooled to room temperature and purified directly by preparative HPLC to give the title compound (0.16 g, 49%) as a light brown solid. LCMS (M+H) + =480.2.

[0445] Step 5-8, Preparation of tert-butyl N-(2-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}ethyl)carbamate: Preparation of 2-[6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}ethyl]carbamate in DCE (0.6 mL) and MeOH (0.6 mL). A mixture of ,2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile (80 mg, 0.17 mmol), tert-butyl(2-oxoethyl)carbamate (62 mg, 0.39 mmol), acetic acid (195 mg, 3.25 mmol), and NaCNBH3 (51 mg, 0.81 mmol) was stirred at room temperature for 15 h. After removal of the volatile solvents, the residue was purified by preparative HPLC to give the title compound (73 mg, 70%) as a light brown solid. LCMS (M+H) + =623.3.

[0446] Step 5-9, Preparation of 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl N-(2-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}ethyl)carbamate (73 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.25 mL) at room temperature. The reaction was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (49 mg, 74%) as a white solid. LCMS (M+H) + =523.3.

[0447] The following compounds were prepared similarly to Example 5 using the appropriate substituting reagents and substrates at the various steps.

[0448] [Table 5]

[0449] Example 6: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[3-(methylamino)propanoyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-50)

[0450] [ka]

[0451] Step 6-1, preparation of tert-butyl N-(3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}-3-oxopropyl)-N-methylcarbamate: In an 8 mL vial, add 3-[(tert-butoxycarbonyl(methyl)amino]propanoic acid (55 mg, 0.27 mmol), HATU (61 mg, 0.16 mmol), DIEA (74 mg, 0.5 mmol), and 100 mL of ... 7 mmol), and DMF (1 mL). After stirring for 5 min at room temperature, the reaction was treated with 2-[6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile (60 mg, 0.13 mmol) from step 5-7 of Example 5. The resulting solution was stirred for 1 h at room temperature and purified directly by preparative HPLC to give the title compound (56 mg, 67%) as a pale yellow oil. LCMS (M+H) + =665.3.

[0452] Step 6-2, Preparation of 2-[6'-(2-ethoxypyridin-3-yl)-1'-[3-(methylamino)propanoyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl N-(3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}-3-oxopropyl)-N-methylcarbamate (56 mg, 0.084 mmol) in DCM (2 mL), TFA (0.4 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC to give the title compound (33.8 mg, 66%) as a white solid. LCMS (M+H) + =565.3.

[0453] The following compounds were prepared similarly to Example 6 using the appropriate substitution reagents and substrates at the various steps.

[0454] [Table 6]

[0455] Example 7: 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide (compound 1-59)

[0456] [ka]

[0457] Step 7-1, Preparation of 4-nitrophenyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxylate: To a solution of 2-[6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (350 mg, 0.73 mmol) from Step 5-7 of Example 5 in ACN (4 mL) was added sodium bicarbonate (184 mg, 2.19 mmol) and 4-nitrophenyl carbonochloridate (191 mg, 0.95 mmol) under a N2 atmosphere. The resulting solution was stirred for 16 h at room temperature, diluted with water (20 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. This gave the title compound (475 mg, 86%) as a yellow solid, which is used in the next step without further purification. LCMS (M+H) + =645.3.

[0458] Step 7-2, preparation of tert-butyl N-{2-[({1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}carbonyl)amino]ethyl}-N-methylcarbamate: In an 8 mL vial, 4-nitrophenyl 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydro Drospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxylate (100 mg, 0.15 mmol), TEA (48 mg, 0.47 mmol), tert-butyl(2-aminoethyl)(methylcarbamate (27 mg, 0.15 mmol), and DMF (2 mL) were charged. The resulting mixture was stirred at 80°C for 2 h and cooled to room temperature. The reaction was directly purified by preparative HPLC to give the title compound (60 mg, 57%) as a yellow oil. LCMS (M+H) + =680.3.

[0459] Step 7-3, Preparation of 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-yl}carbonyl)amino]ethyl}-N-methylcarbamate (60 mg, 0.088 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC to give the title compound (42 mg, 76%) as a white solid. LCMS (M+H) + =580.3.

[0460] The following compounds were prepared similarly to Example 7 using the appropriate substitution reagents and substrates at the various steps.

[0461] [Table 7]

[0462] Example 8: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-60)

[0463] [ka]

[0464] Step 8-1, Preparation of 1-benzyl-4-(2,6-dichloropyridin-3-yl)piperidine-4-carboxamide: A 50 mL round bottom flask was charged with 1-benzyl-4-(2,6-dichloropyridin-3-yl)piperidine-4-carbonitrile (1.0 g, 2.9 mmol) from step 5-3 of Example 5, DMSO (10 mL), 25% aqueous NaOH (5.0 g, 31 mmol), and 30%-hydrogen peroxide (3.0 g, 26 mmol). The resulting mixture was stirred at 25° C. for 1 h and then quenched with water (100 mL). The resulting solution was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded the title compound (1.0 g, 90%) as a yellow solid. LCMS (M+H) + =364.2.

[0465] Step 8-2, Preparation of 1-benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one: A 50 mL round bottom flask was charged with 1-benzyl-4-(2,6-dichloropyridin-3-yl)piperidine-4-carboxamide (1.0 g, 2.7 mmol), KOH (0.6 g, 10.7 mmol), and DMSO (10 mL). The resulting mixture was stirred for 2 h at 25° C., quenched with water (100 mL), and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (650 mg, 72%) as a yellow solid. LCMS (M+H) + =328.1.

[0466] Step 8-3, Preparation of 1-benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one: Into a thick-walled tube purged and maintained with an inert atmosphere of nitrogen was added 1-benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one (650 mg, 1.98 mmol), (2-ethoxypyridin-3-yl)boronic acid (331 mg, 1.98 mmol), Pd(DtBPF)Cl2 (129 mg, 0.1 equiv.), KCO 3 (822 mg, 5.95 mmol), and dioxane (7 mL) / H2O (0.7 mL) were added. The resulting mixture was degassed with N2 for 5 min, sealed, stirred at 80 °C for 1 h, and cooled to room temperature. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This afforded the title compound (600 mg, 73%) as a pale yellow solid. LCMS (M+H) + =415.2.

[0467] Step 8-4, Preparation of 6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one: To a solution of 1-benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one (550 mg, 1.33 mmol) in MeOH (10 mL) was added 10%-Pd / C (140 mg), and Pd(OH)2 (186 mg, 1.32 mmol). The reaction flask was evacuated and flushed with nitrogen three times, then with hydrogen. The mixture was stirred under hydrogen (balloon) for 2 h at room temperature. The reaction was diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound as a white oil (300 mg, 70%). LCMS (M+H) + =325.2.

[0468] Step 8-5, Preparation of 2-[6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile: A solution of 6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'-one (280 mg, 0.86 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (163 mg, 0.86 mmol), and DIEA (335 mg, 2.59 mmol) in DMSO (3 mL) was stirred at 50° C. for 1 h and cooled to room temperature. The reaction was purified by preparative HPLC to give the title compound (240 mg, 56%) as a yellow oil. LCMS (M+H) + =494.3.

[0469] Step 8-6, Preparation of tert-butyl N-(2-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}ethyl)carbamate: 2-[6'-(2-ethoxypyridine-3 To a solution of tert-butyl (2-chloroethyl)carbamate (20 mg, 0.11 mmol) and tert-butyl (2-chloroethyl)carbamate (55 mg, 0.11 mmol) was added potassium carbonate (45 mg, 0.33 mmol). The resulting mixture was stirred at 70° C. for 1 h and cooled to room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (40 mg, 56%) as a white oil. LCMS (M+H) + =637.7.

[0470] Step 8-7, Preparation of 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl N-(2-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1'-yl}ethyl)carbamate (40 mg, 0.063 mmol) in DCM (1 mL), TFA (0.25 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC to give the title compound (21 mg, 59%) as a white solid. LCMS (M+H) + =537.2.

[0471] The following compounds were prepared similarly to Example 8 using the appropriate substitution reagents and substrates at the various steps.

[0472] [Table 8]

[0473] Example 9: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-64)

[0474] [ka]

[0475] Step 9-1, Preparation of 1-benzyl-7'-bromo-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one: A mixture of 1-benzylpiperidin-4-one (2.0 g, 11 mmol) and 1-(3-bromophenyl)urea (1.8 g, 8.4 mmol) in PPA (15 mL) was heated at 120°C for 1 h. The mixture was quenched with water (100 mL), basified with saturated NaHCO3(aq) to pH 9, and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to give the title compound (2.3 g, 56% yield) as a light brown solid. LCMS (M+H) + =386.1.

[0476] Step 9-2, Preparation of 1-benzyl-7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one: A mixture of 1-benzyl-7'-bromo-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one (2 g, 5 mmol), (2-ethoxypyridin-3-yl)boronic acid (2.1 g, 13 mmol), potassium carbonate (2.3 g, 17 mmol), and Pd(DtBPF)Cl2 (0.29 g, 0.44 mmol) in 1,4-dioxane (20 mL) and water (2 mL) under nitrogen was heated at 80° C. for 1 h. The mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by reverse phase CC to give the title compound (0.44 g, 22% yield) as a pale yellow solid. LCMS (M+H) + =429.3.

[0477] Step 9-3, Preparation of 7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one: To a solution of 1-benzyl-7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one (0.44 g, 1.0 mmol) in MeOH (10 mL) was added Pd / C (80 mg, 0.8 mmol) and Pd(OH)2 (90 mg, 0.6 mmol). The mixture was stirred at room temperature under H2 (3 bar) for 1.5 h. The mixture was filtered and the filtrate was concentrated to dryness in vacuo to give the title compound (0.33 g, 95% yield) as a pale yellow solid. LCMS (M+H) + =339.2.

[0478] Step 9-4, Preparation of 2-(7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile: A solution of 7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazolin]-2'(3'H)-one (330 mg, 975 μmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (410 mg, 2.17 mmol), and DIEA (0.5 mL, 3 mmol) in DMSO (3 mL) was heated at 66° C. for 3 h. The mixture was purified by reverse phase CC to give the title compound (250 mg, 50.5% yield) as a yellow solid. LCMS (M+H) + =508.2.

[0479] Step 9-5, Preparation of tert-butyl (2-(1-(2-cyano-4-(trifluoromethyl)phenyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-1'-yl)ethyl)carbamate: 2-(7'-(2-ethoxypyridin-3-yl)-2' in DMF (1 mL) A mixture of 1'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile (100 mg, 197 μmol), tert-butyl (2-chloroethyl)carbamate (113 mg, 629 μmol), and Cs2CO3 (155 mg, 476 μmol) was heated at 125° C. for 3 h. The mixture was purified by reverse phase CC to give the title compound (26 mg, 20% yield) as an off-white solid. LCMS (M+H) + =651.3.

[0480] Step 9-6, Preparation of 2-(1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile formate: To a solution of tert-butyl (2-(1-(2-cyano-4-(trifluoromethyl)phenyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1'-yl)ethyl)carbamate (26 mg, 40 μmol) in DCM (4 mL), TFA (1 mL) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in MeOH (3 mL), basified with ammonium hydroxide (aq) to pH 9 and concentrated in vacuo. The residue was purified by reverse phase CC to give the title compound (11.2 mg, 47% yield). LCMS (M+H) + =551.3.

[0481] Example 10: 2-[7'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-65)

[0482] [ka]

[0483] Step 10-1, Preparation of 2-(7'-(2-ethoxypyridin-3-yl)-1'-(2-(methylamino)ethyl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile: 2-(1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-1'-(2-methylamino)ethyl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile from Step 9-6 in HFIP (1 mL). A mixture of pyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl)-5-(trifluoromethyl)benzonitrile formate (22 mg, 40 μmol), K2CO3 (10 mg, 72 μmol), and methyl trifluoromethanesulfonate (6.4 mg, 39 μmol) was stirred at room temperature for 3 h. The mixture was purified by reverse phase CC to give the title compound (1.6 mg, 7.1% yield) as an off-white solid. LCMS (M+H) + =565.3.

[0484] Example 11: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-66)

[0485] [ka]

[0486] Step 11-1, Preparation of 6-bromo-2,3-dihydro-1H-inden-1-ol: To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (20 g, 95 mmol) in EtOH (200 mL) was added NaBH4 (5.4 g, 0.14 mol) in small portions at 0° C. The resulting solution was stirred for 1 h at 0° C. and 3 h at room temperature. The mixture was quenched with saturated NH4Cl(aq) (10 mL) and the solid was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (18 g, 89% yield) as a white solid. LCMS (M+H) + =213.0.

[0487] Step 11-2, Preparation of 5-Bromo-1H-indene: To a solution of 6-bromo-2,3-dihydro-1H-inden-1-ol (18 g, 84 mmol) in THF (180 mL) was added 40% H2SO4(aq) (60 mL). The resulting solution was heated at 80° C. for 16 h. The mixture was quenched with water (50 mL), neutralized with 5M NaOH(aq), and extracted with EtOAc (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (11 g, 67% yield) as a white solid. LCMS (M+H) + =195.0.

[0488] Step 11-3, Preparation of tert-butyl 5-bromospiro[indene-1,4'-piperidine]-1'-carboxylate: To a solution of 5-bromo-1H-indene (15.7 g, 80.5 mmol) in THF (150 mL) at 0° C. under nitrogen was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in THF (0.2 L, 200 mmol) and the resulting solution was stirred at 0° C. for 1 h. To this was added dropwise a solution of tert-butyl bis(2-chloroethyl)carbamate (24 g, 99 mmol) in THF (100 mL). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH4Cl(aq) (200 mL) and extracted with EtOAc (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel CC to give a mixture of tert-butyl 5-bromospiro[indene-1,4'-piperidine]-1'-carboxylate and tert-butyl 6-bromospiro[indene-1,4'-piperidine]-1'-carboxylate (26 g) as a yellow oil. The mixed product was purified by Dynamic Axial Compression (instrument name: DAC-150, concentration of pump B: 85.0%, total flow rate: 400 mL / min, phase A: water, phase B: ACN, column name: HS-C18(DAC-150), 10 μm) to give the title compound (8.3 g, 28% yield) as a yellow solid. LCMS (M+H) + =364.1.

[0489] Step 11-4, Preparation of tert-butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate: To a solution of tert-butyl 5-bromospiro[indene-1,4'-piperidine]-1'-carboxylate (8.0 g, 22 mmol) in DCM (200 mL) at 0° C. was added 35% HBr in AcOH (100 mL). The resulting solution was stirred for 6 h at 0° C. The solution was adjusted to pH 12 by adding 40% NaOH (aq), followed by the addition of DCM (100 mL) and di-tert-butyl dicarbonate (150 mg, 687 μmol). The resulting solution was stirred for 3 h at room temperature. The mixture was treated with 3N HCl (aq) until pH 8-9 and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to give the title compound (7.0 g, 83% yield) as a yellow oil. LCMS (M+H) + =382.1.

[0490] Step 11-5, Preparation of tert-butyl 5-bromo-3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate: To a solution of tert-butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (7.2 g, 19 mmol) in DCM (120 mL) was added Dess-Martin periodinane (12 g, 28 mmol). The resulting solution was stirred at room temperature for 3 h. The solids were filtered and the filtrate was diluted with water (150 mL) and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (4.2 g, 59% yield) as a white solid. LCMS (M+H) + =380.1.

[0491] Step 11-6, Preparation of tert-butyl (Z)-5-bromo-3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate: To a solution of tert-butyl 5-bromo-3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (2.0 g, 5.3 mmol) in EtOH (30 mL) was added sodium acetate (0.65 g, 7.9 mmol) and hydroxylamine hydrochloride (0.44 g, 6.3 mmol). The resulting solution was heated at 80° C. for 1 h. The reaction was quenched with water (70 mL) and extracted with DCM (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the title compound (2.4 g, 114% yield) as a pale yellow solid. LCMS (M+H) + =395.1.

[0492] Step 11-7, Preparation of tert-butyl (E)-5-bromo-3-(((methylsulfonyl)oxy)imino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate: To a solution of tert-butyl (E)-5-bromo-3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (2.4 g, 6.1 mmol) in DCM (40 mL) at 0° C. was added triethylamine (1.2 g, 12 mmol) and methanesulfonyl chloride (1.0 g, 8.7 mmol) dropwise. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched with water (60 mL) and extracted with DCM (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (2.6 g, 90% yield) as a yellow solid. LCMS (M+H) + =473.1.

[0493] Step 11-8, Preparation of tert-butyl 7'-bromo-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-carboxylate: To a solution of tert-butyl (E)-5-bromo-3-(((methylsulfonyl)oxy)imino)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (2.1 g, 4.4 mmol) in 1,2-dichloroethane (30 mL) at 0°C, aluminum trichloride (1.8 g, 14 mmol) was added in small portions. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NaHCO3(aq) until pH 9, diluted with DCM (30 mL) and triturated with di-tert-butyl dicarbonate (1.9 g, 8.7 mmol). The resulting solution was stirred again for 2 hours at room temperature and then filtered through Celite. The filtrate was diluted with water (40 mL) and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (830 mg, 47% yield) as a yellow solid. The regioisomer, tert-butyl 7-bromo-1-oxo-2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidine]-1'-carboxylate (820 mg, 47% yield) was also obtained as a yellow solid. LCMS (M+H) + =395.1.

[0494] Step 11-9, Preparation of 2,2,2-trifluoroacetaldehyde-7'-bromo-1'H-spiro[piperidine-4,4'-quinoline]-2'(3'H)-one (1 / 1): To a solution of tert-butyl 7'-bromo-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-carboxylate (830 mg, 2.10 mmol) in DCM (10 mL), TFA (2 mL) was added and the resulting solution was stirred at room temperature for 1 h. The mixture was concentrated to dryness in vacuo to give the title compound (800 mg, 96.9% yield) as a yellow solid. LCMS (M+H) + =295.1.

[0495] Step 11-10, Preparation of 2-(7'-bromo-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl)-5-(trifluoromethyl)benzonitrile: To a solution of 2,2,2-trifluoroacetaldehyde-7'-bromo-1'H-spiro[piperidine-4,4'-quinoline]-2'(3'H)-one (1 / 1) (800 mg, 2.03 mmol) in DMSO (10 mL) was added 2-fluoro-5-(trifluoromethyl)benzonitrile (465 mg, 2.46 mmol) and DIEA (1.6 g, 12 mmol). The resulting solution was heated at 70° C. for 2 h. The mixture was quenched with water and extracted with DCM (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (800 mg, 84.7% yield) as a yellow solid. LCMS (M+H) + =464.2.

[0496] Step 11-11. Preparation of 2-(7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl)-5-(trifluoromethyl)benzonitrile: 2-(7'-bromo-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl) in 1,4-dioxane (10 mL) and water (1 mL). To a mixture of 2-[piperidine-4,4'-quinolin]-1-yl)-5-(trifluoromethyl)benzonitrile (800 mg, 1.72 mmol), (2-ethoxypyridin-3-yl)boronic acid (450 mg, 2.70 mmol), potassium carbonate (714 mg, 5.17 mmol), and Pd(DtBPF)Cl2 (60 mg, 0.092 mmol) were added. The resulting mixture was heated at 80°C for 1 h. The solid was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (810 mg, 92.8% yield) as a yellow solid. LCMS (M+H) + =507.3.

[0497] Step 11-12, Preparation of tert-butyl (2-(1-(2-cyano-4-(trifluoromethyl)phenyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1'-yl)ethyl)carbamate: 2-(7'-(2-ethoxypyridin-3-yl) To a solution of )-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl)-5-(trifluoromethyl)benzonitrile (140 mg, 276 μmol) was added tert-butyl (2-chloroethyl)carbamate (100 mg, 557 μmol) and 60 wt% NaH in mineral oil (33 mg, 0.83 mmol). The resulting mixture was heated at 60° C. for 3 h. The reaction was quenched with saturated NH4Cl(aq) and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel CC to give the title compound (140 mg, 78.0% yield) as a white solid. LCMS (M+H) + =650.3.

[0498] Step 11-13, preparation of 2-(1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-yl)-5-(trifluoromethyl)benzonitrile: To a solution of tert-butyl (2-(1-(2-cyano-4-(trifluoromethyl)phenyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1'-yl)ethyl)carbamate (90 mg, 0.14 mmol) in DCM (2 mL), TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, diluted with water (10 mL), neutralized with saturated NaHCO3(aq) and extracted with EtOAc (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to give the title compound (70 mg, 92% yield) as a yellow solid. LCMS (M+H) + =550.2.

[0499] The following compounds were prepared similarly to Example 11 using the appropriate substitution reagents and substrates at the various steps.

[0500] [Table 9]

[0501] Example A-1: ​​Parenteral pharmaceutical composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of the water-soluble salt of the compound of formula (I) or its pharma- ceutically acceptable salt or solvate is dissolved in sterile water, and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer is optionally added, together with an optional acid or base, to adjust the pH. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0502] Example A-2: Oral Solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is added to water (along with an optional solubilizer, optional buffer, and taste masking excipient) to obtain a 20 mg / mL solution.

[0503] Example A-3: Oral Tablet Tablets are prepared by mixing 20-50% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0504] Example A-4: Oral Capsules To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is mixed with starch or other suitable powder mixture, and the mixture is incorporated into an oral dosage form, such as a hard gelatin capsule, suitable for oral administration.

[0505] In another embodiment, 10-500 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is placed into a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

[0506] Example A-5: Topical gel composition To prepare a pharmaceutical topical gel composition, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is mixed with hydroxypropylcellulose, propylene glycol, isopropyl myristate, and purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0507] Example B-1: MC2R Assay Membrane Preparation: Crude membrane fractions are prepared from CRE-bla-CHO-K1 cells stably expressing the hMC2 receptor and hMRAP accessory protein (Thermo Fisher). Cells are grown to 85-100% confluence on standard tissue culture dishes in GlutaMax DMEM growth medium (Gibco) supplemented with the following supplements: 10% dialyzed FBS (Gemini), 0.1 mM NEAA (Gibco), 25 mM HEPES (Gibco), 5 μg / mL blasticidin (Goldbio), 100 μg / mL zeocin (Invitrogen), and 600 μg / mL hygromycin (Goldbio). To prepare membranes, cells are scraped, collected in 1X Dulbecco's Phosphate Buffered Saline (Corning), and pelleted at 1000 RPM. The cell pellet is reconstituted in Membrane Prep Buffer (20 mM HEPES, 6 mM MgCl2, and 1 mM EGTA, protease inhibitor tablets (Pierce) adjusted to pH 7.4), homogenized using a Dounce homogenizer, and the resulting membrane fraction is pelleted by centrifugation at 12,000 RPM. The membrane pellet is resuspended in Membrane Prep Buffer, flash frozen, and stored at -80°C for later use.

[0508] Binding assay for hMC2 antagonists protocol: The hMC2 membrane binding assay contains the following components: radiolabeled [ 125 We utilize [I]ACTH(1-39)Tyr23 (PerkinElmer), wheat agritinin-coated PVT SPA beads (PerkinElmer), crude hMC2R membranes, and compounds. Briefly, hMC2R membranes are incubated with SPA beads in binding assay buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA, protease inhibitor tablets (Pierce) adjusted to pH 7.4) prior to the start of the assay. Compounds (final concentrations of compounds are typically 0-10,000 nM), SPA membranes, and a final concentration of 0.2 nM [I]ACTH(1-39)Tyr23 (PerkinElmer) are incubated with SPA beads in binding assay buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA, protease inhibitor tablets (Pierce) adjusted to pH 7.4) prior to the start of the assay. 125Dose responses of [I]ACTH(1-39)Tyr23) are plated into 96-well assay plates and allowed to incubate at room temperature for 1.5 hours. The assay plates are read using a Top Count NXT and the K i Values ​​are determined by nonlinear regression analysis in GraphPad Prism 6.

[0509] Exemplary binding affinities of selective compounds are listed in Table A. Potency is divided into four scales: + is K i ++ means that K is between 1,000nM and 10,000nM. i +++ means that the K is between 100nM and 1,000nM. i means that the K is between 10nM and 100nM. i This means that the concentration is less than 10 nM.

[0510] [Table 10]

[0511] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this specification and the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, R Ａ is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R Ａ When R is substituted, Ａ is R ａ , R ｂ , and R ｃ and is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C ２ -C ７ is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl; R ａ , R ｂ , and R ｃ Any substituted group may be one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is hydrogen, —C(═O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, R Ｂ is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where R Ｂ When R is substituted, Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, three, or four groups selected from R ｄ , R ｅ , and R ｆ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , -C(=O)N(R ４ ) ２ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C ２ -C ７ is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, where R ｄ , R ｅ , and R ｆ Any substituted group may be one or more R ６ is substituted with a group, Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is hydrogen, —C(═O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, X １ is CR １１ or N, X ３ is CR １３ or N, X ４ is CR １４ or N, R １１ , R １３ , and R １４ are each independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, -CN, -OR ４ , -SR ４ , -CO ２ R ４ , -C(=O)N(R ４ ) ２ , or -N(R ４ ) ２ wherein any substituted groups of R 11 , R 13 , and R 14 are substituted with one or more halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted monocyclic heterocycle, —N(R 4 ) 2 , —OR 5 , —CN, —CO 2 R 5 , —C(═O)N(R 4 ) 2 , —SR 5 , —S(═O)R 7 , —S(═O) 2 R 7 , —NR 4 C(═O)R 5 , —NR 4 SO 2 R 7 , —SO 2 R 7 , or —SO 2 N(R 4 ) 2 ; W is absent or -C(R ３ ) ２ -, -C(R ３ ) ２ -C(R ３ ) ２ -, -C(=O)-, ＃ -C(=O)-O-, ＃ -C(=O)-C(R ３ ) ２ -,or ＃ -C(=O)NR ２ - where: ＃ indicates the point of attachment to the N atom of the ring, Y is absent or -(C=O)-, ＊ -O(C=O)-, ＊ -NR ２ -(C=O)-,-(SO ２ )-,or ＊ -NR ２ - (SO ２ )—where: ＊ is R １ indicates the point of attachment to R １ is unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C ２ -C ７ Heterocycloalkyl, unsubstituted or substituted -(C １ -C ６ alkyl)-(C ３ -C ６ cycloalkyl), or unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), where R １ Any substituted group may be one or more halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by R ２ each independently represents hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, R ３ are each independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl or unsubstituted or substituted C ２ -C ７ is heterocycloalkyl, R ４ each independently represents hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ selected from the group consisting of fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Or, two R ４ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle; R ５ are each independently hydrogen, substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ selected from the group consisting of fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ６ each independently represents a halogen, an unsubstituted or substituted C １ -C ４ Alkyl, unsubstituted or substituted C １ -C ４ Alkoxy, unsubstituted or substituted C １ -C ４ Fluoroalkyl, unsubstituted or substituted C １ -C ４ Fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -CO ２ R ５ , -CH ２ CO ２ R ５ , -C(=O)N(R ４ ) ２ , -C(=O)N(R ４ ) OR ５ , -CH ２ C(=O)N(R ４ ) ２ , -N(R ４ ) ２ , -CH ２ N (R ４ ) ２ , -C(R ５ ) ２ N (R ４ ) ２ , -NR ４ C(=O)R ５ , -CH ２ N.R. ４ C(=O)R ５ , -NR ４ C(=O)N(R ５ ) ２ , -NR ４ C(=O)N(R ４ ) ２ , C(R ５ )=N(R ４ ) -OR ５ , -SR ５ , -S(=O)R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ and R ７ Each independently represents a substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C １ -C ６ A compound selected from the group consisting of fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, or a pharma- ceutically acceptable salt or solvate thereof.

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

3. R Ａ teeth 【Chemistry 2】 and R Ｂ teeth 【Chemistry 3】 2. The compound of claim 1, wherein:

4. The compound has the structure of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 4】 During the ceremony, V is CH, CR ａ , C.R. ｂ or N, Z is CH, CR ｄ , C.R. ｅ or N, R ａ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; R ａ Any substituted group may be one or more R ６ is substituted with a group, R ｂ and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ and unsubstituted or substituted C １ -C ６ alkyl; R ｂ and R ｃ Any substituted group may be one or more R ６ is substituted with a group, R ｄ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C ２ -C ７ is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group may be one or more R ６ group, and R ｅ and R ｆ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ and unsubstituted or substituted C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of alkyl.

5. The compound has the structure of Formula (VIa), Formula (VIb), Formula (VIIa), or Formula (VIIb), or a pharma- ceutically acceptable salt or solvate thereof; 【Chemistry 5】 During the ceremony, V is CH, CR ａ , C.R. ｂ or N, R ａ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -C(O)CH ３ , -C(O)CH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NH ２ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ) ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ N.H.C.H. ３ , -CH ２ CH ２ N (CH ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R ｂ and R ｃ each independently is hydrogen, Cl, Br, -CN, -OH, -OCH ３ -, -OCH ２ CH ３ -, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ -, -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ -, -CF ３ -, -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ -, -CH ２ CF ３ -, -CH ２ OCH ３ -, -CH ２ CH ２ OCH ３ -, -CH ２ NH ２ -, -CH ２ NHCH ３ -, -CH ２ N(CH ３ ) ２ -, -CH ２ CH ２ NH ２ -, -CH ２ CH ２ NHCH ３ and -CH ２ CH ２ N (CH ３ ) ２ is selected from the group consisting of R ｄ is hydrogen, Cl, Br, -CN, -OH, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ NH ２ , -CH ２ NHCH ３ , -CH ２ N(CH ３ ) ２ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ , -CH ２ CH ２ N(CH ３ ) ２ , unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C ２ -C ７ is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group may be one or more R ６ group, and R ｅ and R ｆ are independently F, Cl, Br, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CH(CH ３ ) (CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, -OCH ３ , and -OCH ２ CH ３ 5. The compound of claim 4, selected from the group consisting of: or a pharma- ceutically acceptable salt or solvate thereof.

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

7. R １ is a C substituted with -N(R 4 ) 2 １ -C6 alkyl; Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 7. The compound of claim 6, 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 atom, or a pharma- ceutically acceptable salt or solvate thereof.

8. The compound has the structure of formula (XIIa), (XIIb), (XIIc), or (XIId), or a pharma- ceutically acceptable salt or solvate thereof; 【Chemistry 6】 During the ceremony, V is CH, CR ａ , C.R. ｂ or N, Z is CH, CR ｄ , C.R. ｅ or N, X １ is CR １１ And X ３ is CR １３ and X ４ is CR １４ and Or, X １ is N, and X ３ is CR １３ and X ４ is CR １４ and R ａ is hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; R ｂ and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C １ -C ６ fluoroalkyl; R ｄ is hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; and R ｅ and R ｆ are independently hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C １ -C ６ 5. The compound of claim 4, or a pharma- ceutically acceptable salt or solvate thereof, selected from the group consisting of fluoroalkyl.

9. X １ is CR １１ And X ３ is CR １３ and X ４ is CR １４ and Or, X １ is N, and X ３ is CR １３ and X ４ is CR １４ That is, 2. A compound according to claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

10. The compound has the structure of formula (XV): 【Chemistry 7】 During the ceremony, R Ａ is an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, or an unsubstituted or substituted phenyl, where R Ａ When R is substituted, Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R ａ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; R ａ Any substituted group may be one or more R ６ group, and R ｂ and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl; R ｂ and R ｃ Any substituted group may be one or more R ６ is substituted with a group, Here, R ａ , R ｂ , or R ｃ When is attached to the N atom of a heteroaryl, it is hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, R Ｂ is an unsubstituted or substituted phenyl or an unsubstituted or substituted 5- or 6-membered heteroaryl containing 1 or 2 N atoms, where R Ｂ When R is substituted, Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from R ｄ is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ , unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, unsubstituted or substituted C ２ -C ７ is selected from the group consisting of heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl; R ｄ Any substituted group may be one or more R ６ group, and R ｅ and R ｆ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ) ２ and unsubstituted or substituted C １ -C ６ is selected from the group consisting of alkyl, Here, R ｄ , R ｅ , or R ｆ When is attached to the N atom of a heteroaryl, it is hydrogen, —C(═O)R ７ or unsubstituted or substituted C １ -C ６ is alkyl, X １ is CR １１ or N, R １１ is hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, -CN, -OR ４ , or -N(R ４ ) ２ wherein the optionally substituted C 1 -C 6 alkyl is selected from one or more of F, —N(R ４ ) ２ or -OR ５ is replaced by W is -C(R ３ ) ２ - or -C(=O)-, Y is absent or -(C=O)-, ＊ -NR ２ -(C=O)- or -(SO ２ )—where: ＊ is R １ indicates the point of attachment to, and R １ is unsubstituted or substituted C １ -C ６ alkyl, where R １ Any substituted group may be one or more halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted monocyclic heterocycle, -N(R ４ ) ２ , -OR ５ , -CN, -CO ２ R ５ , -C(=O)N(R ４ ) ２ , -SR ５ , -S(=O)R ７ , -S(=O) ２ R ７ , -NR ４ C(=O)R ５ , -NR ４ SO ２ R ７ , -SO ２ R ７ , or -SO ２ N (R ４ ) ２ is replaced by Or, R １ is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 2. The compound of claim 1, wherein: R is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms; or a pharma- ceutically acceptable salt or solvate thereof.

11. R Ａ is unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R Ａ When R is substituted, Ａ is R ａ , R ｂ , and R ｃ and is substituted with one or two groups selected from R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ When R is substituted, Ｂ is R ｄ , R ｅ , and R ｆ and is substituted with one, two, or three groups selected from X １ is CR １１ or N, R １１ is hydrogen, F, Cl, -CH ３ , C.F. ３ , -CN, -OR ４ , or -N(R ４ ) ２ and R １ is unsubstituted or substituted C １ -C alkyl, where any substituted C １ -C6 alkyl is one or more halogens, C １ -C ４ Alkyl, -N(R ４ ) ２ or -OR ５ is replaced by Or, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R １ is an unsubstituted or substituted bridge C containing 1-2 N atoms ２ -C ７ is heterocycloalkyl, Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 11. The compound of claim 10, wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, or a pharma- ceutically acceptable salt or solvate thereof.

12. R Ａ teeth 【Chemistry 8】 and V is CH or N; R Ｂ teeth, 【Chemistry 9】 and Z is CH or N, or a pharma- ceutically acceptable salt or solvate thereof.

13. The compound has the structure of formula (XVIa) or (XVIb), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 10】 During the ceremony, R ａ is hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl; R ｂ and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ Alkyl, and unsubstituted or substituted C １ -C ６ fluoroalkyl; and 11. The compound of claim 10, or a pharma- ceutically acceptable salt or solvate thereof, wherein V is CH or N.

14. The compound has the structure of formula (XVIc) or (XVId), or a pharma- ceutically acceptable salt or solvate thereof; 【Chemistry 11】 V is CH or N, and X １ is N; or a pharma- ceutically acceptable salt or solvate thereof.

15. R １ is unsubstituted or substituted C １ -C alkyl, where any substituted C １ -C6 alkyl is one or more halogens, C １ -C ４ Alkyl, -N(R ４ ) ２ or -OR ５ is replaced by Or, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl; Or, R １ is unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ 14. The compound of claim 13, wherein: R is an integer from 1 to 10; and R is an integer from 1 to 10. The compound of claim 13, wherein R is an integer from 1 to 10; and R is an integer from 1 to 10.

16. 1-1: 2-[1-(2-aminoacetyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-2: 2-[1-(2-aminoacetyl)-6-(2-ethoxyphenyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-3: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-4: 2-[1-(3-aminopropanoyl)-6-(2-ethoxyphenyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-5: 2-{1-[(3S)-3-aminobutanoyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-6: 2-{1-[(3R)-3-aminobutanoyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-7: 3-amino-1-{1'-[2-chloro-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-8: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-9: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-10: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3S)-pyrrolidine-3-carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-11: 2-[1-(4-aminobutanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-12: 2-[1-(2-aminoethyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-13: 2-{1-[(2R)-2-aminopropyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-14: 2-{1-[(2S)-2-aminopropyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-15: 2-{6-(2-ethoxypyridin-3-yl)-1-[2-(methylamino)ethyl]-2-oxospiro[indoline-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-16: 2-[1-(2-aminoethyl)-6-(2-ethoxypyridin-3-yl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-17: 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3S)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-18: 2-[6-(2-ethoxypyridin-3-yl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-19: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-6-(trifluoromethyl)pyridine-4-carbonitrile, 1-20: 3-amino-1-[6-(2-ethoxypyridin-3-yl)-1'-[5-fluoro-6-(trifluoromethyl)pyridin-2-yl]-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl]propan-1-one, 1-21: 2-[6-(2-ethoxypyridin-3-yl)-1-[(3R)-1-methylpyrrolidin-3-yl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-22: 3-amino-1-{1'-[4-chloro-2-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-23: 3-amino-1-{1'-[6-ethoxy-2-(trifluoromethyl)pyridin-3-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-24: 6-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-4-(trifluoromethyl)pyridine-2-carbonitrile, 1-25: 3-amino-1-{1'-[5-ethoxy-6-(trifluoromethyl)pyridin-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-1-one, 1-26: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-2-methyl-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-27: N-(2-aminoethyl)-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-28: 2-[1'-(3-aminopropanoyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-29: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-30: N-[(2R)-2-aminopropyl]-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-31: N-[(2S)-2-aminopropyl]-1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-32: 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-33: 1'-[2-cyano-4-(trifluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-N-[(3S)-pyrrolidin-3-yl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxamide, 1-34: 2-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-chlorobenzonitrile, 1-35: 2-[1-(3-aminopropanoyl)-6-[2-(hydroxymethyl)phenyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-36: 3-amino-1-[6-(2-ethoxypyridin-3-yl)-1'-[4-methoxy-6-(trifluoromethyl)pyridin-2-yl]-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl]propan-1-one, 1-37: 2-[1-(2-aminoethanesulfonyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-5-(trifluoromethyl)benzonitrile, 1-38: 2-(1-{[(2R)-azetidin-2-yl]methyl}-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl)-5-(trifluoromethyl)benzonitrile, 1-39: 2-(1-{[(2S)-azetidin-2-yl]methyl}-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl)-5-(trifluoromethyl)benzonitrile, 1-40: 2-{1-[(2R)-1-aminopropan-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-41: 2-{1-[(2S)-1-aminopropan-2-yl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-42: 2-{1-[(2R)-2-aminopropyl]-6-[2-(hydroxymethyl)phenyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl}-5-(trifluoromethyl)benzonitrile, 1-43: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-6-methoxypyridine-2-carbonitrile, 1-44: 3-[1-(3-aminopropanoyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidine]-1′-yl]-6-ethoxypyridine-2-carbonitrile, 1-45: (2R)-1-{1'-[4-chloro-2-(difluoromethyl)phenyl]-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidin]-1-yl}propan-2-amine, 1-46: 2-{1'-[(2R)-2-aminopropyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-47: 2-{1'-[(2R)-2-aminopropanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-48: 2-{1'-[(2S)-2-aminopropanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-49: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3R)-pyrrolidine-3-carbonyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-50: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[3-(methylamino)propanoyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-51: 2-{1'-[(2S)-2-amino-3-hydroxypropyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-52: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3R)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-53: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[(3S)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-54: 2-[1'-(3-aminopropyl)-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-55: N-(2-aminoethyl)-1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-56: N-[(2S)-2-aminopropyl]-1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-57: 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-58: 2-{1'-[3-(dimethylamino)propanoyl]-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-59: 1-[2-cyano-4-(trifluoromethyl)phenyl]-6'-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1'-carboxamide, 1-60: 2-[1'-(2-aminoethyl)-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-61: 2-{1'-[(2R)-2-aminopropyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-62: 2-{1'-[2-(dimethylamino)ethyl]-6'-(2-ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-63: 2-[6'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-64: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-65: 2-[7'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-66: 2-[1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-67: 2-[1'-(3-aminopropyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-68: 2-{1'-[(2S)-2-aminopropyl]-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl}-5-(trifluoromethyl)benzonitrile, 1-69: 2-[7'-(2-ethoxypyridin-3-yl)-1'-[2-(methylamino)ethyl]-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl]-5-(trifluoromethyl)benzonitrile, 1-70: 2-{1'-[(2R)-2-aminopropyl]-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl}-5-(trifluoromethyl)benzonitrile, or a pharma- ceutically acceptable salt or solvate thereof.

17. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

18. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in a method for treating Cushing's syndrome, ectopic Cushing's syndrome, or congenital adrenal hyperplasia (CAH) in a mammal, said method comprising administering to said mammal a compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

19. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in a method for reducing secretion of adrenocorticotropic hormone (ACTH) in a mammal, said method comprising administering to said mammal a compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

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