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

Abstract

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

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 953,001, filed December 23, 2019, which is hereby incorporated by reference in its entirety.

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

Background Art

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

Summary of the Invention

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

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

[0006] [Chemical formula] wherein, R A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, wherein when R A is substituted, R A is substituted with one, two, three, or four groups selected from R a , R b , and R c , R a , R b , and R c are independently selected from the group consisting of 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, and any substituted group of R a , R b , and R c is substituted with one or more R 6 groups, wherein, R a , R b , or Rc When it is attached to the N atom of a heteroaryl, it is 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, when R B is substituted, R B is substituted with one, two, three, or four groups selected from R d , R e , and R f , and R d , R e , and R f are independently hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7 , -C(=O)N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, where any substituted group of R d , R e , and R f is substituted with one or more R 6 groups, where, when R d , R e , or R f is attached to the N atom of a heteroaryl, it is 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 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, -OR 4 , -SR 4 , -CO2R 4 , -C(=O)N(R 4 )2, or -N(R 4 )2, 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 # represents the point of attachment to the ring N atom, Y is absent or -(C=O)-, * -O(C=O)-, * -NR 2 -(C=O)-, -(SO2)-, or * -NR 2 -(SO2)-, where * represents the point of attachment to R 1 , 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 any substituted group of is one or more halogens, 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, and 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 4They combine with the nitrogen atoms to which they are attached to form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle, R 5 each independently is 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 each independently is 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, -CO2R 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 7Each is independently selected from the group consisting of substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl.

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

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

[0009] In any of the foregoing embodiments, further embodiments comprising a single administration of an effective amount of the compound include further embodiments 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 a day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

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

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

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

[0013] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it will be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

Embodiments for Carrying Out the Invention

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

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

[0016] It is possible to selectively regulate any one of the MCRs, or a combination thereof. In some embodiments, selectively regulating any one of the MCRs, or a combination thereof, with respect to other MCRs is useful in various clinical applications. In some embodiments, selectively regulating any one of the MCRs, or a combination thereof, with respect 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 antagonists selective for 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 be activated, and ACTH selectively activates MC2R. Importantly, the other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, have no affinity for MC2R (Gantz, I. and T. M. Fong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003). The main function of MC2R is to stimulate the fasciculata cells of the adrenal cortex to synthesize and secrete cortisol. MC2R requires the GPCR accessory protein MRAP (melanocortin 2 receptor accessory protein) to be successfully secreted and function on the cell surface. MRAP is a small protein with one transmembrane domain, forms a stable complex with MC2R, and is required for both the cell surface expression of MC2R and its ability to bind ACTH. MRAP can bind to any MCR and affect its activity, but is essential only for the activity of MC2R. When ACTH binds to the MC2R / MRAP complex of adrenal cortical cells, GS is activated, intracellular cAMP levels increase, and ultimately, cortisol synthesis and secretion are promoted by regulating multiple steps in the steroid production pathway.

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

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

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

[0022] In some embodiments, the compounds described herein are capable of being administered 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, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof is provided herein:

[0025]

Chemical formula

[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 # represents 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 )2-. 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 from each other. 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, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. 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, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. 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 # represents 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 # represents the point of attachment to the N atom of the ring.

[0033] In some embodiments, W is # -C(=O)-C(R 3 )2-, where # represents the point of attachment to the N atom of the ring. In some embodiments, W is # -C(=O)-C(R 3 )2-, where # represents the point of attachment to the N atom of the ring, and R 3 are the same. In some embodiments, W is # -C(=O)-C(R 3 )2-, where # represents the point of attachment to the N atom of the ring, and R 3 are different. In some embodiments, W is # -C(=O)-C(R 3 )2-, where # represents 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 # represents the point of attachment to the N atom of the ring, and R 3 are each independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, W is #-C(=O)-CH2-, where # represents the bonding point to the N atom of the ring.

[0034] In some embodiments, W is # -C(=O)NR 2 -, where # represents the bonding point to the N atom of the ring. In some embodiments, W is # -C(=O)NR 2 -, where # represents the bonding point 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 # represents the bonding point 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 # represents the bonding point to the N atom of the ring, and R 2 is hydrogen or -CH3. In some embodiments, W is # -C(=O)NH-, where # represents the bonding point 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 * represents the bonding point to R 1 In some embodiments, Y is absent, or -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * represents the bonding point to R 1 and

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

[0040]

[0041] ​ In some embodiments, R 2 is each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 2 is each independently hydrogen or C1-C6 alkyl. In some embodiments, R 2 is each independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 2 is each independently hydrogen or -CH3. In some embodiments, R 2 is each -CH3. In some embodiments, R 2 is each hydrogen.

[0042] In some embodiments, R 3 is each independently hydrogen, halogen, or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 is each independently hydrogen or unsubstituted or substituted C1-C6 alkyl. In some embodiments, R 3 is each independently hydrogen or C1-C6 alkyl. In some embodiments, R 3 is each independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 3 is each independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 3 is each independently hydrogen or -CH3. In some embodiments, R 3 is each -CH3. In some embodiments, R 3 is each hydrogen.

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

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

[0046] In some embodiments, R A is unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted phenyl, where when R A is substituted, R A is substituted with one, two, three, or four groups selected from R a , R b , and R c . In some embodiments, R A is unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted phenyl, where when R A is substituted, R A is substituted with one, two, or three groups selected from R a , R b , and R c . In some embodiments, R Ais unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted phenyl, where R A when substituted, R A is substituted with one or two groups selected from R a R b and R c . In some embodiments, R A is unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted phenyl, where R A when substituted, R A is substituted with a group of R a R b or R c .

[0047] In some embodiments, R A is substituted with one, two, three, or four groups selected from R a R b and R c . In some embodiments, R A is substituted with one, two, or three groups selected from R a R b and R c . In some embodiments, R A is substituted with one or two groups selected from R a R b and R c . In some embodiments, R A is substituted with one group selected from R a R b and R c . In some embodiments, R A is substituted with one R a . In some embodiments, R A is substituted with one R c .

[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, wherein, R A when substituted, R A is substituted with one, two, three, or four groups selected from R a R b and R c c . In some embodiments, when R A is substituted, R A is substituted with one, two, or three groups selected from R a R b and R c c . In some embodiments, when R A is substituted, R A is substituted with one or two groups selected from R a R b and R c c . In some embodiments, when R A is substituted, R A is substituted with one group of R a R b or R c c .

[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, wherein, when R A is substituted, R A is R a Rb and R c is substituted with one, two, three, or four groups selected from A When R A is substituted, 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 when R A is substituted, R A is substituted with one, two, three, or four groups selected from a R b and R c In some embodiments, when R A is substituted, R A is substituted with one or two groups selected from a R b and R c In some embodiments, R

[0051] In some embodiments, R A is

[0052]

Chemical formula

[0053] In some embodiments, R A is

[0054]

Chemical formula

[0055]

Chemical formula

[0056] [Chemical formula] .

[0057] In some embodiments, R A is

[0058] [Chemical formula] and V is CH, CR a , CR b , or N. In some embodiments, V is CH or N.

[0059] In some embodiments, R A is

[0060] [Chemical formula] and V is CH, CR a , CR b , or N. In some embodiments, V is CH or N.

[0061] In some embodiments, the compound has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof,

[0062] [Chemical formula] wherein V is CH, CR a , CR b , or N. 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 pharmaceutically acceptable salt or solvate thereof.

[0064] [Chemical] Here, V is CH, CR a , CR b , or N. In some embodiments, V is CH or N.

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

[0066] In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl, where when R A is substituted, R A is substituted with one or two groups selected from 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 when R A is substituted, R A is substituted with one, two, or three groups selected from 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 when R A is substituted, R A is substituted with one, two, or three groups selected from R a , R b , and R cis substituted with one or two groups selected therefrom. In some embodiments, R A is an unsubstituted or substituted monocyclic 5-membered heteroaryl containing one heteroatom selected from N, O, and S, where, when R A is substituted, R A is substituted with a group of R a , R b , or R c .

[0067] In some embodiments, R A is an 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, when R A is substituted, R A is substituted with one, two, or three groups selected from R a , R b , and R c . In some embodiments, when R A is substituted, R A is substituted with one or two groups selected from R a , R b , and R c . In some embodiments, when R A is substituted, R A is substituted with one group of R a , R b , or R c .

[0068] In some embodiments, R A is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted isoxazolyl, where, when R AWhen it is replaced, R A is R a R b and R c substituted with one, two, or three groups selected from. In some embodiments, when R A is replaced, R A is R a R b and R c substituted with one or two groups selected from. In some embodiments, when R A is replaced, R A is one R a R b or R c group.

[0069] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, or unsubstituted or substituted thienyl, where when R A is replaced, R A is R a R b and R c substituted with one, two, or three groups selected from. In some embodiments, when R A is replaced, R A is R a R b and R c substituted with one or two groups selected from. In some embodiments, when R A is replaced, R A is one R a R b or R c group.

[0070] In some embodiments, R A is

[0071]

Chemical formula

[0072]

Chem.

[0073] In some embodiments, R A is

[0074]

Chem.

[0075]

Chem.

[0076] In some embodiments, R A is

[0077]

Chem.

[0078]

Chem.

[0079] In some embodiments, R A is

[0080]

Chem.

[0081]

Chem.

[0082] In some embodiments, R A is

[0083]

Chem.

[0084]

Chem.

[0085]

Chem.

[0086]

Chem.

[0087] [Chemical formula] is.

[0088] In some embodiments, R A is

[0089] [Chemical formula] is, or R A is

[0090] [Chemical formula] is. 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 is

[0092] [Chemical formula] is, or R A is

[0093] [Chemical formula] is, and 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.

[0094] In some embodiments, R A is

[0095] [Chemical formula] and wherein 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 C1-C6 alkyl. In some embodiments, R c is hydrogen, or C1-C6 alkyl. In some embodiments, R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. In some embodiments, R c is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R c is hydrogen or -CH3. In some embodiments, R c is -CH3. In some embodiments, R c is hydrogen. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl. In some embodiments, R c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, or -CH2CH2CH(CH3)2. In some embodiments, R 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 is

[0097] [Chemical formula] and Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , CR 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 is

[0098] [Chemical formula] and Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , CR 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 is

[0099]

Chem.

[0100]

Chem.

[0101] In some embodiments, R A is

[0102]

Chem.

[0103]

Chem.

[0104] In some embodiments, R A is

[0105]

Chem.

[0106]

Chem.

[0107]

Chem.

[0108] [Chemical formula] and Y 1 is NR c and Y 2 and Y 3 are each 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), or a pharmaceutically acceptable salt or solvate thereof,

[0110] [Chemical formula] wherein Y 1 is NR c , O, or S, Y 2 and Y 3 are independently CH, CR a CR 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 pharmaceutically acceptable salt or solvate thereof.

[0112] [Chemical formula] In the formula, Y 1 is NR c , O, or S, and Y 2 and Y 3 are independently CH, CR a , CR 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 pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IIId), or a pharmaceutically acceptable salt or solvate thereof.

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

[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 azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, where R A when substituted, R A is substituted with one, two, three, or four groups selected from R a R b and R c . In some embodiments, when R A is substituted, R A is substituted with one or two groups selected from R a R b and R c .

[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, wherein R B when substituted, R B is substituted with one, two, three, or four groups selected from R d R e and R f . In some embodiments, when R B is substituted, R B is substituted with one, two, or three groups selected from R d R e and R f .

[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 oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein, R B when substituted, R B is substituted with one, two, three, or four groups selected from R d R e and R f . In some embodiments, when R B is substituted, RB is substituted with one, two, or three groups selected from R d , R e , and R f .

[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 when R B is substituted, R B is substituted with one, two, three, or four groups selected from R d , R e , and R f . In some embodiments, when R B is substituted, R B is substituted with one, two, or three groups selected from R d , R e , and R f .

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

[0120] In some embodiments, R B is

[0121]

Chemical Structure

[0122]

Chemical formula

[0123]

Chemical formula

[0124]

Chemical formula

[0125] In some embodiments, R B is

[0126]

Chemical formula

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

[0128]

Chemical formula

[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), or a pharmaceutically acceptable salt or solvate thereof,

[0131] [Chemical formula] wherein V is CH, CR a , CR b , or N, and Z is CH, CR d , CR 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), or a pharmaceutically acceptable salt or solvate thereof,

[0134] [Chemical formula] wherein V is CH, CR a , CR b , or N. In some embodiments, V is CH or N.

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

[0136] [Chemical formula] wherein V is CH, CR a , CR bor N. In some embodiments, V is CH or N.

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

[0138] In some embodiments, the compound has the structure of formula (VIc), or a pharmaceutically acceptable salt or solvate thereof,

[0139]

Chemical formula

[0140] In some embodiments, the compound has the structure of formula (VId), or a pharmaceutically acceptable salt or solvate thereof,

[0141]

Chemical formula

[0142] In some embodiments, the compound has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof,

[0143]

Chemical formula

[0144] In some embodiments, the compound has the structure of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof.

[0145]

Chemical formula

[0146] In some embodiments, the compound has the structure of formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (VIIb), or a pharmaceutically acceptable salt or solvate thereof.

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

[0148]

Chemical formula

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

[0150]

Chemical formula

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

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

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

[0154] [Chemistry]

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

[0156] In some embodiments, W is -CH2-, -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 independently CH, CR a , CR b , or N. In some embodiments, Y 1 is NR c and Y 2 and Y 3 are independently CH, CR a , or CR b . In some embodiments, Y 1 is NR c and Y 2 and Y 3 are each CH.

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

[0160]

Chemical formula

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

[0162] In some embodiments, W is -CH2-, -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 C1-C6 alkyl. In some embodiments, R c is hydrogen or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

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

[0166]

Chemical formula

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

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

[0169] In some embodiments, W is -CH2-, -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 C1-C6 alkyl. In some embodiments, R c is hydrogen or C1-C6 alkyl. In some embodiments, R c is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R c is C1-C6 alkyl.

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

[0173] [Chemical formula] Z is CH, CR d , CR e , or N.

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

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

[0176] In some embodiments, W is -CH2-, -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), or a pharmaceutically acceptable salt or solvate thereof,

[0179]

Chemical Structure

[0180] In some embodiments, Y is absent, -(C=O)-, *-NH-(C=O)-, or -(SO2)-, where * is R 1 indicates the point of attachment to R. 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 pharmaceutically acceptable salt or solvate thereof.

[0182]

Chemical Structure

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

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

[0185]

Chemical Structure

[0186] In some embodiments, the compound has the structure of formula (Xd), or a pharmaceutically acceptable salt or solvate thereof,

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

[0188] In some embodiments, the compound has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof,

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

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

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

[0192] [Chemical formula] In the formula, R c is hydrogen, -C(=O)R 7is 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 pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XIb), or a pharmaceutically acceptable salt or solvate thereof.

[0194] In some embodiments, the compound has the structure of formula (XIc), or a pharmaceutically acceptable salt or solvate thereof,

[0195]

Chemical formula

[0196] In some embodiments, the compound has the structure of formula (XId), or a pharmaceutically acceptable salt or solvate thereof,

[0197]

Chemical formula

[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 when substituted, R B is substituted with one, two, or three groups selected from R d R e and R f .

[0199] In some embodiments, R B is

[0200]

Chemical formula

[0201]

Chemical formula

[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 Any substituted group is one or more halogens, 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 unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycloalkyl containing 1 to 4 N atoms and 0 or 1 O or S atom, unsubstituted or substituted bridged C2-C7 heterocycloalkyl containing 1 to 2 N atoms, or unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), where any substituted group of R 1 is one or more halogens, 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 unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where any substituted group of R 1 is one or more halogens, 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-membered, 5-membered, 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 unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), and the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

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

[0206] In some embodiments, R 1 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, where any substituted group of R 1 is one or more halogens, 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 unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom. In some embodiments, R 1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, where any substituted group of R 1 is one or more halogens, 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 is substituted.

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

[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 unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), and the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom.

[0211] In some embodiments, R 1 is unsubstituted or substituted C1-C6 heteroalkyl containing 1 N atom, where any substituted group of R 1 is substituted with one or more halogens, 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), and the 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 unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, wherein any substituted group of R 1 is substituted with one or more halogens, C1-C4 alkyl, -N(R 4 )2, or -OR 5 .

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

[0215] [Chemical formula] wherein V is CH, CR a , CR b , or N, and Z is CH, CR d , CR e , or N.

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

[0219]

Chemical formula

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

[0223]

Chemical formula

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

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

[0226] In some embodiments, R 11 , R 13 , and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, -CN, or -OR 4 . In some embodiments, R 11 , R 13 , and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, fluoroalkyl, unsubstituted C3-C6 cycloalkyl, -CN, or -OR 4 . In some embodiments, R 11 , R 13 , and R 14 are each independently hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, or cyclopropyl. In some embodiments, R 11 , R 13 , and R 14 are each independently hydrogen or F.

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

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

[0230] In some embodiments, the compound has the structure of formula (XV), or a pharmaceutically acceptable salt or solvate thereof,

[0231]

Chemical formula

[0232] In some embodiments, R A is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where when R A is substituted, R A is substituted with one or two groups selected from R a , R b , and R c , and here, when R a , R b , or R c is bonded to the N atom of heteroaryl, it is hydrogen, -C(=O)R7 or unsubstituted or substituted C1-C6 alkyl, R B is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where, when R B is substituted, R B is substituted with one, two, or three groups selected from R d , R e , and R f and is substituted with one, two, or three groups selected from R 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 unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where any substituted group of R 1 is substituted with one or more halogens, 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 bridged C2-C7 heterocycloalkyl containing 1-2 N atoms, or, R 1 is unsubstituted or substituted -(C1-C6 alkyl)-(C2-C7 heterocycloalkyl), and the heterocycloalkyl is unsubstituted or substituted monocyclic 4-membered, 5-membered, 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 -CH2-, -CH(R 3) or -(C=O)-. In some embodiments, W is -CH2- or -(C=O)-.

[0235] In some embodiments, R A is

[0236]

Chemical formula

[0237]

Chemical formula

[0238]

Chemical formula

[0239] In some embodiments, R A is

[0240]

Chemical formula

[0241]

Chemical formula

[0242] In some embodiments, R A is

[0243]

Chemical formula

[0244] [Chemical formula] wherein Z is CH or N.

[0245] In some embodiments, the compound has the structure of formula (XVIa) or (XVIb), or a pharmaceutically acceptable salt or solvate thereof.

[0246] [Chemical formula]

[0247] In some embodiments, the compound has the structure of formula (XVIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVIb), or a pharmaceutically acceptable salt or solvate thereof.

[0248] In some embodiments, R a is selected from the group consisting of 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 selected from the group consisting of 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, and 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 a structure of formula (XVIc) or (XVId), or a pharmaceutically acceptable salt or solvate thereof.

[0251] [Chemical formula] V is CH or N.

[0252] In some embodiments, the compound has a structure of formula (XVIc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has a structure of formula (XVId), or a pharmaceutically 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, -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * represents the bonding point to R 1 . In some embodiments, Y is absent or -(C=O)-.

[0255] In some embodiments, the compound has a structure of formula (XVIIa) or (XVIIb), or a pharmaceutically acceptable salt or solvate thereof.

[0256] [Chemical formula] wherein R c is hydrogen, -C(=O)R 7is 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 pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVIIb), or a pharmaceutically acceptable salt or solvate thereof.

[0258] In some embodiments, R a and R b are independently selected from the group consisting of 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 are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, and cyclopropyl, and R c is hydrogen, -C(=O)R 7 , unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl.

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

[0261]

Chemical formula

[0262] In some embodiments, the compound has the structure of formula (XVIIc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVII d), or a pharmaceutically 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, -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * represents the point of attachment to R 1 . In some embodiments, Y is absent or -(C=O)-.

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

[0267]

Chemical formula

[0268] In some embodiments, the compound has the structure of formula (XVIIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVIIIb), or a pharmaceutically acceptable salt or solvate thereof.

[0269] In some embodiments, R d is selected from the group consisting of 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 selected from the group consisting of 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 are 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 pharmaceutically acceptable salt or solvate thereof,

[0272]

Chemical formula

[0273] In some embodiments, the compound has the structure of formula (XVIIIc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (XVIIId), or a pharmaceutically 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 is -(C=O)-, * -NR 2 -(C=O)-, or -(SO2)-, where * indicates the point of attachment to R 1 . In some embodiments, Y is absent or is -(C=O)-.

[0277] In some embodiments, R 1 is unsubstituted or substituted C1-C6 heteroalkyl containing one N atom, where any substituted group of R 1 is substituted with one or more halogens, 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), and the 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 any substituted group is substituted with one or more halogens, C1-C4 alkyl, -N(R 4 )2, or -OR 5 .

[0280] In some embodiments, R a , R b , and R c are independently selected from the group consisting of 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, and any substituted group of R a , R b , and R c is substituted with one or more R 6 groups, or one R a and one R b , when present on adjacent atoms of R A , together with the intervening atoms connecting R a to R b , form a 5- to 6-membered monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring, where the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or more R 6 groups, and where, when R a , R b , or R c is bonded to the N atom of heteroaryl, it 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 R d , R e , and Rf independently is 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, where R d , R e , and R f any substituted group of is substituted with one or more R 6 groups, where R d , R e , or R f when is bonded to the N atom of heteroaryl, it 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.

[0281] In some embodiments, R a is selected from the group consisting of 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, any substituted group of R a is substituted with one or more R 6 groups, and R b and R c independently are hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, -C(=O)R 7, selected from the group consisting of 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 of is substituted with one or more R 6 groups, where R a , R b , or R c is attached to the N atom of heteroaryl, it is hydrogen, -C(=O)R 7 , or unsubstituted or substituted C1-C6 alkyl.

[0282] In some embodiments, R a is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and R b and R cis independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -C(O)CH3, -C(O)CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2, and R a , R b , or when R c is attached to the N atom of 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, one R A and one R a on adjacent atoms of R b combine with the intervening atoms connecting R a to R b to form a 5- to 6-membered monocyclic cycloalkyl or a 5- to 6-membered monocyclic heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more R 6 groups. In some embodiments, RA One R on an adjacent atom of a and one R b are combined with an intervening atom connecting R a to R b to form a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl is unsubstituted or substituted with one or more R 6 groups.

[0284] In some embodiments, R d is selected from the group consisting of 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, and any substituted group of R d is substituted with one or more R 6 groups, and R e and R f are independently selected from the group consisting of hydrogen, halogen, -OR 4 , -CN, -N(R 4 )2, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted C1-C6 heteroalkyl, where when R d , R e , or R f is bonded to the N atom of heteroaryl, it is hydrogen, -C(=O)R 7 , or unsubstituted or substituted C1-C6 alkyl.

[0285] In some embodiments, R dis selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2OH, -CH2CH2CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OCH3, -CH2CH2OCH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted C2-C7 heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, R d Any substituted group of is substituted with one or more R 6 groups, and R e and R f are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2CH(CH3)2, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, and -OCH2CH3, where R d R e or R fWhen it 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 following structure.

[0287]

Chemical formula

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

[0289] In some embodiments, R A , R B , X 1 , W, Y, and R 1 are as described in Table 1.

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

[0291] Typical compounds of formula (I) include the compounds described in the following table:

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

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

[0301] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or alternatively, 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. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than the non-ionized species and rapidly soluble in gastric and intestinal fluids and are thus useful in solid dosage forms. Furthermore, since their solubility is often pH-dependent, selective dissolution in one or another part of the gastrointestinal tract is possible, and this ability can be manipulated as one aspect of controlled-release and sustained-release behavior. Additionally, since the salt-forming molecules can be in equilibrium with the neutral form, passage through biological membranes can be regulated.

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

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

[0304] In some embodiments, the pharmaceutically acceptable salts are obtained by reacting the compound of formula (I) with a base. In some embodiments, the compound of formula (I) is acidic and is reacted with a base. In such situations, the acidic proton of the compound of formula (I) is replaced with a metal ion, for example, an ion of lithium, sodium, potassium, magnesium, calcium, or aluminum. Optionally, 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, etc. In other cases, the compounds described herein form salts with amino acids such as arginine, lysine, etc. 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, etc. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

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

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

[0307] In some embodiments, the sites of the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds of formula (I) are susceptible to various metabolic reactions. By incorporating appropriate substituents onto the organic radicals, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or removing the sensitivity of the aromatic ring to metabolic reactions are, by way of example, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0308] In another embodiment, the compounds described herein are labeled with isotopes (e.g., radioactive isotopes) 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 described in the various formulas and structures presented herein except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33Examples of isotopes include those of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, such as P. In one aspect, the isotope-labeled compounds described herein, for example, 3 H and 14 compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as an extended half-life or a reduced required dose in vivo.

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

[0311] Individual stereoisomers can be obtained as needed by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, or separation of diastereomers by achiral or chiral chromatography 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 diastereomeric isomer compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation / decomposition techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is effected by chromatography or by separation of diastereomeric salts and 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, the 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 in vivo to the parent drug. Prodrugs are often useful because in some situations they are easier to administer than the parent drug. For example, a prodrug may be bioavailable by oral administration while the parent drug is not. Additionally or alternatively, a prodrug may have improved solubility in a pharmaceutical composition compared to the parent drug. In some embodiments, the design of the prodrug increases effective water solubility. An example of a prodrug is, but is not limited to, a compound described herein, which is administered as an ester ("prodrug") and is then metabolically hydrolyzed to yield the active entity. A further example of a prodrug is a short peptide (polyamino acid) attached to an acidic group, which upon metabolism exposes the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0313] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyl oxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonic acid esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and, Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38 (each of these references is incorporated herein by reference). In some embodiments, the hydroxyl groups of the compounds disclosed herein are used to form prodrugs, and the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, etc. In some embodiments, the hydroxyl groups in the compounds disclosed herein are prodrugs, and the carboxylic acid groups are provided by the metabolism of the hydroxyl groups in vivo. In some embodiments, carboxyl groups are used to provide esters or amides (i.e., prodrugs), which are then metabolized in vivo to provide carboxylic acid groups. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0314] Prodrug forms of the compounds described herein (prodrugs are metabolized in vivo to produce the compounds 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 a hydroxyl group, an amino group, and / or a carboxylic acid group is functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0316] In additional or further embodiments, the compounds described herein are metabolized upon administration to a living being to produce metabolites, which are used to produce the desired effects, including the desired therapeutic effect.

[0317] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized" as used herein refers to the entire process by which a particular substance is changed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can bring about specific structural changes to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronosyltransferase catalyzes the transfer of an activated glucuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. The metabolites of the compounds disclosed herein are optionally identified by either administration of the compound to a host and analysis of tissue samples from the host, or in vitro incubation of the compound with hepatocytes and analysis of the resulting compound.

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

[0319] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used.

[0320] Compounds are prepared using standard organic chemistry techniques such as those described in March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, such as changes in solvents, reaction temperatures, reaction times, and various chemical reagents and other reaction conditions, may also be used.

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

[0322]

Chemical formula

[0323] Spiro[indoline-3,4'-piperidine] I is obtained by Fischer indole synthesis of (3-bromophenyl)hydrazine and benzyl 4-formylpiperidine-1-carboxylate in the presence of TFA and reduction of the indole intermediate. Compound I is further subjected to an organometallic coupling reaction such as a Suzuki-Miyaura reaction with R A B(OH)2 or its corresponding ester, followed by standard deprotection to produce Compound II. Compound II is converted to Intermediate III by reacting with R B X in the presence of an organic base. Thereafter, HATU-activated amide coupling with R 1 CO2H, triphosgene-activated urea formation with R 1 NH2, 1Reductive amination with CHO, or R 1 The final compound IV is obtained by triphosgene-activated sulfonylation with RSO3H. In some cases, further deprotection of R is required to obtain compound IV after amide formation. 1

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

[0325]

Chemical Structure

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

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

[0328]

Chemical Structure

[0329] ​​​Hydrolysis of the cyano group gives amide intermediate X, which is subjected to an intramolecular cyclization reaction in the presence of a strong inorganic base such as KOH to obtain azaspiroindolinone XI. R A Perform an organometallic coupling reaction such as the Suzuki-Miyaura reaction using B(OH)2 or its corresponding ester, and then perform standard debenzylation to obtain compound XII. In the presence of an organic base, R B React with X to convert it to compound XIII. Then, R 1 By N-alkylation with X, compound XIV is obtained. R 1 When R contains a protecting group, a further deprotection step is performed to obtain XIV.

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

[0331]

Chemical formula

[0332] Subject commercially available compound XV to a Suzuki-Miyaura coupling reaction with R A B(OH)2 and deprotection to obtain intermediate XVI. The conversion to XVII is achieved in the same manner as described in steps e and f of Scheme C. When R 1 contains a protecting group, a further deprotection step is performed to obtain XVII.

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

[0334]

Chemical formula

[0335] The indanone of the starting material was reduced with NaBH4 to obtain the corresponding alcohol, and then the alcohol was dehydrated in the presence of sulfuric acid to obtain indene, XVIII. Next, spiro-piperidinyl ring formation was carried out at the benzylic position of indene to obtain XIV. The alkene, XIV, can be converted to the ketone XXI by hydrobromination of the alkene, hydroxylation of the alkyl bromide, and Dess-Martin oxidation of the alcohol. Dihydroquinolinone, XXIII, is obtained by ring expansion of O-mesylated indanone oxime with AlCl3 catalyst. Next, R B For the SNAr reaction with R A X, deprotection was set. Then R B B(OH)2 or its corresponding ester, compound XXIV is obtained by the Suzuki-Miyaura reaction. Then, in the presence of an organic base, R N The final compound XXV is obtained from the S

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

[0337] Specific terms Unless otherwise specified, the definitions of the following terms used in this application are shown below. In addition to the term "including", the use of other forms such as "include", "includes", and "included" is not limiting. The headings of the paragraphs used in this specification are for organization purposes only and should not be construed as limiting the subject matter described.

[0338] As used herein, C1-C x refers to C1-C2, C1-C3... C1-C xIt includes. As just one example, a group designated as "C1-C6" indicates that there are 1 to 4 carbon atoms in that moiety, that is, the group contains one carbon atom, two carbon atoms, three carbon atoms, or four carbon atoms. Thus, as just one example, "C1-C4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0339] The term "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group can be branched or straight-chain. In some embodiments, the "alkyl" group has 1 to 10 carbon atoms, that is, C1-C10 alkyl. A range of numbers such as "1 to 10" always refers to each integer within the specified range when it appears in this specification. For example, "1 to 10 carbon atoms" means that the alkyl group consists of one carbon atom, two carbon atoms, three carbon atoms, etc., up to a maximum of 10 carbon atoms, but this definition also encompasses the occurrences of the term "alkyl" for which no range of numbers is specified. In some embodiments, the alkyl is C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

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

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

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

[0343] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by a 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 by an 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, the alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, 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 there is at least one carbon-carbon triple bond. In one embodiment, the alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, 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 of the skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). Heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, heteroalkyl is C1-C6 heteroalkyl.

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

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

[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 aryl. Depending on the structure, the aryl group is 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., the skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic compound or a bridged compound. In some embodiments, the cycloalkyl is optionally condensed with an aromatic ring, and the point of attachment is to a carbon other than an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 cyclic atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, norbornenyl, bicyclo[1.1.1]pentyl, adamantyl, norbornyl, norbornenyl, decalinyl, or 7,7-dimethyl-bicyclo[2.2.1]heptanyl. In some embodiments, 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, etc.

[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 by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0354] The terms "heterocyclic ring" or "heterocyclic" refer to aromatic heterocyclic rings (also known as heteroaryl) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom of the ring is selected from O, S, and N, and where each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyl) include rings having 3 to 10 atoms in their ring systems, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring systems. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The aforementioned groups are, where possible, C-bonded (or C-linked) or N-bonded. For example, groups derived from pyrrole include pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-bonded), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-bonded). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

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

[0356] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with 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" includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, the heterocycloalkyl is C2-C 10 heterocycloalkyl. In another embodiment, the heterocycloalkyl is C4-C 10 heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atom in the ring.

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

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

[0359] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups independently selected individually from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl.In some other embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is substituted with one or two of the foregoing groups. In some embodiments, the optional substituent on an aliphatic carbon atom (acyclic or cyclic) contains oxo (=O).

[0360] As used herein, the term "acceptable" with respect to a formulation, composition, or component means that there is no persistent adverse effect on the health of the subject being treated.

[0361] As used herein, the term "modulate" includes, by way of example only, enhancing the activity of a target, inhibiting the activity of a target, restricting the activity of a target, or expanding the activity of a target, and means interacting directly or indirectly with the target so as to change the activity of the target.

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

[0363] As used herein, terms such as "administer", "administering", "administration" 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 route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are proficient in the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0364] Terms such as "co - administration" as used herein are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment 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 administered agent or compound that, to some extent, reduces one or more of the symptoms of a disease or disorder being treated. The results include a decrease and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to clinically and significantly reduce the disease symptoms. The appropriate "effective" amount in an individual case is optionally determined using techniques such as dose - escalation studies.

[0366] As used herein, the terms "enhance" or "enhancing" mean increasing or prolonging a desired effect, either in potency or duration. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong the effect of another therapeutic agent on a system, either in potency or duration. 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] As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or co-administration of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient as separate entities simultaneously, concurrently or sequentially without a specific time limit of interference, where such administration provides the patient with effective levels of two compounds in the body. The latter term also applies to cocktail therapies, e.g., the administration of more than three active ingredients.

[0368] The terms "product" 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 classes of mammals: humans; non-human primates such as chimpanzees; and other apes and monkey species; farm animals such as cows, horses, sheep, goats, pigs; laboratory animals including rabbits, dogs, and cats; and rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

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

[0371] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated by conventional methods using one or more pharmaceutically acceptable inert ingredients that facilitate the processing of the active compound into a pharmaceutically used preparation. Suitable formulations depend on the route of administration selected. Summaries of the 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and, Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are hereby incorporated by reference for such disclosure.

[0372] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by methods that enable delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric, or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (including injection or infusion such as intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, dermal, enema, ophthalmic, otic, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the area in need of treatment, for example, by intraoperative local injection, topical application such as creams or ointments, injection, catheter, or implantation. Administration can also be by direct injection at the site of the diseased tissue or organ.

[0373] In some embodiments, a pharmaceutical composition suitable for oral administration is presented 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 oil, as a dispersion unit such as a capsule, cachet, or tablet, each containing a predetermined amount of the active ingredient. In some embodiments, the active ingredient is provided as a bolus, a lozenge, or a 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 together with one or more accessory ingredients. Compressed tablets can be prepared by optionally mixing with a binder, an inert diluent or lubricant, a surfactant, or a dispersant and compressing the active ingredient in a free-flowing form such as powder or granules with a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent with a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration must be in an amount suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, as well as a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablets or the sugar-coated tablet coating for identification or to characterize various combinations of the dosage of the active compound.

[0375] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The formulations for injection may be provided in unit dosage forms, for example, in ampoules or multi-dose containers, together with additional preservatives. The composition may take the form of a suspension, solution, or emulsion, etc. in an oily or aqueous vehicle, and may contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. The composition may be provided in containers for single-dose or multi-dose use, such as sealed ampoules and vials, and may be stored in powder form, or alternatively, in a lyophilized (freeze-dried) state that requires only the addition of a sterile liquid carrier, such as physiological saline or pyrogen-free distilled water, immediately prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types described above.

[0376] Pharmaceutical compositions for parenteral administration may include aqueous and non-aqueous (oily) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that 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 enable the preparation of highly concentrated solutions.

[0377] The pharmaceutical composition may also be formulated as a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in a tolerable oil) or ion exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

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

[0379] The pharmaceutical composition can be administered topically, i.e., by non-systemic administration. This includes the application of the above compound to the external epidermis or buccal cavity and the instillation of the above compound into the ear, eye, and nose so that the compound of the present invention does not enter the bloodstream in large amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

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

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

[0382] In addition to the components specifically mentioned above, the compounds and compositions described herein include other conventional agents in the art that take into account the type of formulation in question. For example, those suitable for oral administration may include flavoring agents.

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

[0384] In certain embodiments, the compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. For certain therapeutic uses, the compositions are administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or disorder. The amount effective for this use depends on the severity and course of the disease or disorder, previous treatment, the health status, weight, and response of the patient to the drug, as well as the judgment of the physician administering the treatment. A therapeutically effective amount is optionally determined by methods including, but not limited to, clinical trials of dose escalation and / or dosing determination.

[0385] For prophylactic use, a composition comprising a compound described herein is administered to a patient who is predisposed to, or at risk of, a particular disease, disorder, or illness. Such an amount is defined as a "prophylactically effective amount or dosage". In this use, the exact amount will vary depending on factors such as the patient's health, weight, etc. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder, or illness, previous treatment, the patient's health and response to the drug, as well as the judgment of the treating physician. In one aspect, a prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a compound of formula (I), or a pharmaceutically acceptable salt thereof, to prevent recurrence of symptoms of the disease or illness.

[0386] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, the administration of the compound is chronic, i.e., over a long period including the patient's lifetime, to relieve, or suppress or limit, the symptoms of the patient's disease or illness.

[0387] When improvement in the patient's condition occurs, a maintenance amount is administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced to a level at which the improved disease, disorder, or illness is maintained, depending on the symptoms. However, in some embodiments, the patient will require intermittent treatment over a long period if symptoms recur.

[0388] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the state and severity of the disease, and the idiosyncrasies (e.g., weight, gender) of the subject or host in need of treatment, but nevertheless is determined according to, for example, the particular agent being administered, the route of administration, the disease being treated, and the particular circumstances surrounding the case, including the subject or host being treated.

[0389] However, generally, the dosages used for the treatment of adult humans typically range from 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is preferably provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as 2, 3, 4 or more sub-doses per day.

[0390] In one embodiment, an appropriate daily dosage of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of the active ingredient in the dosage form may be less than or more than the ranges indicated herein, based on many variables regarding the individual treatment regimen. In various embodiments, the daily dosage and unit dosage are varied depending on many variables including, but not limited to, the activity of the compound used, the disease or disorder being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the physician.

[0391] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 50 and ED 50 The dose ratio between toxicity and therapeutic effect is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in 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 within the range of blood concentrations that include the ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dosage vary within this range depending on the dosage form used and the route of administration utilized.

[0392] In any of the foregoing embodiments, in a further embodiment, an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by infusion to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal, there being further embodiments.

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

[0394] In any of the foregoing embodiments, there are further embodiments that include multiple administrations of an effective amount of the compound, including (i) the compound being administered continuously or intermittently, as in a single administration, (ii) the interval between multiple administrations being every 6 hours, (iii) the compound being administered to the mammal every 8 hours, (iv) the compound being administered to the mammal every 12 hours, (v) the compound being administered to the mammal every 24 hours. In a further or alternative embodiment, the method includes a drug holiday, where the administration of the compound is temporarily interrupted or the amount of the compound being administered is temporarily reduced, and at the end of the drug holiday, the 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 is appropriate to administer at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

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

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

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

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

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

[0401] In combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered before, during, or after the onset of a disease or disorder, and the timing of administration of the composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as a prophylactic agent to prevent the onset of a disease or disorder and are administered continuously to a subject predisposed to the disease or disorder. In another embodiment, the compound and composition are administered to the subject as soon as possible during or after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or disorder has been detected or suspected and for the duration required for treatment of the disease. In some embodiments, the duration required for treatment can vary and the treatment duration is adjusted according to the specific needs of each subject.

[0402] Omitted: 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: Methanol - d, CDCl3: Chloroform - d, DME: 1,2 - Dimethoxyethane, H2O: Water, KOAc: Potassium acetate, NaOAc: Sodium acetate, Cs2CO3: Cesium carbonate, P - TsOH: p - Toluenesulfonic acid, NaNO2: Sodium nitrite, THF: Tetrahydrofuran, 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]palladium(II) dichloride, PdAMphos or Pd(AMPhos)Cl2 or, Bis(di - tert - butyl(4 - dimethylaminophenyl)phosphine)palladium(II) dichloride, Pd(DtBPF)Cl2: [1,1’ - Bis(di - tert - butylphosphino)ferrocene]palladium(II) dichloride, Pd2(dba)3.CHCl3: Tris(dibenzylideneacetone)dipalladium(0) - chloroform adduct, Xphos: 2 - Dicyclohexylphosphino - 2’,4’,6’ - triisopropylbiphenyl, rt: Room temperature, h: Hour, CPD: Compound.

Example

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

[0404] Synthesis of Compounds 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]

Chem.

[0406] Step 1-1, Preparation of Benzyl 6-Bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: To a purged 250 mL round-bottom flask, benzyl 4-formylpiperidine-1-carboxylate (2.9 g, 12 mmol) and DCM (30 mL) were added. The resulting solution was treated with (3-bromophenyl)hydrazine (2.0 g, 11 mmol) at 0 °C and then with 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 portionwise with NaBH4 (0.82 g, 22 mmol) 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 CH2Cl2 (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 using 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] Preparation of Benzyl 6-(2-Ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: To a 100 mL round-bottom flask maintained under an inert atmosphere of nitrogen purged with nitrogen, benzyl 6-bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (650 mg, 1.62 mmol) and dioxane / H2O (8.0 mL / 0.8 mL) were added. To the resulting solution, (2-Ethoxypyridin-3-yl)boronic acid (540 mg, 3.23 mmol), Pd(DtBPF)Cl2 (63 mg, 0.06 equivalent), and K2CO 3 (675 mg, 4.88 mmol) were added under N2. The reaction mixture was degassed with N2 for 5 minutes and stirred at 80 °C for 1 hour. The reaction was cooled to room temperature and the solid precipitate was filtered. The filtrate was concentrated in vacuo. The residue was applied onto a silica gel column using ethyl acetate / petroleum ether (1:1). Thereby, the title compound (600 mg, 84%) was obtained as a yellow oil. LCMS (M+H) + =444.2.

[0408] Preparation of 6-(2-Ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]: To a 100 mL round-bottom flask maintained under an inert atmosphere of nitrogen purged with nitrogen, 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) were added. Hydrogen was bubbled through the reaction. The resulting solution was stirred at room temperature for 4 hours and then filtered through a pad of celite. The filtrate was concentrated to obtain the title compound (400 mg, 95%) as a yellow solid. LCMS (M+H) + =310.2.

[0409] Preparation of 1-4,2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile: Into an 8 mL vial were 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 hour and cooled to room temperature. The reaction was purified directly by preparative HPLC to afford the title compound (150 mg, 57%) as a white solid. LCMS (M+H) + =479.1.

[0410] Preparation of 1-5, 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) were added HATU (56 mg, 0.15 mmol) and DIEA (60 mg, 0.46 mmol). The resulting mixture was stirred at room temperature for 10 minutes, 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 hours, 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 using ethyl acetate / petroleum ether (1:1). This afforded the title compound (65 mg, 68%) as a white solid. LCMS (M+H) + =650.2.

[0411] Preparation of 1-6,2-[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 hour 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 in the same manner as in Example 1 using appropriate substitution reagents and substrates in 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]

Chemical formula

[0416] Preparation of Step 2-1, 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 equivalent), potassium carbonate (217 mg, 1.57 mmol), and dioxane / water (4 mL / 0.4 mL) were charged into a thick-walled tube. The resulting mixture was degassed with N2 for 5 minutes, sealed, and stirred at 90 °C for 1.5 hours. The reaction was cooled to room temperature and concentrated. The residue was purified directly by reverse-phase C18 column chromatography to give the title compound (290 mg, 87%). LCMS (M+H) + =424.3.

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

[0418] Preparation of 2-3,2-[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 then the resulting solution was stirred at 125 °C for 16 h. The reaction mixture was cooled to room temperature and then purified directly by reverse-phase C18 column chromatography to afford the title compound (190 mg, 89%). LCMS (M+H) + =493.3.

[0419] 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 mixture was cooled to room temperature and the inorganic solids were removed by filtration. The filtrate was purified directly by reverse-phase C18 column chromatography to afford the title compound (22 mg, 55%). LCMS (M+H) + =662.3.

[0420] 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) was added TFA (0.1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by reverse-phase C18 CC to give the title compound (14 mg, 75%). LCMS (M+H) + =562.4.

[0421] 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) were added paraformaldehyde (12 mg, 0.39 mmol) and then sodium cyanotrihydroborate (12 mg, 0.2 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with TFA (0.1 mL) and purified directly from 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 in the same manner as in Example 2 using appropriate substitution reagents and substrates in 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]

Chem.

[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: To a purged 50 mL round bottom flask were added 2-[6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4’-piperidine]-1’-yl]-5-(trifluoromethyl)benzonitrile (120 mg, 0.58 mmol), ACN (3.0 mL), sodium hydrogen carbonate (100 mg, 1.19 mmol), and 4-nitrophenyl carbonochloridate (120 mg, 0.60 mmol) from Step 1-4 of Example 1. The resulting solution was stirred at room temperature for 2 hours, 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 using ethyl acetate / petroleum ether (1:4). Thereby, the title compound (320 mg, 85%) was obtained as a white solid. LCMS (M+H) + =644.4.

[0427] 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) were added tert-butyl (2-aminoethyl)carbamate (27 mg, 0.169 mmol) and TEA (26 mg, 0.257 mmol) under a N2 atmosphere. The resulting solution was stirred at 60 °C for 2 h and cooled to room temperature. The reaction mixture was purified by flash preparative HPLC to afford the title compound (40 mg, 70%) as a yellow solid. LCMS (M+H) + =665.5.

[0428] 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 afford the title compound (30 mg, 82%) as a white solid. LCMS (M+H) + =565.3.

[0429] The following compounds were prepared in the same manner as in Example 3 using appropriate substitution reagents and substrates in 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]

Chemical formula

[0433] Step 4-1, Preparation of tetrabutylammonium 2-((tert-butoxycarbonyl)amino)ethane-1-sulfonate: To an 8 mL vial were added 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 at room temperature for 16 h. After removal of the 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 afford the title compound (300 mg, 80%) as a yellow oil.

[0434] 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 using ethyl acetate / petroleum ether (1:1) to afford the title compound (40 mg, 56%) as a yellow solid. LCMS (M+H) + =686.2.

[0435] Preparation of 4-3,2-[1-(2-Aminoethanesulfonyl)-6-(2-ethoxypyridin-3-yl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-5-(trifluoromethyl)benzonitrile formate: TFA (0.2 mL) was added 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) at room temperature. The resulting solution was stirred at room temperature for 1 hour 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]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-29)

[0437]

Chemical Structure

[0438] Step 5-1, Preparation of Methyl (2,6-Dichloropyridin-3-yl)methanesulfonate: TEA (5.1 g, 50 mmol) and MsCl (3.1 g, 27 mmol) were added to a solution of (2,6-dichloropyridin-3-yl)methanol (3 g, 16.9 mmol) in DCM (40 mL) in a 250 mL flask at 0 °C. The resulting solution was stirred at room temperature for 1 hour 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 was 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: Sodium cyanide (2.1 g, 43 mmol) was added to a solution of methyl (2,6-dichloropyridin-3-yl)methanesulfonate (4.1 g, 16 mmol) in EtOH (90 mL) and water (10 mL). The resulting mixture was stirred at 80 °C for 2 h, cooled to 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 in vacuo. The residue was applied onto a silica gel column using ethyl acetate / petroleum ether (EA: 0 - 30%) to afford 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)ethan-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 (3x). 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 using ethyl acetate / petroleum ether (EA: 0 - 50%) to afford the title compound (1.2 g, 50%) as a dark green oil. LCMS (M+H) + =346.0.

[0441] Preparation of 5-4, 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-methylpropane-2-olate) hydride (3.0 g, 12 mmol) in dioxane (10 mL) was stirred at 100 °C for 15 h. The reaction mixture 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 was separated from the filtrate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was applied onto a silica gel column using 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] Preparation of 5-5, 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 eq), potassium carbonate (0.63 g, 4.6 mmol), and dioxane (4 mL) / water (0.4 mL) were charged into 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 mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was applied onto a silica gel column using 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] Preparation of 5-6,6'-(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 Pd(OH)2 (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 as a brown oil (0.21 g, 100%), which was used in the next step without further purification. LCMS (M+H) + =311.3.

[0444] 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 as a pale brown solid (0.16 g, 49%). LCMS (M+H) + =480.2.

[0445] 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]pyridine]-1’-yl}ethyl)carbamate: A mixture of 2-[6’-(2-ethoxypyridin-3-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-b]pyridine]-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) in DCE (0.6 mL) and MeOH (0.6 mL) was stirred at room temperature for 15 h. After removal of the volatile solvents, the residue was purified by preparative HPLC to afford the title compound (73 mg, 70%) as a pale brown solid. LCMS (M+H) + =623.3.

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

[0447] The following compounds were prepared in the same manner as in Example 5 using appropriate substitution reagents and substrates in 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]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-50)

[0450]

Chem.

[0451] Step 6-1, Preparation of methyl N-(3-{1-[2-cyano-4-(trifluoromethyl)phenyl]-6’-(2-ethoxypyridin-3-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-b]pyridine]-1’-yl}-3-oxopropyl)carbamate: Into an 8 mL vial were placed 3-[(tert-butoxycarbonyl(methyl)amino]propanoic acid (55 mg, 0.27 mmol), HATU (61 mg, 0.16 mmol), DIEA (74 mg, 0.57 mmol), and DMF (1 mL). After stirring at room temperature for 5 minutes, the reaction mixture was treated with 2-[6’-(2-ethoxypyridin-3-yl)-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (60 mg, 0.13 mmol) from Step 5-7 of Example 5. The resulting solution was stirred at room temperature for 1 hour 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] Preparation of 6-2,2-[6'-(2-ethoxypyridin-3-yl)-1'-[3-(methylamino)propanoyl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-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]pyridine]-1'-yl}-3-oxopropyl)-N-methylcarbamate (56 mg, 0.084 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour 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 in the same manner as in Example 6 using appropriate substitution reagents and substrates in 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]

Chemical formula

[0457] Preparation of 7-1, 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), sodium bicarbonate (184 mg, 2.19 mmol) and 4-Nitrophenyl Carbonochloridate (191 mg, 0.95 mmol) were added under a N2 atmosphere. The resulting solution was stirred at room temperature for 16 hours, 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. Thereby, the title compound (475 mg, 86%) was obtained as a yellow solid, which was used in the next step without further purification. LCMS (M+H) + =645.3.

[0458] Preparation of Methyl 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]pyridine]-1’-yl}carbonyl)amino]ethyl}-N-carbamate: Into an 8 mL vial were placed 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 (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). The resulting mixture was stirred at 80 °C for 2 hours and cooled to room temperature. The reaction product was purified directly by preparative HPLC to give the title compound (60 mg, 57%) as a yellow oil. LCMS (M+H) + =680.3.

[0459] 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’-carboxamide 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]pyridine]-1’-yl}carbonyl)amino]ethyl}-N-carbamate (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 hour 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 in the same manner as in Example 7 using appropriate substitution reagents and substrates in 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]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-60)

[0463]

Chemical formula

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

[0465] Preparation of 8-2, 1-Benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-2'-one: 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) were placed into a 50 mL round-bottom flask. The resulting mixture was stirred at 25 °C for 2 hours, quenched with water (100 mL), and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford the title compound (650 mg, 72%) as a yellow solid. LCMS (M+H) + =328.1.

[0466] Preparation of 8-3, 1-Benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-2'-one: 1-Benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-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), K2CO 3 (822 mg, 5.95 mmol), and dioxane (7 mL) / H2O (0.7 mL) were added to a thick-walled tube maintained under an inert atmosphere of nitrogen. The resulting mixture was degassed with N2 for 5 minutes, sealed, stirred at 80 °C for 1 hour, 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 using 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] Preparation of 8-4, 6'-(2-Ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-2'-one: To a solution of 1-benzyl-6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-2'-one (550 mg, 1.33 mmol) in MeOH (10 mL) were added 10%-Pd / C (140 mg) and Pd(OH)2 (186 mg, 1.32 mmol). The reaction flask was emptied and flushed three times with nitrogen and then with hydrogen. The mixture was stirred at room temperature under hydrogen (balloon) for 2 h. The reaction was diluted with MeOH and filtered through a pad of celite. The filtrate was concentrated in vacuo to afford the title compound (300 mg, 70%) as a white oil. LCMS (M+H) + =325.2.

[0468] Preparation of 8-5, 2-[6'-(2-Ethoxypyridin-3-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile: A solution of 6'-(2-ethoxypyridin-3-yl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-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 afford the title compound (240 mg, 56%) as a yellow oil. LCMS (M+H) + =494.3.

[0469] 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]pyridine]-1’-yl}ethyl)carbamate: To a solution of 2-[6’-(2-ethoxypyridin-3-yl)-2’-oxo-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile (55 mg, 0.11 mmol) and tert-butyl (2-chloroethyl)carbamate (20 mg, 0.11 mmol) in DMF (1 mL) 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 mixture 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] Preparation of 2-[1’-(2-aminoethyl)-6’-(2-ethoxypyridin-3-yl)-2’-oxo-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-b]pyridine]-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]pyridine]-1’-yl}ethyl)carbamate (40 mg, 0.063 mmol) in DCM (1 mL) was added TFA (0.25 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 (21 mg, 59%) as a white solid. LCMS (M+H) + =537.2.

[0471] The following compounds were prepared in the same manner as in Example 8 using appropriate substitution reagents and substrates in 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’-quinazoline]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-64)

[0474]

Chem.

[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 hour. The mixture was quenched with water (100 mL), basified to pH 9 with saturated NaHCO3(aq), 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 pale brown solid. LCMS (M+H) + = 386.1.

[0476] Preparation of 9-2, 1-Benzyl-7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazoline]-2'(3'H)-one: A mixture of 1-benzyl-7'-bromo-1'H-spiro[piperidine-4,4'-quinazoline]-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] Preparation of 9-3, 7'-(2-Ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazoline]-2'(3'H)-one: To a solution of 1-benzyl-7'-(2-ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazoline]-2'(3'H)-one (0.44 g, 1.0 mmol) in MeOH (10 mL) were 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] Preparation of 9-4,2-(7'-(2-Ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-1-yl)-5-(trifluoromethyl)benzonitrile: A solution of 7'-(2-Ethoxypyridin-3-yl)-1'H-spiro[piperidine-4,4'-quinazoline]-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 hours. 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] Preparation of 9-5, 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: A mixture of 2-(7'-(2-Ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-1-yl)-5-(trifluoromethyl)benzonitrile (100 mg, 197 μmol), tert-Butyl (2-chloroethyl)carbamate (113 mg, 629 μmol), and Cs2CO3 (155 mg, 476 μmol) in DMF (1 mL) was heated at 125 °C for 3 hours. 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] Preparation of 9-6,2-(1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-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'-quinazoline]-1'-yl)ethyl)carbamate (26 mg, 40 μmol) in DCM (4 mL) was added TFA (1 mL), 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) and 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'-quinazoline]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-65)

[0482]

Chemical Structure

[0483] Preparation of 10-1,2-(7'-(2-ethoxypyridin-3-yl)-1'-(2-(methylamino)ethyl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-1-yl)-5-(trifluoromethyl)benzonitrile: A mixture of 2-(1'-(2-aminoethyl)-7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline]-1-yl)-5-(trifluoromethyl)benzonitrile formate (22 mg, 40 μmol) from Step 9-6, K2CO3 (10 mg, 72 μmol), and methyl trifluoromethanesulfonate (6.4 mg, 39 μmol) in HFIP (1 mL) was stirred at room temperature for 3 hours. 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'-quinoline]-1-yl]-5-(trifluoromethyl)benzonitrile (Compound 1-66)

[0485]

Chem.

[0486] Procedure 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) portionwise at 0 °C. The resulting solution was stirred at 0 °C for 1 h and then at room temperature for 3 h. 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 (3x). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by silica gel CC gave the title compound (18 g, 89% yield) as a white solid. LCMS (M+H) + =213.0.

[0487] Procedure 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 (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by silica gel CC gave the title compound (11 g, 67% yield) as a white solid. LCMS (M+H) + =195.0.

[0488] Preparation of 11-3, 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 hour. 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 at room temperature for 16 hours. 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 (26 g) of tert-butyl 5-bromospiro[indene-1,4'-piperidine]-1'-carboxylate and tert-butyl 6-bromospiro[indene-1,4'-piperidine]-1'-carboxylate as a yellow oil. Purification of the mixed product by Dynamic Axial Compression (equipment 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) gave the title compound (8.3 g, 28% yield) as a yellow solid. LCMS (M+H) + =364.1.

[0489] 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 at 0 °C for 6 h. 40% NaOH(aq) was added to this solution to adjust the pH to 12, and then DCM (100 mL) and di-tert-butyl dicarbonate (150 mg, 687 μmol) were added. The resulting solution was stirred at room temperature for 3 h. The mixture was treated with 3N HCl(aq) until the pH reached 8 - 9 and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness to give the title compound as a yellow oil (7.0 g, 83% yield). LCMS (M+H) + =382.1.

[0490] 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 solid was filtered off, 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 as a white solid (4.2 g, 59% yield). LCMS (M+H) + =380.1.

[0491] 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) were 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 (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness to afford the title compound (2.4 g, 114% yield) as a pale yellow solid. LCMS (M+H) + =395.1.

[0492] 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 were added triethylamine (1.2 g, 12 mmol) and methanesulfonyl chloride (1.0 g, 8.7 mmol) dropwise. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with water (60 mL) and extracted with DCM (3X). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the title compound (2.6 g, 90% yield) as a yellow solid. LCMS (M+H) + =473.1.

[0493] Preparation of 11-8, tert-Butyl 7'-bromo-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinoline]-1-carboxylate: Aluminum trichloride (1.8 g, 14 mmol) was added portionwise 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. The resulting mixture was stirred at room temperature for 16 h. 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 at room temperature for 2 h 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 afford the title compound (830 mg, 47% yield) as a yellow solid. The positional isomer, 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] Preparation of 11-9, 2,2,2-Trifluoroacetaldehyde-7'-bromo-1'H-spiro[piperidine-4,4'-quinoline]-2'(3'H)-one (1 / 1): TFA (2 mL) was added 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), and the resulting solution was stirred at room temperature for 1 h. The mixture was concentrated to dryness in vacuo to afford the title compound (800 mg, 96.9% yield) as a yellow solid. LCMS (M+H) + =295.1.

[0495] Preparation of 11-10,2-(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) were 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 (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 afford the title compound (800 mg, 84.7% yield) as a yellow solid. LCMS (M+H) + =464.2.

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

[0497] 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'-quinolin]-1'-yl)ethyl)carbamate: To a solution of 2-(7'-(2-ethoxypyridin-3-yl)-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinolin]-1-yl)-5-(trifluoromethyl)benzonitrile (140 mg, 276 μmol) in DMF (2 mL) 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. Purification of the residue by silica gel CC afforded the title compound (140 mg, 78.0% yield) as a white solid. LCMS (M+H) + =650.3.

[0498] Preparation of 11-13,2-(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: TFA (0.5 mL) was added 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). The resulting solution was stirred at room temperature for 1 hour. 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 afford the title compound (70 mg, 92% yield) as a yellow solid. LCMS (M+H) + =550.2.

[0499] The following compounds were prepared in the same manner as in Example 11 using appropriate substitution reagents and substrates in 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), a water-soluble salt of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in an amount of 1 - 100 mg, 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 an oral delivery pharmaceutical composition, a sufficient amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is added to water (with an optional solubilizing agent, an optional buffer, and a taste masking excipient) to obtain a 20 mg / mL solution.

[0503] Example A-3: Oral Tablets Tablets are prepared by mixing 20 - 50 wt% of the compound of formula (I), or a pharmaceutically acceptable salt thereof, 20 - 50 wt% of microcrystalline cellulose, 1 - 10 wt% of low-substituted hydroxypropyl cellulose, and 1 - 10 wt% of magnesium stearate, or other suitable excipients. The 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 an oral delivery pharmaceutical composition, 10 - 500 mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder mixtures. The mixture is incorporated into an oral dosage form, such as a hard gelatin capsule, suitable for oral administration.

[0505] In another embodiment, 10 - 500 mg of the compound of formula (I), or a pharmaceutically 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, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate, and purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0507] Example B-1: Preparation of MC2R Assay Membrane: The crude membrane fraction is prepared from CRE-bla-CHO-K1 cells that stably express the hMC2 receptor and the hMRAP accessory protein (Thermo Fisher). The cells are grown to 85 - 100% confluence on standard tissue culture dishes in GlutaMax DMEM growth medium (Gibco) supplemented with the following additives: 10% dialyzed FBS (Gemini), 0.1 mM NEAA (Gibco), 25 mM HEPES (Gibco), 5 μg / mL blasticidin (Goldbio), 100 μg / mL zeocin (Invitrogen), 600 μg / mL hygromycin (Goldbio). To prepare the membranes, the cells are scraped, collected in 1X Dulbecco's phosphate buffered saline (Corning), and pelleted at 1000 RPM. The cell pellet is reconstituted in membrane preparation 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. For later use, the membrane pellet is resuspended in membrane preparation buffer, snap frozen, and stored at -80°C.

[0508] Binding assay for the hMC2 antagonist protocol: The hMC2 membrane binding assay utilizes the following components: radiolabeled 125 I] ACTH(1 - 39)Tyr23 (PerkinElmer), wheat agglutinin-coated PVT SPA beads (PerkinElmer), crude hMC2R membrane, and the compound. Briefly, the hMC2R membrane is incubated with the 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. The compound (final concentration of the compound is typically 0 - 10,000 nM), SPA membrane, and 125I] Seed the dose response of ACTH(1-39)Tyr23) in a 96-well assay plate and incubate at room temperature for 1.5 hours. The assay plate is read using Top Count NXT, and the K i value of the compound is determined by non-linear regression analysis with GraphPad Prism 6.

[0509] Exemplary binding affinities of the selected compounds are set forth in Table A. The potencies are divided into four categories. + means that K i is from 1,000 nM to 10,000 nM. ++ means that K i is from 100 nM to 1,000 nM. +++ means that K i is from 10 nM to 100 nM. ++++ means that K i is less than 10 nM.

[0510] [Table 10]

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

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical 1】 In the formula,[[]] R Ａ is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, where R Ａ when substituted, R Ａ is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ and is substituted with one, two, three, or four groups selected from R R ａ 、R ｂ 、and R ｃ are independently selected from the group consisting of hydrogen, halogen, -OR ４ 、-CN, -N(R ４ ), ２ 、-C(=O)R ７ 、unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, and any substituted group of R ａ 、R ｂ 、and R ｃ is substituted with one or more R ６ groups, Here, when R ａ , R ｂ , or R ｃ is bonded to the N atom of heteroaryl, it is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, and R Ｂ is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, where R Ｂ when substituted, R Ｂ is substituted with one, two, three, or four groups selected from R ｄ , R ｅ , and R ｆ and is substituted with one, two, three, or four groups selected from R R ｄ 、 R ｅ 、 and R ｆ are independently selected from the group consisting of 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 １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heteroaryl, where any substituted group of R ｄ 、 R ｅ 、 and R ｆ is substituted with one or more R ６ groups, Here, R ｄ , R ｅ , or R ｆ is bonded to the N atom of a heteroaryl, and it is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, and X １ is CR １１ or N, and X ３ is CR １３ or N, and X ４ is CR １４ or N, and R １１ 、 R １３ 、 and R １４ are each independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C １ -C ６ -fluoroalkyl, unsubstituted or substituted C １ -C ６ -heteroalkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, -CN, -OR ４ 、 -SR ４ 、 -CO ２ R ４ 、 -C(=O)N(R ４ ), or -N(R ２ ), or -N(R ４ ), and ２ is W is absent, -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 ＃ represents the bonding point to the N atom of the ring, Y is absent, -(C=O)-, ＊ -O(C=O)-, ＊ -NR ２ -(C=O)-, -(SO ２ )-, or ＊ -NR ２ -(SO ２ )-, where ＊ represents the attachment point to R １ and indicates R １ is unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C １ -C ６ -fluoroalkyl, unsubstituted or substituted C １ -C ６ -heteroalkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, unsubstituted or substituted C ２ -C ７ -heterocycloalkyl, unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ３ -C ６ -cycloalkyl), or unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), where any substituted group of R １ is one or more halogens, 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 and is substituted with, R ２ is each independently hydrogen, unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, or unsubstituted or substituted C ２ -C ７ -heterocycloalkyl, and R ３ is 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 -heterocycloalkyl, and R ４ is each independently selected from the group consisting of hydrogen, unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, unsubstituted or substituted C １ -C ６ -fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl Alternatively, the two Rs ４ together with the nitrogen atom to which they are attached form an unsubstituted or substituted 3- to 6-membered monocyclic heterocycle, R ５ is each independently selected from the group consisting of hydrogen, substituted C １ -C ６ -alkyl, unsubstituted or substituted C ３ -C ６ -cycloalkyl, unsubstituted or substituted C １ -C ６ -fluoroalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl R ６ is each independently hydrogen, halogen, unsubstituted or substituted C １ -C ４ alkyl, unsubstituted or substituted C １ -C ４ alkoxy, unsubstituted or substituted C １ -C ４ fluoroalkyl, unsubstituted or substituted C １ -C ４ fluoroalkoxy, unsubstituted or substituted monocyclic carbocyclic ring, unsubstituted or substituted monocyclic heterocyclic ring, -CN, -OH, -CO ２ R ５ , -CH ２ CO ２ R ５ , -C(=O)N(R ４ ) ２ , -C(=O)N(R ４ )OR ５ , -CH ２ C(=O)N(R ４ ) ２ , -N(R ４ ) ２ , -CH ２ N(R ４ ) ２ , -C(R ５ ) ２ N(R ４ ) ２ , -NR ４ C(=O)R ５ , -CH ２ NR ４ C(=O)R ５ , -NR ４ C(=O)N(R ５ ) ２ , -NR ４ C(=O)N(R ４ ) ２ , C(R ５ )=N(R ４ )-OR ５ , -SR ５ , -S(=O)R ７ , -SO ２ R ７ , or -SO ２ N(R ４ ) ２ and, R ７ is each independently a substituted C １ -C ６ -alkyl, an unsubstituted or substituted C ３ -C ６ -cycloalkyl, an unsubstituted or substituted C １ -C ６ -fluoroalkyl, an unsubstituted or substituted phenyl, and an unsubstituted or substituted heteroaryl, or a pharmaceutically acceptable salt or solvate thereof.

2. W is -C(R ３ ) ２ - or -C(=O)-, and Y is absent, -(C=O)-, ＊ -NR ２ -(C=O)-, or -(SO ２ )-, where ＊ represents the point of attachment to R １ and R ２ is each independently hydrogen, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , or -CH(CH ３ ) ２ and, R ３ is each independently hydrogen, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , or -CH(CH ３ ), ２ and is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. W is -CH ２ -, -CH(CH ３ ), or -C(=O)-, and Y is absent, -(C=O)-, ＊ -NH-(C=O)-, or -(SO ２ )-, where ＊ represents the point of attachment to R １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, which indicates the point of attachment to R.

4. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein R Ａ when substituted, R Ａ is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ ; a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof.

5. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein R Ａ when substituted, R Ａ is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ ; a compound according to any one of claims 1 - 4, or a pharmaceutically acceptable salt or solvate thereof.

6. R Ａ is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein R Ａ when substituted, R Ａ is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof.

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

8. R Ａ is 【Chemical 2】 The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof.

9. R Ａ is 【Chemical 3】 wherein V is CH, CR ａ , CR ｂ , or N, a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound has a structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 4】 Here, V is CH, CR ａ , CR ｂ , or N, a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of formula (II) has a structure of formula (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, [Chemical Formula 5] Here, V is CH, CR ａ , CR ｂ , or N, the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof.

12. R Ａ is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein R Ａ when substituted, R Ａ is substituted with one, two, or three groups selected from R ａ , R ｂ , and R ｃ ; a compound according to any one of claims 1 - 5, or a pharmaceutically acceptable salt or solvate thereof.

13. R Ａ is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, or unsubstituted or substituted thienyl, wherein R Ａ when substituted, R Ａ is substituted with one, two, or three groups selected from R ａ , R ｂ , and R ｃ The compound according to any one of claims 1-5 or 12, or a pharmaceutically acceptable salt or solvate thereof.

14. R Ａ is [Chemical Formula 6] or R Ａ is 【Chemical Formula 7】 wherein R ｃ is hydrogen, -C(=O)R ７ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, a compound according to any one of claims 1-5 or 12, or a pharmaceutically acceptable salt or solvate thereof.

15. R Ａ is [Chemical Formula 8] wherein Y １ is NR ｃ , O, or S, and Y ２ and Y ３ are independently CH, CR ａ CR ｂ or N, and R ｃ is hydrogen, -C(=O)R ７ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, a compound according to any one of claims 1-5 or 12, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound has a structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 9】 In the formula,[[]] Y １ is NR ｃ , O, or S, and Y ２ and Y ３ are independently CH, CR ａ CR ｂ or N, and R ｃ is hydrogen, -C(=O)R ７ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, a compound according to any one of claims 1-5, 12, or 15, or a pharmaceutically acceptable salt or solvate thereof.

17. The compound has a structure of formula (IIIa), (IIIb), (IIIc), or (IIId), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 10】 In the formula,[[]] Y １ is NR ｃ , O, or S, and Y ２ and Y ３ are independently CH, CR ａ CR ｂ or N, and, R ｃ is hydrogen, -C(=O)R ７ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, the compound according to claim 16, or a pharmaceutically acceptable salt or solvate thereof.

18. R Ａ is an unsubstituted or substituted bicyclic 9- to 10-membered heteroaryl, where R Ａ when substituted, R Ａ is selected from one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, which is substituted with

19. 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 azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein R Ａ when substituted, R Ａ is substituted with one, two, three, or four groups selected from R ａ , R ｂ , and R ｃ ; a compound according to any one of claims 1 - 3 or 18, or a pharmaceutically acceptable salt or solvate thereof.

20. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, where R Ｂ is substituted, R Ｂ is R ｄ , R ｅ , and R ｆ is substituted with one, two, three, or four groups selected from, a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof.

21. R Ｂ is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted cinnolinyl, unsubstituted or substituted phthalazinyl, unsubstituted or substituted quinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstituted or substituted naphthyridinyl, unsubstituted or substituted pteridinyl, unsubstituted or substituted indolizinyl, unsubstituted or substituted azaindolizinyl, unsubstituted or substituted indolyl, unsubstituted or substituted azaindolyl, unsubstituted or substituted indazolyl, unsubstituted or substituted azaindazolyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted azabenzimidazolyl, unsubstituted or substituted benzotriazolyl, unsubstituted or substituted azabenzotriazolyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted azabenzoxazolyl, unsubstituted or substituted benzisoxazolyl, unsubstituted or substituted azabenzisoxazolyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted azabenzofuranyl, unsubstituted or substituted benzothienyl, unsubstituted or substituted azabenzothienyl, unsubstituted or substituted benzothiazolyl, unsubstituted or substituted azabenzothiazolyl, or unsubstituted or substituted purinyl, wherein R Ｂ when substituted, R Ｂ is R ｄ R ｅ and R ｆ The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, which is substituted with one, two, three, or four groups selected from .

22. 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 when substituted, R Ｂ is substituted with one, two, three, or four groups selected from R ｄ , R ｅ , and R ｆ ; a compound according to any one of claims 1 - 21, or a pharmaceutically acceptable salt or solvate thereof.

23. R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl, where R Ｂ when substituted, R Ｂ is selected from one, two, three, or four groups selected from R ｄ , R ｅ , and R ｆ and is substituted, a compound according to any one of claims 1 - 22, or a pharmaceutically acceptable salt or solvate thereof.

24. R Ｂ is 【Chemical 11】 The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof.

25. R Ｂ is 【Chemical 12】 wherein Z is CH, CR ｄ , CR ｅ , or N, a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof.

26. R Ｂ is 【Chemical Formula 13】 The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof.

27. The compound has a structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 14】 Here, V is CH, CR ａ , CR ｂ , or N, and Z is CH, CR ｄ , CR ｅ , or N, the compound according to any one of claims 1 - 10, or a pharmaceutically acceptable salt or solvate thereof.

28. The compound has a structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 15】 Here, V is CH, CR ａ , CR ｂ , or N, and Z is CH, CR ｄ , CR ｅ , or N, the compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof.

29. The compound has a structure of formula (VI), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 16】 Here, V is CH, CR ａ , CR ｂ , or N, a compound according to claim 27 or 28, or a pharmaceutically acceptable salt or solvate thereof.

30. The compound has a structure of formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 17】 Here, V is CH, CR ａ , CR ｂ , or N, the compound according to claim 29, or a pharmaceutically acceptable salt or solvate thereof.

31. The compound has a structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 18】 Here, V is CH, CR ａ , CR ｂ , or N, a compound according to claim 27 or 28, or a pharmaceutically acceptable salt or solvate thereof.

32. The compound has a structure of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 19】 Here, V is CH, CR ａ , CR ｂ , or N, the compound according to claim 31, or a pharmaceutically acceptable salt or solvate thereof.

33. The compound has a structure of formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 20】 In the formula,[[]] Y １ is NR ｃ , O, or S, and Y ２ and Y ３ are independently CH, CR ａ CR ｂ or N, and R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, and, Z is CH, CR ｄ , CR ｅ , or N, a compound according to any one of claims 1 - 5, 12, or 15 - 16, or a pharmaceutically acceptable salt or solvate thereof.

34. The compound has the structure of formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 21】 Z is CH, CR ｄ , CR ｅ or N, a compound according to claim 33, or a pharmaceutically acceptable salt or solvate thereof.

35. The compound according to claim 33 or 34, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (X), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 22】

36. The compound according to claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (Xa) or (Xb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 23】

37. The compound according to claim 33 or 34, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 24】

38. The compound according to claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (XIa) or (XIb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 25】

39. R Ｂ is unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, or unsubstituted or substituted thiadiazolyl, wherein R Ｂ when substituted, R Ｂ is substituted with one, two, or three groups selected from R ｄ , R ｅ , and R ｆ , a compound according to any one of claims 1 - 21, or a pharmaceutically acceptable salt or solvate thereof.

40. R Ｂ is 【Chemical 26】 or R Ｂ is 【Chemical 27】 and wherein R ｆ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, a compound according to any one of claims 1-21 or 39, or a pharmaceutically acceptable salt or solvate thereof.

41. R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocycloalkyl containing 1 to 4 N atoms and 0 or 1 O or S atom, unsubstituted or substituted bridged C ２ -C ７ heterocycloalkyl, or unsubstituted or substituted -(C １ -C ６ alkyl)-(C ２ -C ７ heterocycloalkyl), wherein any substituted group of R １ is one or more halogens, 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 and is substituted, a compound according to any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof.

42. R １ is unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C １ -C ６ -heteroalkyl, where any substituted group of R １ is one or more halogens, 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 and is substituted with Alternatively, R １ is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, Alternatively, R １ is an unsubstituted or substituted crosslinked C ２ -C ７ heterocycloalkyl containing 1 to 2 N atoms, Alternatively, R １ is unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom, a compound according to any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof.

43. R １ is an unsubstituted or substituted C １ -C ６ heteroalkyl containing one N atom, Alternatively, R １ is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1 to 4 N atoms and 0 or 1 O or S atom, Alternatively, R １ is unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-4 N atoms and 0 or 1 O or S atom, the compound according to claim 42, or a pharmaceutically acceptable salt or solvate thereof.

44. The compound has the structure of formula (XIIa), (XIIb), (XIIc), or (XIId), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 28】 Here, V is CH, CR ａ , CR ｂ , or N, and Z is CH, CR ｄ , CR ｅ , or N, a compound according to claim 27 or 28, or a pharmaceutically acceptable salt or solvate thereof.

45. The compound has the structure of formula (XIIIa), (XIIIb), (XIIIc), or (XIId), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 29】 Z is CH, CR ｄ , CR ｅ , or N, the compound according to claim 34, or a pharmaceutically acceptable salt or solvate thereof.

46. The compound has the structure of formula (XIV), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 30】 wherein, R Ａ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ａ when substituted, R Ａ is substituted by R ａ , R ｂ , and R ｃ and is substituted with R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where R Ｂ when substituted, R Ｂ is substituted by R ｄ , R ｅ , and R ｆ and is substituted with W is -C(R ３ ) ２ - or -C(=O)-, and, Y is absent, -(C=O)-, -(C=O)NR ２ -, ＊ or -(SO ２ ), where ＊ indicates the point of attachment to R １ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

47. X １ is CR １１ and X ３ is CR １３ and, X ４ is CR １４ and is a compound according to any one of claims 1 - 46, or a pharmaceutically acceptable salt or solvate thereof.

48. X １ is N, and X ３ is CR １３ and X ４ is CR １４ is, a compound according to any one of claims 1 - 46, or a pharmaceutically acceptable salt or solvate thereof.

49. The compound has the structure of formula (XV), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 31】 wherein, 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 substituted, R Ａ is substituted with one or two groups selected from R ａ , R ｂ , and R ｃ and R ａ is selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl, and any substituted group of R ａ is substituted with one or more R ６ groups, 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, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, and any substituted group of R ｂ and R ｃ is substituted with one or more R ６ groups, Here, R ａ , R ｂ , or R ｃ is bonded to the N atom of the heteroaryl, and it is hydrogen, -C(=O)R ７ , or unsubstituted or substituted C １ -C ６ alkyl, R Ｂ is unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heteroaryl containing one or two N atoms, where R Ｂ when substituted, R Ｂ is substituted with one, two, or three groups selected from R ｄ , R ｅ , and R ｆ and R ｄ is selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, and any substituted group of R ｄ is substituted with one or more R ６ groups, and R ｅ and R ｆ each independently is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, and is selected from the group consisting of Here, R ｄ , R ｅ , or R ｆ is bonded to the N atom of a heteroaryl, it is hydrogen, -C(=O)R ７ , or unsubstituted or substituted C １ -C ６ alkyl, X １ is CR １１ or N, and R １１ is hydrogen, halogen, C １ -C ６ -alkyl, C １ -C ６ -fluoroalkyl, or C １ -C ６ -heteroalkyl, -CN, -OR ４ , or -N(R ４ ) ２ and W is -C(R ３ ) ２ - or -C(=O)-, and Y is absent, -(C=O)-, ＊ -NR ２ -(C=O)-, or -(SO ２ )-, where ＊ represents the point of attachment to R １ and, R １ is unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ heteroalkyl containing one N atom, where any substituted group of R １ is one or more halogens, 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 and is substituted with Alternatively, R １ is an unsubstituted or substituted monocyclic 4-membered, 5-membered, or 6-membered heterocyclic ring containing 1-4 N atoms and 0 or 1 O or S atom, Alternatively, R １ is an unsubstituted or substituted crosslinked C ２ -C ７ heterocycloalkyl containing 1-2 N atoms, Alternatively, R １ is unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), and the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1 to 2 N atoms, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

50. R Ａ is unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted phenyl, where R Ａ when substituted, R Ａ is substituted with one or two groups selected from R ａ , R ｂ , and R ｃ and is selected from one or two groups, Here, R ａ , R ｂ , or R ｃ is bonded to the N atom of the heteroaryl, it is hydrogen, -C(=O)R ７ , or unsubstituted or substituted C １ -C ６ alkyl, R Ｂ is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, where when R Ｂ is substituted, R Ｂ is substituted with one, two, or three groups selected from R ｄ , R ｅ , and R ｆ and X １ is CR １１ or N, and R １１ is hydrogen, F, Cl, -CH ３ , CF ３ , -CN, -OR ４ , or -N(R ４ ) ２ and, R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where any substituted group of R １ is substituted with one or more halogens, C １ -C ４ alkyl, -N(R ４ ) ２ , or -OR ５ and is substituted with Alternatively, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl, Alternatively, R １ is an unsubstituted or substituted crosslinked C ２ -C ７ heterocycloalkyl containing 1 to 2 N atoms, Alternatively, R １ is unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), wherein the heterocycloalkyl is an unsubstituted or substituted monocyclic 4-, 5-, or 6-membered heterocycloalkyl containing 1-2 N atoms, the compound according to claim 49, or a pharmaceutically acceptable salt or solvate thereof.

51. R Ａ is 【Chemical 32】 or R Ａ is 【Chemical 33】 wherein V is CH or N, R Ｂ is 【Chemical 34】 The compound according to any one of claims 1, 49, or 50, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is CH or N.

52. The compound according to claim 1, or any one of claims 49 - 51, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (XVIa) or (XVIb), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical 35】 wherein, R ａ is selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl, and, R ｂ and R ｃ are independently selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ alkyl, and unsubstituted or substituted C １ -C ６ fluoroalkyl, and wherein V is CH or N.

53. R ａ is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ), ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ), ３ , -CH ２ F, -CHF ２ , and -CF ３ . R ｂ and R ｃ are independently selected from the group consisting of hydrogen, F, Cl, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CN, and -OCH ３ The compound according to claim 52, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

54. The compound has a structure of formula (XVIc) or (XVId), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 36】 V is CH or N, and X １ is N, a compound according to claim 52 or 53, or a pharmaceutically acceptable salt or solvate thereof.

55. The compound has a structure of formula (XVIIa) or (XVIIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 37】 wherein, R ａ and R ｂ each independently 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 is selected from the group consisting of R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, or unsubstituted or substituted C ２ -C ７ heterocycloalkyl, a compound according to any one of claims 1 or 49 - 51, or a pharmaceutically acceptable salt or solvate thereof.

56. R ａ and R ｂ are independently selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH ３ -, -OCH ２ CH ３ -, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ -, -CH ２ F, -CHF ２ -, -CF ３ -, and cyclopropyl, R ｃ is hydrogen, -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, the compound according to claim 55, or a pharmaceutically acceptable salt or solvate thereof.

57. The compound has a structure of formula (XVIIc) or (XVII d), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 38】 wherein, X １ is N, and, R ｃ is hydrogen, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ), ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ), ３ , -CH ２ CH ２ CH(CH ３ ), ２ or an unsubstituted C ３ -C ６ cycloalkyl, the compound according to claim 55 or 56, or a pharmaceutically acceptable salt or solvate thereof.

58. The compound has a structure of formula (XVIIIa) or (XVIIIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical Formula 39】 wherein, Z is CH or N, R ｄ is selected from the group consisting of 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 each independently hydrogen, halogen, -OR ４ , -CN, unsubstituted or substituted C １ -C ６ -alkyl, and unsubstituted or substituted C １ -C ６ -fluoroalkyl, a compound according to any one of claims 1 or 49 - 51, or a pharmaceutically acceptable salt or solvate thereof.

59. R ｄ is selected from the group consisting of hydrogen, F, Cl, Br, -CN, -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ F, -CHF ２ , and -CF ３ . R ｅ and R ｆ are independently selected from the group consisting of hydrogen, F, Cl, Br, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, and -OCH ３ The compound according to claim 58, or a pharmaceutically acceptable salt or solvate thereof.

60. The compound has a structure of formula (XVIIIa) or (XVIIIb), or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 40】 wherein, X １ is N, Z is CH or N, and, R ｄ is a compound according to claim 58 or 59, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of F, Cl, -CN, -OCH ３ , -CH ３ , -CH ２ F, -CHF ２ , and -CF ３ .

61. R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, where any substituted group of R １ is substituted with one or more halogens, C １ -C ４ alkyl, -N(R ４ ) ２ , or -OR ５ and is substituted with Alternatively, R １ is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl, Alternatively, R １ is unsubstituted or substituted -(C １ -C ６ -alkyl)-(C ２ -C ７ -heterocycloalkyl), and the heterocycloalkyl is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl, a compound according to any one of claims 49 - 60, or a pharmaceutically acceptable salt or solvate thereof.

62. R １ is a compound according to any one of claims 49 - 61, which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, or unsubstituted or substituted piperidinyl, or a pharmaceutically acceptable salt or solvate thereof.

63. R １ is an unsubstituted or substituted C containing one N atom １ -C ６ heteroalkyl, wherein R １ any substituted group of is one or more halogens, C １ -C ４ alkyl, -N(R ４ ) ２ , or -OR ５ substituted with, the compound according to claim 62, or a pharmaceutically acceptable salt or solvate thereof.

64. R ａ 、R ｂ 、and R ｃ are each 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 １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, and any substituted group of R ａ 、R ｂ 、and R ｃ is substituted with one or more R ６ groups, and R ｄ 、R ｅ 、and R ｆ are independently selected from the group consisting of 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 １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, wherein any substituted group of R ｄ 、R ｅ 、and R ｆ is substituted with one or more R ６ groups, a compound according to any one of claims 1 - 48, or a pharmaceutically acceptable salt or solvate thereof.

65. R ａ is selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ , -C(=O)R ７ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, and unsubstituted or substituted C ３ -C ６ cycloalkyl, and any substituted group of R ａ is substituted with one or more R ６ groups, and R ｂ and R ｃ are independently hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ , unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, and any substituted group of R ｂ and R ｃ is substituted with one or more R ６ groups, the compound according to any one of claims 1-48 or 64, or a pharmaceutically acceptable salt or solvate thereof.

66. 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 NHCH ３ 、 - CH ２ CH ２ N(CH ３ ) ２ selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and, R ｂ and R ｃ are independently hydrogen, Cl, Br, -CN, -OH, -OCH ３ -OCH ２ CH ３ -CH ３ -CH ２ CH ３ -CH ２ CH ２ CH ３ -CH(CH ３ ) ２ -CH ２ CH ２ CH ２ CH ３ -CH ２ CH(CH ３ ) ２ -CH(CH ３ )(CH ２ CH ３ )-C(CH ３ ) ３ -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ -CF ３ -CH ２ CH ２ OH, -CH ２ CH ２ CN, -CH ２ CH ２ F, -CH ２ CHF ２ -CH ２ CF ３ -CH ２ OCH ３ -CH ２ CH ２ OCH ３ -CH ２ NH ２ -CH ２ NHCH ３ -CH ２ N(CH ３ ) ２ -CH ２ CH ２ NH ２ -CH ２ CH ２ NHCH ３ and -CH ２ CH ２ N(CH ３ ) ２ The compound according to any one of claims 1-48 and 64-65, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

67. R ｄ is selected from the group consisting of hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted C ３ -C ６ cycloalkyl, unsubstituted or substituted C ２ -C ７ heterocycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted bicyclic heteroaryl, and any substituted group of R ｄ is substituted with one or more R ６ groups, and R ｅ and R ｆ each independently is hydrogen, halogen, -OR ４ , -CN, -N(R ４ ), ２ unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, and unsubstituted or substituted C １ -C ６ heteroalkyl, and is a compound according to any one of claims 1 - 48 or 64 - 66, or a pharmaceutically acceptable salt or solvate thereof.

68. 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 , -CH ２ CH ２ , -CH ２ CH ２ , -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 , non-replaced or replaced cyclopropyl, non-replaced or replaced cyclobutyl, non-replaced or replaced cyclopentyl, non-replaced or replaced cyclohexyl, non-replaced or replaced C ２ -C ７ -heterocycloalkyl, non-replaced or replaced phenyl, non-replaced or replaced monocyclic heteroaryl, and non-replaced or replaced bicyclic heteroaryl, and any substituted group of R ｄ is substituted with one or more R ６ groups, and R ｅ and R ｆ is independently selected from the group consisting of F, Cl, Br, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ), ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ), ３ , -CH ２ OH, -CH ２ CN, -CH ２ F, -CHF ２ , -CF ３ , -CN, -OH, -OCH ３ , and -OCH ２ CH ３ ; a compound according to any one of claims 1-48 or 64-67, or a pharmaceutically acceptable salt or solvate thereof.

69. 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'-piperidine]-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'-piperidine]-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'-piperidine]-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'-piperidine]-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'-piperidine]-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]pyridine]-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]pyridine]-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'-piperidine]-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'-piperidine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-1-yl}-5-(trifluoromethyl)benzonitrile; 1-52: 2-[6'-(2-Ethoxypyridin-3-yl)-1'-[(3R)-pyrrolidine-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl]-5-(trifluoromethyl)benzonitrile; 1-53: 2-[6'-(2-Ethoxypyridin-3-yl)-1'-[(3S)-pyrrolidine-3-yl]-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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]pyridine]-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'-quinazoline]-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'-quinazoline]-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'-quinoline]-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'-quinoline]-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'-quinoline]-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'-quinoline]-1-yl}-5-(trifluoromethyl)benzonitrile; which is a compound, or a pharmaceutically acceptable salt or solvate thereof.

70. A pharmaceutical composition comprising a compound according to any one of Claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

71. The pharmaceutical composition according to Claim 70, which is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, transdermal administration, or ophthalmic administration.

72. The pharmaceutical composition according to Claim 70, which is in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersants, solutions, emulsions, ointments, or lotions.

73. A method of treating a mammalian disease or disorder that would benefit from modulation of melanocortin subtype-2 receptor (MC2R) activity, the method comprising administering to said mammalian in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof.

74. The method of claim 73, wherein the disease or disorder includes growth of fat pads in the clavicle, back of the neck, face, and trunk, excessive sweating, capillary dilation, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease.

75. A method of treating Cushing's syndrome in a mammal, the method comprising administering to said mammal in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof.

76. A method of treating ectopic Cushing's syndrome in a mammal, the method comprising administering to said mammal in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof.

77. A method of treating congenital adrenal hyperplasia (CAH) in a mammal, the method comprising administering to said mammal in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof.

78. A method of reducing the secretion of adrenocorticotropic hormone (ACTH) in a mammal, the method comprising administering to said mammal in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof.

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