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WO2021076448A1 - Somatostatin modulators for treating pituitary adenomas - Google Patents

Somatostatin modulators for treating pituitary adenomas Download PDF

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Publication number
WO2021076448A1
WO2021076448A1 PCT/US2020/055245 US2020055245W WO2021076448A1 WO 2021076448 A1 WO2021076448 A1 WO 2021076448A1 US 2020055245 W US2020055245 W US 2020055245W WO 2021076448 A1 WO2021076448 A1 WO 2021076448A1
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Prior art keywords
fluoro
amino
pyridin
agonist
benzodiazol
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PCT/US2020/055245
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French (fr)
Inventor
Stephen Betz
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Crinetics Pharmaceuticals, Inc.
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Publication of WO2021076448A1 publication Critical patent/WO2021076448A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH

Definitions

  • NFPA pituitary adenoma
  • Pituitary adenomas are common neoplasms comprising approximately 10-20% of intracranial tumors.
  • Non-functioning pituitary adenomas are generally benign neoplasms and are not associated with clinical evidence of hormonal hypersecretion that is common in diseases such as acromegaly, Cushing’s Disease, or from prolactinomas.
  • NFPAs can be further classified according to their originating cell type, hormonal, and transcription factor profile.
  • Many NFPAs present basal and stimulated serum concentrations of hormones within normal to slightly elevated levels with endocrine effects ranging from no clinical signs to mild, often overlooked, clinical symptoms.
  • the deleterious effects of NFPAs are typically due to macroadenomas, and patients suffer from symptoms related to mass effects from the tumor, commonly headache, blurred vision or rapid onset of blindness, and/or cranial nerve dysfunction.
  • Somatostatin receptor activation promotes antitumor effects through the induction of cell cycle arrest to inhibit tumor growth, the inhibition of growth factor secretion (e.g. GH, IGF-1, VEGF) necessary for tumor growth, or through the inhibition of angiogenesis in newly formed endothelial cells.
  • Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.
  • somatostatin receptor proteins Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity, including NFPA.
  • somatostatin modulator compounds are somatostatin modulator compounds. In some embodiments, compounds described herein modulate one or more of the subtype somatostatin receptor proteins. In some embodiments, compounds described herein modulate one subtype somatostatin receptor.
  • compounds described herein modulate two or more subtype somatostatin receptor.
  • Somatostatin peptide analogs such as octreotide, lanreotide and pasireotide, formulated as depot injections, are routinely used to normalize hormone levels for the treatment of Growth Hormone (GH) secreting adenomas, pancreatic neuroendocrine tumors, and carcinoid tumors.
  • GH Growth Hormone
  • the depot preparations of these peptide drugs are extremely expensive and require frequent doctor’s office visits for painful injections that can lead to injection site reactions.
  • Compounds described herein are molecules that are structurally different from peptide analogs.
  • the compounds described herein are somatostatin modulators that are useful for the treatment of pituitary adenomas.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • 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.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
  • the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • NFPA non-functioning pituitary adenoma
  • SSTR non-peptidic small molecule somatostatin receptor
  • a method of stabilizing a NFPA tumor size in a patient comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • Also described herein is a method of treating headache, blurred vision, cranial nerve dysfunction, hyperprolactinemia, or pituitary apoplexy associated with NFPA, or a combination thereof, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. Also described herein is a method of stabilizing tumor size of a recurrent NFPA tumor after incomplete resection surgery in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • Also described herein is a method of preventing recurrence of tumor growth in a patient after surgery, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof, wherein the tumor is a NFPA tumor.
  • the NFPA has been treated by incomplete surgery.
  • the surgery is to resect a portion of the pituitary adenoma.
  • administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect.
  • the therapeutic effect is an inhibition of growth of the NFPA.
  • the therapeutic effect is a decrease in size of the NFPA.
  • the non-peptidic small molecule SSTR agonist is a selective agonist. In some embodiments, the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist. In some embodiments, the non-peptidic small molecule SSTR agonist is a pan-SSTR agonist. In some embodiments, the method further comprises a secondary therapy. In some embodiments, the secondary therapy is a dopamine agonist, an alkylating agent, radiotherapy, or surgery. In some embodiments, the secondary therapy is a dopamine agonist. In some embodiments, the secondary therapy is radiotherapy or surgery.
  • Also described herein is a method of reducing tumor volume of a NFPA in a patient, comprising: administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; and administering a dopamine agonist to the patient in need thereof.
  • a method of treating a NFPA in a patient comprising: first, administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; then, resecting a portion of the NFPA.
  • Also described herein is a method of reducing the rate of proliferation of pituitary adenoma cells, the method comprises contacting said pituitary adenoma cells with a non-peptidic small molecule SSTR agonist.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is administered on a continuous daily dosing schedule.
  • the mammal is a human.
  • compounds provided herein are orally administered to a human.
  • Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating one or more subtype somatostatin receptor proteins, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating one or more subtype somatostatin receptor proteins, are provided. [0017] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description.
  • Somatostatin SST
  • SRIF somatotropin release inhibiting factor
  • SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH).
  • GH growth hormone
  • somatostatins are produced by a wide variety of cell types in the central nervous system (CNS) and gut and have multiple functions including modulation of secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are anti-proliferative.
  • GH growth hormone
  • glucagon growth hormone
  • SSTR5 somatostatin receptor proteins
  • the six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev.16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997).
  • All the receptors are members of the class-A subgroup of the GPCR superfamily. [0020] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to the other somatostatin receptor subtypes reduces unwanted side effects in a variety of clinical applications.
  • the compounds described herein are SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective. In some embodiments, the compounds described herein are pan-SSTR active. [0021] In some embodiments, compounds described here are amenable to oral administration to a mammal in need of treatment with a somatostatin modulator.
  • Pituitary adenomas comprise approximately 10-20% of intracranial tumors.
  • Non- functioning pituitary adenomas are benign adenohypophyseal tumors not associated with clinical evidence of hormonal hypersecretion.
  • NFPAs comprise different histological subtypes, classified according to their immunostaining to different adenohypophyseal hormones and transcription factors.
  • the silent gonadotroph adenoma is the most common subtype, followed by corticotroph, PIT1 (POU1F1) gene lineage and null cell tumors.
  • NFPAs neurotrophic factor
  • mass effects symptoms such as headaches, visual disorders and/or cranial nerve dysfunction caused by lesions large enough to damage surrounding structures.
  • hypopituitarism caused by the compression of the normal anterior pituitary, and hyperprolactinemia, due to pituitary stalk deviation, are also present.
  • Surgical resection is the primary treatment for symptomatic patients with NFPAs, i.e., those with neuro-ophthalmologic complaints and/or tumors affecting the optic pathway.
  • visual deficits and hormone deficiencies improve following surgical treatment.
  • new hormone deficiencies develop after a surgical approach.
  • NFPA tumors present progressive tumor growth after incomplete tumor resection.
  • follow up is individualized and should consider tumor size, prior treatments, and clinical symptoms. In some instances, such as those of tumors not completely resected by surgery, those cases that present progressive tumor growth during follow-up, or for patients who, at diagnosis, already have tumors with aggressive features, radiotherapy in the postoperative period is a follow up consideration.
  • NFPAs manifest as impaired vision, caused by suprasellar extension of the adenoma that compresses the optic chiasm.
  • diplopia induced by oculomotor nerve compression resulting from parasellar expansion of the adenoma, occurs.
  • the typical visual field defect associated with pituitary tumors is bitemporal hemianopia, reported in approximately 40% of the patients.
  • NFPAs manifest as headaches in 19-75% of patients with pituitary tumors, regardless of size of the tumor.
  • headaches are caused by increased intrasellar pressure, stretching of dural membrane pain receptors, and activation of trigeminal pain pathways.
  • the tumor causes erosion of the sellar floor and extends inferiorly to the sphenoid sinus leading to cerebrospinal fluid (CSF) rhinorrhea, associated or not with headache.
  • CSF cerebrospinal fluid
  • NFPAs lead to pituitary apoplexy (sudden hemorrhage into a pituitary macroadenoma).
  • Pituitary apoplexy causes acute onset of a severe headache associated with visual disturbances and can occur in all types of pituitary tumors.
  • this “disconnection hyperprolactinemia” or non-tumoral hyperprolactinemia is characterized by compression of the pituitary stalk, which prevents the arrival of dopamine to the anterior pituitary, the main inhibitor of prolactin (stalk effect).
  • NFPAs affect the GH axis, hypogonadism, or adrenal insufficiency.
  • gonadotroph adenomas are usually considered to be "nonfunctioning" although they can secrete intact gonadotropins, as they do not generally result in a clinical syndrome.
  • Gonadotropin-releasing hormone is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • gonadotroph adenomas secrete primarily FSH but also LH in quantities high enough to raise serum gonadotropin levels, which in turn, lead to the development of some specific symptoms, such as ovarian hyperstimulation in young women or precocious puberty or testicular enlargement in men.
  • low serum LH:FSH ratios (usually ⁇ 1.0) have been described in clinically-secreting gonadotroph adenomas.
  • NFPAs are characterized by the expression of somatostatin receptors (SSTR).
  • SSTR somatostatin receptors
  • somatostatin receptor activation promotes antitumor effects through different pathways including the induction of cell cycle arrest to inhibit tumor growth, the inhibition of growth factor secretion (e.g. GH, IGF-1, VEGF) necessary for tumor growth, as well as through the inhibition of angiogenesis in newly formed endothelial cells.
  • NFPAs express a wide variety of SSTRs. Described herein is the use of somatostatin receptor agonists for the treatment of NFPAs. In some embodiments described herein, a broad-spectrum SSTR agonist therapy can prove useful for the treatment of NFPA or associated symptoms thereof.
  • Methods of Use [0031] Described herein, in some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of pituitary adenomas. In some embodiments, the non-peptidic small molecule SSTR agonist described herein induces a therapeutic effect.
  • the therapeutic effect is an inhibition of growth of the adenoma. In some embodiments, the therapeutic effect is a decrease in size of the adenoma.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of symptoms related to pituitary adenomas, such as headache, blurred vision, cranial nerve dysfunction, hyperprolactinemia, or pituitary apoplexy, or combinations thereof.
  • the pituitary adenoma is a non-functional pituitary adenoma.
  • described herein is a method of treating NFPA in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof are used in a method to inhibit the growth of, or decrease the size of, a pituitary adenoma.
  • the pituitary adenoma is a non-functional pituitary adenoma.
  • the tumor size of a pituitary adenoma does not increase while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor size of a pituitary adenoma is stabilized while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor size does not increase over a time of 6 months, 1 year, 3 years, 5 years, or 10 years. In some embodiments, the tumor size of a pituitary adenoma decreases while being treated with the non- peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof.
  • the tumor size of a pituitary adenoma decreases while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, in combination with additional dopamine agonist therapy.
  • described herein is a method of stabilizing a NFPA tumor size in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • use of somatostatin agonist therapy after surgery has been demonstrated to decrease tumor volume after incomplete surgery.
  • use of somatostatin agonist therapy after surgery has been demonstrated to stabilize tumor volume after incomplete surgery.
  • the methods described herein are useful for treating pituitary adenomas in a subject, wherein the subject has undergone a medical procedure, such as surgery, in order to resect a portion of the adenoma.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof is administered before said medical procedure.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof is administered after said medical procedure.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof is administered before and after said medical procedure.
  • described herein is a method of treating NFPA in a patient, comprising: first, administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; then, resecting a portion of the NFPA.
  • described herein is a method of stabilizing tumor size of a recurrent NFPA tumor after incomplete resection surgery in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • described herein is a method of preventing recurrence of tumor growth in a patient after surgery, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof, wherein the tumor is a NFPA tumor.
  • the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof are used in a method to treat symptoms due to a pituitary adenoma.
  • described herein is a method of increasing patient-reported health-related quality of life (HR-QoL) in patients having NFPA, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof.
  • described herein is a method of treating headache, blurred vision, or cranial nerve dysfunction associated with NFPA, or a combination thereof, comprising administering a non- peptidic small molecule SSTR agonist to the patient in need thereof.
  • Also described herein, in another embodiment is a method of reducing the rate of proliferation of pituitary adenoma cells, the method comprises contacting said pituitary adenoma cells with a non-peptidic small molecule SSTR agonist.
  • the pituitary adenoma cells comprise a pituitary adenoma in a subject. In some embodiments, the pituitary adenoma cells comprise a NFPA in a subject. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor size does not increase. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor size decreases. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor shrinks.
  • SSTR non-peptidic small molecule somatostatin receptor
  • the SSTR agonist is selective for one or more somatostatin receptor(s) relative to the other somatostatin receptors.
  • the SSTR agonist is SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective.
  • the SSTR agonist is a pan-SSTR agonist.
  • SSTR2-Selective Agonists [0041]
  • SSTR non-peptidic small molecule somatostatin receptor
  • the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,902,703, US Patent Number 9,896,432, US Patent Number 10,351,547, US Patent Number 10,597,377, US Patent Number 10,696,689, International Patent Application Publication Number WO 2017/003724, International Patent Application Publication Number WO 2019/023278, International Patent Application Publication Number WO 2018/013676, International Patent Application Publication Number WO 2018/170284, International Patent Application Publication Number WO 2020/061046, or related applications or application publications.
  • the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,902,703.
  • the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) of US Patent Number 9,902,703.
  • the non-peptidic small molecule SSTR agonist is a compound described in Formula (I) or (Ia) of US Patent Number 9,902,703.
  • the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of US Patent Number 9,902,703.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R A is hydrogen, -F, -C1, -CH 3 , -CF 3 , or -SO 2 CH 3 ; R is hydrogen, -CH 3 , or -CH 2 CH 3 ; R 13 is hydrogen or -CH 3 ; R 16 is -C1, -CH 3 , or -OCH 3 ; R 17 is -F, -C1, or -CH 3 ; R 18 is hydrogen, -F, -CN, -CF 3 , -OH, -CONH 2 , -CH 2 CO 2 H, -CH 2 CO 2 CH 2 CH 3 , -SO 2 CH 3 , or tetrazolyl; and R 19 is hydrogen, -F, -C1, -CN, -CH 3 , or -CF 3 . [0044] In some embodiments, the
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: [0046]
  • the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/023278.
  • the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il) of International Patent Application Publication Number WO 2019/023278.
  • the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) of International Patent Application Publication Number WO 2019/023278. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of International Patent Application Publication Number WO 2019/023278.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 9 is -CH 3 ; R 10 is hydrogen, -F, -C1, -CN, -OH, -OCH 3 , -CH 3 , -CH 2 CH 2 OH, -CH 2 CO 2 H, -CH 2 CO 2 CH 3 , - CH 2 CH 2 CO 2 H, -CH 2 CH 2 CO 2 CH 3 , -CH 2 NHCOCH 3 , or pyrazol-1-yl; R 11 is hydrogen, -F, or -CH 3 ; R 12 is -CN, -OH, or -CONH2; and R 13 is hydrogen, -F, or -CN. [0049] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: ;
  • the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,896,432.
  • the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (A), (AI), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (AII), (II), (A2), (AIIa), (AIIb), (AIIc), (AIId), (AIIe), (AIIf), (AIII), (III), (AIIIa), (AIIIb), (AIIIc), (AIIId), (AIIIe), (AIIIf), (IIIa), (IIIb), (IV), (V), (AV), (AVa), (AVb), (AVc), (AVd), (AVe), or (AVf) of US Patent Number 9,896,432.
  • the non-peptidic small molecule SSTR agonist is a compound described in Formula (A), (AII), (AIIb), (AIII), (AIIIb), (AV), or (AVb) of US Patent Number 9,896,432.
  • the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, or Table 4 of US Patent Number 9,896,432.
  • the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(phenyl)cinnoline, 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3- phenyl)cinnoline, or 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)cinnoline compound.
  • the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3- (phenyl)cinnoline, 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-phenyl)cinnoline, or 4-[3- (aminomethyl)azetidin-1-yl]-3-(phenyl)cinnoline compound, wherein the phenyl is substituted with R a and/or R b , R a is -F, -C1, or -CH 3 ; and R b is -F, -C1, -CH 3 , or -CONH2.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-2: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-3: 1-[6,7-dichloro-3-(3,5-dimethylphenyl)cinnolin-4-yl]piperidin-4-amine; 1-4: 3-[4-(4-aminopiperidin-1-yl)-7-chloro
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)quinoline, 3- ⁇ 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3- (phenyl)quinoline, or 3- ⁇ 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)quinoline compound.
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3- (phenyl)quinoline, 3- ⁇ 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(phenyl)quinoline, or 3- ⁇ 4- [3-(aminomethyl)azetidin-1-yl]-3-(phenyl)quinoline compound, wherein the phenyl is substituted with R a and/or R b , R a is -F or -C1; and R b is -F, -C1, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 2 OCH 3 [0055]
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: O
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-2: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-3: 3- ⁇ 4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl ⁇ -2- hydroxybenzonitrile; 2-4
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)-1,5-naphthyridine, 3- ⁇ 4-[octahydro-1H-pyrido[3,4-b]morpholin-6- yl]-3-(phenyl)-1,5-naphthyridine, or 3- ⁇ 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)-1,5- naphthyridine compound.
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3-(phenyl)-1,5-naphthyridine, 3- ⁇ 4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-3-(phenyl)-1,5-naphthyridine, or 3- ⁇ 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)- 1,5-naphthyridine compound, wherein the phenyl is substituted with R a and/or R b , R a is -F or -C1; and R b is -F or -CH 3 .
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: O O R a is -F or -C1; and R b is -F or -CH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5- fluorobenzamide; 3-2: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2- hydroxybenzonitrile; 3-3: 4-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-6-fluoro-2,3- dihydro-1H-1,3-benzodiazol-2-one; 3-4: 5-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphen
  • 3-9 6-[8-(4-aminopiperidin-1-yl)-7-(3,5-difluorophenyl)-1,5-naphthyridin-2-yl]-4-fluoro-2,3- dihydro-1H-1,3-benzodiazol-2-one; 3-10: 6- ⁇ 8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5-difluorophenyl)-1,5- naphthyridin-2-yl ⁇ -4-fluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one; 3-11: 4- ⁇ 8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3-fluoro-5-methylphenyl)-1,5- naphthyridin-2-yl ⁇ -6-fluoro-2,3-dihydro-1H-1,3-benz
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)-1,8-naphthyridine, 3- ⁇ 4-[octahydro-1H-pyrido[3,4-b]morpholin-6- yl]-3-(phenyl)-1,8-naphthyridine, or 3- ⁇ 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)-1,8- naphthyridine compound.
  • the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3-(phenyl)-1,8-naphthyridine, 3- ⁇ 4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-3-(phenyl)-1,8-naphthyridine, or 3- ⁇ 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)- 1,8-naphthyridine compound, wherein the phenyl is substituted with R a and/or R b , R a is -F or -C1; and R b is -F, -C1, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R a is -F or -C1; and R b is -F, -C1, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-[5-(4-aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2- hydroxybenzonitrile; 4-2: 3-[5-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-2- hydroxybenzonitrile; 4-3: 3-[5-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-5-fluoro-2- hydroxybenzonitrile; 4-4: 3-[5-(4-aminopiperidin-1-yl)-6-(3-chloro-5-methylphenyl)-1,8-
  • the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2018/170284. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) of International Patent Application Publication Number WO 2018/170284. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (II), or (III) of International Patent Application Publication Number WO 2018/170284.
  • the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, or Table 4 of International Patent Application Publication Number WO 2018/170284. [0064] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-2-amine or 4-(4-aminopiperidin-1- yl)-3-(indol-2-yl)-5-(phenyl)pyridin-2-amine compound.
  • the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5- (phenyl)pyridin-2-amine or 4-(4-aminopiperidin-1-yl)-3-(indol-2-yl)-5-(phenyl)pyridin-2-amine compound, wherein the phenyl is substituted with R 8 and/or R 9 , R 8 is -F, -C1, -CN, or -CH 3 ; and R 9 is hydrogen, -F, -C1, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • R 13 is hydrogen, -CN, or -OCH 3 ;
  • R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 OCH 3 ;
  • R 8 is -F, -C1, -CN, or -CH 3 ;
  • R 9 is hydrogen, -F, -C1, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-2: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-3: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-4: 4-(4-aminopiperidin-1-yl)-3-(1-ethenyl-5,6-difluor
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 1 is -C1, -OH, or -OCH 3 ; R 8 is -F, -C1, or -CN; and R 9 is -F or -CH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-2: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-3: 1-[5-(3-fluoro-5-methylphenyl)-2-methoxy-3-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]piperidin-4-amine; 2-4: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)
  • the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridazine or 4-(4-aminopiperidin-1-yl)-3- (indol-2-yl)-5-(phenyl) pyridazine compound.
  • the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl) pyridazine amine or 4-(4-aminopiperidin-1-yl)-3-(indol-2-yl)-5-(phenyl) pyridazine compound, wherein the phenyl is substituted with R 8 and/or R 9 , R 8 is -F, -C1, -CN, or -CH 3 ; and R 9 is hydrogen, -F, -C1, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 1-[3-(5-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-2: 1-[3-(6-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-3: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4- amine; 3-4: 1-[3-(6-fluoro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4- amine; 3-4:
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R a is o R 1 is R 11 is hydrogen or -CH 3 ; R 8 is -F; and R 9 is hydrogen or -CH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methyl-4-[4- (methylamino)piperidin-1-yl]pyridin-2-amine; 4-2: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1-yl]pyridin-3-yl]-1H- 1,3-benzodiazole-6-carbonitrile; 4-3: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1-yl]pyridin-3-yl]-7- fluoro-1H-1,3-benzodiazole-5-carbonitrile; 4-4: 4-(4-aminopiperidin-1-yl)-5-
  • the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 10,696,689. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), (IIIb), (IIIc), or (IIId), of US Patent Number 10,696,689. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of US Patent Number 10,696,689.
  • the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(3-phenyl)pyridin-2-amine compound.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 2 is hydrogen or -CH 3 ; R 3 is hydrogen or -CH 3 ; R 8 is -F; and R 9 is -C1 or -CH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H- 1,3-benzodiazole-6-carbonitrile; 1-2: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-4-methoxy-1H- 1,3-benzodiazole-6-carbonitrile; 1-3: 2-[4-(4-aminopiperidin-1-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4- methoxy-1H-1,3-benzodiazole-6-carbonitrile; or a pharmaceutically acceptable salt, or solvate thereof.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 1 is -CN, -CO 2 CH 3 , -CONH 2 , or -CONHCH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: methyl 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro- 5-methylphenyl)pyridine-2-carboxylate; 2-2: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridine-2-carbonitrile; 2-3: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridine-2-carboxamide; 2-4: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy
  • the non-peptidic small molecule SSTR agonist is a 4-[(4 ⁇ S,8 ⁇ S)- octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-2-amine compound.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 2 is hydrogen or -CH 3 ; R 8 is -F or -C1; and R 9 is hydrogen, -F, -CH 3 , or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 4-[(4 ⁇ S,8 ⁇ S)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 3-2: 4-[(4 ⁇ S,8 ⁇ S)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3,5-difluorophenyl)pyridin-2-amine; 3-3: 4-[(4 ⁇ S,8 ⁇ S)-octahydro-1H-pyrido[3,4-b
  • non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is selective for SSTR5.
  • the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/157458, International Patent Application Number PCT/US2020/045610 or related applications or application publications.
  • the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/157458.
  • the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (II), (IIa), (III), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (V), of International Patent Application Publication Number WO 2019/157458.
  • the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (II), (IIa), (IV), (IVb), or (IVc) of International Patent Application Publication Number WO 2019/157458.
  • the non-peptidic small molecule SSTR agonist is a compound described in Table 1 or Table 2 of International Patent Application Publication Number WO 2019/157458.
  • the non-peptidic small molecule SSTR agonist is a 1- ⁇ 1-[3-(1,3- benzodiazol-2-yl)-5-(phenyl)pyridin-4-yl]azetidin-3-yl ⁇ methanamine compound. [0086] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 1- ⁇ 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl ⁇ methanamine; 1-2: 1- ⁇ 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl ⁇ methanamine; 1-3: 1- ⁇ 1-[3-(4-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methyl
  • the non-peptidic small molecule SSTR agonist is a 1-[3-(1,3- benzodiazol-2-yl)-5-(phenyl)pyridin-4-yl]pyrrolidin-3-amine compound or a 1-[3-(1,3-benzodiazol- 2-yl)-5-(pyridinyl)pyridin-4-yl]pyrrolidin-3-amine compound.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-2: (3R)-1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-3: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-4: 1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)
  • the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Number PCT/US2020/045610. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVa-1), (IVb-1), (IVa-2), (IVb-2), (IVa-3), (IVb-3), (IVa-4), (IVb-4), (IVa-5), (IVb-5), (V), (Va), (Vb), (Va-1), (Vb-1), (Va-2), (Vb-2), (Va-3), (Vb-3), (VI), (VI), (VIa), (VIb), (VIa-1), (VIb-1), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (I), (II
  • the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7 of International Patent Application Number PCT/US2020/045610. [0092] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3- aminopyrrolidin-1-yl]-5-(phenyl)pyridine-3-carboxamide compound. In some embodiments, the non- peptidic small molecule SSTR agonist is a 1-[3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-4- yl]pyrrolidin-3-amine compound. [0093] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 4-[(3S)-3-aminopyrrolidin-1-yl]-N
  • the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3- methylpyrrolidin-1-yl]-5-(phenyl)-pyridine-3-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3-methylpyrrolidin-1-yl]-5- (phenyl)pyridine-3-carboxamide compound. [0096] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-5: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2'-cyano-N-(3-methylphenyl)-[3,4'-bipyridine]-5- carboxamide; 1-6: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,5-dimethylphenyl)-2'-methyl-[3,4'-bipyridine]-5- carboxamide; 1-121: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl- 1H-pyrazol-3-yl)pyridine-3-
  • the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3- methylpyrrolidin-1-yl]-5-(1,3-benzodiazol-2-yl)-pyridine-3-carboxamide compound. [0099] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: ,
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridine-3-carboxamide; 2-2: (3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-(pyrrolidine-1-carbonyl)pyridin-4- yl]pyrrolidin-3-amine; 2-3: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-N-methyl-5-(4-methyl-1H-1,3-benzodiazol- 2-yl)pyridine-3-carboxamide; 2-4: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-N-methyl-5-(4-methyl-1H-1,3
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R c is hydrogen or -OCH 3 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-161: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl-1H- indazol-6-yl)pyridine-3-carboxamide; 1-162: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl-1H- indazol-4-yl)pyridine-3-carboxamide; 1-182: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl
  • the non-peptidic small molecule SSTR agonist is a 4-[3-amino- pyrrolidin-1-yl]-5-(phenyl)-pyridine-3-carboxamide compound. In some embodiments, the non- peptidic small molecule SSTR agonist is a 4-[3-amino-pyrrolidin-1-yl]-5-(phenyl)pyridine-3- carboxamide compound. [00104] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 1-2: 4-[(3R)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-36: 4-[3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-63: 4-[3-(1-aminoethyl)azetidin-1-yl]-N- ⁇ bicyclo[1.1.1]pentan-1-yl ⁇ -5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-75: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl;
  • the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3- methylpyrrolidin-1-yl]-2-(phenyl)-pyridine-4-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3-methylpyrrolidin-1-yl]-2- (phenyl)pyridine-4-carboxamide compound.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: [00108]
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-(3,5- difluorophenyl)pyridine-4-carboxamide; 3-2: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2-(3,5-difluorophenyl)pyridine-4- carboxamide; 3-3: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-(3,5-difluorophenyl)-N-[(1S)-1- phenylethyl
  • the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3- methylpyrrolidin-1-yl]-4-(phenyl)-pyridine-2-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3-methylpyrrolidin-1-yl]-4- (phenyl)pyridine-2-carboxamide compound.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R c is -C1, -CN, -CH 3 , -CO 2 CH 3 , or -CONH 2 .
  • the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-chloro-N-[(1S)-1-cyclopropylethyl]-4-(3,5- difluorophenyl)pyridine-2-carboxamide; 4-2: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-4-(3,5-difluorophenyl)- 5-methylpyridine-2-carboxamide; 4-3: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-cyano-N-[(1S)-1-cyclopropylethyl]-4-(3,5- difluorophenyl)pyridine-2-carboxamide; 4-4: methyl 5-[(3S)-3-amino-3-methylpyrrol
  • non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is selective for SSTR2 and SSTR4.
  • the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,957,267, US Patent Application Publication Number US 2017/0002001, International Patent Application Publication Number WO 2017/003723, or related applications or application publications.
  • the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (II), (III), or (IV) of US Patent Number 9,957,267.
  • the non-peptidic small molecule SSTR agonist is a compound described in Formula (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) of US Patent Number 9,957,267.
  • the non-peptidic small molecule SSTR agonist is a compound described in Table A, Table B, or Table C of US Patent Number 9,957,267. [00113] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
  • R 13 is -C1, -CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -(CH 2 ) 2 OH, or -CH 2 OH;
  • R 14 is hydrogen, -F, -C1, -CH 3 , -CH 2 OH;
  • R 15 is -CN, -OH, -CONH2, -CONHCH 3 , or -CH 2 OH;
  • R 16 is hydrogen, -F, -C1, -CN, -CH 3 , -CF 3 , -OCF 3 ;
  • R A is hydrogen; and
  • R B is hydrogen, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 )2.
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 13 is -CH 3 or -OCH 3 ; R 14 is -F, -C1, or -CH 3 ; R 15 is -OH; R 16 is hydrogen, -F, -CN, -CF 3 ; R A is hydrogen; and R B is hydrogen, -CN, -CH 3 , -CF 3 .
  • the non-peptidic small molecule SSTR agonist has the following structure: or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R 13 is -CH 3 or -OCH 3 ; R 14 is -F, -C1, or -CH 3 ; R 15 is -OH; R 16 is hydrogen, -F, -CN, -CF 3 ; R A is hydrogen; and R B is hydrogen.
  • SSTR small molecule somatostatin receptor
  • the non-peptidic small molecule SSTR agonist is a compound active against all SSTR subtypes. Additional Agonist Compounds [00117] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US9643951, which is herein incorporated for such compounds. [00118] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US9630976, which is herein incorporated for such compounds.
  • such compounds include, but are not limited to: 1- ⁇ 3-(3,5-dimethylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl ⁇ -4-piperidinamine; 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]piperidin-4-amine; 3- ⁇ (E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl ⁇ benzonitrile; rac-(4aR,8aR)-6-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-piperidinamine
  • the non-peptidic small molecule SSTR agonist is a compound described in US20200000816, which is herein incorporated for such compounds.
  • such compounds include, but are not limited to: rac-(3R,4S)-4-amino-1-[3-(3, 5-dimethoxypheny1)-5-(4,6-dimethy1-1H-benzimidazol-2-y1)-4- pyridinyl]-3-piperidinol; rac-(3R,4S)-4-amino-1-[3-(6-fluoro-1H-benzimidazol-2-y1)-5-(3-fluoro-5-methoxypheny1)-4- pyridinyl]-3-piperidinol; rac-(3R,4 S)-4-amino-1-[3-(6-chloro -1 H-benzimidazol-2-y1)-5-(3-fluoro-5-methoxyphenyl)
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use.
  • salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid.
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, 1-hydroxy-2- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluc
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base.
  • the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure described herein, as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 C1, 123 I, 124 I, 125 I, 131 I, 32 P and 33 P.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound described herein exists in the R configuration. In some embodiments, the compound described herein exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • Z isomers as well as the appropriate mixtures thereof.
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs. [00135] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds are prodrugs for another derivative or active compound.
  • any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety.
  • the prodrug moiety is as described above.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • heterocyclic rings may exist in tautomeric forms.
  • the term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
  • the term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • the term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an agonist.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • effective amount or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • subject or patient encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Pharmaceutical compositions [00152] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • prophylactic treatments include administering to a mammal, which previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight.
  • the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the secondary therapy is surgery.
  • the surgery is to resect or remove a portion of the pituitary adenoma.
  • at least one compound described herein, or a pharmaceutically acceptable salt thereof is administered after surgery.
  • surgery completely removes the adenoma.
  • surgery is incomplete, or only removes part of the adenoma.
  • the tumor recurs after complete or incomplete surgery.
  • administering a non-peptidic small molecule SSTR agonist described herein after incomplete surgery stabilizes tumor size of the remaining pituitary adenoma.
  • At least one compound described herein, or a pharmaceutically acceptable salt thereof is administered before surgery. In some embodiments, administering a non-peptidic small molecule SSTR agonist described herein before surgery leads to better surgical outcomes. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered both before and after surgery.
  • the secondary therapy is radiation therapy. Radiation therapy is often used after surgery in cases of residual or recurrent tumor. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered after radiation therapy. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered before radiation therapy.
  • At least one compound described herein, or a pharmaceutically acceptable salt thereof is administered before and after radiation therapy.
  • radiation therapy has a long- term risk of hypopituitarism.
  • administering a non-peptidic small molecule SSTR agonist described herein, or a pharmaceutically acceptable salt thereof, with radiation therapy decreases incidence of hypopituitarism due to a pituitary adenoma.
  • the radiation therapy is stereotactic radiosurgery or fractionated stereotactic radiotherapy.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.
  • Dopamine Agonist Therapy [00182] In some instances, NFPAs are associated with expression of dopamine receptor type 2 (D2R).
  • NFPA pituitary adenoma
  • SSTR non-peptidic small molecule somatostatin receptor
  • the NFPA has been treated by incomplete surgery. In some embodiments, the surgery is to resect a portion of the pituitary adenoma. In some embodiments, administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect. In some embodiments, the therapeutic effect is a decrease in size of the NFPA.
  • the dopamine agonist is a dopamine receptor type 2 (D2R) agonist.
  • D2R agonists to be used in the methods described herein include cabergoline, bromocriptine, piribedil, pramipexole, quinelorane, quinpirole, ropinirole, sumanirole, or talipexole.
  • Alkylating Chemotherapeutic Drugs [00184] In some instances, pituitary adenomas are also treated with alkylating chemotherapeutic drugs. In some instances, pituitary adenomas are treated with temozolomide. In some instances, patients with low expression of O(6)-methylguanine DNA methyltransferase (MGMT) in pituitary tumors have higher response rates to temozolomide.
  • MGMT O(6)-methylguanine DNA methyltransferase
  • low MGMT expression is associated with tumor aggressiveness in NFPAs.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with an alkylating chemotherapeutic.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with temozolomide.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • Example A-1 SSTR2, SSTR3, and SSTR2/3 Efficacy Assay(s)
  • Cell models human non-functioning pituitary tumors in primary cell culture ( ⁇ 30/year); alphaT3-1 murine immortalized gonadotroph cells overexpressing human SSTR3.
  • Assays CellTiter-Glo® Cell Viability and Caspase-Glo® 3/7 Luminescent assays (Promega; high sensitivity, 10-20,000 cells /condition, 96-well plate format).
  • Example A-2 SSTR3 and SSTR5 Efficacy Assay(s) [00191]
  • Assays ACTH radioimmunoassay on supernatants of human and mouse corticotroph cultures; POMC luciferase assay; secreted POMC-Gaussia luciferase assay, CellTiter-Glo® Cell Viability assay.
  • Animal models Syndromic multiple endocrine neoplasia (MEN1/4) model of homozygote Cdkn1b mutated rats; Pomc knockout in mice (results in null cell tumors similar to benign pituitary adenomas which highly express mouse SSTR3).
  • Example A-3 C1inical Trial for Non-Functioning Pituitary Adenomas
  • SSTR non-peptidic small molecule somatostatin receptor
  • the purposes of this study is to evaluate the safety, tolerability and efficacy of therapy with a non-peptidic small molecule somatostatin receptor (SSTR) agonist in patients with non-functioning pituitary adenomas concerning tumor growth.
  • Study Arms [00200] One of three study arms is used. In study arm 1, all patients receive a non-peptidic small molecule SSTR agonist daily for about 24 weeks. In study arm 2, all patients receive a non-peptidic small molecule SSTR selective agonist daily for about 24 weeks, either a different selectivity or a different dose. In study arm 3, all patients receive a placebo daily for about 24 weeks. Inclusion Criteria: [00201] Male or female patients aged 18 years or greater. Patients with confirmed diagnosis of NFPA. Non-functioning pituitary adenoma ⁇ 1cm, patients without any previous treatment, other than surgery, for the tumor. Patients who sign the informed consent.
  • Exclusion Criteria Patients who have any current or prior medical condition(s) that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms.
  • Example A-4 C1inical Trial for Combination Therapy in Non-Functioning Pituitary Adenomas with Somatostatin Receptor (SSTR) Agonist and Dopamine Agonist
  • SSTR Somatostatin Receptor
  • Dopamine Agonist A non-limiting example of a clinical trial in humans to evaluate the efficacy and safety of a non-peptidic small molecule somatostatin receptor (SSTR) agonist together with a dopamine agonist on the treatment of patients with clinically non-functioning pituitary adenomas is described below.
  • D2R dopamine receptor type 2
  • SSTR non-peptidic small molecule somatostatin receptor
  • the patients with NFPA will be randomized into three groups: (A) the first group receive SSTR agonist therapy daily for at least 3 months; (B) the second group receive cabergoline at about 3 mg/week for at least 3 months; (C) the third group receive SSTR agonist therapy daily and cabergoline at about 3 mg/week for at least 3 months. [00206]
  • treatment is started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. In this case, the drug efficacy is evaluated clinically by visual field and by MRI after at least three months of therapy.
  • Inclusion Criteria Male or female patients aged 18 years or greater. Patients with confirmed diagnosis of NFPA evidenced by: magnetic resonance imaging (MRI) confirmation of pituitary adenoma and no pituitary tumoral hormone hypersecretion. Patients who had been submitted to surgery but not cured. Lack of cure is defined as presence of remnant tumor on MRI at least three months after surgery (without any possible misinterpretation of postsurgical changes). Patients who sign the informed consent. Exclusion Criteria [00208] Patients who have any current or prior medical condition(s) that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control.
  • MRI magnetic resonance imaging
  • Example B-1 Parenteral Pharmaceutical Composition
  • a parenteral pharmaceutical composition suitable for administration by injection 1-100 mg of a water-soluble salt of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline.
  • a suitable buffer is optionally added as well as optional acid or base to adjust the pH.
  • Example B-2 Oral Solution
  • a pharmaceutical composition for oral delivery a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
  • Example B-3 Oral Tablet [00211] A non-limiting example of a tablet formulation is described below.
  • a tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
  • Non-limiting examples of capsule formulations are described below. To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend.
  • Example B-5 Topical Gel Composition
  • a compound described herein, 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 containers, such as tubes, which are suitable for topical administration.

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Abstract

Described herein are compounds that are somatostatin modulators, 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 somatostatin activity.

Description

SOMATOSTATIN MODULATORS FOR TREATING PITUITARY ADENOMAS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of U.S. Provisional Patent Application No. 62/914,848, filed on October 14, 2019, and U.S. Provisional Patent Application No. 62/914,855, filed on October 14, 2019, each of which is incorporated herein by reference in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under grant number DK115290 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0003] Described herein are compounds that are somatostatin modulators, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity including, for example, non-functioning pituitary adenoma (NFPA). BACKGROUND OF THE INVENTION [0004] Pituitary adenomas are common neoplasms comprising approximately 10-20% of intracranial tumors. Non-functioning pituitary adenomas (NFPAs) are generally benign neoplasms and are not associated with clinical evidence of hormonal hypersecretion that is common in diseases such as acromegaly, Cushing’s Disease, or from prolactinomas. NFPAs can be further classified according to their originating cell type, hormonal, and transcription factor profile. Many NFPAs present basal and stimulated serum concentrations of hormones within normal to slightly elevated levels with endocrine effects ranging from no clinical signs to mild, often overlooked, clinical symptoms. The deleterious effects of NFPAs are typically due to macroadenomas, and patients suffer from symptoms related to mass effects from the tumor, commonly headache, blurred vision or rapid onset of blindness, and/or cranial nerve dysfunction. [0005] Most NFPAs express different subtypes of the somatostatin receptor (SSTR) family. In some aspects, somatostatin receptor activation promotes antitumor effects through the induction of cell cycle arrest to inhibit tumor growth, the inhibition of growth factor secretion (e.g. GH, IGF-1, VEGF) necessary for tumor growth, or through the inhibition of angiogenesis in newly formed endothelial cells. Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity, including NFPA. SUMMARY OF THE INVENTION [0006] Compounds described herein are somatostatin modulator compounds. In some embodiments, compounds described herein modulate one or more of the subtype somatostatin receptor proteins. In some embodiments, compounds described herein modulate one subtype somatostatin receptor. In some embodiments, compounds described herein modulate two or more subtype somatostatin receptor. Somatostatin peptide analogs, such as octreotide, lanreotide and pasireotide, formulated as depot injections, are routinely used to normalize hormone levels for the treatment of Growth Hormone (GH) secreting adenomas, pancreatic neuroendocrine tumors, and carcinoid tumors. The depot preparations of these peptide drugs are extremely expensive and require frequent doctor’s office visits for painful injections that can lead to injection site reactions. Compounds described herein are molecules that are structurally different from peptide analogs. The compounds described herein are somatostatin modulators that are useful for the treatment of pituitary adenomas. [0007] Also described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule. [0008] Also described herein is a method of treating non-functioning pituitary adenoma (NFPA) in a patient, comprising administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof. Also described herein is a method of stabilizing a NFPA tumor size in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. Also described herein is a method of treating headache, blurred vision, cranial nerve dysfunction, hyperprolactinemia, or pituitary apoplexy associated with NFPA, or a combination thereof, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. Also described herein is a method of stabilizing tumor size of a recurrent NFPA tumor after incomplete resection surgery in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. Also described herein is a method of preventing recurrence of tumor growth in a patient after surgery, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof, wherein the tumor is a NFPA tumor. In some embodiments, the NFPA has been treated by incomplete surgery. In some embodiments, the surgery is to resect a portion of the pituitary adenoma. In some embodiments, administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect. In some embodiments, the therapeutic effect is an inhibition of growth of the NFPA. In some embodiments, the therapeutic effect is a decrease in size of the NFPA. In some embodiments, the non-peptidic small molecule SSTR agonist is a selective agonist. In some embodiments, the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist. In some embodiments, the non-peptidic small molecule SSTR agonist is a pan-SSTR agonist. In some embodiments, the method further comprises a secondary therapy. In some embodiments, the secondary therapy is a dopamine agonist, an alkylating agent, radiotherapy, or surgery. In some embodiments, the secondary therapy is a dopamine agonist. In some embodiments, the secondary therapy is radiotherapy or surgery. [0009] Also described herein is a method of reducing tumor volume of a NFPA in a patient, comprising: administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; and administering a dopamine agonist to the patient in need thereof. [0010] Also described herein is a method of treating a NFPA in a patient, comprising: first, administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; then, resecting a portion of the NFPA. [0011] Also described herein is a method of reducing the rate of proliferation of pituitary adenoma cells, the method comprises contacting said pituitary adenoma cells with a non-peptidic small molecule SSTR agonist. [0012] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal. [0013] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule. [0014] In any of the embodiments disclosed herein, the mammal is a human. [0015] In some embodiments, compounds provided herein are orally administered to a human. [0016] Articles of manufacture, which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating one or more subtype somatostatin receptor proteins, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating one or more subtype somatostatin receptor proteins, are provided. [0017] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION [0018] Somatostatin (SST), also known as somatotropin release inhibiting factor (SRIF) was initially isolated as a 14-amino acid peptide from ovine hypothalami (Brazeau et al., Science 179, 77- 79, 1973). An N-terminal extended 28-amino acid peptide with similar biological activity to 14- amino acid somatostatin was subsequently isolated (Pradayrol et, al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. U S A, 77, 6827–6831, 1980). SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and gut and have multiple functions including modulation of secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are anti-proliferative. [0019] These pleotropic actions of somatostatins are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev.16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All the receptors are members of the class-A subgroup of the GPCR superfamily. [0020] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to the other somatostatin receptor subtypes reduces unwanted side effects in a variety of clinical applications. In some embodiments, the compounds described herein are SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective. In some embodiments, the compounds described herein are pan-SSTR active. [0021] In some embodiments, compounds described here are amenable to oral administration to a mammal in need of treatment with a somatostatin modulator. Pituitary Adenomas [0022] Pituitary adenomas comprise approximately 10-20% of intracranial tumors. Non- functioning pituitary adenomas (NFPAs) are benign adenohypophyseal tumors not associated with clinical evidence of hormonal hypersecretion. NFPAs comprise different histological subtypes, classified according to their immunostaining to different adenohypophyseal hormones and transcription factors. The silent gonadotroph adenoma is the most common subtype, followed by corticotroph, PIT1 (POU1F1) gene lineage and null cell tumors. Data from Europe, North and South America have estimated that the prevalence of clinically relevant NFPAs is 7–41.3 cases per 100,000 of population, however this is likely an underestimate of the true prevalence, as many NFPAs go undiagnosed until they are very large and cause mass effect or are accidentally discovered. [0023] In some instances, patients with NFPAs come to medical attention as a result of “mass effects” symptoms such as headaches, visual disorders and/or cranial nerve dysfunction caused by lesions large enough to damage surrounding structures. In some instances, hypopituitarism, caused by the compression of the normal anterior pituitary, and hyperprolactinemia, due to pituitary stalk deviation, are also present. [0024] Surgical resection is the primary treatment for symptomatic patients with NFPAs, i.e., those with neuro-ophthalmologic complaints and/or tumors affecting the optic pathway. In some instances, visual deficits and hormone deficiencies improve following surgical treatment. However, in some instances, new hormone deficiencies develop after a surgical approach. In some instances, NFPA tumors present progressive tumor growth after incomplete tumor resection. Follow up is individualized and should consider tumor size, prior treatments, and clinical symptoms. In some instances, such as those of tumors not completely resected by surgery, those cases that present progressive tumor growth during follow-up, or for patients who, at diagnosis, already have tumors with aggressive features, radiotherapy in the postoperative period is a follow up consideration. In instances which present as microadenomas and asymptomatic patients, a “watch and wait” option is often preferred. [0025] In some instances, NFPAs manifest as impaired vision, caused by suprasellar extension of the adenoma that compresses the optic chiasm. In some instances, diplopia, induced by oculomotor nerve compression resulting from parasellar expansion of the adenoma, occurs. The typical visual field defect associated with pituitary tumors is bitemporal hemianopia, reported in approximately 40% of the patients. [0026] NFPAs manifest as headaches in 19-75% of patients with pituitary tumors, regardless of size of the tumor. In some instances, headaches are caused by increased intrasellar pressure, stretching of dural membrane pain receptors, and activation of trigeminal pain pathways. In some instances, the tumor causes erosion of the sellar floor and extends inferiorly to the sphenoid sinus leading to cerebrospinal fluid (CSF) rhinorrhea, associated or not with headache. [0027] In rare instances, NFPAs lead to pituitary apoplexy (sudden hemorrhage into a pituitary macroadenoma). Pituitary apoplexy causes acute onset of a severe headache associated with visual disturbances and can occur in all types of pituitary tumors. It some instances the combination of the high metabolism of pituitary adenomas combined with their special blood supply makes them more prone to vascular events. [0028] Most patients with macroadenomas present with deficiency of at least one pituitary hormone resulting from the compression of the normal anterior pituitary and/or pituitary stalk, preventing the stimulation of pituitary cells by hypothalamic factors. In some instances, hypogonadism results from either a compressive effect on gonadotropic cells or by hyperprolactinemia. In some instances, this “disconnection hyperprolactinemia” or non-tumoral hyperprolactinemia is characterized by compression of the pituitary stalk, which prevents the arrival of dopamine to the anterior pituitary, the main inhibitor of prolactin (stalk effect). In some instances, NFPAs affect the GH axis, hypogonadism, or adrenal insufficiency. [0029] In some instances, gonadotroph adenomas are usually considered to be "nonfunctioning" although they can secrete intact gonadotropins, as they do not generally result in a clinical syndrome. Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. In some instances, gonadotroph adenomas secrete primarily FSH but also LH in quantities high enough to raise serum gonadotropin levels, which in turn, lead to the development of some specific symptoms, such as ovarian hyperstimulation in young women or precocious puberty or testicular enlargement in men. In addition, low serum LH:FSH ratios (usually < 1.0) have been described in clinically-secreting gonadotroph adenomas. Although use of GnRH analogues (agonists or antagonists) has been hypothesized as a method of treating gonadotroph adenomas, in some instances, these GnRH analogues have had no effect in hormone levels nor in tumor dimensions. [0030] NFPAs are characterized by the expression of somatostatin receptors (SSTR). In some instances, somatostatin receptor activation promotes antitumor effects through different pathways including the induction of cell cycle arrest to inhibit tumor growth, the inhibition of growth factor secretion (e.g. GH, IGF-1, VEGF) necessary for tumor growth, as well as through the inhibition of angiogenesis in newly formed endothelial cells. Unlike acromegaly, which predominantly expresses SSTR2 and SSTR5, NFPAs express a wide variety of SSTRs. Described herein is the use of somatostatin receptor agonists for the treatment of NFPAs. In some embodiments described herein, a broad-spectrum SSTR agonist therapy can prove useful for the treatment of NFPA or associated symptoms thereof. Methods of Use [0031] Described herein, in some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of pituitary adenomas. In some embodiments, the non-peptidic small molecule SSTR agonist described herein induces a therapeutic effect. In some embodiments, the therapeutic effect is an inhibition of growth of the adenoma. In some embodiments, the therapeutic effect is a decrease in size of the adenoma. In some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of symptoms related to pituitary adenomas, such as headache, blurred vision, cranial nerve dysfunction, hyperprolactinemia, or pituitary apoplexy, or combinations thereof. In some embodiments, the pituitary adenoma is a non-functional pituitary adenoma. [0032] In one embodiment, described herein is a method of treating NFPA in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. [0033] In some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, are used in a method to inhibit the growth of, or decrease the size of, a pituitary adenoma. In some embodiments, the pituitary adenoma is a non-functional pituitary adenoma. In some embodiments, the tumor size of a pituitary adenoma does not increase while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor size of a pituitary adenoma is stabilized while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor size does not increase over a time of 6 months, 1 year, 3 years, 5 years, or 10 years. In some embodiments, the tumor size of a pituitary adenoma decreases while being treated with the non- peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor size of a pituitary adenoma decreases while being treated with the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, in combination with additional dopamine agonist therapy. [0034] In one embodiment, described herein is a method of stabilizing a NFPA tumor size in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. [0035] In some instances, use of somatostatin agonist therapy after surgery has been demonstrated to decrease tumor volume after incomplete surgery. In some instances, use of somatostatin agonist therapy after surgery has been demonstrated to stabilize tumor volume after incomplete surgery. In some instances of recurrent tumors, better surgical outcomes are achieved in patients who are pre- treated with somatostatin agonist therapy before a planned surgery. The methods described herein are useful for treating pituitary adenomas in a subject, wherein the subject has undergone a medical procedure, such as surgery, in order to resect a portion of the adenoma. In some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, is administered before said medical procedure. In some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, is administered after said medical procedure. In some embodiments, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, is administered before and after said medical procedure. In one embodiment, described herein is a method of treating NFPA in a patient, comprising: first, administering a non-peptidic small molecule SSTR agonist to the patient in need thereof; then, resecting a portion of the NFPA. [0036] In one embodiment, described herein is a method of stabilizing tumor size of a recurrent NFPA tumor after incomplete resection surgery in a patient, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. [0037] In one embodiment, described herein is a method of preventing recurrence of tumor growth in a patient after surgery, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof, wherein the tumor is a NFPA tumor. [0038] In some embodiments of the methods described herein, the non-peptidic small molecule SSTR agonists described herein, or a pharmaceutically acceptable salt thereof, are used in a method to treat symptoms due to a pituitary adenoma. In one embodiment, described herein is a method of increasing patient-reported health-related quality of life (HR-QoL) in patients having NFPA, comprising administering a non-peptidic small molecule SSTR agonist to the patient in need thereof. In one embodiment, described herein is a method of treating headache, blurred vision, or cranial nerve dysfunction associated with NFPA, or a combination thereof, comprising administering a non- peptidic small molecule SSTR agonist to the patient in need thereof. [0039] Also described herein, in another embodiment, is a method of reducing the rate of proliferation of pituitary adenoma cells, the method comprises contacting said pituitary adenoma cells with a non-peptidic small molecule SSTR agonist. In some embodiments, the pituitary adenoma cells comprise a pituitary adenoma in a subject. In some embodiments, the pituitary adenoma cells comprise a NFPA in a subject. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor size does not increase. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor size decreases. In some embodiments, rate of proliferation of pituitary adenoma cells is such that the pituitary adenoma tumor shrinks. Compounds [0040] Described herein are non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein. In some embodiments, the SSTR agonist is selective for one or more somatostatin receptor(s) relative to the other somatostatin receptors. In some embodiments, the SSTR agonist is SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective. In some embodiments, the SSTR agonist is a pan-SSTR agonist. SSTR2-Selective Agonists [0041] In some embodiments, described herein are non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is selective for SSTR2. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,902,703, US Patent Number 9,896,432, US Patent Number 10,351,547, US Patent Number 10,597,377, US Patent Number 10,696,689, International Patent Application Publication Number WO 2017/003724, International Patent Application Publication Number WO 2019/023278, International Patent Application Publication Number WO 2018/013676, International Patent Application Publication Number WO 2018/170284, International Patent Application Publication Number WO 2020/061046, or related applications or application publications. [0042] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,902,703. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) of US Patent Number 9,902,703. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (I) or (Ia) of US Patent Number 9,902,703. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of US Patent Number 9,902,703. [0043] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000011_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: RA is hydrogen, -F, -C1, -CH3, -CF3, or -SO2CH3;
Figure imgf000011_0002
R is hydrogen, -CH3, or -CH2CH3; R13 is hydrogen or -CH3; R16 is -C1, -CH3, or -OCH3; R17 is -F, -C1, or -CH3; R18 is hydrogen, -F, -CN, -CF3, -OH, -CONH2, -CH2CO2H, -CH2CO2CH2CH3, -SO2CH3, or tetrazolyl; and R19 is hydrogen, -F, -C1, -CN, -CH3, or -CF3. [0044] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000011_0003
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000012_0001
[0045] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000012_0002
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000012_0003
[0046] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/023278. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il) of International Patent Application Publication Number WO 2019/023278. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) of International Patent Application Publication Number WO 2019/023278. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of International Patent Application Publication Number WO 2019/023278. [0047] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000013_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000013_0002
R9 is -CH3; R10 is -F, -C1, -CH3, -OCH3, -CH2CH2OH, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CO2H, - C(CH3)2OH, -C(CH3)=CH2, or -CONMe2; R11 is hydrogen, -F, -C1, -CH3, or -OH; R12 is -F, -CN, -CF3, -OH, -OCH3, -CO2H, -CH2CO2H, -CH2CO2CH3, -(CH2)2CO2H, -CONH2, - CH2CONH2, -SO2NH2, or -SONH2; and R13 is hydrogen, -F, -C1, -CN, -CH3, -CF3, -OH, -OCH3, -CO2H, -O(CH2)3CO2H, -CH2OCH3, - CONH2, or -CONHCH3. [0048] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000013_0003
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000014_0001
R9 is -CH3; R10 is hydrogen, -F, -C1, -CN, -OH, -OCH3, -CH3, -CH2CH2OH, -CH2CO2H, -CH2CO2CH3, - CH2CH2CO2H, -CH2CH2CO2CH3, -CH2NHCOCH3, or pyrazol-1-yl; R11 is hydrogen, -F, or -CH3; R12 is -CN, -OH, or -CONH2; and R13 is hydrogen, -F, or -CN. [0049] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000014_0002
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000014_0003
;
Figure imgf000014_0004
Figure imgf000015_0001
Figure imgf000016_0001
[0050] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,896,432. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (A), (AI), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (AII), (II), (A2), (AIIa), (AIIb), (AIIc), (AIId), (AIIe), (AIIf), (AIII), (III), (AIIIa), (AIIIb), (AIIIc), (AIIId), (AIIIe), (AIIIf), (IIIa), (IIIb), (IV), (V), (AV), (AVa), (AVb), (AVc), (AVd), (AVe), or (AVf) of US Patent Number 9,896,432. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (A), (AII), (AIIb), (AIII), (AIIIb), (AV), or (AVb) of US Patent Number 9,896,432. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, or Table 4 of US Patent Number 9,896,432. [0051] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(phenyl)cinnoline, 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3- phenyl)cinnoline, or 4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)cinnoline compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3- (phenyl)cinnoline, 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-phenyl)cinnoline, or 4-[3- (aminomethyl)azetidin-1-yl]-3-(phenyl)cinnoline compound, wherein the phenyl is substituted with Ra and/or Rb, Ra is -F, -C1, or -CH3; and Rb is -F, -C1, -CH3, or -CONH2. [0052] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000016_0002
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000017_0001
o ; Ra is -F, -C1, or -CH3; and Rb is -F, -C1, -CH3, or -CONH2. [0053] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-2: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-3: 1-[6,7-dichloro-3-(3,5-dimethylphenyl)cinnolin-4-yl]piperidin-4-amine; 1-4: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5- fluorobenzamide; 1-5: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6- yl}-5-fluorobenzamide; 1-6: 3-{4-[cis-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}- 5-fluorobenzamide; 1-7: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-8: 5-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro- 1H-1,3-benzodiazol-2-one; 1-9: 4-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro- 1H-1,3-benzodiazol-2-one; 1-10: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin- 6-yl}-5-fluorobenzamide; 1-11: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-12: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2- hydroxybenzonitrile; 1-13: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-14: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-15: 3-[4-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)cinnolin-3-yl]-5-fluorobenzamide; 1-16: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro-1H-1,3- benzodiazol-2-one; 1-17: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-18: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-19: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-fluorophenyl)cinnolin-6-yl]-2- hydroxybenzonitrile; 1-20: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-21: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-22: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2- hydroxybenzonitrile; 1-23: 6-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-4-fluoro-2,3-dihydro- 1H-1,3-benzodiazol-2-one; 1-24: 4-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6-fluoro-2,3-dihydro- 1H-1,3-benzodiazol-2-one; 1-25: 3-[7-chloro-3-(3-fluoro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin-6- yl]-5-fluorobenzamide; 1-26: 3-{4-[trans-4-amino-3-hydroxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin- 6-yl}-5-fluorobenzamide; 1-27: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluoro-2- hydroxybenzonitrile; 1-28: 6-[4-(4-aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-4-fluoro-2,3-dihydro-1H- 1,3-benzodiazol-2-one; 1-29: 2-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6-fluorophenol; 1-30: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-31: 3-[3-(3,5-dichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6-yl]-5- fluorobenzamide; 1-32: 3-[3-(3,5-dichlorophenyl)-4-{4-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}cinnolin-6-yl]-5- fluorobenzamide; 1-33: 3-[3-(3,5-dichlorophenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin-6-yl]-5- fluorobenzamide; 1-34: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3,5-dichlorophenyl)cinnolin-6-yl}-5-fluorobenzamide 1-35: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin- 6-yl]-5-fluorobenzamide; 1-36: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin- 6-yl]-5-fluoro-2-hydroxybenzonitrile; 1-37: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(3,3,3-trifluoropropyl)amino]piperidin-1- yl}cinnolin-6-yl]-5-fluorobenzamide; 1-38: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6- yl]-5-fluorobenzamide; 1-39: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6- yl]-5-fluoro-2-hydroxybenzonitrile; 1-40: 3-[3-(3-chloro-5-methylphenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6-yl]-5- fluoro-2-hydroxybenzonitrile; 1-41: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6- yl}-5-fluorobenzamide; 1-42: 6-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]pyridine-2- carboxamide; 1-43: 6-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5- chloropyridine-2-carboxamide; 1-44: 2-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]pyridine-4- carboxamide; 1-45: 2-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6-fluoro-3- methylphenol; 1-46: 3-{4-[(3S)-3-aminopiperidin-1-yl]-3-(3-chloro-5-methylphenyl)cinnolin-6-yl}-5- fluorobenzamide; 1-47: 3-{4-[(3R)-3-aminopiperidin-1-yl]-3-(3-chloro-5-methylphenyl)cinnolin-6-yl}-5- fluorobenzamide; 1-48: 3-{4-[cis-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5-methylphenyl)cinnolin-6- yl}-5-fluorobenzamide; 1-49: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5-methylphenyl)cinnolin- 6-yl}-5-fluorobenzamide; 1-50: 3-[3-(3-chloro-5-methylphenyl)-4-{1,7-diazaspiro[3.5]nonan-7-yl}cinnolin-6-yl]-5- fluorobenzamide; 1-51: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-dichlorophenyl)cinnolin-6-yl}- 2-hydroxybenzonitrile; 1-52: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5-methylphenyl)cinnolin- 6-yl}-2-hydroxybenzonitrile; 1-53: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)cinnolin- 6-yl}-2-hydroxybenzonitrile; 1-54: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)cinnolin-6-yl}- 2-hydroxybenzonitrile; 1-55: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)cinnolin-6-yl}- 4-aminopyridine-3-carbonitrile; 1-56: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)cinnolin- 6-yl}-4-aminopyridine-3-carbonitrile; 1-57: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)cinnolin-6-yl}- 3-aminopyridine-4-carbonitrile; 1-58: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)cinnolin- 6-yl}-3-aminopyridine-4-carbonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0054] In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)quinoline, 3-{4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3- (phenyl)quinoline, or 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)quinoline compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3- (phenyl)quinoline, 3-{4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(phenyl)quinoline, or 3-{4- [3-(aminomethyl)azetidin-1-yl]-3-(phenyl)quinoline compound, wherein the phenyl is substituted with Ra and/or Rb, Ra is -F or -C1; and Rb is -F, -C1, -CH3, -CF3, -OCH3, -OCH2CH2OCH3
Figure imgf000021_0001
Figure imgf000021_0002
[0055] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000021_0003
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: O
Figure imgf000021_0004
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
, , o ; Ra is -F or -C1; and Rb is -F, -C1, -CH3, -CF3, -OCH3, -OCH2CH2OCH3,
Figure imgf000026_0002
Figure imgf000026_0003
[0056] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-2: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-3: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-4: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}benzonitrile; 2-5: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile; 2-6: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]phenol; 2-7: 6-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]pyridine-2- carboxamide; 2-8: 4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1H-1,3- benzodiazol-2-one; 2-9: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1H-1,3- benzodiazol-2-one; 2-10: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2- hydroxybenzonitrile; 2-11: 1-[3-(3,5-dichlorophenyl)quinolin-4-yl]piperidin-4-amine; 2-12: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-13: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-14: 3-{4-[3-(aminomethyl)-3-methylazetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5- fluorobenzamide; 2-15: 3-{4-[3-(aminomethyl)-3-methylazetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}-5- fluoro-2-hydroxybenzonitrile; 2-16: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2- hydroxybenzonitrile; 2-17: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-18: 3-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5- fluoro-2-hydroxybenzonitrile. 2-19: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 2-hydroxybenzonitrile; 2-20: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin- 6-yl}-2-hydroxybenzonitrile; 2-21: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-fluorophenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-22: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-23: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-24: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-fluoroethyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-25: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(propan-2-yl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-26: 3-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5- fluorobenzamide; 2-27: 3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-methoxyethyl)amino]methyl}azetidin-1-yl)quinolin- 6-yl]-5-fluoro-2-hydroxybenzonitrile; 2-28: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3-fluoropropyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-29: 3-(4-{3-[(cyclopropylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)- 5-fluoro-2-hydroxybenzonitrile; 2-30: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(pyrrolidin-1-ylmethyl)azetidin-1-yl]quinolin-6- yl]-2-hydroxybenzonitrile; 2-31: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1-yl}quinolin-6- yl]-2-hydroxybenzonitrile; 2-32: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-33: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(oxetan-3-yl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-34: 3-(4-{3-[(cyclopentylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)- 5-fluoro-2-hydroxybenzonitrile; 2-35: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-4-ylmethyl)azetidin-1-yl]quinolin-6- yl]-2-hydroxybenzonitrile; 2-36: 3-[3-(3-fluoro-5-methylphenyl)-4-[3-(piperazin-1-ylmethyl)azetidin-1-yl]quinolin-6-yl]-5- fluoro-2-hydroxybenzonitrile; 2-37: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(oxan-4-yl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-38: 2-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-6- fluoro-3-methylphenol; 2-39: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(1-methoxy-2-methylpropan-2- yl)amino]methyl}azetidin-1-yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-40: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-hydroxy-2- methylpropyl)amino]methyl}azetidin-1-yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-41: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(1-hydroxybutan-2-yl)amino]methyl}azetidin- 1-yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-42: 3-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1-yl}quinolin-6-yl]-2- hydroxybenzonitrile; 2-43: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-hydroxyethyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-44:3-[4-(3-{[ethyl(2-hydroxyethyl)amino]methyl}azetidin-1-yl)-3-(3-fluoro-5- methylphenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile; 2-45: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(oxolan-3-yl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-46: 3,6-difluoro-2-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1- yl}quinolin-6-yl]phenol; 2-47: 3-(4-{3-[(3,3-difluoropyrrolidin-1-yl)methyl]azetidin-1-yl}-3-(3-fluoro-5- methylphenyl)quinolin-6-yl)-5-fluoro-2-hydroxybenzonitrile; 2-48: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}azetidin- 1-yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-49: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}azetidin- 1-yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-50: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(piperidin-1-ylmethyl)azetidin-1-yl]quinolin-6- yl]-2-hydroxybenzonitrile; 2-51: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-hydroxypropyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-52: 2,6-difluoro-4-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1- yl}quinolin-6-yl]phenol; 2-53: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3-hydroxypropyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-(methoxymethoxy)benzonitrile; 2-54: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3-hydroxypropyl)amino]methyl}azetidin-1- yl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-55: 4-fluoro-6-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1-yl}quinolin-6- yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one; 2-56: 2-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}acetic acid; 2-57: 4-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6- cyanophenoxy}butanoic acid; 2-58: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- (methoxymethoxy)benzonitrile; 2-59: 3-{4-[(3R, 4R)-4-amino-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-60: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-61: 3-{4-[(3S,4R)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-62: 3-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- (methoxymethoxy)benzonitrile; 2-63: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-5-fluoro-2- hydroxybenzonitrile; 2-64: 2-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}ethyl acetate; 2-65: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2- hydroxyethoxy)benzonitrile; 2-66: 3-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-67: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(1,3-dihydroxypropan-2- yl)oxy]benzamide; 2-68: 3-[4-(4-aminopiperidin-1-yl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]quinolin-6-yl]-2- hydroxybenzonitrile; 2-69: 3-[4-(4-aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2- hydroxybenzonitrile; 2-70: 3-[4-(4-aminopiperidin-1-yl)-3-{3-fluoro-5-[(1E)-(methoxyimino)methyl]phenyl}quinolin-6- yl]-2-hydroxybenzonitrile; 2-71: 3-[4-(4-aminopiperidin-1-yl)-3-{3-[(3,3-difluoroazetidin-1-yl)methyl]-5- fluorophenyl}quinolin-6-yl]-2-hydroxybenzonitrile; 2-72: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2- methoxyethoxy)benzonitrile; 2-73: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(oxetan-3- yloxy)benzonitrile; 2-74: 1-[3-(3,5-difluorophenyl)-6-[5-fluoro-4-(oxetan-3-yloxy)pyridin-3-yl]quinolin-4-yl]piperidin- 4-amine; 2-75: 5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-(azetidin-1-yl)pyridine-3- carbonitrile; 2-76: 5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-(azetidin-1-yl)pyridine-3- carboxamide; 2-77: 2-amino-3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile; 2-78: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2- (methoxymethoxy)benzonitrile; 2-79: 3-[4-(4-aminopiperidin-1-yl)-3-{3-[(ethoxyimino)methyl]-5-fluorophenyl}quinolin-6-yl]-2- hydroxybenzonitrile; 2-80: 6-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-fluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one; 2-81: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-[- (methoxyimino)methyl]phenol; 2-82: 3-(4-{3-[(1S)-1-aminopropyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5- fluoro-2-hydroxybenzonitrile; 2-83: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6- difluorophenyl}carbamate; 2-84: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- (methoxymethoxy)benzonitrile; 2-85: 6-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridine-2-carboxamide; 2-86: N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6- difluorophenyl}methanesulfonamide; 2-87: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(2- methoxyethoxy)methoxy]benzonitrile; 2-88: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-(azetidine-1- carbonyl)phenol; 2-89: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-90: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6- yl}-2-hydroxybenzonitrile; 2-91: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3-fluoro-5-methoxyphenyl)quinolin- 6-yl}-2-hydroxybenzonitrile; 2-92: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine- 3-carbonitrile; 2-93: propan-2-yl trans-4-amino-1-[3-(3,5-difluorophenyl)-6-(3-ethynyl-2-hydroxyphenyl)quinolin- 4-yl]piperidine-3-carboxylate; 2-94: cis-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3- carbonitrile; 2-95: 3-{4-[trans-4-amino-3-(2-hydroxyethoxy)piperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 2-hydroxybenzonitrile; 2-96: 3-{4-[cis-4-amino-3-(2-hydroxyethoxy)piperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-97: 3-{4-[trans-4-amino-3-(2-methoxyethoxy)piperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 2-hydroxybenzonitrile; 2-98: 3-{4-[cis-4-amino-3-(2-methoxyethoxy)piperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2- hydroxybenzonitrile; 2-99: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,5-difluoro-2- hydroxybenzonitrile; 2-100: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4,5-difluoro-2-hydroxybenzonitrile; 2-101: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4,5-difluoro-2-hydroxybenzonitrile; 2-102: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-4,5- difluoro-2-hydroxybenzonitrile; 2-103: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,5-difluoro-2- hydroxybenzonitrile; 2-104: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin- 6-yl}-4,5-difluoro-2-hydroxybenzonitrile; 2-105: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3-fluoro-5-methylphenyl)quinolin- 6-yl}-4,5-difluoro-2-hydroxybenzonitrile; 2-106: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}- 4,5-difluoro-2-hydroxybenzonitrile; 2-107: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl}-4,5- difluoro-2-hydroxybenzonitrile; 2-108: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluoro-3- methylphenol; 2-109: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4,6-difluoro-3-methylphenol; 2-110: 2-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4,6-difluoro-3-methylphenol; 2-111: 2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-4,6- difluoro-3-methylphenol; 2-112: 2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}- 4,6-difluoro-3-methylphenol; 2-113: cis-4-amino-1-[6-(3,5-difluoro-2-hydroxy-6-methylphenyl)-3-(3-fluoro-5- methoxyphenyl)quinolin-4-yl]piperidin-3-ol; 2-114: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-fluoro-6- [(methoxyimino)methyl]phenol; 2-115: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6- [(methoxyimino)methyl]phenol; 2-116: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-fluoro-6- [(methoxyimino)methyl]phenol; 2-117: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-3,4-difluoro-6- [(methoxyimino)methyl]phenol; 2-118: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin- 6-yl}-4-fluoro-6-[(1E)-(methoxyimino)methyl]phenol; 2-119: trans-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin- 4-yl]piperidine-3-carbonitrile; 2-120: cis-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4- yl]piperidine-3-carbonitrile; 2-121: trans-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5- methylphenyl)quinolin-4-yl]piperidine-3-carbonitrile; 2-122: cis-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5- methylphenyl)quinolin-4-yl]piperidine-3-carbonitrile; 2-123: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6- trifluorophenyl}carbamate; 2-124: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoropyridin- 4-yl}carbamate; 2-125: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-cyanopyridin- 4-yl}carbamate; 2-126: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}quinolin-4- yl]piperidin-4-amine; 2-127: 1-(6-{3-chloro-2-[(hydroxyimino)methyl]phenyl}-3-(3,5-difluorophenyl)quinolin-4- yl)piperidin-4-amine; 2-128: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2- [(hydroxyimino)methyl]benzonitrile; 2-129: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(methoxyimino)methyl]phenyl}quinolin-4- yl]piperidin-4-amine; 2-130: 1-(6-{3-chloro-2-[(methoxyimino)methyl]phenyl}-3-(3,5-difluorophenyl)quinolin-4- yl)piperidin-4-amine; 2-131: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(1E)- (methoxyimino)methyl]benzonitrile; 2-132: 1-{6-[3-(1-amino-2,2,2-trifluoroethyl)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl}piperidin- 4-amine; 2-133: 1-{6-[2-(1-amino-2,2,2-trifluoroethyl)-3-fluorophenyl]-3-(3,5-difluorophenyl)quinolin-4- yl}piperidin-4-amine; 2-134: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chloro-3,4- difluorophenol; 2-135: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 6-chloro-3,4-difluorophenol; 2-136: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chloro-4-fluorophenol; 2-137: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chlorophenol; 2-138: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 6-chlorophenol 2-139: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}-3- methoxyurea; 2-140: 1-(2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}-4,6-difluorophenyl)-3-methoxyurea; 2-141: 6-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-chloro-2,3-dihydro-1H- 1,3-benzodiazol-2-one; 2-142: 5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2,3-dihydro-1,3- benzoxazol-2-one; 2-143: methyl trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4- yl]piperidine-3-carboxylate; 2-144: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}-6-fluorophenol; 2-145: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4- yl]piperidine-3-carboxylic acid; 2-146: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4- yl]piperidine-3-carboxamide; 2-147: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro-4-fluoro-2- hydroxybenzonitrile; 2-148: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6- cyanophenyl}carbamate; 2-149: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-N- methylpiperidine-3-carboxamide; 2-150: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6-trifluorophenol; 2-151: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-N,N- dimethylpiperidine-3-carboxamide; 2-152: 1-[3-(3,5-difluorophenyl)-6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}quinolin-4- yl]piperidin-4-amine; 2-153: N-[(2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-6-fluorophenyl)methylidene]hydroxylamine; 2-154: N-[(2-{4-[(trnas)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-4,6-difluorophenyl)methylidene]hydroxylamine; 2-155: N-[(2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5- methoxyphenyl)quinolin-6-yl}-6-fluorophenyl)methylidene]hydroxylamine; 2-156: 4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-[3-fluoro-2-(1H-imidazol-2- yl)phenyl]-3-(3-fluoro-5-methoxyphenyl)quinoline; 2-157: 4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-[3-fluoro-2-(1H-imidazol-5- yl)phenyl]-3-(3-fluoro-5-methoxyphenyl)quinoline; 2-158: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5- methoxyphenyl)quinolin-6-yl}-4,5-difluoro-2-hydroxybenzonitrile; 2-159: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5- methoxyphenyl)quinolin-6-yl}-4,5-difluoro-2-hydroxybenzonitrile; 2-160: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5- methoxyphenyl)quinolin-6-yl}-3,4,6-trifluorophenol; 2-161: 1-[3-(3-fluoro-5-methoxyphenyl)-6-(2,3,5-trifluoro-6-hydroxyphenyl)quinolin-4-yl]piperidin- 4-ol; 2-162: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-hydroxypyridin-4- yl}-3-methoxyurea; 2-163: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6- chlorophenyl}-3-methoxyurea; 2-164: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3-methoxyurea; 2-165: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-4,6- difluorophenyl}carbamate; 2-166: 1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methoxyphenyl)quinolin-4- yl)piperidin-4-amine; 2-167: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6- cyanophenyl}carbamate; 2-168: 1-(6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-(3-fluoro-5-methylphenyl)quinolin- 4-yl)piperidin-4-amine; 2-169: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4- amine; 2-170: methyl (trans)-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4- yl]piperidine-3-carboxylate; 2-171: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5- fluoropyridin-4-yl}carbamate; 2-172: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin- 4-yl}-3-methoxyurea; 2-173: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6- fluorophenyl}carbamate; 2-174: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6- fluorophenyl}-3-methoxyurea; 2-175: N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6- fluorophenyl}azetidine-1-carboxamide; 2-176: 1-(6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-[3-fluoro-5- (trifluoromethyl)phenyl]quinolin-4-yl)piperidin-4-amine; 2-177: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]pyridine-3- carbonitrile; 2-178: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2- amine; 2-179: 2-amino-3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,5- difluorobenzonitrile; 2-180: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyano-3,4- difluorophenyl}carbamate; 2-181: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4- amine; 2-182: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5- fluoropyridin-2-yl}carbamate; 2-183: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin- 2-yl}-3-methoxyurea; 2-184: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5- chloropyridin-4-yl}carbamate; 2-185: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4- cyanophenyl}carbamate; 2-186: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin- 4-yl}-3-methoxyurea; 2-187: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]pyridine-3- carbonitrile; 2-188: 1-[3-(3,5-difluorophenyl)-6-{5-[(hydroxyimino)methyl]-1-methyl-1H-pyrazol-4-yl}quinolin- 4-yl]piperidin-4-amine; 2-189: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-cyanophenyl}-3- methoxyurea; 2-190: 3-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-2-hydroxybenzonitrile; 2-191: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin- 6-yl]-6-cyano-3,4-difluorophenyl}-3-methoxy-3-methylurea; 2-192: 1-(6-{5-chloro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-(3,5-difluorophenyl)quinolin-4- yl)piperidin-4-amine; 2-193: 3-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile; 2-194: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2- (methoxymethoxy)benzonitrile; 2-195: 1-[3-(3,5-difluorophenyl)-6-{3-[(hydroxyimino)methyl]pyridin-2-yl}quinolin-4-yl]piperidin- 4-amine; 2-196: 1-[3-(3,5-difluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-3-yl}quinolin-4-yl]piperidin- 4-amine; 2-197: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}carbamate; 2-198: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3-methoxy-3-methylurea; 2-199: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3,3-dimethylurea; 2-200: 1-[3-(3,5-difluorophenyl)-6-{6-[(hydroxyimino)methyl]pyridin-2-yl}quinolin-4-yl]piperidin- 4-amine; 2-201: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenyl methyl carbonate; 2-202: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]-6-methylphenyl}quinolin-4- yl]piperidin-4-amine; 2-203: 1-[3-(3,5-difluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-4-yl}quinolin-4-yl]piperidin- 4-amine; 2-204: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-(2- methoxyethoxy)benzonitrile; 2-205: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-cyano- 3,4-difluorophenyl}carbamate; 2-206: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-cyano-3,4- difluorophenyl}-3-methoxy-3-methylurea; 2-207: 1-(2-{4-[cis-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}- 4,6-difluorophenyl)-3-methoxyurea; 2-208: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-cyano-3,4- difluorophenyl}-3-methylurea; 2-209: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6- fluorophenyl}carbamate; 2-210: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-fluorophenyl}- 3-methoxy-3-methylurea; 2-211: 1-[6-(3-amino-1-methyl-1H-pyrazol-4-yl)-3-(3-fluoro-5-methylphenyl)quinolin-4- yl]piperidin-4-amine; 2-212: 1-{4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-1-methyl-1H- pyrazol-3-yl}-3-methoxyurea; 2-213: 4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2- [(methoxyimino)methyl]phenol; 2-214: methyl N-{4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-1-methyl- 1H-pyrazol-3-yl}carbamate; 2-215: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-methylpyridin- 2-yl}-3-methoxyurea; 2-216: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3-(propan-2-yloxy)urea; 2-217: trans-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methylphenyl)quinolin- 4-yl)-3-methoxypiperidin-4-amine; 2-218: methyl N-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5- methylphenyl)quinolin-6-yl}-6-cyanophenyl)carbamate; 2-219: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5- fluoro-2-hydroxybenzonitrile; 2-220: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5- fluoro-2-(2-methoxyethoxy)benzonitrile; 2-221: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin- 6-yl}-6-[(methoxyimino)methyl]phenol; 2-222: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-cyanophenyl}- 3-methoxyurea; 2-223: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluorophenyl}- 3-methoxyurea; 2-224: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-2-(2- methoxyethoxy)benzonitrile; 2-225: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(2- methoxyethoxy)benzonitrile; 2-226: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]pyridin-2-yl}-3- methoxyurea; 2-227: cis-4-amino-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5- methylphenyl)quinolin-4-yl)piperidin-3-ol; 2-228: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3-ethoxyurea; 2-229: 1-[3-(3-fluoro-5-methylphenyl)-6-{3-[(2-methoxyethyl)amino]-1-methyl-1H-pyrazol-4- yl}quinolin-4-yl]piperidin-4-amine; 2-230: N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-2-methoxyacetamide; 2-231: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2- (cyanomethoxy)benzonitrile; 2-232: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-5-fluoro-2- (2-methoxyethoxy)benzonitrile; 2-233: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6- difluorophenyl}-3-(2,2,2-trifluoroethoxy)urea; 2-234: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-N-(2- methoxyethyl)pyridin-2-amine; 2-235: methyl N-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5- methylphenyl)quinolin-6-yl}-4,6-difluorophenyl)carbamate; 2-236: 1-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}- 4,6-difluorophenyl)-3-methoxyurea; 2-237: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-cyano-6- fluorophenyl}-3-methoxyurea; 2-238: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-cyanophenyl}-3- (2,2,2-trifluoroethoxy)urea; 2-239: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-methylpyridin- 2-yl}-3-methoxyurea; 2-240: 1-{4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]phenyl}-3- methoxyurea; 2-241: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-bromo-3,4- difluorophenol; 2-242: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-[(2- methoxyethyl)amino]pyridine-3-carbonitrile; 2-243: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 6-[(1E)-(methoxyimino)methyl]phenol; 2-244: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-aminopyridine-3-carbonitrile; 2-245: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 1-methyl-1H-pyrazol-3-amine; 2-246: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridin-2-amine; 2-247: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-methylpyridin-3-amine; 2-248: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridin-2-ol; 2-249: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 1-methyl-1H-pyrazol-5-amine; 2-250: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-methylpyridin-3-amine; 2-251: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 3-hydroxypyridine-4-carbonitrile; 2-252: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-[(2-methoxyethyl)amino]pyridine-3-carbonitrile; 2-253: N-[(4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-1-methyl-1H-pyrazol-5-yl)methylidene]hydroxylamine 2-254: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-hydroxypyridine-3-carbonitrile; 2-255: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyrimidin-5-amine; 2-256: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-fluoropyridin-4-ol; 2-257: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 1-methyl-1H-pyrazole-3-carboxamide; 2-258: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-methylpyridin-3-ol; 2-259: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-fluoropyridin-2-ol; 2-260: N-[(4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-1-methyl-1H-pyrazol-3-yl)methylidene]hydroxylamine; 2-261: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 3-fluoropyridine-4-carbonitrile; 2-262: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 3-aminopyridine-4-carbonitrile; 2-263: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridin-3-ol; 2-264: N-[(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}pyridin-2-yl)methylidene]hydroxylamine; 2-265: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-fluoropyridin-3-amine; 2-266: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-[(methoxyimino)methyl]pyridin-4-amine; 2-267: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-cyclopropylpyridin-4-amine; 2-268: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 1-(oxetan-3-yl)-1H-pyrazol-5-amine; 2-269: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-[(methoxyimino)methyl]pyridin-3-amine; 2-270: 3-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6-yl]-2- hydroxybenzonitrile; 2-271: 3-[3-(3,5-difluorophenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6-yl]-2- hydroxybenzonitrile; 2-272: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-(prop-1-yn-1-yl)pyridin-4-amine; 2-273: 1-(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridin-2-yl)-3-methoxyurea; 2-274: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 5-ethynylpyridin-4-amine; 2-275: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-chloropyridin-3-amine; 2-276: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-cyclopropylpyridin-3-amine; 2-277: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-ethynylpyridin-3-amine; 2-278: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 6-(oxetan-3-yl)phenol; 2-279: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 6-(oxetan-2-yl)phenol; 2-280: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-(oxetan-3-yl)pyridin-3-amine; 2-281: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-(oxetan-2-yl)pyridin-3-amine; 2-282: 3-amino-2-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6- yl]pyridine-4-carbonitrile; 2-283: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6- yl}pyridin-3-amine; 2-284: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}- 4-methoxypyridin-3-amine; 2-285: 2-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-6-[(methoxyimino)methyl]phenol; 2-286: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-6-[(methoxyimino)methyl]phenol; 2-287: 2-{4-[(4aR,8aR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; 2-288: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; 2-289: 2-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-3-aminopyridine-4-carbonitrile; 2-290: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-3-aminopyridine-4-carbonitrile; 2-291: (5-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-4-aminopyridin-3-carbonitrile; 2-292: (5-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-4-aminopyridin-3-carbonitrile; 2-293: 3-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}pyridin-2-amine; 2-294: 3-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}pyridin-2-amine; 2-295: 2-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-4-methylpyridin-3-amine; 2-296: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-4-methylpyridin-3-amine; 2-297: 2-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-4-methylpyridin-3-ol; 2-298: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-4-methylpyridin-3-ol; 2-299: 3-{4-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5- difluorophenyl)quinolin-6-yl}-5-fluoro-2-hydroxybenzonitrile; 2-300: 3-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-5-fluoro-2-hydroxybenzonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0057] In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)-1,5-naphthyridine, 3-{4-[octahydro-1H-pyrido[3,4-b]morpholin-6- yl]-3-(phenyl)-1,5-naphthyridine, or 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)-1,5- naphthyridine compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3-(phenyl)-1,5-naphthyridine, 3-{4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-3-(phenyl)-1,5-naphthyridine, or 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)- 1,5-naphthyridine compound, wherein the phenyl is substituted with Ra and/or Rb, Ra is -F or -C1; and Rb is -F or -CH3. [0058] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000044_0002
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: O O
Figure imgf000044_0001
Ra is -F or -C1; and Rb is -F or -CH3. [0059] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5- fluorobenzamide; 3-2: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2- hydroxybenzonitrile; 3-3: 4-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-6-fluoro-2,3- dihydro-1H-1,3-benzodiazol-2-one; 3-4: 5-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-2,3-dihydro- 1H-1,3-benzodiazol-2-one; 3-5: 6-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-4-fluoro-2,3- dihydro-1H-1,3-benzodiazol-2-one; 3-6: 3-[8-(4-aminopiperidin-1-yl)-7-(3-chloro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2- hydroxybenzonitrile; 3-7: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-2- hydroxybenzonitrile; 3-8: 2-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-6- fluorophenol. 3-9: 6-[8-(4-aminopiperidin-1-yl)-7-(3,5-difluorophenyl)-1,5-naphthyridin-2-yl]-4-fluoro-2,3- dihydro-1H-1,3-benzodiazol-2-one; 3-10: 6-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5-difluorophenyl)-1,5- naphthyridin-2-yl}-4-fluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one; 3-11: 4-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3-fluoro-5-methylphenyl)-1,5- naphthyridin-2-yl}-6-fluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one; 3-12: 4-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5-difluorophenyl)-1,5- naphthyridin-2-yl}-1H,2H,3H-imidazo[4,5-c]pyridin-2-one or a pharmaceutically acceptable salt, or solvate thereof. [0060] In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4- aminopiperidin-1-yl)-3-(phenyl)-1,8-naphthyridine, 3-{4-[octahydro-1H-pyrido[3,4-b]morpholin-6- yl]-3-(phenyl)-1,8-naphthyridine, or 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)-1,8- naphthyridine compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[4-(4-aminopiperidin-1-yl)-3-(phenyl)-1,8-naphthyridine, 3-{4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-3-(phenyl)-1,8-naphthyridine, or 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(phenyl)- 1,8-naphthyridine compound, wherein the phenyl is substituted with Ra and/or Rb, Ra is -F or -C1; and Rb is -F, -C1, -CH3, or -OCH3. [0061] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000046_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000046_0002
Ra is -F or -C1; and Rb is -F, -C1, -CH3, or -OCH3. [0062] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-[5-(4-aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2- hydroxybenzonitrile; 4-2: 3-[5-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-2- hydroxybenzonitrile; 4-3: 3-[5-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-5-fluoro-2- hydroxybenzonitrile; 4-4: 3-[5-(4-aminopiperidin-1-yl)-6-(3-chloro-5-methylphenyl)-1,8-naphthyridin-3-yl]-2- hydroxybenzonitrile; 4-5: 3-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)-1,8- naphthyridin-3-yl}-2-hydroxybenzonitrile; 4-6: 3-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)-1,8- naphthyridin-3-yl}-2-hydroxybenzonitrile; 4-7: 3-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)-1,8- naphthyridin-3-yl}-5-fluoro-2-hydroxybenzonitrile; 4-8: 3-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)-1,8- naphthyridin-3-yl}-5-fluoro-2-hydroxybenzonitrile; 4-9: 3-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-5-fluoro-2-hydroxybenzonitrile; 4-10: 3-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-5-fluoro-2-hydroxybenzonitrile; 4-11: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-12: 2-{5-[(4aS,8aS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-methylphenyl)-1,8- naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-13: 5-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-4-aminopyridine-3-carbonitrile; 4-14: 5-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-4-aminopyridine-3-carbonitrile; 4-15: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-16: 2-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-17: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-fluorophenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-18: 2-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-fluorophenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-19: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-20: 2-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-3-aminopyridine-4-carbonitrile; 4-21: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; 4-22: 2-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5-difluorophenyl)-1,8- naphthyridin-3-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; 4-23: 2-{5-[(4 αR,8 αR)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; 4-24: 2-{5-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl)- 1,8-naphthyridin-3-yl}-4-[(methoxyimino)methyl]pyridin-3-amine; or a pharmaceutically acceptable salt, or solvate thereof. [0063] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2018/170284. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) of International Patent Application Publication Number WO 2018/170284. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (II), or (III) of International Patent Application Publication Number WO 2018/170284. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, or Table 4 of International Patent Application Publication Number WO 2018/170284. [0064] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-2-amine or 4-(4-aminopiperidin-1- yl)-3-(indol-2-yl)-5-(phenyl)pyridin-2-amine compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5- (phenyl)pyridin-2-amine or 4-(4-aminopiperidin-1-yl)-3-(indol-2-yl)-5-(phenyl)pyridin-2-amine compound, wherein the phenyl is substituted with R8 and/or R9 , R8 is -F, -C1, -CN, or -CH3; and R9 is hydrogen, -F, -C1, -CH3, or -OCH3. [0065] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000048_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000048_0002
Figure imgf000049_0001
,
Figure imgf000050_0001
R13 is hydrogen, -CN, or -OCH3; R2 is hydrogen, -CH3, -CH2CH3, or -CH2CH2OCH3; R8 is -F, -C1, -CN, or -CH3; and R9 is hydrogen, -F, -C1, -CH3, or -OCH3. [0066] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-2: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-3: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-4: 4-(4-aminopiperidin-1-yl)-3-(1-ethenyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-5: 4-(4-aminopiperidin-1-yl)-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-6: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-7: 4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-8: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(5-methoxy-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-9: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1H-1,3- benzodiazole-5-sulfonamide; 1-10: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methyl-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-11: 4-(4-aminopiperidin-1-yl)-3-(7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-12: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1H-1,3- benzodiazole-5-carbonitrile; 1-13: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-14: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(trifluoromethoxy)-1H-1,3- benzodiazol-2-yl]pyridin-2-amine; 1-15: 4-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amineine; 1-16: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(oxetan-3-yloxy)-1H-1,3- benzodiazol-2-yl]pyridin-2-amine; 1-17: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy- 1H-1,3-benzodiazole-7-carboxamide; 1-18: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy-N- methyl-1H-1,3-benzodiazole-7-carboxamide; 1-19: 4-(4-aminopiperidin-1-yl)-3-(5-cyclobutoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-20: 4-(4-aminopiperidin-1-yl)-3-(5-cyclopropoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-21: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1H-1,3- benzodiazole-7-carbonitrile; 1-22: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-[(hydroxyimino)methyl]-1H-1,3- benzodiazol-2-yl}pyridin-2-amine; 1-23: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy- 1H-1,3-benzodiazole-5-carboxamide; 1-24: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy-N- methyl-1H-1,3-benzodiazole-5-carboxamide; 1-25: 3-[6-amino-4-(4-aminopiperidin-1-yl)-5-(5-chloro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-5- methylbenzonitrile; 1-26: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(3-fluoroazetidin-1-yl)-1H-1,3- benzodiazol-2-yl]pyridin-2-amine; 1-27: methyl N-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]- 1H-1,3-benzodiazol-7-yl}carbamate; 1-28: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)- N-methylpyridin-2-amine; 1-29: 4-(4-aminopiperidin-1-yl)-3-(6-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-30: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-31: 4-(4-aminopiperidin-1-yl)-3-{5,5-difluoro-4,6-dioxa-10,12-diazatricyclo[7.3.0.0³,⁷]dodeca- 1,3(7),8,10-tetraen-11-yl}-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 1-32: 3-[6-amino-4-(4-aminopiperidin-1-yl)-5-(5-chloro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-5- fluorobenzonitrile; 1-33: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1H-indole-6- carbonitrile; 1-34: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[(propan-2- yloxy)imino]methyl]pyridin-2-amine; 1-35: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3-fluoro-5-methylphenyl)pyridin- 2-amine; 1-36: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3,5-dimethylphenyl)pyridin-2- amine; 1-37: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(propan-2- yloxy)imino]methyl]pyridin-2-amine; 1-38: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3-chloro-5-methylphenyl)pyridin- 2-amine; 1-39: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(hydroxyimino)methyl]pyridin-2- amine; 1-40: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5-[(methoxyimino)methyl]-1H-1,3- benzodiazol-2-yl}pyridin-2-amine; 1-41: trans-4-amino-1-[2-amino-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5- dimethylphenyl)pyridin-4-yl]piperidine-3-carbonitrile; 1-42: trans-4-amino-1-[2-amino-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-4-yl]piperidine-3-carbonitrile; 1-43: 4-(4-aminopiperidin-1-yl)-3-[5-(azetidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-44: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{4-[(methoxyimino)methyl]-1H-1,3- benzodiazol-2-yl}pyridin-2-amine; 1-45: methyl N-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]- 1H-1,3-benzodiazol-5-yl}carbamate; 1-46: 1-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1H-1,3- benzodiazol-5-yl}-3-methoxyurea; 1-47: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5-[(hydroxyimino)methyl]-1H-1,3- benzodiazol-2-yl}pyridin-2-amine; 1-48: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N-methylpyridin-2-amine; 1-49: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-50: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-51: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1H-imidazo[4,5-c]pyridin-2- yl}pyridin-2-amine; 1-52: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1H-imidazo[4,5-b]pyridin-2- yl}pyridin-2-amine; 1-53: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(5-methanesulfonyl-1H-1,3- benzodiazol-2-yl)pyridin-2-amine; 1-54: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-55: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N-methylpyridin-2-amine; 1-56: 3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-(2-methoxyethyl)-4- (4-methylpiperidin-1-yl)pyridin-2-amine; 1-57: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-58: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-59: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(4-fluoro-6-methoxy-1H-1,3- benzodiazol-2-yl)pyridin-2-amine. 1-60: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-fluoro- 1H-1,3-benzodiazol-6-yl}oxy)acetonitrile; 1-61: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-fluoro-5- [(methoxyimino)methyl]-1H-1,3-benzodiazol-2-yl}pyridin-2-amine; 1-62: 4-(4-aminopiperidin-1-yl)-3-{6-fluoro-4-[(hydroxyimino)methyl]-1H-1,3-benzodiazol-2-yl}-5- (3-fluoro-5-methylphenyl)pyridin-2-amine; 1-63：4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{4-[(hydroxyimino)methyl]-1H- imidazo[4,5-c]pyridin-2-yl}pyridin-2-amine； 1-64：4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-[(hydroxyimino)methyl]-3H- imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine； 1-65: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-66: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-67: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methoxyphenyl)pyridin-2-amine; 1-68: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methoxyphenyl)pyridin-2-amine; 1-69: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-7-fluoro-1H- 1,3-benzodiazole-5-carbonitrile; 1-70: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridin-3-yl]-1H- 1,3-benzodiazole-6-carbonitrile; 1-71: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-1,3-benzodiazol-2- yl)-N-methylpyridin-2-amine; 1-72: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)- N-methylpyridin-2-amine; 1-73: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-74: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-5-fluoro- 1H-1,3-benzodiazol-7-yl}oxy)acetonitrile; 1-75: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N-methylpyridin-2-amine; 1-76: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-methoxy-5- [(methoxyimino)methyl]-1H-1,3-benzodiazol-2-yl}pyridin-2-amine; 1-77: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-78: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5- dimethylphenyl)pyridin-2-amine; 1-79: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-80: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methoxy-5- methylphenyl)pyridin-2-amine; 1-81: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5- difluorophenyl)pyridin-2-amine; 1-82: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5- difluorophenyl)pyridin-2-amine; 1-83: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol- 2-yl)pyridin-2-amine; 1-84: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol- 2-yl)pyridin-2-amine; 1-85: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-7-fluoro-1H- 1,3-benzodiazole-5-carbonitrile; 1-86: 4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-3-[5-(trifluoromethoxy)-1H-1,3-benzodiazol- 2-yl]pyridin-2-amine; 1-87: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-5-fluoro- 1H-1,3-benzodiazol-7-yl}oxy)acetonitrile; 1-88: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-7-fluoro- 1H-1,3-benzodiazol-5-yl}oxy)acetonitrile; 1-89: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridin-3-yl]-7- fluoro-1H-1,3-benzodiazole-5-carbonitrile; 1-90: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5-fluoro-7-methoxy-1H-1,3- benzodiazol-2-yl)pyridin-2-amine; 1-91: 4-(4-aminopiperidin-1-yl)-5-(4-fluoro-3-methylphenyl)-3-(5-fluoro-7-methoxy-1H-1,3- benzodiazol-2-yl)pyridin-2-amine; 1-92: 4-(4-aminopiperidin-1-yl)-5-(3-chlorophenyl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2- yl)pyridin-2-amine; 1-93: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3- methylphenyl)pyridin-2-amine; 1-94: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-amine; or a pharmaceutically acceptable salt, or solvate thereof. [0067] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000056_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000056_0002
R1 is -C1, -OH, or -OCH3; R8 is -F, -C1, or -CN; and R9 is -F or -CH3. [0068] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-2: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-3: 1-[5-(3-fluoro-5-methylphenyl)-2-methoxy-3-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]piperidin-4-amine; 2-4: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-ol; 2-5: 1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-6: 3-[4-(4-aminopiperidin-1-yl)-5-(5-chloro-1H-1,3-benzodiazol-2-yl)-6-methoxypyridin-3-yl]-5- methylbenzonitrile; 2-7: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-ol; 2-8: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-3-yl]-1H-1,3- benzodiazole-5-carbonitrile; 2-9: 1-(3-{6-chloro-3H-imidazo[4,5-c]pyridin-2-yl}-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin- 4-yl)piperidin-4-amine; 2-10: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-2-ol; 2-11: 1-[2-chloro-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]piperidin-4-amine; 2-12: 1-{3-[(1E)-[(tert-butoxy)imino]methyl]-5-(3-chloro-5-methylphenyl)-2-methoxypyridin-4- yl}piperidin-4-amine; 2-13: 1-(3-{5-chloro-1H-imidazo[4,5-b]pyridin-2-yl}-5-(3-fluoro-5-methylphenyl)-2- methoxypyridin-4-yl)piperidin-4-amine; 2-14: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)-2-methoxypyridin-4- yl]piperidin-4-amine; 2-15: 1-[3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2- methylpyridin-4-yl]piperidin-4-amine; or a pharmaceutically acceptable salt, or solvate thereof. [0069] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridazine or 4-(4-aminopiperidin-1-yl)-3- (indol-2-yl)-5-(phenyl) pyridazine compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(phenyl) pyridazine amine or 4-(4-aminopiperidin-1-yl)-3-(indol-2-yl)-5-(phenyl) pyridazine compound, wherein the phenyl is substituted with R8 and/or R9 , R8 is -F, -C1, -CN, or -CH3; and R9 is hydrogen, -F, -C1, -CH3, or -OCH3. [0070] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000057_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000058_0001
R13 is hydrogen or -OCH3; R8 is -F; and R9 is -CH3. [0071] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 1-[3-(5-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-2: 1-[3-(6-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-3: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4- amine; 3-4: 1-[3-(6-fluoro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-5: 1-[5-(3-fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin-4-amine; 3-6: 1-[3-(4-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-7: 1-[3-(7-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-8: 1-[3-(5-fluoro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-amine; 3-9: 1-[5-(3-fluoro-5-methylphenyl)-3-(5-methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin-4-amine; 3-10: 1-[5-(3-fluoro-5-methylphenyl)-3-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridazin-4- yl]piperidin-4-amine; 3-11: trans-1-[3-(6-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]-3- methoxypiperidin-4-amine; 3-12: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-6- carbonitrile; 3-13: 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin- 4-amine; 3-14: 1-[3-(3,6-dichloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4- amine; 3-15: 1-[5-(3-fluoro-5-methylphenyl)-3-[6-(2H-1,2,3,4-tetrazol-5-yl)-1H-indol-2-yl]pyridazin-4- yl]piperidin-4-amine; 3-16: 1-[5-(3-fluoro-5-methylphenyl)-3-(6-methyl-1H-indol-2-yl)pyridazin-4-yl]piperidin-4-amine; 3-17: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-5- carbonitrile; 3-18: methyl 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-6- carboxylate; 3-19: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-6- carboxamide; 3-20: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-N-methoxy-1H- indole-6-carboxamide; 3-21: 1-[3-(3-chloro-6-methoxy-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin- 4-amine; 3-22: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-1,3- benzodiazole-5-carbonitrile; 3-23: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-7- carbonitrile; 3-24: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-3-chloro-1H-indole- 6-carbonitrile; 3-25: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-6-methoxy-1H- indole-3-carbonitrile; 3-26: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-1H-indole-3,6- dicarbonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0072] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000060_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: Ra is o R1 is
Figure imgf000060_0002
R11 is hydrogen or -CH3; R8 is -F; and R9 is hydrogen or -CH3. [0073] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methyl-4-[4- (methylamino)piperidin-1-yl]pyridin-2-amine; 4-2: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1-yl]pyridin-3-yl]-1H- 1,3-benzodiazole-6-carbonitrile; 4-3: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1-yl]pyridin-3-yl]-7- fluoro-1H-1,3-benzodiazole-5-carbonitrile; 4-4: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-1,3-benzodiazol-2-yl)- N,N-dimethylpyridin-2-amine; 4-5: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N,N-dimethylpyridin-2-amine; 4-6: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N,N-dimethylpyridin-2-amine; 4-7: 1-[3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(3- fluoroazetidin-1-yl)pyridin-4-yl]piperidin-4-amine; 4-8: 1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(morpholin-4- yl)pyridin-4-yl]piperidin-4-amine; 4-9: 1-[3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-2-(3-fluoroazetidin-1-yl)-5-(3- fluorophenyl)pyridin-4-yl]piperidin-4-amine; 4-10: 3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-[4- (methylamino)piperidin-1-yl]pyridin-2-amine; 4-11: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1- yl)pyridin-4-yl]piperidin-4-amine; 3286: 3-(6-amino-5-(5-fluoro-7-methoxy-1H-benzo[d]imidazol-2-yl)-4-(4-(methylamino)piperidin-1- yl)pyridin-3-yl)-5-fluorobenzonitrile; 3063: 3-(6-amino-5-(4-methoxy-1H-benzo[d]imidazol-2-yl)-4-((4aS,8aS)-octahydro-6H-pyrido[3,4- b][1,4]oxazin-6-yl)pyridin-3-yl)-5-fluorobenzonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0074] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 10,696,689. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), (IIIb), (IIIc), or (IIId), of US Patent Number 10,696,689. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, or Table 3 of US Patent Number 10,696,689. [0075] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-3-(1,3-benzodiazol-2-yl)-5-(3-phenyl)pyridin-2-amine compound. [0076] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000061_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R2 is hydrogen or -CH3; R3 is hydrogen or -CH3; R8 is -F; and R9 is -C1 or -CH3. [0077] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H- 1,3-benzodiazole-6-carbonitrile; 1-2: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-4-methoxy-1H- 1,3-benzodiazole-6-carbonitrile; 1-3: 2-[4-(4-aminopiperidin-1-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4- methoxy-1H-1,3-benzodiazole-6-carbonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0078] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000062_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein: R1 is -CN, -CO2CH3, -CONH2, or -CONHCH3. [0079] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: methyl 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro- 5-methylphenyl)pyridine-2-carboxylate; 2-2: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridine-2-carbonitrile; 2-3: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridine-2-carboxamide; 2-4: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)-N-methylpyridine-2-carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [0080] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[(4 αS,8 αS)- octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-2-amine compound. [0081] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000063_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000063_0002
R2 is hydrogen or -CH3; R8 is -F or -C1; and R9 is hydrogen, -F, -CH3, or -OCH3. [0082] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 3-2: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3,5-difluorophenyl)pyridin-2-amine; 3-3: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluorophenyl)pyridin-2-amine; 3-4: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-2-amine; 3-5: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluoro-5-methoxyphenyl)-N-methylpyridin-2-amine; 3-6: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3,5-difluorophenyl)-N-methylpyridin-2-amine; 3-7: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(4,6- difluoro-1H-1,3-benzodiazol-2-yl)pyridin-2-amine; 3-8: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol- 2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-2-amine; 3-9: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3- benzodiazol-2-yl)-5-(3-fluorophenyl)pyridin-2-amine: 3-10: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3- benzodiazol-2-yl)-5-(3-fluorophenyl)-N-methylpyridin-2-amine; 3-11: 2-{4-[(4 αS, ^ αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3- fluorophenyl)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile; 3-12: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-fluorophenyl)-2- (methylamino)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile; 3-13: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(6- fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-N-methylpyridin-2-amine; 3-14: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 3-15: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methylpyridin-2-amine; 3-16: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 3-17: 4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(6- fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-2-amine; 3-18: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3,5- difluorophenyl)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile; 3-19: 2-{4-[(4 αS,8 αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3,5- difluorophenyl)pyridin-3-yl}-4-fluoro-1H-1,3-benzodiazole-6-carbonitrile; or a pharmaceutically acceptable salt, or solvate thereof. SSTR5-Selective Agonists [0083] In some embodiments, described herein are non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is selective for SSTR5. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/157458, International Patent Application Number PCT/US2020/045610 or related applications or application publications. [0084] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Publication Number WO 2019/157458. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (II), (IIa), (III), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (V), of International Patent Application Publication Number WO 2019/157458. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (I), (II), (IIa), (IV), (IVb), or (IVc) of International Patent Application Publication Number WO 2019/157458. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Table 1 or Table 2 of International Patent Application Publication Number WO 2019/157458. [0085] In some embodiments, the non-peptidic small molecule SSTR agonist is a 1-{1-[3-(1,3- benzodiazol-2-yl)-5-(phenyl)pyridin-4-yl]azetidin-3-yl}methanamine compound. [0086] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000065_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000065_0002
,
Figure imgf000066_0001
R3 is hydrogen, -CH3, -CH2CH3, or -CH2OH; and R5 is hydrogen, -F, -OH, or -CH3. [0087] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 1-{1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-2: 1-{1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-3: 1-{1-[3-(4-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-4: 1-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-5: 2-{4-[3-(aminomethyl)azetidin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-3-yl}-1H-1,3- benzodiazole-4-carbonitrile; 1-6: 1-{1-[3-(4,5-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-7: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-8: 2-{4-[3-(aminomethyl)azetidin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-3-yl}-1H-1,3- benzodiazole-5-carbonitrile; 1-9: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]azetidin- 3-yl}methanamine; 1-10: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-(5-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]azetidin- 3-yl}methanamine; 1-11: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-(4-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-12: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-13: 1-{1-[3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-14: 1-{1-[3-(5-chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-15: 1-{1-[3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-16: 2-{4-[3-(aminomethyl)azetidin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-3-yl}-4-fluoro-1H- 1,3-benzodiazole-6-carbonitrile; 1-17: 2-{4-[3-(aminomethyl)azetidin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-3-yl}-6-fluoro-1H- 1,3-benzodiazole-5-carbonitrile; 1-18: 1-{1-[3-(6-chloro-4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-19: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-dimethylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-20: 1-{1-[3-(3-chloro-5-methylphenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-21: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-22: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-{3H-imidazo[4,5-c]pyridin-2-yl}pyridin-4-yl]azetidin-3- yl}methanamine; 1-23: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-{1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4-yl]azetidin-3- yl}methanamine; 1-24: 1-{1-[3-(4-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-25: 1-{1-[3-(7-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-26: 3-(aminomethyl)-1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-4-yl]azetidin-3-ol; 1-27: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-phenylpyridin-4-yl]azetidin-3- yl}methanamine; 1-28: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluorophenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-29: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-30: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(2-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-31: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(4-methylphenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-32: 1-{1-[5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5'-methyl-[3,3'-bipyridin]-4-yl]azetidin-3- yl}methanamine; 1-33: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-[3-methyl-5-(trifluoromethyl)phenyl]pyridin- 4-yl]azetidin-3-yl}methanamine; 1-34: 3-{4-[3-(aminomethyl)azetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 1-35: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(1H-indol-6-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-36: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(1H-indol-7-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-37: 1-{1-[3-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-38: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-39: 1-{1-[3-(3-chloro-5-fluorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-40: 1-(1-{3-[3-chloro-5-(trifluoromethyl)phenyl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl}azetidin-3-yl)methanamine; 1-41: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(naphthalen-2-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-42: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; 1-43: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(4-fluorophenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-44: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(2-fluorophenyl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-45: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(2-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-46: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(5-fluoro-2-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-47: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(4-fluoro-3-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-48: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,4,5-trifluorophenyl)pyridin-4-yl]azetidin- 3-yl}methanamine; 1-49: 2-amino-2-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin- 4-yl]azetidin-3-yl}ethan-1-ol; 1-50: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-3- methylazetidin-3-yl}methanamine; 1-51: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]azetidin-3-yl}propan-1-amine; 1-52: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(naphthalen-1-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-53: 1-{1-[3-(3-chlorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-54: 3-{4-[3-(aminomethyl)azetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 1-55: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-4-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-56: 1-{1-[3-(3-fluoro-5-methylphenyl)-5-(1H-imidazol-2-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-57: 1-{1-[3-(3-chloro-2-fluorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine 1-58: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-59: 1-{1-[3-(3-chloro-5-methoxyphenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-60: 1-{1-[3-(3,5-dichlorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]azetidin-3- yl}methanamine; 1-61: 1-{1-[3-(3-chloro-5-fluorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; 1-62: 1-{1-[3-(3-chloro-5-fluorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]-3- fluoroazetidin-3-yl}methanamine; 1-63: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-[3-fluoro-5-(trifluoromethyl)phenyl]pyridin- 4-yl]azetidin-3-yl}ethan-1-amine; 1-64: 3-{4-[3-(1-aminoethyl)azetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 1-65: 5-{4-[3-(1-aminoethyl)azetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 1-66: 1-{1-[3-(3-chloro-2-methylphenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-67: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(2-fluoro-3-methylphenyl)pyridin-4- yl]azetidin-3-yl}methanamine; 1-68: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluorophenyl)pyridin-4-yl]-3- methylazetidin-3-yl}ethan-1-amine; 1-69: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-[3-(trifluoromethyl)phenyl]pyridin-4-yl]-3- methylazetidin-3-yl}ethan-1-amine; 1-70: 3-{4-[3-(1-aminoethyl)-3-methylazetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzonitrile; 1-71: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-[3-fluoro-5-(trifluoromethyl)phenyl]pyridin- 4-yl]azetidin-3-yl}ethan-1-amine; 1-72: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(4-ethoxy-3-fluorophenyl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; 1-73: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-2-methoxyphenyl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; 1-74: 1-{1-[3-(2-chloro-3-fluorophenyl)-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; 1-75: 2-{4-[3-(1-aminoethyl)azetidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-6- fluorophenol; 1-76: 1-{1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(2-fluoro-3-methylphenyl)pyridin-4- yl]azetidin-3-yl}ethan-1-amine; or a pharmaceutically acceptable salt, or solvate thereof. [0088] In some embodiments, the non-peptidic small molecule SSTR agonist is a 1-[3-(1,3- benzodiazol-2-yl)-5-(phenyl)pyridin-4-yl]pyrrolidin-3-amine compound or a 1-[3-(1,3-benzodiazol- 2-yl)-5-(pyridinyl)pyridin-4-yl]pyrrolidin-3-amine compound. [0089] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000071_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
[0090] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-2: (3R)-1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-3: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-4: 1-[3-(3-chloro-5-fluorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-5: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- chlorobenzonitrile; 2-6: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-5- fluorobenzonitrile; 2-7: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-8: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-9: (3S)-1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-{3-fluoro-5- [(methoxyimino)methyl]phenyl}pyridin-4-yl]pyrrolidin-3-amine; 2-10: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-[3-(trifluoromethoxy)phenyl]pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-11: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methoxyphenyl)pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-12: (3S)-1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-{3-[(methoxyimino)methyl]phenyl}pyridin-4- yl]pyrrolidin-3-amine; 2-13: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl]benzonitrile; 2-14: 4'-(3-amino-3-methylpyrrolidin-1-yl)-5'-(4-fluoro-1H-1,3-benzodiazol-2-yl)-N,N-dimethyl- [3,3'-bipyridin]-6-amine; 2-15: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridin]-2'- amine; 2-16: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-[3-(1H-pyrazol-1-yl)phenyl]pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-17: 3-{3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl]phenyl}-1,3-oxazolidin-2-one; 2-18: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl]benzamide; 2-19: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-N- methylbenzamide; 2-20: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-5- fluorobenzamide; 2-21: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methanesulfonylphenyl)pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-22: 1-[3-(2,3-dihydro-1-benzofuran-6-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-23: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-24: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-25: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorophenol; 2-26: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}thiophene-2-carbonitrile; 2-27: 2-{3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 5-fluorophenoxy}acetonitrile; 2-28: 1-[3-(3-chlorophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin- 3-amine; 2-29: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(1H-indol-6-yl)pyridin-4-yl]-3-methylpyrrolidin-3- amine 2-30: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(1H-indol-5-yl)pyridin-4-yl]-3-methylpyrrolidin-3- amine; 2-31: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- N,N-dimethylbenzamide; 2-32: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2,6- difluorobenzonitrile; 2-33: 3-{4-[3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzonitrile; 2-34: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-35: 4-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-36: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- hydroxybenzonitrile; 2-37: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-38: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-39: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- chlorobenzonitrile; 2-40: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-6- fluorobenzonitrile; 2-41: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,5,6,7-tetrafluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-42: 4-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-43: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzamide; 2-44: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-45: 3-{4-[trans-3-amino-4-methoxypyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin- 3-yl}benzonitrile; 2-46: 3-{4-[cis-3-amino-4-methoxypyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-47: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-6- chlorobenzonitrile; 2-48: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- (trifluoromethyl)benzonitrile; 2-49: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- methylbenzonitrile; 2-50: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-3-yl}- 2-fluorobenzonitrile; 2-51: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-52: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,5-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-53: 1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-[3-(1H-imidazol-1-yl)phenyl]pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-54: 3-{4-[3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzonitrile; 2-55: 3-{4-[trans-3-amino-4-fluoropyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-56: 3-{4-[trans-3-amino-4-phenylpyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-57: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-bromo-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-58: (3S)-1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methanesulfonylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-59: (3S)-1-[3-(2,3-dihydro-1-benzofuran-6-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-60: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-[4-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]pyridin-3- yl}-2-fluorobenzonitrile; 2-61: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzamide; 2-62: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-63: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-64: 3-{4-[3-amino-3-(trifluoromethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzamide; 2-65: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzamide; 2-66: 3-{4-[(2R,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}-5-fluorobenzonitrile; 2-67: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-N-methyl-[3,4'- bipyridin]-2'-amine; 2-68: 3-{4-[cis-3-amino-4-hydroxypyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-69: trans-4-amino-1-[3-(3-cyanophenyl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidine-3-carboxamide; 2-70: 3-{4-[cis-3-amino-4-fluoropyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-71: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzamide; 2-72: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzamide; 2-73: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- methoxybenzamide; 2-74: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-75: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-76: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-77: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-78: 3-{4-[3-amino-3-(trifluoromethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}-5-fluorobenzonitrile; 2-79: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(6-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-80: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-81: 3-{4-[trans-3-amino-4-hydroxypyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-82: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)pyridin-3-yl}-1H-1,3-benzodiazole-4- carboxylic acid; 2-83: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)pyridin-3-yl}-1H-1,3-benzodiazole-4- carboxamide; 2-84: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-ethynyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-85: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzamide; 2-86: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(5-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-87: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-88: 3-{4-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}-5-fluorobenzonitrile; 2-89: 3-{4-[trans-3-amino-4-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzonitrile; 2-90: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)pyridin-3-yl}-N-methyl-1H-1,3- benzodiazole-4-carboxamide; 2-91: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-[4-(hydroxymethyl)-1H-1,3-benzodiazol-2-yl]pyridin-3- yl}benzonitrile; 2-92: (3S)-1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methanesulfonylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-93: (3S)-1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methanesulfonylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-94: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(6-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-95: (3S)-1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-chloro-5-fluorophenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-96: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzamide; 2-97: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzamide; 2-98: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- chlorobenzonitrile; 2-99: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,5-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-100: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-ethyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-101: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-102: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(5-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-103: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)pyridin-3-yl}-1H-1,3- benzodiazole-5-carbonitrile; 2-104: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-105: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]- 2'-carboxamide; 2-106: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carbonitrile; 2-107: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carboxamide; 2-108: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin- 3-yl]-5-fluorobenzonitrile; 2-109: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-110: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-111: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1-propyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-112: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]pyridin- 3-yl}-5-fluorobenzonitrile; 2-113: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-[1-(cyanomethyl)-1H-1,3-benzodiazol-2-yl]pyridin-3- yl}-5-fluorobenzonitrile; 2-114: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1,4-dimethyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-115: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1,7-dimethyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-116: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-117: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-118: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 5-fluorobenzamide; 2-119: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin- 3-yl]-2-fluorobenzonitrile; 2-120: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]-2- fluorobenzamide; 2-121: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]- 2'-carbonitrile; 2-122: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin- 3-yl]benzonitrile; 2-123: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]- 2'-carbonitrile; 2-124: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 2-fluorobenzamide; 2-125: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-3-yl]-2-fluorobenzamide; 2-126: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 2,3-difluorobenzoic acid; 2-127: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 2,3-difluorobenzamide; 2-128: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]-2'- carbonitrile; 2-129: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-indol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-130: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-6'-methyl-[3,4'- bipyridin]-2'-amine; 2-131: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-2-fluorobenzonitrile; 2-132: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1,4-dimethyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-133: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-2-fluorobenzonitrile; 2-134: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1,7-dimethyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2- fluorobenzonitrile; 2-135: 3-{4-[(3S)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}-5-fluorobenzonitrile; 2-136: 3-{4-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}-5-fluorobenzonitrile; 2-137: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(7-methyl-1H-indol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-138: 3-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl]- 2-fluorobenzamide; 2-139: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-2,3- difluorobenzonitrile; 2-140: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin- 3-yl]-2,3-difluorobenzonitrile; 2-141: (3S)-1-{3-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-4-yl}pyrrolidin-3-amine; 2-142: 5-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1-ethyl-4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-2-fluorobenzonitrile; 2-143: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1-ethyl-4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-144: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(1-ethyl-4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}-5-fluorobenzonitrile; 2-145: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carbonitrile; 2-146: (3S)-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-methylphenyl)pyridin-4-yl]pyrrolidin-3- amine; 2-147: 2-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-(3-cyano-4-fluorophenyl)pyridin-3-yl]-1H-1,3- benzodiazole-4-carbonitrile; 2-148: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-[4-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]-[3,4'- bipyridine]-2'-carbonitrile; 2-149: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{7-methyl-3H-imidazo[4,5-c]pyridin-2-yl}pyridin- 3-yl]-2-fluorobenzonitrile; 2-150: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)- [3,4'-bipyridine]-2'-carbonitrile; 2-151: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)- [3,4'-bipyridine]-2'-carbonitrile; 2-152: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(1,4-dimethyl-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carbonitrile; 2-153: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1-methyl-1H-1,3-benzodiazol-2- yl)pyridin-3-yl}benzonitrile; 2-154: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2-fluorobenzonitrile; 2-155: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}benzonitrile; 2-156: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carboxamide; 2-157: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]- 2'-carbonitrile; 2-158: 2-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyano-4-fluorophenyl)pyridin-3-yl}-1H-1,3- benzodiazole-4-carbonitrile; 2-159: 5-[4-(3-amino-3-methylpyrrolidin-1-yl)-5-{4-methyl-3H-imidazo[4,5-c]pyridin-2-yl}pyridin- 3-yl]-2-fluorobenzonitrile; 2-160: 4-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-cyano-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]- 2'-carbonitrile; 2-161: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-chloro-1H-1,3-benzodiazol-2-yl)-[3,4'-bipyridine]-2'- carbonitrile; 2-162: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carbonitrile; 2-163: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-1H-1,3-benzodiazol-2-yl)-[3,4'- bipyridine]-2'-carbonitrile; 2-164: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(5-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)- [3,4'-bipyridine]-2'-carbonitrile; 2-165: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2,3-difluorobenzonitrile; 2-166: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(6-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)- [3,4'-bipyridine]-2'-carbonitrile; 2-167: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{1H-imidazo[4,5-b]pyridin-2-yl}pyridin-3- yl}-2-fluorobenzonitrile; 2-168: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{6-fluoro-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2-fluorobenzonitrile; 2-169: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-5-fluorobenzamide; 2-170: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{6-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2-fluorobenzonitrile; 2-171: 2-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-4-fluorophenyl)pyridin-3-yl}-1H- 1,3-benzodiazole-7-carbonitrile; 2-172: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methoxy-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2-fluorobenzonitrile; 2-173: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{5,7-dimethyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}benzonitrile; 2-174: 5-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{5,7-dimethyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-2-fluorobenzonitrile; 2-175: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[7-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]- [3,4'-bipyridine]-2'-carbonitrile; 2-176: 2-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-4-fluorophenyl)pyridin-3-yl}-1H- imidazo[4,5-b]pyridine-7-carbonitrile; 2-177: 2-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyanophenyl)pyridin-3-yl}-1H-1,3- benzodiazole-7-carbonitrile; 2-178: (3S)-1-[5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-2'-methyl-[3,4'-bipyridin]-4-yl]-3- methylpyrrolidin-3-amine; 2-179: 2-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-4-methoxyphenyl)pyridin-3-yl}-1H- imidazo[4,5-b]pyridine-7-carbonitrile; 2-180: (3S)-1-[3-(3-chlorophenyl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-181: (3S)-1-[5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-2'-methyl-[3,4'-bipyridin]-4-yl]pyrrolidin-3- amine; 2-182: (3S)-1-[3-(3-fluoro-5-methylphenyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-183: (3S)-1-[3-(3-chloro-5-fluorophenyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-184: (3S)-1-[3-(3-fluoro-5-methoxyphenyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]pyrrolidin-3-amine; 2-185: (3S)-1-{3-[3-fluoro-5-(trifluoromethyl)phenyl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl}pyrrolidin-3-amine; 2-186: (3S)-1-[5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-2'-(trifluoromethyl)-[3,4'-bipyridin]-4-yl]-3- methylpyrrolidin-3-amine; 2-187: (3S)-1-[5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-2'-methoxy-[3,4'-bipyridin]-4-yl]-3- methylpyrrolidin-3-amine; 2-188: (3S)-1-[3-(4-fluoro-3-methylphenyl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-189: (3S)-1-[3-(4-fluoro-3-methoxyphenyl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-190: (3S)-1-[3-(3,4-difluorophenyl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4-yl]-3- methylpyrrolidin-3-amine; 2-191: (3S)-1-{3-[4-fluoro-3-(trifluoromethyl)phenyl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-4-yl}-3-methylpyrrolidin-3-amine; 2-192: (3S)-1-[3-(3-chloro-4-fluorophenyl)-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2-yl}pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-193: (3S)-1-[3-(4-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-194: 1-[3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-195: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-196: (3S)-1-[3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-197: (3S)-1-[3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]pyrrolidin-3-amine; 2-198: 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(6-chloro-1H-1,3-benzodiazol-2-yl)pyridin-3-yl}-5- fluorobenzonitrile; 2-199: (3R)-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-methylphenyl)pyridin-4-yl]pyrrolidin-3- amine; 2-200: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)pyridin-3- yl}benzonitrile; 2-201: (3S)-1-[3-(3,5-difluorophenyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]pyrrolidin- 3-amine; 2-202: 3-{4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{7-methyl-1H-imidazo[4,5-b]pyridin-2- yl}pyridin-3-yl}-5-fluorobenzonitrile; or a pharmaceutically acceptable salt, or solvate thereof. [0091] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in International Patent Application Number PCT/US2020/045610. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVa-1), (IVb-1), (IVa-2), (IVb-2), (IVa-3), (IVb-3), (IVa-4), (IVb-4), (IVa-5), (IVb-5), (V), (Va), (Vb), (Va-1), (Vb-1), (Va-2), (Vb-2), (Va-3), (Vb-3), (VI), (VIa), (VIb), (VIa-1), (VIb-1), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIa-1), (VIIIb-1), (IX), (IXa), (IXb), (IXa-1), (IXb-1), (X), (Xa), (Xb), (A1), or (A2) of International Patent Application Number PCT/US2020/045610. In some embodiments, the non- peptidic small molecule SSTR agonist is a compound described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7 of International Patent Application Number PCT/US2020/045610. [0092] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3- aminopyrrolidin-1-yl]-5-(phenyl)pyridine-3-carboxamide compound. In some embodiments, the non- peptidic small molecule SSTR agonist is a 1-[3-(1,3-benzodiazol-2-yl)-5-(phenyl)pyridin-4- yl]pyrrolidin-3-amine compound. [0093] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000086_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000087_0001
,
Figure imgf000088_0003
R3 is hydrogen, -CH3, -CH2OH, -CH2OCH3, or -CH2CHF2; R4 is hydrogen or -F; and Rc is hydrogen, -CN, -CH3, -CF3, -OCH3, -OCH2CH3, -OCH2CF3, -OCH2CHF2, -OCH2CH2OCH3, - OCH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CH2CO2CH2CH3, -OCH2CO2H, - OCH2CH2CO2H, -OCH2CH2CH2CO2H, cyclopropyl,
Figure imgf000088_0001
or
Figure imgf000088_0002
[0094] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-1: 4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-3: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-(3-chloro-5-fluorophenyl)-5-(3,5-dimethylphenyl)pyridine-3- carboxamide; 1-4: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-4-fluorophenyl)-N-(2- fluorophenyl)pyridine-3-carboxamide; 1-7: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)-N-cyclohexylpyridine-3-carboxamide; 1-8: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)-N-(1-methylcyclobutyl)pyridine-3- carboxamide; 1-9: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-benzyl-5-(3-cyanophenyl)pyridine-3-carboxamide; 1-10: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyanophenyl)-N-(4,4- difluorocyclohexyl)pyridine-3-carboxamide; 1-11: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-dimethylcyclohexyl)-5-(3,5- dimethylphenyl)pyridine-3-carboxamide; 1-12: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5- dimethylphenyl)pyridine-3-carboxamide; 1-13: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-14: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclohexyl)-5-(3,5- dimethylphenyl)pyridine-3-carboxamide; 1-15: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5-methylphenyl)-N-[1- (trifluoromethyl)cyclopentyl]pyridine-3-carboxamide; 1-16: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-17: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2,3-dihydro-1H-inden-1-yl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-18: N-(adamantan-2-yl)-4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-19: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-ethylcyclobutyl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-20: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,4,5- trifluorophenyl)pyridine-3-carboxamide; 1-21: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-22: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3,3- dimethylcyclobutyl)pyridine-3-carboxamide; 1-23: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-24: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropylethyl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-25: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-26: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-5-(3-fluoro-5- methylphenyl)pyridine-3-carboxamide; 1-27: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5-methylphenyl)-N-(1-methyl-1H- pyrazol-3-yl)pyridine-3-carboxamide; 1-28: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2,2- trifluoroethyl)pyridine-3-carboxamide; 1-29: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-tert-butyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-30: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-31: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(pentan-3-yl)pyridine-3- carboxamide; 1-32: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1- methylcyclopropyl)methyl]pyridine-3-carboxamide; 1-33: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclobutylmethyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-34: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1- methylcyclobutyl)pyridine-3-carboxamide; 1-35: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3,3- difluorocyclobutyl)pyridine-3-carboxamide; 1-37: 4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-38: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3-methylbutan-2- yl)pyridine-3-carboxamide; 1-39: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,4-dimethylpentan-3- yl)pyridine-3-carboxamide; 1-40: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-cyclopropylpropan-2-yl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-41: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-42: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(2,2-difluorocyclopropyl)methyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-43: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2,2- dimethylcyclopropyl)methyl]pyridine-3-carboxamide; 1-44: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1R)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-45: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1,1,1-trifluoro-3- methylbutan-2-yl)pyridine-3-carboxamide; 1-46: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-methylpropyl)pyridine- 3-carboxamide; 1-47: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1- fluorocyclobutyl)methyl]pyridine-3-carboxamide; 1-48: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(4,4-difluorocyclohexyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-49: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-50: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(3,3-difluorocyclobutyl)methyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-51: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-52: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[trans-2- fluorocyclohexyl]pyridine-3-carboxamide; 1-53: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2R)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-54: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-55: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(trans-3- fluorocyclobutyl]pyridine-3-carboxamide; 1-56: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclobutyl-2,2,2-trifluoroethyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-57: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-methylbutyl)pyridine-3- carboxamide; 1-58: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-ethylbutyl)pyridine-3- carboxamide; 1-59: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[cis-3- fluorocyclobutyl]pyridine-3-carboxamide; 1-60: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(4,4,4-trifluorobutan-2- yl)pyridine-3-carboxamide; 1-61: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N- (dicyclopropylmethyl)pyridine-3-carboxamide; 1-62: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2- difluoropropyl)pyridine-3-carboxamide; 1-64: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-65: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3- fluorophenyl)pyridine-3-carboxamide; 1-66: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,4- difluorophenyl)pyridine-3-carboxamide; 1-67: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(4,4-difluorocyclohexyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-68: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobutyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-69: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-70: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(dicyclopropylmethyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-71: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1-trifluoropropan- 2-yl]pyridine-3-carboxamide; 1-72: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(pentan-3-yl)pyridine-3- carboxamide; 1-73: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cycloheptyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-74: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)-6-methylpyridine-3-carboxamide; 1-76: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(pentan-3- yl)pyridine-3-carboxamide; 1-77: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-78: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclopentyl-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-79: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobutyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-80: 4-[(3S)-3-aminopyrrolidin-1-yl]-3-(3,5-difluorophenyl)-5-(piperidine-1-carbonyl)pyridine-2- carbonitrile; 1-81: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cyclohexyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-82: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cyclopentyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-83: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[cis-2- fluorocyclohexyl]pyridine-3-carboxamide; 1-84: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3-chlorophenyl)-6- cyanopyridine-3-carboxamide; 1-85: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(2- methylpropyl)pyridine-3-carboxamide; 1-86: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-87: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclobutyl-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-88: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(oxan-4- yl)pyridine-3-carboxamide; 1-89: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(oxan-3- yl)pyridine-3-carboxamide; 1-90: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3-chloro-5-fluorophenyl)-6- cyanopyridine-3-carboxamide; 1-91: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(propan-2- yl)pyridine-3-carboxamide; 1-92: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(2,2,2- trifluoroethyl)pyridine-3-carboxamide; 1-93: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclohexyl-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-94: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3-cyano-5- methoxyphenyl)pyridine-3-carboxamide; 1-95: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1-(pyridin-2- yl)ethyl]pyridine-3-carboxamide; 1-96: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(1S)-1- cyclopropylethyl]pyridine-3-carboxamide; 1-97: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1- phenylethyl]pyridine-3-carboxamide; 1-98: 4-[(3S)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-101: 4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-103: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1-(pyridin- 2-yl)ethyl]pyridine-3-carboxamide; 1-104: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1-methyl-1H- pyrazol-5-yl)methyl]pyridine-3-carboxamide; 1-105: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1-methyl-1H- pyrazol-3-yl)methyl]pyridine-3-carboxamide; 1-106: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1-methyl-1H- imidazol-2-yl)methyl]pyridine-3-carboxamide; 1-107: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1-methyl-1H- pyrazol-4-yl)methyl]pyridine-3-carboxamide; 1-108: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(pyrimidin-2- yl)methyl]pyridine-3-carboxamide; 1-109: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-benzylpiperazine-1-carbonyl)-3-(3,5- difluorophenyl)pyridine-2-carbonitrile; 1-110: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(3-phenylpropyl)pyridine- 3-carboxamide; 1-111: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(1-phenylpiperidin-4- yl)pyridine-3-carboxamide; 1-112: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-difluorophenyl)pyridine-3- carboxamide; 1-113: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(2,2- dimethyloxan-4-yl)pyridine-3-carboxamide; 1-114: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1,2-oxazol-3- yl)methyl]pyridine-3-carboxamide; 1-115: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2- hydroxyphenyl)methyl]pyridine-3-carboxamide; 1-116: 4-[(3R)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-118: 4-[(3S)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]- 5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-120: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-[3- (difluoromethoxy)phenyl]pyridine-3-carboxamide; 1-122: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-methylpyridine-3-carboxamide; 1-123: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-124: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-fluorophenyl)-6- methylpyridine-3-carboxamide; 1-125: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-126: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[1-(pyrimidin-2- yl)ethyl]pyridine-3-carboxamide; 1-127: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-[3- (trifluoromethoxy)phenyl]pyridine-3-carboxamide; 1-130: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-132: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[1-(1,2-oxazol- 3-yl)ethyl]pyridine-3-carboxamide; 1-133: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[1-(1-methyl- 1H-1,2,3-triazol-4-yl)ethyl]pyridine-3-carboxamide; 1-135: 4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-137: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)- 6-methoxypyridine-3-carboxamide; 1-138: 4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cyano-N-[(1S)-1- cyclopropylethyl]pyridine-3-carboxamide; 1-140: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-141: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-143: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3- (difluoromethoxy)-5-fluorophenyl]pyridine-3-carboxamide; 1-144: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)- 6-methoxypyridine-3-carboxamide; 1-145: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-3,3-difluorocyclopentyl]-5-(3,5- difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-146: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)- 6-methylpyridine-3-carboxamide; 1-147: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-149: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3- (difluoromethoxy)phenyl]pyridine-3-carboxamide; 1-150: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6- methoxypyridine-3-carboxamide; 1-151: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-152: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)-6- methoxypyridine-3-carboxamide; 1-153: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-154: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-methoxy-5-[3- (trifluoromethoxy)phenyl]pyridine-3-carboxamide; 1-163: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(2,2-difluoro-2H- 1,3-benzodioxol-4-yl)pyridine-3-carboxamide; 1-164: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-fluoro-5- (trifluoromethyl)phenyl]-6-methoxypyridine-3-carboxamide; 1-165: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3- (difluoromethoxy)phenyl]-6-methoxypyridine-3-carboxamide; 1-168: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromethoxy)phenyl]-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-171: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6-methyl- N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-172: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-[3- (difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide; 1-173: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3- (difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide; 1-174: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-[3- (difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide; 1-175: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(2,2-difluoro-2H- 1,3-benzodioxol-5-yl)pyridine-3-carboxamide; 1-176: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-ethoxypyridine-3-carboxamide; 1-177: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-(2,2- difluoroethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-178: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6- (cyclopropylmethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-179: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-(2-methoxyethoxy)pyridine-3-carboxamide; 1-180: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromethoxy)-5-fluorophenyl]- N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-181: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)- 6-methylpyridine-3-carboxamide; 1-184: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-6- methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-188: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6- methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-189: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; 1-190: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide; 1-191: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropoxy-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-192: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-193: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[4- (trifluoromethyl)cyclohexyl]pyridine-3-carboxamide; 1-194: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(3,5- difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-195: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide; 1-196: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3-fluorobicyclo[1.1.1]pentan-1- yl}-6-methoxypyridine-3-carboxamide; 1-197: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(1S)-1- cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide; 1-198: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyclopropylethyl]-6- (trifluoromethyl)pyridine-3-carboxamide; 1-199: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)-6- (trifluoromethyl)pyridine-3-carboxamide; 1-200: ethyl 2-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)acetate; 1-201: ethyl 3-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)propanoate; 1-202: ethyl 4-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)butanoate;; 1-203: 2-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)acetic acid 1-204: 3-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)propanoic acid; 1-205: 4-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-3-(3,5- difluorophenyl)pyridin-2-yl}oxy)butanoic acid; 1-209: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,4- difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; 1-210: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-difluorophenyl)-6- (trifluoromethyl)pyridine-3-carboxamide; 1-211: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)- 6-(trifluoromethyl)pyridine-3-carboxamide; 1-212: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-(trifluoromethyl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-213: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-difluorophenyl)-6- (trifluoromethyl)pyridine-3-carboxamide; 1-214: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6- (trifluoromethyl)pyridine-3-carboxamide; 1-215: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-dichlorophenyl)-6- (trifluoromethyl)pyridine-3-carboxamide; 1-216: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3-fluorobicyclo[1.1.1]pentan-1- yl}-6-(trifluoromethyl)pyridine-3-carboxamide; 1-217: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3- fluorobicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)pyridine-3-carboxamide; 1-218: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5-(3,5- difluorophenyl)-N-methylpyridine-3-carboxamide; 1-219: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-N-methylpyridine-3-carboxamide; 1-222: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2R)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-223: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1- hydroxycyclopentyl)methyl]-6-methylpyridine-3-carboxamide; 1-224: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropyl-2-hydroxyethyl)-5-(3,5- difluorophenyl)-6-methylpyridine-3-carboxamide; 1-225: 4-(3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-trifluoropropan-2- yl)pyridine-3-carboxamide; 1-226: 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-trifluoropropan-2- yl)pyridine-3-carboxamide; 1-227: 4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2R)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-228: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-229: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-230: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-231: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6-methyl-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-232: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)phenyl]-6-methyl-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-233: 4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6- methylpyridine-3-carboxamide; 1-234: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-{3- fluorobicyclo[1.1.1]pentan-1-yl}pyridine-3-carboxamide; 1-235: (3S)-1-[3-(3,5-difluorophenyl)-2-methoxy-5-(piperidine-1-carbonyl)pyridin-4-yl]pyrrolidin-3- amine; 1-236: (3S)-1-[3-(3,5-difluorophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-2-methoxypyridin-4- yl]pyrrolidin-3-amine; 1-237: (3S)-1-[3-(3,5-difluorophenyl)-5-(3,3-difluoropiperidine-1-carbonyl)-2-methoxypyridin-4- yl]pyrrolidin-3-amine; 1-238: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[(1,2- oxazol-3-yl)methyl]pyridine-3-carboxamide; 1-239: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6- methoxy-N-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide; 1-240: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[(1S)-1- (pyridin-2-yl)ethyl]pyridine-3-carboxamide; 1-241: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6- methoxy-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide; 1-242: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methyl-N-[(1,2- oxazol-3-yl)methyl]pyridine-3-carboxamide; 1-243: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methyl-N-[(1S)-1- (pyridin-2-yl)ethyl]pyridine-3-carboxamide; 1-244: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cyano-N-[(1,2- oxazol-3-yl)methyl]pyridine-3-carboxamide; 1-245: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cyano-N-[(1S)-1- (pyridin-2-yl)ethyl]pyridine-3-carboxamide; 1-246: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-(2-hydroxyethoxy)pyridine-3-carboxamide; 1-247: 2-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]carbamoyl}-3- (3,5-difluorophenyl)pyridin-2-yl}oxy)acetic acid; 1-259: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methoxy-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-260: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-6-methoxy-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-261: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-6-methoxy-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-262: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,4- difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-263: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-264: 3-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]carbamoyl}-3- (3,5-difluorophenyl)pyridin-2-yl}oxy)propanoic acid; 1-265: 4-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]carbamoyl}-3- (3,5-difluorophenyl)pyridin-2-yl}oxy)butanoic acid; 1-266: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)-6-[(oxetan-3-yl)methoxy]pyridine-3-carboxamide; 1-267: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-(benzyloxy)-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-268: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-(4,4- difluorocyclohexyl)-6-methylpyridine-3-carboxamide; 1-269: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-(3,3- difluorocyclobutyl)-6-methylpyridine-3-carboxamide; 1-272: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyclopropylethyl]-6- methylpyridine-3-carboxamide; 1-273: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3- fluorobicyclo[1.1.1]pentan-1-yl}-6-methoxypyridine-3-carboxamide; 1-275: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-6-methyl-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-276: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methyl-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-277: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(4,4-difluorocyclohexyl)-6- methylpyridine-3-carboxamide; 1-278: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-{3- fluorobicyclo[1.1.1]pentan-1-yl}-6-methylpyridine-3-carboxamide; 1-279: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methyl-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-280: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(1S)-1- cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-281: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-N-(4,4-difluorocyclohexyl)-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-282: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyclopropylethyl]-6- methoxypyridine-3-carboxamide; 1-283: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 1-284: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(4,4-difluorocyclohexyl)-6- methoxypyridine-3-carboxamide; 1-285: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3,3-difluorocyclobutyl)-6- methoxypyridine-3-carboxamide; 1-286: 4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-{3- fluorobicyclo[1.1.1]pentan-1-yl}-6-methoxypyridine-3-carboxamide; 1-287: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-6-methyl-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-288: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,4- difluorophenyl)-6-methylpyridine-3-carboxamide; 1-289: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-N-[(1S)-1- cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-290: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-5-(3,5-difluorophenyl)-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [0095] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3- methylpyrrolidin-1-yl]-5-(phenyl)-pyridine-3-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3-methylpyrrolidin-1-yl]-5- (phenyl)pyridine-3-carboxamide compound. [0096] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000102_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000103_0001
, , ; Rc is hydrogen, -CN, -CH3, -CF3, or -OCH3. [0097] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-5: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2'-cyano-N-(3-methylphenyl)-[3,4'-bipyridine]-5- carboxamide; 1-6: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,5-dimethylphenyl)-2'-methyl-[3,4'-bipyridine]-5- carboxamide; 1-121: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl- 1H-pyrazol-3-yl)pyridine-3-carboxamide; 1-128: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(2-methyl- 1,3-thiazol-5-yl)pyridine-3-carboxamide; 1-129: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-[(1S)-1-cyclopropylethyl]-2'- (trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; 1-131: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2',6'-dimethyl-[3,4'- bipyridine]-5-carboxamide; 1-134: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(1,2- oxazol-4-yl)pyridine-3-carboxamide; 1-142: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5'-fluoro-[3,3'- bipyridine]-5-carboxamide; 1-148: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-methyl-5-(1-methyl- 1H-pyrazol-4-yl)pyridine-3-carboxamide; 1-155: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-methyl-5-[1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide; 1-156: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(1S)-1- cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-157: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2'-methoxy-2-methyl- [3,4'-bipyridine]-5-carboxamide; 1-158: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5'-chloro-N-[(1S)-1-cyclopropylethyl]-2-methyl- [3,3'-bipyridine]-5-carboxamide; 1-159: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-methyl-2'- (trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; 1-160: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5'-fluoro-2-methyl- [3,3'-bipyridine]-5-carboxamide; 1-166: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-methoxy-2'- (trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; 1-167: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5'-chloro-N-[(1S)-1-cyclopropylethyl]-2-methoxy- [3,3'-bipyridine]-5-carboxamide; 1-169: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-(trifluoromethyl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]-[3,4'-bipyridine]-5-carboxamide; 1-170: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-[(2S)-1,1,1-trifluoropropan- 2-yl]-[3,4'-bipyridine]-5-carboxamide; 1-185: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(2-methylpyrimidin-5-yl)-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-187: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-N- [(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-206: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2'-ethoxy-2- (trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; 1-208: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2'-methoxy-2- (trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; 1-248: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclopentyl-2'-(trifluoromethyl)-[3,4'- bipyridine]-5-carboxamide; 1-249: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-(pentan-3-yl)-2'-(trifluoromethyl)-[3,4'- bipyridine]-5-carboxamide; 1-250: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-(2-methylpropyl)-2'-(trifluoromethyl)- [3,4'-bipyridine]-5-carboxamide; 1-251: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-butyl-2-cyano-2'-(trifluoromethyl)-[3,4'- bipyridine]-5-carboxamide; 1-252: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclohexyl-2'-methoxy-[3,4'- bipyridine]-5-carboxamide; 1-253: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-(pentan-3-yl)-[3,4'- bipyridine]-5-carboxamide; 1-254: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclopentyl-2'-methoxy-[3,4'- bipyridine]-5-carboxamide; 1-255: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2'-methoxy-2-methyl-[3,4'- bipyridine]-5-carboxamide; 1-256: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2'-methoxy-2-methyl-[3,4'- bipyridine]-5-carboxamide; 1-257: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2-methyl-2'-(trifluoromethyl)-[3,4'- bipyridine]-5-carboxamide; 1-258: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2-methyl-2'-(trifluoromethyl)-[3,4'- bipyridine]-5-carboxamide; 1-270: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-(2-methylpropyl)-[3,4'- bipyridine]-5-carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [0098] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3-amino-3- methylpyrrolidin-1-yl]-5-(1,3-benzodiazol-2-yl)-pyridine-3-carboxamide compound. [0099] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000105_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000105_0002
,
Figure imgf000106_0001
R11 is -F, -C1 or -CH3; and R12 is hydrogen or -F. [00100] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 2-1: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridine-3-carboxamide; 2-2: (3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-(pyrrolidine-1-carbonyl)pyridin-4- yl]pyrrolidin-3-amine; 2-3: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-N-methyl-5-(4-methyl-1H-1,3-benzodiazol- 2-yl)pyridine-3-carboxamide; 2-4: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridine-3-carboxamide; 2-5: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-(oxolan-3- yl)pyridine-3-carboxamide; 2-6: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N- phenylpyridine-3-carboxamide; 2-7: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-(2,2,2- trifluoroethyl)pyridine-3-carboxamide; 2-8: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-methoxyethyl)-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-9: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-hydroxyethyl)-5-(4-methyl-1H-1,3-benzodiazol- 2-yl)pyridine-3-carboxamide; 2-10: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-methyl-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N- (2,2,2-trifluoroethyl)pyridine-3-carboxamide; 2-11: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 2-12: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridine-3-carboxamide; 2-13: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-14: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropylethyl)-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-15: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-16: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-N-methyl-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-17: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-18: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-[(2R)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 2-19: (3S)-1-[3-(3,3-dimethylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl]-3-methylpyrrolidin-3-amine; 2-20: (3S)-1-[3-(2,2-dimethylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl]-3-methylpyrrolidin-3-amine; 2-21: (3S)-1-[3-(3,3-dimethylazetidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-22: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-N-methyl-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-23: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-N-methyl-5-(4-methyl-1H- 1,3-benzodiazol-2-yl)pyridine-3-carboxamide; 2-24: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-yl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]pyridine-3-carboxamide; 2-25: (3S)-1-[3-(3,3-difluoropyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-26: (3S)-1-(3-{2-azatricyclo[3.3.1.1³,⁷]decane-2-carbonyl}-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine; 2-27: (3S)-1-[3-(3-tert-butylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-28: (3S)-1-{3-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-4-yl}-3-methylpyrrolidin-3-amine; 2-29: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-N-methyl-5-(4-methyl- 1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; 2-30: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benzodiazol-2-yl)-N- [(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 2-31: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclobutylmethyl)-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-32: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-(4,4,4- trifluorobutan-2-yl)pyridine-3-carboxamide; 2-33: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[2.2.1]heptan-1-yl}-5-(4-methyl-1H-1,3- benzodiazol-2-yl)pyridine-3-carboxamide; 2-34: (3S)-1-[3-(2,3-dihydro-1H-indole-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-4- yl]-3-methylpyrrolidin-3-amine; 2-35: (3S)-1-(3-{2-azabicyclo[2.2.2]octane-2-carbonyl}-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine; 2-36: (3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-[2-(propan-2-yl)pyrrolidine-1- carbonyl]pyridin-4-yl]pyrrolidin-3-amine; 2-37: (3S)-1-{3-[(3aR)-octahydrocyclopenta[b]pyrrole-1-carbonyl]-5-(4-methyl-1H-1,3-benzodiazol- 2-yl)pyridin-4-yl}-3-methylpyrrolidin-3-amine; 2-38: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(4-methyl-1H-1,3-benzodiazol-2- yl)pyridine-3-carboxamide; 2-39: (3S)-1-(3-{5-azaspiro[2.4]heptane-5-carbonyl}-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl)-3-methylpyrrolidin-3-amine; 2-40: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-[(2S)- 1,1,1-trifluorobutan-2-yl]pyridine-3-carboxamide; 2-41: (3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-[(2S)-2- (trifluoromethyl)pyrrolidine-1-carbonyl]pyridin-4-yl]pyrrolidin-3-amine; 2-42: (3S)-1-[3-(3-cyclopropylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl]-3-methylpyrrolidin-3-amine; 2-43: (3S)-1-[3-(2-cyclopropylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin- 4-yl]-3-methylpyrrolidin-3-amine; 2-44: (3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-[3-(trifluoromethyl)pyrrolidine-1- carbonyl]pyridin-4-yl]pyrrolidin-3-amine; 2-45: (3S)-1-(3-{2-azatricyclo[3.3.1.1³,⁷]decane-2-carbonyl}-5-(7-chloro-1H-1,3-benzodiazol-2- yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine; or a pharmaceutically acceptable salt, or solvate thereof. [00101] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000109_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000109_0002
Rc is hydrogen or -OCH3. [00102] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-161: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl-1H- indazol-6-yl)pyridine-3-carboxamide; 1-162: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-methyl-1H- indazol-4-yl)pyridine-3-carboxamide; 1-182: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(1-methyl-1H-1,3-benzodiazol-6-yl)- N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-183: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(1-methyl-1H-indazol-4-yl)-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-186: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(2,1,3-benzoxadiazol-5-yl)-6-methoxy-N-[(2S)- 1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-2: 4-[(3R)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-36: 4-[3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-63: 4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-75: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyanopyridine-3- carboxamide; 1-99: 4-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-100: 4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-102: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-117: 4-[(3S)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-119: 4-[(3R)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]- 5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-136: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-139: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cyano-N-[(1S)-1- cyclopropylethyl]pyridine-3-carboxamide; 1-220: 4-[(3S)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-221: 4-[(3R)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-274: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-bromo-6-methoxy-N-[(2S)-1,1,1-trifluoropropan- 2-yl]pyridine-3-carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [00103] In some embodiments, the non-peptidic small molecule SSTR agonist is a 4-[3-amino- pyrrolidin-1-yl]-5-(phenyl)-pyridine-3-carboxamide compound. In some embodiments, the non- peptidic small molecule SSTR agonist is a 4-[3-amino-pyrrolidin-1-yl]-5-(phenyl)pyridine-3- carboxamide compound. [00104] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000110_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000111_0001
Rc is hydrogen, -CN, or -OCH3. [00105] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 1-2: 4-[(3R)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-36: 4-[3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-63: 4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-75: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyanopyridine-3- carboxamide; 1-99: 4-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-100: 4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-102: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(3,5- difluorophenyl)pyridine-3-carboxamide; 1-117: 4-[(3S)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-119: 4-[(3R)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]- 5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-136: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5- difluorophenyl)pyridine-3-carboxamide ; 1-139: 4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cyano-N-[(1S)-1- cyclopropylethyl]pyridine-3-carboxamide; 1-220: 4-[(3S)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-221: 4-[(3R)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5- (3,5-difluorophenyl)pyridine-3-carboxamide; 1-274: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-bromo-6-methoxy-N-[(2S)-1,1,1-trifluoropropan- 2-yl]pyridine-3-carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [00106] In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3- methylpyrrolidin-1-yl]-2-(phenyl)-pyridine-4-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3-methylpyrrolidin-1-yl]-2- (phenyl)pyridine-4-carboxamide compound. [00107] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000112_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000112_0002
[00108] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 3-1: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-(3,5- difluorophenyl)pyridine-4-carboxamide; 3-2: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2-(3,5-difluorophenyl)pyridine-4- carboxamide; 3-3: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-(3,5-difluorophenyl)-N-[(1S)-1- phenylethyl]pyridine-4-carboxamide; 3-4: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-2-(3,5- difluorophenyl)pyridine-4-carboxamide; 3-5: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[2.2.1]heptan-1-yl}-2-(3,5- difluorophenyl)pyridine-4-carboxamide; 3-6: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cycloheptyl-2-(3,5-difluorophenyl)pyridine-4- carboxamide; 3-7: N-(adamantan-1-yl)-3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-(3,5-difluorophenyl)pyridine- 4-carboxamide; 3-8: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2-(3,5-difluorophenyl)pyridine-4- carboxamide; or a pharmaceutically acceptable salt, or solvate thereof. [00109] In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3- methylpyrrolidin-1-yl]-4-(phenyl)-pyridine-2-carboxamide compound. In some embodiments, the non-peptidic small molecule SSTR agonist is a 3-[3-amino-3-methylpyrrolidin-1-yl]-4- (phenyl)pyridine-2-carboxamide compound. [00110] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000113_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000113_0002
Rc is -C1, -CN, -CH3, -CO2CH3, or -CONH2. [00111] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound selected from: 4-1: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-chloro-N-[(1S)-1-cyclopropylethyl]-4-(3,5- difluorophenyl)pyridine-2-carboxamide; 4-2: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-4-(3,5-difluorophenyl)- 5-methylpyridine-2-carboxamide; 4-3: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-cyano-N-[(1S)-1-cyclopropylethyl]-4-(3,5- difluorophenyl)pyridine-2-carboxamide; 4-4: methyl 5-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-{[(1S)-1-cyclopropylethyl] carbamoyl}-4- (3,5-difluorophenyl)pyridine-3-carboxylate; 4-5: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N2-[(1S)-1-cyclopropylethyl]-4-(3,5- difluorophenyl)pyridine-2,5-dicarboxamide; or a pharmaceutically acceptable salt, or solvate thereof. SSTR2/4-Selective Agonists [00112] In some embodiments, described herein are non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is selective for SSTR2 and SSTR4. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US Patent Number 9,957,267, US Patent Application Publication Number US 2017/0002001, International Patent Application Publication Number WO 2017/003723, or related applications or application publications. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in any one of Formulas (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (II), (III), or (IV) of US Patent Number 9,957,267. In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in Formula (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) of US Patent Number 9,957,267. In some embodiments, the non- peptidic small molecule SSTR agonist is a compound described in Table A, Table B, or Table C of US Patent Number 9,957,267. [00113] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000114_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000115_0001
; R13 is -C1, -CH3, -CH(CH3)2, -OCH3, -(CH2)2OH, or -CH2OH; R14 is hydrogen, -F, -C1, -CH3, -CH2OH; R15 is -CN, -OH, -CONH2, -CONHCH3, or -CH2OH; R16 is hydrogen, -F, -C1, -CN, -CH3, -CF3, -OCF3; RA is hydrogen; and RB is hydrogen, -CN, -CH3, -CH2CH3, -CH(CH3)2. [00114] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000116_0001
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000116_0002
R13 is -CH3 or -OCH3; R14 is -F, -C1, or -CH3; R15 is -OH; R16 is hydrogen, -F, -CN, -CF3; RA is hydrogen; and RB is hydrogen, -CN, -CH3, -CF3. [00115] In some embodiments, the non-peptidic small molecule SSTR agonist has the following structure:
Figure imgf000116_0003
or a pharmaceutically acceptable salt, or solvate, thereof, wherein:
Figure imgf000116_0004
R13 is -CH3 or -OCH3; R14 is -F, -C1, or -CH3; R15 is -OH; R16 is hydrogen, -F, -CN, -CF3; RA is hydrogen; and RB is hydrogen. Pan-Active Agonists [00116] In some embodiments, described herein are non-peptidic small molecule somatostatin receptor (SSTR) agonists to be used in the methods described herein, wherein the SSTR agonist is a pan-agonist. In some embodiments the non-peptidic small molecule SSTR agonist is a compound active against all SSTR subtypes. Additional Agonist Compounds [00117] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US9643951, which is herein incorporated for such compounds. [00118] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US9630976, which is herein incorporated for such compounds. In some embodiments, such compounds include, but are not limited to: 1-{3-(3,5-dimethylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine; 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]piperidin-4-amine; 3-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl}benzonitrile; rac-(4aR,8aR)-6-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4- pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine; 1-[3-(3,5-dimethoxyphenyl)-5-(5-fluoro-1H-indol-2-yl)-4-pyridinyl]-4-piperidinamine; 4'-(4-amino-1-piperidinyl)-5'-(3-methoxy-5-methylphenyl)-N,N-dimethyl-3,3'-bipyridin-6-amine; 4-[3-(aminomethyl)-1-pyrrolidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 4-(4-amino-1-piperidinyl)-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; 5-[(E)-2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6- yl]-3-pyridinyl}vinyl]nicotinonitrile; 1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine; 1-[3-(3,5-dimethyl phenyl)-5-(2-methyl-2H-indazol-5-yl)-4-pyridinyl]-4-piperidinamine; 1-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-4- piperidinamine; 1-{3-(3-fluoro-5-methylphenyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-4-pyridinyl}-4-piperidinamine; N-{3-[4-(4-amino-1-piperidinyl)-5-(3-chloro-5-fluorophenyl)-3-pyridinyl] phenyl}acetamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-chlorobenzamide; 1-{4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenyl}ethenone; methyl 3-{[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]carbamoyl}benzoate; 1-[3-(1,3-benzothiazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine; 6-{5-(3,5-dimethoxyphenyl)-4-[4-(3-oxetanylamino)-1-piperidinyl]-3-pyridinyl}-1,3-dihydro-2H- indol-2-one; 1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-4-pyridinyl}-4- piperidinamine; 1-[3-(3,5-dimethylphenyl)-5-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-pyridinyl]-4- piperidinamine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4-methoxybenzamide; 4-[3-(5,7-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]butan-1-amine; 1-[3-(1,3-benzoxazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine; 3-(3,5-dimethylphenyl)-5-[(E)-2-(3,5-dimethylphenyl)vinyl]-4-[2-(2-piperidinyl)ethoxy]pyridine; 5-[3-(3-fluoro-5-methyl-phenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridyl]-1,4,6,7- tetrahydropyrazolo[4,3-c]pyridine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-pyridinecarboxamide; 4-(2,7-diazaspiro[3.5]non-7-yl)-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-pyrazole-4- carboxamide; N-{4-[(3-aminopropyl)(methyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide; 1-[3-(3,5-dimethylphenyl)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-4-piperidinamine; 1-[3-[(3,5-dimethylphenoxy)methyl]-5-(3,5-dimethylphenyl)-4-pyridyl]piperidin-4-amine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-imidazole-5- carboxamide; 5-[4-[4-(aminomethyl)-3,6-dihydro-2H-pyridin-1-yl]-5-(3-chloro-5-fluoro-phenyl)-3-pyridyl]-2- fluoro-phenol; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethyl-1- piperidinecarboxamide; N-(3,5-dimethylbenzyl)-5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]-3-pyridinamine; 5-[3-(5,7-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]pyridin-2-amine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-phenoxyacetamide; 5-acetyl-N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-thiophenecarboxamide; N-{5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-6-quinazolinamine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4,6-dimethoxy-2- pyrimidinecarboxamide; 1-[3-[6-(dimethylamino)-3-pyridyl]-5-(3,5-dimethylphenyl)-4-pyridyl]azepan-4-amine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethyl phenyl)-3-pyridinyl]-1,5-dimethyl-1H-1,2,3-triazole-4- carboxamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-thiazole-4-carboxamide; benzyl [4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]carbamate; 4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-[3-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3- carboxamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-methyl-1,2-oxazole-3- carboxamide; N-{5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-6-quinazolinamine; 4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide; 5-[4-[2-(aminomethyl)morpholin-4-yl]-5-(3,5-dimethylphenyl)-3-pyridyl]-N,N-dimethyl-pyridin-2- amine; N-(3-carbamoylphenyl)-5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-oxazole-4-carboxamide; N-(2-aminoethyl)-3-[(3-chloro-4-fluorobenzoyl)amino]-5-(3,5-dimethylphenyl)pyridine-4- carboxamide; 5-[4-(2,7-diazaspiro[3.4]octan-7-yl)-5-(3,5-dimethylphenyl)-3-pyridyl]-N,N-dimethyl-pyridin-2- amine; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-(methylsulfonyl)-2- thiophenecarboxamide; N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl][1,2,4]triazolo[1,5-a]pyrimidine-2- carboxamide; 5-[4-(1,4-diazepan-1-yl)-5-(3,5-dimethylphenyl)-3-pyridyl]-N,N-dimethyl-pyridin-2-amine N,5-bis(3,5-dimethylphenyl)-4-(1-piperazinyl)pyridine-3-carboxamide; 2-{4-[4-(aminomethyl)-1-piperidinyl]-5-(3,5-dimethylphenyl)-3-pyridinyl}-1H-isoindole-1,3(2H)- dione; or a pharmaceutically acceptable salt, or solvate thereof. [00119] In some embodiments, the non-peptidic small molecule SSTR agonist is a compound described in US20200000816, which is herein incorporated for such compounds. In some embodiments, such compounds include, but are not limited to: rac-(3R,4S)-4-amino-1-[3-(3, 5-dimethoxypheny1)-5-(4,6-dimethy1-1H-benzimidazol-2-y1)-4- pyridinyl]-3-piperidinol; rac-(3R,4S)-4-amino-1-[3-(6-fluoro-1H-benzimidazol-2-y1)-5-(3-fluoro-5-methoxypheny1)-4- pyridinyl]-3-piperidinol; rac-(3R,4 S)-4-amino-1-[3-(6-chloro -1 H-benzimidazol-2-y1)-5-(3-fluoro-5-methoxyphenyl)-4- pyridi-ny1]-3-piperidinol); (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-y1)-5-(3,5-difluoropheny1)-4-pyridinyl]-4-(3-oxeta- nylamino)-3-piperidinol; (3S,4R)-1-[3-(3-chloro-5-fluoropheny1)-5-(5,6-dif-luoro-1H-benzimidazol-2-y1)-4-pyridiny1]-4- [(3,3,3-trifluoropropyl)amino]-3-piperidinol; (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-y1)-5-(2,5-difluoropheny1)-4-pyridinyl]-4- (ethylamino)-3-piperidinol; (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-y1)-5-(3-fluoro-5-methoxypheny1)-4-pyridinyl]-4- [(3,3,3-tri-fluoropropyl)amino]-3-piperidinol; (3S,4R)-1-[3-(3,5-difluoropheny1)-5-(6-fluoro-5-methoxy-1H-benzimidazol-2-y1)-4-pyridiny1]-4- [(3,3,3-trifluoropropyl)amino]-3-piperidinol; (3S,4R)-4-amino-1-[3-(5,6-difluoro- 1H-benzimidazol-2-y1)-5 -(3,5 -difluoropheny1)-2-(1 -methyl- 1H-pyrazol-4-y1)-4-pyridiny1]-3-piperidinol; methyl 2-[4-[(3S,4R)-4-amino-3-hydroxy-l-piperidiny1]-5-(3-chloro-5-fluoropheny1)-2-methyl-3- pyridi-nyl]-5-fluoro-1H-benzimidazole-7-carboxylate; methyl 2-14-[(3S,4R)-4-amino-3-hydroxy-1-piperidinyl]-5-(2,5-difluoropheny1)-2-methyl-3- pyridinyl]-5-fluoro-1H-benzimidazole-7-carboxylate; ((3 S,4R)-4-amino- 1-[5-(3,5 -difluoropheny1)-2-methyl-3-(5,6,7-trifluoro-1H-benzimidazol-2-y1)-4- pyridinyl] 3-piperidinol; (3 S,4R)- 1-[5 -(3 -chloro-5 -fluoropheny1)-3 -(6-methoxy-1H-benzimidazol-2-y1)-2-methy1-4- pyridi-ny1]-4-(3-oxetanylamino)-3-piperidinol; (3 S,4R)- 1-[5 -(3,5 -difluoropheny1)-3 -(5 -fluoro-6-methoxy-1H-benzimidazol-2-y1)-2-methy1-4- pyridi-ny1]-4-(ethylamino)-3-piperidinol; (3S,4R)-1-[5-(3-chloro-5-fluoropheny1)-3-(5,6-dif-luoro-1H-benzimidazol-2-y1)-2-methy1-4- pyridiny1]-4-(3-oxetanylamino)-3-piperidinol; (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-y1)-5-(3,5-difluoropheny1)-2-methyl-4-pyridinyl]-4- [(3,3,3-trifluoropropyl)amino]-3-piperidinol; (3S,4R)-1-[5-(3,5 -difluoropheny1)-2-methy1-3 -(5,6,7-trifluoro-1H-benzimidazol-2-y1)-4- pyridiny1]-4-(ethylamino)-3-piperidinol; methyl- 2-{4-[(3 S,4R)-4-amino-3-hydroxy-1-piperidiny1]-5-(3,5-difluoropheny1)-2-(4- morpholiny1)-3-pyridinyl}-5-fluoro-1H-benzimidazole-7-carboxylate; (3S,4R)-4-amino-1-[3-(5,6-difluoro-1H-benzimidazol-2-y1)-5-(3,5-difluoropheny1)-4-pyridinyl]-3- piperidinol; (3S,4R)-4-amino-1-[3-(1H-benzimidazol-2-y1)-5-(3,5-difluoropheny1)-4-pyridiny1]-3-piperidinol; (3S,4R)-4-amino-1-[3-(2,5-difluoropheny1)-5-(6-methoxy-1H-benzimidazol-2-y1)-4-pyridiny1]-3- piperidinol; or methyl 2-14-[(3S,4R)-4-amino-3-hydroxy-l-piperidiny1]-5-(2,5-difluoropheny1)-3-pyridinyll-5- fluoro- 1H-benzimidazole-7-carboxylate; or a pharmaceutically acceptable salt, or solvate thereof. [00120] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00121] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [00122] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley- VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. [00123] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. [00124] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. [00125] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base. In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. [00126] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. [00127] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure described herein, as well as active metabolites of these compounds having the same type of activity. [00128] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group. [00129] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00130] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36C1, 123I, 124I, 125I, 131I, 32P and 33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. [00131] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound described herein exists in the R configuration. In some embodiments, the compound described herein exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. [00132] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. [00133] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [00134] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs. [00135] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds are prodrugs for another derivative or active compound. [00136] In some embodiments, any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above. [00137] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. [00138] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. [00139] In some instances, heterocyclic rings may exist in tautomeric forms. In such situations, it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below. For example, benzimidazoles or imidazoles could exist in the following tautomeric forms:
Figure imgf000125_0001
Certain Terminology [00140] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [00141] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [00142] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. [00143] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist. [00144] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. [00145] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00146] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study. [00147] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system. [00148] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients. [00149] The terms “article of manufacture” and “kit” are used as synonyms. [00150] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. [00151] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. Pharmaceutical compositions [00152] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00153] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ. [00154] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste. [00155] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses. [00156] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00157] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [00158] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [00159] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. [00160] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. [00161] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. [00162] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Methods of Dosing and Treatment Regimens [00163] In some embodiments, the methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal. [00164] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [00165] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, which previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition. [00166] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [00167] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms. [00168] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [00169] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [00170] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [00171] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. [00172] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal. [00173] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day. [00174] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Treatments [00175] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapies. In some embodiments, the secondary therapy includes surgery, radiotherapy, or the administration of a second therapeutic agent. In some embodiments, the secondary therapy includes surgery. In some embodiments, the secondary therapy includes radiotherapy. In some embodiments, the secondary therapy includes the administration of a second therapeutic agent. [00176] In certain embodiments, the secondary therapy is surgery. In some embodiments, the surgery is to resect or remove a portion of the pituitary adenoma. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered after surgery. In some embodiments, surgery completely removes the adenoma. In some embodiments, surgery is incomplete, or only removes part of the adenoma. In some instances, the tumor recurs after complete or incomplete surgery. In some embodiments, administering a non-peptidic small molecule SSTR agonist described herein after incomplete surgery stabilizes tumor size of the remaining pituitary adenoma. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered before surgery. In some embodiments, administering a non-peptidic small molecule SSTR agonist described herein before surgery leads to better surgical outcomes. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered both before and after surgery. [00177] In certain embodiments, the secondary therapy is radiation therapy. Radiation therapy is often used after surgery in cases of residual or recurrent tumor. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered after radiation therapy. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered before radiation therapy. In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered before and after radiation therapy. In certain instances, radiation therapy has a long- term risk of hypopituitarism. In some embodiments, administering a non-peptidic small molecule SSTR agonist described herein, or a pharmaceutically acceptable salt thereof, with radiation therapy decreases incidence of hypopituitarism due to a pituitary adenoma. In some instances, the radiation therapy is stereotactic radiosurgery or fractionated stereotactic radiotherapy. [00178] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. [00179] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00180] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00181] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit. Dopamine Agonist Therapy [00182] In some instances, NFPAs are associated with expression of dopamine receptor type 2 (D2R). In some instances, patients treated with a D2R agonist post-surgery exhibit tumor shrinkage after 12 months. In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a D2R agonist. In some embodiments, cotreatment with a D2R agonist leads to tumor shrinkage after 12-months. [00183] In one embodiment, described herein is a method of reducing tumor volume of a non- functioning pituitary adenoma (NFPA) in a patient, comprising: administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof; and administering a dopamine agonist to the patient in need thereof. In some embodiments, the NFPA has been treated by incomplete surgery. In some embodiments, the surgery is to resect a portion of the pituitary adenoma. In some embodiments, administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect. In some embodiments, the therapeutic effect is a decrease in size of the NFPA. The method of any one of claims 36-45, wherein the dopamine agonist is a dopamine receptor type 2 (D2R) agonist. D2R agonists to be used in the methods described herein include cabergoline, bromocriptine, piribedil, pramipexole, quinelorane, quinpirole, ropinirole, sumanirole, or talipexole. Alkylating Chemotherapeutic Drugs [00184] In some instances, pituitary adenomas are also treated with alkylating chemotherapeutic drugs. In some instances, pituitary adenomas are treated with temozolomide. In some instances, patients with low expression of O(6)-methylguanine DNA methyltransferase (MGMT) in pituitary tumors have higher response rates to temozolomide. In some instances, low MGMT expression is associated with tumor aggressiveness in NFPAs. In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with an alkylating chemotherapeutic. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with temozolomide. [00185] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. [00186] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00187] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. EXAMPLES [00188] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Example A-1: SSTR2, SSTR3, and SSTR2/3 Efficacy Assay(s) [00189] Cell models: human non-functioning pituitary tumors in primary cell culture (~30/year); alphaT3-1 murine immortalized gonadotroph cells overexpressing human SSTR3. [00190] Assays: CellTiter-Glo® Cell Viability and Caspase-Glo® 3/7 Luminescent assays (Promega; high sensitivity, 10-20,000 cells /condition, 96-well plate format). Example A-2: SSTR3 and SSTR5 Efficacy Assay(s) [00191] Cell models: human corticotroph tumors in primary cell culture (5-7/year); AtT-20 immortalized murine corticotroph tumor cells (express SSTR2<SSTR5=SSTR3; can overexpress human SSTR5); stable AtT-20/POMC-Gluc (stable expression of Gaussia luciferase gene downstream the proximal human POMC promoter); AtT-20 overexpressing USP8wt/mutants found in Cushing’s disease; clinically non-functioning/gonadotroph pituitary adenomas including gonadotroph cell lines αT1-1, αT3-1, LβT2, LβT4, HP75 and the plurihormonal RC-4B (functional SSTR expression is often low). [00192] Assays: ACTH radioimmunoassay on supernatants of human and mouse corticotroph cultures; POMC luciferase assay; secreted POMC-Gaussia luciferase assay, CellTiter-Glo® Cell Viability assay. [00193] Animal models: Syndromic multiple endocrine neoplasia (MEN1/4) model of homozygote Cdkn1b mutated rats; Pomc knockout in mice (results in null cell tumors similar to benign pituitary adenomas which highly express mouse SSTR3). [00194] An overall increase in vascularity of the tumor tissue is observed, with clusters of highly proliferating cells (high Ki67) with nodular appearance. Pituitaries from treated and untreated mice are assessed in ex vivo experiments. Viability is assessed after one week of agonist/vehicle treatment using Alamar Blue. Furthermore, apoptosis is measured using a caspase 3 assay, and migration and invasion is measured using Boyden chambers. [00195] In vivo characterization in Pomc-/- animals consists of dosing either SST3 agonist or vehicle for 16 weeks starting when the animals are 3 months of age. Following treatment, the animals are sacrificed, and tumor size and weight is determined. Example A-3: C1inical Trial for Non-Functioning Pituitary Adenomas [00196] A non-limiting example of a clinical trial in humans to evaluate the efficacy and safety of a non-peptidic small molecule somatostatin receptor (SSTR) agonist on the treatment of patients with clinically non-functioning pituitary adenomas is described below. Purpose [00197] The purposes of this study is to evaluate the safety, tolerability and efficacy of therapy with a non-peptidic small molecule somatostatin receptor (SSTR) agonist in patients with non-functioning pituitary adenomas concerning tumor growth. Primary Outcome Measures [00198] Proportion of patients with non-functioning pituitary adenomas (NFPA) who achieve tumor volume reduction after about 24-week treatment with a non-peptidic small molecule somatostatin receptor (SSTR) agonist. Mean change of tumor volume assessed by pituitary MRI (Time Frame: from baseline to about week 4, about week 12 and about week 24). Secondary Outcome Measures [00199] Change in tumor volume (Time Frame: 4, 12 and 24 weeks). The effect of non-peptidic small molecule somatostatin receptor (SSTR) agonist therapy on hormonal response, and relevant disease-related symptoms (Time Frame: at screening (it will be considered as baseline) and at about weeks 4, 12 and 24). Percent change of tumor volume assessed by pituitary MRI (Time Frame: from baseline to week 4, 12 and 24). Study Arms [00200] One of three study arms is used. In study arm 1, all patients receive a non-peptidic small molecule SSTR agonist daily for about 24 weeks. In study arm 2, all patients receive a non-peptidic small molecule SSTR selective agonist daily for about 24 weeks, either a different selectivity or a different dose. In study arm 3, all patients receive a placebo daily for about 24 weeks. Inclusion Criteria: [00201] Male or female patients aged 18 years or greater. Patients with confirmed diagnosis of NFPA. Non-functioning pituitary adenoma ≥1cm, patients without any previous treatment, other than surgery, for the tumor. Patients who sign the informed consent. Exclusion Criteria: [00202] Patients who have any current or prior medical condition(s) that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms. Male patients who a.re sexually active are required to use condoms during the study and for 1 month afterwards Example A-4: C1inical Trial for Combination Therapy in Non-Functioning Pituitary Adenomas with Somatostatin Receptor (SSTR) Agonist and Dopamine Agonist [00203] A non-limiting example of a clinical trial in humans to evaluate the efficacy and safety of a non-peptidic small molecule somatostatin receptor (SSTR) agonist together with a dopamine agonist on the treatment of patients with clinically non-functioning pituitary adenomas is described below. Purpose [00204] The goals of this study are: to verify whether dopamine receptor type 2 (D2R) agonist therapy and non-peptidic small molecule somatostatin receptor (SSTR) agonist therapy are effective in NFPA to control tumor re-growth as adjuvant therapy after neurosurgery; to assess the mRNA levels of dopamine receptor type 2 (D2R) and SSTR1-5 and their protein expression; to evaluate the in vitro hormonal response to D2R agonist therapy and SSTR agonist therapy; and to determine whether the mRNA DR2/SSTR1-5 and/or protein expression and/or in vitro hormonal response to D2R agonist therapy and SSTR agonist therapy correlates with the in vivo response. Study Arms [00205] The patients with NFPA will be randomized into three groups: (A) the first group receive SSTR agonist therapy daily for at least 3 months; (B) the second group receive cabergoline at about 3 mg/week for at least 3 months; (C) the third group receive SSTR agonist therapy daily and cabergoline at about 3 mg/week for at least 3 months. [00206] For patients harboring a NFPA, treatment is started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. In this case, the drug efficacy is evaluated clinically by visual field and by MRI after at least three months of therapy. Inclusion Criteria [00207] Male or female patients aged 18 years or greater. Patients with confirmed diagnosis of NFPA evidenced by: magnetic resonance imaging (MRI) confirmation of pituitary adenoma and no pituitary tumoral hormone hypersecretion. Patients who had been submitted to surgery but not cured. Lack of cure is defined as presence of remnant tumor on MRI at least three months after surgery (without any possible misinterpretation of postsurgical changes). Patients who sign the informed consent. Exclusion Criteria [00208] Patients who have any current or prior medical condition(s) that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms. Male patients who are sexually active are required to use condoms during the study and for 1 month afterwards. Example B-1: Parenteral Pharmaceutical Composition [00209] A non-limiting example of a parenteral pharmaceutical composition is described below. To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection Example B-2: Oral Solution [00210] A non-limiting example of an oral solution is described below. To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution. Example B-3: Oral Tablet [00211] A non-limiting example of a tablet formulation is described below. A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg. Example B-4: Oral Capsule [00212] Non-limiting examples of capsule formulations are described below. To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. [00213] In another embodiment, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed. Example B-5: Topical Gel Composition [00214] To prepare a pharmaceutical topical gel composition, a compound described herein, 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 containers, such as tubes, which are suitable for topical administration. [00215] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A method of treating non-functioning pituitary adenoma (NFPA) in a patient, comprising administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof.
2. A method of stabilizing a non-functioning pituitary adenoma (NFPA) tumor size in a patient, comprising administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof.
3. A method of treating headache, blurred vision, cranial nerve dysfunction, hyperprolactinemia, or pituitary apoplexy associated with NFPA, or a combination thereof, comprising administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof.
4. The method of any one of claims 1-3, wherein the NFPA has been treated by incomplete surgery.
5. A method of stabilizing tumor size of a recurrent non-functioning pituitary adenoma (NFPA) tumor after incomplete resection surgery in a patient, comprising administering a non- peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof.
6. A method of preventing recurrence of tumor growth in a patient after surgery, comprising administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof, wherein the tumor is a non-functioning pituitary adenoma (NFPA) tumor.
7. The method of any one of claims 5-6, wherein the surgery is to resect a portion of the pituitary adenoma.
8. The method of any one of claims 1-7, wherein administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect.
9. The method of claim 8, wherein the therapeutic effect is an inhibition of growth of the NFPA.
10. The method of claim 8, wherein the therapeutic effect is a decrease in size of the NFPA.
11. The method of any one of claims 1-10, wherein the non-peptidic small molecule SSTR agonist is a selective agonist.
12. The method of claim 11, wherein the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist.
13. The method of any one of claims 1-10, wherein the non-peptidic small molecule SSTR agonist is a pan-SSTR agonist.
14. The method of any one of claims 1-10, wherein the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-quinoline compound, 4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-quinoline compound, 4-[3-(aminomethyl)azetidin-1-yl]-quinoline compound, 4-(4-aminopiperidin-1-yl)-pyridine compound, 4-[3-amino-pyrrolidin-1-yl]- pyridine compound, 4-(3-(aminomethyl)azetidin-1-yl)-pyridine compound, or 4-(octahydro- 1H-pyrido[3,4-b]morpholin-6-yl)-pyridine compound, or a pharmaceutically acceptable salt, or solvate thereof.
15. The method of any one of claims 1-10, wherein the non-peptidic small molecule SSTR agonist is a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
16. The method of any one of claims 1-15, wherein the method further comprises a secondary therapy.
17. The method of claim 16, wherein the secondary therapy is a dopamine agonist, an alkylating agent, radiotherapy, or surgery.
18. A method of reducing tumor volume of a non-functioning pituitary adenoma (NFPA) in a patient, comprising: a. administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof; and b. administering a dopamine agonist to the patient in need thereof.
19. The method of claim 18, wherein the NFPA has been treated by incomplete surgery.
20. The method of claim 19, wherein the surgery is to resect a portion of the pituitary adenoma.
21. The method of any one of claims 18-20, wherein administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect.
22. The method of claim 21, wherein the therapeutic effect is a decrease in size of the NFPA.
23. The method of any one of claims 18-22, wherein the non-peptidic small molecule SSTR agonist is a selective agonist.
24. The method of claim 23, wherein the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist.
25. The method of any one of claims 18-22, wherein the non-peptidic small molecule SSTR agonist is a pan-SSTR agonist.
26. The method of any one of claims 18-22, wherein the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-quinoline compound, 4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-quinoline compound, 4-[3-(aminomethyl)azetidin-1-yl]-quinoline compound, 4-(4-aminopiperidin-1-yl)-pyridine compound, 4-[3-amino-pyrrolidin-1-yl]- pyridine compound, 4-(3-(aminomethyl)azetidin-1-yl)-pyridine compound, or 4-(octahydro- 1H-pyrido[3,4-b]morpholin-6-yl)-pyridine compound, or a pharmaceutically acceptable salt, or solvate thereof.
27. The method of any one of claims 18-22, wherein the non-peptidic small molecule SSTR agonist is a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
28. The method of any one of claims 18-27, wherein the dopamine agonist is a dopamine receptor type 2 (D2R) agonist.
29. The method of claim 28, wherein the D2R agonist is cabergoline, bromocriptine, piribedil, pramipexole, quinelorane, quinpirole, ropinirole, sumanirole, or talipexole.
30. A method of treating non-functioning pituitary adenoma (NFPA) in a patient, comprising: a. first, administering a non-peptidic small molecule somatostatin receptor (SSTR) agonist to the patient in need thereof; b. then, resecting a portion of the non-functioning pituitary adenoma (NFPA).
31. The method of claim 30, wherein administering the non-peptidic small molecule SSTR agonist induces a therapeutic effect.
32. The method of claim 31, wherein the therapeutic effect is an inhibition of growth of the NFPA.
33. The method of claim 31, wherein the therapeutic effect is a decrease in size of the NFPA.
34. The method of any one of claims 30-33, wherein the non-peptidic small molecule SSTR agonist is a selective agonist.
35. The method of claim 34, wherein the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist.
36. The method of any one of claims 30-35, wherein the non-peptidic small molecule SSTR agonist is a pan-SSTR agonist.
37. The method of any one of claims 30-33, wherein the non-peptidic small molecule SSTR agonist is a 4-(4-aminopiperidin-1-yl)-quinoline compound, 4-[octahydro-1H-pyrido[3,4- b]morpholin-6-yl]-quinoline compound, 4-[3-(aminomethyl)azetidin-1-yl]-quinoline compound, 4-(4-aminopiperidin-1-yl)-pyridine compound, or 4-[3-amino-pyrrolidin-1-yl]- pyridine-3-carboxamide compound, or a pharmaceutically acceptable salt, or solvate thereof.
38. The method of any one of claims 30-33, wherein the non-peptidic small molecule SSTR agonist is a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
39. A method of reducing the rate of proliferation of pituitary adenoma cells, the method comprises contacting said pituitary adenoma cells with a non-peptidic small molecule somatostatin receptor (SSTR) agonist.
40. The method of claim 39, wherein the non-peptidic small molecule SSTR agonist is a selective agonist.
41. The method of claim 40, wherein the non-peptidic small molecule SSTR agonist is an SSTR2 selective, SSTR3 selective, SSTR5 selective, or SSTR2/4 selective agonist.
42. The method of claim 39, wherein the non-peptidic small molecule SSTR agonist is a pan- SSTR agonist.
43. The method of claim 39, wherein the non-peptidic small molecule SSTR agonist is a 4-(4- aminopiperidin-1-yl)-quinoline compound, 4-[octahydro-1H-pyrido[3,4-b]morpholin-6-yl]- quinoline compound, 4-[3-(aminomethyl)azetidin-1-yl]-quinoline compound, 4-(4- aminopiperidin-1-yl)-pyridine compound, 4-[3-amino-pyrrolidin-1-yl]-pyridine compound, 4- (3-(aminomethyl)azetidin-1-yl)-pyridine compound, or 4-(octahydro-1H-pyrido[3,4- b]morpholin-6-yl)-pyridine compound, or a pharmaceutically acceptable salt, or solvate thereof.
44. The method of claim 39, wherein the non-peptidic small molecule SSTR agonist is a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
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