Non-peptide somatostatin type 5 receptor agonists and uses thereof

Abstract

Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of diseases, disorders, or conditions that would benefit from modulation of somatostatin activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,764, filed August 14, 2019, which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. DK115290 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Described herein are compounds that are somatostatin modulators, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods for using such compounds in the treatment of diseases, disorders, or conditions that would benefit from modulating somatostatin activity. [Background technology]

[0004] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six somatostatin receptor protein subtypes have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5), encoded by five different somatostatin receptor genes. Modulation of specific somatostatin receptor subtypes, or combinations thereof, is attractive for the treatment of diseases, disorders, or conditions that would benefit from modulation of somatostatin activity. Summary of the Invention

[0005] The compounds described herein are somatostatin modulator compounds. In some embodiments, the compounds described herein modulate one or more somatostatin receptor subtype proteins. In some embodiments, the compounds described herein modulate one somatostatin receptor subtype. In some embodiments, the compounds described herein modulate the SST5 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. Octreotide has also been reported to be used as a treatment for congenital hyperinsulinism (CHI, often referred to as congenital hyperinsulinism of infancy or persistent hyperinsulinemic hypoglycemia of early childhood), a condition in which individuals have abnormally high levels of insulin, leading to frequent episodes of low blood sugar (hypoglycemia). Depot formulations of these peptide drugs are prohibitively expensive and require frequent visits to the doctor for painful injections that can cause injection site reactions. The compounds described herein are structurally distinct molecules from peptide analogs. The compounds described herein are somatostatin modulators that selectively activate somatostatin receptor subtype 5 (SSTR5), which inhibits insulin secretion, promotes glucose release, and also inhibits GH secretion.

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

[0007] [ka] During the ceremony, Ring A is a carbocyclic or heterocyclic ring; X is N or CR a and Y is N or CR b and Z is N or CR c and R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle; R f Ha-L 1 -R g and L 1 is absent, C1-C6 alkylene, C1-C6 fluoroalkylene, or C1-C6 heteroalkylene; R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic heterocycle; R 1 and R 2 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C5 heterocycloalkyl; R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 4 and R 5 are each independently hydrogen, halogen, or -OR9 , -N(R 9 )2, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 8 , R11 , and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2, Or R 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting them form a fused substituted or unsubstituted carbocyclic ring or a fused substituted or unsubstituted heterocyclic ring, R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 10are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; and n is 0 to 3.

[0008] Any combination of the groups described above in various variations is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0009] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal via intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal via oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0010] Also described herein are methods for treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor activity, comprising administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered orally. In some embodiments, the disease or condition is persistent or recurrent hyperinsulinemia, hypoglycemia, acromegaly, neuroendocrine tumors, insulinoma, Cushing's disease, an eye disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or a combination thereof. In some embodiments, the disease or condition is hyperinsulinemic hypoglycemia. In some embodiments, the disease or condition is hypoglycemia due to endogenous insulin, drug-induced hyperinsulinism, or exogenous insulin.

[0011] In any of the foregoing aspects, further embodiments are provided, wherein an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation, and / or (e) administered intranasally, or / and (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by eye drops, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0012] In any of the foregoing aspects, further embodiments comprising a single administration of an effective amount of the compound include further embodiments in which the compound is administered to the mammal once daily, or in which the compound is administered to the mammal multiple times over the span of a day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0013] In any of the embodiments disclosed herein, the mammal is a human.

[0014] In some embodiments, the compounds provided herein are administered orally to a human.

[0015] An article of manufacture is provided that includes packaging material; a compound of Formula (I) or a pharmaceutically acceptable salt thereof within the packaging material; and a label indicating that the compound or composition, or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically acceptable active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used to modulate one or more somatostatin receptor subtype proteins or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that would benefit from modulation of one or more somatostatin receptor subtype proteins.

[0016] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It will be understood, however, that the detailed description and the specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0017] Somatostatin (SST), also known as somatotropin-releasing inhibitory factor (SRIF), was originally isolated as a 14-amino acid peptide from sheep hypothalamus (Brazeau et al., Science 179, 77–79, 1973). An N-terminally extended 28-amino acid peptide with similar biological activity to the 14-amino acid somatostatin was subsequently isolated (Pradayrol et al., FEBS Letters, 109, 55–58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827–6831, 1980). SST is a regulatory peptide produced by multiple cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts via 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 intestine and have multiple functions, including regulating the secretion of growth hormone (GH), insulin, and glucagon, as well as many other hormones that are antiproliferative.

[0018] These pleiotropic actions of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5), which 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 receptors are members of the A-class subgroup of the GPCR superfamily.

[0019] It is possible to selectively modulate any one or a combination of somatostatin receptor subtypes, and in some embodiments, selectively modulating any one somatostatin receptor subtype relative to other somatostatin receptor subtypes reduces undesirable side effects in various clinical applications.

[0020] In one aspect, the compounds described herein are modulators of SSTR5. In some embodiments, the compounds described herein selectively modulate the activity of SSTR5 relative to other somatostatin receptors. In some embodiments, the compounds described herein selectively modulate the activity of SSTR5 relative to SSTR2.

[0021] In some embodiments, the compounds described herein are amenable to oral administration to a mammal in need of treatment with a somatostatin modulator.

[0022] In some embodiments, the somatostatin receptor modulators described herein have utility across a wide range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of various diseases or conditions, including, but not limited to, acromegaly, neuroendocrine tumors, and hyperinsulinism. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of hyperinsulinism in a mammal.

[0023] In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals. In some embodiments, the compounds are used to suppress specific endocrine secretions, including, but not limited to, GH, IGF-1, and insulin. Suppression of specific endocrine secretions is useful for treating conditions such as acromegaly, hyperinsulinism, endocrine tumors, such as carcinoids, VIP tumors, insulinomas, and glucagonomas. In some embodiments, the somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach, and intestine for the treatment of conditions such as pancreatitis, fistulas, bleeding ulcers, and diarrhea associated with diseases such as AIDS or cholera. Diseases involving autocrine or paracrine secretion of trophic factors such as IGF-1 (as well as multiple endocrine factors) that can be treated by administration of the compounds described herein include cancers of the breast, prostate, and lung (both small cell and non-small cell epidermoid), as well as hepatocellular carcinoma, neuroblastoma, insulinoma, adenocarcinoma (ductal type) of the colon and pancreas, chondrosarcoma, and melanoma, retinopathies, and atherosclerosis associated with vascular grafts and restenosis after angioplasty.

[0024] In some embodiments, somatostatin receptor modulators described herein are used to inhibit mediators of neurogenic inflammation (e.g., substance P or tachykinins) and may be used in the treatment of local inflammation such as that associated with rheumatoid arthritis, psoriasis, sunburn, eczema, or other sources of itch, inflammatory bowel disease, irritable bowel syndrome, allergies, including asthma and other respiratory diseases. In other embodiments, somatostatin receptor modulators described herein function as neuromodulators in the central nervous system, useful for the treatment of Alzheimer's disease and other forms of dementia, pain, and headaches. In some embodiments, somatostatin receptor modulators described herein provide cytoprotection in disorders involving splanchnic blood flow, including liver cirrhosis and esophageal varices.

[0025] In some embodiments, somatostatin receptor modulators described herein are used to treat hyperinsulinemia in a mammal. Hyperinsulinemia can lead to several diseases, including, but not limited to, hypoglycemia or low blood sugar, diabetes, or uncontrollable blood sugar that fluctuates between high and low levels, increased risk of polycystic ovary syndrome (PCOS), increased production of very low density lipoprotein (VLDL) (called hypertriglyceridemia), increased risk of cardiovascular or heart disease, coronary artery disease (high insulin levels damage the endothelial cells lining the coronary arteries), hypertension or high blood pressure, an underactive thyroid gland, weight gain, and lethargy.

[0026] Hyperinsulinism refers to higher-than-normal levels of insulin in the blood of a human or animal. Normal insulin secretion and blood concentration are closely related to the level of glucose in the blood, and a given level of insulin may be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly classified into two broad and largely non-overlapping categories: those prone to decreased sensitivity to insulin and high blood glucose levels (hyperglycemia) and those prone to excessive insulin secretion and low blood glucose levels (hypoglycemia).

[0027] Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in young children. It is a heterogeneous disease caused by increased insulin secretion by pancreatic beta-cells. HH can lead to apnea, seizures, developmental delays, learning disabilities, epilepsy, and even death. The most severe form of HH is hereditary and is called congenital hyperinsulinism (CHI). As with many rare diseases, there are no medications specifically tailored for patients with CHI, although there are medications that are suitable for use, including, but not limited to, diazoxide and octreotide.

[0028] The pancreas is the primary site of somatostatin action, which inhibits the synthesis and secretion of two major hormones that control glucose homeostasis: glucagon and insulin. Different somatostatin receptor subtypes control these important processes: the sst2 receptor inhibits glucagon, while both sst2 and sst5 are involved in the inhibition of insulin.

[0029] Hypoglycemia due to excess endogenous insulin can be congenital or acquired and can be evident in the early years of life or years later. Hypoglycemia can be severe and life-threatening, or mild and occasionally unpleasant. The most common type of severe but transient hyperinsulinemic hypoglycemia occurs incidentally in people with type 1 diabetes who take insulin.

[0030] Hypoglycemia due to endogenous insulin includes, but is not limited to, congenital hyperinsulinism, transient neonatal hyperinsulinism, focal hyperinsulinism (KATP channelopathy), diffuse hyperinsulinism, acquired forms of hyperinsulinism, insulinoma (insulin-secreting tumor), adult nesidioblastosis, autoimmune insulin syndrome, hypoglycemia of non-insulinoma pancreatic origin, reactive hypoglycemia, a side effect of gastric bypass surgery, or gastric dumping syndrome.

[0031] Drug-induced hyperinsulinism results from exposure to certain drugs, including, but not limited to, sulfonylureas, aspirin, pentamidine, quinine, disopyramide, Bordetella pertussis vaccine or infection, D-chiro-inositol and myo-inositol.

[0032] Hypoglycemia due to exogenous (injected) insulin includes, but is not limited to, self-injected insulin for the treatment of diabetes (i.e., diabetic hypoglycemia), surreptitiously self-injected insulin (e.g., Munchausen syndrome), self-injected insulin in suicide attempts or suicides, insulin augmentation therapy, and insulin-induced coma for the treatment of depression.

[0033] compound The compound of formula (I), including its pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, is a somatostatin receptor modulator. In some embodiments, the compound of formula (I), including its pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, is an SST5 receptor modulator.

[0034] In some embodiments, the compounds described herein are SST5-selective modulators. In some embodiments, the compounds described herein are at least 10-fold, at least 15-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, or more than 500-fold selective in modulating SST5 receptor activity over SST1, SST2, SST3, and / or SST4 receptor activity. In some embodiments, the compounds described herein are at least 10-fold, at least 15-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, or more than 500-fold selective in modulating SST5 receptor activity over SST2 receptor activity.

[0035] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0036] [ka] During the ceremony, Ring A is a carbocyclic or heterocyclic ring; X is N or CR a and Y is N or CR b and Z is N or CR c and R a , Rb , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle; R f Ha-L 1 -R g and L 1 is absent, C1-C6 alkylene, C1-C6 fluoroalkylene, or C1-C6 heteroalkylene; R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic heterocycle; R 1 and R 2 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C5 heterocycloalkyl; R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9)2, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 8 , R 11 , and R 12are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2, Or R 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting them form a fused substituted or unsubstituted carbocyclic ring or a fused substituted or unsubstituted heterocyclic ring, R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 10are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; and n is 0 to 3.

[0037] For any or all of the embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, R 1 and R 2 are independently hydrogen, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. 1 and R 2 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 and R 2 are independently hydrogen or C1-C6 alkyl. In some embodiments, R 1 is hydrogen, and R 2 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl. 1 is hydrogen, and R 2 is hydrogen or C1-C6 alkyl. In some embodiments, R 1 and R 2 are hydrogen atoms.

[0038] In some embodiments, R 3is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl. 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 3 is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, or substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 3 is hydrogen or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 3 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or C1-C6 heteroalkyl. 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl. In some embodiments, R 3is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl. In some embodiments, R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 3 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 3 is hydrogen or C1-C6 alkyl. In some embodiments, R 3 are hydrogen, -CN, -CO2R 9 , -C(=O)N(R 9 )2, or C1-C6 alkyl. In some embodiments, R 3 is hydrogen, —CN, —CO2CH3, —CO2CH2CH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CH3, —CH2OH, —CH2OCH3, —CH2CH2F, —CH2CHF2, or —CH2CF3. In some embodiments, R 3 is hydrogen, —CN, —CO2CH3, —CO2CH2CH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CH3, —CH2OH, —CH2OCH3, or —CH2CHF2. In some embodiments, R 3 is hydrogen, —CH, —CHOH, —CHOCH, —CHCHF, —CHCHF, or —CHCF. In some embodiments, R 3 is hydrogen, —CH, —CHOH, CHOCH, or —CHCHF. In some embodiments, R 3 is hydrogen or -CH3. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -CH3.

[0039] In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R9 )2, -CN, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. 4 and R 5 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 4 and R 5 are each independently hydrogen or halogen. In some embodiments, R 4 and R 5 are each independently hydrogen or -F.

[0040] In some embodiments, R 1 is hydrogen and R 2 is hydrogen or C1-C6 alkyl, and R 3 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, and R 4 and R 5 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 1 and R 2 are hydrogen, and R 3 is hydrogen or -CH3, and R 4 and R 5 are each hydrogen. In some embodiments, R 1 is hydrogen and R 2 is hydrogen or C1-C6 alkyl, and R 3 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, and R 5is hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 1 is hydrogen and R 2 is hydrogen and R 3 is hydrogen, -CH3, -CH2OH, -CH2OCH3, -CH2CH2F, -CH2CHF2, or -CH2CF3, and R 4 is hydrogen or F, and R 5 is hydrogen or F. In some embodiments, R 1 is hydrogen and R 2 is hydrogen or C1-C6 alkyl, and R 3 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl; R 4 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl, and R 5 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl.

[0041] In some embodiments, the compound has the structure of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0042] [ka]

[0043] In some embodiments, the compound has the structure of Formula (Ia): or a pharmaceutically acceptable salt or solvate thereof.

[0044] [ka]

[0045] In some embodiments, the compound has the structure of Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof.

[0046] [ka]

[0047] In some embodiments, X is CR a and Y is N and Z is CR c or X is CH, Y is N, and Z is CR c or X is CR a and Y is N and Z is CH, or X is N and Y is CR b and Z is CR c or X is CR a and Y is CR b and Z is N, or X is N, Y is N, and Z is CR c or X is CR a and Y is N and Z is N. In some embodiments, X is CR a and Y is N and Z is CR c In some embodiments, X is CH, Y is N, and Z is CR c In some embodiments, X is CR a and Y is N and Z is CH. In some embodiments, X is N and Y is CR b and Z is CR c In some embodiments, X is CR a and Y is CR b and Z is N. In some embodiments, X is N, Y is N, and Z is CR c In some embodiments, X is CR a and Y is N and Z is N.

[0048] In some embodiments, X is N or CH, Y is N or CH, and Z is N or CR c is.

[0049] In some embodiments, Ra , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle. a , R b , and R c are each independently hydrogen, halogen, -CN, or -OR f , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, or a substituted or unsubstituted monocyclic carbocycle. a , R b , and R c are each independently hydrogen, halogen, -CN, or -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or a monocyclic carbocyclic ring. a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl. a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl.

[0050] In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; and R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl. In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, or -CO2R9 is.

[0051] In some embodiments, R a , R b , and R c are each independently hydrogen, -F, -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCF3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, - OCH2CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CH2CO2CH2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -CONHCH3, -C(=O)N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. a , R b , and R c are each independently hydrogen, -F, -Cl, -CN, -CH3, -CF3, -OCH3, -OCH2CH3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, -OCH2CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CO2CH2CH3, or -OCH2CH2CH2CO2CH2CH3. In some embodiments, R a , R b , and R care each independently hydrogen, —CN, —CH, —CF, —OCH, —OCF, —COCH, —C(═O)NH, —CONHCH, or —C(═O)N(CH). In some embodiments, R a , R b , and R c are each independently hydrogen, —CN, —CH, —CF, —OCH, —OCF, —COCH, —C(═O)NH, —CONHCH, or —C(═O)N(CH), or cyclopropyl. a , R b , and R c are each independently hydrogen or —CN.

[0052] In some embodiments, the compound has the structure of Formula (II): or a pharmaceutically acceptable salt or solvate thereof.

[0053] [ka]

[0054] In some embodiments, the compound has the structure of Formula (IIa) or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0055] [ka]

[0056] In some embodiments, the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof.

[0057] [ka]

[0058] In some embodiments, the compound has the structure of Formula (IIb): or a pharmaceutically acceptable salt or solvate thereof.

[0059] [ka]

[0060] In some embodiments, the compound has the structure of Formula (IX): or a pharmaceutically acceptable salt or solvate thereof.

[0061] [ka]

[0062] In some embodiments, the compound has the structure of Formula (IIa) or (IIb), or a pharmaceutically acceptable salt or solvate thereof.

[0063] [ka]

[0064] In some embodiments, the compound has the structure of Formula (X): or a pharmaceutically acceptable salt or solvate thereof.

[0065] [ka]

[0066] In some embodiments, the compound has the structure of Formula (Xa) or (Xb), or a pharmaceutically acceptable salt or solvate thereof.

[0067] [ka]

[0068] In some embodiments, ring A is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl.

[0069] In some embodiments, ring A is phenyl.

[0070] In some embodiments, ring A is a monocyclic heteroaryl and n is 0, 1, or 2. In some embodiments, ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl. In some embodiments, ring A is pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, or pyrimidinyl. In some embodiments, ring A is pyridinyl.

[0071] In some embodiments, Ring A is phenyl or monocyclic heteroaryl. In some embodiments, Ring A is phenyl, or Ring A is pyridinyl, or Ring A is pyrazolyl, thiazolyl, isoxazolyl, or pyrimidinyl. In some embodiments, Ring A is phenyl or pyridinyl.

[0072] In some embodiments, the compound has the structure of Formula (III): or a pharmaceutically acceptable salt or solvate thereof.

[0073] [ka]

[0074] In some embodiments, the compound has the structure of Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt or solvate thereof.

[0075] [ka]

[0076] In some embodiments, the compound has the structure of formula (IV):

[0077] [ka] During the ceremony, A 1 and A 2 are each independently, CR 8 or N, and A 3 is CR 12 Or N.

[0078] In some embodiments, the compound has the structure of Formula (IVa) or (IVb), or a pharmaceutically acceptable salt or solvate thereof:

[0079] [ka]

[0080] In some embodiments, A 1 is CR 8 and A 2 is CR 8 and A 3 is CR 12 or A 1 is N and A 2 is CR 8 and A 3 is CR 12 or A 1 is CR 8 and A 2 is N, and A 3 is CR 12 or A 1 is CR 8 and A 2 is CR 8 and A 3 is N. In some embodiments, A 1 is CR 8 and A 2 is CR 8 and A 3 is CR 12 In some embodiments, A 1is N and A 2 is CR 8 and A 3 is CR 12 In some embodiments, A 1 is CR 8 and A 2 is N, and A 3 is CR 12 In some embodiments, A 1 is CR 8 and A 2 is CR 8 and A 3 is N.

[0081] In some embodiments, the compound has the structure of formula (IVa-1) or (IVb-1), or a pharmaceutically acceptable salt or solvate thereof:

[0082] [ka] During the ceremony, A 1 is CR 8 and A 2 is CR 8 or A 1 is N, and A 2 is CR 8 or A 1 is CR 8 and A 2 is N.

[0083] In some embodiments, the compound has the structure of formula (IVa-2), (IVb-2), (IVa-3), (IVb-3), (IVa-4), (IVb-4), (IVa-5), or (IVb-5), or a pharmaceutically acceptable salt or solvate thereof.

[0084] [ka]

[0085] In some embodiments, the compound has the structure of Formula (V):

[0086] [ka] During the ceremony, A 2 is CR 8 Or N.

[0087] In some embodiments, the compound has the structure of Formula (Va) or (Vb), or a pharmaceutically acceptable salt or solvate thereof.

[0088] [ka]

[0089] In some embodiments, the compound has the structure of Formula (Va-1), (Vb-1), (Va-2), or (Vb-2), or a pharmaceutically acceptable salt or solvate thereof.

[0090] [ka]

[0091] In some embodiments, R 8 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted monocyclic carbocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 8are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 In some embodiments, R 8 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. 8 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 8 are each independently hydrogen or halogen. In some embodiments, R 8 are each independently hydrogen, —F, or —Cl.

[0092] In some embodiments, the compound has the structure of formula (Va-3) or (Vb-3), or a pharmaceutically acceptable salt or solvate thereof.

[0093] [ka]

[0094] In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 , substituted or unsubstituted monocyclic C3-C8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or substituted or unsubstituted monocyclic C1-C5 heteroaryl. 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic carbocycle. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, -CH, -CF, -OCH, -OCF, or -OCHF. In some embodiments, R 11 and R 12 are each independently a halogen. In some embodiments, R 11 and R 12 are each independently -F or -Cl. In some embodiments, R 11 and R 12 are -F respectively.

[0095] In some embodiments, R 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 and together with the atoms connecting them form a fused substituted or unsubstituted carbocyclic ring or a fused substituted or unsubstituted heterocyclic ring. 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting R to form a fused substituted or unsubstituted C3-C8 cycloalkyl or a fused substituted or unsubstituted C2-C5 heterocycloalkyl. 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting R to form a fused substituted or unsubstituted C-C heterocycloalkyl. 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting them to form a fused substituted or unsubstituted dioxolane or a fused substituted or unsubstituted dioxane.

[0096] In some embodiments, R 8 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 and R 11 and R 12are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 8 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic carbocycle. In some embodiments, R 8 are each independently hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 8are each independently hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 8 are each independently hydrogen, -F, or -Cl, and R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, -CH3, -CF3, -OCH3, -OCF3, or -OCHF2.

[0097] In some embodiments, the compound has the structure of Formula (VI): or a pharmaceutically acceptable salt or solvate thereof.

[0098] [ka]

[0099] In some embodiments, R 3 is hydrogen or -CH3, and R 8 is hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 and R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; and R f Ha-L 1 -R g and L1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R 9 )2, a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl.

[0100] In some embodiments, the compound has the structure of Formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof.

[0101] [ka]

[0102] In some embodiments, R 3 is hydrogen or -CH3, and R 8 is hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 and R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; and R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R9 )2, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl. In some embodiments, R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, or -CO2R 9 is.

[0103] In some embodiments, R 8 is hydrogen, -F, or -Cl, and R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, -CH3, -CF3, -OCH3, -OCF3, or -OCHF2, and R care hydrogen, -F, -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCF3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, -OCH2 CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CH2CO2CH2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -CONHCH3, -C(=O)N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. c is hydrogen, -F, -Cl, -CN, -CH3, -CF3, -OCH3, -OCH2CH3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, -OCH2CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CO2CH2CH3, or -OCH2CH2CH2CO2CH2CH3. In some embodiments, R c is hydrogen, —CN, —CH, —CF, —OCH, —OCF, —COCH, —C(═O)NH, —CONHCH, or —C(═O)N(CH), or cyclopropyl. c is hydrogen, -CN, -CH3, -CF3, -OCH3, -OCF3, -CO2CH3, -C(=O)NH2, -CONHCH3, or -C(=O)N(CH3)2.

[0104] In some embodiments, the compound has the structure of formula (VIa-1) or (VIb-1), or a pharmaceutically acceptable salt or solvate thereof:

[0105] [ka]

[0106] In some embodiments, R 3 is hydrogen or -CH3, and R c is hydrogen, —CN, —CH, —CF, —OCH, —OCF, —COCH, —C(═O)NH, —CONHCH, or —C(═O)N(CH). In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, -CH, -CF, -OCH, -OCF, or -OCHF. In some embodiments, R 11 and R 12 are each independently a halogen. In some embodiments, R 11 and R 12 are each independently -F or -Cl. In some embodiments, R 11 and R 12 are -F respectively.

[0107] In some embodiments, ring A is a bicyclic heteroaryl. In some embodiments, ring A is a 9- or 10-membered bicyclic heteroaryl. In some embodiments, ring A is indolyl, isoindolyl, indazolyl, benzimidazolyl, azaindolyl, benzisoxazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or quinazolinyl. In some embodiments, ring A is benzimidazolyl, indazolyl, or benzoxadiazolyl. In some embodiments, ring A is benzimidazolyl.

[0108] In some embodiments, the compound has the structure of Formula (VII):

[0109] [ka] During the ceremony, R 8 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C6 cycloalkyl.

[0110] In some embodiments, the compound has the structure of Formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof:

[0111] [ka]

[0112] In some embodiments, R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1-R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, or -CO2R 9 In some embodiments, R 8 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3, and R c are hydrogen, -F, -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCF3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, -OCH2 CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CH2CO2CH2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -CONHCH3, -C(=O)N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. 8 is hydrogen, -CH3, -CH2CH3, and R cis hydrogen, -F, -F, -Cl, -CN, -CH, -CF, -OCH, -OCHCH, -OCHCHF, -OCHCF, -OCHCHOCH, -O-(cyclopropyl), -O-CH-(cyclopropyl), -O-CH-(phenyl), -OCHCOH, -OCHCHCOH, -OCHCHCHCOH, -OCHCOCH, -OCHCHCOCH, -OCHCHCOCH, -OCHCHCOCH, -OCHCOCHCH, -OCHCOCHCH, -OCHCOCHCH, or -OCHCHCHCOCHCH. In some embodiments, R c is hydrogen, —CN, —CH, —CF, —OCH, —OCF, —COCH, —C(═O)NH, —CONHCH, or —C(═O)N(CH), or cyclopropyl. c is hydrogen, -CN, -CH3, -CF3, -OCH3, -OCF3, -CO2CH3, -C(=O)NH2, -CONHCH3, or -C(=O)N(CH3)2.

[0113] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0114] In some embodiments,

[0115] [ka] teeth,

[0116] [ka] wherein A 1 and A 2 are each independently, CR 8or N, and A 3 is CR 12 or N. In some embodiments,

[0117] [ka] teeth,

[0118] [ka] wherein A 2 is CR 8 or N. In some embodiments,

[0119] [ka] teeth,

[0120] [ka] In some embodiments,

[0121] [ka] teeth,

[0122] [ka] In some embodiments,

[0123] [ka] teeth

[0124] [ka] In some embodiments,

[0125] [ka] teeth,

[0126] [ka] In some embodiments,

[0127] [ka] teeth,

[0128] [ka] In some embodiments,

[0129] [ka] teeth,

[0130] [ka] where R 8 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C6 cycloalkyl.

[0131] In some embodiments, R 7 is hydrogen, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C fluoroalkyl, substituted or unsubstituted C-C cycloalkyl, or substituted or unsubstituted C-C heterocycloalkyl. 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted 3- or 4-membered heterocycloalkyl. In some embodiments, R 7is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 7 is hydrogen or C1-C6 alkyl. In some embodiments, R 7 is hydrogen or -CH3. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -CH3.

[0132] In some embodiments, R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl, R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0133] In some embodiments, R 6 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 fluoroalkyl, or substituted or unsubstituted C1-C8 heteroalkyl. 6 is C1-C8 alkyl, C1-C8 fluoroalkyl, or substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl. In some embodiments, R 6is C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl. In some embodiments, R 6 is a substituted or unsubstituted C1-C8 alkyl, or a substituted or unsubstituted C1-C8 fluoroalkyl. In some embodiments, R 6 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 6 is C1-C6 alkyl or C1-C6 fluoroalkyl. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C6 fluoroalkyl. In some embodiments, R 6 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)(CH2CH3), -CH(CH2CH2CH3)(CH2CH3), -C(CH3)(CHCH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)(CH3), -CH(CF3)(CH2CH3), -CH2CF2CH3, or -CH(CH3)(CH2CF3). In some embodiments, R 6 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)(CH2CH3), -CH2CF3, -CH(CF3)(CH3), or -CH(CF3)(CH2CH3).

[0134] In some embodiments, R 6 Ha-L 2 -R 6a is.

[0135] In some embodiments, L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b In some embodiments, L 2is absent, substituted or unsubstituted C1-C6 alkylene, or -CHR 6b In some embodiments, L 2 is absent, C1-C6 alkylene, or -CHR 6b In some embodiments, L 2 is absent, C1-C4 alkylene, or -CHR 6b In some embodiments, L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b In some embodiments, L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b In some embodiments, L 2 is -CH2- or -CHR 6b In some embodiments, L 2 is —CH2—, —CH(CH3)—, or —CH(CF3)—.

[0136] In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or C-C cycloalkyl. In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or C-C cycloalkyl. In some embodiments, R 6b is hydrogen, —CH, —CHCH, —CHCH, —CH(CH), —CHF, —CHF, —CF, cyclopropyl, or cyclobutyl. 6bis hydrogen, —CH, —CHF, —CF, cyclopropyl, or cyclobutyl. In some embodiments, R 6b is hydrogen, —CH, —CF, or cyclopropyl. In some embodiments, R 6b is hydrogen, -CH3, or -CF3.

[0137] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted polycyclic C5-C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, substituted or unsubstituted polycyclic C5-C 10 In some embodiments, R is a heterocycloalkyl, a substituted or unsubstituted monocyclic C-C heteroaryl, or a substituted or unsubstituted bicyclic C-C heteroaryl. 6a is a substituted or unsubstituted monocyclic C3-C6 cycloalkyl, a substituted or unsubstituted bridged C5-C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 In some embodiments, R is cycloalkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, or substituted or unsubstituted naphthyl. 6a is a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, a substituted or unsubstituted bridged C5-C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 It is a heterocycloalkyl, a substituted or unsubstituted monocyclic C1-C5 heteroaryl, or a substituted or unsubstituted bicyclic C6-C9 heteroaryl.

[0138] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl, or substituted or unsubstituted C1-C9 heteroaryl. In some embodiments, R 6a is a substituted or unsubstituted monocyclic 3- or 4-membered monocyclic cycloalkyl, a 3- or 4-membered monocyclic heterocycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 It is a cycloalkyl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0139] In some embodiments, R 6a is a substituted or unsubstituted C-C cycloalkyl, or a substituted or unsubstituted 3- or 4-membered C-C heterocycloalkyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, or substituted or unsubstituted oxetanyl. In some embodiments, R 6a is a substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl. In some embodiments, R 6a is a substituted or unsubstituted cyclobutyl.

[0140] In some embodiments, L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl, and R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted polycyclic C5-C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, substituted or unsubstituted polycyclic C5-C 10 heterocycloalkyl, substituted or unsubstituted monocyclic C-C heteroaryl, or substituted or unsubstituted bicyclic C-C heteroaryl, and R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0141] In some embodiments, L 2 is absent, C1-C4 alkylene, or -CHR 6b - and R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C6 cycloalkyl, a substituted or unsubstituted bridged C5-C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 In some embodiments, R is cycloalkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, or substituted or unsubstituted naphthyl. 6ais a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, a substituted or unsubstituted bridged C5-C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 It is a heterocycloalkyl, a substituted or unsubstituted monocyclic C1-C5 heteroaryl, or a substituted or unsubstituted bicyclic C6-C9 heteroaryl.

[0142] In some embodiments, R 6a is a substituted or unsubstituted C3-C4 cycloalkyl or a substituted or unsubstituted 3- or 4-membered C2-C3 heterocycloalkyl, and R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C4 cycloalkyl. In some embodiments, L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b - and R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, or substituted or unsubstituted oxetanyl, and R 6b is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CH2F, -CF3, cyclopropyl, or cyclobutyl.

[0143] In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle. In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle that is monocyclic, bicyclic, or polycyclic. 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, R 6 and R 7together with the nitrogen to which they are attached form a substituted or unsubstituted monocyclic N-containing heterocycloalkyl or a substituted or unsubstituted polycyclic N-containing heterocycloalkyl. In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted monocyclic N-containing heterocycloalkyl containing 1-2 N atoms, 0-2 O atoms, and 0-1 S. In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted bicyclic N-containing C5-C 10 Forming heterocycloalkyl, bicyclic N-containing C5-C 10 Heterocycloalkyl is a fused bicyclic C5-C 10 Heterocycloalkyl, Bridged Bicyclic C5-C 10 Heterocycloalkyl or spiro bicyclic C5-C 10 It is heterocycloalkyl.

[0144] In some embodiments, R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, and R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6bis hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; Or R 6 and R 7 taken together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycloalkyl.

[0145] In some embodiments, X is N or CH; Y is N or CH; Z is N or CR c and R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1 -R g and L 1 is absent, C1-C6 alkylene, or C1-C6 fluoroalkylene; R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , or -C(=O)N(R 9 )2, R 1 is hydrogen, R 2 is hydrogen or C1-C6 alkyl, R 3 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 5 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 6is C1-C8 alkyl, C1-C8 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle.

[0146] In some embodiments, X is N or CH; Y is N or CH; Z is N or CR c and R c is hydrogen, -CN, -CH3, -CF3, -OCH3, -OCF3, -CO2CH3, -C(=O)NH2, -CONHCH3, or -C(=O)N(CH3)2; R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, -CH3, -CH2OH, -CH2OCH3, -CH2CH2F, -CH2CHF2, or -CH2CF3; R 4 is hydrogen or F, R 5 is hydrogen or F, R6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle.

[0147] In some embodiments, the compound has the structure of Formula (VIII):

[0148] [ka] During the ceremony, Ring A is phenyl or pyridinyl; R a and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9)2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , or -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R 1 is hydrogen, R 2 is hydrogen or C1-C6 alkyl, R 3 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl; R 4 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; R 5 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, R 8 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or a substituted or unsubstituted monocyclic C1-C5 heteroaryl; R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 10 are each independently substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 fluoroalkyl, and n is 0 to 3.

[0149] In some embodiments, the compound has the structure of Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt or solvate thereof:

[0150] [ka]

[0151] In some embodiments, the compound has the structure of Formula (VIIIa-1) or (VIIIb-1), or a pharmaceutically acceptable salt or solvate thereof:

[0152] [ka]

[0153] In some embodiments, R 3 is hydrogen or -CH3, and R 4 and R 5 are hydrogen, and R 8 are each independently hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 is.

[0154] In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic 3- to 4-membered C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C5-C 10 Cycloalkyl, substituted or unsubstituted 6- to 10-membered C6-C 10 Aryl, substituted or unsubstituted monocyclic 3- to 4-membered C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C4-C 10 heterocycloalkyl or substituted or unsubstituted 5- to 10-membered C1-C9 heteroaryl, R6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl.

[0155] In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C4 alkylene, or -CHR 6b - and R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted oxetanyl, or substituted or unsubstituted theitanyl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl.

[0156] In some embodiments, the compound has the structure of formula (IX):

[0157] [ka] During the ceremony, A 1 is CR 8 and A 2 is CR 8 or A 1 is N, and A 2 is CR 8 or A 1 is CR 8 and A 2 is N, R a and R care each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , or -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R 3 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 heteroalkyl; R 4 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; R 5 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, R 8 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or a substituted or unsubstituted monocyclic C1-C5 heteroaryl; R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 fluoroalkyl.

[0158] In some embodiments, the compound has the structure of Formula (IXa) or (IXb), or a pharmaceutically acceptable salt or solvate thereof.

[0159] [ka]

[0160] In some embodiments, the compound has the structure of Formula (VIIIa-1) or (VIIIb-1), or a pharmaceutically acceptable salt or solvate thereof:

[0161] [ka]

[0162] In some embodiments, R 3 is hydrogen or -CH3, and R 4 and R 5 are hydrogen, and R 8 are each independently hydrogen or halogen, and R 11 and R 12 are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 is.

[0163] In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic 3- to 4-membered C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C5-C 10 Cycloalkyl, substituted or unsubstituted 6- to 10-membered C6-C 10Aryl, substituted or unsubstituted monocyclic 3- to 4-membered C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C4-C 10 heterocycloalkyl or substituted or unsubstituted 5- to 10-membered C1-C9 heteroaryl, R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl.

[0164] In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C4 alkylene, or -CHR 6b - and R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted oxetanyl, or substituted or unsubstituted theitanyl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl.

[0165] In some embodiments, R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, or two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, or two R 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 fluoroalkyl. 9 are each independently hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, or two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently C1-C6 alkyl or C1-C6 fluoroalkyl.

[0166] In one aspect, provided herein is a compound of formula (A1), or a pharmaceutically acceptable salt or solvate thereof:

[0167] [ka] During the ceremony, Ring A is a carbocyclic or heterocyclic ring; X is N or CR a and Y is N or CR b and Z is N or CR c and R L is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl; R a , R b , and R care each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle; R f Ha-L 1 -R g and L 1 is absent, C1-C6 alkylene, C1-C6 fluoroalkylene, or C1-C6 heteroalkylene; R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic heterocycle; R 1 and R 2 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C3-C5 heterocycloalkyl; R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9 )2, -CN, -CO2R 9 , -C(=O)N(R 9)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 8 , R 11 , and R 12are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2, Or R 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting them form a fused substituted or unsubstituted carbocyclic ring or a fused substituted or unsubstituted heterocyclic ring, R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 10are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; and n is 0 to 3.

[0168] In some embodiments, R L is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R L is C1-C6 alkyl or C1-C6 fluoroalkyl. In some embodiments, R L is C1-C6 alkyl. In some embodiments, R L is -CH3.

[0169] In some embodiments, R 1 and R 2 are independently hydrogen, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. 1 and R 2 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 and R 2 are independently hydrogen or C1-C6 alkyl. In some embodiments, R 1 is hydrogen, and R 2 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl. 1 is hydrogen, and R 2is hydrogen or C1-C6 alkyl. In some embodiments, R 1 and R 2 are hydrogen atoms.

[0170] In some embodiments, R 1 is hydrogen and R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl, and R L is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 is hydrogen and R 2 is hydrogen, and R L is -CH3.

[0171] In some embodiments, X, Y, Z, R a , R b , R c is as described for formula (I).

[0172] In some embodiments, X is CR a and Y is N and Z is CR c or X is CH, Y is N, and Z is CR c or X is CR a and Y is N and Z is CH, or X is N and Y is CR b and Z is CR c or X is CR a and Y is CR b and Z is N, or X is N, Y is N, and Z is CR c or X is CR a and Y is N and Z is N. In some embodiments, X is N or CH, Y is N or CH, and Z is N or CR c is.

[0173] In some embodiments, R a , R b , and R care each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, and R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, or -CO2R 9 In some embodiments, R a , R b , and R c are each independently hydrogen, -CN, -CH3, -CF3, -OCH3, -OCF3, -CO2CH3, -C(=O)NH2, -CONHCH3 or -C(=O)N(CH3)2, or cyclopropyl.

[0174] In some embodiments, ring A, each R 8 , R 11 , R 12 , and n is as described for formula (I).

[0175] In some embodiments, ring A is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ring A is phenyl or monocyclic heteroaryl. In some embodiments, ring A is phenyl; alternatively, ring A is pyridinyl; alternatively, ring A is pyrazolyl, thiazolyl, isoxazolyl, or pyrimidinyl. In some embodiments, ring A is phenyl or pyridinyl. In some embodiments, ring A is bicyclic heteroaryl. In some embodiments, ring A is benzimidazolyl, indazolyl, or benzoxadiazolyl.

[0176] In some embodiments, R 8are each independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted monocyclic carbocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 8 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 8 are each independently hydrogen or halogen.

[0177] In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 11is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 , substituted or unsubstituted monocyclic C3-C8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or substituted or unsubstituted monocyclic C1-C5 heteroaryl. 11 is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic carbocycle. In some embodiments, R 11is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 11 is halogen, substituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 In some embodiments, R 11 is halogen, C1-C6 fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 is -F, -Cl, -CN, -CF, -OCH, -OCF, or -OCHF. In some embodiments, R 11 is halogen. In some embodiments, R 11 is -F or -Cl. In some embodiments, R 11 is -F. In some embodiments, R 11 is -Cl.

[0178] In some embodiments, R11 is the adjacent R 8 , and ,R 11 and adjacent R 8 and together with the atoms connecting them form a fused substituted or unsubstituted carbocyclic ring or a fused substituted or unsubstituted heterocyclic ring. 11 is the adjacent R 8 , and ,R 11 and adjacent R 8 together with the atom connecting them form a fused substituted or unsubstituted C3-C8 cycloalkyl or a fused substituted or unsubstituted C2-C5 heterocycloalkyl.

[0179] In some embodiments, R 12 is hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, -NR 9 C(=O)R 10 , -NR 9 C(=O)OR 10 , -NR 9 C(=O)N(R 9 )2, -C(R 9 )=N-OR 9 , -SR 9 , -S(=O)R 9 , -SO2R 9 , or -SO2N(R 9 )2. In some embodiments, R 12 is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10, substituted or unsubstituted monocyclic C3-C8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or substituted or unsubstituted monocyclic C1-C5 heteroaryl. 12 is hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C-C cycloalkyl. In some embodiments, R 12 is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, or -OR 9 In some embodiments, R 12 is hydrogen, -F, -Cl, -CN, -CH, -CF, -OCH, -OCF, or -OCHF. In some embodiments, R 12 is hydrogen or halogen. In some embodiments, R 12 is hydrogen, -F, or -Cl.

[0180] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0181] In some embodiments,

[0182] [ka] teeth,

[0183] [ka] and In the formula, A 1 and A 2are each independently, CR 8 or N, and A 3 is CR 12 or N. In some embodiments,

[0184] [ka] teeth,

[0185] [ka] wherein A 2 is CR 8 or N. In some embodiments,

[0186] [ka] teeth,

[0187] [ka] In some embodiments,

[0188] [ka] teeth,

[0189] [ka] In some embodiments,

[0190] [ka] teeth

[0191] [ka] In some embodiments,

[0192] [ka] teeth,

[0193] [ka] In some embodiments,

[0194] [ka] teeth,

[0195] [ka] In some embodiments,

[0196] [ka] teeth,

[0197] [ka] where R 8 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C6 cycloalkyl.

[0198] In some embodiments, R 6 and R 7 is as described for formula (I).

[0199] In some embodiments, R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C4 cycloalkyl, or substituted or unsubstituted 3- or 4-membered heterocycloalkyl. In some embodiments, R 7is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 7 is hydrogen or C1-C6 alkyl.

[0200] In some embodiments, R 6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl, R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0201] In some embodiments, R 6 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 fluoroalkyl, or substituted or unsubstituted C1-C8 heteroalkyl. 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl. In some embodiments, R 6 is a substituted or unsubstituted C1-C8 alkyl, or a substituted or unsubstituted C1-C8 fluoroalkyl. In some embodiments, R 6 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C1-C6 fluoroalkyl. In some embodiments, R 6 is C1-C6 alkyl or C1-C6 fluoroalkyl.

[0202] In some embodiments, R 6 Ha-L 2 -R 6a is.

[0203] In some embodiments, L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b In some embodiments, L 2 is absent, substituted or unsubstituted C1-C6 alkylene, or -CHR 6b In some embodiments, L 2 is absent, C1-C6 alkylene, or -CHR 6b In some embodiments, L 2 is absent, C1-C4 alkylene, or -CHR 6b In some embodiments, L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b In some embodiments, L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b In some embodiments, L 2 is -CH2- or -CHR 6b In some embodiments, L 2 is —CH2—, —CH(CH3)—, or —CH(CF3)—.

[0204] In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or C-C cycloalkyl. In some embodiments, R6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or C-C cycloalkyl. In some embodiments, R 6b is hydrogen, —CH, —CHCH, —CHCH, —CH(CH), —CHF, —CHF, —CF, cyclopropyl, or cyclobutyl. 6b is hydrogen, —CH, —CHF, —CF, cyclopropyl, or cyclobutyl. In some embodiments, R 6b is hydrogen, —CH, —CF, or cyclopropyl. In some embodiments, R 6b is hydrogen, -CH3, or -CF3.

[0205] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted polycyclic C5-C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, substituted or unsubstituted polycyclic C5-C 10 In some embodiments, R is a heterocycloalkyl, a substituted or unsubstituted monocyclic C-C heteroaryl, or a substituted or unsubstituted bicyclic C-C heteroaryl. 6a is a substituted or unsubstituted monocyclic C3-C6 cycloalkyl, a substituted or unsubstituted bridged C5-C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 In some embodiments, R is cycloalkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, or substituted or unsubstituted naphthyl. 6a is a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, a substituted or unsubstituted bridged C5-C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C5-C 10It is a heterocycloalkyl, a substituted or unsubstituted monocyclic C1-C5 heteroaryl, or a substituted or unsubstituted bicyclic C6-C9 heteroaryl.

[0206] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl, or substituted or unsubstituted C1-C9 heteroaryl. In some embodiments, R 6a is a substituted or unsubstituted monocyclic 3- or 4-membered monocyclic cycloalkyl, a 3- or 4-membered monocyclic heterocycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 It is a cycloalkyl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0207] In some embodiments, R 6a is a substituted or unsubstituted C-C cycloalkyl, or a substituted or unsubstituted 3- or 4-membered C-C heterocycloalkyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, or substituted or unsubstituted oxetanyl. In some embodiments, R 6a is a substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl. In some embodiments, R 6a is substituted or unsubstituted cyclopropyl. In some embodiments, R 6a is a substituted or unsubstituted cyclobutyl.

[0208] In some embodiments, R6 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 fluoroalkyl, a substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, substituted or unsubstituted C1-C8 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl, and R 6b is hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6 is C1-C8 alkyl, C1-C8 fluoroalkyl, substituted or unsubstituted C1-C8 heteroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted polycyclic C5-C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, substituted or unsubstituted polycyclic C5-C 10 heterocycloalkyl, substituted or unsubstituted monocyclic C-C heteroaryl, or substituted or unsubstituted bicyclic C-C heteroaryl, and R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0209] In some embodiments, R 6is C1-C6 alkyl, C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C4 alkylene, or -CHR 6b - and R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 6a is a substituted or unsubstituted monocyclic C3-C6 cycloalkyl, a substituted or unsubstituted bridged C5-C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 In some embodiments, R is cycloalkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, or substituted or unsubstituted naphthyl. 6a is a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, a substituted or unsubstituted bridged C5-C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C5-C 10 It is a heterocycloalkyl, a substituted or unsubstituted monocyclic C1-C5 heteroaryl, or a substituted or unsubstituted bicyclic C6-C9 heteroaryl.

[0210] In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C4 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C4 cycloalkyl or a substituted or unsubstituted 3- or 4-membered C2-C3 heterocycloalkyl, and R 6bis hydrogen, C-C alkyl, C-C fluoroalkyl, or substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, or -L 2 -R 6a and L 2 is absent or is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CHR 6b - and R 6a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl, or substituted or unsubstituted oxetanyl, and R 6b is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CH2F, -CF3, cyclopropyl, or cyclobutyl.

[0211] In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycle. In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted monocyclic N-containing heterocycloalkyl containing 1-2 N atoms, 0-2 O atoms, and 0-1 S.

[0212] In some embodiments, X is N or CH; Y is N or CH; Z is N or CR c and R c are hydrogen, halogen, -CN, -N(R 9 )2, -OR f, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, or substituted or unsubstituted C1-C6 heteroalkyl; R f Ha-L 1 -R g and L 1 is absent, C1-C6 alkylene, or C1-C6 fluoroalkylene; R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , or -C(=O)N(R 9 )2, R 1 is hydrogen, R 2 is hydrogen or C1-C6 alkyl, R L is C1-C6 alkyl or C1-C6 fluoroalkyl; R 6 is C1-C8 alkyl, C1-C8 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle.

[0213] In some embodiments, X is N or CH; Y is N or CH; Z is N or CR c and R c is hydrogen, -F, -Cl, -CN, -CH3, -CF3, -OCH3, -OCH2CH3, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, -O-(cyclopropyl), -O-CH2-(cyclopropyl), -O-CH2-(phenyl), -OCH2CO2H, -OCH2CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CO2CH3, -OCH2CH2CO2CH3, -OCH2CH2CH2CO2CH3, -OCH2CH2CO2CH2CH3, -OCH2CH2CO2CH2CH3, or -OCH2CH2CH2CO2CH2CH3; R 1 is hydrogen, R 2 is hydrogen, R L is C1-C6 alkyl, R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6bis hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, Or R 6 and R 7 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle.

[0214] In some embodiments, the compound has the structure of Formula (A2):

[0215] [ka] During the ceremony, Ring A is phenyl or pyridinyl; R a and R c are each independently hydrogen, halogen, -CN, -N(R 9 )2, -OR f , -CO2R 9 , -C(=O)N(R 9 )2, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, substituted or unsubstituted monocyclic C3-C6 cycloalkyl, or substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R f Ha-L 1 -R g and L 1 is absent or is C1-C6 alkylene, R g is hydrogen, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -CO2R 9 , or -C(=O)N(R 9 )2, or a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl; R 1 is hydrogen, R 2is hydrogen or C1-C6 alkyl, R L is C1-C6 alkyl or C1-C6 fluoroalkyl; R 6 is C1-C6 alkyl, C1-C6 fluoroalkyl, or -L 2 -R 6a and L 2 is absent, C1-C6 alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3-C4 cycloalkyl, a substituted or unsubstituted monocyclic or bicyclic C5-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted monocyclic C2-C3 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C4-C 10 heterocycloalkyl or substituted or unsubstituted C1-C9 heteroaryl; R 6b is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or substituted or unsubstituted monocyclic C3-C4 cycloalkyl; R 7 is hydrogen or C1-C6 alkyl, R 8 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OR 9 , -CO2R 9 , -C(=O)N(R 9 )2, -N(R 9 )2, or -NR 9 C(=O)R 10 or a substituted or unsubstituted monocyclic C3-C8 cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic C2-C5 heterocycloalkyl, or a substituted or unsubstituted monocyclic C1-C5 heteroaryl; R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl; Or, two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 fluoroalkyl; n is 0 to 3.

[0216] In some embodiments, R 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, or two R on the same N atom 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. 9 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, or two R 9 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 fluoroalkyl. 9 are each independently hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, or two R on the same N atom 9together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle, and R 10 are each independently C1-C6 alkyl or C1-C6 fluoroalkyl.

[0217] In some embodiments, the compounds described herein have the structure:

[0218] [ka] During the ceremony,

[0219] [ka] is as listed in Table 1, R 3 is as listed in Table 1, R 4 is as listed in Table 1, R c is as set forth in Table 1, and NR 6 R 7 are as listed in Table 1.

[0220] In some embodiments, the compounds described herein have the structure:

[0221] [ka] During the ceremony,

[0222] [ka] is as listed in Table 2, R c is as set forth in Table 2, and NR 6 R 7 are as listed in Table 2.

[0223] In some embodiments, the compounds described herein have the structure:

[0224] [ka] During the ceremony, R 11 is as listed in Table 3, R 12 is as set forth in Table 3, and NR 6 R 7 are as listed in Table 3.

[0225] In some embodiments, the compounds described herein have the structure:

[0226] [ka] During the ceremony,

[0227] [ka] is as listed in Table 4, R c is as set forth in Table 4, and NR 6 R 7 is as listed in Table 4.

[0228] In some embodiments, the compounds described herein have the structure:

[0229] [ka] During the ceremony, R c is as listed in Table 5, R d is as listed in Table 5, R e is as set forth in Table 5, and NR 6 R7 are as listed in Table 5.

[0230] In some embodiments, the compounds described herein have the structure:

[0231] [ka] During the ceremony, NR 6 R 7 are as listed in Table 6.

[0232] In some embodiments, the compounds described herein have the structure:

[0233] [ka] During the ceremony, R c is as set forth in Table 7, and NR 6 R 7 are as listed in Table 7.

[0234] In some embodiments, the compounds described herein have the structure:

[0235] [ka] During the ceremony, X is N or CR as described herein. a and Y is N or CH; Z is N or CR as described herein. c and R d is as described herein

[0236] [ka] and R eis as described herein

[0237] [ka] and R 6 and R 7 is as described herein.

[0238] In some embodiments, R d is as described herein

[0239] [ka] is.

[0240] In some embodiments, X is N. In some embodiments, X is CR a In some embodiments, X is CH.

[0241] In some embodiments, Y is N. In some embodiments, Y is CH.

[0242] In some embodiments, Z is N. In some embodiments, Z is a CR α- or β-amino group as set forth in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. c In some embodiments, Z is CH.

[0243] In some embodiments, X is CH, Y is N, and Z is CR as described herein, as set forth in Table 1, Table 2, Table 3, Table 4, or Table 5. c is.

[0244] In some embodiments, X is CH, Y is CH, and Z is N.

[0245] In some embodiments, X is N, Y is CH, and Z is CR as described herein, as set forth in Table 7. c is.

[0246] In some embodiments, R d as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7,

[0247] [ka] is.

[0248] In some embodiments, R d as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7,

[0249] [ka] In some embodiments, R d is as described in Table 1.

[0250] [ka] In some embodiments, R d teeth,

[0251] [ka] is.

[0252] In some embodiments, R d is as described in Table 2.

[0253] [ka] In some embodiments, R d teeth,

[0254] [ka] is.

[0255] In some embodiments, R d is as described in Table 3.

[0256] [ka] In some embodiments, R d teeth,

[0257] [ka] is.

[0258] In some embodiments, R d is as described in Table 4.

[0259] [ka] In some embodiments, R d teeth,

[0260] [ka] is.

[0261] In some embodiments, R e as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7,

[0262] [ka] is.

[0263] In some embodiments, R e as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7,

[0264] [ka] In some embodiments, R e teeth,

[0265] [ka] is.

[0266] In some embodiments, R e as described in Table 1, Table 2, Table 3, Table 4, Table 6, or Table 7,

[0267] [ka] In some embodiments, R e teeth,

[0268] [ka] In some embodiments, R e teeth,

[0269] [ka] In some embodiments, R e teeth,

[0270] [ka] In some embodiments, R e teeth,

[0271] [ka] is.

[0272] In some embodiments, R e as described in Table 5

[0273] [ka] In some embodiments, R e teeth,

[0274] [ka] is.

[0275] In some embodiments, R 6 and R 7 is as set forth in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. In some embodiments,

[0276] [ka] is as set forth in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. In some embodiments,

[0277] [ka] teeth,

[0278] [ka]

[0279] [ka] In some embodiments,

[0280] [ka] teeth,

[0281] [ka] is.

[0282] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0283] Exemplary compounds described herein include those set forth in the table below.

[0284] [Table 1-1]

[0285] [Table 1-2]

[0286] [Table 1-3]

[0287] [Table 1-4]

[0288] [Table 1-5]

[0289] [Table 1-6]

[0290] [Table 1-7]

[0291] [Table 1-8]

[0292] [Table 1-9]

[0293]

Table 1-10

[0294]

Table 1-11

[0295]

Table 1-12

[0296]

Table 1-13

[0297]

Table 1-14

[0298]

Table 1-15

[0299]

Table 1-16

[0300]

Table 1-17

[0301]

Table 1-18

[0302]

Table 1-19

[0303]

Table 1-20

[0304]

Table 1-21

[0305]

Table 1-22

[0306]

Table 1-23

[0307]

Table 1-24

[0308]

Table 1-25

[0309]

Table 1-26

[0310]

Table 1-27

[0311]

Table 1-28

[0312]

Table 1-29

[0313] The compounds in Table 1 are named as follows: 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.

[0314] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 1.

[0315] [Table 2-1]

[0316] [Table 2-2]

[0317] [Table 2-3]

[0318] [Table 2-4]

[0319] The compounds in Table 2 are named as follows: 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.

[0320] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 2.

[0321] [Table 3-1]

[0322] [Table 3-2]

[0323] [Table 3-3]

[0324] [Table 3-4]

[0325] The compounds in Table 3 are named as follows: 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[3.3.1.1 3 , 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[3.3.1.1 3 , 7 ]decane-2-carbonyl}-5-(7-chloro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine.

[0326] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 3.

[0327] [Table 4]

[0328] The compounds in Table 4 are named as follows: 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.

[0329] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 4.

[0330] [Table 5-1]

[0331] [Table 5-2]

[0332] The compounds in Table 5 are named as follows: 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.

[0333] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 5.

[0334] [Table 6]

[0335] The compounds in Table 6 are named as follows: 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.

[0336] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 6.

[0337] [Table 7]

[0338] The compounds in Table 7 are named as follows: 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.

[0339] In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds set forth in Table 7.

[0340] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included within the scope of this disclosure.In addition, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0341] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0342] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often correlated with pH, ​​allowing for selective dissolution in any part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, thereby modulating their passage through biological membranes.

[0343] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with an acid. In some embodiments, the compound of Formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucohedral acid. Examples of the carboxylic acids include protonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0344] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0345] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with a base. In some embodiments, the compound of Formula (I) is acidic and reacts with a base. In such a situation, the acidic proton of the compound of Formula (I) is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein cooperate with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0346] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates comprise either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the crystallization process with pharmaceutically acceptable solvents such as water and ethanol.When the solvent is water, hydrates are formed, and when the solvent is alcohol, alcoholates are formed.The solvates of the compounds described herein are conveniently prepared or formed during the process described herein.In addition, the compounds provided herein optionally exist in both solvated and non-solvated forms.

[0347] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds that have the same type of activity.

[0348] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) portion of a compound of Formula (I) is susceptible to various metabolic reactions. By incorporating appropriate substituents into the organic radical, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, halogen, deuterium, an alkyl group, a haloalkyl group, or a deuterated alkyl group.

[0349] In another embodiment, the compounds described herein are isotopically labeled (e.g., with a radioisotope) or labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0350] The compounds described herein include isotopically labeled compounds, which are identical to the compounds detailed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the present compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33and isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one aspect, isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0351] In some embodiments, compounds of Formula (I) have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, compounds of Formula (I) exist in the R configuration. In some embodiments, compounds of Formula (I) exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0352] Individual stereoisomers can be obtained, as appropriate, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, compounds of Formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by forming diastereomeric salts and separating them 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.

[0353] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. A prodrug may be bioavailable, for example, by oral administration, while the parent drug is not. Additionally or alternatively, a prodrug has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug is designed to increase its effective water solubility. An example of a prodrug is, without limitation, a compound described herein, which is administered as an ester (the "prodrug") and then metabolically hydrolyzed to yield the active entity. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, which is metabolized to reveal the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to yield the biologically, pharmaceutically, or therapeutically active form of the compound.

[0354] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38 (each of which is incorporated herein by reference). In some embodiments, the hydroxyl group of the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, etc. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, where the hydroxyl is metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0355] Prodrug forms of the compounds described herein that are metabolized in vivo to produce compounds of formula (I) as described herein are included within the scope of the claims. In some instances, some of the compounds described herein are prodrugs of another derivative or active compound.

[0356] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety, which in some embodiments is as described above.

[0357] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolic products that are then used to provide a desired effect, including a desired therapeutic effect.

[0358] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the entire process by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can cause specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein can optionally be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0359] In some cases, heterocycles may exist in tautomeric forms. In such cases, the structure of the compound is illustrated or named in one tautomeric form, but it is understood that it may also be illustrated or named in an alternative tautomeric form. Alternative tautomeric forms are expressly included in the present disclosure, such as the structures illustrated below. For example, benzimidazole or imidazole can exist in the following tautomeric forms:

[0360] [ka]

[0361] Compound synthesis Compounds of formula (I) are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0362] Unless otherwise specified, conventional methods of mass spectrometry, NMR, and HPLC are employed.

[0363] The compounds are prepared using standard organic chemistry techniques, for example, as described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents, as well as other reaction conditions.

[0364] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0365] [ka]

[0366] Nucleophilic substitution of I with a protected aminopyrrolidine gives intermediate II, which is then reacted with a boronic acid (R dB(OH)2) or its ester or organotrifluoroborate (R d This intermediate was converted to intermediate III via an organometallic coupling reaction, such as the Suzuki-Miyaura reaction with BF3K. Aldehyde III was treated with an oxidizing reagent, such as NaClO2, to generate the corresponding acid IV, which was then coupled with an amine to generate the amide intermediate V in the presence of a coupling reagent, such as HATU or 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez's reagent). Alternatively, aldehyde II was treated with an oxidizing reagent, such as NaClO2, to generate acid VII, which could then be reacted with an amine to generate the amide intermediate VIII in the presence of a coupling reagent, such as HATU. This compound then underwent an organometallic coupling reaction, such as the Suzuki-Miyaura reaction, to generate compound V. Removal of the protecting groups using an appropriate deprotection method afforded the final compound VI.

[0367] In some other embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0368] [ka]

[0369] Nucleophilic substitution of IX with a protected aminopyrrolidine afforded intermediate X, which was then halogenated to give compound XI. d B(OH)2) or its ester or organic trifluoroborate (R dXI was converted to intermediate XII by an organometallic coupling reaction, such as the Suzuki-Miyaura reaction with BF3K. Compound XII was converted to nitrile XIII using an organometallic cyanation reaction, which was treated with an oxidation reagent such as NaClO2 to generate acid XIV. This compound was reacted with an amine to generate amide XV in the presence of a coupling reagent such as HATU. Alternatively, 4,6-dichloronicotinate XVII was converted to nitrile XVIII by an organometallic cyanation reaction, which underwent nucleophilic substitution with a protected aminopyrrolidine to generate intermediate XIX. This compound was then treated with a halogenating reagent such as NBS or 1-bromopyrrolidine-2,5-dione to generate XX. Intermediate XX was converted to XXI using an organometallic coupling reaction, such as the Suzuki-Miyaura reaction, which was hydrolyzed to acid XIV in the presence of base. Intermediate XIX could also be converted to acid XXV, which was reacted with an amine to generate amide XXVI. Subsequent halogenation followed by organometallic coupling reactions such as the Suzuki-Miyaura reaction afforded intermediate XV. Intermediate XXVI was also synthesized by a different method. Nucleophilic substitution of XVII with a protected aminopyrrolidine gave intermediate XXII, which was hydrolyzed under basic conditions and then coupled with an appropriate amine to afford amide XXIII. Subsequent exposure of this compound to organometallic carbonylation conditions converted the resulting ester XIV to the corresponding amide, which could be readily dehydrated to the nitrile XXVI. Removal of the protecting group of intermediate XV using an appropriate deprotection method afforded the final compound XVI.

[0370] In some other embodiments, the compounds described herein are prepared as depicted in Scheme C.

[0371] [ka]

[0372] Nucleophilic substitution of IX with a protected aminopyrrolidine gives intermediate X, which is brominated to give intermediate XI. Compound XI is then converted to intermediate XII by an organometallic coupling reaction such as the Suzuki-Miyaura reaction, which is then subjected to another organometallic coupling reaction to give R c Introduction of the R group afforded XXVIII. Treatment of this compound with an oxidizing reagent such as NaClO2 yielded the acid XXIX, which could be reacted with an amine to give the amide XXX in the presence of a coupling reagent such as HATU or Ghosez's reagent. Alternatively, nucleophilic substitution of 4,6-dichloronicotinate XVII with a protected aminopyrrolidine gave intermediate XXXII, which was hydrolyzed under basic conditions and then coupled with an amine to give the amide XXXIII. c This compound was converted to intermediate XXXIV by organometallic coupling to introduce the aryl group. Halogenation of intermediate XXXIV formed intermediate XXXV, which could be converted to compound XXX by organometallic coupling reactions such as the Suzuki-Miyaura reaction. Alternatively, 4,6-dichloronicotinate XVII was converted to XXXII, which was then converted to XXXVI by organometallic coupling followed by halogenation to give compound XXVII. This compound was converted to intermediate XXXVIII by organometallic coupling reactions such as the Suzuki-Miyaura reaction, which was then hydrolyzed under basic conditions to give acid XXIX. Removal of the protecting group of intermediate XXX using an appropriate deprotection method afforded the final compound XXXI.

[0373] In some other embodiments, the compounds described herein are prepared as depicted in Scheme D.

[0374] [ka]

[0375] Nucleophilic substitution of 4,6-dichloronicotinate XVII with a protected aminopyrrolidine gave intermediate XXXII, which was treated with an alkoxide with or without an organometallic catalyst to produce compound XXXIX. Subsequent halogenation followed by an organometallic coupling reaction, such as the Suzuki-Miyaura reaction, gave intermediate XLI. This compound was converted to acid XLII under basic conditions, which was then coupled with an amine to produce amide XLIII in the presence of a coupling reagent, such as HATU or Ghosez's reagent. Removal of the protecting group from intermediate XLIII using an appropriate deprotection method gave final compound XLIV. Alternatively, ester XXXII was converted to acid XLV under basic conditions, which was then coupled with an amine to produce amide XLVI in the presence of a coupling reagent, such as HATU or Ghosez's reagent. Subsequent halogenation followed by an organometallic coupling reaction, such as the Suzuki-Miyaura reaction, gave intermediate XLVIII. Removal of the protecting group using an appropriate deprotection method followed by treatment with an alkoxide gave final compound XLIV.

[0376] In some other embodiments, the compounds described herein are prepared as depicted in Scheme E.

[0377] [ka]

[0378] Nucleophilic substitution of I with a protected aminopyrrolidine gave intermediate II, which was treated with 1,2-diaminobenzene by heating under atmospheric pressure in moist DMF, NMP, DMSO, or other solvents with or without NaSO to give benzimidazole LII. LII was subsequently converted to ester LIII by organometallic carbonylation. Alternatively, compound II could be converted to ester L by organometallic carbonylation, which was treated with 1,2-diaminobenzene by heating under atmospheric pressure in moist DMF, NMP, DMSO, or other solvents with or without NaSO to give benzimidazole LIII. Alternatively, aldehyde I was reacted with 1,2-diaminobenzene by heating under atmospheric oxygen pressure in wet DMF, NMP, DMSO, or other solvents with or without NaSO to give imidazole LI, which underwent nucleophilic substitution with a protected aminopyrrolidine to generate intermediate LII. Subsequently, ester LIII was converted to acid LIV under basic conditions, which was treated with an amine to generate amide LV in the presence of a coupling reagent such as HATU. Removal of the protecting group using an appropriate deprotection method afforded the final compound LVI.

[0379] In some other embodiments, the compounds described herein are prepared as depicted in Scheme F.

[0380] [ka]

[0381] Nucleophilic substitution of LVII with a protected aminopyrrolidine gave intermediate LVIII, which was converted to compound LIX via organometallic coupling reactions such as the Suzuki-Miyaura reaction. Basic hydrolysis of the ester LIX formed acid LX, which was reacted with an amine in the presence of an amide coupling reagent such as HATU to generate intermediate LXI. Removal of the protecting groups using an appropriate deprotection method afforded the final compound LXII.

[0382] In some other embodiments, the compounds described herein are prepared as depicted in Scheme G.

[0383] [ka]

[0384] Transition metal-catalyzed cyanation of bromopyridine LXIII gave nitrile intermediate LXIV, which was subjected to iodination in the presence of a strong base such as LDA to generate LXV. Compound LXV was converted to intermediate LXVI by an organometallic coupling reaction such as the Suzuki-Miyaura reaction. Subsequent nucleophilic substitution with a protected aminopyrrolidine gave intermediate LXVII, which was hydrolyzed to acid LXVIII under basic conditions. Treatment of compound LXVIII with an amine in the presence of a coupling reagent such as HATU produced amide LXIX. Removal of the protecting group using an appropriate deprotection method gave the final compound LXX. Compound LXIX could be converted to intermediate LXXI by an organometallic coupling reaction such as the Suzuki-Miyaura reaction. Removal of the protecting group using an appropriate deprotection method gave the final compound LXXII.

[0385] In some embodiments, the compounds are prepared as described in the Examples.

[0386] Specific Terms Unless otherwise specified, definitions of the following terms used in this application are provided below. The use of the term "including" and other forms such as "include," "includes," and "included" is non-limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0387] As used herein, C1-C x is C1-C2, C1-C3...C1-Cx By way of example only, a group designated as "C1-C6" indicates that there are 1 to 6 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0388] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight chain. In some embodiments, an "alkyl" group can contain 1 to 10 carbon atoms, i.e., C1-C 10 The term "alkyl" includes alkyl. Numeric ranges such as "1 to 10," whenever they appear herein, refer to each integer within the specified range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0389] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0390] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0391] The term "alkylamine" refers to an -N(alkyl) x H y refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0392] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with a hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0393] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with an amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0394] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0395] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0396] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). The heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0397] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (n ​​is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic and fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0398] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from "heterocyclic" or "heterocycle," in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0399] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C 10 Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0400] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl.

[0401] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0402] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0403] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocycle group has 3 to 10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocycle groups (also known as heterocycloalkyls) contain rings having 3 to 10 atoms in their ring system, and aromatic heterocycle groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, and benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-bonded (or C-linked) or N-bonded where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0404] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain zero to four N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0405] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0406] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a single bond, the reference group is absent, thereby allowing for the formation of a single bond between the remaining specified groups.

[0407] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0408] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituents are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0409] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is selected from the group consisting of halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR 21 , -CO2R 21 , -C(=O)N(R 21 )2, -N(R 21 )2, -NR 21 C(=O)R 22 , -SR 21 , -S(=O)R 22 , -SO2R 22 , or -SO2N(R 21 ) substituted with one or more R groups independently selected from the group consisting of: 21 are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 21 groups together with the N atom to which they are attached form an N-containing heterocycle, and R 22 are each independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0410] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0411] As used herein, the term "modulate" means to interact with a target directly or indirectly so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0412] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0413] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0414] "Co-administration" and like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0415] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic purposes is the quantity of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0416] 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. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0417] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or co-administration of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the auxiliary agent are both administered to a patient at the same time in the form of a single entity or dosage. The term "unfixed combination" means that the active ingredients, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the auxiliary agent are administered to a patient as separate entities simultaneously, concurrently, or sequentially, without any specific intervening time limit, such that such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0418] The terms "article of manufacture" and "kit" are used synonymously.

[0419] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; livestock animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0420] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., suppressing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition prophylactically and / or therapeutically.

[0421] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner, using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the route of administration selected. Summary summaries of pharmaceutical compositions described herein can be found, for example, in The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0422] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by a method that allows delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, although the most appropriate route can depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implantation. Administration may also be by direct injection at the site of the diseased tissue or organ.

[0423] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion in an oil liquid. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0424] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient. All formulations for oral administration should be in a quantity suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize various combinations of active compound dosages.

[0425] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0426] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0427] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0428] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0429] Pharmaceutical compositions can be administered topically, i.e., by non-systemic administration. This includes applying the compounds of the present invention to the epidermis or externally to the buccal cavity, and instilling the compounds into the ears, eyes, and nose so that the compounds do not enter the bloodstream in significant amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0430] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise from 0.001% w / w to 10% w / w, for example 1% to 2% by weight, of the formulation for topical administration.

[0431] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, a nebulizer, a pressurized pack, or other convenient means for delivering an aerosol spray.Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, the formulation can take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch.The powder composition can be presented in a unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0432] For example, in addition to the ingredients specifically mentioned above, it will be understood that the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0433] Dosage and treatment regimens In one embodiment, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from modulation of somatostatin activity. Methods for treating any of the diseases or disorders described herein in a mammal in need of such treatment comprise administering to the mammal a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0434] In some embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0435] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dosage." For this application, the precise amount will vary depending on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition symptoms.

[0436] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise suppress or limit the symptoms of the patient's disease or disorder.

[0437] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, however, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0438] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0439] In general, however, dosages employed in adult human treatment are typically in the range of 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0440] In one embodiment, a suitable daily dosage for a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or effective amount of the active ingredient in the dosage form will be less than or greater than the ranges set forth herein, depending on many variables related to the particular treatment regimen. In various embodiments, the daily dosage amount and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0441] The toxicity and therapeutic efficacy of such treatment regimens may include, but are not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In some embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is the ED400 with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dose varies within this range depending on the dosage form employed and the route of administration utilized.

[0442] In any of the foregoing aspects, in further embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0443] In any of the foregoing aspects, there are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0444] In any of the foregoing aspects, there are further embodiments comprising multiple administrations of an 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 interval between multiple doses is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, in which administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0445] Combination treatment In certain instances, it will be appropriate to administer at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0446] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic effect by itself, but when combined with another therapeutic agent, enhances the overall therapeutic effect on the patient). Alternatively, in some embodiments, the effect experienced by the patient is increased by administering one of the compounds described herein with another agent (including a therapeutic regimen) that also has a therapeutic effect.

[0447] In one particular embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent administered alone.

[0448] In all cases, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic effect.

[0449] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the particular co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0450] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0451] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, and combination therapy are administered before, during, or after the onset of a disease or condition, and the timing of administration of a composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as prophylactics to prevent the onset of a disease or condition and are administered continuously to a subject prone to a disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period necessary to treat the condition. In some embodiments, the period required for treatment varies, and the treatment period is adjusted to suit the specific needs of each subject. [Example]

[0452] As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise specified, shall be understood to have the following meanings: Abbreviation: Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0), Pd2(dba)3·CHCl3: Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, Pd(dppf)Cl2: [1',1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium(II) dichloride, PdAMphos or Pd(amphos)Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(DtBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), DIEA or DIPEA: N,N-diisopropylethylamine, Preparative HPLC: Preparative High Performance Liquid Chromatography; LCMS: liquid chromatography-mass spectrometry; MS: mass spectrometry; AcOH: acetic acid, TFA: trifluoroacetic acid; HCl: Hydrochloric acid or hydrochloride, MeCN or CH3CN or ACN: acetonitrile, H2O: water, DMSO: dimethyl sulfoxide; DMF: dimethylformamide, DCM: dichloromethane, NBS: N-bromosuccinimide, Br2: bromine, NCS: N-chlorosuccinimide; rt: room temperature, SST: somatostatin; SSTR: somatostatin receptor; hrs: hours, h or hr: hours, min:minutes, N2: nitrogen gas, mg: milligram, mL: milliliter, eq. or equiv: equivalent weight, mmol: millimolar, μmol: micromolar, ppts: precipitate, K2CO3: Potassium carbonate, NaClO2: sodium chlorite, t-BuOH: tert-butyl alcohol, EtOAc: ethyl acetate, Na2SO4: sodium sulfate, NaHSO4: sodium bisulfate, Na2S2O3: Sodium thiosulfate.

[0453] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0454] Compound synthesis Example 1. 4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound 1-1)

[0455] [ka]

[0456] Step 1-1, Preparation of tert-butyl (S)-(1-(3-(3,5-dimethylphenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: tert-butyl N-[(3S)-1-(3-bromo-5-formylpyridin-4-yl)pyrrolidin-3-yl]carbamate (120 mg, 1.0 equivalent, 0.32 mmol), "Step 9-1, Example 9"). To a mixture of Pd(t-phenyl)boronic acid (97 mg, 2.0 equiv., 0.65 mmol), Pd(dba)·CHCl (33 mg, 0.10 equiv., 0.032 mmol), P(t-Bu)·HBF (19 mg, 0.20 equiv., 0.064 mmol), and KPO (206 mg, 3.0 equiv., 0.97 mmol) was added toluene (3.0 mL) and water (0.3 mL) under atmospheric nitrogen. The resulting mixture was stirred at 70 °C for 1 h. The reaction solution was concentrated in vacuo, and the remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1:1) to give 100 mg of the title compound. MS (M+H) + =396.5.

[0457] Step 1-2, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-dimethylphenyl)nicotinic acid: To a round-bottom flask was added tert-butyl (S)-(1-(3-(3,5-dimethylphenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (100 mg, 1.0 equiv., 0.25 mmol), tert-butyl alcohol (4.2 mL), DCM (4.2 mL), NaHPO (91 mg, 3.0 equiv., 0.76 mmol), 2-methylbut-2-ene (532 mg, 30 equiv., 7.59 mmol), water (1.4 mL), and NaClO (46 mg, 2.0 equiv., 0.51 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under vacuum, and the remaining residue was diluted with water (10 mL). The pH of the resulting aqueous solution was adjusted to 4, causing the solid product to precipitate. The resulting suspension was filtered, and the solid was collected and dried under vacuum. This resulted in 70 mg of the title compound as a yellow solid. MS (M+H) + =412.5.

[0458] Step 1-3, Preparation of tert-butyl (S)-(1-(3-(3,5-dimethylphenyl)-5-((3,5-dimethylphenyl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate: To a solution of (S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-dimethylphenyl)nicotinic acid (50 mg, 1.0 equiv., 0.12 mmol) in DCM (3.0 mL) was added Ghosez's reagent (33 mg, 2.0 equiv., 0.24 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes, after which pyridine (29 mg, 3.0 equiv., 0.36 mmol) and 3,5-dimethylaniline (18 mg, 1.2 equiv., 0.15 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction crude was concentrated under vacuum, and the remaining residue was purified by preparative HPLC using the following conditions: column, XBridge Shield PR18 OBD, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH₄HCO₃ + 0.1% NH₃·H₂O) and ACN (from 46% phase B to 61% in 6 min); detector, UV 220 & 254 nm. This resulted in 15 mg of the title compound as a pale yellow solid. MS (M+H) + =515.2.

[0459] Step 1-4, Preparation of 4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide: To a solution of tert-butyl (S)-(1-(3-(3,5-dimethylphenyl)-5-((3,5-dimethylphenyl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate in DCM (1.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction crude was concentrated and dried under lyophilization to give 5.6 mg of the TFA salt of 4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide as a pale yellow solid. MS (M+H) + =415.2.

[0460] By appropriate substitution of reagents and substrates at various steps, the following compounds can be prepared similarly to Example 1, which may require additional functional group modification using appropriate reagents according to well-known chemistry. The coupling reaction with aniline can be carried out using other coupling reagents, such as HATU, under appropriate conditions. Various salts, such as HCl, formic acid, or TFA salts, can be obtained.

[0461] [Table 8]

[0462] Example 2. 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound 1-16)

[0463] [ka]

[0464] Step 2-1, Preparation of tert-butyl N-[(3S)-1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl]carbamate: To a solution of 5-bromo-4-chloropyridine-3-carbaldehyde (12 g, 1.0 equivalent, 54 mmol) in MeCN (100 mL) was added tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate (12 g, 1.1 equivalent, 60 mmol) and DIPEA (21 g, 3.0 equivalent, 160 mmol). The resulting solution was stirred at 70 °C for 24 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried, and concentrated. The remaining residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give tert-butyl (S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (18 g, 86%) as a yellow solid. MS (M+H) + =384.1,386.1.

[0465] Step 2-2, Preparation of (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)nicotinic acid: To a solution of tert-butyl (S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (190 mg, 1.0 equiv., 0.49 mmol) in tert-butyl alcohol (9.0 mL) was added 2-methylbut-2-ene (0.66 mL, 12 equiv., 5.9 mmol), sodium chlorite (0.43 g, 7.8 equiv., 3.8 mmol, 85% by weight), sodium dihydrogen phosphate (0.35 g, 5.9 equiv., 2.9 mmol), and water (2.8 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction crude was concentrated to remove most of the tert-butyl alcohol, and saturated NaHSO4 (~2 mL) was added. The resulting aqueous solution was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined, dried, and concentrated to give 160 mg of the title compound as a pale yellow solid. This material was used in the next step without further purification. MS (M+H) + =400.1,402.1.

[0466] Step 2-3, Preparation of tert-butyl (S)-(1-(3-bromo-5-((4,4-difluorocyclohexyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a solution of (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)nicotinic acid (250 mg, 1.0 equiv., 0.63 mmol) in DMF (2.0 mL) was added HATU (356 mg, 1.5 equiv., 0.94 mmol), DIPEA (0.60 mL, 5.5 equiv., 3.4 mmol), and 4,4-difluorocyclohexan-1-amine hydrochloride (161 mg, 1.5 equiv., 0.94 mmol). The resulting mixture was stirred at ambient temperature for 0.5 hours. The reaction crude was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-60%). Pure fractions were combined and concentrated to remove most of the MeCN, neutralized with saturated NaHCO3 (5 mL), added with solid NaCl (15 g), and extracted with ethyl acetate (30 mL). The organic layer was dried over Mg2SO4, filtered, and concentrated to give 270 mg of the title compound. MS (M+H) + =517.2,519.2.

[0467] Step 2-4, Preparation of tert-butyl (S)-(1-(3-((4,4-difluorocyclohexyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: tert-butyl (S)-(1-(3-bromo-5-((4,4-difluorocyclohexyl)carbamoyl)pyridin-4-yl)-3-methyl To a mixture of (3,5-difluorophenyl)pyrrolidin-3-ylcarbamate (90 mg, 1.0 equiv., 0.17 mmol), (3,5-difluorophenyl)boronic acid (55 mg, 2.0 equiv., 0.35 mmol), K2CO3 (72 mg, 3.0 equiv., 0.52 mmol), and Pd(amphos)Cl2 (12 mg, 0.10 equiv., 0.017 mmol) was added dioxane (2.0 mL). Nitrogen gas was bubbled through the reaction solution for 1 minute, and then water (0.20 mL) was added. Nitrogen was bubbled through for an additional 5 minutes. The reaction mixture was heated at 100 °C for 1 hour. The crude reaction was concentrated onto silica gel, and the remaining residue was purified by silica gel chromatography to give 66 mg of the title compound as a clear oil. MS (M+H) + =551.4.

[0468] Step 2-5, Preparation of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)nicotinamide: To a solution of tert-butyl (S)-(1-(3-((4,4-difluorocyclohexyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (66 mg, 1.0 equiv., 0.12 mmol) in DCM (0.8 mL) was added TFA (0.8 mL). The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction crude was concentrated, and the remaining residue was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-35%). The pure fractions were combined, neutralized with saturated NaHCO (4 mL), solid NaCl (8 g) was added, and extracted with ethyl acetate (25 mL). The organic layer was dried over MgSO, filtered, and concentrated with 1.0 M HCl in ethyl acetate (0.3 mL) to give 33 mg of the HCl salt of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)nicotinamide as a white solid. MS (M+H) + =451.2.

[0469] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 2, which may require additional functional group modification using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0470] [Table 9]

[0471] Example 3. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound 1-30)

[0472] [ka]

[0473] Step 3-1, Preparation of tert-butyl (S)-(1-(3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a mixture of tert-butyl (S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (380 mg, 1.0 equivalent, 0.989 mmol), “Step 2-1, Example 2”), (3,5-difluorophenyl)boronic acid (312 mg, 2.0 equivalents, 1.98 mmol), KCO (410 mg, 3.0 equivalents, 2.97 mmol), and Pd(amphos)Cl (35 mg, 0.05 equivalents, 0.050 mmol), dioxane (4.0 mL) and water (0.4 mL) were added. Nitrogen was bubbled through the reaction solution for 5 minutes and the resulting mixture was heated at 100° C. for 1 hour. The crude reaction was concentrated onto silica gel and the remaining residue was purified by silica gel chromatography to give 372 mg of the title compound as a clear oil. MS (M+H) + =418.1.

[0474] Step 3-2, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid: To a solution of tert-butyl (S)-(1-(3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate in tert-butyl alcohol (11 mL) was added 2-methylbut-2-ene (1.2 mL, 12 equivalents, 10.7 mmol), sodium chlorite (0.84 g, 8.9 equivalents, 7.9 mmol, 85% by weight), sodium dihydrogen phosphate (0.75 g, 7.0 equivalents, 6.3 mmol), and water (4.0 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction crude was concentrated to remove most of the tert-butyl alcohol, and saturated NaHSO4 (~3 mL) was added. The resulting aqueous solution was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined, dried, and concentrated to give 370 mg of the title compound. This material was used in the next step without further purification. MS (M+H) + =434.3.

[0475] Step 3-3, Preparation of tert-butyl (S)-(1-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a solution of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid (44 mg, 1.0 equiv., 0.10 mmol) in DMF (0.6 mL) was added HATU (58 mg, 1.5 equiv., 0.15 mmol) and DIPEA (0.2 mL, 11 equiv., 1.0 mmol). The resulting mixture was stirred at ambient temperature for 5 minutes, after which 3,3-difluorocyclobutan-1-amine hydrochloride (44 mg, 3.0 equiv., 0.30 mmol) was added. The resulting mixture was stirred at ambient temperature for 0.5 hours. The crude reaction was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-55%). Pure fractions were combined, concentrated to remove most of the MeCN, neutralized with saturated NaHCO3 (3 mL), added with solid NaCl (5 g), and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give 42 mg of the title compound. MS (M+H) + =534.1.

[0476] Step 3-4, Preparation of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide: To a solution of tert-butyl (S)-(1-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (42 mg, 1.0 equiv., 0.08 mmol) in DCM (0.7 mL) was added TFA (0.7 mL). The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction crude was concentrated, and the remaining residue was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-35%). The pure fractions were combined, neutralized with saturated NaHCO (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over MgSO, filtered, and concentrated with 1.0 M HCl in ethyl acetate (0.10 mL) to give 25 mg of the HCl salt of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide as a white solid. MS (M+H) + =423.2.

[0477] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 3, which may require additional functional group modification using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0478] [Table 10-1]

[0479] [Table 10-2]

[0480] Example 4. 4-[(3S)-3-Aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound 1-71)

[0481] [ka]

[0482] Step 4-1, Preparation of tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: To a DMF (70 mL) solution, 4,6-dichloronicotinaldehyde (6.8 g, 1.0 equiv., 39 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (7.6 g, 1.1 equiv., 41 mmol), and TEA (16 mL, 3.1 equiv., 120 mmol) were added. The resulting mixture was stirred at 50° C. for 4 hours. The reaction crude was quenched with water (100 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1 / 3) to give tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (5.3 g, 42%) as a yellow solid. MS (M+H) + =326.2.

[0483] Step 4-2, Preparation of tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: To a solution of tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (5.3 g, 1.0 equiv., 16 mmol) in AcOH (60 mL) was added NBS (3.1 g, 1.1 equiv., 17 mmol) at 10 °C. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO and extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1 / 4) to give tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (3.5 g, 53%) as a yellow solid. MS (M+H) + =404.1,406.1.

[0484] Step 4-3, Preparation of tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: To a mixture of tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (3.5 g, 1.0 equivalent, 8.6 mmol), (3,5-difluorophenyl)boronic acid (0.88 equivalent, 7.6 mmol, 1.2 g), Pd(DtBPF)Cl (300 mg, 0.05 equivalent, 0.46 mmol), and potassium phosphate (5.4 g, 2.9 equivalent, 25 mmol) was added toluene (140 mL) and water (14 mL) under atmospheric nitrogen. The resulting mixture was stirred at 40 °C for 2 hours. The reaction crude was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (3:1) to give tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (2.7 g, 71%) as a yellow solid. MS (M+H) + =438.0,440.0.

[0485] Step 4-4, Preparation of tert-butyl (S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (2.7 g, 1.0 equiv., To a mixture of Pd(dba) CHCl (310 mg, 0.05 equiv., 0.31 mmol), Zn(CN) (1.4 g, 1.9 equiv., 12 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (720 mg, 0.20 equiv., 1.24 mmol) under atmospheric nitrogen was added DMF (30 mL). The resulting mixture was heated at 135 °C under microwave irradiation for 1 h. The reaction crude was quenched with water (100 mL) and extracted with EtOAc (3 × 40 mL). The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (1:1) to give tert-butyl (S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (2.2 g, 83%) as a yellow solid. MS (M+H) + =429.2.

[0486] Step 4-5, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinic acid: To a solution of (S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (2.4 g, 1.0 equivalent, 5.1 mmol) in tert-butyl alcohol (20 mL), sodium dihydrogen phosphate (2.4 g, 3.0 equivalent, 15 mmol), 2-methylbut-2-ene (11.0 g, 31 equivalents, 157 mmol), sodium chlorite (1.0 g, 2.2 equivalents, 11 mmol), and water (6.6 mL) were added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NaHSO4 (50 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo to give (S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinic acid (2.0 g, 88%) as a yellow solid. This material was used in the next step without purification. MS (M+H) + =445.2.

[0487] Step 4-6, Preparation of tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate: (S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl) To a solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (35 mg, 1.5 equiv., 0.23 mmol), N-ethyl-N-isopropylpropan-2-amine (4.4 equiv., 0.70 mmol, 0.12 mL), and HATU (60 mg, 1.0 equiv., 0.16 mmol) in DMF (2.0 mL) was added. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction crude was purified by preparative HPLC using the following conditions: SunFire Prep C18 OBD Column, 19 * 150 mm 5 μm; mobile phase, water (0.1% FA) and ACN (24.0% ACN to 46.0% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This gave tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate (45 mg, 53%) as a pale yellow solid. MS (M+H) + =540.3.

[0488] Step 4-7, Preparation of 4-((S)-3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)nicotinamide: To a solution of tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate (45 mg, 1.0 equivalent, 0.083 mmol) in DCM (2.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The reaction solution was concentrated and freeze-dried under vacuum to give the TFA salt of 4-((S)-3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)nicotinamide bis(2,2,2-trifluoroacetate) (40.2 mg, 72%) as a pale yellow solid. MS (M+H) + =440.2.

[0489] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 4, which may require additional functional group modifications using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0490] [Table 11]

[0491] Example 5. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide (Compound 1-103)

[0492] [ka]

[0493] Step 5-1, Preparation of ethyl 4-chloro-6-cyanonicotinate: To a mixture of ethyl 4,6-dichloronicotinanate (200.0 g, 1.0 equivalent, 909 mmol), zinc(II) cyanide (0.600 equivalent, 545 mmol, 64 g), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.41 g, 0.01 equivalent, 9.09 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (10.5 g, 0.02 equivalent, 18.1 mmol) was added DMF (1600 mL) under atmospheric nitrogen. was added. The reaction mixture was stirred at 130°C for 2 hours. The reaction mixture was poured into water (3000 mL) and extracted with EtOAc (3 x 1000 mL). The organic layers were combined, washed with water (3 x 2000 mL) and brine (1000 mL), dried over anhydrous Na2SO4, and concentrated. The remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc / DCM (10 / 1 / 2). This gave a pure batch (78 g, 95% pure) and a less pure batch (63 g, 50% pure). MS (M+H) + =211.1,212.1.

[0494] Step 5-2, Preparation of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate: To a mixture of ethyl 4-chloro-6-cyanonicotinate (15 g, 1.0 equiv., 71 mmol), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (10 g, 0.92 equiv., 66 mmol), and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (30 g, 2.1 equiv., 150 mmol), MeCN (200 mL) was added. The resulting mixture was stirred at 50° C. for 1 hour. The reaction crude was quenched with water (100 mL) and extracted with EtOAc (3×40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (3 / 1) to give ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate (16.0 g, 60%) as a yellow solid. MS (M+H) + =375.1.

[0495] Step 5-3, Preparation of ethyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate: To a round-bottom flask, ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate (3.0 g, 1.0 equiv, 8.0 mmol), AcOH (60 mL), and DCM (12 mL) were added. At 0 °C, 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (5.8 g, 2.0 equiv, 16 mmol) was added portionwise. The resulting mixture was stirred at the same temperature for 30 minutes. The reaction crude was quenched with aqueous NaHSO at 0 °C. The resulting suspension was filtered, and the filtrate was extracted with EtOAc (3 x 100 mL). The organic layers were combined and washed with water (3 x 30 mL) and aqueous NaHCO3. The organic layers were dried and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc / (4 / 1) to give ethyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate (2.2 g, 61%) as a yellow solid. MS (M+H) + =453.0,455.0.

[0496] Step 5-4, Preparation of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinate: To a mixture of ethyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinate (5.0 g, 1.0 equiv, 11 mmol), (3,5-difluorophenyl)boronic acid (3.5 g, 2.0 equiv, 22 mmol), potassium phosphate (7.2 g, 3.1 equiv, 34 mmol), and Pd(DtBPF)Cl (350 mg, 0.049 equiv, 0.537 mmol) was added toluene (50 mL) and water (5 mL) under atmospheric nitrogen. The resulting mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1) to give ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinate (4.4 g, 82%) as a yellow solid. MS (M+H) + =487.4.

[0497] Step 5-5, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinic acid: To a solution of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinate (5.0 g, 1.0 equiv., 10 mmol) in MeOH (50 mL) was added water (5.0 mL). The resulting mixture was cooled to 10 °C, and lithium hydroxide (2.5 g, 10 equiv., 100 mmol) was added portionwise. The reaction mixture was stirred at 50 °C for 3 h. The reaction crude was concentrated under vacuum, and saturated NaHSO was added until the crude solution became acidic (pH 4-5). The resulting mixture was extracted with EtOAc (3x40 mL). The organic layers were combined, washed with water, dried, and concentrated in vacuo to give (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)nicotinic acid (4.0 g, 85%) as a yellow solid. This material was used in the next step without further purification. MS (M+H) + =459.2.

[0498] Step 5-6, Preparation of tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5-( To a mixture of (3,5-difluorophenyl)nicotinic acid (90 mg, 1.0 equiv., 0.20 mmol), HATU (0.11 g, 1.5 equiv., 0.29 mmol), and (S)-1-(pyridin-2-yl)ethan-1-amine (36 mg, 1.50 equiv., 0.29 mmol), DMF (0.8 mL) and DIPEA (0.10 mL, 3.0 equiv., 0.59 mmol) were added. The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction crude was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-65%). Pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), added with solid NaCl (5 g), and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO, filtered, and concentrated to give 75 mg of tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate as a clean oil. MS (M+H) + =563.5.

[0499] Step 5-7, Preparation of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-((S)-1-(pyridin-2-yl)ethyl)nicotinamide: To a solution of tert-butyl ((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (75 mg, 1.0 equivalent, 0.13 mmol) in DCM (0.6 mL) was added TFA (0.6 mL). The resulting mixture was stirred at ambient temperature for 0.5 hours. The crude reaction mixture was concentrated, and the remaining residue was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-35%). Pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated with 1.0 M HCl in ethyl acetate (0.2 mL) to give the HCl salt of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-((S)-1-(pyridin-2-yl)ethyl)nicotinamide as a white solid. MS (M+H) + =463.2.

[0500] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 5, which may require additional functional group modification using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0501] [Table 12]

[0502] Example 6. 4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound 1-63)

[0503] [ka]

[0504] Step 6-1, Preparation of 1-(azetidin-3-yl)ethan-1-one: To a solution of tert-butyl 3-acetylazetidine-1-carboxylate (500 mg, 1.0 equiv., 2.51 mmol) in DCM (5 mL) was added TFA (5 mL). The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL), and saturated NaHCO solution was added until the pH was 7.0. The resulting mixture was concentrated under reduced pressure, and the remaining residue was washed with DCM / MeOH (3 × 50 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under vacuum. This resulted in 280 mg of 1-(azetidin-3-yl)ethan-1-one (80% purity) as a colorless oil. This material was used in the next step without further purification.

[0505] Step 6-2, Preparation of 4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde: To a mixture of 1-(azetidin-3-yl)ethan-1-one (280 mg, 1.0 equiv., 2.3 mmol), 5-bromo-4-chloronicotinaldehyde (446 mg, 0.90 equiv., 2.02 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.00 g, 3.4 equiv., 7.74 mmol) was added MeCN (5 mL). The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (5:1) to give 4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde (250 mg, 39%) as a colorless oil. MS (M+H) + =285.0.

[0506] Step 6-3, Preparation of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde: To a mixture of 4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde (90 mg, 1.0 equivalent, 0.32 mmol), (3,5-difluorophenyl)boronic acid (150 mg, 3.0 equivalent, 0.95 mmol), potassium phosphate (200 mg, 3.0 equivalent, 0.942 mmol), and dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (21 mg, 0.10 equivalent, 0.032 mmol)) was added 1,4-dioxane (1.0 mL) and water (0.1 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 1 hour. The resulting mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography, resulting in 65 mg of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde (65%) as a yellow solid. MS (M+H) + =317.1.

[0507] Step 6-4, Preparation of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid: To a solution of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde (150 mg, 1.0 equivalent, 0.474 mmol) in tert-butyl alcohol (6.0 mL) was added 2-methylbut-2-ene (1.66 g, 50 equivalents, 23.7 mmol), sodium chlorite (86 mg, 2.0 equivalents, 0.95 mmol), sodium dihydrogen phosphate dihydrate (222 mg, 3.0 equivalents, 1.42 mmol), and water (2 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified by preparative HPLC using the following conditions: column, C18; mobile phase, water (0.1% TFA) and ACN (25% ACN to 45% in 8 min); total flow rate, 70 mL / min; detector, UV 220 nm. This resulted in 120 mg of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid as a colorless oil. MS (M+H) +=333.1.

[0508] Step 6-5, Preparation of 4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)nicotinamide: To a solution of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid (120 mg, 1.0 equiv., 0.361 mmol) in DMF (2.0 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (65 mg, 1.5 equiv., 0.54 mmol), N-ethyl-N-isopropylpropan-2-amine (163 mg, 3.49 equiv., 1.26 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1 ,3,3-Tetramethylisouronium hexafluorophosphate (V) (206 mg, 1.50 equiv., 0.54 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction crude was purified by preparative HPLC using the following conditions: column, C18; mobile phase, water (0.1% TFA) and ACN (35% ACN to 60% in 8 min); total flow rate, 70 mL / min; detector, UV 220 nm. This resulted in 4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)nicotinamide (110 mg, 76.6%) as a yellow solid. MS (M+H) + =398.3.

[0509] Step 6-6, Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimethoxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide: To a solution of 4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)nicotinamide (100 mg, 1.0 equiv., 0.252 mmol) in DCE (2.0 mL) was added acetic acid (15 mg, 0.99 equiv., 0.25 mmol), (2,4-dimethoxyphenyl)methanamine (63 mg, 1.5 equiv., 0.38 mmol), and sodium triacetoxyhydroborate (160 mg, 3.0 equiv., 0.755 mmol). The resulting mixture was stirred at ambient temperature for 6 hours. The reaction crude was concentrated under reduced pressure, and the remaining residue was purified by preparative HPLC using the following conditions: column, C18; mobile phase, water (0.1% TFA) and ACN (30% ACN to 60% in 8 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. This resulted in N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimethoxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide (110 mg, 72%, 90% purity) as a yellow oil. MS (M+H) + =549.3.

[0510] Step 6-7, Preparation of 4-(3-(1-aminoethyl)azetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)nicotinamide: N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimethoxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide (100 mg, 1.0 equiv., 0.182 mmol) was combined with TFA (2.0 mL) and the resulting mixture was heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure, and the remaining residue was purified by preparative HPLC using the following conditions: Column, SunFire Prep C18 OBD, 19 *150 mm, 5 μm; mobile phase, water (0.1% TFA) and ACN (12% ACN to 17% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This resulted in the TFA salt of 4-(3-(1-aminoethyl)azetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)nicotinamide (38.8 mg, 34.0%) as a white solid. MS (M+H) + =399.2.

[0511] Example 7. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide (Compound 1-74)

[0512] [ka]

[0513] Step 7-1, Preparation of tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (3.4 g, 35%) was prepared from 4,6-dichloronicotinaldehyde (5.0 g, 1.0 equivalent, 28 mmol) and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (6.0 g, 1.1 equivalent, 30 mmol) using a method similar to that described in "Example 4, Step 4-1." MS (M+H) + =340.1,342.1.

[0514] Step 7-2, Preparation of tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (2.3 g, 55%) was prepared from tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (3.4 g, 1.0 equivalent, 10 mmol) using a method similar to that described in "Example 4, Step 4-2." MS (M+H) + =418.0,420.0.

[0515] Step 7-3, Preparation of tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (1.7 g, 68%) was prepared from tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (2.3 g, 1.0 equivalent, 5.5 mmol) and (3,5-difluorophenyl)boronic acid (0.80 g, 0.92 equivalent, 5.07 mmol) using a method similar to that described in "Example 4, Step 4-3." MS (M+H) + =452.2,454.2.

[0516] Step 7-4, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinic acid: The title compound (100 mg, 97%, 80% purity) was prepared from tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (80 mg, 1.0 equiv., 0.18 mmol) using a method similar to that described in "Example 4, Step 4-5." MS (M+H) + =539.7,541.7.

[0517] Step 7-5, Preparation of tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (60 mg, 66%) was prepared from (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinic acid (100 mg, 1.0 equivalent, 0.17 mmol, 80% purity) using a method similar to that described in "Example 4, Step 4-6." MS (M+H) + =533.2,535.2.

[0518] Step 7-6, Preparation of tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluorophenyl)pyridin-4-yl)-3- To a mixture of methylpyrrolidin-3-ylcarbamate (35 mg, 1.0 equiv., 0.066 mmol), potassium carbonate (28 mg, 3.1 equiv., 0.20 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (30 mg, 3.6 equiv., 0.24 mmol), and Pd(amphos)Cl (15 mg, 0.11 equiv., 0.007 mmol) was added dioxane (1.0 mL) under atmospheric nitrogen. The resulting solution was stirred at 100 °C for 1 h. The reaction mixture was concentrated in vacuo, and the remaining residue was purified by silica gel column eluting with ethyl acetate / petroleum ether (1:1). This resulted in tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 59%) as a yellow solid. MS (M+H) + =513.1.

[0519] Step 7-7, Preparation of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-6-methylnicotinamide: To a solution of tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1.0 equiv., 0.039 mmol) in DCM (2.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The reaction solution was concentrated under vacuum, and the remaining residue was purified by preparative HPLC using the following conditions: Column, SunFire Prep C18 OBD, 19 * 150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (16% ACN to 33% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This resulted in the TFA salt of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-6-methylnicotinamide (11.8 mg, 47%) as a white solid. MS (M+H) + =413.2.

[0520] Example 8. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyanopyridine-3-carboxamide (Compound 1-75)

[0521] [ka]

[0522] Step 8-1, Preparation of tert-butyl (S)-(1-(2-cyano-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (20 mg, 59%) was prepared from tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (50 mg, 1.0 equivalent, 0.10 mmol) using a method similar to that described in "Example 4, Step 4-4." MS (M+H) + =331.3.

[0523] Step 8-2, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinic acid: The title compound (25 mg, 83%) was prepared from tert-butyl (S)-(1-(2-cyano-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1.0 equivalent, 0.061 mmol) using a method similar to that described in "Example 4, Step 4-5." MS (M+H) + =347.1.

[0524] Step 8-3, Preparation of tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-cyanopyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: The title compound (10 mg, 48%) was prepared from (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonicotinic acid (25 mg, 1.0 equivalent, 0.051 mmol) using a method similar to that described in "Example 4, Step 4-6." MS (M+H) + =412.2.

[0525] Step 8-4, Preparation of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-cyanonicotinamide: The TFA salt of the title compound (2.7 mg, 21%) was prepared from tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-cyanopyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (10 mg, 1.0 equivalent, 0.024 mmol) using a method similar to that described in "Example 4, Step 4-7." MS (M+H) + =312.2.

[0526] Example 9. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-[3-(difluoromethoxy)phenyl]pyridine-3-carboxamide (Compound 1-120)

[0527] [ka]

[0528] Step 9-1, Preparation of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate: To a mixture of ethyl 4,6-dichloronicotinate (5.00 g, 1.0 equivalent, 22.7 mmol), tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (4.55 g, 1.0 equivalent, 22.7 mmol), and N-ethyl-N-isopropylpropan-2-amine (8.81 g, 3.0 equivalents, 68.2 mmol), MeCN (50 mL) was added. The resulting mixture was stirred at 0° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by recrystallization. This resulted in 6.0 g of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl-)-6-chloronicotinate (68%). MS (M+H) + =384.3.

[0529] Step 9-2, Preparation of (S)-4-(3-(tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinic acid: To a solution of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate (6.0 g, 1.0 equiv., 15.6 mmol) in MeOH (50 mL) was added lithium hydroxide (3.74 g, 9.99 equiv., 156 mmol) and water (5.0 mL). The resulting mixture was stirred at 50° C. for 1 hour. The organic layer was separated and concentrated in vacuo to give crude (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinic acid (5.60 g, 93%). This material was used in the next step without further purification. MS (M+H) + =356.2.

[0530] Step 9-3, Preparation of tert-butyl ((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinic acid (1.0 equiv., 15.5 mmol, 5 To a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (8.82 g, 1.50 equivalents, 23.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.0 equivalents, 46.3 mmol, 5.99 g) were added. The resulting mixture was stirred at ambient temperature for 10 minutes, after which (S)-1-cyclopropylethan-1-amine (2.63 g, 2.00 equivalents, 30.9 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1:2). This resulted in tert-butyl ((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (6.0 g, 87%). MS (M+H) + =423.3.

[0531] Step 9-4, Preparation of methyl 4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1-cyclopropylethyl)carbamoyl)picolinate: To a solution of tert-butyl ((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (1.2 g, 1.0 equiv., 2.8 mmol) in MeOH (20 mL), triethylamine (1.0 g, 3.5 equiv., 9.9 mmol) and Pd(dppf)Cl (200 mg, 0.096 equiv., 0.273 mmol) were added under atmospheric nitrogen. The resulting mixture was heated at 130 °C under 20 bar of carbon monoxide for 8 hours. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (1:2) to give methyl 4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1-cyclopropylethyl)carbamoyl)picolinate (1.0 g, 79%). MS (M+H) + =447.4.

[0532] Step 9-5, Preparation of tert-butyl ((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a sealed tube, methyl 4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1-cyclopropylethyl)carbamoyl)picolinate (1.3 g, 1.0 equivalent, 2.9 mmol) and ammonia (12 mL, 28 equivalents, 82.2 mmol) in MeOH (7.0 M) were added. The resulting mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated in vacuo to give crude tert-butyl ((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (1.0 g, 80%). This material was used in the next step without further purification. MS (M+H)+ =432.2.

[0533] Step 9-6, Preparation of tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a solution of tert-butyl ((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (1.0 g, 1.0 equiv., 2.3 mmol) in DCM (30 mL) was added TEA (1.1 mL, 3.4 equiv., 7.82 mmol) and TFAA (1.3 mL, 4.1 equiv., 9.5 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with aqueous KCO and extracted with EtOAc (3 × 40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1 / 1) to give tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (700 mg, 73%) as a yellow solid. MS (M+H) + =414.2.

[0534] Step 9-7, Preparation of tert-butyl ((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a solution of tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (700 mg, 1.0 equiv., 1.69 mmol) in DCM (4.0 mL) was added AcOH (20 mL). 1,3,5-Tribromo-1,3,5-triazinane-2,4,6-trione (620 mg, 1.0 equiv., 1.70 mmol) was added at 0 ° C., and the resulting mixture was stirred at the same temperature for 20 minutes. The reaction crude was quenched with saturated NaSO (10 mL) and extracted with EtOAc (3 x 40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1 / 3) to give tert-butyl ((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (410 mg, 49.2%) as a yellow solid. MS (M+H) + =492.1,494.1.

[0535] Step 9-8, Preparation of tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluoromethoxy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: Preparation of tert-butyl ((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate To a mixture of (lysin-3-yl)carbamate (50 mg, 1.0 equiv., 0.10 mmol), (3-(difluoromethoxy)phenyl)boronic acid (45 mg, 2.2 equiv., 0.22 mmol), potassium phosphate (66 mg, 3.1 equiv., 0.31 mmol), and Pd(DtBPF)Cl (7.0 mg, 0.11 equiv., 0.011 mmol) under atmospheric nitrogen was added toluene (2.0 mL) and water (0.2 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1:1) to give the crude product. This material was repurified by preparative HPLC using the following conditions: Column, SunFire prep OBD 19 * 150 mm 5 μm C-01; mobile phase, water (0.05% TFA) and ACN (30% ACN to 44% in 14 min); detector, 254 nm. This resulted in tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluoromethoxy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (30 mg, 52%) as a white solid. MS (M+H) + =574.4.

[0536] Step 9-9, Preparation of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-N-((S)-1-cyclopropylethyl)-5-(3-(difluoromethoxy)phenyl)nicotinamide: To a solution of tert-butyl ((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluoromethoxy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (21 mg, 1.0 equiv., 0.037 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated and freeze-dried under vacuum to give the TFA salt of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-N-((S)-1-cyclopropylethyl)-5-(3-(difluoromethoxy)phenyl)nicotinamide (12.4 mg, 48%) as a white solid. MS (M+H) + =474.2.

[0537] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 9, which may require additional functional group modification using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0538] [Table 13]

[0539] Example 10. 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide (Compound 1-122)

[0540] [ka]

[0541] Step 10-1, Preparation of tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: Preparation of tert-butyl ((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (400 mg, 1.0 equiv., 0.946 mmol, Example 9, Step 10-2). To a mixture of (Chem. 9-3), tetrachlorobis{[4-(N,N-dimethylamino)phenyl]-di-t-butylphosphino}dipalladium(II) (67.0 mg, 0.10 equiv., 0.095 mmol), potassium carbonate (392 mg, 3.0 equiv., 2.84 mmol), and 2,4-dimethyl-1,3,5,2,4,6-trioxatriborinane (2.0 equiv., 1.89 mmol, 209 mg) was added 1,4-dioxane (5.0 mL) under atmospheric nitrogen. The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (2:1) to give tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (400 mg, 95%). MS (M+H) + =403.4.

[0542] Step 10-2, Preparation of tert-butyl ((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: To a mixture of tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (400 mg, 1.0 equivalent, 0.994 mmol), AcOH (5.0 mL), and DCM (1.0 mL) was added 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (550 mg, 1.51 equivalent, 1.50 mmol) at 0 ° C. The resulting mixture was stirred at the same temperature for 15 minutes. The reaction mixture was quenched with aqueous NaHSO3 at °C, and the solid was filtered. The filtrate was collected and extracted with EtOAc (2 x 30 mL). The organic layers were combined, washed with water (3 x 30 mL), aqueous NaHCO3, dried, and concentrated in vacuo. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1 / 2) to give tert-butyl ((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (300 mg, 60%). MS (M+H) + =481.2,483.2.

[0543] Step 10-3, Preparation of tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: tert-butyl ((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate ( To a mixture of (3,5-difluorophenyl)boronic acid (110 mg, 1.0 equiv., 0.228 mmol), (3,5-difluorophenyl)boronic acid (72 mg, 2.0 equiv., 0.457 mmol), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (15 mg, 0.10 equiv., 0.023 mmol), and potassium phosphate (145 mg, 3.0 equiv., 0.683 mmol) was added toluene (3.0 mL) and water (0.3 mL) under atmospheric nitrogen. The resulting mixture was heated at 70°C for 1 hour. The reaction crude was purified by preparative HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 19 * 150 mm 5 μm; mobile phase, water (0.05% TFA) and ACN (22.0% ACN to 45.0% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This resulted in tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (40 mg, 33%). MS (M+H) + =515.4.

[0544] Step 10-4, Preparation of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N-((S)-1-cyclopropylethyl)-5-(3,5-difluorophenyl)-6-methylnicotinamide: To tert-butyl ((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (40 mg, 1.0 equiv., 0.078 mmol) in DCM (4.0 mL) was added TFA (2.0 mL). The resulting mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated and lyophilized under vacuum to give the TFA salt of 4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N-((S)-1-cyclopropylethyl)-5-(3,5-difluorophenyl)-6-methylnicotinamide as an off-white solid. MS (M+H) + =415.2.

[0545] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 10, which may require additional functional group modifications using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0546] [Table 14]

[0547] Example 11. 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide (Compound 1-144)

[0548] [ka]

[0549] Step 11-1, Preparation of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate: To a mixture of methyl 4,6-dichloronicotinate (1.10 g, 1.0 equivalent, 5.34 mmol) and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (1.05 g, 0.982 equivalent, 5.24 mmol), MeCN (10 mL) was added. At 0 ° C., DIPEA (2.8 mL, 3.0 equivalent, 16.0 mmol) was added, and the resulting mixture was stirred at the same temperature for 2 hours. The reaction solution was stirred at ambient temperature overnight. The reaction crude was concentrated and purified by silica gel chromatography eluting with EtOAc / hexanes (0-60%) to give methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate (1.97 g, 98%). MS (M+H) + =370.3.

[0550] Step 11-2, Preparation of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate: To a solution of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate (1.95 g, 1.0 equiv, 5.27 mmol) in MeOH (5 mL) was added 25% sodium methoxide in MeOH (10.0 mL, 8.3 equiv, 44 mmol). The resulting mixture was heated at 65 °C overnight. The reaction mixture was concentrated, diluted with ethyl acetate (30 mL), and washed with saturated NH4Cl and brine. The organic layer was concentrated, and the remaining residue was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-45%). The pure fractions were combined, concentrated, neutralized with saturated NaHCO3 (5.0 mL), solid NaCl (10 g) was added, and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate (1.1 g, 57%) as a clear oil. MS (M+H) + =366.2.

[0551] Step 11-3, Preparation of methyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate: To a solution of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate (1.06 g, 1.0 equiv, 2.90 mmol) in DMF (5.0 mL) was added NBS (568 mg, 1.1 equiv, 3.19 mmol) in portions. The resulting mixture was stirred at ambient temperature for 15 minutes, and LCMS showed complete conversion to the desired product. The crude reaction mixture was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-85%). Pure fractions were dried under vacuum to remove water and MeCN. The resulting residue was redissolved in ethyl acetate, washed with saturated NaHCO3 (5.0 mL) and brine, dried, and concentrated to give (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate (809 mg, 63%) as a clear oil. MS (M+H) + =444.3,446.1.

[0552] Step 11-4, Preparation of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinate: Methyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate (754 mg, 1. To a mixture of (3,5-difluorophenyl)boronic acid (1.07 g, 4.0 equiv, 6.79 mmol), potassium carbonate (1.17 g, 5.0 equiv, 8.48 mmol), and Pd(amphos)Cl (120 mg, 0.10 equiv, 0.170 mmol) under atmospheric nitrogen was added 1,4-dioxane (7.0 mL) and water (0.7 mL). The reaction mixture was heated at 95 °C for 1 h. LCMS showed ∼50% conversion. A second batch of (3,5-difluorophenyl)boronic acid (1.07 g, 4.0 equiv., 6.79 mmol), potassium carbonate (1.17 g, 5.0 equiv., 8.48 mmol), and Pd(amphos)Cl (120 mg, 0.10 equiv., 0.170 mmol) was added under atmospheric nitrogen, and the resulting mixture was heated at 95 °C for an additional 1 h. The reaction crude was diluted with ethyl acetate, washed with brine, concentrated, and dried. The remaining residue was purified by silica gel chromatography eluting with EtOAc / hexanes (0-35%) to give methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinate (286 mg, 35%) as a clear oil. MS (M+H) + =478.2.

[0553] Step 11-5, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinic acid: To a solution of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinate (286 mg, 1.0 equiv., 0.599 mmol) in MeOH (5 mL) was added lithium hydroxide hydrate (276 mg, 11.0 equiv., 6.59 mmol) and water (1.0 mL). The resulting mixture was stirred at 50° C. for 24 hours. The reaction crude was concentrated, diluted with ethyl acetate, washed with saturated NaHSO4, dried and concentrated to give crude (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinic acid (220 mg, 79%) as a white solid. This material was used in the next step without further purification. MS (M+H) + =464.4.

[0554] Step 11-6, Preparation of tert-butyl (S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: Dissolve (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-difluorophenyl)-6-methoxynicotinic acid (30 mg, 1.0 equiv., 0.065 mmol) in DMF (0.5 mL) To a solution of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (37 mg, 1.5 equiv., 0.097 mmol), 4,4-difluorocyclohexane-1-amine hydrochloride (17 mg, 1.5 equiv., 0.097 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.045 mL, 4.0 equiv., 0.26 mmol) were added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, concentrated, and purified by silica gel chromatography eluting with EtOAc / hexane (0-80%). This resulted in 30 mg of tert-butyl (S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate as a white solid. MS (M+H) + =581.2.

[0555] Step 11-7, Preparation of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide: To a solution of tert-butyl (S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-methoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (30 mg, 1.0 equiv., 0.051 mmol) in DCM (0.6 mL) was added TFA (0.5 mL). The resulting mixture was stirred at ambient temperature for 0.5 hours. The crude reaction mixture was concentrated, and the remaining residue was purified by C18 reverse-phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). Pure fractions were combined, dried under vacuum, and treated with 2.0 N HCl in ether (1.0 mL) for 1 hour. The resulting mixture was concentrated and dried under vacuum to give the HCl salt of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide. MS (M+H) + =481.3.

[0556] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared in a manner similar to Example 11, which may require additional functional group modification using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0557] [Table 15]

[0558] Example 12. 4-[(3S)-3-Amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide (Compound 1-130)

[0559] [ka]

[0560] Step 12-1, Preparation of tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5- To a solution of (3,5-difluorophenyl)nicotinic acid (100 mg, 1.0 equivalent, 0.17 mmol, "Step 7-3, Example 7") in DMF (2.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (65 mg, 1.0 equivalent, 0.17 mmol). The resulting mixture was stirred at 30° C. for 5 minutes, after which N-ethyl-N-isopropylpropan-2-amine (90 mg, 4.1 equivalents, 0.70 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (25 mg, 1.2 equivalents, 0.21 mmol) were added. The reaction mixture was stirred at 30° C. for 2 hours. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The remaining residue (60 mg, 66%) was used in the next step without further purification. MS (M+H) + =533.2,535.2.

[0561] Step 12-2, Preparation of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinamide: To tert-butyl (S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1.0 equiv., 0.038 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated, and the remaining residue was purified by preparative HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 19 * 150 mm 5 μm 10 nm; mobile phase, water (0.05% TFA) and ACN (15% ACN to 27% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This resulted in the TFA salt of (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinamide (14.1 mg, 57%) as a white solid. MS (M+H) + =433.2,435.2.

[0562] Step 12-3, Preparation of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide: (S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinamide Bis(2,2,2-trifluoroacetate) (11 mg, 1.0 equiv, 0.017 mmol) was added to 25% sodium methoxide (0.038 mL, 10 equiv, 0.17 mmol). The resulting mixture was stirred at 65° C. overnight. LCMS showed that most of the starting material was converted to the desired product. The reaction crude was concentrated, 0.5 mL of 25% sodium methoxide was added, and the resulting mixture was heated at 65° C. for an additional 6 hours. The reaction crude was concentrated, diluted with EtOAc, and saturated The mixture was washed with aqueous NaHSO and brine, dried, and concentrated. The remaining residue was mixed with 2N HCl in ether (1.0 mL) and stirred at ambient temperature for 1 hour. The resulting suspension was filtered, and the solid was collected and dried under vacuum to give the HCl salt of 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide as a white solid. MS (M+H) + =429.4.

[0563] By appropriate substitution of reagents and substrates at various steps, the following compounds are prepared similarly to Example 12, which may require additional functional group modifications using appropriate reagents via well-known chemistry. Various salts, such as HCl or formate or TFA salts, may be obtained.

[0564] [Table 16]

[0565] Example 13. 4-[(3S)-3-amino-3-methylpyridin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound 2-11)

[0566] [ka]

[0567] Step 13-1, Preparation of methyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloronicotinate: To a mixture of tert-butyl (S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (1.50 g, 1.0 equivalent, 3.9 mmol "Step 2-1, Example 2"), 3-methylbenzene-1,2-diamine (1.40 g, 2.9 equivalents, 11.0 mmol), and sodium pyrosulfite (1.50 g, 2.0 equivalents, 7.9 mmol), DMSO (15 mL) was added. The resulting mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (3:1) to give tert-butyl (S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (960 mg, 49%). MS (M+H) + =486.2,488.2.

[0568] Step 13-2, Preparation of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate: To a solution of tert-butyl (S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (400 mg, 1.0 equiv., 0.822 mmol) in EtOH (10 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (68 mg, 0.10 equiv., 0.083 mmol) and triethylamine (250 mg, 3.0 equiv., 2.47 mmol). The resulting mixture was saturated with CO and then heated at 120° C. under 20 bar of CO for 12 hours. The reaction mixture was concentrated in vacuo, and the remaining residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc (1:1). This resulted in ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate (120 mg, 30.4%) as a brown solid. MS (M+H) + =480.3.

[0569] Step 13-3, Preparation of (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-benzo[d]imidazol-2-yl)nicotinic acid: To a solution of ethyl (S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate (100 mg, 1.0 equiv., 0.209 mmol) in EtOH ...

Claims

1. 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, 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, 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[3.3.1.1 ３，７ ]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[3.3.1.1 ３，７ ]decane-2-carbonyl}-5-(7-chloro-1H-1,3-benzodiazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine, 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, 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, 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, and 4-5: 3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N2-[(1S)-1-cyclopropylethyl]-4-(3,5-difluorophenyl)pyridine-2,5-dicarboxamide, or a pharma- ceutically acceptable salt thereof.

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

3. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperinsulinemia in a mammal.

4. The compound according to claim 1, wherein the compound is 1-30: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is 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, or a pharma- ceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is 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, or a pharma- ceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is 1-77: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is 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, or a pharma- ceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 2, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 1-30: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 2, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 2, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 2, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 1-77: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 2, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

14. The use according to claim 3, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 1-30: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

15. The use according to claim 3, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

16. The use according to claim 3, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

17. The use according to claim 3, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 1-77: 4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

18. The use according to claim 3, wherein the compound, or a pharma- ceutically acceptable salt thereof, is 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, or a pharma- ceutically acceptable salt thereof.

19. A compound of formula (VIa), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R ｃ is hydrogen, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , -CO ２ CH ３ , -C(=O)NH ２ , -C(=O)NHCH ３ or -C(=O)N(CH ３ ) ２ and R ３ is hydrogen or -CH ３ and R ６ is C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, or -L ２ -R ６ａ and L ２ is not present or -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ - or -CHR ６ｂ - and R ６ａ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidine, or substituted or unsubstituted oxetanyl; R ６ｂ is hydrogen, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CH ２ F, -CF ３ , cyclopropyl, or cyclobutyl; R ７ is hydrogen or C １ -C ６ is alkyl, R ８ is hydrogen, -F, or -Cl; R １１ is hydrogen, -F, -Cl, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , or -OCHF ２ and R １２ is hydrogen, -F, -Cl, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , or -OCHF ２ or a pharma- ceutically acceptable salt thereof.

20. The compound has the structure of formula (VIa-1), or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】 During the ceremony, R ６ は-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CH ２ CH ２ CH ２ CH ３ 、-CH ２ CH(CH ３ ) ２ 、-CH(CH ３ )(CH ２ CH ３ )、-CH(CH ２ CH ３ )(CH ２ CH ３ )、-CH(CH ２ CH ２ CH ３ )(CH ２ CH ３ )、-C(CH ３ )(CHCH ３ ) ２ 、-C(CH ３ ) ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ CF ３ 、-CH(CF ３ )(CH ３ )、-CH(CF ３ )(CH ２ CH ３ )、-CH ２ CF ２ CH ３ 、または-CH(CH ３ )(CH ２ CF ３ )であり、 R ７ is hydrogen or -CH ３ and R １１ is -F or -Cl, and R １２ is -F or -Cl, or a pharma- ceutically acceptable salt thereof.

21. The compound has the structure of formula (VIa-1): 【Chemistry 3】 R ６ Ha-L ２ -R ６ａ and R ７ is hydrogen or -CH ３ and R １１ is -F or -Cl, and R １２ is -F or -Cl, or a pharma- ceutically acceptable salt thereof.

22. A compound of formula (VIb), or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 During the ceremony, R ｃ is hydrogen, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , -CO ２ CH ３ , -C(=O)NH ２ , -C(=O)NHCH ３ or -C(=O)N(CH ３ ) ２ and R ３ is hydrogen or -CH ３ and R ６ is C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, or -L ２ -R ６ａ and L ２ does not exist or -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ - or -CHR ６ｂ - and R ６ａ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted azetidine, or substituted or unsubstituted oxetanyl; R ６ｂ is hydrogen, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CH ２ F, -CF ３ , cyclopropyl, or cyclobutyl; R ７ is hydrogen or C １ -C ６ is alkyl, R ８ is hydrogen, -F, or -Cl; R １１ is hydrogen, -F, -Cl, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , or -OCHF ２ and R １２ is hydrogen, -F, -Cl, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , or -OCHF ２ or a pharma- ceutically acceptable salt thereof.

23. The compound has the structure of formula (VIb-1): 【Chemistry 5】 During the ceremony, R ６ は-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CH ２ CH ２ CH ２ CH ３ 、-CH ２ CH(CH ３ ) ２ 、-CH(CH ３ )(CH ２ CH ３ )、-CH(CH ２ CH ３ )(CH ２ CH ３ )、-CH(CH ２ CH ２ CH ３ )(CH ２ CH ３ )、-C(CH ３ )(CHCH ３ ) ２ 、-C(CH ３ ) ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ CF ３ 、-CH(CF ３ )(CH ３ )、-CH(CF ３ )(CH ２ CH ３ )、-CH ２ CF ２ CH ３ 、または-CH(CH ３ )(CH ２ CF ３ )であり、 R ７ is hydrogen or -CH ３ and R １１ is -F or -Cl, and R １２ is -F or -Cl, or a pharma- ceutically acceptable salt thereof.

24. The compound has the structure of formula (VIb-1): 【Chemistry 6】 During the ceremony, R ６ Ha-L ２ -R ６ａ and R ７ is hydrogen or -CH ３ and R １１ is -F or -Cl, and R １２ is -F or -Cl, or a pharma- ceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to claim 19, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

26. Use of a compound according to claim 19, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating hyperinsulinemia in a mammal.

27. A pharmaceutical composition comprising the compound of claim 22, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

28. Use of a compound according to claim 22, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating hyperinsulinemia in a mammal.

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