Nonpeptide somatostatin type 5 receptor agonists and uses thereof

Abstract

To provide the use of compounds that are somatostatin modulators in the manufacture of a medicament for the treatment of hyperinsulinemia in a mammal.SOLUTION: Disclosed herein is the use of, for example, 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 pharmaceutically acceptable salt thereof, or 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 pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,764, filed Aug. 14, 2019, which is incorporated by reference herein 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 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 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 a number of secondary hormones. Six somatostatin receptor protein subtypes have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are 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 of the proteins of the subtypes of somatostatin receptors. 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 called congenital hyperinsulinism of infancy or persistent hyperinsulinemic hypoglycemia of infancy), a disease in which individuals have abnormally high levels of insulin, causing frequent episodes of low blood sugar (hypoglycemia). Devopment formulations of these peptide drugs are very 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 analogues. 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 embodiment, the compound of formula (I) or a pharma- ceutically 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 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, a substituted or unsubstituted monocyclic carbocycle, or a substituted or unsubstituted monocyclic heterocycle; R f -L 1 -R g and L 1 does not exist or C 1 -C 6 Alkylene, C 1 -C 6 Fluoroalkylene, or C 1 -C 6 is heteroalkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 3 -C 5 is heterocycloalkyl, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9 ) 2 , -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C1 -C 8 Heteroalkyl, or -L 2 -R 6a and L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is 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 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 and 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 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 10 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 terms of various variations is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

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

[0010] Also described herein are methods of 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 pharma- ceutically acceptable salt or solvate thereof, to a mammal in need thereof. In some embodiments, the compound described herein, or a pharma- ceutically 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, eye disease or condition, cancer, pain, neurodegenerative disease or condition, inflammatory disease or condition, 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 endogenous insulin-induced hypoglycemia, drug-induced hyperinsulinemia, or exogenous insulin-induced hypoglycemia.

[0011] In any of the above aspects, further embodiments are provided, wherein an effective amount of a compound of formula (I), or a pharma- ceutically 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, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by eye drops, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0012] In any of the above aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments in which the compound is administered to the mammal once a day, or in which the compound is administered to the mammal multiple times 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 pharma- ceutically acceptable salt thereof within the packaging material, and a label indicating that the compound or composition, or a pharma- ceutically acceptable salt, tautomer, pharma- ceutically acceptable N-oxide, pharma- ceutically acceptable active metabolite, pharma- ceutically acceptable prodrug, or pharma- ceutically acceptable solvate thereof, is used for modulating one or more 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, however, it will be understood that the detailed description and specific examples, while illustrating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 by 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 regulation of growth hormone (GH), insulin, and glucagon secretion, 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) that 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 of the somatostatin receptor subtypes, or a combination thereof, and in some embodiments, selectively modulating any one of the somatostatin receptor subtypes 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 regulate the activity of SSTR5 relative to other somatostatin receptors. In some embodiments, the compounds described herein selectively regulate 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 broad range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of a variety of 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 the secretion of certain endocrine glands, including but not limited to GH, IGF-1, and insulin. Suppression of the secretion of certain endocrine glands is useful for treating diseases 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 intestines for the treatment of diseases 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 may be treated by administration of the compounds described herein include carcinomas 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, the 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 localized 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, the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system, useful in the treatment of Alzheimer's disease and other forms of dementia, pain, and headaches. In some embodiments, the somatostatin receptor modulators described herein provide cytoprotection in disorders involving splanchnic blood flow, including liver cirrhosis and esophageal varices.

[0025] In some embodiments, the 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 ovarian 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 that line the coronary arteries), hypertension or high blood pressure, underactive thyroid, weight gain, and lethargy.

[0026] Hyperinsulinemia refers to a higher than normal level 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 may be low or high for another. Hyperinsulinemia may be associated with several types of medical problems, which can be roughly classified into two broad and largely non-overlapping categories: those that tend to be less sensitive to insulin and high blood glucose levels (hyperglycemia) and those that tend to be more sensitive to excess 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 in the beta-cells of the pancreas. HH can cause apnea, seizures, developmental delays, learning failure, 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 drugs specifically tailored for patients with CHI, although there are drugs that are suitable for use, including but not limited to diazoxide and octreotide.

[0028] The pancreas is the primary site of somatostatin action, where it inhibits the synthesis and secretion of the two main 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 during 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 accidentally 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), insulin self-injected covertly (e.g., Munchausen syndrome), insulin self-injected 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 salt, prodrug, active metabolite, and pharmaceutically acceptable solvate, is a somatostatin receptor modulator.In some embodiments, the compound of formula (I), including its pharmaceutically acceptable salt, prodrug, active metabolite, and pharmaceutically acceptable solvate, 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 regulating 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 regulating SST5 receptor activity over SST2 receptor activity.

[0035] In one aspect, provided herein is a compound of formula (I), or a pharma- ceutically 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 , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, a substituted or unsubstituted monocyclic carbocycle, or a substituted or unsubstituted monocyclic heterocycle; R f -L 1 -R g and L 1 does not exist or C 1 -C 6 Alkylene, C 1 -C 6 Fluoroalkylene, or C 1 -C 6 is heteroalkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 3 -C 5 is heterocycloalkyl, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9 ) 2 , -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a and L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6Heteroalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is 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 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 and Or R 11 is the adjacent R8 , 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 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 10 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 1 -C 6 Alkyl, substituted or unsubstituted C1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 1 and R 2 are independently hydrogen or substituted or unsubstituted C 1 -C 6 In some embodiments, R 1 and R 2 are independently hydrogen or C 1 -C 6 In some embodiments, R 1 is hydrogen, and R 2 is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl or substituted or unsubstituted C 3 -C 6 In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or substituted or unsubstituted C 1 -C 6 It is an alkyl group. 1 is hydrogen, and R 2 is hydrogen or C 1 -C 6 In some embodiments, R 1 and R 2 are each hydrogen.

[0038] In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C6 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, or substituted or unsubstituted C 1 -C 4 In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, or substituted or unsubstituted C 1 -C 4 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , or substituted or unsubstituted C 1 -C 6 In some embodiments, R 3 is hydrogen or substituted or unsubstituted C 1 -C 6In some embodiments, R 3 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Fluoroalkoxy, or C 1 -C 6 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 1 -C 4 In some embodiments, R 3 is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 1 -C 4 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 3 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 3 is hydrogen or C 1 -C 6 In some embodiments, R 3 is hydrogen, -CN, -CO 2 R9 , -C(=O)N(R 9 ) 2 , or C 1 -C 6 In some embodiments, R 3 is hydrogen, -CN, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , or -CH 2 CF 3 In some embodiments, R 3 is hydrogen, -CN, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -CH 3 , -CH 2 OH, -CH 2 OCH 3 , or -CH 2 CHF 2 In some embodiments, R 3 is hydrogen, -CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , or -CH 2 CF 3 In some embodiments, R 3 is hydrogen, -CH3 , -CH 2 OH, CH 2 OCH 3 , or -CH 2 CHF 2 In some embodiments, R 3 is hydrogen or -CH 3 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 Ha-CH 3 It is.

[0039] In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9 ) 2 , -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 4 and R 5 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 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 C 1 -C 6 is alkyl, R 3 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 fluoroalkyl, and R 4 and R 5 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 1 and R 2 are hydrogen, and R 3 is hydrogen or -CH 3 and R 4 and R 5 Each is hydrogen. In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or C 1 -C 6 is alkyl, R 3 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 fluoroalkyl, R 4 is hydrogen, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 fluoroalkyl, and R 5 is hydrogen, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 1 is hydrogen, and R 2 is hydrogen, and R 3 is hydrogen, -CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH2 CH 2 F, -CH 2 CHF 2 , or -CH 2 CF 3 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 C 1 -C 6 is alkyl, R 3 is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 1 -C 4 Heteroalkyl, R 4 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 fluoroalkyl, and R 5 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 It is a fluoroalkyl.

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

[0042] [ka]

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

[0044] [ka]

[0045] In some embodiments, the compound has the structure of Formula (Ib), or a pharma- ceutically 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; alternatively, 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 It is.

[0049] In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 In some embodiments, R is a heteroalkyl, a substituted or unsubstituted monocyclic carbocycle, or a substituted or unsubstituted monocyclic heterocycle. a , R b , and R c are each independently hydrogen, halogen, -CN, -OR f , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 In some embodiments, R is a substituted or unsubstituted monocyclic carbocycle. a , R b , and R c are each independently hydrogen, halogen, -CN, -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 In some embodiments, R a , R b , and Rc are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 It is a heterocycloalkyl.

[0050] In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6fluoroalkoxy or substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted monocyclic C 2 -C 5 In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 Heteroalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, or -CO 2 R9 It is.

[0051] In some embodiments, R a , R b , and R c are each independently hydrogen, -F, -Cl, -CN, or -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH 3 , -OCH2 CH 2 CO 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 3 , -OCH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , -C(=O)N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. a , R b , and R c are each independently hydrogen, -F, -Cl, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH 3 , -OCH 2 CH 2 CO 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 3 , -OCH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , or -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 In some embodiments, R a , R b , and R c are each independently hydrogen, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 In some embodiments, R a , R b , and R c are each independently hydrogen, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH3 Or -C(=O)N(CH 3 ) 2 or cyclopropyl. In some embodiments, R 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 pharma- ceutically acceptable salt or solvate thereof.

[0053] [ka]

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

[0055] [ka]

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

[0057] [ka]

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

[0059] [ka]

[0060] In some embodiments, the compound has the structure of formula (IX): or a pharma- ceutically acceptable salt or solvate thereof.

[0061] [ka]

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

[0063] [ka]

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

[0065] [ka]

[0066] In some embodiments, the compound has the structure of Formula (Xa) or (Xb), or a pharma- ceutically 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, alternatively ring A is pyridinyl, alternatively 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 pharma- ceutically acceptable salt or solvate thereof.

[0073] [ka]

[0074] In some embodiments, the compound has the structure of Formula (IIIa) or (IIIb), or a pharma- ceutically 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 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 pharma- ceutically 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 1 is N and A 2 is CR 8and 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt or solvate thereof.

[0090] [ka]

[0091] In some embodiments, R 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted monocyclic carbocycle, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , -NR 9 C(=O)R 10 , -SO 2 R 9 , or -SO2 N(R 9 ) 2 In some embodiments, R 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , or -NR 9 C(=O)R 10 In some embodiments, R 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 8 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 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 pharma- ceutically acceptable salt or solvate thereof.

[0093] [ka]

[0094] In some embodiments, R 11 and R 12each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , or -NR 9 C(=O)R 10 , substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 In some embodiments, R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 3 -C 8 In some embodiments, R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 11 and R12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C 3 -C 8 In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C 3 -C 8 In some embodiments, R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , or -OCHF 2 In some embodiments, R 11 and R 12 are each independently a halogen. In some embodiments, R 11 and R 12are 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 atom 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 3 -C 8 Cycloalkyl or fused substituted or unsubstituted C 2 -C 5 In some embodiments, R 11 is the adjacent R 8 , and R 11 and adjacent R 8 Together with the atom connecting 2 -C 5 In some embodiments, 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 dioxolane or a fused substituted or unsubstituted dioxane.

[0096] In some embodiments, R 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 9, -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , or -NR 9 C(=O)R 10 and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl, and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 8 are each independently hydrogen or halogen, and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 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, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , or -OCHF 2 It is.

[0097] In some embodiments, the compound has the structure of formula (VI): or a pharma- ceutically acceptable salt or solvate thereof.

[0098] [ka]

[0099] In some embodiments, R 3 is hydrogen or -CH 3 and R 8 is hydrogen or halogen, and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 and R c is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9, -C(=O)N(R 9 ) 2 , substituted or unsubstituted monocyclic C 2 -C 5 It is a heterocycloalkyl.

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

[0101] [ka]

[0102] In some embodiments, R 3 is hydrogen or -CH 3 and R 8 is hydrogen or halogen, and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 and R c is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, R f -L1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted monocyclic C 2 -C 5 In some embodiments, R c is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 Heteroalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, or -CO 2 R 9 It 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, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , or -OCHF2 and, R c is hydrogen, -F, -Cl, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH 3 , -OCH 2 CH 2 CO 2 CH 3 , -OCH 2 CH 2CH 2 CO 2 CH 3 , -OCH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , -C(=O)N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. c are hydrogen, -F, -Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH3 , -OCH 2 CH 2 CO 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 3 , -OCH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , or -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 In some embodiments, R c is hydrogen, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 or cyclopropyl. In some embodiments, R c is hydrogen, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 It is.

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

[0105] [ka]

[0106] In some embodiments, R 3 is hydrogen or -CH 3 and R c is hydrogen, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 In some embodiments, R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 and R 12 are each independently hydrogen, -F, -Cl, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , or -OCHF 2 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-membered or 10-membered bicyclic heteroaryl. In some embodiments, ring A is indolyl, isoindolyl, indazolyl, benzimidazolyl, azaindolyl, benzisoxazolyl, benzoxazolyl, benzoisoxazolyl, 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0110] In some embodiments, the compound has the structure of Formula (VIIa) or (VIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0111] [ka]

[0112] In some embodiments, R c is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1-C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 Heteroalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, or -CO 2 R 9 In some embodiments, R 8 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), or -C(CH 3 ) 3 and R c are hydrogen, -F, -Cl, -CN, -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(CH3 ) 2 、-CH(CH 3 )(CH 2 CH 3 )、-C(CH 3 ) 3 、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 ,-AND 3 ,-AND 2 CH 3 、-OCF 3 ,-AND 2 CHF 2 ,-AND 2 CF 3 ,-AND 2 CH 2 AND 3 、-O-(シクロロロピル)、-O-CH 2 -(シクロロロピル)、-O-CH 2 -(phenyl)、-AND 2 CO 2 H、-AND 2 CH 2 CO 2 H、-AND 2 CH 2 CH 2 CO 2 H、-AND 2 CO 2 CH 3 ,-AND 2 CH 2 CO 2 CH 3 ,-AND 2 CH 2 CH 2 CO 2 CH 3 ,-AND 2 CO 2 CH 2 CH 3 ,-AND 2 CH 2 CO 2 CH 2 CH 3 ,-AND 2 CH 2 CH 2 CO 2 CH2 CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , -C(=O)N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. 8 is hydrogen, -CH 3 , -CH 2 CH 3 and R c are hydrogen, -F, -F, -Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH 3 , -OCH 2 CH 2 CO 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 3 , -OCH 2 CO2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , or -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 In some embodiments, R c is hydrogen, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 or cyclopropyl. In some embodiments, R c is hydrogen, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 ) 2 It is.

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

[0117] [ka] teeth,

[0118] [ka] In the formula, 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0131] In some embodiments, R 7 is hydrogen, substituted or unsubstituted C 1 -C6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 4 Cycloalkyl, or substituted or unsubstituted C 2 -C 3 In some embodiments, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 4 In some embodiments, R is a cycloalkyl, or a substituted or unsubstituted 3- or 4-membered heterocycloalkyl. 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 7 is hydrogen or C 1 -C 6 In some embodiments, R 7 is hydrogen or -CH 3 In some embodiments, R 7 is hydrogen. In some embodiments, R 7 Ha-CH 3 It is.

[0132] In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a And L 2 is absent or substituted or unsubstituted C 1 -C 8Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 Heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0133] In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 fluoroalkyl, or substituted or unsubstituted C 1 -C 8 In some embodiments, R 6 is C 1 -C 8 Alkyl, C 1 -C 8 fluoroalkyl, or substituted or unsubstituted C 1 -C 8 In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, or C 1 -C 6 In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, or C 1-C 6 In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, or substituted or unsubstituted C 1 -C 8 In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 6 is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R 6 is C 1 -C 6 In some embodiments, R 6 is C 1 -C 6 In some embodiments, R 6 Ha-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 , or -CH(CH 3 )(CH 2 CF 3 In some embodiments, R 6 Ha-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 )(CH 2 CH 3 ), -CH 2 CF 3 , -CH(CF 3 )(CH 3 ), or -CH(CF 3 )(CH 2 CH 3 ).

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

[0135] In some embodiments, L 2 is absent or substituted or unsubstituted C 1-C 8 Alkylene or -CHR 6b In some embodiments, L 2 is absent or substituted or unsubstituted C 1 -C 6 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or C 1 -C 6 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or C 1 -C 4 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CHR 6b In some embodiments, L 2 does not exist or -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CHR 6b In some embodiments, L 2 is -CH 2 -, or -CHR 6b In some embodiments, L 2 is -CH 2 -, -CH(CH 3 )-, or -CH(CF 3 )-.

[0136] In some embodiments, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C6 In some embodiments, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 4 In some embodiments, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, or C 3 -C 4 In some embodiments, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 3 -C 4 In some embodiments, 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. In some embodiments, R 6b is hydrogen, -CH 3 , -CHF 2 , -CF 3 , cyclopropyl, or cyclobutyl. In some embodiments, R 6b is hydrogen, -CH 3 , -CF 3 or cyclopropyl. In some embodiments, R 6b is hydrogen, -CH 3 , or -CF 3 It is.

[0137] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C 5 -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 C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 It is heteroaryl.

[0138] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 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 C 5 -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 3 -C 4 Cycloalkyl or substituted or unsubstituted 3- or 4-membered C 2 -C 3 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 3 -C 4 In some embodiments, R 6a is substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl. In some embodiments, R 6ais substituted or unsubstituted cyclopropyl. In some embodiments, R 6a is a substituted or unsubstituted cyclobutyl.

[0140] In some embodiments, L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 Heteroaryl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, L is cycloalkyl. 2 does not exist or C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 Heteroaryl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0141] In some embodiments, L 2 does not exist or C 1 -C 4 Alkylene, or -CHR 6b - and R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C 5 -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 C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 It is heteroaryl.

[0142] In some embodiments, R 6a is a substituted or unsubstituted C 3 -C 4 Cycloalkyl or substituted or unsubstituted 3- or 4-membered C 2 -C 3 heterocycloalkyl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 4 In some embodiments, L is cycloalkyl. 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 azetidinyl, or substituted or unsubstituted oxetanyl, and 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.

[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, R6 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. 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 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 C 5 -C 10 Forming heterocycloalkyl, bicyclic N-containing C 5 -C 10 Heterocycloalkyl is a fused bicyclic C 5 -C 10 Heterocycloalkyl, Bridged Bicyclic C 5 -C 10 Heterocycloalkyl or spiro bicyclic C 5 -C 10 It is a heterocycloalkyl.

[0144] In some embodiments, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 is fluoroalkyl, and R 6 is a substituted or unsubstituted C 1 -C 8Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a and L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is 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 is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R f -L 1 -R g and L 1 does not exist or C 1 -C 6 Alkylene, or C 1 -C 6 is a fluoroalkylene; R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , or -C(=O)N(R 9 ) 2 and R 1 is hydrogen, R 2 is hydrogen or C 1 -C 6 is alkyl, R 3 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 4 is hydrogen, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 5 is hydrogen, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 6 is C 1 -C 8 Alkyl, C 1 -C 8 Fluoroalkyl, or -L 2-R 6a and L 2 does not exist or C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is 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, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 , or -C(=O)N(CH 3 )2 and R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, -CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , or -CH 2 CF 3 and R 4 is hydrogen or F, R 5 is hydrogen or F, 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 4Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is 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 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 is heterocycloalkyl, R f -L 1 -R g and L 1 does not exist or C 1 -C6 is alkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , or -C(=O)N(R 9 ) 2 or a substituted or unsubstituted monocyclic C 2 -C 5 is heterocycloalkyl, R 1 is hydrogen, R 2 is hydrogen or C 1 -C 6 is alkyl, R 3 is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 1 -C 4 is heteroalkyl, R 4 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 is a fluoroalkyl; R 5 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 is a fluoroalkyl; 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is alkyl, R 8 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 3 -C 8Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 is heteroaryl, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 is a 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 is fluoroalkyl, and n is 0 to 3.

[0149] In some embodiments, the compound has the structure of Formula (VIIIa) or (VIIIb), or a pharma- ceutically 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 pharma- ceutically 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 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 It is.

[0154] In some embodiments, 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic 3- to 4-membered C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C 5 -C 10 Cycloalkyl, substituted or unsubstituted 6- to 10-membered C 6 -C 10 Aryl, substituted or unsubstituted monocyclic 3- to 4-membered C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted 5- to 10-membered C 1 -C 9 Heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C3 -C 4 cycloalkyl, R 7 is hydrogen or C 1 -C 6 It is an alkyl.

[0155] In some embodiments, 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 C 1 -C 4 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, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 cycloalkyl, R 7 is hydrogen or C 1 -C 6 It is an 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 1is N, and A 2 is CR 8 or A 1 is CR 8 and A 2 is N, R a and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 is heterocycloalkyl, R f -L 1 -R g and L 1 does not exist or C 1 -C 6 is alkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , or -C(=O)N(R 9 ) 2 or a substituted or unsubstituted monocyclic C 2 -C 5 is heterocycloalkyl, R 3 is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C1 -C 4 is heteroalkyl, R 4 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 is a fluoroalkyl; R 5 is hydrogen, halogen, C 1 -C 4 Alkyl, or C 1 -C 4 is a fluoroalkyl; 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is alkyl, R 8 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 3 -C 8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 is heteroaryl, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 is a 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C6 It is a fluoroalkyl.

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

[0161] [ka]

[0162] In some embodiments, R 3 is hydrogen or -CH 3 and R 4 and R 5 are hydrogen, and R 8 are each independently hydrogen or halogen, and R 11 and R 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 It is.

[0163] In some embodiments, 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 C 1 -C 6 Alkylene, or -CHR6b - and R 6a is a substituted or unsubstituted monocyclic 3- to 4-membered C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C 5 -C 10 Cycloalkyl, substituted or unsubstituted 6- to 10-membered C 6 -C 10 Aryl, substituted or unsubstituted monocyclic 3- to 4-membered C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted 5- to 10-membered C 1 -C 9 Heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 cycloalkyl, R 7 is hydrogen or C 1 -C 6 It is an alkyl.

[0164] In some embodiments, 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 C 1 -C 4 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 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 cycloalkyl, R 7 is hydrogen or C 1 -C 6 It is an alkyl.

[0165] In some embodiments, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C1 -C 6 In some embodiments, R 9 are each independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 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 1 -C 6 Alkyl or C 1 -C 6 It is a fluoroalkyl.

[0166] In one embodiment, provided herein is a compound of formula (A1), or a pharma- ceutically 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 C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 is a fluoroalkyl; R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, a substituted or unsubstituted monocyclic carbocycle, or a substituted or unsubstituted monocyclic heterocycle; R f -L 1 -R g and L 1 does not exist or C 1 -C 6 Alkylene, C 1 -C 6 Fluoroalkylene, or C 1 -C 6 is heteroalkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, or substituted or unsubstituted C 3 -C 5 is heterocycloalkyl, R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 4 and R 5 are each independently hydrogen, halogen, or -OR 9 , -N(R 9 ) 2 , -CN, -CO 2 R 9 , -C(=O)N(R 9 ) 2 , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a and L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is 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 12 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 and 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 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 10 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 7 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 C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R L is C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R L is C 1 -C 6 In some embodiments, R L Ha-CH 3 It is.

[0169] In some embodiments, R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 1 and R 2 are independently hydrogen or substituted or unsubstituted C 1 -C 6 In some embodiments, R 1 and R 2 are independently hydrogen or C 1-C 6 In some embodiments, R 1 is hydrogen, and R 2 is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl or substituted or unsubstituted C 3 -C 6 In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or substituted or unsubstituted C 1 -C 6 It is an alkyl group. 1 is hydrogen, and R 2 is hydrogen or C 1 -C 6 In some embodiments, R 1 and R 2 are each hydrogen.

[0170] In some embodiments, R 1 is hydrogen, and R 2 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl, and R L is a substituted or unsubstituted C 1 -C 6 In some embodiments, R 1 is hydrogen, and R 2 is hydrogen, and R L Ha-CH 3 It is.

[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 cor 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; alternatively, 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 It is.

[0173] In some embodiments, R a , R b , and R c are each independently hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 Heteroalkyl, R f -L 1 -R g And L 1 does not exist or C 1 -C 6 alkylene, and R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, or -CO 2 R 9 In some embodiments, R a , R b , and R care each independently hydrogen, -CN, or -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -CO 2 CH 3 , -C(=O)NH 2 , -CONHCH 3 Or -C(=O)N(CH 3 ) 2 or cyclopropyl.

[0174] In some embodiments, ring A, each R 8 , R 11 , R 12 , and n are 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, or ring A is pyridinyl, or 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 8 each independently represents hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted monocyclic carbocycle, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , -NR 9 C(=O)R10 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 8 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments, R 8 are each independently hydrogen or halogen.

[0177] In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -C(=O)R 10 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 11 is halogen, substituted C 1 -C 6Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , or -NR 9 C(=O)R 10 , substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 In some embodiments, R11 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 3 -C 8 In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic cycloalkyl. In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C 3 -C 8In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C 3 -C 8 In some embodiments, R 11 is halogen, substituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 In some embodiments, R 11 is halogen, C 1 -C 6 Fluoroalkyl, -CN, or -OR 9 In some embodiments, R 11 -F, -Cl, -CN, -CF 3 , -OCH 3 , -OCF 3 , or -OCHF 2 In some embodiments, R 11 is a 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, R 11 is the adjacent R 8 , and R 11 and adjacent R 8 and together with the atom 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 connecting3 -C 8 Cycloalkyl or fused substituted or unsubstituted C 2 -C 5 Forms a heterocycloalkyl.

[0179] In some embodiments, R 12 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR 9 , -CO 2 R 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 , -SO 2 R 9 , or -SO 2 N(R 9 ) 2 In some embodiments, R 12 is hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , -N(R 9 ) 2 , or -NR 9C(=O)R 10 , substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 In some embodiments, R 12 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, -CN, -OR 9 or a substituted or unsubstituted monocyclic C 3 -C 8 In some embodiments, R 12 is hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, or -OR 9 In some embodiments, R 12 is hydrogen, -F, -Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , or -OCHF 2 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 2 are each independently 8 or N, and A 3 is CR 12 or N. In some embodiments,

[0184] [ka] teeth,

[0185] [ka] In the formula, 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 6 It is 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 C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 4 In some embodiments, R is a cycloalkyl, or a substituted or unsubstituted 3- or 4-membered heterocycloalkyl. 7 is hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 7 is hydrogen or C 1 -C 6 It is an alkyl.

[0200] In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a And L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 Heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0201] In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 fluoroalkyl, or substituted or unsubstituted C 1 -C 8 In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, or C 1 -C 6 In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, or substituted or unsubstituted C 1 -C 8 In some embodiments, R 6 is a substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 In some embodiments, R 6 is C 1 -C 6 Alkyl or C 1 -C 6 It is a fluoroalkyl.

[0202] In some embodiments, R 6 -L 2 -R6a It is.

[0203] In some embodiments, L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b In some embodiments, L 2 is absent or substituted or unsubstituted C 1 -C 6 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or C 1 -C 6 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or C 1 -C 4 Alkylene or -CHR 6b In some embodiments, L 2 does not exist or -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CHR 6b In some embodiments, L 2 does not exist or -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CHR 6b In some embodiments, L 2 is -CH 2 -, or -CHR 6b In some embodiments, L 2 is -CH 2 -, -CH(CH 3 )-, or -CH(CF 3 )-.

[0204] In some embodiments, R6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 4 In some embodiments, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, or C 3 -C 4 In some embodiments, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, or C 3 -C 4 In some embodiments, 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. In some embodiments, R 6b is hydrogen, -CH 3 , -CHF 2 , -CF 3 , cyclopropyl, or cyclobutyl. In some embodiments, R 6b is hydrogen, -CH 3 , -CF 3or cyclopropyl. In some embodiments, R 6b is hydrogen, -CH 3 , or -CF 3 It is.

[0205] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C 5 -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 C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 It is heteroaryl.

[0206] In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 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 C 5 -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 3 -C 4 Cycloalkyl or substituted or unsubstituted 3- or 4-membered C 2 -C 3 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 3 -C 4In 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, R 6 is a substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8 Heteroalkyl, or -L 2 -R 6a And L 2 is absent or substituted or unsubstituted C 1 -C 8 Alkylene or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 Heteroaryl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 6 is C 1 -C 8 Alkyl, C 1 -C 8 Fluoroalkyl, substituted or unsubstituted C 1 -C 8Heteroalkyl, or -L 2 -R 6a And L 2 does not exist or C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 8 Cycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted polycyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 Heteroaryl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 It is cycloalkyl.

[0209] In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, or -L 2 -R 6a And L 2 does not exist or C 1 -C 4 Alkylene, or -CHR 6b - and R 6b is hydrogen, C1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 In some embodiments, R 6a is a substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Cycloalkyl, substituted or unsubstituted spirocyclic C 5 -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 C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted bridged C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted spirocyclic C 5 -C 10 Heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 Heteroaryl or substituted or unsubstituted bicyclic C 6 -C 9 It is heteroaryl.

[0210] In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Heteroalkyl, or -L 2 -R 6a And L 2 does not exist or C 1 -C 4 Alkylene, or -CHR 6b - and R 6ais a substituted or unsubstituted C 3 -C 4 Cycloalkyl or substituted or unsubstituted 3- or 4-membered C 2 -C 3 heterocycloalkyl, and R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 4 In some embodiments, R 6 is C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Heteroalkyl, 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 azetidinyl, or substituted or unsubstituted oxetanyl, and 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.

[0211] In some embodiments, R 6 and R 7together 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 is hydrogen, halogen, -CN, -N(R 9 ) 2 , -OR f , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 fluoroalkoxy or substituted or unsubstituted C 1 -C 6 is heteroalkyl, R f -L 1 -R g and L 1 does not exist or C 1 -C 6 Alkylene, or C 1 -C 6 is a fluoroalkylene; R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , or -C(=O)N(R 9 ) 2 and R 1 is hydrogen, R 2 is hydrogen or C 1 -C 6 is alkyl, R L is C 1 -C 6 Alkyl or C 1 -C 6 is a fluoroalkyl; R 6 is C 1 -C 8 Alkyl, C 1 -C 8 Fluoroalkyl, or -L 2 -R 6a and L 2 does not exist or C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 2 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is 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 are hydrogen, -F, -Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -O-(cyclopropyl), -O-CH 2 -(cyclopropyl), -O-CH 2 -(phenyl), -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, -OCH 2 CO 2 CH 3 , -OCH 2 CH 2 CO 2 CH 3 , -OCH 2 CH 2 CH 2 CO 2 CH 3 , -OCH 2 CO 2 CH 2 CH 3 , -OCH 2 CH 2 CO 2 CH 2 CH 3 , or -OCH 2 CH 2 CH 2 CO 2 CH 2 CH 3 and R 1 is hydrogen, R 2 is hydrogen, R L is C 1 -C 6 is alkyl, 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 is cycloalkyl, R 7 is hydrogen or C 1 -C 6 is alkyl, Or R 6 and R 7together 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 , -CO 2 R 9 , -C(=O)N(R 9 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Fluoroalkoxy, substituted or unsubstituted monocyclic C 3 -C 6 Cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 5 is heterocycloalkyl, R f -L 1 -R g and L 1 does not exist or C 1 -C 6 is alkylene, R g is hydrogen, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, -CO 2 R 9 , or -C(=O)N(R 9 ) 2 or a substituted or unsubstituted monocyclic C 2 -C5 is heterocycloalkyl, R 1 is hydrogen, R 2 is hydrogen or C 1 -C 6 is alkyl, R L is C 1 -C 6 Alkyl or C 1 -C 6 is a fluoroalkyl; 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 C 1 -C 6 Alkylene, or -CHR 6b - and R 6a is a substituted or unsubstituted monocyclic C 3 -C 4 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 5 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted monocyclic C 2 -C 3 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4 -C 10 Heterocycloalkyl or substituted or unsubstituted C 1 -C 9 is heteroaryl, R 6b is hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 fluoroalkyl or substituted or unsubstituted monocyclic C 3 -C 4 is cycloalkyl, R 7is hydrogen or C 1 -C 6 is alkyl, R 8 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, or C 1 -C 6 is a fluoroalkyl; R 11 and R 12 are each independently hydrogen, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, -CN, -OR 9 , -CO 2 R 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 3 -C 8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl or substituted or unsubstituted monocyclic C 1 -C 5 is heteroaryl, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 is a 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 is a fluoroalkyl; n is 0 to 3.

[0216] In some embodiments, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Fluoroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, R 9 each independently represents hydrogen, a substituted or unsubstituted C 1 -C 6 Alkyl, or substituted or unsubstituted C 1 -C 6 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 each independently represents a substituted or unsubstituted C 1 -C 6 Alkyl or substituted or unsubstituted C 1 -C 6 In some embodiments, R 9 are each independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6fluoroalkyl, 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 1 -C 6 Alkyl or C 1 -C 6 It is a fluoroalkyl.

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

[0218] [ka] During the ceremony,

[0219] [ka] is as set forth in Table 1; R 3 is as set forth in Table 1; R 4 is as set forth 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 set forth in Table 2; R c is as set forth in Table 2, and NR 6 R 7 is 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 set forth in Table 3, R 12 is as set forth in Table 3, and NR 6 R 7 is 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 set forth 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 set forth in Table 5; R dis as set forth in Table 5; R e is as set forth in Table 5, and NR 6 R 7 is 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 is as set forth 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 is as set forth 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 e is 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] It 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 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 It 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 It 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] It 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 As described in Table 1,

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

[0251] [ka] It is.

[0252] In some embodiments, R d As described in Table 2,

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

[0254] [ka] It is.

[0255] In some embodiments, R d As described in Table 3,

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

[0257] [ka] It is.

[0258] In some embodiments, R d As described in Table 4,

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

[0260] [ka] It 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] It 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] It 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] It is.

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

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

[0274] [ka] It 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] It is.

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

[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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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.Furthermore, the compounds described herein can exist in unsolvated form as well as 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., the material 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 "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that is composed of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined 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 are rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often correlated with pH, ​​allowing 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, allowing for regulated passage through biological membranes.

[0343] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucohedric acid; 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, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, a compound of formula (I) is acidic and reacts with a base. In such a situation, the acidic proton of a compound of formula (I) is replaced with a metal ion, for example, an ion of lithium, sodium, potassium, magnesium, calcium, or aluminum. In some cases, the compounds described herein cooperate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine, 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 salt includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the process of crystallization 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.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 solvated as well as unsolvated form.

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

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

[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 33Isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14 Compounds incorporating a radioactive isotope such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0351] In some embodiments, the compound of formula (I) has one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of formula (I) exists in the R configuration. In some embodiments, the compound of formula (I) exists in the S configuration. The compounds 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] The individual stereoisomers can be obtained, as appropriate, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of the stereoisomers is carried out by chromatography, or by forming diastereomeric salts and separating 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 to the parent drug in vivo. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, the prodrug has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. An example of a prodrug is, without limitation, a compound described herein that is administered as an ester ("prodrug"), but is subsequently metabolically hydrolyzed to yield the active entity. A further example of a prodrug is a short peptide (polyamino acid) that is bonded to an acid group, and the peptide is metabolized to reveal the active moiety. In some embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to yield the biologically, pharma- ceutical, 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, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38 (each of which is incorporated herein by reference). In some embodiments, the hydroxyl group of the compounds disclosed herein is used to form a prodrug, where the hydroxyl group is incorporated into acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, 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 a 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 cases, 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, in some embodiments, the prodrug moiety 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 which 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 said compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of said compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the totality of processes by which a particular substance is changed by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can 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 are optionally identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with liver cells in vitro and analyzing the resulting compounds.

[0359] In some cases, heterocycles may exist in tautomeric forms. In such a situation, 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 alternative tautomeric forms. Alternative tautomeric forms are expressly included in the present disclosure, such as, for example, 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 using 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 displacement of I with a protected aminopyrrolidine gives intermediate II, which is then reacted with a boronic acid (R d B(OH)2 ) or its ester or organotrifluoroborate (R d BF 3 The aldehyde III was converted to intermediate III by organometallic coupling reactions such as the Suzuki-Miyaura reaction with NaClO 2 The corresponding acid IV was then coupled with an amine to give 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 NaClO 2 Treatment with an oxidizing reagent such as HO to generate acid VII, which could be reacted with an amine in the presence of a coupling reagent such as HATU to generate the amide intermediate VIII. This compound could then undergo an organometallic coupling reaction such as the Suzuki-Miyaura reaction to generate compound V. Removal of the protecting groups using an appropriate deprotection method gave 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 gives intermediate X, which is halogenated to give compound XI. d B(OH) 2 ) or its ester or organic trifluoroborate (R d BF 3 XI was converted to intermediate XII by organometallic coupling reactions such as the Suzuki-Miyaura reaction with NaClO. Compound XII was converted to nitrile XIII using an organometallic cyanation reaction, which was then reacted with NaClO 2The acid XIV was generated by treatment with an oxidation reagent such as . This compound was reacted with an amine to generate the amide XV in the presence of a coupling reagent such as HATU. Alternatively, an organometallic cyanation reaction converted 4,6-dichloronicotinate XVII to the nitrile XVIII, which underwent nucleophilic displacement with a protected aminopyrrolidine to generate intermediate XIX. This compound was then treated with a halogenation reagent such as NBS or 1-bromopyrrolidine-2,5-dione to generate XX. An organometallic coupling reaction such as the Suzuki-Miyaura reaction was used to convert intermediate XX to XXI, 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 an organometallic coupling reaction such as the Suzuki-Miyaura reaction generated intermediate XV. Intermediate XXVI was also synthesized by another 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 generate amide XXIII. Submission 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 can then be converted to intermediate XII via an organometallic coupling reaction such as the Suzuki-Miyaura reaction, which can then be subjected to another organometallic coupling reaction to give R cThe introduction of the aryl group gave XXVIII. 2 Treatment with an oxidizing reagent such as XXIX afforded acids XXIX, which could be reacted with amines to afford amides XXX in the presence of coupling reagents such as HATU or Ghosez's reagent. Alternatively, nucleophilic displacement of 4,6-dichloronicotinates XVII with protected aminopyrrolidines afforded intermediates XXXII, which were hydrolyzed under basic conditions and then coupled with amines to afford amides XXXIII. c This compound was converted to intermediate XXXIV by organometallic coupling reactions to introduce a group. Halogenation of intermediate XXXIV formed intermediate XXXV, which could be converted to compound XXX by organometallic coupling reactions such as Suzuki-Miyaura reaction. Alternatively, 4,6-dichloronicotinate XVII was converted to XXXII, which was then converted to XXXVI by organometallic coupling reactions followed by halogenation to give compound XXVII. This compound was converted to intermediate XXXVIII by organometallic coupling reactions such as Suzuki-Miyaura reaction, which was hydrolyzed under basic conditions to give acid XXIX. Removal of the protecting group of intermediate XXX using an appropriate deprotection method gave final compound XXXI.

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

[0374] [ka]

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

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

[0377] [ka]

[0378] Nucleophilic displacement of I with a protected aminopyrrolidine gives intermediate II, which is then reacted with wet DMF or NMP or DMSO or Na 2 S 2 O 5Treatment with 1,2-diaminobenzene by heating in other solvents with or without HCl gave benzimidazole LII. LII was subsequently converted to ester LIII by organometallic carbonylation. Alternatively, compound II can be converted to ester L by organometallic carbonylation, which can be carried out by heating in moist DMF or NMP or DMSO or NaCl under atmospheric pressure oxygen. 2 S 2 O 5 Treatment with 1,2-diaminobenzene by heating in other solvents with or without NaOH gave benzimidazole LIII. Alternatively, treatment with 1,2-diaminobenzene by heating in other solvents with or without NaOH gave benzimidazole LIII. Alternatively, treatment with 1,2-diaminobenzene by heating in other solvents with or without NaOH under atmospheric pressure gave benzimidazole LIII. 2 S 2 O 5 Aldehyde I was reacted with 1,2-diaminobenzene by heating in other solvents with or without , to give imidazole LI, which underwent nucleophilic displacement with protected aminopyrrolidine to generate intermediate LII. Ester LIII was then converted under basic conditions to acidic LIV, 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 gave 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 by organometallic coupling reactions such as the Suzuki-Miyaura reaction. Basic hydrolysis of 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 gave 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 to generate LXV in the presence of a strong base such as LDA. Compound LXV was converted to intermediate LXVI by organometallic coupling reactions such as Suzuki-Miyaura reaction. Subsequent nucleophilic displacement with a protected aminopyrrolidine gave intermediate LXVII, which was hydrolyzed to acid LXVIII under basic conditions. Compound LXVIII was treated with an amine in the presence of a coupling reagent such as HATU to generate amide LXIX. Removal of the protecting group using an appropriate deprotection method gave final compound LXX. Compound LXIX could be converted to intermediate LXXI by organometallic coupling reactions such as Suzuki-Miyaura reaction. Removal of the protecting group using an appropriate deprotection method gave final compound LXXII.

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

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

[0387] As used herein, C 1 -C x is C1 -C 2 , C 1 -C 3 ...C 1 -C x As just one example, "C 1 -C 6 A group designated as "C" indicates that the moiety has 1 to 6 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C 1 -C 4 "Alkyl" indicates that the alkyl group has from 1 to 4 carbon atoms, ie, 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., C 1 -C 10 A numerical range such as "1-10" whenever it occurs herein refers to each integer within the given range. For example, "1-10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1 -C 6 In one embodiment, the 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 monovalent alkyl groups listed above may be an alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C 1 -C 6 In another embodiment, the alkylene is C 1 -C 4 Exemplary alkylene groups include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 In some embodiments, alkylene is -CH 2 -It is.

[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 It refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0392] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with a hydroxyl. In some embodiments, hydroxyalkyl is C 1 -C 4 Exemplary hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2OH, etc.

[0393] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with amino. In some embodiments, aminoalkyl is C 1 -C 4 Exemplary aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 etc.

[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)=CR 2 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, the 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=CH 2 , -C(CH 3 )=CH 2 , -CH=CHCH 3 , -C(CH 3 )=CHCH 3 , and -CH 2 CH=CH 2 Examples include:

[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 an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH 3 , -C≡CCH 2 CH 3 , -CH 2 C≡CH is an example.

[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, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is C 1 -C 6 It is heteroalkyl.

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

[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 different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes 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, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is C 6 -C 10 Depending on the structure, the aryl group may 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, where each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, the cycloalkyl group is selected from C 3 -C 6 In some embodiments, cycloalkyl is C 3 -C 4It is 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 embodiment, a fluoroalkyl is 1 -C 6 It is a fluoroalkyl.

[0403] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocycle group has from 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) include rings having from 3 to 10 atoms in their ring system, and aromatic heterocycle groups include rings having from 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, 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 are C-linked (or C-linked) or N-linked where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Additionally, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0404] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0-4 N atoms in the ring. In some embodiments, 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 C 1 -C 9 In some embodiments, the monocyclic heteroaryl is C 1 -C 5 In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C 6 -C 9 It is heteroaryl.

[0405] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, the heterocycloalkyl is C 2 -C 10 In another embodiment, the heterocycloalkyl is C 4 -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 not present, 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 that is embedded in or appended to a molecule.

[0408] The term "optionally substituted" or "substituted" refers to any group to which the referenced group is added, including halogen, -CN, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -OH, -CO 2 H, -CO 2 Alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 In some other embodiments, the optional substituents are optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -N, -N- ... 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 Alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1 -C 4 Alkyl), -S(=O) 2N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Fluoroalkyl, C 1 -C 4 Heteroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, -SC 1 -C 4 Alkyl, -S(=O)C 1 -C 4 Alkyl, and -S(=O) 2 C 1 -C 4 In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCHF 2 , and -OCF 3 In some embodiments, the substituents are substituted with one or two of the aforementioned 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, C 1 -C 6 Alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR 21 , -CO 2 R 21 , -C(=O)N(R 21 )2 , -N(R 21 ) 2 , -NR 21 C(=O)R 22 , -SR 21 , -S(=O)R 22 , -SO 2 R 22 , or -SO 2 N(R 21 ) 2 substituted with one or more R groups independently selected from the group consisting of: 21 are each independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 Cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 21 The groups, together with the N atom to which they are attached, form an N-containing heterocycle; R 22 are each independently 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 Cycloalkyl, C 2 -C 6 It is selected from 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 deleterious effects on the health status of the subject being treated.

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

[0412] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, that 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] "Concomitant 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 agents are administered by the same or different routes of administration or at the same or different times.

[0415] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount 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 reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to clinically significantly reduce a disease symptom. An appropriate "effective" amount in an individual case is optionally determined using techniques such as dose escalation studies.

[0416] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. 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 combination of more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the active ingredients, for example, the compound of formula (I) or its pharmaceutically acceptable salt, and auxiliary agents, both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" refers to the active ingredients, for example, the compound of formula (I) or its pharmaceutically acceptable salt, and auxiliary agents, administered to a patient as separate entities at the same time, concurrently, and sequentially, without any specific intervening time limit, such administration providing 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; farm 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 prophylactically and / or therapeutically arresting a symptom of a disease or condition.

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

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

[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 powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated to provide a delayed or controlled release of the active ingredient. All preparations 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 the tablets or dragee coatings for identification or to characterize various combinations of doses of the active compound.

[0425] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The preparation for injection may be provided in unit dosage form, for example, in ampoules or multi-dose containers, together with additional preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The composition may be provided in unit or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

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

[0427] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection.Thus, for example, the compound 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 contain 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 external buccal cavity, and dropping the compounds into the ears, eyes, and nose, so that the compounds do not enter the bloodstream in large 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, nebulizer, pressurized pack, or other convenient means of delivering an aerosol spray. Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for administration by inhalation or insufflation, the formulation can take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be presented in unit dosage form, for example capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[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, those suitable for oral administration may include flavoring agents.

[0433] Dosage and treatment regimens In one embodiment, the compounds of formula (I), or pharma- ceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from modulation of somatostatin activity. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of at least one compound of formula (I), or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0434] In some embodiments, the compositions comprising the compounds described herein are administered for preventive 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 of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0435] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dosage." In this application, the exact amount will vary depending on the patient's health, weight, and the like. When used in patients, 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 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 pharmacologic 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.

[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 inhibit 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, depending on the symptoms, is reduced to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, patients require intermittent treatment on a long-term basis upon 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 used in adult human treatment will typically be 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 the compound of formula (I), or a pharma- ceutically 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, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage 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 at or near the ED 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 pharma- ceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or, (b) administered orally to a mammal, and / or, (c) administered intravenously to a mammal, and / or, (d) administered by injection to a mammal, and / or, (e) administered locally to a mammal, and / or, (f) administered non-systemically or locally to a mammal.

[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 in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal over the course of a day.

[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; and (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, where administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

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

[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 treatment regimen) that also has a therapeutic effect.

[0447] In one particular embodiment, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is co-administered with a second therapeutic agent, where the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent 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, alternatively, 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 with the one or more other therapeutic agents, or sequentially.

[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 can be provided in a single, unified form, or in multiple forms (e.g., as a single pill, or as two separate pills), by way of example only.

[0451] The compound of formula (I), or its pharma- ceutically acceptable salt, and combination therapy are administered before, during, or after the onset of disease or illness, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to disease or illness to prevent the onset of disease or illness. In another embodiment, the compounds and compositions are administered to subjects during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of disease or illness is detected or suspected, and for the period required for the treatment of the illness. In some embodiments, the period required for treatment varies, and the treatment period is adjusted to the specific needs of each subject. EXAMPLES

[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(PPh 3 ) 4 : Tetrakis(triphenylphosphine)palladium(0), Pd 2 (dba) 3 CHCl 3 : Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, Pd(dppf)Cl 2 : [1',1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(PPh 3 ) 2 Cl 2 : Bis(triphenylphosphine)palladium(II) dichloride, PdAMphos or Pd(amphos)Cl 2 : 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 salt; MeCN or CH 3 CN or ACN: acetonitrile; H 2 O:Water, DMSO: dimethyl sulfoxide; DMF: dimethylformamide, DCM: dichloromethane, NBS: N-bromosuccinimide, Br 2 :bromine, NCS: N-chlorosuccinimide; rt: room temperature, SST: somatostatin; SSTR: somatostatin receptor; hrs: hours, h or hr: hours, min: minutes, N 2 : Nitrogen gas, mg: milligram, mL: milliliter, eq. or equiv: equivalent weight, mmol: millimolar, μmol: micromolar, ppts: Precipitate, K 2 CO 3 : Potassium carbonate, NaClO 2 : Sodium chlorite, t-BuOH: tert-butyl alcohol, EtOAc: ethyl acetate, Na2 SO 4 : Sodium sulfate, NaHSO 4 : Sodium bisulfate, Na 2 S 2 O 3 :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: preparation of 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”), (3,5-dimethylphenyl)boronic acid (97 mg, 2.0 equivalent, 0.65 mmol), Pd 2 (dba) 3 CHCl 3 (33mg, 0.10eq, 0.032mmol), P(t-Bu) 3 ·HBF 4 (19 mg, 0.20 equiv., 0.064 mmol), and K 3 PO 4To a mixture of (206 mg, 3.0 equiv, 0.97 mmol), toluene (3.0 mL) and water (0.3 mL) were added under atmospheric nitrogen. The resulting mixture was stirred at 70° C. for 1 h. The reaction solution was concentrated under vacuum 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: In a round-bottom flask, add 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), NaH 2 PO 4 (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 2 (46 mg, 2.0 equiv, 0.51 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 h. 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 .about.4 to precipitate the solid product. 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 min, 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 h. 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 NH 4 HCO 3 +0.1% NH 3 H 2 0) and ACN (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 h. 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 are prepared similarly to Example 1, which may require additional functional group modification by well-known chemistry with appropriate reagents. The coupling reaction with aniline can be carried out using other coupling reagents such as HATU under appropriate conditions. Various salts such as HCl or 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 equiv., 54 mmol) in MeCN (100 mL) was added tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate (12 g, 1.1 equiv., 60 mmol) and DIPEA (21 g, 3.0 equiv., 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 eq, 0.49 mmol) in tert-butyl alcohol (9.0 mL) was added 2-methylbut-2-ene (0.66 mL, 12 eq, 5.9 mmol), sodium chlorite (0.43 g, 7.8 eq, 3.8 mmol, 85% by weight), sodium dihydrogen phosphate (0.35 g, 5.9 eq, 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 washed with saturated NaHSO 4(~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 h. 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 and washed with saturated NaHCO 3 (5 mL), solid NaCl (15 g) was added, and the organic layer was extracted with ethyl acetate (30 mL). 2 SO 4 The mixture was dried at 40° C., 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-methylpyrrolidin-3-yl)carbamate (90 mg, 1.0 equivalent, 0.17 mmol), (3,5-difluorophenyl)boronic acid (55 mg, 2.0 equivalent, 0.35 mmol), K 2 CO 3 (72 mg, 3.0 equiv., 0.52 mmol), and Pd(amphos)Cl 2 (12 mg, 0.10 equiv, 0.017 mmol) was added dioxane (2.0 mL). Nitrogen gas was bubbled through the reaction solution for 1 min, then water (0.20 mL) was added. Nitrogen was bubbled through for an additional 5 min. The reaction mixture was heated at 100° C. for 1 h. The reaction crude 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%). Combine the pure fractions and add saturated NaHCO 3(4 mL), solid NaCl (8 g) was added, and the organic layer was extracted with ethyl acetate (25 mL). 4 The mixture was dried at 40° C. for 1 hour, 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 by well-known chemistry with appropriate reagents. Various salts such as HCl or formic acid 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: preparation 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 equivalent, 1.98 mmol), K 2 CO 3(410 mg, 3.0 equiv., 2.97 mmol), and Pd(amphos)Cl 2 To a mixture of (35 mg, 0.05 equiv, 0.050 mmol) was added dioxane (4.0 mL) and water (0.4 mL). Nitrogen was bubbled through the reaction solution for 5 min and the resulting mixture was heated at 100° C. for 1 h. The reaction crude 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 equiv, 10.7 mmol), sodium chlorite (0.84 g, 8.9 equiv, 7.9 mmol, 85% by weight), sodium dihydrogen phosphate (0.75 g, 7.0 equiv, 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 washed with saturated NaHSO 4 (~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 min, 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 h. The reaction crude was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-55%). Pure fractions were combined and concentrated to remove most of the MeCN and washed with saturated NaHCO 3 (3 mL), added solid NaCl (5 g) and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and washed with MgSO 4 After drying at 40° C., filtration and concentration, 42 mg of the title compound was obtained. 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%). Combine the pure fractions and add saturated NaHCO 3 (3 mL), added solid NaCl (5 g) and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and washed with MgSO 4 The mixture was dried at 40° C. for 24 hours, 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 by well-known chemistry with appropriate reagents. Various salts such as HCl or formic acid 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 solution of DMF (70 mL) was added 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). The resulting mixture was stirred at 50° C. for 4 h. 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 under vacuum. 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 h. The reaction mixture was diluted with saturated NaHCO 3The mixture was quenched with ethyl acetate (3×40 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 / 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: tert-butyl (S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (3.5 g, 1.0 equiv., 8.6 mmol), (3,5-difluorophenyl)boronic acid (0.88 equiv., 7.6 mmol, 1.2 g), Pd(DtBPF)Cl 2 To a mixture of (300 mg, 0.05 equiv, 0.46 mmol) and potassium phosphate (5.4 g, 2.9 equiv, 25 mmol) under atmospheric nitrogen was added toluene (140 mL) and water (14 mL). The resulting mixture was stirred at 40° C. for 2 h. 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: Preparation of tert-butyl (S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (2.7 g, 1.0 equiv., 6.2 mmol), Pd 2 (dba) 3 CHCl 3 (310mg, 0.05eq, 0.31mmol), Zn(CN) 2 To a mixture of (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) was added DMF (30 mL) under atmospheric nitrogen. The resulting mixture was heated at 135° C. for 1 h under microwave radiation conditions. The reaction crude was quenched with water (100 mL) and extracted with EtOAc (3×40 mL). The organic layers were combined, washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried at 40° C., 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 equiv., 5.1 mmol) in tert-butyl alcohol (20 mL) was added sodium dihydrogen phosphate (2.4 g, 3.0 equiv., 15 mmol), 2-methylbut-2-ene (11.0 g, 31 equiv., 157 mmol), sodium chlorite (1.0 g, 2.2 equiv., 11 mmol) and water (6.6 mL). The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with saturated NaHSO 4 (50 mL) and extracted with ethyl acetate (3×40 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 h. 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 equiv, 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 modification by well-known chemistry with appropriate reagents. Various salts, such as HCl or formic acid 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: Ethyl 4,6-dichloronicotinate (200.0 g, 1.0 equiv., 909 mmol), zinc(II) cyanide (0.600 equiv., 545 mmol, 64 g), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.41 g, 0.01 equiv., 9.09 mmol), (9,9-dimethyl-9H-xanthene To a mixture of (10.5 g, 0.02 equiv., 18.1 mmol) and 1,2,3-phenyl-4,5-diyl)bis(diphenylphosphane) (10.5 g, 0.02 equiv., 18.1 mmol) under atmospheric nitrogen was added DMF (1600 mL). The reaction mixture was stirred at 130° C. for 2 h. The reaction mixture was poured into water (3000 mL) and extracted with EtOAc (3×1000 mL). The organic layers were combined, washed with water (3×2000 mL) and brine (1000 mL), and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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 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 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: In 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 in portions. The resulting mixture was stirred at the same temperature for 30 min. The reaction crude was dissolved in NaHSO at 0 °C. 3 The resulting suspension was filtered and the filtrate was extracted with EtOAc (3×100 mL). The organic layers were combined and washed with water (3×30 mL) and NaHCO 3The organic layer was 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: Preparation of ethyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-nicotinate (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 2 To a mixture of (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 h. 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), water (5.0 mL) was added. The resulting mixture was cooled to 10 °C, and lithium hydroxide (2.5 g, 10 equiv, 100 mmol) was added in portions. The reaction mixture was stirred at 50 °C for 3 h. The reaction crude was concentrated under vacuum and washed with saturated NaHSO until the crude solution was acidic (pH 4-5). 4 was added. 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) was added DMF (0.8 mL) and DIPEA (0.10 mL, 3.0 equiv, 0.59 mmol). 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 and washed with saturated NaHCO 3 (3 mL), solid NaCl (5 g) was added, and the organic layer was extracted with ethyl acetate (20 mL). 4 The mixture was dried at 40° C. for 1 hour, 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 equiv., 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 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%). Pure fractions were combined and purified by elution with saturated NaHCO 3 (3 mL), solid NaCl (5 g) was added, and the organic layer was extracted with ethyl acetate (20 mL). 4 The mixture was dried at 40° C. for 24 hours, 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 by well-known chemistry with appropriate reagents. Various salts such as HCl or formic acid 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 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and saturated NaHCO until pH ∼7.0. 3 The solution was added. 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 and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. 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 h. 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 equiv., 0.32 mmol), (3,5-difluorophenyl)boronic acid (150 mg, 3.0 equiv., 0.95 mmol), potassium phosphate (200 mg, 3.0 equiv., 0.942 mmol), and dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (21 mg, 0.10 equiv., 0.032 mmol)) under atmospheric nitrogen, 1,4-dioxane (1.0 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 80° C. for 1 h. 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 equiv, 0.474 mmol) in tert-butyl alcohol (6.0 mL) was added 2-methylbut-2-ene (1.66 g, 50 equiv, 23.7 mmol), sodium chlorite (86 mg, 2.0 equiv, 0.95 mmol), sodium dihydrogen phosphate dihydrate (222 mg, 3.0 equiv, 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 h. 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, 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 min); total flow, 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 eq, 28 mmol) and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (6.0 g, 1.1 eq, 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 eq, 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 eq, 5.5 mmol) and (3,5-difluorophenyl)boronic acid (0.80 g, 0.92 eq, 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&pure) 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 eq, 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 equiv., 0.17 mmol, 80% purity) using a method similar to that described in "Example 4, Steps 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: 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 (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 2 To a mixture of (l5 mg, 0.11 equiv, 0.007 mmol) under atmospheric nitrogen was added dioxane (1.0 mL). The resulting solution was stirred at 100° C. for 1 h. The reaction mixture was concentrated under vacuum 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 h. 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 eq, 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 eq, 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 equiv., 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 eq, 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 equiv, 22.7 mmol), tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (4.55 g, 1.0 equiv, 22.7 mmol), and N-ethyl-N-isopropylpropan-2-amine (8.81 g, 3.0 equiv, 68.2 mmol) was added MeCN (50 mL). The resulting mixture was stirred at 0° C. for 16 h. 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 h. The organic layer was separated and concentrated under vacuum 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 equiv., 23.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.0 equiv., 46.3 mmol, 5.99 g) were added. The resulting mixture was stirred at ambient temperature for 10 min, after which (S)-1-cyclopropylethan-1-amine (2.63 g, 2.00 equiv., 30.9 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 h. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (2×100 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), Pd(dppf)Cl 2 (200 mg, 0.096 equiv., 0.273 mmol) was added under atmospheric nitrogen. The resulting mixture was heated at 130° C. under 20 bar of carbon monoxide for 8 h. 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: In 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 equiv, 2.9 mmol) and ammonia (12 mL, 28 equiv, 82.2 mmol) in MeOH (7.0 M) were added. The resulting mixture was stirred at 80° C. for 2 h. 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 cooled to 5° C. for 1 h and cooled to 5° C. for 1 h. 2 CO 3It was quenched with aqueous solution 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), AcOH (20 mL) was added. 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 min. The reaction crude was dissolved in saturated Na 2 SO 3 (10 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 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 (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 2 To a mixture of (7.0 mg, 0.11 equiv, 0.011 mmol) was added toluene (2.0 mL) and water (0.2 mL) under atmospheric nitrogen. 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), TFA (1.0 mL) was added. The resulting mixture was stirred at 25° C. for 1 h. 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 by well-known chemistry with appropriate reagents. Various salts, such as HCl or formic acid 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 equivalent, 0.946 mmol, "Example 9, Process To a mixture of 1,4-dimethyl-1,3,5,2,4,6-trioxatriborinane (2.0 equiv., 1.89 mmol, 209 mg) (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 x 20 mL). The organic layers were combined, washed with brine (2 x 20 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 (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 equiv., 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 equiv., 1.50 mmol) at 0° C. The resulting mixture was stirred at the same temperature for 15 min. The reaction mixture was cooled to 37°C with NaHSO 3 The mixture was quenched with aqueous ethyl acetate and the solid was filtered off. The filtrate was collected and extracted with EtOAc (2×30 mL). The organic layers were combined and washed with water (3×30 mL), NaHCO 3 It was washed with aqueous solution, 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: 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 (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) under atmospheric nitrogen was added toluene (3.0 mL) and water (0.3 mL). The resulting mixture was heated at 70° C. for 1 h. 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 h. 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 modification by well-known chemistry with appropriate reagents. Various salts, such as HCl or formic acid 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 eq, 5.34 mmol) and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (1.05 g, 0.982 eq, 5.24 mmol), MeCN (10 mL) was added. At 0° C., DIPEA (2.8 mL, 3.0 eq, 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 diluted with saturated NH 4 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%). Pure fractions were combined, concentrated and washed with saturated NaHCO 3 (5.0 mL), added solid NaCl (10 g) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with MgSO 4The mixture was dried at 40° C. for 1 hour, 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 min 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 and saturated NaHCO 3 (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: Preparation of methyl (S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxynicotinate (754 mg, 1.0 equiv., 1.70 mmol), (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 2 To a mixture of (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. (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 2 A second batch of (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 h. The reaction crude was concentrated, diluted with ethyl acetate and washed with saturated NaHSO 4 4 After washing with ethyl acetate...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, Ring A is a carbocyclic or heterocyclic ring; X is N or C-R ａ and Y is N or C-R ｂ and Z is N or C-R ｃ and R ａ , R ｂ , and R ｃ are each independently hydrogen, halogen, -CN, -N(R ９ ) ２ , -OR ｆ , -CO ２ R ９ , -C(=O)N(R ９ ) ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ fluoroalkoxy, substituted or unsubstituted C １ -C ６ heteroalkyl, a substituted or unsubstituted monocyclic carbocycle, or a substituted or unsubstituted monocyclic heterocycle; R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ Alkylene, C １ -C ６ Fluoroalkylene, or C １ -C ６ is heteroalkylene, R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, -CO ２ R ９ or -C(=O)N(R ９ ) ２ , a substituted or unsubstituted monocyclic heterocycle; R １ and R ２ are independently hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C ６ Cycloalkyl, or substituted or unsubstituted C ３ -C ５ is heterocycloalkyl, R ３ is hydrogen, -CN, -CO ２ R ９ , -C(=O)N(R ９ ) ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Alkoxy, substituted or unsubstituted C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ is heteroalkyl, R ４ and R ５ are each independently hydrogen, halogen, or -OR ９ , -N(R ９ ) ２ , -CN, -CO ２ R ９ , -C(=O)N(R ９ ) ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Alkoxy, substituted or unsubstituted C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ is heteroalkyl, R ６ is a substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted C １ -C ８ Fluoroalkyl, substituted or unsubstituted C １ -C ８ Heteroalkyl, or -L ２ -R ６ａ and L ２ is absent or is a substituted or unsubstituted C １ -C ８ Alkylene or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted C ２ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is heteroaryl, R ６ｂ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ３ -C ６ is cycloalkyl, R ７ is hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted C ２ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is 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 １２ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, -CN, -OR ９ , -C(=O)R １０ , -CO ２ R 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 , -SO ２ R ９ , or -SO ２ N (R ９ ) ２ and 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 each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C ７ 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 １０ each independently represents a substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C ７ 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; The compound, or a pharma- ceutically acceptable salt or solvate thereof.

2. R １ is hydrogen, R ２ is hydrogen or C １ -C ６ is alkyl, R ３ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is fluoroalkyl, and R ４ and R ５ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, or C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is fluoroalkyl.

3. R １ and R ２ are hydrogen, R ３ is hydrogen or -CH ３ and R ４ and R ５ 4. The compound of claim 2 or 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein each is hydrogen.

4. 2. The compound of claim 1, wherein the compound has the structure of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 2】

5. X is C-R ａ where Y is N and Z is C-R ｃ or X is CH, Y is N, and Z is C-R ｃ or X is C-R ａ and Y is N and Z is CH; or X is N and Y is C-R ｂ and Z is C-R ｃ or X is C-R ａ and Y is C-R ｂ and Z is N; or X is N, Y is N, and Z is C-R ｃ or X is C-R ａ 5. The compound of any one of claims 1-4, wherein: Y is N and Z is N; or a pharma- ceutically acceptable salt or solvate thereof.

6. The compound of any one of claims 1-4, wherein the compound has the structure of Formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof: embedded image wherein: R is an integer from 1 to 4; 【Chemistry 3】

7. 7. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ring A is phenyl, a monocyclic heteroaryl, or a bicyclic heteroaryl.

8. 8. The compound of claim 6 or 7, wherein the compound has the structure of Formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 4】

9. Ring A is a monocyclic heteroaryl, and 7. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.

10. 10. The compound of claim 9, wherein Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, or a pharma- ceutically acceptable salt or solvate thereof.

11. Ring A is phenyl; or Ring A is pyridinyl; or 8. The compound of claim 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein Ring A is pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, or pyrimidinyl.

12. The compound has the structure of formula (IVa), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 5】 During the ceremony, A １ and A ２ are each independently C-R ８ or N, and A ３ is C-R １２ or N, or a pharma- ceutically acceptable salt or solvate thereof.

13. A １ is C-R ８ And A ２ is C-R ８ and A ３ is C-R １２ or A １ is N, and A ２ is C-R ８ and A ３ is C-R １２ or A １ is C-R ８ And A ２ is N, and A ３ is C-R １２ or A １ is C-R ８ And A ２ is C-R ８ and A ３ is N; or a pharma- ceutically acceptable salt or solvate thereof.

14. The compound has the structure of formula (IVa-1), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 6】 During the ceremony, A １ is C-R ８ and A ２ is C-R ８ or A １ is N, and A ２ is C-R ８ or A １ is C-R ８ and A ２ is N; or a pharma- ceutically acceptable salt or solvate thereof.

15. 13. The compound of claim 12, wherein the compound has the structure of Formula (IVa-2), Formula (IVa-3), Formula (IVa-4), or Formula (IVa-5), or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 7】

16. 13. The compound of claim 12, wherein the compound has the structure of Formula (Va), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 8】

17. 17. The compound of claim 16, wherein the compound has the structure of Formula (Va-1) or Formula (Va-2), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 9】

18. R ８ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, -CN, -OR ９ , -CO ２ R ９ , -C(=O)N(R ９ ) ２ , -N(R ９ ) ２ , or -NR ９ C(=O)R １０ 18. The compound of any one of claims 1-17, which is: or a pharma- ceutically acceptable salt or solvate thereof.

19. R ８ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, or substituted or unsubstituted C １ -C ６ 19. The compound of any one of claims 1-18, or a pharma- ceutically acceptable salt or solvate thereof, which is fluoroalkyl.

20. R ８ The compound of any one of claims 1-19, or a pharma- ceutically acceptable salt or solvate thereof, wherein each is independently hydrogen or halogen.

21. 17. The compound of claim 16, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (Va-3): embedded image or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 10】

22. R １１ and R １２ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, -CN, -OR ９ , -CO ２ R 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, or a pharma- ceutically acceptable salt or solvate thereof.

23. R １１ and R １２ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, -CN, -OR ９ or a substituted or unsubstituted monocyclic cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof.

24. R １１ and R １２ or a pharma- ceutically acceptable salt or solvate thereof. The compound of any one of claims 1-23, wherein each is independently a halogen.

25. The compound has the structure of formula (VIa) or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 11】 During the ceremony, R ３ is hydrogen or -CH ３ and R ８ is hydrogen or a halogen, R １１ and R １２ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, -CN, -OR ９ and R ｃ is hydrogen, halogen, -CN, -N(R ９ ) ２ , -OR ｆ , -CO ２ R ９ , -C(=O)N(R ９ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted monocyclic C ３ -C ６ Cycloalkyl, substituted or unsubstituted monocyclic C ２ -C ５ is heterocycloalkyl, R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ is alkylene, and R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, -CO ２ R ９ , -C(=O)N(R ９ ) ２ , substituted or unsubstituted monocyclic C ２ -C ５ 9. The compound of claim 8, or a pharma- ceutically acceptable salt or solvate thereof, which is heterocycloalkyl.

26. R ｃ is hydrogen, halogen, -CN, -N(R ９ ) ２ , -OR ｆ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ is heteroalkyl, R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ is alkylene, and R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, or -CO ２ R ９ 26. The compound of claim 25, wherein:

27. R ８ is hydrogen, -F, or -Cl; R １１ and R １２ are each independently hydrogen, -F, -Cl, -CN, or -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , or -OCHF ２ and R ｃ is hydrogen, -F, -Cl, -CN, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -CH(CH ３ )(CH ２ CH ３ ), -C(CH ３ ) ３ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CF ３ , -OCH ３ , -OCH ２ CH ３ , -OCF ３ , -OCH ２ CHF ２ , -OCH ２ CF ３ , -OCH ２ CH ２ OCH ３ , -O-(cyclopropyl), -O-CH ２ -(cyclopropyl), -O-CH ２ -(phenyl), -OCH ２ CO ２ H, -OCH ２ CH ２ CO ２ H, -OCH ２ CH ２ CH ２ CO ２ H, -OCH ２ CO ２ CH ３ , -OCH ２ CH ２ CO ２ CH ３ , -OCH ２ CH ２ CH ２ CO ２ CH ３ , -OCH ２ CO ２ CH ２ CH ３ , -OCH ２ CH ２ CO ２ CH ２ CH ３ , -OCH ２ CH ２ CH ２ CO ２ CH ２ CH ３ , -CO ２ CH ３ , -CO ２ CH ２ CH ３ , -C(=O)NH ２ , -CONHCH ３ , -C(=O)N(CH ３ ) ２ 27. The compound of claim 25 or 26, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl, or a pharma- ceutically acceptable salt or solvate thereof.

28. The compound has the structure of formula (VIa-1), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 12】 During the ceremony, R ３ is hydrogen or -CH ３ and R ｃ is hydrogen, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , -CO ２ CH ３ , -C(=O)NH ２ , -CONHCH ３ or -C(=O)N(CH ３ ) ２ and R １１ and R １２ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, -CN, or -OR ９ 28. The compound of any one of claims 25-27, which is: or a pharma- ceutically acceptable salt or solvate thereof.

29. The compound has the structure of formula (VIIa), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 13】 During the ceremony, R ８ is hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C ３ -C ６ is cycloalkyl, R ｃ is hydrogen, halogen, -CN, -N(R ９ ) ２ , -OR ｆ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ is heteroalkyl, R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ is alkylene, R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, or -CO ２ R ９ 8. The compound of claim 1, wherein:

30. R ７ is hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, or substituted or unsubstituted C １ -C ６ is fluoroalkyl, and R ６ is a substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted C １ -C ８ Fluoroalkyl, substituted or unsubstituted C １ -C ８ Heteroalkyl, or -L ２ -R ６ａ and L ２ is absent or is a substituted or unsubstituted C １ -C ８ Alkylene or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted C ２ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is heteroaryl, R ６ｂ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ３ -C ６ is cycloalkyl, Or, R ６ and R ７ or a pharma- ceutically acceptable salt or solvate thereof. The compound of any one of claims 1-29, wherein: R is 0 or 1; and R is 1 or 2; and R is 2 or 3; and R is 4 or 5.

31. R ７ is hydrogen or C １ -C ６ 31. The compound of any one of claims 1-30, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

32. R ７ is hydrogen or -CH ３ 32. The compound of any one of claims 1-31, which is: or a pharma- ceutically acceptable salt or solvate thereof.

33. R ６ is a substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted C １ -C ８ Fluoroalkyl, substituted or unsubstituted C １ -C ８ 33. The compound of any one of claims 30-32, or a pharma- ceutically acceptable salt or solvate thereof, which is heteroalkyl.

34. R ６ is C １ -C ６ Alkyl or C １ -C ６ 33. The compound of any one of claims 30-32, or a pharma- ceutically acceptable salt or solvate thereof, which is fluoroalkyl.

35. R ６ Ha-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 , or -CH(CH ３ ) (CH ２ CF ３ 35. The compound of claim 34, wherein:

36. R ６ Ha-L ２ -R ６ａ and R ６ａ is a substituted or unsubstituted monocyclic C ３ -C ８ Cycloalkyl, substituted or unsubstituted polycyclic C ５ -C １０ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic C ２ -C ５ Heterocycloalkyl, substituted or unsubstituted polycyclic C ５ -C １０ Heterocycloalkyl, substituted or unsubstituted monocyclic C １ -C ５ Heteroaryl or substituted or unsubstituted bicyclic C ６ -C ９ 33. The compound of any one of claims 30-32, or a pharma- ceutically acceptable salt or solvate thereof, which is heteroaryl.

37. R ６ａ is a substituted or unsubstituted monocyclic C ３ -C ６ Cycloalkyl, substituted or unsubstituted bridged C ５ -C １０ Cycloalkyl, substituted or unsubstituted spirocyclic C ５ -C １０ 37. The compound of claim 36, which is cycloalkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetrahydronaphthyl, or substituted or unsubstituted naphthyl, or a pharma- ceutically acceptable salt or solvate thereof.

38. R ６ａ is a substituted or unsubstituted monocyclic C ２ -C ５ Heterocycloalkyl, substituted or unsubstituted bridged C ５ -C １０ Heterocycloalkyl, substituted or unsubstituted spirocyclic C ５ -C １０ Heterocycloalkyl, substituted or unsubstituted monocyclic C １ -C ５ Heteroaryl or substituted or unsubstituted bicyclic C ６ -C ９ 37. The compound of claim 36, or a pharma- ceutically acceptable salt or solvate thereof, which is heteroaryl.

39. L ２ does not exist or C １ -C ４ Alkylene, or -CHR ６ｂ - and R ６ｂ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ fluoroalkyl, or substituted or unsubstituted C ３ -C ６ 39. The compound of any one of claims 36-38, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

40. L ２ does not exist or C １ -C ４ Alkylene, or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted C ３ -C ４ Cycloalkyl or substituted or unsubstituted 3- or 4-membered C ２ -C ３ is heterocycloalkyl, R ６ｂ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ３ -C ４ 40. The compound of any one of claims 36-39, or a pharma- ceutically acceptable salt or solvate thereof, which is cycloalkyl.

41. 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 41. The compound of any one of claims 36-40, wherein R is cyclopropyl, cyclopropyl, or cyclobutyl, or a pharma- ceutically acceptable salt or solvate thereof.

42. 【Catalogue 14】 teeth, 【Chemistry 15】 【Chemistry 16】 30. The compound of any one of claims 1-29, which is: or a pharma- ceutically acceptable salt or solvate thereof.

43. R ９ each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl or substituted or unsubstituted C １ -C ６ is a 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 each independently represents a substituted or unsubstituted C １ -C ６ Alkyl or substituted or unsubstituted C １ -C ６ 43. The compound of any one of claims 1-42, or a pharma- ceutically acceptable salt or solvate thereof, which is fluoroalkyl.

44. X is N or CH; Y is N or CH; Z is N or C-R ｃ and R ｃ is hydrogen, halogen, -CN, -N(R ９ ) ２ , -OR ｆ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ fluoroalkoxy or substituted or unsubstituted C １ -C ６ is heteroalkyl, R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ Alkylene, or C １ -C ６ is a fluoroalkylene; R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, -CO ２ R ９ or -C(=O)N(R ９ ) ２ and R １ is hydrogen, R ２ is hydrogen or C １ -C ６ is alkyl, R ３ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is a fluoroalkyl; R ４ is hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ is a fluoroalkyl; R ５ is hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ is a fluoroalkyl; R ６ is C １ -C ８ Alkyl, C １ -C ８ Fluoroalkyl, or -L ２ -R ６ａ and L ２ does not exist or C １ -C ６ Alkylene, or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted C ２ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is heteroaryl, R ６ｂ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ３ -C ６ is cycloalkyl, R ７ is hydrogen or C １ -C ６ is alkyl, Or, R ６ and R ７ and R 1 and R 2 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle, or a pharma- ceutically acceptable salt or solvate thereof.

45. X is N or CH; Y is N or CH; Z is N or C-R ｃ and R ｃ is hydrogen, -CN, -CH ３ , -CF ３ , -OCH ３ , -OCF ３ , -CO ２ CH ３ , -C(=O)NH ２ , -CONHCH ３ or -C(=O)N(CH ３ ) ２ and R １ is hydrogen, R ２ is hydrogen, R ３ is hydrogen, -CH ３ , -CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , or -CH ２ CF ３ and R ４ is hydrogen or F, R ５ is hydrogen or F, 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 C １ -C ６ Alkylene, or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted monocyclic C ３ -C ４ Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ５ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted monocyclic C ２ -C ３ Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ４ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is heteroaryl, R ６ｂ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ fluoroalkyl, or a substituted or unsubstituted monocyclic C ３ -C ４ is cycloalkyl, R ７ is hydrogen or C １ -C ６ is alkyl, Or, R ６ and R ７ and R 1 and R 2 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle, or a pharma- ceutically acceptable salt or solvate thereof.

46. The compound has the structure of formula (VIII), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 17】 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 , -CO ２ R ９ , -C(=O)N(R ９ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ fluoroalkoxy, substituted or unsubstituted monocyclic C ３ -C ６ Cycloalkyl or substituted or unsubstituted monocyclic C ２ -C ５ is heterocycloalkyl, R ｆ Ha-L １ -R ｇ and L １ does not exist or C １ -C ６ is alkylene, R ｇ is hydrogen, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted phenyl, -CO ２ R ９ or -C(=O)N(R ９ ) ２ or a substituted or unsubstituted monocyclic C ２ -C ５ is heterocycloalkyl, R １ is hydrogen, R ２ is hydrogen or C １ -C ６ is alkyl, R ３ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, or C １ -C ４ is heteroalkyl, R ４ is hydrogen, halogen, C １ -C ４ Alkyl, or C １ -C ４ is a fluoroalkyl; R ５ is hydrogen, halogen, C １ -C ４ Alkyl, or C １ -C ４ is a fluoroalkyl; 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 C １ -C ６ Alkylene, or -CHR ６ｂ - and R ６ａ is a substituted or unsubstituted monocyclic C ３ -C ４ Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ５ -C １０ Cycloalkyl, substituted or unsubstituted C ６ -C １０ Aryl, substituted or unsubstituted monocyclic C ２ -C ３ Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ４ -C １０ Heterocycloalkyl or substituted or unsubstituted C １ -C ９ is heteroaryl, R ６ｂ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ fluoroalkyl, or a substituted or unsubstituted monocyclic C ３ -C ４ is cycloalkyl, R ７ is hydrogen or C １ -C ６ is alkyl, R ８ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, or C １ -C ６ is a fluoroalkyl; R １１ and R １２ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, -CN, -OR ９ , -CO ２ R 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 ３ -C ８ Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic C ２ -C ５ Heterocycloalkyl or substituted or unsubstituted monocyclic C １ -C ５ is heteroaryl, R ９ each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl or substituted or unsubstituted C １ -C ６ is a 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 each independently represents a substituted or unsubstituted C １ -C ６ Alkyl or substituted or unsubstituted C １ -C ６ is a fluoroalkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0 to 3.

47. The compound has the structure of formula (IXa-1), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 18】 During the ceremony, A １ is C-R ８ and A ２ is C-R ８ or A １ is N, and A ２ is C-R ８ or A １ is C-R ８ and A ２ is N; or a pharma- ceutically acceptable salt or solvate thereof.

48. R ３ is hydrogen or -CH ３ and R ４ and R ５ are hydrogen, R ８ are each independently hydrogen or halogen; and R １１ and R １２ each independently represents hydrogen, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, -CN, -OR ９ 48. The compound of claim 46 or 47, which is: or a pharma- ceutically acceptable salt or solvate thereof.

49. 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 or solvate thereof.

50. 50. A pharmaceutical composition comprising a compound according to any one of claims 1-49, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

51. 51. The pharmaceutical composition of claim 50, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, dermal, or ocular administration.

52. 51. The pharmaceutical composition of claim 50, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

53. 50. A method of treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor subtype 5 (SSTR5) activity, comprising administering to said mammal a compound according to any one of claims 1-49, or a pharma- ceutically acceptable salt or solvate thereof.

54. 54. The method of claim 53, wherein the disease or condition is hyperinsulinemic hypoglycemia.

55. 54. The method of claim 53, wherein the disease or condition is endogenous insulin induced hypoglycemia, drug induced hyperinsulinism, or exogenous insulin induced hypoglycemia.

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