NAMPT modulators

Abstract

Increasing the rate of NAMPT catalysis with small molecule activators would be an effective strategy to boost NAD levels and thereby address a wide range of disease states. JPEG2025542258000899.jpg44150 or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, R B , R C , n, and p are as defined herein. Pharmaceutically acceptable compositions comprising the compounds of formula (I), or pharmaceutically acceptable salts thereof, are also provided. Methods of using the compounds of formula (I), or pharmaceutically acceptable salts thereof, are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 434,849, filed December 22, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Provided herein are alkyl carbamate compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat various diseases and conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT). [Background technology]

[0003] The present disclosure relates to the use of modulators of nicotinamide phosphoribosyltransferase (NAMPT) and its derivatives, as well as enhancers or inducers of NAMPT expression, NAMPT activity, or NAMPT-mediated signaling, to prevent or treat various pathological conditions.

[0004] Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme (enzyme cofactor) involved in fundamental biological processes in both catabolic and anabolic metabolism. As a coenzyme, NAD associates with many oxidative enzymes (usually dehydrogenases) involved in energy metabolism and functions as a universal electron carrier. NAD exists within cells in both oxidized (NAD+ and NADP+) and reduced (NADH and NADPH) states, acting as a chemical means to capture and transfer free energy from oxidation processes in catabolism or to provide small blocks of energy to build macromolecules in anabolism. NADH, produced from the oxidation of carbohydrates, lipids, and amino acids, provides reducing equivalents for the mitochondrial electron transport chain, ultimately facilitating the synthesis of ATP in oxidative phosphorylation.

[0005] Over 200 enzymes use either NAD+ or NADP+ as a coenzyme, and their functions are not limited to energy metabolism. NAD+ is now recognized to be involved in regulating diverse functions, including mitochondrial function, respiratory capacity, and biogenesis, as well as mitochondrial-nuclear signaling. Furthermore, NAD+ regulates cell signaling, gene expression, DNA repair, hematopoiesis, immune function, the unfolded protein response, and autophagy. Furthermore, NAD is anti-inflammatory and is a precursor of NADPH, the primary source of reducing power for suppressing oxidative stress. A growing body of literature has demonstrated that increasing NAD levels is an effective approach to prevent or ameliorate a wide range of disease states (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13).

[0006] Levels of NAD+ and NADP+ related enzymes play important roles in normal physiological function and are altered in various diseases and under stress conditions, including aging. Cellular NAD+ levels decrease during aging, metabolic and inflammatory diseases, ischemia / reperfusion injury, and other conditions in humans (Massudi et al., PLoS ONE. 2012,7(7):e42357) and animals (Yang et al., Cell. 2007,130(6):1095-107; Braidy et al. PLoS One. 2011,26;6(4):e19194; Peek et al. Science. 2013,342(6158):1243417; Ghosh et al., J Neurosci. 2012,32(17):5821-32), suggesting that modulation of cellular NAD+ levels influences the rate and severity of decline and deterioration of bodily function. Therefore, increasing cellular NAD+ concentrations may be beneficial in the context of aging and age-related diseases. The cellular NAD+ pool is regulated by the balance between the activities of NAD+ synthesizing enzymes and NAD+ consuming enzymes. In mammals, NAD+ is synthesized from various dietary sources, including one or more of its major precursors, such as tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide (NAM). There are three routes of NAD+ synthesis in cells based on the bioavailability of its precursors: (i) from Trp via the de novo biosynthetic pathway or the kynurenine pathway; (ii) from NA via the Preiss-Handler pathway; and (iii) from NAM, NR, and NMN via the salvage pathway (Verdin et al., Science. 2015, 350(6265):1208-13). Among these, the main NAD+ biosynthetic pathway involves the synthesis of nicotinamide mononucleotide (NMN) using nicotinamide and 5'-phosphoribosylpyrophosphate by nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme important in determining lifespan and responses to various stresses (Fulco et al., Dev Cell. 2008, 14(5):661-73; Imai, Curr Pharm Des. 2009, 15(1):20-8; Revollo et al., J Biol Chem. 2004, 279(49):50754-63; Revollo et al., Cell Metab. 2007, Nov;6(5):363-75; van der Veer et al., J Biol Chem. 2007, 282(15):10841-5; Yang et al. al., Cell. 2007, 130(6):1095-107). Thus, increasing the rate of NAMPT catalysis with small molecule activators would be an effective strategy to boost NAD levels and thereby address a wide range of disease states, including cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscle disease, neurological disease and injury, diseases caused by stem cell dysfunction, DNA damage and primary mitochondrial disorders, and eye diseases.CNS-penetrable NAMPT activators also have the ability to boost NAD levels in the brain, which is advantageous for treating CNS-related diseases. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Stromland et al.,Biochem Soc Trans.2019,47(1):119-130 [Non-patent document 2] Ralto et al., Nat Rev Nephrol. 2019 [Non-patent document 3] Fang et al.,Trends Mol Med. 2017,23(10):899-916 [Non-patent document 4] Yoshino et al.,Cell Metab. 2011,14(4):528-36 [Non-patent document 5] Yang and Sauve, Biochim Biophys Acta. 2016,1864:1787-1800 [Non-patent document 6] Verdin,Science. 2015,350(6265):1208-13 [Non-Patent Document 7] Massudi et al.,PLoS ONE. 2012,7(7): e42357 [Non-patent document 8] Yang et al.,Cell. 2007,130(6):1095-107 [Non-Patent Document 9] Braidy et al. PLoS One. 2011,26;6(4):e19194 [Non-Patent Document 10] Peek et al. Science. 2013,342(6158):1243417 [Non-Patent Document 11] Ghosh et al.,J Neurosci. 2012,32(17):5821-32 [Non-Patent Document 12] Fulco et al,Dev Cell.2008,14(5):661-73 [Non-Patent Document 13] Imai,Curr Pharm Des.2009,15(1):20-8 [Non-Patent Document 14] Revollo et al.,J Biol Chem.2004,279(49):50754-63 [Non-Patent Document 15] Revollo et al.,Cell Metab.2007,Nov;6(5):363-75 [Non-Patent Document 16] van der Veer et al.,J Biol Chem.2007,282(15):10841-5 Summary of the Invention [Means for solving the problem]

[0008] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring having i) 1 to 4 R A or a 5-6 membered heteroaryl optionally substituted with ii) [ka] and; Each R A are independently selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; R D is selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L )-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L)-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L are independently hydrogen or C1-C6 alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R B are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; -C(O)(3- to 8-membered cycloalkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(4-8 membered heterocycloalkyl) optionally substituted with 1-3 independently selected halogens; -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -S(O)2(4-8 membered heterocycloalkyl); -C(O)NR B1 R B2 ; -S(O)2NR B1 R B2 ; -NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C1-C6 alkyl); where R C1 , R B1 and R B2 are each independently hydrogen or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R C is halogen, cyano, C1-C6 alkyl, OH, —O(C1-C6 alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2.

[0009] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring having i) 1 to 4 R A or a 5-6 membered heteroaryl optionally substituted with ii) [ka] and; Each R A are independently selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; R D is selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2, where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L )-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L are independently hydrogen or C1-C6 alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R B are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; —C(O)(3-8 membered cycloalkyl); —C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ; -S(O)2NR B1 R B2 ; -NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, and —O(C1-C6 alkyl); where R C1 , R B1 and R B2 are each independently hydrogen or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R C is halogen, cyano, C1-C6 alkyl, OH, —O(C1-C6 alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2.

[0010] In another embodiment, there is provided a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0011] In a further aspect, provided herein are pharmaceutical compositions comprising at least one compound of Formula (I) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing, and optionally further comprising a pharmaceutically acceptable excipient.

[0012] In another aspect, provided herein is a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound of Formula (I), e.g., a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (I). In some embodiments, the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or condition, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle wasting disorder. In some embodiments, the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

[0013] Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description, as well as by practice of the disclosure.

[0014] For the sake of brevity, the disclosures of the publications cited herein, including patents, are hereby incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition As used herein, the following words and phrases are generally intended to have the following meanings, unless the context in which they are used dictates otherwise:

[0016] Throughout this application, unless the context dictates otherwise, a reference to compounds of Formula (I) includes all subgroups of Formula (I) defined herein, including all substructures, subgenera, selections, embodiments, examples, and specific compounds defined and / or described herein. References to compounds of Formula (I) and subgroups thereof include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopic and / or protected forms thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes their isomers, tautomers, and / or oxides. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes solvates thereof. Similarly, the term "salt" includes solvates of salts of the compounds.

[0017] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6 Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbon atoms is specified, all branched and straight-chain forms having that number of carbon atoms are intended to be included; thus, for example, "propyl" includes N-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, N-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0018] As used herein, the term "alkylene" refers to a divalent alkyl group, as defined herein above, having 1 to 20 carbon atoms. Unless otherwise specified, alkylene refers to a moiety having 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene.

[0019] When a range of values ​​is given (e.g., C 1-6 alkyl), including each value within that range and all ranges therebetween. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 Contains alkyl.

[0020] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic), spiro, branched, and / or bridged. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, caged, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). In addition, one ring of a polycyclic cycloalkyl group can be aromatic, so long as the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (which is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (which is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0021] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). Furthermore, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic alkenyl group is connected to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (which is connected to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (which is connected to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are set forth below.

[0022] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, a polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure via an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some examples, an aryl is phenyl or naphthyl. In certain examples, an aryl is phenyl. Further examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0023] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise stated, a heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom, valence permitting. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0024] In some examples, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0025] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[3,4 ... Pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo thiazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0026] In other cases, polycyclic heteroaryl groups can contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.

[0027] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., a 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic), spiro, branched, and / or bridged. Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Examples of spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane. Furthermore, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.

[0028] "Heterocycloalkenyl" refers to a non-aromatic ring having the indicated number of atoms (e.g., a 3- to 10-, or 3- to 7-membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and having at least one double bond derived by removing one hydrogen atom from the adjacent carbon atom, adjacent nitrogen atom, or adjacent carbon and nitrogen atom of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Furthermore, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

[0029] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo [d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As described herein, whether each ring is considered an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group depends on the atom through which it is attached to the parent structure.

[0030] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0031] Unless otherwise specified, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, it is intended that the compound include both the E and Z isomers. When a compound described herein contains a moiety capable of tautomerization, it is intended that the compound include all possible tautomers, unless otherwise specified.

[0032] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to be selectively carried out at an otherwise unprotected reactive site, and that allows the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" comprises at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0033] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and commonly used in pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] When the compounds described herein are obtained as acid addition salts, the solution of the acid salt can be basified to obtain free base.On the other hand, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid according to the conventional procedure for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19).Those skilled in the art will understand that various synthetic methods can be used to prepare pharmaceutically acceptable addition salts.

[0035] A "solvate" is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0036] The term "substituted" means that the specified group or moiety has one or more substituents, including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term "unsubstituted" means that the specified group does not bear any substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position of the system, including valence-allowed positions that are heteroatoms. For example, an "optionally substituted piperazin-2-yl" group can be substituted at any valence-allowed position, including nitrogen. Groups with variable substitution, such as [ka] Where is shown, the shown substituent is [ka] In addition, when bicyclic groups with variable substitution are depicted, the depicted substituents can be in any valence-allowed position on either ring, or on both rings. For example, [ka] R BSubstituents can be on either the cyclopentyl or cyclopropyl component of the fused system, or on both the cyclopentyl and cyclopropyl components of the fused system. When a group or moiety has multiple substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety has 1 to 5 substituents. In some embodiments, a substituted group or moiety has 1 substituent. In some embodiments, a substituted group or moiety has 2 substituents. In some embodiments, a substituted group or moiety has 3 substituents. In some embodiments, a substituted group or moiety has 4 substituents. In some embodiments, a substituted group or moiety has 5 substituents.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those of skill in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically infeasible, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0038] The compounds disclosed and / or described herein may be present in isotopically enriched form, e.g. 2 H, 3 H, 11 C. 13 C and / or 14The compound may be enriched in C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the means described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989,45(21),6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0039] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0040] The terms "patient," "individual," and "subject" refer to an animal, e.g., a mammal, a bird, or a fish. In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the object of treatment, observation, or experimentation. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0041] As used herein, the term "therapeutic" refers to the ability to modulate nicotinamide phosphoribosyltransferase (NAMPT). As used herein, "modulation" refers to a change in activity relative to the activity in the absence of a chemical compound described herein, either directly or indirectly, in response to the chemical compound. This change can be an increase or decrease in activity and can result from the direct interaction of the chemical compound with the target, or from the interaction of the chemical compound with one or more other factors that ultimately affect the activity of the target. For example, the presence of a chemical compound can increase or decrease the activity of a target, for example, by directly binding to the target, by increasing or decreasing (directly or indirectly) the target activity through another factor, or by increasing or decreasing (directly or indirectly) the amount of the target present in a cell or organism.

[0042] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of treatment as defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of nicotinamide phosphoribosyltransferase (NAMPT). A therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one skilled in the art. A therapeutically effective amount can be ascertained experimentally, for example, by assessing blood levels of the chemical substance, or theoretically by calculating bioavailability.

[0043] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of delaying or preventing the onset of clinical symptoms of a disease or disorder and / or alleviating the disease or disorder (i.e., causing a reduction or regression of clinical symptoms). The term encompasses both complete and partial reduction or prevention of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder.

[0044] compound Compounds and salts thereof (e.g., pharmaceutically acceptable salts) are described in detail herein, including in the Summary of the Invention and the accompanying Claims. Also provided are all uses of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts, and solvates, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0045] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring having i) 1 to 4 R A or a 5-6 membered heteroaryl optionally substituted with ii) [ka] and; Each R A are independently selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; R D is selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L )-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L are independently hydrogen or C1-C6 alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R B are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; -C(O)(3- to 8-membered cycloalkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(4-8 membered heterocycloalkyl) optionally substituted with 1-3 independently selected halogens; -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -S(O)2(4-8 membered heterocycloalkyl); -C(O)NR B1 R B2 ; -S(O)2NR B1 R B2 ; -NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C1-C6 alkyl); where R C1 , R B1 and R B2 are each independently hydrogen or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R C is halogen, cyano, C1-C6 alkyl, OH, —O(C1-C6 alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2.

[0046] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring having i) 1 to 4 R A or a 5-6 membered heteroaryl optionally substituted with ii) [ka] and; Each R Aare independently selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; R D is selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L)-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L are independently hydrogen or C1-C6 alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R B are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; —C(O)(3-8 membered cycloalkyl); —C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ; -S(O)2NR B1 R B2 ; -NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, and —O(C1-C6 alkyl); where R C1 , R B1 and R B2 are each independently hydrogen or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R C is halogen, cyano, C1-C6 alkyl, OH, —O(C1-C6 alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, RD is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2.

[0047] In some embodiments of compounds of Formula (I), ring A is selected from 1 to 4 R A or ring A is a 5-6 membered heteroaryl optionally substituted with [ka] In some embodiments, ring A is selected from 1 to 4 R A In some embodiments, ring A is a 5-6 membered heteroaryl optionally substituted with [ka] is.

[0048] In some embodiments of the compounds of Formula (I), ring A is [ka] In some embodiments, R D is halogen, or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens. In some embodiments, R D is halogen. In some embodiments, R D is halogen; cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens or —OH; —O(C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens; or —C(O)NR A1 R A2 where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R Dis halogen; cyano; C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens or —OH; —O(C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens; or —C(O)NR A1 R A2 where R A1 and R A2 are each independently hydrogen or C1-C3 alkyl. In some embodiments, R D is chloro or fluoro; cyano; methyl optionally substituted with 1 to 3 independently selected chloro, fluoro, or —OH substituents; —OCH3 optionally substituted with 1 to 3 independently selected chloro or fluoro substituents; or —C(O)NR A1 R A2 where R A1 and R A2 are each independently hydrogen or methyl. In some embodiments, R D is chloro or fluoro; cyano; —CH; methyl substituted with 1 to 3 independently selected fluoro or —OH substituents; —OCH optionally substituted with 1 to 3 fluoro substituents; or —C(O)NH. In some embodiments, R D is chloro or fluoro; cyano; —CH; —CHOH; —CHF; —OCH; —OCHF; or —C(O)NH. In some embodiments, R D is chloro. In some embodiments, R D is fluoro. In some embodiments, R D is cyano. In some embodiments, R D is —CHOH. In some embodiments, R D is -CH3. In some embodiments, R D is —CHOH. In some embodiments, R D is -CHF. In some embodiments, R D is —OCH. In some embodiments, R D is -OCHF. In some embodiments, RD is -C(O)NH2.

[0049] In some embodiments of the compounds of Formula (I), ring A is [ka] and R A is halogen. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] and R A is halogen. In some embodiments, ring A is [ka] is.

[0050] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R form a moiety selected from the group consisting of A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R DLet's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings A, R A , and R D Let's get together and [ka] Form.

[0051] In some embodiments of compounds of Formula (I), ring A is selected from 1 to 4 R Ais a 5- to 6-membered heteroaryl optionally substituted with

[0052] In some embodiments of compounds of Formula (I), ring A is selected from 1 to 4 R A In some embodiments, Ring A is oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, or isoxazolyl, each of which is substituted with 1-3 R A In some embodiments, ring A is optionally substituted with 1 to 3 R A In some embodiments, ring A is oxazolyl optionally substituted with 1 to 2 R A In some embodiments, ring A is oxazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is pyrazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is thiazolyl optionally substituted with 1 to 2 R A In some embodiments, ring A is thiazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is 1H-pyrazol-4-yl, isothiazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, or thiazol-5-yl, each of which is substituted with 1 to 3 R A In some embodiments, ring A is optionally substituted with 1 to 3 R A In some embodiments, ring A is 1H-pyrazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazol-5-yl optionally substituted with 1 to 3 R AIn some embodiments, ring A is isoxazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is oxazol-5-yl optionally substituted with 1 to 2 R A In some embodiments, ring A is oxazol-5-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is thiazol-5-yl optionally substituted with 1 to 2 R A is thiazol-5-yl optionally substituted with

[0053] In some embodiments of compounds of Formula (I), ring A is selected from 1 to 4 R A In some embodiments, Ring A is oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, or isoxazolyl, each of which is substituted with 1-3 R A In some embodiments, ring A is optionally substituted with 1 to 3 R A In some embodiments, ring A is oxazolyl optionally substituted with 1 to 2 R A In some embodiments, ring A is oxazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is pyrazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is thiazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazolyl optionally substituted with 1 to 3 R A In some embodiments, ring A is 1H-pyrazol-4-yl, isothiazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, or thiazol-5-yl, each of which is substituted with 1 to 3 R A In some embodiments, ring A is optionally substituted with 1 to 3 R AIn some embodiments, ring A is 1H-pyrazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is isothiazol-5-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is isoxazol-4-yl optionally substituted with 1 to 3 R A In some embodiments, ring A is oxazol-5-yl optionally substituted with 1 to 2 R A In some embodiments, ring A is oxazol-5-yl optionally substituted with 1 to 3 R A is thiazol-5-yl optionally substituted with

[0054] In some embodiments of the compound of Formula (I), Ring A is an unsubstituted 5-membered heteroaryl. In some embodiments, Ring A is an oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, or isoxazolyl, each of which is unsubstituted.

[0055] In some embodiments of compounds of Formula (I), ring A is selected from 1 to 4 R A In some embodiments, ring A is pyridinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with 1 to 4 R A In some embodiments, ring A is optionally substituted with 1 to 4 R A In some embodiments, ring A is pyridazinyl optionally substituted with 1 to 4 R A In some embodiments, ring A is pyridinyl optionally substituted with 1 to 4 R A In some embodiments, Ring A is pyridazin-4-yl, pyridin-4-yl, or pyrimidin-4-yl, each of which is selected from the group consisting of 1 to 4 R AIn some embodiments, ring A is optionally substituted with 1 to 4 R A In some embodiments, ring A is pyridazin-4-yl optionally substituted with 1 to 4 R A In some embodiments, ring A is pyridin-4-yl optionally substituted with 1 to 4 R A is pyrimidin-4-yl optionally substituted with

[0056] In some embodiments of the compounds of Formula (I), R A is halogen or C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens. In some embodiments, R A is halogen, or C1-C6 alkyl. In some embodiments, R A is halogen. In some embodiments, R A is halogen; cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens or —OH; —O(C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens; or —C(O)NR A1 R A2 where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R A is halogen; cyano; C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens or —OH; —O(C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens; or —C(O)NR A1 R A2 where R A1 and R A2 are each independently hydrogen or C1-C3 alkyl. In some embodiments, R A is chloro or fluoro; cyano; methyl optionally substituted with 1 to 3 independently selected chloro, fluoro, or —OH substituents; —OCH3 optionally substituted with 1 to 3 independently selected chloro or fluoro substituents; or —C(O)NRA1 R A2 where R A1 and R A2 are each independently hydrogen or methyl. In some embodiments, R A is chloro or fluoro; cyano; —CH; methyl substituted with 1 to 3 independently selected fluoro or —OH substituents; —OCH optionally substituted with 1 to 3 fluoro substituents; or —C(O)NH. In some embodiments, R A is chloro or fluoro; cyano; —CH; —CHOH; —CHF; —OCH; —OCHF; or —C(O)NH. In some embodiments, R A is chloro. In some embodiments, R A is fluoro. In some embodiments, R A is cyano. In some embodiments, R A is —CHOH. In some embodiments, R A is -CH3. In some embodiments, R A is —CHOH. In some embodiments, R A is -CHF. In some embodiments, R A is —OCH. In some embodiments, R A is -OCHF. In some embodiments, R A is -C(O)NH2.

[0057] In some embodiments, R A1 and R A1 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R A1 and R A1 are each hydrogen. In some embodiments, R A1 and R A1 are each C1-C6 alkyl. In some embodiments, R A1 is hydrogen. In some embodiments, R A1 is C1-C6 alkyl. In some embodiments, RA1 is hydrogen. In some embodiments, R A1 is C1-C6 alkyl.

[0058] In some embodiments of the compounds of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R form a moiety selected from the group consisting of: A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and RA Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] In some embodiments of the compound of Formula (I), rings A and R A Let's get together and [ka] Form.

[0059] In some embodiments of a compound of Formula (I), Ring B is a 4-10 membered heterocycloalkyl, a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl, or a phenyl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, a 3-8 membered cycloalkyl, or a 5-6 membered heteroaryl. In some embodiments of a compound of Formula (I), Ring B is a 4-8 membered heterocycloalkyl, a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl, or a phenyl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, a 3-8 membered cycloalkyl, or a 5-6 membered heteroaryl. In some embodiments, Ring B is a 4-10 membered heterocycloalkyl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl. In some embodiments, Ring B is a 3-8 membered cycloalkyl. In some embodiments, Ring B is a 5-6 membered heteroaryl. In some embodiments, Ring B is monocyclic. In some embodiments, Ring B is polycyclic. In some embodiments, Ring B is spirocyclic. In some embodiments, Ring B is a bridged bicyclic. In some embodiments, Ring B is a fused bicyclic.

[0060] In some embodiments of the compound of Formula (I), Ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, oxazolyl, or pyrazolyl. In some embodiments, Ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl. In some embodiments, Ring B is [ka] In some embodiments, ring B is [ka] is.

[0061] In some embodiments of the compound of Formula (I), Ring B is selected from the group consisting of bicyclo[3.1.0]hexanyl; [3.3]heptanyl; 1,2,4-oxadiazolyl; 1,3,4-oxadiazolyl; pyrazolyl; pyrrolyl; 2,5-diazabicyclo[4.1.0]heptanyl; 2-azabicyclo[3.1.0]hexanyl; 3-azabicyclo[3.1.0]hexanyl; 5-azaspiro[2.4]heptanyl; 8-oxa-3-azabicyclo[3.2.1]octanyl; 2-azaspiro[3.3]heptanyl; 6-azaspiro[3.4]octanyl; 8-azabicyclo[3.2.1]octanyl; 4-azaspiro[2 In some embodiments, Ring B is selected from the group consisting of bicyclo[3.1.0]hexanyl; 3-azabicyclo[3.2.1]octanyl; 3-azabicyclo[3.1.1]heptanyl; 2-azabicyclo[4.1.0]heptanyl; azetidinyl; cyclobutyl; cyclohexyl; cyclopentyl; cyclopropyl; isothiazolyl; isoxazolyl; morpholinyl; oxazolyl; oxazolidinyl; oxetanyl; phenyl; piperazinyl; piperidinyl; pyrazinyl; pyridazinyl; pyridinyl; pyrimidinyl; pyrrolidinyl; tetrahydro-2H-pyranyl; tetrahydro-2H-thiopyranyl; tetrahydrofuranyl; and thiazolyl. In some embodiments, Ring B is bicyclo[3.1.0]hexanyl. In some embodiments, Ring B is [3.3]heptanyl. In some embodiments, Ring B is 2-azaspiro[3.3]heptanyl. In some embodiments, Ring B is 6-azaspiro[3.4]octanyl. In some embodiments, Ring B is 8-azabicyclo[3.2.1]octanyl. In some embodiments, Ring B is 4-azaspiro[2.5]octanyl. In some embodiments, Ring B is 3-azabicyclo[3.2.1]octanyl. In some embodiments, Ring B is 3-azabicyclo[3.1.1]heptanyl. In some embodiments, Ring B is 2-azabicyclo[4.1.0]heptanyl. In some embodiments, Ring B is 1,2,4-oxadiazolyl. In some embodiments, Ring B is 1,3,4-oxadiazolyl. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is pyrrolyl.In some embodiments, Ring B is 2,5-diazabicyclo[4.1.0]heptanyl. In some embodiments, Ring B is 2-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is 3-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is 5-azaspiro[2.4]heptanyl. In some embodiments, Ring B is 8-oxo-3-azabicyclo[3.2.1]octanyl. In some embodiments, Ring B is azetidinyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclohexyl. In some embodiments, Ring B is cyclopentyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is isothiazolyl. In some embodiments, Ring B is isoxazolyl. In some embodiments, Ring B is morpholinyl. In some embodiments, Ring B is oxazolyl. In some embodiments, Ring B is oxazolidinyl. In some embodiments, Ring B is oxetanyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is piperazinyl. In some embodiments, Ring B is piperidinyl. In some embodiments, Ring B is pyrazinyl. In some embodiments, Ring B is pyridazinyl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyrimidinyl. In some embodiments, Ring B is pyrrolidinyl. In some embodiments, Ring B is tetrahydro-2H-pyranyl. In some embodiments, Ring B is tetrahydro-2H-thiopyranyl. In some embodiments, Ring B is tetrahydrofuranyl. In some embodiments, Ring B is thiazolyl.

[0062] In some embodiments of the compound of Formula (I), Ring B is selected from the group consisting of bicyclo[3.1.0]hexanyl; [3.3]heptanyl; 1,2,4-oxadiazolyl; 1,3,4-oxadiazolyl; pyrazolyl; pyrrolyl; 2,5-diazabicyclo[4.1.0]heptanyl; 2-azabicyclo[3.1.0]hexanyl; 3-azabicyclo[3.1.0]hexanyl; 5-azaspiro[2.4]heptanyl; 8-oxa-3-azabicyclo[3.2.1]octa In some embodiments, Ring B is selected from the group consisting of yl; azetidinyl; cyclobutyl; cyclohexyl; cyclopentyl; cyclopropyl; isothiazolyl; isoxazolyl; morpholinyl; oxazolyl; oxazolidinyl; oxetanyl; phenyl; piperazinyl; piperidinyl; pyrazinyl; pyridazinyl; pyridinyl; pyrimidinyl; pyrrolidinyl; tetrahydro-2H-pyranyl; tetrahydro-2H-thiopyranyl; tetrahydrofuranyl; and thiazolyl. In some embodiments, Ring B is bicyclo[3.1.0]hexanyl. In some embodiments, Ring B is [3.3]heptanyl. In some embodiments, Ring B is 1,2,4-oxadiazolyl. In some embodiments, Ring B is 1,3,4-oxadiazolyl. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is pyrrolyl. In some embodiments, Ring B is 2,5-diazabicyclo[4.1.0]heptanyl. In some embodiments, Ring B is 2-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is 3-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is 5-azaspiro[2.4]heptanyl. In some embodiments, Ring B is 8-oxo-3-azabicyclo[3.2.1]octanyl. In some embodiments, Ring B is azetidinyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclohexyl. In some embodiments, Ring B is cyclopentyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is isothiazolyl. In some embodiments, Ring B is isoxazolyl.In some embodiments, Ring B is morpholinyl. In some embodiments, Ring B is oxazolyl. In some embodiments, Ring B is oxazolidinyl. In some embodiments, Ring B is oxetanyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is piperazinyl. In some embodiments, Ring B is piperidinyl. In some embodiments, Ring B is pyrazinyl. In some embodiments, Ring B is pyridazinyl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyrimidinyl. In some embodiments, Ring B is pyrrolidinyl. In some embodiments, Ring B is tetrahydro-2H-pyranyl. In some embodiments, Ring B is tetrahydro-2H-thiopyranyl. In some embodiments, Ring B is tetrahydrofuranyl. In some embodiments, Ring B is thiazolyl.

[0063] In some embodiments of the compounds of Formula (I), ring B is [ka] [ka] In some embodiments of the compounds of Formula (I), Ring B is selected from the group consisting of: [ka] [ka] is selected from the group consisting of:

[0064] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0065] In some embodiments of the compound of Formula (I), each R Bis halogen; -OH; oxo; cyano; phenyl or -O(C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl);phenyl;5-6 membered heteroaryl;4-8 membered heterocycloalkyl;3-8 membered cycloalkyl;-C(O)(3-8 membered cycloalkyl); -C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ;-S(O)2NR B1 R B2 ;-NR C1 S(O)NR B1 R B2 ;-(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ;-NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, and —O(C1-C6 alkyl), where R B1 and R B2 are each independently hydrogen or C1-C6 alkyl.

[0066] In some embodiments of the compound of Formula (I), each R B is selected from halogen; oxo; phenyl or —O(C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogens; C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C1-C6 alkyl); —S(O)2(C1-C6 alkyl); —S(O)2(4- to 8-membered heterocycloalkyl); —S(O)2(3- to 8-membered cycloalkyl); —S(O)2NRB1 R B2 ;-C(O)NR B1 R B2 In some embodiments of a compound of Formula (I), each R is independently selected from the group consisting of: -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); -C(O)(3-8 membered cycloalkyl optionally substituted with 1-3 independently selected halogens); -C(O)(4-8 membered heterocycloalkyl optionally substituted with 1-3 independently selected halogens); 4-8 membered heterocycloalkyl; and 5-6 membered heteroaryl. B is halogen; oxo; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl); —S(O)2(C1-C6 alkyl); —S(O)2NR B1 R B2 ;-C(O)NR B1 R B2 -C(O)(C1-C6 alkyl); 4- to 8-membered heterocycloalkyl; and 5- to 6-membered heteroaryl. In some embodiments of the compound of Formula (I), each R B is independently selected from the group consisting of phenyl or —O(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; and C1-C4 alkyl optionally substituted with 1-5 substituents independently selected from halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C1-C4 alkyl). In some embodiments, each R B is chloro, fluoro, or bromo; oxo; unsubstituted -O(C1-C3 alkyl); -O(C1-C3 alkyl) substituted with phenyl; -O(C1-C3 alkyl) substituted with 1 to 3 fluoro; -S(O)2(C1-C3 alkyl); -S(O)2NR B1 R B2 unsubstituted C1-C3 alkyl; C1-C3 alkyl substituted with 1 to 5 substituents independently selected from chloro, fluoro, -OH, and -O(C1-C3 alkyl); In some embodiments, each R is independently selected from the group consisting of: -C(O)NH; -C(O)NMe; -C(O)(C1-C3 alkyl); 4- to 6-membered heterocycloalkyl; and 6-membered heteroaryl. B is independently selected from the group consisting of chloro; fluoro; oxo; —OCH optionally substituted with 1-3 fluoro; —CH; —C(O)NH; C(O)NMe; —C(O)(C1-C3 alkyl); 4- to 6-membered heterocycloalkyl; and 6-membered heteroaryl. In some embodiments, each R B is oxo, -C(O)(C1-C6 alkyl), -C(O)NR B1 R B2 , -S(O)2(C1-C6 alkyl), -S(O)2NR B1 R B2 , unsubstituted C1-C6 alkyl, 4-8 membered heterocycloalkyl, and 5-6 membered heteroaryl. In some embodiments, each R B is independently selected from the group consisting of oxo, —C(O)(C1-C3 alkyl), —C(O)N(Me)2, —C(O)(4-8 membered heterocycloalkyl) optionally substituted with 1-3 independently selected halogens, —C(O)(3-8 membered cycloalkyl) optionally substituted with 1-3 independently selected halogens; —S(O)2(C1-C3 alkyl), —S(O)2N(Me)2, —C(O)O(C1-C4 alkyl), —S(O)2(4-8 membered heterocycloalkyl), —S(O)2(3-4 membered cycloalkyl), methyl, oxetanyl, and pyridinyl. In some embodiments, each R B is independently selected from the group consisting of oxo, —C(O)(C1-C3 alkyl), —C(O)N(Me)2, —S(O)2Me, —S(O)2N(Me)2, methyl, oxetanyl, and pyridinyl. B is oxo. In some embodiments, R B is -S(O)NR B1 R B2 In some embodiments, R B is —S(O)2(C1-C3 alkyl). In some embodiments, RB is —S(O)2(4-6 membered heterocycloalkyl). In some embodiments, R B is —C(O)O(C1-C3 alkyl). In some embodiments, R B is —C(O)(C1-C3 alkyl). In some embodiments, R B is —C(O)(C alkyl). In some embodiments, R B is —C(O)(C alkyl). In some embodiments, R B is —C(O)(Me). In some embodiments, R B is —C(O)N(Me)2. In some embodiments, R B is methyl. In some embodiments, R B is oxetanyl. In some embodiments, R B is pyridinyl. In some embodiments, R B is —S(O)N(Me). In some embodiments, R B is -S(O)Et. In some embodiments, R B is -S(O)Me.

[0067] In some embodiments of the compound of Formula (I), each R B is halogen; oxo; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl); -S(O)2(C1-C6 alkyl); -S(O)2NR B1 R B2 ;-C(O)NR B1 R B2 -C(O)(C1-C6 alkyl); 4- to 8-membered heterocycloalkyl; and 5- to 6-membered heteroaryl. In some embodiments of the compound of Formula (I), each R Bis halogen; oxo; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl); —S(O)2(C1-C6 alkyl); —S(O)2NR B1 R B2 ;-C(O)NR B1 R B2 -C(O)(C1-C6 alkyl); 4- to 8-membered heterocycloalkyl; and 5- to 6-membered heteroaryl. In some embodiments, each R B is chloro, fluoro, or bromo; oxo; unsubstituted -O(C1-C3 alkyl); -O(C1-C3 alkyl) substituted with phenyl; -O(C1-C3 alkyl) substituted with 1 to 3 fluoro; -S(O)2(C1-C3 alkyl); -S(O)2NR B1 R B2 unsubstituted C1-C3 alkyl; C1-C3 alkyl substituted with 1 to 5 substituents independently selected from chloro, fluoro, -OH, and -O(C1-C3 alkyl); In some embodiments, each R is independently selected from the group consisting of: -C(O)NH; -C(O)NMe; -C(O)(C1-C3 alkyl); 4- to 6-membered heterocycloalkyl; and 6-membered heteroaryl. B is independently selected from the group consisting of chloro; fluoro; oxo; —OCH optionally substituted with 1-3 fluoro; —CH; —C(O)NH; C(O)NMe; —C(O)(C1-C3 alkyl); 4- to 6-membered heterocycloalkyl; and 6-membered heteroaryl. In some embodiments, each R B is oxo, -C(O)(C1-C6 alkyl), -C(O)NR B1 R B2 , -S(O)2(C1-C6 alkyl), -S(O)2NR B1 R B2 , unsubstituted C1-C6 alkyl, 4-8 membered heterocycloalkyl, and 5-6 membered heteroaryl. In some embodiments, each R Bis independently selected from the group consisting of oxo, —C(O)(C1-C3 alkyl), —C(O)N(Me)2, —S(O)2Me, —S(O)2N(Me)2, methyl, oxetanyl, and pyridinyl. B is oxo. In some embodiments, R B is -S(O)NR B1 R B2 In some embodiments, R B is —S(O)2(C1-C3 alkyl). In some embodiments, R B is —C(O)(C1-C3 alkyl). In some embodiments, R B is —C(O)N(Me)2. In some embodiments, R B is methyl. In some embodiments, R B is oxetanyl. In some embodiments, R B is pyridinyl. In some embodiments, R B is —S(O)N(Me). In some embodiments, R B is -S(O)Me.

[0068] In some embodiments, R B1 and R B2 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R B1 and R B2 are each hydrogen. In some embodiments, R B1 and R B2 are each C1-C6 alkyl. In some embodiments, R B1 is hydrogen. In some embodiments, R B1 is C1-C6 alkyl. In some embodiments, R B2 is hydrogen. In some embodiments, R B2 is C1-C6 alkyl.

[0069] In some embodiments, R C1is hydrogen, or C1-C6 alkyl. In some embodiments, R C1 is hydrogen. In some embodiments, R C1 is C1-C6 alkyl. In some embodiments, R C1 is methyl. In some embodiments, R C1 is ethyl.

[0070] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] [ka] [ka] [ka] [ka] In some embodiments of the compound of Formula (I), rings B and R form a moiety selected from the group consisting of: B Let's get together and [ka] [ka] [ka] forming a site selected from the group consisting of:

[0071] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and RB Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] In some embodiments of the compounds of Formula (I), rings B and R B Let's get together and [ka] Form.

[0072] In some embodiments of the compound of Formula (I), L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L )-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; and wherein each R L are independently hydrogen or C1-C6 alkyl.

[0073] In some embodiments, L is a bond, C1-C3 alkylene, #-O-(C1-C3 alkylene)-$, #-C(O)-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-C(O)-$, #-N(R L )-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-N(R L )-$, #-(C1-C3 alkylene)-N(R L )-(C1-C3 alkylene)-$, #-C(O)-N(R L )-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-C(O)-N(R L )-$, #-N(R L )-C(O)-CH2-$, #-(C1-C3 alkylene)-N(R L )-C(O)-$, #-(C1-C3 alkylene)-C(O)-N(R L )-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-N(R L )-C(O)-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C3 alkylene)-$, #-(C1-C3 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C3 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C3 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C3 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C3 alkyl; and wherein each R L are independently hydrogen or C1-C3 alkyl.

[0074] In some embodiments, L is a bond, C-C alkylene, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, and #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C6 alkylene of L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; and wherein each R L are independently hydrogen or C1-C6 alkyl.

[0075] In some embodiments, L is a bond, C1-C3 alkylene, #-C(O)-N(R L )-(C1-C3 alkylene)-$, #-C(O)-(C1-C3 alkylene)-$, or #-(C1-C3 alkylene)-C(O)-N(R L)-(C1-C3 alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C3 alkylene of L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C3 alkyl; and wherein each R L are independently hydrogen or C1-C3 alkyl.

[0076] In some embodiments, each C1-C6 alkylene of L is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl. In some embodiments, each C1-C6 alkylene of L is substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C1-C6 alkyl. In some embodiments, each C1-C6 alkylene of L is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl. In some embodiments, each C1-C6 alkylene of L is unsubstituted.

[0077] In some embodiments, L is a bond, C1-C3 alkylene, or #-C(O)-N(R L )-(C1-C3 alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; and wherein each R L is independently hydrogen or C1-C6 alkyl. In some embodiments, L is a bond, -CH2-, -CH2CH2-, or [ka] is.

[0078] In some embodiments, L is a bond, #-(CO)CF2-$, #C(O)CH(CH3)-$, #C(O)CH2-$, #-C(O)-N(CH3)CH(CH3)-$, #-C(O)-N(CH3)CH2-$, #-C(O)N(H)CH(CH3)-$, #-C(O)N(H)CH2-$, #-CH2C(O)N(H)CH(CH3)-$, #-CH2C(O)N(H)CH2-$, #-CH2N(CH3)SO2-$, #-CH2N(H)C(O)CH2-$, #-CH2SO2N(H)-$, #-N(CH2CH3)SO2-$, #-N(CH3)SO2-$, #-N(CH3)C(O)CH2-$, #-N(H)C(O)CH2-$, #-N(H)CH2-$, #-OCH2-$, #-S(O)2N(H)CH2-$, #-C(CH3)(OH)-$, ethylene, methylene, and In some embodiments, L is selected from the group consisting of #-S(O)2-$. In some embodiments, L is a bond. In some embodiments, L is #-(CO)CF2-$. In some embodiments, L is #C(O)CH(CH3)-$. In some embodiments, L is #C(O)CH2-$. In some embodiments, L is #-C(O)-N(CH3)CH(CH3)-$. In some embodiments, L is #-C(O)-N(CH3)CH2-$. In some embodiments, L is #-C(O)N(H)CH(CH3)-$. In some embodiments, L is #-C(O)N(H)CH2-$. In some embodiments, L is #-CH2C(O)N(H)CH(CH3)-$. In some embodiments, L is #-CH2C(O)N(H)CH2-$. In some embodiments, L is #-CHN(CH3)SO2-$. In some embodiments, L is #-CH2N(H)C(O)CH2-$. In some embodiments, L is #-CH2SON(H)-$. In some embodiments, L is #-N(CH2CH3)SO2-$. In some embodiments, L is #-N(CH3)SO2-$. In some embodiments, L is #-N(CH3)C(O)CH2-$. In some embodiments, L is #-N(H)C(O)CH2-$. In some embodiments, L is #-N(H)CH2-$. In some embodiments, L is #-OCH2-$. In some embodiments, L is #-S(O)2N(H)CH2-$. In some embodiments, L is #-C(CH3)(OH)-$. In some embodiments, L is ethylene. In some embodiments, L is methylene. In some embodiments, L is #-S(O)2-$.

[0079] In some embodiments of compounds of Formula (I), m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0080] In some embodiments of a compound of Formula (I), n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0081] In some embodiments of compounds of Formula (I), p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0082] In some embodiments of the compounds of Formula (I), p is 0, m is 0, and n is 0, 1, or 2.

[0083] In some embodiments of the compounds of Formula (I), R C is halogen, cyano, C1-C6 alkyl, or 3- to 8-membered cycloalkyl. In some embodiments, R C is halogen. In some embodiments, R C is fluoro, chloro, or bromo. In some embodiments, R C is fluoro. In some embodiments, R C is chloro. In some embodiments, R C is bromo. In some embodiments, R C is cyano. In some embodiments, R C is C1-C6 alkyl. In some embodiments, R C is methyl. In some embodiments, R C is ethyl. In some embodiments, R C is propyl. In some embodiments, R C is cyclopropyl. In some embodiments, RC is cyclobutyl. In some embodiments, R C is cyclopentyl. In some embodiments, R C is cyclohexyl. In some embodiments, R C is cyclopentyl. In some embodiments, R C is cyclooctyl.

[0084] In some embodiments of the compounds of Formula (I): a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2. In some embodiments of the compound of Formula (I), each R B is halogen; -OH; oxo; cyano; phenyl or -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C3 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; -C(O)(3-8 membered cycloalkyl); -C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ;-S(O)2NR B1 R B2 ;-NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ;-NR C1-(C=NR C1 )-NR B1 R B2 ;-NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl), wherein R B1 and R B2 are each independently hydrogen or C1-C6 alkyl.

[0085] In some embodiments of the compounds of Formula (I): a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, n is 0, 1, or 2. In some embodiments of the compound of Formula (I), each R B is halogen; -OH; oxo; cyano; phenyl or -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C3 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; -C(O)(3-8 membered cycloalkyl); -C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ;-S(O)2NR B1 R B2 ;-NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ;-NR C1 -(C=NR C1 )-NR B1 R B2 ;-NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl), wherein R B1 and R B2 are each independently hydrogen or C1-C6 alkyl.

[0086] In some embodiments of compounds of Formula (I), Ring B is a 4-8 membered heterocycloalkyl and R B is a 5-6 membered heteroaryl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is —S(O)2(C1-C6 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is —S(O)2(C1-C3 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is -S(O)2(Me). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is -S(O)NR B1 R B2 In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is —S(O)2NMe2. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is —C(O)(C1-C6 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is —C(O)(C1-C3 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R Bis —C(O)Me. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is -C(O)NR B1 R B2 In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is a 4-8 membered heterocycloalkyl. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and R B is oxetanyl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and L is #-C(O)-N(R L )-(C1-C6 alkylene)-$. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and L is C1-C6 alkylene. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and L is a bond. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and n is 0. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and n is 2, and one R B is C1-C6 alkyl, and the other R B In some embodiments, Ring B is a 5-6 membered heteroaryl and R B is C1-C6 alkyl. In some embodiments, ring B is a 5-6 membered heteroaryl and R B is methyl. In some embodiments, ring B is a 5-6 membered heteroaryl and L is #-C(O)-N(R L )-(C1-C6 alkylene)-$. In some embodiments, ring B is a 5-6 membered heteroaryl and L is C1-C6 alkylene. In some embodiments, ring A is phenyl and R Dis chloro. In some embodiments, ring A is a 5-6 membered heteroaryl and m is 0. In some embodiments, ring A is thiazolyl and m is 0. In some embodiments, ring A is oxazolyl and m is 0. In some embodiments, ring A is thiazol-5-yl and m is 0. In some embodiments, ring A is oxazol-5-yl and m is 0.

[0087] In some embodiments of compounds of Formula (I), Ring B is a 4-8 membered heterocycloalkyl and R B is a 5-6 membered heteroaryl. In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is —S(O)2(C1-C6 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is —S(O)2(C1-C3 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is -S(O)NR B1 R B2 In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is —C(O)(C1-C6 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is —C(O)(C1-C3 alkyl). In some embodiments, Ring B is a 4-8 membered heterocycloalkyl and R B is -C(O)NR B1 R B2 In some embodiments, Ring B is a 4-8 membered heterocycloalkyl, and R B is a 4-8 membered heterocycloalkyl. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and L is #-C(O)-N(R L)-(C1-C6 alkylene)-$. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and L is C1-C6 alkylene. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and L is a bond. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and n is 0. In some embodiments, ring B is a 4-8 membered heterocycloalkyl and n is 2, and one R B is C1-C6 alkyl, and the other R B In some embodiments, Ring B is a 5-6 membered heteroaryl and R B is C1-C6 alkyl. In some embodiments, ring B is a 5-6 membered heteroaryl and R B is methyl. In some embodiments, ring B is a 5-6 membered heteroaryl and L is #-C(O)-N(R L )-(C1-C6 alkylene)-$. In some embodiments, ring B is a 5-6 membered heteroaryl and L is C1-C6 alkylene. In some embodiments, ring A is phenyl and R D is chloro. In some embodiments, ring A is a 5-6 membered heteroaryl and m is 0. In some embodiments, ring A is thiazolyl and m is 0. In some embodiments, ring A is oxazolyl and m is 0. In some embodiments, ring A is thiazol-5-yl and m is 0. In some embodiments, ring A is oxazol-5-yl and m is 0.

[0088] In some embodiments, the compound of formula (I) is [ka] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, provided herein are compounds, and salts thereof, or pharmaceutically acceptable salts thereof, as set forth in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 [Table 1-72] [Table 1-73] [Table 1-74] [Table 1-75] [Table 1-76] [Table 1-77] [Table 1-78] [Table 1-79] [Table 1-80] [Table 1-81] [Table 1-82]

[0090] In some embodiments, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, of any of the foregoing, selected from the group consisting of: 4-Methoxybenzyl (4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; 4-Carbamoylbenzyl (4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; Pyridin-4-ylmethyl (4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; 4-(Hydroxymethyl)benzyl(4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1,3,4-trimethyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(6,6-difluorospiro[3.3]heptane-2-carboxamido)ethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(4-fluorobenzamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-fluoroisonicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3,4-dimethylisoxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Methoxybenzyl (4-(1-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-(2-methoxyethyl)-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3,5-difluoroisonicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(6-methylnicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-((4-methoxycyclohexyl)amino)-2-oxoethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(6,6-difluorobicyclo[3.1.0]hexane-3-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methoxypiperidine-1-carboxamido)ethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(3,3-difluorocyclobutane-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(6-ethylnicotinamido)ethyl)phenyl)carbamate; 4-chloro-2-fluorobenzyl(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(N-methylazetidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4 methoxy-1-methyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methoxy-1-methyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(azetidine-1-carboxamido)ethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(3,3-difluorocyclopentane-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(6-methoxynicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-ethyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(pyrrolidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(1-(isonicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(5-methoxy-6-methylnicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(tetrahydro-2H-pyran-4-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(1-(nicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(oxetane-3-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(2,4-dimethyloxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-isobutyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methoxy-N-methylpiperidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-ethyl-1-methyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1,3-dimethyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-fluoro-1,3-dimethyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methylisoxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(N-methylpyrrolidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methylazetidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methylpiperidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-methyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methylisoxazole-4-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methyloxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(morpholine-4-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(5-fluoronicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-methoxypiperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(6-isopropylnicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(6-(difluoromethyl)nicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methoxyazetidine-1-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-hydroxypiperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-isopropyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methyloxetane-3-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-methylisoxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-(Difluoromethyl)benzyl(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(1-cyclobutyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(2-methoxy-6-methylnicotinamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(2-methyloxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-chlorobenzyl (4-(2-((-4-(difluoromethoxy)cyclohexyl)amino)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(2-(oxazol-2-yl)acetamido)ethyl)phenyl)carbamate; 4-chlorobenzyl(4-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-methoxypiperidin-1-yl)-2-oxoethyl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(6,6-difluorobicyclo[3.1.0]hexane-3-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(1-cyclobutyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(5-methyloxazole-4-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-methyloxazole-2-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-methylpyrrolidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(oxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-((2-oxo-5-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(2-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(3-(difluoromethyl)-1-methyl-1H-pyrazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-ethyloxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Methoxybenzyl(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(cyclopropanecarboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(5-methyloxazole-2-carboxamido)ethyl)phenyl)carbamate; 4-Fluorobenzyl(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-((-4-methoxycyclohexyl)amino)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(2-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl(4-(1-(4-cyclopropyloxazole-5-carboxamido)ethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(1-isopropyl-5-oxopiperazin-2-yl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)phenyl)carbamate; 4-Chlorobenzyl (4-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl)phenyl)carbamate; 4-Chlorobenzyl(4-(2-oxo-2-((4-(trifluoromethoxy)cyclohexyl)amino)ethyl)phenyl)carbamate; 4-Methoxybenzyl (4-(1-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-(6-(methylsulfonyl)-6-azaspiro[3.4]octan-2-yl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-(6-isobutyryl-6-azaspiro[3.4]octan-2-yl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(6-(dimethylcarbamoyl)-6-azaspiro[3.4]octan-2-yl)-3-fluorophenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(methylsulfonyl)piperidin-3-yl)phenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(N,N-dimethylsulfamoyl)piperidin-3-yl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-((6-propionyl-6-azaspiro[3.4]octan-2-yl)methyl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-((6-isobutyryl-6-azaspiro[3.4]octan-2-yl)methyl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-((6-(ethylsulfonyl)-6-azaspiro[3.4]octan-2-yl)methyl)phenyl)carbamate; Oxazol-5-ylmethyl(3-fluoro-4-((6-(methylsulfonyl)-6-azaspiro[3.4]octan-2-yl)methyl)phenyl)carbamate; Methyl 2-(2-fluoro-4-(((oxazol-5-ylmethoxy)carbonyl)amino)benzyl)-6-azaspiro[3.4]octane-6-carboxylate; Oxazol-5-ylmethyl (4-(6-acetyl-6-azaspiro[3.4]octan-2-yl)-3-fluorophenyl)carbamate; Oxazol-5-ylmethyl (4-((6-acetyl-6-azaspiro[3.4]octan-2-yl)methyl)-3-fluorophenyl)carbamate; Oxazol-5-ylmethyl(4-(1-acetylpiperidin-3-yl)phenyl)carbamate; tert-Butyl 2-(2-fluoro-4-(((oxazol-5-ylmethoxy)carbonyl)amino)benzyl)-6-azaspiro[3.4]octane-6-carboxylate; Oxazol-5-ylmethyl(4-((6-azaspiro[3.4]octan-2-yl)methyl)-3-fluorophenyl)carbamate; Oxazol-5-ylmethyl (4-((6-(dimethylcarbamoyl)-6-azaspiro[3.4]octan-2-yl)methyl)-3-fluorophenyl)carbamate; Oxazol-5-ylmethyl(4-(1-(oxetan-3-yl)piperidin-3-yl)phenyl)carbamate; Methyl 3-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)phenyl)piperidine-1-carboxylate; Oxazol-5-ylmethyl(4-(1-(dimethylcarbamoyl)piperidin-3-yl)phenyl)carbamate; and 4-chlorobenzyl (4-(1-(oxetan-3-yl)-5-oxopiperazin-2-yl)phenyl)carbamate, or a pharmaceutically acceptable salt of any of the foregoing.

[0091] In some variations, any of the compounds described herein, such as the compound of Formula (I), or any variation thereof, or the compounds in Table 1, can be deuterated (e.g., one or more hydrogen atoms are replaced with deuterium atoms). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Other methods known in the art can also be used to replace hydrogen atoms with deuterium atoms.

[0092] Formula (I) is intended to represent compounds having the structure depicted by the structural formula, as well as specific variations or forms. In particular, compounds of any formula depicted herein may have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of a compound of the general formula, as well as mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula depicted herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. When a compound in Table 1 is depicted in a specific stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of stereoisomers of the compound in any ratio, are also provided herein. For example, if a compound in Table 1 has a stereocenter that is in the "S" stereochemical configuration, enantiomers of that compound in which that stereocenter is in the "R" stereochemical configuration are also provided herein. Similarly, if a compound of Table 1 has a stereocenter that is the "R" configuration, then enantiomers of that compound that are the "S" stereochemical configuration are also provided herein. Also provided are mixtures of compounds having both the "S" and "R" stereochemical configurations. Furthermore, if a compound of Table 1 has more than one stereocenter, then any enantiomer or diastereomer of that compound is also provided. For example, if a compound of Table 1 contains a first stereocenter and a second stereocenter that have the stereochemical configurations that are "R" and "R", respectively, then also provided are stereoisomers of that compound that have the stereochemical configurations that are "S" and "S", respectively, "S" and "R", respectively, and the first and second stereocenters that have the stereochemical configurations that are "R" and "S", respectively. Where a compound in Table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations that are "S" and "S", respectively, also provided are stereoisomers of that compound with stereochemical configurations that are "R" and "R", respectively, stereochemical configurations that are "S" and "R", respectively, and with first and second stereocenters with stereochemical configurations that are "R" and "S", respectively.When a compound of Table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations that are "S" and "R," respectively, stereoisomers of the compound having first and second stereocenters with stereochemical configurations that are "R" and "S," respectively, "R" and "R," and "S," respectively, are also provided. Similarly, when a compound of Table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations that are "R" and "S," respectively, stereoisomers of the compound having first and second stereocenters with stereochemical configurations that are "S" and "R," respectively, "R" and "R," and "S," respectively, are also provided. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Additionally, any formula given herein is intended to refer to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water and the solvate is a hydrate.

[0093] Representative examples of the compounds detailed herein, including intermediate and final compounds, are shown in the Tables and elsewhere herein. In one aspect, it is understood that any compound may be used in the methods detailed herein, including intermediate compounds, which, where applicable, can be isolated and administered to an individual or subject.

[0094] The compounds provided herein may exist as salts, even if not specified, and as will be appreciated by one of ordinary skill in the art, the compositions and methods provided herein will be understood to encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0095] In one variation, the compound is a synthetic compound herein prepared for administration to an individual or subject. In another variation, a composition is provided comprising the compound in substantially pure form. In another variation, a pharmaceutical composition is provided comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. The purified forms, pharmaceutical compositions, and methods of administering the compound are suitable for any compound or form detailed herein.

[0096] Ring A, ring B, L, R as provided herein A , R B , R C , R D ,m,n,p,R A1 , R A2 , R L , R C1 , R B1 , and R B2 Any variation or embodiment of ring A, ring B, L, R A , R B , R C , R D ,m,n,p,R A1 , R A2 , R L , R C1 , R B1 , and R B2 and all other variations or embodiments of the present invention, and each combination is treated as if it were individually and explicitly set forth.

[0097] Other embodiments will become apparent to those skilled in the art from the following detailed description.

[0098] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0099] The compound names provided herein, including in Table 1, are provided by ChemBioDraw Professional. Those skilled in the art will understand that compounds may be named or identified using a variety of commonly recognized nomenclature systems and symbols. By way of example, compounds may be named or identified by common, systematic, or non-systematic names. Nomenclature systems and symbols commonly recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).

[0100] composition Compositions, such as pharmaceutical compositions, containing the compounds disclosed and / or described herein and one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, etc. are also provided. Suitable agents and pharmaceuticals include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, are provided.

[0101] In some embodiments, a pharmaceutically acceptable composition is provided comprising a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain a synthetic intermediate that can be used in the preparation of a compound described herein. The compositions described herein may also include any other suitable active or inactive agents.

[0102] Any of the compositions described herein can be sterile or contain sterile components.Sterilization can be achieved by methods known in the art.Any of the compositions described herein can contain one or more substantially pure compounds or conjugates.

[0103] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0104] How to use The compounds and compositions detailed herein, for example, pharmaceutical compositions comprising a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein.

[0105] Without being bound by theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by modulating nicotinamide phosphoribosyltransferase (NAMPT). In some embodiments, the compounds and pharmaceutical compositions disclosed herein are activators of NAMPT. In some embodiments, methods are provided for treating a disease or condition mediated by NAMPT activity in an individual or subject, comprising administering a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to the individual or subject in need thereof. In some embodiments, methods are provided for treating cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or condition, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle wasting disorder in an individual or subject, comprising administering a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to the individual or subject in need thereof. In some embodiments, compounds of Formula (I), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are CNS penetrable and have the ability to boost NAD levels in the brain, making them potential treatments for CNS disorders.

[0106] In some embodiments, the compounds and pharmaceutical compositions disclosed herein may have the ability to prevent a disease or disorder (i.e., prevent the clinical symptoms of a disease or disorder from developing). In some embodiments, this includes situations where a disease or disorder is not currently occurring, but is expected to occur. In some embodiments, when used in a prophylactic sense, the compounds and pharmaceutical compositions disclosed and / or described herein may prevent a disease or disorder from occurring, or may reduce the severity of a disease or disorder that may occur.

[0107] In some embodiments, methods of treating a disease or condition are provided, comprising administering a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject in need thereof. In some embodiments, the disease or condition is selected from the group consisting of: Hereditary motor and sensory neuropathies, including Charcot-Marie-Tooth disease and hereditary sensory neuropathy type I, as well as a subset of fatty acid oxidation disorders that lead to peripheral neuropathies; Mitochondrial encephalomyopathy (including but not limited to Leber's hereditary optic neuropathy, MELAS, Leigh's syndrome, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, Alpers disease, autosomal dominant optic atrophy, Friedreich's ataxia, and congenital lactic acidosis); · Concussion syndrome; · Ataxia-telangiectasia; · Dysfunction of various tissues, including the central and peripheral nervous system, muscles, and immune system, following viral infections, including but not limited to SARS-CoV-2; · Treatment of obesity by increasing NAD+ in the hypothalamus and peripheral tissues; · Treatment of hypertension by increasing NAD+ throughout the body, including the medulla and peripheral vasculature; Alzheimer's disease, including mild cognitive impairment; and Encephalitis caused by a viral (including but not limited to COVID-19, herpes simplex, varicella zoster, enterovirus, flavivirus) or bacterial infection, an autoimmune disease, or an insect sting (including Lyme disease).

[0108] Also provided herein is the use of a compound of formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by NAMPT activity in a subject. In some aspects, provided are compounds or compositions described herein for use in methods of treating the human or animal body with therapy. In some embodiments, provided herein are compounds of formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in methods of treating the human or animal body with therapy. In some embodiments, provided herein are compounds of formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by NAMPT activity. In some embodiments, the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or condition, a disease resulting from stem cell dysfunction, a disease resulting from DNA damage, a primary mitochondrial disorder, or a muscle disease or condition.

[0109] Also provided herein are compositions (including pharmaceutical compositions) as described herein for use in treating, preventing, and / or delaying the onset and / or development of the diseases described herein, as well as other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation present in unit dosage form.

[0110] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, rabbit, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.

[0111] There are numerous conditions in which small molecule stimulation of NAMPT activity to boost NAD+ levels may be clinically beneficial (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13). These conditions include, but are not limited to, cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease and injury, diseases resulting from stem cell dysfunction, and DNA damage and primary mitochondrial disorders. In some embodiments, the disease or condition mediated by NAMPT activity is cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease or injury, diseases resulting from stem cell dysfunction, or DNA damage and primary mitochondrial disorders.

[0112] Cardiac Disease. NAD and NAMPT levels are reduced in various preclinical models of heart failure. In these models, cardiac function can be rescued by either oral NAD restoration or NAMPT overexpression (Diguet et al., Circulation. 2018, 137:2256-2273; Zheng et al., Clin Sci (Lond). 2019, 133(13):1505-1521; Smyrnias et al., J Am Coll Cardiol. 2019, 73(14):1795-1806). Therefore, increasing the catalytic efficiency of NAMPT with small molecule activators to compensate for reduced protein levels is a promising strategy for treating various forms of heart failure.

[0113] Chemotherapy-Induced Tissue Damage. The use of chemotherapy regimens is often limited by toxicity to healthy tissues, with severe oxidative stress thought to play a major role. Boosting NAD has previously been shown to induce a potent antioxidant response. Therefore, NAMPT activators are believed to be widely useful for preventing reversible and irreversible secondary pathologies in various chemotherapy settings. Examples include anthracycline and trastuzumab-induced cardiotoxicity, cisplatin-induced renal injury, and peripheral neuropathy induced by cisplatin, paclitaxel, vincristine, and other drugs. Furthermore, neuroprotection via NAMPT activation is useful in the treatment / prevention of chemotherapy-associated cognition ("chemobrain"), which is caused by the destruction of healthy neural tissue, both during active treatment and long after treatment has ceased. See, for example, Zheng et al., Clin Sci (Lond). 2019, 133(13):1505-1521.

[0114] Kidney Disease. Kidney disease is highly prevalent and represents an area of ​​significant unmet medical need. Approximately 3% of hospitalized patients are diagnosed with acute kidney injury (AKI). Some patients progress to chronic kidney disease, which may require long-term dialysis or kidney transplantation. A key feature of renal dysfunction is decreased activity of SIRT1 and SIRT3, characterized by a reduction in NAD, a sirtuin substrate, primarily due to impaired de novo NAD synthesis. Because NAMPT is robustly expressed during renal injury, small molecule activation of NAMPT is considered an effective means of preventing AKI. Similarly, hypertrophy of renal mesangial cells exhibits NAD depletion, and restoration of intracellular NAD levels is thought to be effective. See, for example, Poyan Mehr et al., Nat Med. 2018, Sep;24(9):1351-9.

[0115] Metabolic Disease. Boosting NAD+ improves insulin sensitivity, dyslipidemia, and mitochondrial function in metabolic diseases and prevents / ameliorates nonalcoholic and alcoholic steatohepatitis in preclinical models. Nonalcoholic steatohepatitis is diagnosed in over 3 million people annually in the United States alone, and it is one of the leading causes of liver transplants. See Guarino and Dufour, Metabolites. 2019, Sep 10;9(9), pii:E180; Yoshino et al., Cell Metab. 2011, 14(4):528-36.

[0116] Muscle diseases. Preclinical data suggest that NAD+-boosting strategies may alleviate skeletal muscle dysfunction in several conditions, including Duchenne muscular dystrophy and age-related sarcopenia. Zhang et al., Clin Sci (Lond). 2019, 133(13):1505-1521; Mohamed et al., Aging (Albany NY). 2014, 6(10):820-34; Ryu et al., Sci Transl Med. 2016, 8(361):361ra139

[0117] Neurological Disease and Injury. NAD replenishment through NAMPT activation is neuroprotective and has therapeutic utility in a wide range of preclinical models of neurological disease and injury, including age-related cognitive decline, glaucoma, ischemic stroke, and ALS. See: Johnson et al., NPJ Aging Mech Dis. 2018, 4:10; Harlan et al., J Biol Chem. 2016, 291(20):10836-46; Zhao et al., Stroke. 2015, Jul;46(7):1966-74; Williams et al., Front Neurosci. 2017, Apr 25;11:232; Blacher et al. Nature, 2019, volume 572, 474-480; Harlan et al., 2020. Experimental Neurology 327:113-219.

[0118] Diseases caused by stem cell dysfunction. Boosting NAD promotes stem cell activation and hematopoiesis, and is useful for accelerating the expansion of stem cell populations after stem cell transplantation. See Pi et al., Aging (Albany NY). 2019, 11(11):3505-3522.

[0119] DNA Damage Disorders and Primary Mitochondrial Disorders. NAMPT activators are also useful for treating DNA damage disorders associated with accelerated aging phenotypes, such as xeroderma pigmentosum, Cockayne syndrome, and ataxia-telangiectasia. Similarly, there are several primary mitochondrial disorders with common symptoms and signs, for which boosting NAD through NAMPT activation may be a suitable therapeutic intervention. See Fang et al., Cell. 2014, 157(4):882-896; Khan et al., EMBO Mol Med. 2014, Jun;6(6):721-31; Cerutti et al., Cell Metab. 2014, 19(6):1042-9.

[0120] In some embodiments, provided is a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject in need thereof, wherein the disease or condition is selected from the group consisting of cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscular disease, neurological disease and injury, disease caused by stem cell dysfunction, and DNA damage and primary mitochondrial disorders.

[0121] Additional uses of small molecule NAMPT activators are listed in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0122] In some embodiments, the disease or condition mediated by NAMPT activity is cancer and chemotherapy-induced tissue damage, cardiovascular disease, renal disease, chronic inflammatory and fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, neurological disease or injury, or DNA damage or primary mitochondrial disorder. In some embodiments, provided are methods of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering a compound of Formula (I), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject in need thereof. In some embodiments, the disease or condition is cancer or chemotherapy-induced tissue damage, cardiovascular disease, renal disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, neurological disease or injury, DNA damage or primary mitochondrial disorder, including any disease listed in Table 2.

[0123] Dosage The compounds and compositions disclosed and / or described herein are administered at therapeutically effective doses, e.g., at doses sufficient to provide treatment for a disease state. While human dosage levels for the chemical compounds described herein have not yet been optimized, generally, daily doses range from about 0.01 to 100 mg / kg body weight, in some embodiments, from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg body weight. Thus, for a 70 kg human, the dosage range is, in some embodiments, from about 0.7 to 7000 mg per day, in some embodiments, from about 3.5 to 700 mg per day, and in some embodiments, from about 7 to 100 mg per day. The amount of chemical compound administered will depend, for example, on the subject and disease state being treated, the severity of the condition, the mode and schedule of administration, and the discretion of the prescribing physician. For example, exemplary dosage ranges for oral administration are from about 5 mg to about 500 mg per day, and exemplary dosages for intravenous administration are from about 5 mg to about 500 mg per day, depending on the pharmacokinetics of each compound.

[0124] A daily dose is the total amount administered in one day. A daily dose can be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, but is not limited to this. In some embodiments, a daily dose is administered for a period ranging from one day to the subject's lifetime. In some embodiments, a daily dose is administered once a day. In some embodiments, a daily dose is administered in multiple divided doses, such as two, three, or four divided doses. In some embodiments, a daily dose is administered in two divided doses.

[0125] Administration of the compounds and compositions disclosed and / or described herein can be by any accepted mode of administration for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0126] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for extended timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0127] The compounds disclosed and / or described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, pharmaceutical compositions will contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight, of the compounds disclosed and / or described herein, depending on the intended mode of administration. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0128] In some embodiments, the compositions are in the form of pills or tablets, and thus may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) enclosed in gelatin capsules.

[0129] Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and any excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms: as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient between 0.01% and 10% in solution are usable, and may be higher if the composition is solid and will be subsequently diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of a compound disclosed and / or described herein in solution.

[0130] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for inhalation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0131] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein, as well as one or more additional drugs, pharmaceutical agents, adjuvants, etc. Suitable drugs and pharmaceutical agents include those described herein.

[0132] kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or suppress a condition described herein, and may indicate instructions for either in vivo or in vitro use.

[0133] In one aspect, the present specification provides a kit that contains the compound or composition described herein and instructions for use.The kit can include instructions for use in treating heart disease in individuals or subjects who need it.The kit can also contain any material or equipment that can be used in administering the compound or composition, such as vial, syringe or IV bag.The kit can also contain sterile packaging.

[0134] combination The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0135] Numbered Embodiments The following numbered embodiments are representative of some aspects of the present invention. Numbered Embodiment 1. Compound of Formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring having i) 1 to 4 R A or a 5-6 membered heteroaryl optionally substituted with ii) [ka] and; Each R A are independently selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; R D is selected from the group consisting of: halogen; Cyano; C1-C6 alkyl optionally substituted with 1 to 3 independently selected halogen or -OH; -O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; and -C(O)NR A1 R A2 , where R A1 and R A2 are each independently hydrogen or C1-C6 alkyl; L is a bond, C1-C6 alkylene, #-O-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-$, #-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-$, #-(C1-C6 alkylene)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-$, #-N(R L)-C(O)-CH2-$, #-(C1-C6 alkylene)-N(R L )-C(O)-$, #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-C(O)-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-N(R L )-S(O)2-$, #-N(R L )-S(O)2-(C1-C6 alkylene)-$, #-(C1-C6 alkylene)-S(O)2-N(R L )-$, #-S(O)2-N(R L )-(C1-C6 alkylene)-$, #-S(O)2-N(R L )-$, and #-N(C1-C6 alkyl)-S(O)2-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L are independently hydrogen or C1-C6 alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R B are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(C1-C6 alkyl); -C(O)O(C1-C6 alkyl); phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3-8 membered cycloalkyl; —C(O)(3-8 membered cycloalkyl); —C(O)(4-8 membered heterocycloalkyl); -S(O)2(C1-C6 alkyl); -S(O)2(3-8 membered cycloalkyl); -C(O)NR B1 R B2 ; -S(O)2NR B1 R B2 ; -NR C1 S(O)NR B1 R B2 ; -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=NR C1 )-NR B1 R B2 ; -NR C1 -(C=N-CN)-NR B1 R B2 and C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OH, and —O(C1-C6 alkyl); where R C1 , R B1 and R B2 are each independently hydrogen or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R C is halogen, cyano, C1-C6 alkyl, OH, —O(C1-C6 alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [ka] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R D is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) When L is -CH2-CH2-, then n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 2. Ring A is [ka] or a pharmaceutically acceptable salt thereof. Numbered Embodiment 3.R D is halogen, or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; or a pharmaceutically acceptable salt thereof. Numbered embodiment 4.R D is a halogen; or a pharmaceutically acceptable salt thereof. Numbered Embodiment 5.R D The compound of any one of numbered embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein is fluorine. Numbered Embodiment 6.R D The compound of any one of numbered embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein is chlorine. Numbered Embodiment 7. Ring A is selected from 1 to 4 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 8. Ring A is selected from 1 to 4 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 9. Ring A is oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, or isoxazolyl, each of which is selected from 1 to 3 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 10. Ring A is selected from the group consisting of 1 to 2 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 11. Ring A is selected from the group consisting of 1 to 2 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 12. Ring A is selected from 1 to 4 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 13. Ring A is pyridinyl, pyridazinyl, or pyrimidinyl, each of which contains 1 to 4 R A or a pharmaceutically acceptable salt thereof. Numbered Embodiment 14. Ring A is selected from 1 to 4 R A 14. The compound of any one of numbered embodiments 1, 7, 12, or 13, wherein R is pyridinyl optionally substituted with R, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 15. Ring A is selected from 1 to 4 R A 15. The compound of any one of numbered embodiments 1, 7, or 12-14, wherein R is pyridin-4-yl optionally substituted with R, or a pharmaceutically acceptable salt thereof. Numbered embodiment 16. Each R A is independently selected from the group consisting of halogen and C1-C6 alkyl. Numbered Embodiment 17. The compound of any one of numbered embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 4- to 8-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, or a 5- to 6-membered heteroaryl. Numbered Embodiment 18. The compound of any one of numbered embodiments 1-17, wherein Ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, oxazolyl, or pyrazolyl, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 19. The compound of any one of numbered embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl. Numbered embodiment 20. Ring B is [ka] 20. The compound of any one of numbered embodiments 1 to 19, wherein: Numbered embodiment 21. Each R B are independently selected from the group consisting of: halogen; oxo; phenyl or —O(C1-C6 alkyl) optionally substituted with 1 to 3 independently selected halogens; C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from halogen, —OH, and —O(C1-C6 alkyl); -S(O)2(C1-C6 alkyl); -S(O)2NR B1 R B2 ; -C(O)NR B1 R B2 ; -C(O)(C1-C6 alkyl); 4- to 8-membered heterocycloalkyl; and 5-6 membered heteroaryl, a compound according to any one of numbered embodiments 1-20, or a pharmaceutically acceptable salt thereof. Numbered embodiment 22. Each R B is oxo, -C(O)(C1-C6 alkyl), -C(O)NR B1 R B2 , -S(O)2(C1-C6 alkyl), -S(O)2NR B1 R B2 , unsubstituted C1-C6 alkyl, 4-8 membered heterocycloalkyl, and 5-6 membered heteroaryl, or a pharmaceutically acceptable salt thereof. Numbered embodiment 23. Each R B is independently selected from the group consisting of oxo, —C(O)(C1-C3 alkyl), —C(O)N(Me)2, —S(O)2Me, —S(O)2N(Me)2, methyl, oxetanyl, and pyridinyl, or a pharmaceutically acceptable salt thereof. Numbered embodiment 24.L is a bond, C-C alkylene, #-C(O)-N(R L )-(C1-C6 alkylene)-$, #-C(O)-(C1-C6 alkylene)-$, or #-(C1-C6 alkylene)-C(O)-N(R L )-(C1-C6 alkylene)-$, where # denotes the point of attachment to ring B and $ denotes the point of attachment to the rest of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; Here, each R L is independently hydrogen, or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof. Numbered Embodiment 25. A compound of any one of numbered embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each C1-C6 alkylene in L is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl. Numbered Embodiment 26. A compound according to any one of numbered embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein each C1-C6 alkylene in L is substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C1-C6 alkyl. Numbered Embodiment 27. A compound of any one of numbered embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each C1-C6 alkylene in L is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl. Numbered Embodiment 28. A compound according to any one of numbered embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each C1-C6 alkylene in L is unsubstituted. Numbered embodiment 29.L is a bond, C1-C3 alkylene, or #-C(O)-N(R L )-(C1-C3 alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the remainder of the molecule; wherein each C1-C6 alkylene in L is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —OH, and C1-C6 alkyl; and wherein each R L is independently hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. Numbered embodiment 30.L is a bond, -CH2-, -CH2CH2-, or [ka] 30. The compound of any one of numbered embodiments 1-24, or 29, wherein: Numbered Embodiment 31. A compound according to any one of numbered embodiments 1-6 or 16-30, wherein m is 1, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 32. A compound according to any one of numbered embodiments 1-6 or 17-30, wherein m is 0, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 33. A compound according to any one of numbered embodiments 1 to 32, wherein n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. Numbered embodiment 34.R C The compound of any one of numbered embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, wherein is fluoro. Numbered Embodiment 35. A compound according to any one of numbered embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein p is 0. Numbered Embodiment 36. A compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Numbered Embodiment 37. A pharmaceutical composition comprising a compound according to any one of numbered embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Numbered Embodiment 38. A method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject a compound described in any one of numbered embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in numbered embodiment 37. Numbered Embodiment 39. The method of numbered embodiment 38, wherein the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or condition, a disease resulting from stem cell dysfunction, a disease resulting from DNA damage, a primary mitochondrial disorder, and a muscle disease or condition. Numbered Embodiment 40. The method of numbered embodiment 38, wherein the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

[0136] General synthesis method Compounds of formula (I), or any variations or embodiments thereof, or salts of any of the foregoing, are now described by reference to the following illustrative synthetic schemes for their general preparation and the subsequent specific examples. To obtain the various compounds herein, those skilled in the art will recognize that starting materials may be suitably selected so that the desired substituents ultimately carry through the reaction scheme, with or without protection, as appropriate, to produce the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that will carry through the reaction scheme and that may be replaced with the desired substituent, as appropriate. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chain groups) from the reaction conditions, and that such groups are removed under standard conditions, as appropriate. Unless otherwise specified, variables are as defined above with reference to formula (I).

[0137] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers by using any suitable conventional procedure for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with a suitable chiral compound.The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if necessary, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described.

[0138] Where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction, chromatography, recrystallization, and other conventional separation procedures may be used on intermediates or final products.

[0139] General methods for preparing the compounds described herein are shown in the following exemplary methods. The variable groups in the schemes provided herein are as defined for formula (I), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0140] In some embodiments, compounds provided herein can be synthesized according to Scheme A1, A2, A3, or A4, wherein Ring A, Ring B, L, R B , R C , N, and P are as defined for formula (I) or any variation thereof detailed herein. [ka]

[0141] In certain embodiments, compounds provided herein can be synthesized according to Scheme A1a, A2a, A3a, or A4a, wherein Ring A, Ring B, L, R B , R C , n, and p are as defined for formula (I) or any variation thereof detailed herein. [ka]

[0142] Specific non-limiting examples are provided in the Examples section below. [Example]

[0143] The following examples are presented to illustrate, but not limit, the compositions, uses, and methods provided herein. Compounds are prepared using the general methods described above or below. Starting materials were purchased from commercial sources or prepared according to literature procedures.

[0144] The following abbreviations are used throughout the examples: TEA (triethylamine), DCM (dichloromethane), (Boc)2O (di-tert-butyl decarboxylate), EA (ethyl acetate), PE (petroleum ether), DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), DMAP [4-(dimethylamino)pyridine], HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol). , iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh3 (triphenylphosphine), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), rt or rt (room temperature of approximately 21-24 °C), DCE (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equiv (equivalent), and DSC (bis(2,5-dioxopyrrolidin-1-yl)carbonate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0145] Aniline Synthesis Example A Synthesis of Aniline Intermediates 1.1, 1.2, and 1.3 Step 1: Synthesis of tert-butyl (S)-(4-(1-cyclobutyl-5-oxopiperazin-2-yl)phenyl)carbamate [ka] The ketone (252 mg, 3.6 mmol) and acetic acid (108 mg, 1.8 mmol) were added to a stirred solution of tert-butyl (S)-(4-(5-oxopiperazin-2-yl)phenyl)carbamate (Reference 1) (252 mg, 1.8 mmol) in CHCl (5 mL) at room temperature, and the reaction was stirred for 30 minutes. Sodium triacetoxyborohydride (763 mg, 3.6 mmol) was added, and the reaction was stirred for 2 hours, after which time completion was confirmed by LCMS. The reaction was then quenched with saturated sodium bicarbonate (15 mL), extracted with CHCl (3×15 mL), and the organic solutions were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The crude material was used without further purification. LRMS (ES) m / z: 346.1 [M+H] + .

[0146] Step 2: Synthesis of (S)-5-(4-aminophenyl)-4-cyclobutylpiperazin-2-one [ka] HCl (4 M in dioxane, 2.5 mL, 10 mmol) was added to a stirred solution of tert-butyl (S)-(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate (1.8 mmol) at room temperature. After 6 h, the reaction was concentrated by rotary evaporation, triturated with EtOAc, filtered, and the resulting solid was dried under high vacuum to give the desired product as an off-white solid (400 mg, 70% over two steps). LCMS-APCI (POS.) m / z: 246.1 [M+H] + .

[0147] The compounds in the table below were prepared in a manner analogous to Intermediate 1.1 using the intermediates and reagents listed. [Table 3]

[0148] Example B Synthesis of aniline intermediate 2.1 Step 1: Synthesis of tert-butyl (E)-4-(4-nitrostyryl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-vinylpiperidine-1-carboxylate (5.71 g, 27 mmol, 1.80 equiv.), 1-iodo-4-nitrobenzene (3.74 g, 15 mmol, 1.00 equiv.), and triethylamine (4.55 g, 45 mmol, 3.00 equiv.) in DMF (50 mL) was added bis[tri(o-tolyl)phosphine]palladium(II) chloride (0.59 g, 0.75 mmol, 0.05 equiv.). The reaction mixture was degassed for 10 minutes. It was then heated at 130 °C for 24 hours. The reaction mixture was extracted with ether / EtOAc (50 mL / 50 mL) and HO (80 mL). The organic layer was concentrated and the residue was purified on silica gel using 35% EtOAc / Hex to give the desired product tert-butyl (E)-4-(4-nitrostyryl)piperidine-1-carboxylate as a yellow-reddish solid (1.70 g, 34%). LRMS (ES) m / z: 333 [M+H] + .

[0149] Step 2: Synthesis of tert-butyl 4-(4-aminophenethyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (E)-4-(4-nitrostyryl)piperidine-1-carboxylate (0.83 g, 2.50 mmol) in MeOH (30 mL) was added 10% Pd / C (0.27 g). The reaction mixture was stirred under H at 60 psi for 30 minutes. The catalyst was removed by filtration, and the filtrate was concentrated to give the desired product, tert-butyl 4-(4-aminophenethyl)piperidine-1-carboxylate, as a yellowish solid (0.70 g, 92%). LRMS (ES) m / z: 305 [M+H] + .

[0150] Example C Synthesis of aniline intermediate 3.1 Step 1: Synthesis of tert-butyl (4-acetylphenyl)carbamate [ka] To a solution of 1-(4-aminophenyl)ethanone (2.70 g, 20 mmol, 1.00 equiv.) in dry dioxane (14 mL) was added BocO (5.24 g, 24 mmol, 1.20 equiv.). The resulting mixture was heated at 100° C. for 5 h. The solvent was evaporated and the residue was taken up in EtOAc (100 mL). The organic layer was washed three times with 1 M HCl (30 mL), then with brine (50 mL), dried over NaSO, and evaporated to give the desired product, tert-butyl (4-acetylphenyl)carbamate, as a white solid (3.60 g, 77%). LRMS (ES) m / z: 236 [M+H] + .

[0151] Step 2: Synthesis of tert-butyl (4-(1-hydroxy-1-(pyridin-4-yl)ethyl)phenyl)carbamate [ka] To a solution of tert-butyl (4-acetylphenyl)carbamate (3.53 g, 15 mmol, 2.00 equiv.) in MTBE (30 mL) was added 4-cyanopyridine (0.78 g, 7.50 mmol, 1.00 equiv.) and bis-(pinacolato)diboron (4.57 g, 18 mmol, 2.40 equiv.). The resulting mixture was heated at 90 °C for 16 h. The reaction was cooled to room temperature, quenched with Na2CO3 solution (2 M, 50 mL), and stirred under air for 15 min. Brine (30 mL) was added. The reaction mixture was then extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel to give the desired product, tert-butyl (4-(1-hydroxy-1-(pyridin-4-yl)ethyl)phenyl)carbamate, as a white solid (0.70 g, 30%). LRMS (ES) m / z: 315 [[M+H] + .

[0152] Step 3: Synthesis of 1-(4-aminophenyl)-1-(pyridin-4-yl)ethan-1-ol [ka] To a solution of tert-butyl (4-(1-hydroxy-1-(pyridin-4-yl)ethyl)phenyl)carbamate (0.69 g, 2.20 mmol, 1.00 equiv) in MeOH (1 mL) was added 4 N HCl / dioxane (5.50 mL, 22 mmol, 10 equiv) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was used directly in the next step. LRMS (ES) m / z: 215 [M+H] + .

[0153] Example D Synthesis of aniline intermediates 4.1, 4.2, 4.3, and 4.4 Step 1: Preparation of tert-butyl 4-[(4-nitrophenyl)methoxy]piperidine-1-carboxylate [ka] To a solution of silver(I) oxide (4.61 g, 19.87 mmol, 2.0 equiv.) and TBAI (0.37 g, 0.99 mmol, 0.1 equiv.) in DCM (10 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 9.94 mmol, 1.0 equiv.). Nitrobenzyl bromide (4.29 g, 19.87 mmol, 2.0 equiv.) was added, and the reaction was stirred at 45 °C for 1 h while protected from light. The crude mixture was filtered through Celite, washed with DCM, and concentrated under reduced pressure. The residual brown oil was used directly in the next step without purification. Quantitative yield (3.34 g, 9.94 mmol, quant.). LCMS-APCI (POS.) m / z: 237.1 [M+H-Boc] +.1H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J = 8.9, 2.1 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 4.77 (s, 2H), 3.65 (ddt, J = 13.2, 8.6, 4.2 Hz, 4H), 2.95 (s, 2H), 1.68 (dt, J = 13.1, 4.0 Hz, 2H), 1.58 (s, 1H), 1.39 (s, 9H).

[0154] Step 2: Preparation of 4-[(4-aminophenyl)methoxy]piperidin-1-yl 2,2-dimethylpropanoate [ka] tert-Butyl 4-[(4-nitrophenyl)methoxy]piperidine-1-carboxylate (3.34 g, 9.94 mmol, 1.0 equiv.) and palladium on carbon (1.06 g, 0.99 mmol, 0.2 equiv.) were suspended in methanol (10 mL) and stirred under hydrogen (50 psi) at room temperature for 1 h. The reaction mixture was filtered through Celite, concentrated, and purified using flash chromatography on silica gel (0-20% MeOH:DCM containing 0.1% triethylamine). The product was isolated as a brown oil (1.357 g, 4.429 mmol, 44.6% yield over two steps). LCMS-APCI (POS.) m / z: 207.1 (M+H-Boc). + .1H NMR (400 MHz, methanol-d4) δ 7.09 - 7.05 (m, 2H), 6.72 - 6.67 (m, 2H), 6.64 (d, J = 8.1 Hz, 1H), 4.35 (s, 2H), 3.82 (dt, J = 13.6, 4.8 Hz, 3H), 3.75 (dq, J = 8.6, 4.3 Hz, 2H), 3.03 (s, 3H), 1.81 (dt, J = 10.3, 3.0 Hz, 3H), 1.45 (s, 3H), 1.38 (ddd, J = 13.2, 8.9, 3.9 Hz, 3H).

[0155] The compounds in the table below were prepared in a manner analogous to Intermediate 4.1 using the starting materials listed. [Table 4-1] [Table 4-2]

[0156] Example E Synthesis of intermediates 5.1-5.5 Step 1: Synthesis of (R)-1-(4-nitrobenzyl)-5-(pyridin-3-yl)pyrrolidin-2-one [ka] To a suspension of (5R)-5-(pyridin-3-yl)pyrrolidin-2-one (80 mg, 0.493 mmol) in THF (1.5 mL) was added lithium bis(trimethylsilyl)amide (83 mg, 0.49 mmol) at 0 °C, followed by stirring at room temperature for 1 h. The mixture was cooled to 0 °C, and a solution of 4-nitrobenzyl bromide (109 mg, 0.503 mmol) in THF (1 mL) was added at 0 °C. The mixture was warmed to room temperature and stirred for 4.5 h. The mixture was filtered and purified by reverse-phase HPLC (0–50% MeCN / HO, 0.1% HCOOH) to give (5R)-1-[(4-nitrophenyl)methyl]-5-(pyridin-3-yl)pyrrolidin-2-one (22 mg, 15% yield). LCMS-APCI (POS.) m / z: 298.1 [M+H]+.

[0157] Step 2: Synthesis of (R)-1-(4-aminobenzyl)-5-(pyridin-3-yl)pyrrolidin-2-one [ka] A mixture of (5R)-1-[(4-nitrophenyl)methyl]-5-(pyridin-3-yl)pyrrolidin-2-one (22 mg, 0.078 mmol) and platinum oxide (5 mg) in THF / MeOH (2 mL:1 mL) was stirred under hydrogen (50 psi) at room temperature for 3 hours. The mixture was concentrated to give (5R)-1-[(4-nitrophenyl)methyl]-5-(pyridin-3-yl)pyrrolidin-2-one (15 mg), which was used in the next step without further purification. LCMS-APCI (POS.) m / z: 268.1 [M+H] + .

[0158] The intermediates in the table below were prepared in an analogous manner to Intermediate 5.1 using the starting materials and reagents listed. [Table 5]

[0159] Example R Synthesis of intermediates 27.1–27.3 Step 1: Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate [ka] To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 1 equiv.) in THF (200 mL, 0.118 M) at -78 °C, lithium bis(trimethylsilyl)amide (71 mL, 1 M, 3 equiv.) was added dropwise, and the mixture was stirred at -78 °C for 1 h. Subsequently, phenyltriflimide (16.9 g, 2 equiv.) in THF (100 mL) was added dropwise. The mixture was stirred for 3 h and quenched with water. The organic portion was concentrated, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0–20% EtOAc / hexane gradient) to give tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (4.7 g, 57.8% yield). LRMS (ES) 288.1 [M+H-Bu] + .

[0160] Step 2: Preparation of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate [ka] To a solution of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (2.7 g, 1 equiv.) and potassium acetate (2 equiv.) in dioxane (22 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.3 equiv.) and PdCl2dppf (0.1 equiv.) were added and mixed. The mixture was stirred at 80 °C for 2 h until the reaction was complete. The mixture was cooled, filtered through Celite, concentrated, and purified by silica gel chromatography (0-10% EtOAc / hexanes gradient) to give tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (1.8 g, 69.6% yield). LRMS (ES) 266.1 [M+H-Bu]+ .

[0161] Step 3: Preparation of tert-butyl 6-(2-fluoro-4-nitrophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate [ka] To a solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (1.8 g, 1 equiv.) and 1-bromo-2-fluoro-4-nitrobenzene (1.5 equiv.) in DMF (30 mL) was added potassium carbonate (2 equiv.) and PdCl2dppf (0.1 equiv.). The mixture was stirred at 80 °C for 2 h until the reaction was complete. The mixture was cooled, filtered through Celite, concentrated, and purified by silica gel chromatography (0-10% EtOAc / hexane gradient) to give tert-butyl 6-(2-fluoro-4-nitrophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate as a yellow solid (1.4 g, 74.8% yield). LRMS (ES) 279.1 [[M+H-Bu] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J = 10.5, 2.2 Hz, 1H), 8.10 (dd, J = 8.5, 2.3 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 6.79 (d, J = 3.1 Hz, 1H), 4.12 - 4.03 (m, 4H), 3.07 (s, 2H), 1.39 (s, 9H).

[0162] Step 4: Preparation of tert-butyl 6-(4-amino-2-fluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] A solution of tert-butyl 6-(2-fluoro-4-nitrophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (1.4 g, 1 equiv.) in methanol (8 mL) and dioxane (8 mL) was purged under nitrogen for 5 minutes, followed by the slow addition of Pd / C (0.31 equiv.) and purging for an additional 5 minutes. The mixture was charged with a balloon containing hydrogen, stirred at 24 °C for 16 hours, filtered through Celite, and concentrated to give tert-butyl 6-(4-amino-2-fluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 99.6% yield). LRMS (ES) 251.1 [[M+H-Bu]] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.90 (t, J = 8.6 Hz, 1H), 6.32 (dd, J = 8.3, 2.1 Hz, 1H), 6.24 (dd, J = 13.0, 2.2 Hz, 1H), 5.18 (s, 2H), 3.95 (s, 2H), 3.73 (s, 2H), 3.36 - 3.26 (m, 1H), 2.43 (td, J = 8.6, 2.9 Hz, 2H), 2.16 (td, J = 9.5, 3.0 Hz, 2H), 1.37 (s, 9H).

[0163] The intermediate anilines in the table below were prepared in an analogous manner to Intermediate 27.1 using the starting materials and reagents listed. [Table 6]

[0164] Example S Synthesis of intermediates 28.1–27.8 Step 1: Synthesis of diethyl (2-fluoro-4-nitrobenzyl)phosphonate [ka] 1-(Bromomethyl)-2-fluoro-4-nitrobenzene (3.01 g, 1 equiv.) was mixed with triethyl phosphite (2 equiv.), and the resulting solution was stirred at 120 °C for 40 min, cooled, and purified by silica gel chromatography (10-100% EtOAc / hexanes gradient) to give diethyl (2-fluoro-4-nitrobenzyl)phosphonate as a yellow oil (3.37 g, 89.8% yield). LRMS (ES) 292.1 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 - 8.06 (m, 2H), 7.69 - 7.63 (m, 1H), 4.03 - 3.97 (m, 4H), 3.42 (dd, J = 22.2, 1.2 Hz, 2H), 1.23 - 1.16 (m, 6H).

[0165] Step 2: Synthesis of tert-butyl 6-(2-fluoro-4-nitrobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylate: [ka] To a solution of diethyl (2-fluoro-4-nitrobenzyl)phosphonate (2.2 g, 1 equiv.) in THF (20 mL) was added tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2 equiv.) at 24 °C, and sodium hydride (4 equiv.) was slowly added at 0 °C. The mixture was stirred at 0 °C for 1 h, slowly quenched with ice and water, and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-20% EtOAc / hexane gradient) to give tert-butyl 6-(2-fluoro-4-nitrobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylate as a yellow oil (0.31 g, 11.6% yield). LRMS (ES) 393.2 [M+H-Bu] + .

[0166] Step 3: Preparation of tert-butyl 6-(4-amino-2-fluorobenzyl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] A solution of tert-butyl 6-(2-fluoro-4-nitrobenzylidene)-2-azaspiro[3.3]heptane-2-carboxylate (0.85 g, 1 equiv.) in methanol (6 mL) and dioxane (6 mL) was purged under nitrogen for 5 minutes, and Pd (0.42 equiv.) was slowly added and purged for an additional 5 minutes. The mixture was filled with a balloon containing hydrogen, stirred at 24 °C for 4 hours, filtered through Celite, and concentrated to give tert-butyl 6-(4-amino-2-fluorobenzyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.72 g, 92.8% yield). LRMS (ES) 265.1 [M+H-Bu] + .

[0167] The intermediate anilines in the table below were prepared in a manner similar to that described above using the starting materials and reagents listed. [Table 7-1] [Table 7-2] [Table 7-3]

[0168] Carbamate Synthesis Method 1: Synthesis of carbamates from anilines and chloroformates Example F Preparation of 4-chlorobenzyl (4-((4-methyl-2-oxopiperazin-1-yl)methyl)phenyl)carbamate (compound 28) [ka] To a mixture of aniline (88 mg, 0.40 mmol) in DCM (2 mL) was added DIEA (104 mg, 0.80 mmol), N,N-dimethylaniline (DMAP, 23 mg, 0.20 mmol), followed by 4-Cl-benzylchloroformate (98 mg, 0.48 mmol). The reaction mixture was stirred overnight and concentrated to dryness. The residue was purified by Agilent RP-HPLC on a Phenomenex, Gemini 5u C18 150 x 21.2 mm column, eluting with a gradient of 10% ACN / water to 100% ACN / water over 40 min, to give the desired product as an off-white solid (40 mg, 65% yield). LRMS (ES) m / z: 388.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.47 - 7.24 (m, 6H), 7.22 (d, J = 8.3 Hz, 2H), 5.17 (s, 2H), 4.57 (s, 2H), 3.34 - 3.26 (m, 2H), 3.17 (s, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.35 (s, 3H).

[0169] The compounds in the table below were prepared in a manner similar to compound 28, using the anilines listed. Aniline intermediates were either purchased from commercial sources or prepared according to the above or published patent application WO2021 / 159015. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6]

[0170] Method 2: Preparation of isocyanates from aniline and triphosgene Example G Preparation of 4-chlorobenzyl (S)-(4-(1-methyl-5-oxopiperazin-2-yl)phenyl)carbamate (compound 54) [ka] To a solution of triphosgene (60 mg, 0.20 mmol) in 2 mL of methylene chloride cooled in an ice bath at 0° C., a solution of (S)-5-(4-aminophenyl)-4-methylpiperazin-2-one diHCl salt (Intermediate 1.0, 139 mg, 0.5 mmol) and diisopropylethylamine (0.35 mL, 2.0 mmol) in methylene chloride (4 mL) was added dropwise under a nitrogen atmosphere while maintaining the internal temperature below 5° C. After stirring in the ice bath for 0.5 h, the resulting mixture was slowly added to a solution of 4-chlorobenzyl alcohol (109 mg, 0.75 mmol) and DMAP (6 mg, 0.05 mmol) in methylene chloride (2 mL). The mixture was allowed to warm to room temperature, stirred at room temperature overnight, and concentrated to dryness. The residue was purified by Agilent RP-HPLC on a Phenomenex, Gemini 5u C18 150 x 21.2 mm column using a gradient of 10% ACN / water to 100% ACN / water over 40 min to give the desired product as an off-white solid (115 mg, 62% yield). LRMS (ES) m / z: 374 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.52 - 7.29 (m, 9H), 5.18 (s, 2H), 3.54 (d, J = 17.1 Hz, 1H), 3.42 (s, 2H), 3.50 - 3.37 (m, 1H), 3.29 (d, J = 8.2 Hz, 1H), 3.05 (d, J = 17.0 Hz, 1H), 2.06 (s, 3H).

[0171] The compounds in the table below were prepared in a manner similar to compound 54 using the aniline intermediates and alcohols listed. The aniline intermediates were either purchased from commercial sources or prepared according to procedures described above or published patent application WO2021 / 159015. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15] [Table 9-16] [Table 9-17] [Table 9-18] [Table 9-19] [Table 9-20] [Table 9-21] [Table 9-22] [Table 9-23] [Table 9-24] [Table 9-25]

[0172] Method 3: In situ preparation of isocyanates via Curtius rearrangement Example H Preparation of oxazol-5-ylmethyl (4-(pyridin-4-ylmethyl)phenyl)carbamate (compound 201) Step 1A: Synthesis of methyl 4-(pyridin-4-ylmethyl)benzoate [ka] To a solution of 4-(chloromethyl)pyridine hydrochloride (4.92 g, 30 mmol, 1.00 equiv.) and 4-(methoxycarbonyl)phenylboronic acid (7.02 g, 39 mmol, 1.30 equiv.) in dioxane (70 mL) and HO (30 mL) was added cesium carbonate (14.66 g, 45 mmol, 1.50 equiv.) and PdCl(dppf) (2.20 g, 3 mmol, 0.10 equiv.). The reaction mixture was heated in an oil bath at 110 °C for 3 h. The mixture was cooled to room temperature and then extracted with EtOAc (100 mL) and HO (50 mL). The organic layer was dried, concentrated, and purified on silica gel using 50% EtOAc / Hex to give the desired product, methyl 4-(pyridin-4-ylmethyl)benzoate (1.70 g, 25%) as a white solid. LRMS (ES) m / z: 228[ M+H] + .

[0173] Step 1B: Synthesis of methyl 4-((6-methylpyridin-3-yl)methyl)benzoate [ka]

[0174] To a solution of 5-(chloromethyl)-2-methylpyridine (3.00 g, 21 mmol, 1.00 equiv.) and (4-(methoxycarbonyl)phenyl)boronic acid (5.67 g, 31.50 mmol, 1.50 equiv.) in dioxane (80 mL) and HO (40 mL) was added cesium carbonate (13.68 g, 42 mmol, 2.00 equiv.) and PdCl(dppf) (1.54 g, 2.10 mmol, 0.10 equiv.). The reaction mixture was heated in an oil bath at 110 °C for 3 h. The mixture was cooled to room temperature and then extracted with EtOAc (100 mL) and HO (50 mL). The organic layer was dried, concentrated, and purified on silica gel with 50% EtOAc / Hex to give the desired product, methyl 4-((6-methylpyridin-3-yl)methyl)benzoate, as a white solid (3.87 g, 76%). LRMS (ES) m / z: 242 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.30 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 4.00 (s, 2H), 3.86 (s, 3H), 2.48 (s, 3H).

[0175] Step 1C: Synthesis of ethyl 4-((6-methylnicotinamido)methyl)benzoate [ka] To a solution of 6-methylnicotinic acid (3.43 g, 25 mmol, 1.00 equiv) in DMF solution (100 mL) was added HBTU (12.32 g, 32.50 mmol, 1.30 equiv), DIEA (6.77 g, 52.50 mmol, 2.10 equiv). The mixture was stirred for 10 min. Ethyl 4-(aminomethyl)benzoate (5.38 g, 30 mmol, 1.20 equiv) was added. The reaction mixture was stirred for 1 h. Next, EtOAc (120 mL) and brine (150 mL) were added to the reaction mixture. The organic layer was further washed with saturated NaHCO3 (150 mL), dried over MgSO4, concentrated, and purified on silica gel using 100% EtOAc to give the desired product, ethyl 4-((6-methylnicotinamido)methyl)benzoate, as a brownish solid (2.98 g, 40%). LRMS (ES) m / z: 299 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.91 (d, J = 2.6 Hz, 1H), 8.18 (dd, J = 8.2, 2.3 Hz, 1H), 8.00 (dd, J = 8.3, 2.3 Hz, 2H), 7.53 - 7.23 (m, 3H), 4.66 (d, J = 2.2 Hz, 2H), 4.36 (dd, J = 7.2, 2.2 Hz, 2H), 2.61 (d, J = 2.1 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0176] Step 2: Synthesis of 4-(pyridin-4-ylmethyl)benzoic acid [ka] To a solution of methyl 4-(pyridin-4-ylmethyl)benzoate (1.70 g, 7.50 mmol, 1.00 equiv.) in MeOH (10 mL) and THF (10 mL) was added NaOH (10 mL, 1.50 M, 2.00 equiv.). The reaction mixture was stirred at room temperature for 16 h. THF and MeOH were removed. The residue was adjusted to pH = 3-4 using 2 N HCl (7.50 mL). The precipitate was filtered, washed with HO, and dried under high vacuum to give the desired product, 4-(pyridin-4-ylmethyl)benzoic acid, as a white solid (1.35 g, 84%). LRMS (ES) m / z: 214 [M+H] + .

[0177] Step 3: Synthesis of 4-(pyridin-4-ylmethyl)benzoyl azide [ka]

[0178] To a mixture of 4-(pyridin-4-ylmethyl)benzoic acid (1.75 g, 8.21 mmol, 1.00 equiv.) in toluene / THF (20 mL / 20 mL) was added EtN (0.83 g, 8.21 mmol, 1.00 equiv.), followed by diphenylphosphoryl azide (2.26 g, 8.21 mmol, 1.00 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-100% ethyl acetate / hexanes) to give 4-(pyridin-4-ylmethyl)benzoyl azide as a white solid (1.72 g, 88%). LRMS (ES) m / z: 239 [M+H] + .

[0179] Step 4: Synthesis of thiazol-5-ylmethyl (4-(pyridin-4-ylmethyl)phenyl)carbamate [ka] To a mixture of 4-(pyridin-4-ylmethyl)benzoyl azide (29 mg, 0.12 mmol, 1.0 equiv.) in toluene (1 mL) was added 1,3-thiazol-5-ylmethanol (28 mg, 0.24 mmol, 2.00 equiv.). The reaction mixture was heated at 110° C. for 1 hour. The solvent was removed, and the residue was purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN (0.1% formic acid); Flow Rate: 20 mL / min) to give the desired product, thiazol-5-ylmethyl (4-(pyridin-4-ylmethyl)phenyl)carbamate, as a white solid (35 mg, 90%). LRMS (ES) m / z: 326 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.42 (d, J = 5.2 Hz, 2H), 7.96 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 5.3 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.43 (s, 2H), 4.00 (s, 2H).

[0180] The compounds in the table below were prepared in a manner similar to compound 201 using the starting materials and alcohol listed. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14]

[0181] Method 4: Synthesis of carbamates by phenol substitution Example I Preparation of oxazol-5-ylmethyl (R)-(4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate (compound 6) Step 1: Synthesis of phenyl N-(4-formylphenyl)carbamate [ka] To a solution of 4-aminobenzaldehyde (5 g, 41.28 mmol, 1.00 equiv) in THF (100 mL) and HO (10 mL) at −5° C., KCO (11.4 g, 82.49 mmol, 2.00 equiv) and phenyl chloroformate (9.7 g, 61.96 mmol, 1.50 equiv) were added dropwise over 15 min. The resulting mixture was stirred at 40° C. for 1 h. The resulting mixture was cooled to room temperature, water (50 mL) was added, and extracted twice with EtOAc (40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with hexane / EtOAc (10:1) to give phenyl N-(4-formylphenyl)carbamate as a yellow solid (10.9 g, 93.1%). LRMS (ES) m / z: 242 [M+H] + .

[0182] Step 2: Synthesis of phenyl N-(4-{[(2R)-2-(pyridin-3-yl)pyrrolidin-1-yl]methyl}phenyl)carbamate [ka] To a stirred solution of phenyl N-(4-formylphenyl)carbamate (720 mg, 2.99 mmol, 1.1 equiv.) and (R)-3-(pyrrolidin-2-yl)pyridine (402 mg, 2.71 mmol, 1 equiv.) in DCE (8 mL) was added STAB (1150 mg, 5.43 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the resulting mixture, which was then extracted twice with CHCl (20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with hexane / EtOAc (5:1) to give phenyl N-(4-{[(2R)-2-(pyridin-3-yl)pyrrolidin-1-yl]methyl}phenyl)carbamate as a yellow solid (700 mg, 67.0%). LRMS (ES) m / z: 374 [M+H] + .

[0183] Step 3: Synthesis of oxazol-5-ylmethyl (R)-(4-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)phenyl)carbamate [ka] To a stirred solution of phenyl N-(4-{[(2R)-2-(pyridin-3-yl)pyrrolidin-1-yl]methyl}phenyl)carbamate (70 mg, 0.19 mmol, 1 equiv) in THF (1 mL) was added 1,3-oxazol-5-ylmethanol (22 mg, 0.22 mmol, 1.18 equiv) and TEA (56 mg, 0.55 mmol, 2.95 equiv) at room temperature. The resulting mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature. The crude product was purified by preparative HPLC (2#SHIMADZU (HPLC-01)) using the following conditions: column, XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (33% to 47% ACN in 8 min); detector, uv 254 nm), to give 5.1 mg of 1,3-oxazol-5-ylmethyl N-(4-{[(2R)-2-(pyridin-3-yl)pyrrolidin-1-yl]methyl}phenyl)carbamate as a white solid. LRMS (ES) m / z: 379 [M+H] +.1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.50 - 8.39 (m, 2H), 7.84 (dt, J = 7.9, 2.0 Hz, 1H), 7.43 - 7.33 (m, 3H), 7.30 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 5.20 (s, 2H), 3.58 (d, J = 13.1 Hz, 1H), 3.43 (t, J = 8.1 Hz, 1H), 3.05 (d, J = 13.1 Hz, 1H), 2.96 (td, J = 9.2, 8.3, 3.0 Hz, 1H), 2.20 (q, J = 8.7 Hz, 2H), 1.77 (d, J = 9.9 Hz, 2H), 1.60 (dq, J = 18.0, 10.1, 8.1 Hz, 1H).

[0184] The compounds in the table below were prepared in a similar manner to compound 6 using the amines and alcohols listed. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10]

[0185] Suzuki Coupling Example J Preparation of 4-chlorobenzyl (4-(thiazol-2-ylmethyl)phenyl)carbamate (compound 336) Step 1: Synthesis of 4-chlorobenzyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka] To a mixture of 4-chlorobenzyl(4-bromophenyl)carbamate (2.04 g, 6.00 mmol, 1.00 equiv.), bis(pinacolato)diboron (2.29 g, 9.00 mmol, 1.50 equiv.) in dioxane (20 mL), KOAc (0.88 g, 9.00 mmol, 1.50 equiv.), and PdCl(dppf) (0.44 g, 0.60 mmol, 0.10 equiv.) were added. The resulting mixture was degassed for 10 minutes. It was then heated in a microwave oven at 130° C. for 60 minutes. The reaction mixture was extracted with EtOAc (100 mL) and brine (50 mL). The organic layer was concentrated and purified on silica gel with 25% EtOAc / Hex to give the desired product 4-chlorobenzyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate as a yellowish solid (1.25 g, 54%). LRMS (ES) m / z: 388 [M+H] + .

[0186] Step 2: Synthesis of 4-chlorobenzyl (4-(thiazol-2-ylmethyl)phenyl)carbamate [ka] To a mixture of 4-chlorobenzyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (78 mg, 0.20 mmol, 1.00 equiv.), 2-(chloromethyl)thiazole (40 mg, 0.30 mmol, 1.50 equiv.), and CsCO (77 mg, 0.24 mmol, 1.20 equiv.) in dioxane (2 mL) and HO (1 mL) was added PdCl(dppf) (15 mg, 0.02 mmol, 0.10 equiv.). The resulting mixture was degassed for 2 min. It was then heated in a MW oven at 130 °C for 30 min. The mixture was extracted with EtOAc (10 mL) and brine (3 mL). The organic layer was concentrated and purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30 x 150 mm 5 um; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give 4-chlorobenzyl (4-(thiazol-2-ylmethyl)phenyl)carbamate as a white solid (21 mg, 29%). LRMS (ES) m / z: 359 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.70 (d, J = 3.4 Hz, 1H), 7.52–7.33 (m, 6H), 7.33–7.16 (m, 2H), 5.17 (s, 2H), 4.31 (s, 2H).

[0187] The compounds in the table below were prepared in a similar manner to compound 336 using the intermediates and chlorides listed. [Table 12-1] [Table 12-2] [Table 12-3]

[0188] Amine deprotection Example K Preparation of 4-chlorobenzyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (Compound 231 / Intermediate 6.2) [ka] To a solution of tert-butyl 4-(4-((((4-chlorobenzyl)oxy)carbonyl)amino)benzyl)piperidine-1-carboxylate (1.30 g, 2.84 mmol, 1.00 equiv) in MeOH (2 mL) at 0 °C was slowly added 4 M HCl / dioxane (8.52 mL, 34.08 mmol, 12 equiv). The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was removed and the residue, 4-chlorobenzyl(4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride, was used directly in the next step without further purification. LRMS (ES) m / z: 359 [M+H] + .

[0189] The compounds in the table below were prepared in an analogous manner to Compound 231 / Intermediate 6.2 using the intermediates listed. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9] [Table 13-10]

[0190] Amine derivatization Example L Method A: Synthesis of 4-chlorobenzyl (4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)carbamate (compound 43) [ka] To a mixture of 4-chlorobenzyl(4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (79 mg, 0.20 mmol, 1.00 equiv), 3-oxetanone (29 mg, 0.40 mmol, 1.00 equiv) in DCM (1 mL) was added Na(OAc)BH (93 mg, 0.44 mmol, 2.20 equiv). The reaction mixture was stirred for 30 minutes, then concentrated under reduced pressure and purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give 4-chlorobenzyl (4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)carbamate as a white solid (80 mg, 96%). LRMS (ES) m / z: 415 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.39 (dd, J = 15.4, 7.0 Hz, 6H), 7.11 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 4.77 (t, J = 7.2 Hz, 2H), 4.69 (t, J = 6.6 Hz, 2H), 3.92 (p, J = 6.5 Hz, 1H), 3.12 (d, J = 12.0 Hz, 2H), 2.57 (d, J = 6.9 Hz, 2H), 2.44 - 2.25 (m, 2H), 1.81 (d, J = 14.9 Hz, 3H), 1.41 (qd, J = 12.8, 11.8, 3.7 Hz, 2H).

[0191] Method B: Synthesis of 4-chlorobenzyl (4-((1-acetylpiperidin-4-yl)methyl)phenyl)carbamate (compound 40) [ka] To a mixture of 4-chlorobenzyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (0.20 g, 0.50 mmol, 1.00 equiv.) in DCM (2 mL) was added DIEA (0.19 g, 1.50 mmol, 3.00 equiv.), followed by acetic anhydride (0.10 g, 1.00 mmol, 2.00 equiv.). The reaction mixture was stirred for 30 minutes, then concentrated under reduced pressure and purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30 × 150 mm 5 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: MeCN (0.1% formic acid); Flow Rate: 20 mL / min) to give 4-chlorobenzyl (4-((1-acetylpiperidin-4-yl)methyl)phenyl)carbamate as a white solid (138 mg, 69%). LRMS (ES) m / z: 401[M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.48 - 7.28 (m, 6H), 7.10 (d, J = 8.5 Hz, 2H), 5.17 (s, 2H), 4.49 (ddt, J = 13.4, 4.6, 2.4 Hz, 1H), 3.89 (dp, J = 13.6, 2.3 Hz, 1H), 3.04 (td, J = 13.0, 2.7 Hz, 1H), 2.66 - 2.46 (m, 3H), 2.08 (s, 3H), 1.94 - 1.63 (m, 3H), 1.14 (dqd, J = 37.1, 12.6, 4.3 Hz, 2H).

[0192] Method C. Synthesis of 4-chlorobenzyl (4-((1-isobutyrylpiperidin-4-yl)methyl)phenyl)carbamate (Compound 87) [ka] The same procedure as above was followed. The desired product 4-chlorobenzyl (4-((1-isobutyrylpiperidin-4-yl)methyl)phenyl)carbamate was obtained as a white solid (30 mg, 70%). LRMS (ES) m / z: 429 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.53 - 7.20 (m, 6H), 7.10 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 4.52 (d, J = 13.4 Hz, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.13 - 2.79 (m, 2H), 2.68 - 2.42 (m, 3H), 1.96 - 1.57 (m, 3H), 1.23 - 0.96 (m, 8H).

[0193] Method D. Synthesis of methyl 4-(4-((((4-chlorobenzyl)oxy)carbonyl)amino)benzyl)piperidine-1-carboxylate (Compound 98) [ka] To a mixture of 4-chlorobenzyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (79 mg, 0.20 mmol, 1.00 equiv.) in DCM (2 mL) was added DIEA (52 mg, 0.40 mmol, 2.00 equiv.), followed by methyl chloroformate (19 mg, 0.20 mmol, 1.00 equiv.). The reaction mixture was stirred for 30 minutes, then concentrated under reduced pressure and purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 Column 30×150 mm 5 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: MeCN (0.1% formic acid); Flow Rate: 20 mL / min) to give methyl 4-(4-((((4-chlorobenzyl)oxy)carbonyl)amino)benzyl)piperidine-1-carboxylate as a white solid (76 mg, 91%). LRMS (ES) m / z: 417 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.53 - 7.23 (m, 6H), 7.21 - 6.97 (m, 2H), 5.17 (s, 2H), 4.08 (d, J = 13.1 Hz, 2H), 3.67 (s, 3H), 2.76 (s, 2H), 2.51 (d, J = 7.1 Hz, 2H), 1.64 (d, J = 13.7 Hz, 3H), 1.12 (qd, J = 12.6, 4.4 Hz, 2H).

[0194] Method E. Synthesis of 4-chlorobenzyl (4-((1-(methylsulfonyl)piperidin-4-yl)methyl)phenyl)carbamate (Compound 38) [ka] The same procedure as above was followed. The desired product 4-chlorobenzyl (4-((1-(methylsulfonyl)piperidin-4-yl)methyl)phenyl)carbamate was obtained as a white solid (60 mg, 69%). LRMS (ES) m / z: 437 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.39 (dq, J = 11.5, 8.3, 7.9 Hz, 6H), 7.22 - 6.98 (m, 2H), 5.17 (s, 2H), 3.70 (d, J = 11.5 Hz, 2H), 2.80 (s, 3H), 2.68 (td, J = 12.0, 2.5 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 1.75 (d, J = 14.0 Hz, 3H), 1.38 - 1.16 (m, 2H).

[0195] Method F. Synthesis of 4-chlorobenzyl (4-((1-(N,N-dimethylsulfamoyl)piperidin-4-yl)methyl)phenyl)carbamate (Compound 34) [ka] The same procedure as above was followed. The desired product 4-chlorobenzyl (4-((1-(N,N-dimethylsulfamoyl)piperidin-4-yl)methyl)phenyl)carbamate was obtained as a white solid (77 mg, 83%). LRMS (ES) m / z: 466 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.49 - 7.24 (m, 6H), 7.20 - 7.04 (m, 2H), 5.17 (s, 2H), 3.65 (dp, J = 12.4, 1.9 Hz, 2H), 2.79 (s, 8H), 2.53 (d, J = 6.7 Hz, 2H), 1.76 - 1.51 (m, 3H), 1.34 - 1.12 (m, 2H).

[0196] Method G. Synthesis of 4-chlorobenzyl (4-((1-(dimethylcarbamoyl)piperidin-4-yl)methyl)phenyl)carbamate (Compound 58) [ka] The same procedure as above was followed. The desired product 4-chlorobenzyl (4-((1-(dimethylcarbamoyl)piperidin-4-yl)methyl)phenyl)carbamate was obtained as a white solid (30 mg, 70%). LRMS (ES) m / z: 430 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.52 - 7.26 (m, 6H), 7.10 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 3.65 (d, J = 13.1 Hz, 2H), 2.83 (d, J = 1.2 Hz, 6H), 2.73 (td, J = 12.7, 2.3 Hz, 2H), 2.53 (d, J = 6.9 Hz, 2H), 1.81 - 1.53 (m, 3H), 1.21 (qd, J = 12.3, 4.0 Hz, 2H).

[0197] Method H. Synthesis of oxazol-5-ylmethyl (4-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)phenyl)carbamate (Compound 59) [ka] To a solution of oxazol-5-ylmethyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (70 mg, 0.20 mmol, 1.00 equiv.), DIEA (77 mg, 0.60 mmol, 3.00 equiv.) in DMF (2 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (86 mg, 0.40 mmol, 2.00 equiv.). The reaction mixture was stirred at room temperature for 4 hours. The mixture was purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile phase A: Water (0.1% formic acid), Mobile phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give the desired product oxazol-5-ylmethyl (4-((1-(2,2-difluoro-213-ethyl)piperidin-4-yl)methyl)phenyl)carbamate as a white solid (35 mg, 46%). LRMS (ES) m / z: 380 [M+H]+ . 1 H NMR (400 MHz, methanol-d4) δ 8.23 ​​(d, J = 2.1 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.15 - 6.98 (m, 2H), 6.09 (t, J = 56 Hz, 1H), 5.24 (d, J = 2.2 Hz, 2H), 3.12 (d, J = 11.7 Hz, 2H), 2.96 (tt, J = 15.4, 2.9 Hz, 2H), 2.52 (d, J = 6.9 Hz, 2H), 2.40 (t, J = 12.0 Hz, 2H), 1.81 - 1.49 (m, 3H), 1.37 (q, J = 12.0 Hz, 2H).

[0198] Method I. Preparation of (4-chlorophenyl)methyl N-(4-{[4-(pyrazin-2-yl)piperazin-1-yl]methyl}phenyl)carbamate (Compound 24) [ka] A mixture of (4-chlorophenyl)methyl N-[4-(piperazin-1-ylmethyl)phenyl]carbamate; trifluoroacetic acid (0.17 g, 0.348 mmol), 2-chloropyrazine (0.08 g, 0.70 mmol), and potassium carbonate (0.24 g, 1.74 mmol) in 1 mL of DMF was stirred at 80 °C. After 18 h, the mixture was diluted with EtOAc, washed with HO, dried (NaSO), concentrated, and purified by preparative HPLC (5-70% ACN / HO) to give a clear foam (44 mg, 0.10 mmol, 29%). LCMS-ES (Pos) m / z: 438 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.30 (d, J = 1.4 Hz, 1H), 8.18 - 7.91 (m, 2H), 7.83 (d, J = 2.6 Hz, 1H), 7.44 (m,, 5H), 7.24 (d, J = 8.3 Hz, 2H), 5.15 (s, 2H), 3.68 - 3.01 (m, 9H), 2.45 (m,, 3H).

[0199] Method J. Synthesis of 4-chlorobenzyl (4-((1-carbamoylpiperidin-4-yl)methyl)phenyl)carbamate (Compound 62) [ka] To a mixture of 4-chlorobenzyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (79 mg, 0.20 mmol, 1.00 equiv.) in DMF (1 mL) and HO (1 mL) was added potassium cyanate (49 mg, 0.60 mmol, 3.00 equiv.). The reaction mixture was stirred at 60° C. for 16 h. HO (10 mL) was added to the mixture. The precipitate was filtered, washed with HO (5 mL), and then dried under high vacuum to give the desired product, 4-chlorobenzyl (4-((1-carbamoylpiperidin-4-yl)methyl)phenyl)carbamate as a white solid (55 mg, 68%). LRMS (ES) m / z: 402 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.46 (s, 4H), 7.36 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 5.82 (s, 2H), 5.14 (s, 2H), 3.88 (d, J = 13.1 Hz, 2H), 2.57 (d, J = 12.5 Hz, 1H), 2.43 (d, J = 7.0 Hz, 3H), 1.76 - 1.39 (m, 3H), 1.15 - 0.76 (m, 2H).

[0200] Method K. Synthesis of oxazol-5-ylmethyl (4-(2-(1-(oxetane-3-carbonyl)piperidin-4-yl)ethyl)phenyl)carbamate (Compound 13) [ka] To a solution of oxetane-3-carboxylic acid (20 mg, 0.20 mmol, 2.00 equiv.) in DMF (1 mL) was added HBTU (57 mg, 0.15 mmol, 1.50 equiv.) and DIEA (30 mg, 0.23 mmol, 2.30 equiv.). The mixture was stirred for 10 minutes. Oxazol-5-ylmethyl (4-(2-(piperidin-4-yl)ethyl)phenyl)carbamate hydrochloride (37 mg, 0.12 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 30 minutes. The mixture was purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30 x 150 mm 5 um; Mobile phase A: Water (0.1% formic acid), Mobile phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give the desired product oxazol-5-ylmethyl (4-(2-(1-(oxetane-3-carbonyl)piperidin-4-yl)ethyl)phenyl)carbamate as a white solid (20 mg, 48%). LRMS (ES) m / z: 414 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.23 ​​(s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.25 (s, 1H), 7.20 - 7.07 (m, 2H), 5.24 (s, 2H), 4.85 - 4.70 (m, 4H), 4.51 (ddt, J = 13.2, 4.6, 2.5 Hz, 1H), 4.16 (h, J = 7.7 Hz, 1H), 3.44 (ddt, J = 13.6, 4.5, 2.4 Hz, 1H), 2.96 (ddd, J = 13.6, 12.5, 2.8 Hz, 1H), 2.72 - 2.54 (m, 3H), 1.80 (ddt, J = 13.2, 8.1, 2.2 Hz, 2H), 1.68 - 1.45 (m, 3H), 1.18 - 1.01 (m, 2H).

[0201] The compounds in the table below were prepared in a manner similar to that of the above examples, using the intermediates along with the alkylation / acylation reagents and methods listed. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12] [Table 14-13] [Table 14-14] [Table 14-15] Table 14-16 Table 14-17 Table 14-18 Table 14-19 Table 14-20 Table 14-21 Table 14-22 Table 14-23 Table 14-24 Table 14-25 Table 14-26 Table 14-27 Table 14-28 Table 14-29 Table 14-30 Table 14-31 Table 14-32 Table 14-33 Table 14-34 Table 14-35 Table 14-36 Table 14-37 Table 14-38 Table 14-39 Table 14-40 Table 14-41 Table 14-42 Table 14-43 Table 14-44 Table 14-45 Table 14-46 Table 14-47 Table 14-48

Table 14-49

[0202] Amide Coupling Example M Preparation of (4-chlorophenyl)methyl N-(4-{[(2-methylpyridin-4-yl)formamido]methyl}phenyl)carbamate (Compound 173) [ka] To a solution of (4-chlorophenyl)methyl N-[4-(aminomethyl)phenyl]carbamate hydrochloride (100 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) in dimethylformamide (1 mL) was added 2-methylpyridine-4-carboxylic acid (96.4 mg, 0.71 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (151.1 mg, 0.40 mmol), stirred at room temperature for 2.5 hours, diluted with water, saturated sodium bicarbonate, and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated, purified by silica gel chromatography using a 0-10% MeOH / DCM gradient, concentrated, and repurified by silica gel chromatography using a 0-100% EtOAc / Hex gradient to give (4-chlorophenyl)methyl N-(4-{[(2-methylpyridin-4-yl)formamido]methyl}phenyl)carbamate (21.0 mg, 0.05 mmol, 17% yield). LCMS-APCI (POS.) m / z: 410.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.19 (t, J = 6.1 Hz, 1H), 8.57 (d, J = 5.1 Hz, 1H), 7.65 (s, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.48 - 7.44 (m, 4H), 7.41 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 5.13 (s, 2H), 4.41 (d, J = 5.9 Hz, 2H), 2.53 (s, 3H).

[0203] The compounds in the table below were prepared in a manner similar to compound 173 using the intermediates and acids listed. [Table 15-1] [Table 15-2] Table 15-3 Table 15-4 Table 15-5 Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16 Table 15-17 Table 15-18 Table 15-19 Table 15-20 Table 15-21 Table 15-22 Table 15-23 Table 15-24 Table 15-25 Table 15-26 Table 15-27 Table 15-28 Table 15-29 Table 15-30 Table 15-31 Table 15-32 Table 15-33 Table 15-34 Table 15-35 Table 15-36 Table 15-37 Table 15-38 Table 15-39 Table 15-40 Table 15-41 Table 15-42 Table 15-43 Table 15-44 Table 15-45 Table 15-46 Table 15-47 Table 15-48 Table 15-49 Table 15-50 Table 15-51 Table 15-52 Table 15-53 Table 15-54 Table 15-55 Table 15-56 Table 15-57 Table 15-58 Table 15-59 Table 15-60 Table 15-61 Table 15-62 Table 15-63 Table 15-64 Table 15-65 Table 15-66 Table 15-67 Table 15-68 Table 15-69 Table 15-70 Table 15-71 Table 15-72 Table 15-73 Table 15-74 Table 15-75 Table 15-76 Table 15-77 Table 15-78 Table 15-79 Table 15-80 Table 15-81 Table 15-82 Table 15-83 Table 15-84 Table 15-85 Table 15-86 Table 15-87 Table 15-88 Table 15-89 Table 15-90 Table 15-91 Table 15-92 Table 15-93 Table 15-94 Table 15-95 Table 15-96 Table 15-97 Table 15-98 Table 15-99 Table 15-100 Table 15-101 Table 15-102 Table 15-103 Table 15-104 Table 15-105 Table 15-106 Table 15-107 Table 15-108 Table 15-109

Table 15-110

[0204] Urea synthesis Example N Preparation of (4-chlorophenyl)methyl N-{4-[(morpholine-4-carbonylamino)methyl]phenyl}carbamate (Compound 270). [ka] To a solution of (4-chlorophenyl)methyl N-[4-(aminomethyl)phenyl]carbamate hydrochloride (100 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.22 mmol) in acetonitrile (1 mL) and DCM (1 mL), morpholine (0.14 mL, 1.83 mmol) and carbonyldiimidazole (178.4 mg, 1.1 mmol) were added. The mixture was stirred at 24 °C for 15 h, concentrated, and purified by reverse-phase preparative HPLC using a 3-40% water / acetonitrile gradient containing 0.1% formic acid to give the product (4-chlorophenyl)methyl N-{4-[(morpholine-4-carbonylamino)methyl]phenyl}carbamate (61.0 mg, 0.15 mmol, 49% yield). LCMS-APCI (POS.) m / z: 404.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.49 - 7.42 (m, 4H), 7.37 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.02 (t, J = 6.2 Hz, 1H), 5.13 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 3.56 - 3.51 (m, 4H), 3.30 - 3.24 (m, 4H).

[0205] The compounds in the table below were prepared in a manner similar to compound 270 using the intermediates and amines listed. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] [Table 16-12] [Table 16-13] [Table 16-14] [Table 16-15] [Table 16-16] [Table 16-17] [Table 16-18]

[0206] Ester hydrolysis and amide synthesis Example O Preparation of (4-chlorophenyl)methyl N-{4-[2-(4-hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl]phenyl}carbamate (Compound 116) Step 1: Preparation of [4-({[(4-chlorophenyl)methoxy]carbonyl}amino)phenyl]acetic acid [ka] A mixture of ethyl 2-[4-({[(4-chlorophenyl)methoxy]carbonyl}amino)phenyl]acetate, 150 mL of EtOH, and 150 mL of 1N NaOH was stirred at room temperature for 18 hours. The mixture was concentrated, acidified to pH=2 with 2N HCl, filtered, and dried in vacuo to give an off-white solid (5.96 g, 67%). LCMS-ES (Pos) m / z: 320 [M+H] + .

[0207] Step 2: Preparation of (4-chlorophenyl)methyl N-{4-[2-(4-hydroxy-4-methylpiperidin-1-yl)-2-oxoethyl]phenyl}carbamate [ka] A mixture of [4-({[(4-chlorophenyl)methoxy]carbonyl}amino)phenyl]acetic acid (150 mg, 0.47 mmol, 1 equiv.), 4-methylpiperidin-4-ol (54 mg, 0.47 mmol, 1 equiv.), HATU (214 mg, 0.563 mmol, 1.2 equiv.), DIEA (0.123 mL, 0.704 mmol, 1.5 equiv.) and DMF (1 mL) was stirred at room temperature for 1 h. The mixture was purified by preparative HPLC to give a light brown solid. LCMS-ES (Pos) m / z: 417 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.46 (d, J = 1.8 Hz, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.14 (s, 2H), 4.34 (s, 1H), 3.91 (d, J = 13.1 Hz, 1H), 3.57 (d, J = 13.3 Hz, 1H), 3.33 (s, 2H), 3.33 - 3.25 (m, 1H), 3.04 (t, J = 11.9 Hz, 1H), 1.41 (d, J = 15.1 Hz, 1H), 1.38 - 1.17 (m, 2H), 1.09 (s, 2H).

[0208] The compounds in the table below were prepared in a similar manner to compound 116 using intermediate 21.2 and the listed amine. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8] [Table 17-9] [Table 17-10] [Table 17-11] [Table 17-12] [Table 17-13] [Table 17-14] [Table 17-15] [Table 17-16] [Table 17-17] [Table 17-18] [Table 17-19] [Table 17-20] [Table 17-21] [Table 17-22]

[0209] Example P Preparation of (4-chlorophenyl)methyl N-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}carbamate (Compound 344) [ka] To a solution of [4-({[(4-chlorophenyl)methoxy]carbonyl}amino)phenyl]acetic acid (148 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.85 mmol) in DMF (1.5 mL) was added (Z)-N'-hydroxyethanimidamide (44.6 mg, 0.60 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (228.8 mg, 0.60 mmol). The mixture was stirred at room temperature for 1.5 h, diluted with water, saturated sodium bicarbonate, and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated, and used without further purification. To a crude solution of (Z)-(1-aminoethylidene)amino 2-[4-({[(4-chlorophenyl)methoxy]carbonyl}amino)phenyl]acetate (173.9 mg, 0.46 mmol) in THF (3 mL) was added DBU (0.21 mL, 1.39 mmol). The mixture was stirred at 50 °C for 16 h, cooled, filtered, and purified by reverse-phase preparative HPLC using a 3-40% water / acetonitrile gradient containing 0.1% formic acid to give the product (4-chlorophenyl)methyl N-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}carbamate (13 mg, 0.04 mmol, 8% yield) in two steps. LCMS-APCI (POS.) m / z: 358.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.49 - 7.44 (m, 4H), 7.43 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.13 (s, 2H), 4.21 (s, 2H), 2.29 (d, J = 2.4 Hz, 3H).

[0210] LHS sulfonamide synthesis Example Q Preparation of 4-chlorobenzyl (4-(N-methyl-N-(oxetan-3-yl)sulfamoyl)phenyl)carbamate (Compound 352) [ka] A mixture of (4-chlorophenyl)methyl N-[4-(chlorosulfonyl)phenyl]carbamate (50 mg, 0.14 mmol, 1.0 equiv.), triethylamine (0.028 g, 0.27 mmol, 2.0 equiv.), and amine (1.5 equiv.) was stirred in DCM (1 mL) for 30 min. The reaction mixture was concentrated, resuspended in MeOH, and purified by reverse-phase HPLC, eluting with 0-95% acetonitrile:water containing 0.1% formic acid, to give the desired product. LCMS-APCI (POS.) m / z: 411.1 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.68 (s, 4H), 7.47 (d, J = 2.1 Hz, 4H), 5.18 (s, 2H), 4.54 (s, 4H), 3.17 (d, J = 5.2 Hz, 1H), 2.66 (s, 3H).

[0211] The compounds in the table below were prepared in an analogous manner to compound 352 using intermediate 22.1 and the listed amine. [Table 18-1] [Table 18-2]

[0212] Example R Preparation of oxazol-5-ylmethyl (4-((1-(dimethylcarbamoyl)piperidin-4-yl)methyl)phenyl)carbamate (compound 30) Step 1: Preparation of tert-butyl 4-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)benzyl)piperidine-1-carboxylate: [ka] To a solution of triphosgene (2.38 g, 8.0 mmol) in DCM (100 mL) at 0 °C was added a mixture of tert-butyl 4-(4-aminobenzyl)piperidine-1-carboxylate (5.81 g, 20.0 mmol), DIEA (5.68 g, 44.0 mmol), and DMAP (2.22 g, 20.0 mmol) in DCM (100 mL). The mixture was stirred at 0 °C for 5 min, and oxazol-5-ylmethanol (2.58 g, 26.0 mmol) was added. The resulting mixture was stirred at 24 °C for 1 h and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:1) to give the desired product as a white solid (7.1 g, 85.4%). LRMS (ES) 416.1 [M+H] + .

[0213] Step 2: Preparation of oxazol-5-ylmethyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride [ka] To a mixture of tert-butyl 4-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)benzyl)piperidine-1-carboxylate (7.1 g, 17.1 mmol) in MeOH (10 mL) was added 4 M HCl / dioxane (36 mL, 144 mmol). The reaction mixture was stirred at 24° C. for 2 h and concentrated to dryness to give the crude product as a white solid (6.01 g, 100%). LRMS (m / z): 316.1 [M+H] + .

[0214] Step 3: Preparation of oxazol-5-ylmethyl (4-((1-(dimethylcarbamoyl)piperidin-4-yl)methyl)phenyl)carbamate [ka] To a mixture of oxazol-5-ylmethyl (4-(piperidin-4-ylmethyl)phenyl)carbamate hydrochloride (1.97 g, 5.6 mmol) and DIEA (1.81 g, 14.0 mmol) in DCM at 0° C. was added dimethylcarbamoyl chloride (0.66 g, 6.16 mmol) dropwise. The reaction mixture was warmed to 24° C. and stirred for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with EtOAc to give the desired product as a white solid (1.66 g, 76.7%). LRMS (m / z): 387.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.24 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.18 - 6.98 (m, 2H), 5.24 (s, 2H), 3.64 (d, J = 13.0 Hz, 2H), 2.82 (d, J = 1.4 Hz, 6H), 2.72 (td, J = 12.8, 2.3 Hz, 2H), 2.52 (d, J = 6.9 Hz, 2H), 1.76 - 1.56 (m, 3H), 1.28 - 1.12 (m, 2H).

[0215] Example S Preparation of oxazol-5-ylmethyl (R)-(4-(1-(dimethylcarbamoyl)piperidin-3-yl)phenyl)carbamate (compound 376) Step 1: Preparation of tert-butyl (R)-3-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)phenyl)piperidine-1-carboxylate: [ka] To a mixture of triphosgene (0.715 g, 2.41 mmol) in 60 mL of acetonitrile at 0° C. was added a mixture of tert-butyl (R)-3-(4-aminophenyl)piperidine-1-carboxylate (2.00 g, 7.24 mmol) and N,N-diisopropylethylamine (1.87 g, 14.47 mmol) in 40 mL of MeCN. The mixture was stirred at 0° C. for 15 minutes, warmed to 24° C., and then a mixture of DMAP (44 mg, 0.362 mmol, 0.05 equiv.) and 1,3-oxazol-5-ylmethanol (790 mg, 8.00 mmol) in MeCN (10 mL) was added. The mixture was stirred at 24° C. for 16 hours and at 50° C. for 1 hour. The reaction mixture was cooled and concentrated. The mixture was dissolved in 150 mL of dichloromethane, washed with 0.5 N HCl, brine, dried (Na2SO4), and concentrated to give the crude product as an off-white foam (2.91 g), which was used in the next reaction without further purification. LRMS (ES) 402.2 [M+H] + .

[0216] Step 2: Preparation of oxazol-5-ylmethyl (R)-(4-(piperidin-3-yl)phenyl)carbamate hydrochloride [ka] To a mixture of tert-butyl (R)-3-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)phenyl)piperidine-1-carboxylate (2.90 g, 7.20 mmol) in THF (36 mL) was added 4 M HCl / dioxane (36 mL, 144 mmol). The reaction mixture was stirred at 24° C. for 16 h, filtered, and washed with EtOAc (2×30 mL) to give the crude product as an off-white solid in quantitative yield. LRMS (m / z): 302.1 [M+H] + .

[0217] Step 3: Preparation of oxazol-5-ylmethyl (R)-(4-(1-(dimethylcarbamoyl)piperidin-3-yl)phenyl)carbamate [ka] To a mixture of (3R)-3-(4-{[(1,3-oxazol-5-ylmethoxy)carbonyl]amino}phenyl)piperidin-1-ium chloride (243 mg, 0.72 mmol, 1 equiv.), N,N-diisopropylethylamine (0.5 mL, 2.88 mmol, 4 equiv.) and DCM (5 mL) was added dimethylcarbamyl chloride (1.17 mmol) dropwise, and the mixture was stirred at 24 °C for 2 h, diluted with 5 mL of DCM, washed with 0.5 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile phase A: Water (0.1% formic acid), Mobile phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give oxazol-5-ylmethyl (R)-(4-(1-(dimethylcarbamoyl)piperidin-3-yl)phenyl)carbamate as a white solid (0.15 g, 56%). LRMS (m / z): 373.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.43 (s, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 3.55 (dd, J = 22.5, 12.0 Hz, 2H), 2.73 (s, 6H), 2.74 - 2.66 (m, 2H), 2.64 (d, J = 12.0 Hz, 1H), 1.87 (d, J = 11.0 Hz, 1H),

[0218] Example T Preparation of oxazol-5-ylmethyl (4-(1-isobutyrylpiperidin-4-yl)phenyl)carbamate (compound 7) Step 1: Preparation of tert-butyl 4-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)phenyl)piperidine-1-carboxylate [ka] To a mixture of triphosgene (1.48 g, 5.00 mmol) in 150 mL of acetonitrile at 0° C. was added a mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (4.15 g, 15.0 mmol) and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) in 100 mL of acetonitrile. The mixture was stirred at 0° C. for 15 minutes and then warmed to 24° C., followed by the addition of a mixture of DMAP (92 mg, 0.75 mmol) and 1,3-oxazol-5-ylmethanol (1.82 g, 18.0 mmol) in MeCN (25 mL). The mixture was stirred at 24° C. for 16 hours, then at 50° C. for 1 hour, and then concentrated. The mixture was dissolved in 350 mL of dichloromethane, washed with 0.5 N HCl, brine, dried (Na2SO4), and concentrated to give the crude product as an off-white foam (6.00 g), which was used in the next reaction without further purification. LRMS (ES) 402.2 [M+H] + .

[0219] Step 2: Preparation of oxazol-5-ylmethyl (4-(piperidin-4-yl)phenyl)carbamate hydrochloride [ka] To a mixture of tert-butyl 4-(4-(((oxazol-5-ylmethoxy)carbonyl)amino)phenyl)piperidine-1-carboxylate (5.80 g, 14.4 mmol) in THF (72 mL) was added 4 M HCl / dioxane (72 mL, 288 mmol). The reaction mixture was stirred at 24° C. for 16 h, filtered, and washed with EtOAc (2×60 mL) to give the desired crude product, observed as an off-white solid in quantitative yield. LRMS (m / z): 302.1 [M+H] + .

[0220] Step 3: Preparation of oxazol-5-ylmethyl (4-(1-isobutyrylpiperidin-4-yl)phenyl)carbamate [ka] To a mixture of oxazol-5-ylmethyl (4-(piperidin-4-yl)phenyl)carbamate hydrochloride (0.74 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.88 mmol) in dichloromethane (5 mL) was added isobutyl chloride (0.095 g, 0.89 mmol) dropwise. The mixture was stirred at 24 °C for 2 h, diluted with 5 mL of DCM, washed with 0.5 N HCl, saturated NaHCO3, and brine, respectively, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC using the following conditions (Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile phase A: Water (0.1% formic acid), Mobile phase B: MeCN (0.1% formic acid); Flow rate: 20 mL / min) to give oxazol-5-ylmethyl (4-(1-isobutyrylpiperidin-4-yl)phenyl)carbamate as a white solid (0.15 g, 55%). LRMS (m / z): 372.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.42 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.30 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 4.55 (d, J = 12.8 Hz, 1H), 4.05 (d, J = 13.4 Hz, 1H), 3.09 (t, J = 12.9 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.69 (d, J = 12.1 Hz, 1H), 2.58 (d, J = 12.7 Hz, 1H), 1.78 (t, J = 17.1 Hz, 2H), 1.52 - 1.34 (m, 2H), 1.01 (d, J = 6.6 Hz, 6H).

[0221] Synthesis of comparative compound urea Example U Preparation of 1-(4-chlorobenzyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea (Comparative Compound 1) Step 1: Preparation of tert-butyl 4-(4-(3-(4-chlorobenzyl)ureido)benzyl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-aminobenzyl)piperidine-1-carboxylate (0.55 g, 1 eq.) and 1-chloro-4-(isocyanatomethyl)benzene (1.5 eq.) in DCM (3 mL) was stirred at 24 °C for 1 h and purified by silica gel chromatography (50% EtOAc / hexanes) to give tert-butyl 4-(4-(3-(4-chlorobenzyl)ureido)benzyl)piperidine-1-carboxylate (0.84 g, 96.8% yield). LRMS (ES) 403.1 288.1 [M+H-Bu] + .

[0222] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride [ka] To a mixture of tert-butyl 4-(4-(3-(4-chlorobenzyl)ureido)benzyl)piperidine-1-carboxylate (0.84 g, 1 eq.) in MeOH (1 mL) at 0° C., 4 M HCl in dioxane (12 eq.) was added, and the mixture was stirred at 24° C. for 1 h and concentrated to give 1-(4-chlorobenzyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride (0.72 g, 99.6% yield), which was used in the next reaction without further purification. LRMS (ES) 358.1 [M+H].

[0223] Step 3: Preparation of 1-(4-chlorobenzyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea [ka] To a mixture of 1-(4-chlorobenzyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride (0.47 g, 1 equiv.) and oxetan-3-one (2 equiv.) in DCM (3 mL) was added Na(OAc)BH (2.2 equiv.) and DIPEA (1 equiv.). The reaction mixture was stirred at 24 °C for 16 h, quenched with saturated NaHCO (5 mL), and extracted twice with DCM (5 mL). The organic layers were combined, concentrated, and purified by HPLC (10% AcCN) to give 1-(4-chlorobenzyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea (0.27 g, 53.3% yield). LRMS (ES) 414.1 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.00 (d, J = 8.3 Hz, 2 H), 6.59 (t, J = 6.0 Hz, 1 H), 4.49 (t, J = 6.4 Hz, 2 H), 4.38 (t, J = 6.1 Hz, 2 H), 4.27 (d, J = 6.0 Hz, 2 H), 3.30 (p, J = 6.5 Hz, 1 H), 2.63 (d, J = 11.0 Hz, 2H), 2.41 (d, J = 6.9 Hz, 2 H), 1.64 (t, J = 11.2 Hz, 2 H), 1.53 (d, J = 11.4 Hz, 2 H), 1.48-1.35 (m, 1 H), 1.15 (qd, J = 12.1, 3.7 Hz, 2 H).

[0224] The compounds in the table below were prepared in a similar manner to Comparative Compound 1 using the intermediates along with the alkylation / acylation reagents and methods listed. [Table 19-1] [Table 19-2]

[0225] Example V Preparation of 1-(oxazol-5-ylmethyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea (Comparative Compound 4) Step 1: Preparation of tert-butyl 4-(4-isocyanatobenzyl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-aminobenzyl)piperidine-1-carboxylate (2.4 g, 1 eq) and saturated NaHCO in DCM (50 mL) was stirred at 0° C. Triphosgene (0.33 eq) in DCM (10 mL) was added and the mixture was stirred at 0° C. for 15 min. The organic layer was dried to give tert-butyl 4-(4-isocyanatobenzyl)piperidine-1-carboxylate, which was used in the next reaction without further purification.

[0226] Step 2: Preparation of tert-butyl 4-(4-(3-(oxazol-5-ylmethyl)ureido)benzyl)piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-(4-isocyanatobenzyl)piperidine-1-carboxylate (2.6 g, 1 eq.) in DCM was added oxazol-5-ylmethanamine hydrochloride (1.5 eq.) and DIPEA (1.5 eq.). The mixture was stirred at 24 °C for 1 h, washed with 1 N HCl, brine, dried over Na SO , and concentrated to give tert-butyl 4-(4-(3-(oxazol-5-ylmethyl)ureido)benzyl)piperidine-1-carboxylate. LRMS (ES) 359.1 [M+H].

[0227] Step 3: Preparation of 1-(oxazol-5-ylmethyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride [ka] A mixture of tert-butyl 4-(4-(3-(oxazol-5-ylmethyl)ureido)benzyl)piperidine-1-carboxylate in MeOH was cooled to 0° C., followed by the addition of 4 M HCl in dioxane (12 equiv.), stirring at 24° C. for 1 h, and concentration to give 1-(oxazol-5-ylmethyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride, which was used in the next reaction without further purification. LRMS (ES) 315.1 [M+H].

[0228] Step 4: Preparation of 1-(oxazol-5-ylmethyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea [ka]

[0229] A mixture of 1-(oxazol-5-ylmethyl)-3-(4-(piperidin-4-ylmethyl)phenyl)urea hydrochloride (150 mg, 1 equiv.) and oxetan-3-one (1 equiv.) in DMF (1 mL) was stirred at 24° C. for 20 min. Sodium triacetoxyborohydride (2.2 equiv.) was added and the mixture was stirred for 1 h. The mixture was filtered and purified by preparative HPLC to give 1-(oxazol-5-ylmethyl)-3-(4-((1-(oxetan-3-yl)piperidin-4-yl)methyl)phenyl)urea (49 mg, 31% yield). LRMS (ES) 371.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.7 Hz, 3H), 6.55 (t, J = 5.9 Hz, 1H), 4.48 (t, J = 6.5 Hz, 2H), 4.43 - 4.29 (m, 4H), 3.29 (d, J = 7.5 Hz, 1H), 2.62 (d, J = 11.1 Hz, 2H), 2.41 (d, J = 6.9 Hz, 2H), 1.64 (t, J = 11.4 Hz, 2H), 1.52 (d, J = 12.9 Hz, 2H), 1.41 (s, 1H), 1.16 (t, J = 11.9 Hz, 2H).

[0230] The compounds in the table below were prepared in a similar manner to Comparative Compound 4, using the intermediates along with the alkylation / acylation reagents and methods listed. [Table 20-1] [Table 20-2]

[0231] Biological Example 1 NMN fluorescent biochemical assay Human Recombinant Enzyme Assay The compounds described herein were assayed for their ability to stimulate the synthesis of nicotinamide mononucleotide (NMN) by the enzyme NAMPT. The human recombinant enzyme assay measures compound-mediated activation of enzyme activity using recombinant enzyme and substrate in a buffered, cell-free system. The assay conditions closely mimic the cellular environment. The assay was used to detect the formation of nicotinamide mononucleotide and measure dose response. All experiments were performed in a 384-well format. Generally, 0.5 μL of DMSO containing various concentrations of test compound was mixed with 10 μL of enzyme reagent solution. The enzyme reaction was initiated by the addition of 10 μL of a solution containing the substrate. The final assay conditions were as follows: 6 nM human NAMPT, 2.5 mM ATP, 20 μM PRPP, and 150 μM nicotinamide in 50 mM HEPES, pH 7.2, 1 mM DTT, 1 mM CHAPS, 50 mM NaCl, and 100 mM MgCl2. After 60 minutes of incubation at ambient temperature, 10 μL of 20% acetophenone in DMSO was added, followed by 10 μL of 2 M KOH and 40 μL of formic acid. After 40 minutes of incubation at ambient temperature, the plates were read for fluorescence (excitation / emission = 355 nm / 460 nm) using an EnVision plate reader. Compound potency measurements were quantified and AC 1.4 (the concentration of the compound that produces an activity 40% higher than the basal value) and EC 50 The AC values ​​were expressed as (the concentration of compound that produced half-maximal activation). Table A shows the AC values ​​for the compounds tested. 1.4 and EC 50 Show the data. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8] [Table A-9] [Table A-10] [Table A-11] [Table A-12] [Table A-13]

[0232] Biological Example 2 MDR1-MDCK bidirectional permeability assay The blood-brain barrier (BBB) ​​is composed of brain capillary endothelial cells, which are characterized by highly developed tight junctions. The BBB plays a critical role in drug brain penetration and poses an obstacle to drug discovery when the drug target is located in the central nervous system (CNS). P-glycoprotein (P-gp, MDR1) is highly expressed at the BBB and functions to actively efflux drugs from the brain, potentially limiting brain penetration of drugs with desired targets. Bidirectional permeability assays using Madin-Darby canine kidney cells expressing multidrug resistance gene 1 (MDCK-MDR1) are routinely used to evaluate BBB permeability and drug efflux of discovery compounds toward the advancement of discovery compounds with brain penetration.

[0233] MDCK-MDR1 cells (NIH cell line) were obtained from the National Institutes of Health. MDCK-MDR1 cells were diluted to 1.56 million cells / mL (NIH) with culture medium, and 50 μL of the cell suspension was dispensed into the filter wells of a 96-well HTS Transwell plate. Cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 4–8 days. Cell culture medium was changed every other day, starting within 24 h of initial plating. The buffer used for the permeability assay was Hank's balanced salt solution, pH 7.4, containing 10 mM HEPES. The concentration of the test article dosing solution in the assay buffer was 1 μM. Cell monolayers were dosed apically (A to B) or basolaterally (B to A) and incubated at 37°C in a humidified incubator under a 5% CO2 atmosphere. Samples were collected from the donor and receiver chambers at 120 min. Each measurement was performed in duplicate. After a 120-minute transport period, the flux of Lucifer Yellow was also measured per monolayer to ensure that the cell monolayer was not damaged during the transport period. All samples were evaluated by LC-MS / MS (Waters XSelect HSS T3 C18, 2.5 μm, 2.1 × 50 mm) using electrospray ionization with 0.1% formic acid in water (mobile phase A) and 0.1% formic acid in acetonitrile (mobile phase B) as the mobile phases. For MDCK-MDR1 cell (NIH cell line) drug transport assays, the apparent permeability coefficient (Papp) in units of cm per second was calculated using the following equation: Papp=(V A ×[drugs] アクセプター ) / (area × time × [drug] 初期,ドナー ) In the formula, V A is the volume in the acceptor well (mL), and area is the surface area of ​​the membrane (0.143 cm for Transwell-96 Well permeable support). 2 ) and time is the total transport time in seconds. The discharge ratio (ER) is P app (B→A) / P app It is defined as (A→B). The leakage of Lucifer Yellow (LY) in percentage (%) can be calculated using the following formula: %LY leakage=100×[LY] アクセプター / ([LY] ドナー +[LY] アクセプター ) <1% LY leakage is within the acceptable range to indicate a fully competent MDCK-MDR1(NIH) monolayer.

[0234] The following comparative compounds were made using the procedures described above. [ka] The results are shown in Table B. [Table B-1] [Table B-2]

[0235] Biological Example 3 Brain exposure assay in mice This protocol was used to determine the in vivo brain-to-plasma ratio in mice after oral administration of a test compound. Mice (C57BL / 6JNIFDC, male, non-fasted, 18-30 g body weight, 3 mice per time point) were orally administered 100 mg / kg (10 mg test compound / mL formulation, 10 mL administration volume / kg), and plasma and brain tissue were collected 2 and 6 hours after administration. The composition of the oral administration formulation used was 10% N,N-dimethylacetamide: 20% propylene glycol: 70% 40% 2-hydroxypropyl-β-cyclodextrin in water.

[0236] To isolate mouse plasma from treated animals, approximately 0.3 mL of blood was collected by bleeding from the orbital sinus and centrifuged (4000 g, 5 min, 4° C.) Plasma samples were stored frozen at −75±15° C. until further processing.

[0237] To isolate brain tissue from administered animals, whole brain tissue was collected from euthanized and completely exsanguinated mice. The tissue was quickly rinsed with distilled water, dried using absorbent paper, then quickly frozen on dry ice, and then stored frozen at -75±15°C until further processing. Brain tissue samples obtained from frozen whole brains were weighed, and the samples were homogenized using 3 equivalents of distilled water (3 mL per gram of brain tissue).

[0238] Standard and quality control samples were prepared by adding 3 μL of test compound dimethyl sulfoxide (DMSO) stock solution to blank plasma (30 μL) and blank brain homogenate aliquots (30 μL). Brain and plasma standard curves were generated over a test compound concentration range of 1 to 1,000 ng / g. To extract the test compound from plasma and brain tissue homogenate samples, acetonitrile solution containing the internal standard (400 μL) was added to 30 μL of sample with 3 μL of DMSO added. The sample was then vortex-mixed and subsequently centrifuged at 4,000 rpm (4°C, 15 min). The resulting supernatant was diluted 5-fold with distilled water. Finally, 10 μL of the diluted supernatant was injected into an LC-MS / MS instrument for quantitative analysis of the test compound.

[0239] Brain tissue concentrations were calculated by multiplying the concentration of drug detected in the homogenized brain tissue samples by a dilution factor of four.

[0240] The brain-to-plasma ratio can be calculated using the relationship: brain-to-plasma ratio = C 脳 / C 血漿 The calculation was carried out by: b is the concentration in brain tissue at the corresponding time point, and C p is the concentration in plasma.

[0241] Kp is the total brain-to-plasma concentration ratio, K p =C 脳 / C 血漿 is.

[0242] Kp,uu is the unbound brain-to-plasma partition coefficient (K p,uu,脳) is a measure of the degree of equilibrium of distribution of a compound between the unbound (free) fractions in the brain and plasma, and is p,uu脳 =C u,脳 / C u,血漿である。

[0243] A compound is estimated to be "brain-penetrant" if it has a brain-to-plasma concentration ratio >0.04, since cerebral blood volume is estimated to be 4% of the total brain volume (Shaffer CL (2010), Defining Neuropharmacokinetic Parameters in CNS Drug Discovery to Determine Cross-Species Pharmacologic Exposure-Response Relationships, Annual Reports in Medicinal Chemistry, 45:55-70, https: / / doi.org / 10.1016 / S0065-7743(10)45004-6). [Table 21-1] [Table 21-2] [Table 21-3]

[0244] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference.

[0245] While the disclosure provided herein has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

Claims

1. Compounds of formula (I): 【Chemistry 448】 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring selected from the group consisting of: i) 1 to 4 R Ａ or a 5-6 membered heteroaryl optionally substituted with ii) 【Chemistry 449】 and Each R Ａ are independently selected from the group consisting of: halogen; Cyano; C optionally substituted with 1 to 3 independently selected halogens or —OH １ -C ６ Alkyl; -O(C optionally substituted with 1 to 3 independently selected halogens) １ -C ６ alkyl); and -C(O)NR Ａ１ R Ａ２ , where R Ａ１ and R Ａ２ are each independently hydrogen or C １ -C ６ is alkyl; R Ｄ is selected from the group consisting of: halogen; Cyano; C optionally substituted with 1 to 3 independently selected halogens or —OH １ -C ６ Alkyl; -O(C optionally substituted with 1 to 3 independently selected halogens) １ -C ６ alkyl); and -C(O)NR Ａ１ R Ａ２ , where R Ａ１ and R Ａ２ are each independently hydrogen or C １ -C ６ is alkyl; L is a bond, C １ -C ６ alkylene, #-O-(C １ -C ６ alkylene)-$,#-C(O)-(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-C(O)-$, #-N(R Ｌ )-(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-N(R Ｌ )-$, #-(C １ -C ６ alkylene)-N(R Ｌ )-(C １ -C ６ alkylene)-$, #-C(O)-N(R Ｌ )-(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-C(O)-N(R Ｌ )-$, #-N (R Ｌ )—C(O)—CH ２ -$, #-(C １ -C ６ alkylene)-N(R Ｌ )-C(O)-$, #-(C １ -C ６ alkylene)-C(O)-N(R Ｌ )-(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-N(R Ｌ )-C(O)-(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-N(R Ｌ )-S(O) ２ -$, #-N (R Ｌ )-S(O) ２ -(C １ -C ６ alkylene)-$, #-(C １ -C ６ alkylene)-S(O) ２ -N(R Ｌ )-$, #-S(O) ２ -N(R Ｌ )-(C １ -C ６ Alkylene)-$, #-S(O) ２ -N(R Ｌ )-$, and #-N(C １ -C ６ alkyl)-S(O) ２ -$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; Here, each C of L １ -C ６ Alkylene is substituted with halogen, —OH, and C １ -C ６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Here, each R Ｌ are independently hydrogen or C １ -C ６ is alkyl; Ring B is a 4- to 10-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, a 5- to 6-membered heteroaryl, or phenyl; Each R Ｂ are independently selected from the group consisting of: halogen; -OH; oxo; Cyano; phenyl or —O(C) optionally substituted with 1 to 3 independently selected halogens; １ -C ６ alkyl); -C(O)(C １ -C ６ alkyl); -C(O)O(C １ -C ６ alkyl); Phenyl; 5-6 membered heteroaryl; 4-8 membered heterocycloalkyl; 3- to 8-membered cycloalkyl; -C(O)(3- to 8-membered cycloalkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(4-8 membered heterocycloalkyl) optionally substituted with 1-3 independently selected halogens; -S(O) ２ (C １ -C ６ alkyl); -S(O) ２ (3- to 8-membered cycloalkyl); -S(O) ２ (4-8 membered heterocycloalkyl); -C(O)NR Ｂ１ R Ｂ２ ; -S(O) ２ NR Ｂ１ R Ｂ２ ; -NR Ｃ１ S(O) ２ NR Ｂ１ R Ｂ２ ; -(C=N-R Ｃ１ )-NR Ｂ１ R Ｂ２ ; -NR Ｃ１ -(C=N-R Ｃ１ )-NR Ｂ１ R Ｂ２ ; -NR Ｃ１ -(C=N-CN)-NR Ｂ１ R Ｂ２ and Halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl １ -C ６ Alkyl; Here, R Ｃ１ , R Ｂ１ and R Ｂ２ are each independently hydrogen or C １ -C ６ is alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, or 5; R Ｃ is halogen, cyano, C １ -C ６ Alkyl, OH, —O(C １ -C ６ alkyl), or 3- to 8-membered cycloalkyl; and p is 0, 1, 2, 3 or 4; During the ceremony, a) When L is a bond, ring B is [Chemical 450] selected from the group consisting of: b) When ring B is pyridin-4-yl and A is phenyl, R Ｄ is selected from the group consisting of carbamoyl, chloro, hydroxymethyl, difluoromethyl, methoxy, and cyano; and c) L is -CH ２ -CH ２ -, then n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

2. Ring A is 【Chemistry 451】 2. The compound of claim 1, wherein:

3. R Ｄ is a halogen or —O(C) optionally substituted with 1 to 3 independently selected halogens. １ -C ６ 3. The compound of claim 1 or 2, wherein R is 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R Ｄ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is halogen.

5. R Ｄ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is fluorine.

6. R Ｄ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is chlorine.

7. Ring A is a ring having 1 to 4 R Ａ 2. The compound of claim 1, wherein R is 5-6 membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

8. Ring A is a ring having 1 to 4 R Ａ 8. The compound of claim 1, wherein R is 5-membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

9. Ring A is oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, or isoxazolyl, each of which is selected from 1 to 3 R Ａ 9. The compound of any one of claims 1, 7, or 8, optionally substituted with: or a pharmaceutically acceptable salt thereof.

10. Ring A is a ring having 1 to 2 R Ａ 10. The compound of claim 1, or any one of claims 7 to 9, wherein R is 1 or 2, or a pharmaceutically acceptable salt thereof.

11. Ring A is a ring having 1 to 2 R Ａ 11. The compound of claim 1, or any one of claims 7 to 10, which is oxazol-5-yl optionally substituted by: or a pharmaceutically acceptable salt thereof.

12. Ring A is a ring having 1 to 2 R Ａ 10. The compound of claim 1, or any one of claims 7 to 9, which is thiazolyl optionally substituted with: or a pharmaceutically acceptable salt thereof.

13. Ring A is a ring having 1 to 4 R Ａ 8. The compound of claim 1 or 7, wherein R is 6-membered heteroaryl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

14. Ring A is pyridinyl, pyridazinyl, or pyrimidinyl, each of which is selected from 1 to 4 R Ａ 14. The compound of any one of claims 1, 7, or 13, optionally substituted with: or a pharmaceutically acceptable salt thereof.

15. Ring A is a ring having 1 to 4 R Ａ 15. The compound of any one of claims 1, 7, 13, or 14, wherein R is pyridinyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

16. Ring A is a ring having 1 to 4 R Ａ 16. The compound of any one of claims 1, 7, or 13-15, wherein R is pyridin-4-yl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

17. Each R Ａ is halogen and C １ -C ６ The compound of any one of claims 1 to 16, wherein the compound is independently selected from the group consisting of alkyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 4- to 8-membered heterocycloalkyl, a 3- to 8-membered cycloalkyl, or a 5- to 6-membered heteroaryl.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, oxazolyl, or pyrazolyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein ring B is pyridinyl, piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

21. Ring B is 【Chemistry 452】 19. The compound according to any one of claims 1 to 18, wherein:

22. Each R Ｂ are independently selected from the group consisting of: halogen; oxo; phenyl or —O(C) optionally substituted with 1 to 3 independently selected halogens; １ -C ６ alkyl); Halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C １ -C ６ C optionally substituted with 1 to 5 substituents independently selected from １ -C ６ Alkyl; -S(O) ２ (C １ -C ６ alkyl); -S(O) ２ (4-8 membered heterocycloalkyl); -S(O) ２ (3- to 8-membered cycloalkyl); -S(O) ２ NR Ｂ１ R Ｂ２ ; -C(O)NR Ｂ１ R Ｂ２ ; -C(O)(C １ -C ６ alkyl); -C(O)O(C １ -C ６ alkyl); -C(O)(3- to 8-membered cycloalkyl) optionally substituted with 1 to 3 independently selected halogens; -C(O)(4-8 membered heterocycloalkyl) optionally substituted with 1-3 independently selected halogens; 4- to 8-membered heterocycloalkyl; and 22. A 5- to 6-membered heteroaryl, a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

23. Each R Ｂ is oxo, -C(O)(C １ -C ６ alkyl), —C(O)NR Ｂ１ R Ｂ２ , -S(O) ２ (C １ -C ６ alkyl), -S(O) ２ NR Ｂ１ R Ｂ２ , unsubstituted C １ -C ６ 23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each of the aryl groups is independently selected from the group consisting of alkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.

24. Each R Ｂ is phenyl or —O(C １ -C ４ alkyl); and Halogen, —OH, 4- to 8-membered heterocycloalkyl, and —O(C １ -C ４ C optionally substituted with 1 to 5 substituents independently selected from １ -C ４ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

25. Each R Ｂ is oxo, -C(O)(C １ -C ３ alkyl), —C(O)N(Me) ２ , —C(O)(4- to 8-membered heterocycloalkyl) optionally substituted with 1 to 3 independently selected halogens, —C(O)(3- to 8-membered cycloalkyl) optionally substituted with 1 to 3 independently selected halogens; —S(O) ２ (C １ -C ３ alkyl), -S(O) ２ N (Me) ２ , -C(O)O(C １ -C ４ alkyl), -S(O) ２ (4- to 8-membered heterocycloalkyl), —S(O) ２ 23. The compound according to any one of claims 1 to 22, wherein each of the groups is independently selected from the group consisting of (3- to 4-membered cycloalkyl), methyl, oxetanyl, and pyridinyl, or a pharmaceutically acceptable salt thereof.

26. L is a bond, C １ -C ６ Alkylene, #-C(O)-N(R Ｌ )-(C １ -C ６ alkylene)-$,#-C(O)-(C １ -C ６ alkylene)-$, or #-(C １ -C ６ alkylene)-C(O)-N(R Ｌ )-(C １ -C ６ alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; Each C of L １ -C ６ Alkylene is substituted with halogen, —OH, and C １ -C ６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Each R Ｌ are independently hydrogen or C １ -C ６ 26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

27. Each C of L １ -C ６ Alkylene is substituted with halogen, —OH, and C １ -C ６ 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents independently selected from the group consisting of alkyl.

28. Each C of L １ -C ６ The alkylene is selected from halogen and C １ -C ６ 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents independently selected from the group consisting of alkyl.

29. Each C of L １ -C ６ 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.

30. Each C of L １ -C ６ 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein alkylene is unsubstituted.

31. L is a bond, C １ -C ３ Alkylene, or #-C(O)-N(R Ｌ )-(C １ -C ３ alkylene)-$, where # denotes the point of attachment to Ring B and $ denotes the point of attachment to the rest of the molecule; Here, each C of L １ -C ６ Alkylene is substituted with halogen, —OH, and C １ -C ６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Here, each R Ｌ are independently hydrogen or C １ -C ６ 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

32. L is a bond, —CH ２ -, -CH ２ CH ２ -,or 【Chemistry 453】 32. The compound according to any one of claims 1 to 26 or 31, wherein:

33. The compound according to any one of claims 1 to 6 or 17 to 32, or a pharmaceutically acceptable salt thereof, wherein m is 1.

34. The compound according to any one of claims 1 to 6 or 18 to 32, or a pharmaceutically acceptable salt thereof, wherein m is 0.

35. 35. The compound according to any one of claims 1 to 34, wherein n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

36. R Ｃ The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

37. 37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein p is 0.

38. A compound selected from the group consisting of compounds 1 to 356 in Table 1, or a pharmaceutically acceptable salt thereof.

39. A compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. 【Request Item 40】 【Chemistry 454-1】 【Chemistry 454-2】 or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

42. A method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 41.

43. 43. The method of claim 42, wherein the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or condition, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, and a muscle disease or condition.

44. 43. The method of claim 42, wherein the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

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