NAMPT modulators

Abstract

A compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R1, n and Y1 are as defined herein. A pharmaceutically acceptable composition is also provided, comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof. A method of using a compound of formula (II) or a pharmaceutically acceptable salt thereof is also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 020,904, filed May 6, 2020, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] Provided herein are alkyl urea compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat various diseases and conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT). Background Art

[0004] 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 a variety of pathological conditions.

[0005] Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme (enzyme cofactor) for the basic biological processes involved in catabolism and anabolism. As a coenzyme, NAD is associated with many oxidases (usually dehydrogenases) involved in energy metabolism and serves as a universal electron carrier. NAD is present in cells in an oxidized state (NAD+ and NADP+) and a reduced state (NADH and NADPH), serving as a chemical means for capturing and transferring free energy from the oxidative process in catabolism or providing a small packet of energy to build the macromolecules in anabolism. NADH produced by the oxidation of carbohydrates, lipids, and amino acids provides reducing equivalents for the electron transport chain of mitochondria, ultimately driving ATP synthesis in oxidative phosphorylation.

[0006] More than 200 enzymes use NAD+ or NADP+ as coenzymes, and the functions of enzymes are not limited to energy metabolism. It is now understood that NAD+ plays a role in regulating a variety of functions, including mitochondrial function, respiratory capacity and biogenesis, mitochondrial-nuclear signaling. In addition, it controls cell signaling, gene expression, DNA repair, hematopoiesis, immune function, unfolded protein response and autophagy. In addition, NAD has anti-inflammatory properties and is a precursor to NADPH, which is the main source of reducing power to combat oxidative stress. A large amount of literature shows that increasing NAD levels is an effective strategy to prevent or improve a variety of disease states ( 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).

[0007] The levels of NAD+ and NADP+ related enzymes play an important role in normal physiological function and are altered in various diseases and stress conditions, including aging. Cellular NAD+ levels are reduced during aging, metabolic diseases, inflammatory diseases, during ischemia / reperfusion injury, and in other diseases 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 regulation of cellular NAD+ levels affects the rate and severity of physical decline and deterioration. Therefore, increased cellular NAD+ concentrations may be beneficial in the context of aging and age-related diseases.

[0008] The cellular NAD+ pool is controlled by the balance between the activity of NAD+ synthesis and consumption enzymes. In mammals, NAD+ is synthesized from a variety of dietary sources, including one or more of its main precursors, including: tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and nicotinamide (NAM). Based on the bioavailability of its precursors, there are three pathways for synthesizing NAD+ in cells: (i) synthesized from Trp through the de novo biosynthetic pathway or the kynurenine pathway (ii) synthesized from NA in the Preiss-Handler pathway and (iii) synthesized from NAM, NR and NMN in the salvage pathway (Verdin et al., Science. 2015, 350(6265): 1208-13). Among them, the major NAD+ biosynthetic pathway involves the step of synthesizing nicotinamide mononucleotide (NMN) using nicotinamide and 5'-phosphoribosyl-pyrophosphate through the rate-limiting enzyme nicotinamide phosphoribosyl-transferase (NAMPT), which is crucial for 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., Cell. 2007, 130(6):1095-107). Therefore, increasing the catalytic rate of NAMPT through small molecule activators would be an effective strategy to increase NAD levels and thereby address a wide range of disease states. These include heart disease, chemotherapy-induced tissue damage, kidney disease, metabolic diseases, muscle diseases, neurological diseases and injuries, diseases caused by impaired stem cell function, DNA damage and primary mitochondrial disorders, and eye diseases. Summary of the Invention

[0009] In one aspect, provided herein are compounds of formula (II):

[0010]

[0011] or a pharmaceutically acceptable salt thereof,

[0012] in:

[0013] n is 0 to 6;

[0014] Y 1 for And R1 Selected from the group consisting of:

[0015] or

[0016] Y 1 for And R 1 Selected from the group consisting of:

[0017]

[0018] or

[0019] Y 1 -C(O)-N(R q )-(R s ), where R q is H or C1-C6 alkyl, and R s is C3-C8 cycloalkyl, optionally substituted C6-C 14 aryl, optionally substituted 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(optionally substituted C6-C 14 aryl), and R 1 Selected from the group consisting of:

[0020] or

[0021] Y 1 -C(O)-R b , where R b is an optionally substituted 3- to 18-membered heterocycloalkyl group, and R 1 for

[0022] or

[0023] Y 1 -N(R t )-C(O)R u , where R t is H or C1-C6 alkyl, and R u is an optionally substituted C6-C 14 aryl, optionally substituted 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl), and R 1 for

[0024] or

[0025] Y 1 for And R 1 for in

[0026] R 2a and R 2b Each is independently a halogen, -O(C1-C6 alkyl), a C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and

[0027] R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl;

[0028] G 1 is CH or N;

[0029] p1 and p2 are each independently 0, 1 or 2;

[0030] q1 and q2 are each independently 1 or 2;

[0031] r is 1, 2, or 3;

[0032] Among them, when Y 1 for When , then n is 4, 5 or 6;

[0033] When Y 1 for and r is 1, then n is 2, 3, 4, 5, or 6; and

[0034] When Y 1 -C(O)-N(R q )-(R s )、-C(O)-R b 、-N(R t )-C(O)R u or When , then n is 4 or 5;

[0035] R 3 Selected from the group consisting of:

[0036] i. unsubstituted C1-C6 alkyl;

[0037] ii.C6-C 14 aryl;

[0038] iii. optionally substituted 5- to 18-membered heteroaryl;

[0039] iv.-NR 3a R 3b ,in

[0040] R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0041] v.-OR 3c ,in

[0042] R 3c C6-C 14 Aryl, 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0043] vi.-C(O)R 3d ,in

[0044] R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; optionally substituted C6-C 14 Aryl substituted C3-C8 cycloalkyl; C3-C8 cycloalkenyl; optionally substituted C6-C 14 Aryl; optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl); optionally substituted 3- to 18-membered heterocycloalkyl; and optionally substituted 5- to 18-membered heteroaryl,

[0045] in

[0046] R 3f and R 3g Each independently selected from the group consisting of:

[0047] (a) hydrogen,

[0048] (b) optionally substituted C1-C6 alkyl,

[0049] (c)C6-C 14 Aryl,

[0050] (d) an optionally substituted 3- to 18-membered heterocycloalkyl group,

[0051] (e) optionally substituted 5- to 18-membered heteroaryl,

[0052] (f) optionally substituted C3-C 10 cycloalkyl; and

[0053] (g) optionally substituted C3-C 10 cycloalkenyl;

[0054] vii. by one or more -OH, -C(O)NR 3h R 3i , optionally substituted C6-C 14 aryl, optionally substituted 3- to 18-membered heterocycloalkyl, optionally substituted 5- to 18-membered heteroaryl, -N(R 3p )-C(O)R 3q 、-S(O)2-R 3r or -C(O)-R 3s Substituted C1-C6 alkyl,

[0055] in

[0056] R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl),

[0057] R 3p is H or C1-C6 alkyl,

[0058] R 3q is a C3-C8 cycloalkyl group, an optionally substituted 3- to 18-membered heterocycloalkyl group, or an optionally substituted 5- to 18-membered heteroaryl group,

[0059] R 3r C6-C 14 aryl or 5- to 18-membered heteroaryl, and

[0060] R 3s is an optionally substituted 3- to 18-membered heterocycloalkyl group;

[0061] viii.-C(O)OR 3j ,in

[0062] R 3j is hydrogen or C1-C6 alkyl;

[0063] ix.-NHC(O)R 3k ,in

[0064] R 3k is an optionally substituted C6-C 14 Aryl, optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl), or an optionally substituted 5- to 18-membered heteroaryl;

[0065] x.-NHC(O)OR 3l ,in

[0066] R 3l is hydrogen or C1-C6 alkyl;

[0067] xi.-NHSO2R 3m ,in

[0068] R 3m is an optionally substituted 5- to 18-membered heteroaryl, an optionally substituted C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), each of which is optionally substituted; and

[0069] xii.-SO2R 3n ;in

[0070] R 3n is C1-C6 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 14 Aryl, or optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl);

[0071] R 4 is phenyl or -C(O)NH-CH2-phenyl;

[0072] R 5a and R 5b are independently selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl); and

[0073] R 6 selected from the group consisting of: -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl), -C(O)-(optionally substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), and 5- to 18-membered heteroaryl,

[0074] The prerequisite is that when R 6 is -C(O)-(substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), or 5- to 18-membered heteroaryl, then (1) n is 4 or 5, and (2) R 1 Selected from the group consisting of:

[0075] in

[0076] (1) When Y 1 for And when n is 0 or 1, then R 1 Selected from the group consisting of: and

[0077] (2) When Y 1 for And when n is 0, then R 1 Selected from the group consisting of:

[0078] In one aspect, provided herein are compounds of formula (I):

[0079]

[0080] or a pharmaceutically acceptable salt thereof,

[0081] in:

[0082] Y 1 for And R 1 Selected from the group consisting of:

[0083] or

[0084] Y 1 for And R 1 Selected from the group consisting of:

[0085] in

[0086] R 2a and R 2b Each is independently a halogen, -O(C1-C6 alkyl), a C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and

[0087] R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl;

[0088] G 1 is CH or N;

[0089] p1 and p2 are each independently 0, 1 or 2;

[0090] q1 and q2 are each independently 1 or 2;

[0091] r is 1, 2, or 3;

[0092] n is 0 to 6;

[0093] When Y 1 for When n is 4, 5 or 6; and

[0094] When Y 1 for and when r is 1, n is 2, 3, 4, 5 or 6;

[0095] R 3 Selected from the group consisting of:

[0096] i. C1-C6 alkyl;

[0097] ii.C6-C 14 aryl;

[0098] iii. optionally substituted 5- to 18-membered heteroaryl;

[0099] iv.-NR 3a R 3b ,in

[0100] R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0101] v.-OR 3c ,in

[0102] R 3c C6-C 14 aryl;

[0103] vi.-C(O)R 3d ,in

[0104] R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; optionally substituted C6-C 14 Aryl substituted C3-C8 cycloalkyl; C3-C8 cycloalkenyl; optionally substituted C6-C 14Aryl; optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl); optionally substituted 3- to 18-membered heterocycloalkyl; and optionally substituted 5- to 18-membered heteroaryl,

[0105] in

[0106] R 3f and R 3g Each independently selected from the group consisting of:

[0107] (a) hydrogen,

[0108] (b) optionally substituted C1-C6 alkyl,

[0109] (c)C6-C 14 Aryl,

[0110] (d) an optionally substituted 3- to 18-membered heterocycloalkyl group,

[0111] (e) optionally substituted 5- to 18-membered heteroaryl,

[0112] (f) optionally substituted C3-C 10 cycloalkyl; and

[0113] (g) optionally substituted C3-C 10 cycloalkenyl;

[0114] vii. C(O)NR 3h R 3i , C1-C6 alkyl substituted by an optionally substituted 3- to 18-membered heterocycloalkyl or an optionally substituted 5- to 18-membered heteroaryl,

[0115] where R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl);

[0116] viii.-C(O)OR 3j ,in

[0117] R 3j is hydrogen or C1-C6 alkyl;

[0118] ix.-NHC(O)R 3k ,in

[0119] R 3k is an optionally substituted C6-C 14 Aryl, optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl), or an optionally substituted 5- to 18-membered heteroaryl;

[0120] x.-NHC(O)OR 3l ,in

[0121] R 3l is hydrogen or C1-C6 alkyl;

[0122] xi.-NHSO2R 3m ,in

[0123] R 3m is an optionally substituted 5- to 18-membered heteroaryl, an optionally substituted C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), each of which is optionally substituted; and

[0124] xii.-SO2R 3n ;in

[0125] R 3n is optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 14 Aryl, or optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl);

[0126] R 4 is phenyl or -C(O)NH-CH2-phenyl;

[0127] R 5a and R 5b are independently selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl); and

[0128] R 6 Selected from the group consisting of -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) and -C(O)-phenyl; and

[0129] in

[0130] (1) When Y 1 for When n is 0 or 1, R 1 Selected from the group consisting of: and

[0131] (2) When Y 1 for When n is 0, R 1 Selected from the group consisting of:

[0132] In another aspect, provided herein is a compound of formula (IA):

[0133]

[0134] or a salt thereof, wherein R 1 、R 3 , G 1 , p1, p2, q1, q2 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0135] In another aspect, provided herein is a compound of formula (IB):

[0136]

[0137] or a salt thereof, wherein R 1 、R 4 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0138] In another aspect, provided herein is a compound of formula (IC):

[0139]

[0140] or a salt thereof, wherein R 1 、R 5a 、R 5b and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0141] In another aspect, provided herein is a compound of formula (ID):

[0142]

[0143] or a salt thereof, wherein R 1 、R 6 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0144] In another aspect, provided herein are compounds of Formula (IE) or (IF):

[0145]

[0146] or a salt thereof, wherein R 1 , n and r are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0147] In another aspect, provided herein is a compound of formula (IG):

[0148]

[0149] or a salt thereof, wherein R 1 、R q 、R s and n are as defined for Formula (II) or any variation or embodiment thereof.

[0150] In another aspect, provided herein is a compound of formula (IH):

[0151]

[0152] or a salt thereof, wherein R 1 、R b and n are as defined for Formula (II) or any variation or embodiment thereof.

[0153] In one aspect, provided herein is a compound of formula (IJ):

[0154]

[0155] or a salt thereof, wherein R 1 、R t 、R u and n are as defined herein for Formula (II) or any variation or embodiment thereof.

[0156] In one aspect, provided herein is a compound of formula (IK):

[0157]

[0158] or a salt thereof, wherein R 1 and n are as defined herein for Formula (II) or any variation or embodiment thereof.

[0159] In another aspect, provided herein are pharmaceutical compositions comprising at least one compound of Formula (II), (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), such as a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing compounds, optionally further comprising a pharmaceutically acceptable excipient.

[0160] 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 (II), (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), such as a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (II), (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK). 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 kidney disease, a metabolic disease, a nervous system disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscular dystrophy. 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 syndrome, neonatal nerve damage, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, polio / poliomyelitis, and spinal cord injury.

[0161] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure.

[0162] For the sake of brevity, the disclosures of publications, including patents, cited in this specification are incorporated herein by reference. DETAILED DESCRIPTION

[0163] definition

[0164] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0165] Throughout this application, unless the context indicates otherwise, references to compounds of formula (II) or formula (I) include all subgroups of formula (II) or formula (I) as defined herein, including all substructures, subclasses, preferences, embodiments, examples, and specific compounds defined and / or described herein. References to compounds of formula (II) or 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, isotopes, and / or protected forms thereof. In some embodiments, references to compounds of formula (II) or formula (I) and subgroups thereof include polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of formula (II) or formula (I) and subgroups thereof include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to compounds of formula (II) or formula (I) and subgroups thereof include isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of formula (II) or formula (I) and subgroups thereof include solvates thereof. Similarly, the term "salt" includes solvates of salts of the compound.

[0166] "Alkyl" encompasses straight and branched carbon chains having the specified 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 encompasses straight and branched chain alkyl groups having from 1 to 6 carbon atoms. When naming an alkyl residue having a specific carbon number, it is intended to encompass all branched and straight chain forms having that carbon number; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-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.

[0167] As used herein, the term "haloalkyl" refers to an alkyl moiety as described above wherein one or more of the hydrogen atoms of the alkyl moiety have been replaced by one or more independently selected halogen atoms. For example, the term "haloalkyl" includes, but is not limited to, a methyl moiety wherein one or more of the hydrogen atoms of the methyl moiety have been replaced by one or more independently selected halogen atoms (e.g., -CH2F, -CHF2, -CH2Cl, -CCl3, -CHClF, -CCl2Br, etc.).

[0168] As used herein, the term "alkoxy" refers to an -O-alkyl moiety.

[0169] As used herein, the term "haloalkoxy" refers to an alkoxy moiety as described above wherein one or more of the hydrogen atoms of the alkoxy moiety have been replaced by one or more independently selected halogen atoms. For example, the term "haloalkoxy" includes, but is not limited to, a methoxy moiety wherein one or more of the hydrogen atoms of the methoxy moiety have been replaced by one or more independently selected halogen atoms (e.g., -O-CH2F, -O-CHF2, -O-CH2Cl, -O-CCl3, -O-CHClF, -O-CCl2Br, etc.).

[0170] As used herein, the term "alkylene" refers to a divalent alkyl group as defined above having 1 to 20 carbon atoms. Unless otherwise provided, an alkylene group refers to a portion having 1-20 carbon atoms, 1-16 carbon atoms, 1-10 carbon atoms, 1-7 carbon atoms, or 1-4 carbon atoms. Alkylene includes, but is 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.

[0171] When a range of values ​​is given (e.g., C 1-6 When C is present in the range of alkyl, each value in the stated range and all intermediate ranges are included. 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 , C2-3 and C 1-2 alkyl.

[0172] "Alkenyl" refers to an unsaturated side chain or straight chain alkyl group having a specified number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group can be in cis or trans configuration (Z or E configuration) about one or more double bonds. Alkenyl includes but is not limited to vinyl, propenyl (e.g., prop-1-ene-1-yl, prop-1-ene-2-yl, prop-2-ene-1-yl (allyl), prop-2-ene-2-yl) and butenyl (e.g., but-1-ene-1-yl, but-1-ene-2-yl, 2-methyl-prop-1-ene-1-yl, but-2-ene-1-yl, but-2-ene-1-yl, but-2-ene-2-yl, but-1,3-diene-1-yl, but-1,3-diene-2-yl).

[0173] "Alkynyl" refers to an unsaturated, branched or straight-chain alkyl group having a specified number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0174] " cycloalkyl " represents a non-aromatic, fully saturated carbocyclic ring with a specified number of carbon atoms (for example, 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms).Cycloalkyl can be monocyclic or polycyclic (for example, bicyclic, tricyclic).The example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and bridge ring, cage ring and spirocyclic group (for example, norbornane, bicyclo [2.2.2] octane, spiral [3.3] heptane).In addition, a ring of polycyclic cycloalkyl can be aromatic, and the precursor condition is that polycyclic cycloalkyl is combined with parent structure via non-aromatic carbon.For example, 1,2,3,4-tetrahydronaphthalene-1-yl (wherein said part is bonded to parent structure via non-aromatic carbon atom) is cycloalkyl, and 1,2,3,4-tetrahydronaphthalene-5-yl (wherein said part is combined with parent structure via aromatic carbon atom) is not considered to be cycloalkyl. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0175] " cycloalkenyl " represents the non-aromatic carbocyclic ring containing a specified number of carbon atoms (for example, 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond.Cycloalkenyl can be monocyclic or polycyclic (for example, bicyclic, tricyclic).The example of cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl, and bridged ring and cage ring group (for example, bicyclo [2.2.2] octene).In addition, a ring of polycyclic cycloalkenyl can be aromatic, and the precursor condition is that polycyclic cycloalkenyl is bonded to parent structure via non-aromatic carbon atom.For example, indenes-1-yl (wherein said part is bonded to parent structure via non-aromatic carbon atom) is considered to cycloalkenyl, and indenes-4-yl (wherein said part is bonded to parent structure via aromatic carbon atom) is not considered to cycloalkenyl.The example of the polycyclic cycloalkenyl consisting of the cycloalkenyl of condensing to aromatic ring is described below.

[0176] "Aryl" refers to an aromatic carbocyclic ring with a specified number of carbon atoms (e.g., 6 to 12 or 6 to 10 carbon atoms). Aryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl can include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl is bonded to the parent structure via atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the portion is bonded to the parent structure via aromatic carbon atoms) is considered to be an aryl, while 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered to be an aryl. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is considered to be an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (wherein the portion is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered to be an aryl group. However, no matter how the point of attachment is, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein (for example, quinolin-5-yl and quinolin-2-yl are both heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Other examples of aryl groups comprising aromatic carbocyclic rings fused to non-aromatic rings are described below.

[0177] "Heteroaryl" refers to an aromatic ring containing a specified number of atoms (e.g., 5- to 12-membered or 5- to 10-membered heteroaryl), which is composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms are carbon. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 1. Unless otherwise indicated, the heteroaryl group can be bonded to the parent structure through a carbon or nitrogen atom, as long as valence allows. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl.

[0178] In some cases, 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.

[0179] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzooxadiazole, 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-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 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[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

[0015] Examples of the present invention include thiazoline, 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.

[0180] In other cases, polycyclic heteroaryl can include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaromatic ring, provided that the polycyclic heteroaryl is bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl. Examples of polycyclic heteroaryl groups consisting of heteroaromatic rings fused to non-aromatic rings are described below.

[0181] " Heterocycloalkyl " represents a non-aromatic, fully saturated ring (for example, 3 yuan to 10 yuan or 3 yuan to 7 yuan heterocycloalkyl) with a specified number of atoms, which is composed of one or more heteroatoms (for example, 1, 2, 3, 4 heteroatoms) selected from N, O and S, and the remaining ring atoms are carbon. Heterocycloalkyl can be a monocycle or polycycle (for example, a bicyclic, a tricyclic). The example of heterocycloalkyl includes oxiranyl, aziridine radicals (aziridinyl), azetidinyl (azetidinyl), pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Example includes thiomorpholine S-oxide and thiomorpholine S, S-dioxide. The example of spiro ring heterocycloalkyl includes azaspiro [3.3] heptane, diazaspiro [3.3] heptane, diazaspiro [3.4] octane and diazaspiro [3.5] nonane. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is bonded to the parent structure via a non-aromatic carbon atom or nitrogen atom. For example, 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of heterocycloalkyl groups fused to aromatic rings are described below.

[0182] "Heterocycloalkenyl" refers to a non-aromatic ring having the specified number of atoms (e.g., 3- to 10-membered, or 3- to 7-membered heterocycloalkyl) consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, and at least one double bond, the remaining ring atoms being carbon, and the at least one double bond being derived by removing one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. A heterocycloalkenyl group can 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). In addition, one ring of the polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is bonded to the parent structure via a non-aromatic carbon atom or nitrogen atom. For example, 1,2-dihydroquinolin-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of heterocycloalkenyl groups fused to an aromatic ring are described below.

[0183] 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-tetrahydronaphthyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolyl, 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]thienyl, 1,3-dihydrobenzo[c]thienyl, 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[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 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, quinazoline-4(3H) -one, quinazoline-2,4(1H,3H)-dione, quinoxaline-2(1H)-one, quinoxaline-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]pyridine-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 discussed herein, whether each ring is considered to be aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is determined by the atom to which the moiety is bonded to the parent structure.

[0184] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0185] Unless otherwise indicated, 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 the compounds disclosed and / or described herein contain olefinic double bonds or other geometric asymmetric centers, it is expected that the compounds include both E and Z isomers. When the compounds described herein contain a moiety capable of tautomerism, it is expected that the compounds include all possible tautomers, unless otherwise specified.

[0186] "Protecting group" has the meaning generally associated therewith in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound so that a chemical reaction can be selectively performed on another unprotected reactive site and so that the group can be easily removed after completion of the selective reaction. Various protecting groups are disclosed in, for example, TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxyl protected form" contains at least one hydroxyl group protected by a hydroxyl protecting group. Similarly, amines and other reactive groups can also be similarly protected.

[0187] The term "pharmaceutically acceptable salt" refers to a salt of any compound 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 compound 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 with 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-hydroxyethanesulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with 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, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0188] If the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0189] "Solvates" are 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 compound / water ratio, such as monohydrates, dihydrates, and hemihydrates.

[0190] The term "substituted" means that the specified group or part carries one or more substituents, including but not limited to substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, amido, 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, etc. The term "unsubstituted" means that the specified group does not carry a substituent. When the term "substituted" is used to describe a structural system, the substitution is intended to occur at any valence-allowed position on the system. When a group or part carries more than one substituent, it should be understood that the substituents can be the same or different from each other. In some embodiments, the substituted group or part carries one to five substituents. In some embodiments, the substituted group or part carries one substituent. In some embodiments, the substituted group or moiety has two substituents. In some embodiments, the substituted group or moiety has three substituents. In some embodiments, the substituted group or moiety has four substituents. In some embodiments, the substituted group or moiety has five substituents.

[0191] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples of instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes embodiments where the group or moiety is substituted and embodiments where the group or moiety is not substituted.

[0192] The compounds disclosed and / or described herein may be in isotopically enriched forms, e.g., 2 H. 3 H. 11 C. 13 C and / or 14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy of the compounds disclosed and / or described herein and increase the duration of action. Deuterium-substituted compounds can be synthesized using various 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.

[0193] 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. Unless any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients may also be incorporated into the pharmaceutical compositions.

[0194] The terms "patient," "individual," and "subject" refer to animals such as mammals, birds, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will be the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be used in both human therapy and veterinary applications.

[0195] 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 as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to a direct interaction of the chemical entity with the target or due to an interaction of the chemical entity with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical entity can increase or decrease the activity of the target, for example, by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the activity of the target, or by (directly or indirectly) increasing or decreasing the amount of the target present in a cell or organism.

[0196] The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound disclosed and / or described herein that is sufficient to affect treatment as defined herein when administered to a patient in need of such treatment. A therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation of nicotinamide phosphoribosyltransferase (NAMPT). The therapeutically effective amount will vary depending on factors such as the subject and the disease condition being treated, the subject's weight and age, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the time of administration, the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be determined experimentally, for example, by measuring the blood concentration of the chemical entity, or theoretically by calculating bioavailability.

[0197] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of the following: preventing a disease or condition (i.e., causing clinical symptoms of the disease or condition not to develop); inhibiting a disease or condition; slowing or arresting the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (e.g., causing remission or regression of clinical symptoms). The term encompasses situations where the patient is already experiencing a disease or condition, as well as situations where the patient is not currently experiencing a disease or condition but is expected to develop one. The term encompasses both complete and partial alleviation or prevention of an illness or condition and complete or partial alleviation of clinical symptoms of a disease or condition. Thus, the compounds described and / or disclosed herein can prevent an existing disease or condition from worsening, help manage a disease or condition, or alleviate or eliminate a disease or condition. When used in a prophylactic manner, the compounds disclosed and / or described herein can prevent a disease or condition from developing, or reduce the extent of a disease or condition that may develop.

[0198] Compound

[0199] Compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including in the Brief Summary and the appended claims. Also provided are uses of all compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any proportion, including racemic mixtures, salts, or solvates of the compounds described herein. Any compound described herein may also be referred to as a pharmaceutical.

[0200] In one aspect, provided herein are compounds of formula (II):

[0201]

[0202] or a pharmaceutically acceptable salt thereof,

[0203] in:

[0204] n is 0 to 6;

[0205] Y 1 for And R 1 Selected from the group consisting of:

[0206] or

[0207] Y 1 for And R 1 Selected from the group consisting of:

[0208] or

[0209] Y 1 -C(O)-N(R q )-(R s ), where R q is H or C1-C6 alkyl, and R s is C3-C8 cycloalkyl, optionally substituted C6-C 14 aryl, optionally substituted 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(optionally substituted C6-C 14 aryl), and R 1 Selected from the group consisting of:

[0210] or

[0211] Y 1 -C(O)-R b , where R bis an optionally substituted 3- to 18-membered heterocycloalkyl group, and R 1 for

[0212] or

[0213] Y 1 -N(R t )-C(O)R u , where R t is H or C1-C6 alkyl, and R u is an optionally substituted C6-C 14 aryl, optionally substituted 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl), and R 1 for

[0214] or

[0215] Y 1 for And R 1 for in

[0216] R 2a and R 2b Each is independently a halogen, -O(C1-C6 alkyl), a C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and

[0217] R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl;

[0218] G 1 is CH or N;

[0219] p1 and p2 are each independently 0, 1 or 2;

[0220] q1 and q2 are each independently 1 or 2;

[0221] r is 1, 2, or 3;

[0222] Among them, when Y 1 for When , then n is 4, 5 or 6;

[0223] When Y 1 for and r is 1, then n is 2, 3, 4, 5, or 6; and

[0224] When Y1 -C(O)-N(R q )-(R s )、-C(O)-R b 、-N(R t )-C(O)R u or When , then n is 4 or 5;

[0225] R 3 Selected from the group consisting of:

[0226] i. unsubstituted C1-C6 alkyl;

[0227] ii.C6-C 14 aryl;

[0228] iii. optionally substituted 5- to 18-membered heteroaryl;

[0229] iv.-NR 3a R 3b ,in

[0230] R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0231] v.-OR 3c ,in

[0232] R 3c C6-C 14 Aryl, 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0233] vi.-C(O)R 3d ,in

[0234] R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; optionally substituted C6-C 14 Aryl substituted C3-C8 cycloalkyl; C3-C8 cycloalkenyl; optionally substituted C6-C 14 Aryl; optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl); optionally substituted 3- to 18-membered heterocycloalkyl; and optionally substituted 5- to 18-membered heteroaryl,

[0235] in

[0236] R 3f and R 3g Each independently selected from the group consisting of:

[0237] (a) hydrogen,

[0238] (b) optionally substituted C1-C6 alkyl,

[0239] (c)C6-C 14 Aryl,

[0240] (d) an optionally substituted 3- to 18-membered heterocycloalkyl group,

[0241] (e) optionally substituted 5- to 18-membered heteroaryl,

[0242] (f) optionally substituted C3-C 10 cycloalkyl; and

[0243] (g) optionally substituted C3-C 10 cycloalkenyl;

[0244] vii. by one or more -OH, -C(O)NR 3h R 3i , optionally substituted C6-C 14 aryl, optionally substituted 3- to 18-membered heterocycloalkyl, optionally substituted 5- to 18-membered heteroaryl, -N(R 3p )-C(O)R 3q 、-S(O)2-R 3r or -C(O)-R 3s Substituted C1-C6 alkyl,

[0245] in

[0246] R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl),

[0247] R 3p is H or C1-C6 alkyl,

[0248] R 3q is a C3-C8 cycloalkyl group, an optionally substituted 3- to 18-membered heterocycloalkyl group, or an optionally substituted 5- to 18-membered heteroaryl group,

[0249] R 3r C6-C 14 aryl or 5- to 18-membered heteroaryl, and

[0250] R 3sis an optionally substituted 3- to 18-membered heterocycloalkyl group;

[0251] viii.-C(O)OR 3j ,in

[0252] R 3j is hydrogen or C1-C6 alkyl;

[0253] ix.-NHC(O)R 3k ,in

[0254] R 3k is an optionally substituted C6-C 14 Aryl, optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl), or an optionally substituted 5- to 18-membered heteroaryl;

[0255] x.-NHC(O)OR 3l ,in

[0256] R 3l is hydrogen or C1-C6 alkyl;

[0257] xi.-NHSO2R 3m ,in

[0258] R 3m is an optionally substituted 5- to 18-membered heteroaryl, an optionally substituted C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), each of which is optionally substituted; and

[0259] xii.-SO2R 3n ;in

[0260] R 3n is C1-C6 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 14 Aryl, or optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl);

[0261] R 4 is phenyl or -C(O)NH-CH2-phenyl;

[0262] R 5a and R 5b are independently selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl); and

[0263] R 6selected from the group consisting of —C(O)OC(CH 3 ) 3 , —NHC(O)O(C 1 -C 6 alkyl), —C(O)-(optionally substituted phenyl), —C(O)-(C 1 -C 6 alkylene)-(optionally substituted phenyl), —C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), —C(O)-(optionally substituted 5- to 18-membered heteroaryl), —C(O)-(C 1 -C 6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl) and 5- to 18-membered heteroaryl,

[0264] The prerequisite is that when R 6 is -C(O)-(substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), or 5- to 18-membered heteroaryl, then (1) n is 4 or 5, and (2) R 1 Selected from the group consisting of:

[0265] in

[0266] (1) When Y 1 for And when n is 0 or 1, then R 1 Selected from the group consisting of: and

[0267] (2) When Y 1 for And when n is 0, then R 1 Selected from the group consisting of:

[0268] In one aspect, provided are compounds of formula (I):

[0269]

[0270] or a pharmaceutically acceptable salt thereof,

[0271] in:

[0272] Y 1 for And R 1 Selected from the group consisting of:

[0273] or

[0274] Y 1 for And R 1 Selected from the group consisting of:

[0275] in

[0276] R 2a and R 2b Each is independently a halogen, -O(C1-C6 alkyl), a C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and

[0277] R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl;

[0278] G 1 is CH or N;

[0279] p1 and p2 are each independently 0, 1 or 2;

[0280] q1 and q2 are each independently 1 or 2;

[0281] r is 1, 2, or 3;

[0282] n is 0 to 6;

[0283] When Y 1 for When n is 4, 5 or 6; and

[0284] When Y 1 for and when r is 1, n is 2, 3, 4, 5 or 6;

[0285] R 3 Selected from the group consisting of:

[0286] i. C1-C6 alkyl;

[0287] ii.C6-C 14 aryl;

[0288] iii. optionally substituted 5- to 18-membered heteroaryl;

[0289] iv.-NR 3a R 3b ,in

[0290] R 3a and R 3bEach independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0291] v.-OR 3c ,in

[0292] R 3c C6-C 14 aryl;

[0293] vi.-C(O)R 3d ,in

[0294] R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; optionally substituted C6-C 14 Aryl substituted C3-C8 cycloalkyl; C3-C8 cycloalkenyl; optionally substituted C6-C 14 Aryl; optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl); optionally substituted 3- to 18-membered heterocycloalkyl; and optionally substituted 5- to 18-membered heteroaryl,

[0295] in

[0296] R 3f and R 3g Each independently selected from the group consisting of:

[0297] (a) hydrogen,

[0298] (b) optionally substituted C1-C6 alkyl,

[0299] (c)C6-C 14 Aryl,

[0300] (d) an optionally substituted 3- to 18-membered heterocycloalkyl group,

[0301] (e) optionally substituted 5- to 18-membered heteroaryl,

[0302] (f) optionally substituted C3-C 10 cycloalkyl; and

[0303] (g) optionally substituted C3-C 10 cycloalkenyl;

[0304] vii. C(O)NR 3h R 3i, C1-C6 alkyl substituted by an optionally substituted 3- to 18-membered heterocycloalkyl or an optionally substituted 5- to 18-membered heteroaryl,

[0305] where R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl);

[0306] viii.-C(O)OR 3j ,in

[0307] R 3j is hydrogen or C1-C6 alkyl;

[0308] ix.-NHC(O)R 3k ,in

[0309] R 3k is an optionally substituted C6-C 14 Aryl, optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl), or an optionally substituted 5- to 18-membered heteroaryl;

[0310] x.-NHC(O)OR 3l ,in

[0311] R 3l is hydrogen or C1-C6 alkyl;

[0312] xi.-NHSO2R 3m ,in

[0313] R 3m is an optionally substituted 5- to 18-membered heteroaryl, an optionally substituted C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), each of which is optionally substituted; and

[0314] xii.-SO2R 3n ;in

[0315] R 3n is optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 14 Aryl, or optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl);

[0316] R 4 is phenyl or -C(O)NH-CH2-phenyl;

[0317] R 5a and R5b are independently selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl); and

[0318] R 6 Selected from the group consisting of: -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) and -C(O)-phenyl.

[0319] In some embodiments of Formula (II) or Formula (I): (1) when Y 1 for And when n is 0 or 1, then R 1 Selected from the group consisting of: And (2) when Y 1 for And when n is 0, then R 1 Selected from the group consisting of:

[0320] In some embodiments of Formula (II) or Formula (I), Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In other embodiments, Y 1 for

[0321] In some embodiments of Formula (II), Y 1 for -C(O)-N(R q )-(R s )、-C(O)-R b 、-N(R t )-C(O)R u or In some embodiments of Formula (II), Y 1 -C(O)-N(R q )-(R s )、-C(O)-R b 、-N(R t )-C(O)R u or

[0322] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (IA):

[0323]

[0324] or a salt thereof, wherein R 1 、R 3 , G 1 , p1, p2, q1, q2 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0325] In some embodiments of Formula (II), Formula (I), or Formula (IA), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2a Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 2a is halogen or -O(C1-C6 alkyl). 2a In some embodiments, R 2a In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for

[0326] In some embodiments, the compound of Formula (IA) is a compound of Formula (I-A1) or (I-A2):

[0327]

[0328] or a salt thereof, wherein R 2a 、R 2b 、R 3 , G 1 , p1, p2, q1, q2 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0329] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), G 1 In some embodiments, G 1 is N.

[0330] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), p1 is 0, 1, or 2. In some embodiments, p1 is 0. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p2 is 0, 1, or 2. In some embodiments, p2 is 0. In some embodiments, p2 is 2. In some embodiments, p2 is 2. In some embodiments, q1 is 1 or 2. In some embodiments, q1 is 1. In other embodiments, q1 is 2. In some embodiments, q2 is 1 or 2. In some embodiments, q2 is 1. In other embodiments, q2 is 2.

[0331] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), p1 is 1 and q1 is 1. In some embodiments, p1 is 2 and q1 is 1. In some embodiments, p1 is 2 and q1 is 2. In some embodiments, p2 is 1 and q2 is 1. In some embodiments, p2 is 0 and q2 is 1. In some embodiments, p2 is 1 and q2 is 2.

[0332] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), 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. In other embodiments, n is 6.

[0333] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3is a C1-C6 alkyl group. For example, in some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl or isobutyl. 3 In some embodiments, R 3 C6-C 14 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is a 5- to 18-membered heteroaryl group optionally substituted with a C1-C6 alkyl group. 3 is a 5- to 6-membered heteroaryl group optionally substituted with a C1-C6 alkyl group. 3 is pyridyl or pyrimidinyl optionally substituted by C1-C6 alkyl. 3 is pyridinyl substituted with methyl. 3 for

[0334] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -NR 3a R 3b , where R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 In some embodiments, R 3 -NR 3a R 3b , where R 3a is hydrogen and R 3b Selected from the group consisting of: C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 In some embodiments, R 3 -NR 3a R 3b , where R 3a is hydrogen and R 3b Selected from the group consisting of 5- to 6-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14In some embodiments, R 3 -NR 3a R 3b , where R 3a and R 3b Each is -(C1-C6 alkylene)-(C6-C 14 In some embodiments, R 3 for

[0335] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 OR 3c , where R 3c C6-C 14 In some embodiments, R 3c In some embodiments, R 3 In some embodiments, R 3c C6-C 14 aryl, 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl).

[0336] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d In some embodiments, R 3d -NR 3f R 3g And R 3f and R 3g Each independently selected from the group consisting of: (a) hydrogen, (b) optionally selected from -OH, C6-C 14 C1-C6 alkyl substituted by one or more substituents from the group consisting of aryl and 5-membered to 18-membered heteroaryl, wherein C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of: halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy and CN, (c) C6-C 14 aryl, (d) 3- to 18-membered heterocycloalkyl, (e) 5- to 18-membered heteroaryl optionally substituted with methyl or CN, (f) C3-C4 optionally substituted with one or more substituents selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14aryl and 5- to 18-membered heteroaryl; and (g) C3-C 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 In some embodiments, R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3g Each independently selected from the group consisting of: (b) optionally selected from -OH, C6-C 14 C1-C6 alkyl substituted by one or more substituents from the group consisting of aryl and 5-membered to 18-membered heteroaryl, wherein C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of: halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy and CN, (c) C6-C 14 aryl, (d) 3- to 18-membered heterocycloalkyl, (e) 5- to 18-membered heteroaryl optionally substituted with methyl or CN, (f) C3-C4 optionally substituted with one or more substituents selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 aryl and 5- to 18-membered heteroaryl; and (g) C3-C 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 aryl and 5- to 18-membered heteroaryl.

[0337] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d , R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3g is optionally selected from hydroxyl, C6-C 14 C1-C6 alkyl substituted by one or more substituents from the group consisting of aryl and 5-membered to 18-membered heteroaryl, wherein C6-C 14The aryl and 5- to 18-membered heteroaryl groups are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, and CN. 3f is hydrogen or C1-C6 alkyl, and R 3g is a C1-C6 alkyl group optionally substituted by one or more substituents selected from the group consisting of hydroxy, phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl groups are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy and CN. In some embodiments, R 3f is hydrogen and R 3g is a C1-C6 alkyl group substituted by one or more substituents selected from the group consisting of hydroxy, phenyl, pyrazolyl, pyridinyl, and pyrimidinyl, wherein phenyl, pyrazolyl, pyridinyl, and pyrimidinyl are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, and CN. In some embodiments, R 3 for

[0338] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d , R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3g C6-C 14 In some embodiments, R 3f is H or C1-C6 alkyl, and R 3g It is phenylnaphthyl.

[0339] In some embodiments, R 3 for

[0340] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d , R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3gis a 3- to 18-membered heterocycloalkyl group. 3f is hydrogen or C1-C6 alkyl, and R 3g is a 3- to 18-membered heterocycloalkyl group optionally substituted by a halogen group, a hydroxy group, and a -(C1-C6 alkylene)-OH group.

[0341] In some embodiments, R 3 for

[0342] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d , R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3g is a 5- to 10-membered heteroaryl group optionally substituted with methyl or CN. 3f is hydrogen or C1-C6 alkyl, and R 3g is pyridinyl or pyrimidinyl, each optionally substituted by methyl or CN.

[0343] In some embodiments, R 3 for

[0344] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d , R 3d -NR 3f R 3g , R 3f is hydrogen or C1-C6 alkyl, and R 3g is a C3-C substituted by one or more substituents selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 In other embodiments, R 3f is hydrogen or C1-C6 alkyl, and R 3g is a C3-C substituted by one or more substituents selected from the group consisting of 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 In some embodiments, R 3f is hydrogen or C1-C6 alkyl, and R 3gFor optional C6-C 14 C3-C substituted aryl or 5- to 18-membered heteroaryl 10 In some embodiments, R 3f is hydrogen or C1-C6 alkyl, and R 3g For optional C6-C 10 In some embodiments, R 3f is hydrogen or C1-C6 alkyl, and R 3g For optional C6-C 10 In some embodiments, R 3f is hydrogen or C1-C6 alkyl, and R 3g is a C3-C8 cycloalkyl group optionally substituted with phenyl or pyridyl. 3f is hydrogen or C1-C6 alkyl, and R 3g is a C3-C4-C6 ... 10 Cycloalkenyl: halo, hydroxy, C1-C6 alkyl optionally substituted by halo, hydroxy and -(C1-C6 alkylene)-OH. 3 for In some embodiments, R 3 for

[0345] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d In some embodiments, R 3 -C(O)R 3d And R 3d For C6-C 14 Aryl-substituted C3-C8 cycloalkyl, wherein C6-C 14 Aryl is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. 3 -C(O)R 3d And R 3d For C6-C 10 In some embodiments, R 3 for In some embodiments, R 3-C(O)R 3d And R 3d In some embodiments, R 3 for

[0346] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d is a C6-C 14 Aryl: hydroxy, halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, -C(O)O(C1-C6 alkyl), -NR 3e1 R 3e2 , -S(O)2(C1-C6 alkyl), 5- to 18-membered heteroaryl, and 3- to 18-membered heterocycloalkyl optionally substituted with oxo, wherein R 3e1 and R 3e2 Each is independently H or C1-C6 alkyl. In some embodiments, R 3 -C(O)R 3d And R 3d is a phenyl group optionally substituted by one or more substituents selected from the group consisting of hydroxy, halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, -C(O)O(C1-C6 alkyl), -NR 3e1 R 3e2 , -S(O)2(C1-C6 alkyl), 5- to 18-membered heteroaryl, and 3- to 18-membered heterocycloalkyl optionally substituted with oxo, wherein R 3e1 and R 3e2 Each is independently H or C1-C6 alkyl. In some embodiments, R 3 for

[0347] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d -(C1-C6 alkylene)-(C6-C 14 Aryl): halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy. In some embodiments, R 3 -C(O)R3d And R 3d is -(C1-C6 alkylene)-phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. 3 for

[0348] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d is a 3- to 18-membered heterocycloalkyl group optionally substituted by one or more substituents selected from the group consisting of: (a) a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of: hydroxy, halogen, C3-C 10 Cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents; (b) C6-C 14 Aryl; (c) 3- to 18-membered heterocycloalkyl; (d) -C(O)O(C1-C6 alkyl); (e) -C(O)(C6-C 14 (f) halo; (g) C1-C6 alkoxy optionally substituted with one or more halo substituents; and (h) oxo.

[0349] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d is a 3- to 18-membered heterocycloalkyl group optionally substituted by one or more substituents selected from the group consisting of: (a) a C1-C6 alkyl group optionally substituted by one or more substituents selected from the group consisting of: hydroxy, halogen, C3-C 10 Cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents, (b) C6-C 14 Aryl, (c) 3- to 18-membered heterocycloalkyl, (d) -C(O)O(C1-C6 alkyl), (e) -C(O)(C6-C 14 aryl), (f) halo, and (g) C1-C6 alkoxy optionally substituted with one or more halo substituents. In some embodiments, R 3 -C(O)R 3d And R 3dis a 4- to 10-membered heterocycloalkyl group optionally substituted by one or more substituents selected from the group consisting of: (a) a C1-C6 alkyl group optionally substituted by one or more substituents selected from the group consisting of: hydroxy, halogen, C3-C 10 Cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents, (b) C6-C 14 Aryl, (c) 3- to 18-membered heterocycloalkyl, (d) -C(O)O(C1-C6 alkyl), (e) -C(O)(C6-C 14 aryl), (f) halo, and (g) C1-C6 alkoxy optionally substituted with one or more halo substituents. In some embodiments, R 3 -C(O)R 3d And R 3d is azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, indolinyl, isoindolyl, isoindolinyl, dihydroindanyl, tetrahydroquinolinyl, dihydrobenzoxazinyl or tetrahydronaphthyridinyl, each of which is optionally substituted by one or more substituents selected from the group consisting of: (a) C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy, halo, C3-C6 10 Cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents, (b) C6-C 14 Aryl, (c) 3- to 18-membered heterocycloalkyl, (d) -C(O)O(C1-C6 alkyl), (e) -C(O)(C6-C 14 aryl), (f) halo, and (g) C1-C6 alkoxy optionally substituted with one or more halo substituents. In some embodiments, R 3 for

[0350] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)R 3d And R 3d is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxy, oxo, and 3- to 18-membered heterocycloalkyl. 3 -C(O)R 3d And R 3d is a 5- to 6-membered heteroaryl group optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxy, oxo, and 3- to 18-membered heterocycloalkyl. 3 -C(O)R3d And R 3d is a pyridyl group optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, hydroxy, oxo, and 3- to 18-membered heterocycloalkyl. 3 -C(O)R 3d And R 3d is pyridinyl substituted with methyl. 3 for

[0351] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R is replaced by C(O)NR 3h R 3i Substituted C1-C6 alkyl, wherein R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 In some embodiments, R 3 for

[0352] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 is a C1-C6 alkyl substituted by a 3- to 18-membered heterocycloalkyl, wherein the 3- to 18-membered heterocycloalkyl is optionally independently selected from halogen, oxo, C1-C6 alkyl, C6-C 14 In some embodiments, R 3 is a C1-C6 alkyl substituted by a 3- to 18-membered heterocycloalkyl, wherein the 3- to 18-membered heterocycloalkyl is optionally selected from halogen and C6-C 14 In some embodiments, R 3 is a C1-C6 alkyl substituted by a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heterocycloalkyl is optionally substituted by a C6-C 14 Aryl substitution.

[0353] In some embodiments, R 3 for In some embodiments, R 3 for

[0354] In some embodiments, R 3 is a C1-C6 alkyl group, wherein R 3The C1-C6 alkyl (i) is substituted by a 5- to 18-membered heteroaryl, wherein the 5- to 18-membered heteroaryl is optionally substituted by one or more C1-C6 alkyl, C6-C 14 In some embodiments, R 3 is a C1-C6 alkyl group substituted by a 5- to 18-membered heteroaryl group. 3 is a C1-C6 alkyl group substituted with a 5- to 10-membered heteroaryl group. 3 for In some embodiments, R 3 for

[0355] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -C(O)OR 3j , where R 3j is hydrogen or C1-C6 alkyl. 3 for

[0356] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -NHC(O)R 3k In some embodiments, R 3k is a C6-C 14 Aryl: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl. 3k is phenyl optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl. 3 for In some embodiments, R 3k -(C1-C6 alkylene)(C6-C14 Aryl): C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl. 3k is -(C1-C6 alkylene)-phenyl optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl. 3 for In some embodiments, R 3k is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl. 3k is a 5- to 6-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl substituents. 3k is pyridinyl optionally substituted by a C1-C6 alkyl group. 3 for

[0357] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R is -NHC(O)OR 3l , where R 3l is hydrogen or C1-C6 alkyl. 3 for

[0358] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -NHSO2R 3m , where R 3m is a 5- to 18-membered heteroaryl, a C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein 5- to 18-membered heteroaryl, C6-C14 Aryl and -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted with one or more substituents selected from halo and C1-C6 alkoxy. 3 -NHSO2R 3m , where R 3m is a 5- to 18-membered heteroaryl group optionally substituted with one or more substituents selected from halo and C1-C6 alkoxy. 3 -NHSO2R 3m , where R 3m is a C6-C6 alkyl group optionally substituted by one or more substituents selected from halogen and C1-C6 alkoxy. 14 In some embodiments, R 3 -NHSO2R 3m , where R 3m is -(C1-C6 alkylene)-(C6-C6 alkylene)- 14 In some embodiments, R 3 for

[0359] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -SO2R 3n And R 3n C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein R 3n C3-C 10 Cycloalkyl, C6-C 14 Aryl and -(C1-C6 alkylene)-(C6-C 14 aryl) are each independently optionally substituted with one or more substituents independently selected from halo and -C(O)O(C1-C6 alkyl). In some embodiments, R 3 -SO2R 3n And R 3n In some embodiments, R 3 -SO2R 3n And R 3n In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 -SO2R 3n And R3n C3-C 10 Cycloalkyl, C6-C 14 Aryl or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein C3-C 10 Cycloalkyl, C6-C 14 Aryl and -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted with one or more substituents selected from halo and -C(O)O(C1-C6 alkyl). In some embodiments, R 3 -SO2R 3n And R 3n is a C3-C6 alkyl group optionally substituted with one or more substituents selected from halogen and -C(O)O(C1-C6 alkyl) 10 In some embodiments, R 3 -SO2R 3n And R 3n is a C6-C6 alkyl group optionally substituted with one or more substituents selected from halogen and -C(O)O(C1-C6 alkyl) 14 In some embodiments, R 3 -SO2R 3n And R 3n is a -(C1-C6 alkylene)-(C6-C 14 In some embodiments, R 3 for

[0360] In some embodiments, R 3 for

[0361] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 For one or more -N(R 3p )-C(O)R 3q Substituted C1-C6 alkyl, wherein R 3p is H or C1-C6 alkyl, and R 3q is C3-C8 cycloalkyl, optionally substituted 3- to 18-membered heterocycloalkyl, or optionally substituted 5- to 18-membered heteroaryl. 3p is H or C1-C6 alkyl, and R 3qis (i) C3-C8 cycloalkyl, (ii) 3- to 18-membered heterocycloalkyl optionally substituted with one or more independently selected C1-C6 alkyl or oxo substituents, or (iii) 5- to 18-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments of the foregoing, R 3p In some embodiments, R 3p is H. In some embodiments, R 3p In some embodiments, R 3q In some embodiments, R 3q In some embodiments, R 3q In some embodiments, R 3 for In some embodiments, R 3q is a 3- to 18-membered heterocycloalkyl group optionally substituted with one or more independently selected oxo substituents. 3q is a 5- to 6-membered heterocycloalkyl group optionally substituted with one or more independently selected oxo substituents. 3q is tetrahydropyranyl, tetrahydrothiopyranyl, or piperidinyl optionally substituted with one or more independently selected oxo substituents. 3 for In some embodiments, R 3q is a 5- to 18-membered heteroaryl group optionally substituted with one or more independently selected C1-C6 alkyl substituents. 3q is a 5- to 6-membered heteroaryl group optionally substituted with one or more independently selected C1-C6 alkyl substituents. 3q is pyridyl or pyrazolyl optionally substituted with one or more independently selected C1-C6 alkyl substituents. 3 for

[0362] In some embodiments, R 3 for

[0363] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 For one or more -S(O)2-R 3r Substituted C1-C6 alkyl, wherein R 3r C6-C14 In some embodiments, R 3r C6-C 14 In some embodiments, R 3r In some embodiments, R 3 for In some embodiments, R 3r is a 5- to 18-membered heteroaryl group. 3r is a 5- to 6-membered heteroaryl group. 3r In some embodiments, R 3 for In some embodiments, R 3 for

[0364] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 For one or more -C(O)-R 3s Substituted C1-C6 alkyl, wherein R 3s R 3s is an optionally substituted 3- to 18-membered heterocycloalkyl. 3s is a 3- to 18-membered heterocycloalkyl group optionally substituted with one or more independently selected C1-C6 alkyl substituents, wherein the C1-C6 alkyl group is independently optionally substituted with one or more -OH. 3s is a 5- to 6-membered heterocycloalkyl optionally substituted by one or more independently selected C1-C6 alkyl substituents, wherein C1-C6 alkyl is independently optionally substituted by one or more -OH. 3s is piperazinyl or pyrrolidinyl optionally substituted with one or more independently selected C1-C6 alkyl substituents, wherein C1-C6 alkyl is independently optionally substituted with one or more -OH. 3 for

[0365] In some embodiments of Formula (II), (I), (IA), (I-A1), or (I-A2), R 3 is a C1-C6 alkyl group, wherein R 3 The C1-C6 alkyl group is optionally substituted by one or more independently selected C6-C 14 In some embodiments, R 3 is a C1-C6 alkyl group, wherein R 3The C1-C6 alkyl group (i) is replaced by one or more independently selected C6-C 14 Aryl substituents, wherein C6-C 14 Aryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents, and (ii) is optionally substituted with one or more -OH. 3 for

[0366] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (IB):

[0367]

[0368] or a salt thereof, wherein R 1 、R 4 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0369] In some embodiments of Formula (IB), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for In some embodiments of Formula (IB), R 1 Selected from the group consisting of: In some embodiments of Formula (IB), R 1 Selected from the group consisting of:

[0370] In some embodiments of Formula (IB), 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. In other embodiments, n is 6.

[0371] In some embodiments of Formula (IB), R 4 In other embodiments, R 4 is -C(O)NH-CH2-phenyl. In some embodiments of Formula (IB), when R 4 When phenyl and n is 0, R 1 Selected from the group consisting of:

[0372] In some embodiments of Formula (IB), when R 4 When phenyl and n is 0, R 1 Selected from the group consisting of:

[0373] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (IC):

[0374]

[0375] or a salt thereof, wherein R 1 、R 5a 、R 5b and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0376] In some embodiments of Formula (IC), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2eEach is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for In some embodiments of Formula (IC), R 1 Selected from the group consisting of: In some embodiments of Formula (IC), R 1 Selected from the group consisting of:

[0377] In some embodiments of Formula (IC), 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. In other embodiments, n is 6.

[0378] In some embodiments of Formula (IC), when R 5a and R 5b One of them is H and R 5 and R 5b When the other of the two is methyl and n is 0, R 1 Selected from the group consisting of:

[0379] In some embodiments of Formula (IC), when R 5a and R 5b One of them is H and R 5a and R 5 When the other of the two is methyl and n is 0, R 1 Selected from the group consisting of:

[0380] In some embodiments of Formula (IC), R 5a is selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl). In some embodiments of Formula (IC), R 5b is selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl). In some embodiments of Formula (IC), R 5a is hydrogen, and R 5b is selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl). 5a and R 5b Each is a methyl group.

[0381] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (ID):

[0382]

[0383] or a salt thereof, wherein R 1 、R 6 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0384] In some embodiments of Formula (ID), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for In some embodiments of Formula (ID), R 1 Selected from the group consisting of:

[0385] In some embodiments of Formula (ID), R 1 Selected from the group consisting of:

[0386] In some embodiments of Formula (ID), R 1 Selected from the group consisting of: In some embodiments of Formula (ID), R 1 for In some embodiments of Formula (ID), R 1 for

[0387] In some embodiments of Formula (ID), 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. In other embodiments, n is 6.

[0388] In some embodiments of Formula (ID), R 6 is -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl), -C(O)-(optionally substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), and 5- to 18-membered heteroaryl. In some embodiments, R 6 (a) -C(O)OC(CH3)3; (b) -NHC(O)O(C1-C6 alkyl); (c) -C(O)-(phenyl), wherein phenyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, and 5- to 18-membered heteroaryl; (d) -C(O)-(C1-C6 alkylene)-(phenyl), wherein phenyl is optionally substituted with one or more independently selected C1-C6 alkyl substituents; (e) -C(O)-(3- to 18-membered heterocycloalkyl), wherein wherein the 3- to 18-membered heterocycloalkyl is optionally substituted with one or more independently selected oxo or C1-C6 alkyl substituents; (f) -C(O)-(5- to 18-membered heteroaryl), wherein the 5- to 18-membered heteroaryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents; (g) -C(O)-(C1-C6 alkylene)-(5- to 18-membered heteroaryl), wherein the 5- to 18-membered heteroaryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents; or (h) 5- to 18-membered heteroaryl. In some embodiments, R 6 is -C(O)-(optionally substituted phenyl). In some embodiments, R 6 is -C(O)-(phenyl), wherein phenyl is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or 5- to 18-membered heteroaryl. 6 for In some embodiments of Formula (ID), R 6 is -C(O)OC(CH3)3. In some embodiments, R 6 is -NHC(O)O(C1-C6 alkyl). 6is -C(O)-(C1-C6 alkylene)-(phenyl), wherein the phenyl group is optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 6 is -C(O)-(3- to 18-membered heterocycloalkyl), wherein the 3- to 18-membered heterocycloalkyl is optionally substituted with one or more independently selected oxo or C1-C6 alkyl substituents. In some embodiments, R 6 is -C(O)-(5- to 18-membered heteroaryl), wherein the 5- to 18-membered heteroaryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 6 is -C(O)-(C1-C6 alkylene)-(5- to 18-membered heteroaryl), wherein the 5- to 18-membered heteroaryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 6 It is a 5- to 18-membered heteroaryl group.

[0389] In some embodiments of Formula (ID), R 6 is -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) or -C(O)-(phenyl), and n is 0-6. In some embodiments of Formula (ID), R 6 is -C(O)-(substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), or 5- to 18-membered heteroaryl, and n is 4 or 5. In some embodiments, R 6 for and n is 4 or 5. In some embodiments, R 6 for and n is 4. In some embodiments, R 6 for And n is 5.

[0390] In some embodiments of Formula (ID), R 6 is -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) or -C(O)-(phenyl); n is 0-6; and R 1 Selected from the group consisting of: In some embodiments of Formula (ID), R 6is -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) or -C(O)-(phenyl); n is 0-6; and R 1 Selected from the group consisting of:

[0391] In some embodiments of Formula (ID), R 6 is -C(O)-(substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), or 5- to 18-membered heteroaryl; n is 4 or 5; and R 1 Selected from the group consisting of: In some embodiments of Formula (ID), R 6 is -C(O)-(substituted phenyl), -C(O)-(C1-C6 alkylene)-(optionally substituted phenyl), -C(O)-(optionally substituted 3- to 18-membered heterocycloalkyl), -C(O)-(optionally substituted 5- to 18-membered heteroaryl), -C(O)-(C1-C6 alkylene)-(optionally substituted 5- to 18-membered heteroaryl), or 5- to 18-membered heteroaryl; n is 4 or 5; and R 1 Selected from the group consisting of:

[0392] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (IE):

[0393]

[0394] or a salt thereof, wherein R 1 and n are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0395] In some embodiments of Formula (IE), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2a Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e)C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for where R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for

[0396] In some embodiments of Formula (IE), n is 4. In some embodiments, n is 5. In other embodiments, n is 6.

[0397] In another aspect, the compound of formula (II) or formula (I) is a compound of formula (IF):

[0398]

[0399] or a salt thereof, wherein R 1 , n and r are as defined for Formula (II) or Formula (I) or any variation or embodiment thereof.

[0400] In some embodiments of Formula (IF), R 1 for In some embodiments, R 1 for In some embodiments, R 1 for where R 2a Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each one alone

[0401] R 2bSelected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl); and R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl. 1 for In some embodiments, R 1 for

[0402] In some embodiments of Formula (IF), r is 1. In some embodiments, r is 2. In other embodiments, r is 3.

[0403] In some embodiments of Formula (IF), 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. In other embodiments, n is 6. In some embodiments, n is 4. In some embodiments, n is 5. In other embodiments, n is 6.

[0404] In some embodiments of Formula (IF), r is 1 and n is 2, 3, 4, 5, or 6. In some embodiments, r is 2 and n is 0, 1, 2, 3, 4, 5, or 6. In other embodiments, r is 3 and n is 0, 1, 2, 3, 4, 5, or 6.

[0405] In another aspect, the compound of formula (II) is a compound of formula (IG):

[0406]

[0407] or a salt thereof, wherein R 1 、R q 、R s and n are as defined for Formula (II) or any variation or embodiment thereof.

[0408] In some embodiments of Formula (IG), R q is H or C1-C6 alkyl, and R s is C3-C8 cycloalkyl, optionally substituted C6-C 14 aryl, optionally substituted 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(optionally substituted C6-C 14 In some embodiments, R q is H. In some embodiments, R qIn some embodiments, R q In some embodiments, R s In some embodiments, R s Is cyclopentyl or cyclohexyl. In some embodiments of formula (II), Y 1 for In some embodiments, R s is an optionally substituted C6-C 14 In some embodiments, R s is optionally independently selected from halogen, C1-C6 alkyl and C6-C 14 One or more substituents substituted with aryl C6-C 14 In some embodiments of formula (II), Y 1 for In some embodiments, R s is an optionally substituted 5- to 18-membered heteroaryl. s is a 5- to 18-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl groups. s is pyridinyl optionally substituted with one or more C1-C6 alkyl groups. 1 for In some embodiments, R s -(C1-C6 alkylene)-(optionally substituted C6-C 14 In some embodiments, -(C1-C6 alkylene)-(C6-C 14 aryl), wherein -(C1-C6 alkylene)-(C6-C 14 Aryl) C6-C 14 Aryl is optionally substituted with one or more C1-C6 alkyl groups. s is -(C1-C6 alkylene)-(phenyl), wherein the phenyl group of -(C1-C6 alkylene)-(phenyl) is optionally substituted with one or more C1-C6 alkyl groups. In some embodiments of formula (II), Y 1 for In some embodiments of Formula (II), Y 1 for

[0409]

[0410] In some embodiments of Formula (IG), R 1 Selected from the group consisting of: In some embodiments, R 1 for

[0411] In some embodiments of Formula (IG), n is 4 or 5. In some embodiments, n is 4. In some embodiments, n is 5.

[0412] In another aspect, provided herein is a compound of formula (IH):

[0413]

[0414] or a salt thereof, wherein R 1 、R b and n are as defined for Formula (II) or any variation or embodiment thereof.

[0415] In some embodiments of Formula (IH), R b is an optionally substituted 3- to 18-membered heterocycloalkyl. b is a 3- to 18-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally substituted with one or more -OH groups. b is a 6- to 10-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally substituted with one or more -OH groups. b is 1,2,3,4-tetrahydroquinolinyl, morpholinyl or piperazinyl, each independently optionally substituted with one or more C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more -OH. In some embodiments of formula (II), Y 1 for

[0416] In some embodiments of Formula (IH), R 1 for

[0417] In some embodiments of Formula (IH), n is 4 or 5. In some embodiments, n is 4. In some embodiments, n is 5.

[0418] In another aspect, provided herein is a compound of formula (IJ):

[0419]

[0420] or a salt thereof, wherein R 1、R t 、R u and n are as defined herein for Formula (II) or any variation or embodiment thereof.

[0421] In some embodiments of Formula (IJ), R t is H or C1-C6 alkyl. In some embodiments, R t is H. In some embodiments, R t In some embodiments, R t In some embodiments, R u is an optionally substituted C6-C 14 In some embodiments, R u (a) C6-C6 alkyl or halo substituted with one or more independently selected C1-C6 alkyl or halo substituents 14 (b) 5- to 18-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; or (c) -(C1-C6 alkylene)-(5- to 18-membered heteroaryl). In some embodiments, R u is a C6-C 14 In some embodiments, R u is phenyl optionally substituted with one or more independently selected C1-C6 alkyl or halo substituents. In some embodiments of formula (II), Y 1 for In some embodiments, R u is a 5- to 18-membered heteroaryl group optionally substituted with one or more independently selected C1-C6 alkyl substituents. u is a 5- to 6-membered heteroaryl group optionally substituted with one or more independently selected C1-C6 alkyl substituents. u is pyridinyl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments of formula (II), Y 1 for In some embodiments, R u is -(C1-C6 alkylene)-(5- to 18-membered heteroaryl). u is -(C1-C6 alkylene)-(pyridinyl). In some embodiments of formula (II), Y 1 for In some embodiments of Formula (II), Y 1 for

[0422] In some embodiments of Formula (IJ), R 1 for

[0423] In some embodiments of Formula (IJ), n is 4 or 5. In some embodiments, n is 4. In some embodiments, n is 5.

[0424] In one aspect, provided herein is a compound of formula (IK):

[0425]

[0426] or a salt thereof, wherein R 1 and n are as defined herein for Formula (II) or any variation or embodiment thereof.

[0427] In some embodiments of Formula (IK), R 1 for

[0428] In some embodiments of Formula (IK), n is 4 or 5. In some embodiments, n is 4. In some embodiments, n is 5.

[0429] In some embodiments, provided herein are compounds described in Table 1 and salts thereof.

[0430] Table 1

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493] In some embodiments, provided herein is a compound of Formula (II) or any variation thereof, or a pharmaceutically acceptable salt of any one of the foregoing selected from the group consisting of:

[0494] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-4-ylmethyl)urea;

[0495] tert-Butyl (6-(3-(4-carbamoylbenzyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0496] 4-((3-(4,4-dimethylcyclohexyl)ureido)methyl)benzamide;

[0497] 4-((3-(3-phenylcyclobutyl)ureido)methyl)benzamide;

[0498] tert-Butyl 4-(3-(4-carbamoylbenzyl)ureido)piperidine-1-carboxylate;

[0499] tert-Butyl (6-(3-(pyridin-4-ylmethyl)ureido)spiro[3.3]hept-2-yl)carbamate; tert-Butyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0500] tert-Butyl (6-(3-(4-(hydroxymethyl)benzyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0501] tert-Butyl (6-(3-((1H-pyrazol-4-yl)methyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0502] tert-Butyl (6-(3-(oxazol-5-ylmethyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0503] tert-Butyl (4-(3-(4-carbamoylbenzyl)ureido)cyclohexyl)carbamate;

[0504] 4-((3-(1-benzoylpiperidin-4-yl)ureido)methyl)benzamide;

[0505] N-(6-(3-(4-Carbamoylbenzyl)ureido)spiro[3.3]hept-2-yl)benzamide;

[0506] N-(6-(3-(pyridin-4-ylmethyl)ureido)spiro[3.3]hept-2-yl)benzamide;

[0507] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea;

[0508] N-(6-(3-((1H-pyrazol-4-yl)methyl)ureido)spiro[3.3]hept-2-yl)benzamide;

[0509] N-(6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)benzamide;

[0510] 4-((3-(4-(1-benzoylpiperidin-4-yl)butyl)ureido)methyl)benzamide;

[0511] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(4-methoxybenzyl)urea;

[0512] 4-((3-(3-(Benzylcarbamoyl)cyclobutyl)ureido)methyl)benzamide;

[0513] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(4-(hydroxymethyl)benzyl)urea;

[0514] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(oxazol-5-ylmethyl)urea;

[0515] 4-((3-(6-(Benzylamino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide;

[0516] tert-Butyl 1-((3-(pyridin-4-ylmethyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0517] 4-((3-(6-(pyridin-2-ylamino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide;

[0518] tert-Butyl 1-((3-(4-chlorobenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0519] tert-Butyl 1-((3-(4-methoxybenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0520] tert-Butyl 1-((3-(4-(hydroxymethyl)benzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0521] tert-Butyl 1-((3-(oxazol-5-ylmethyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0522] tert-Butyl 1-((3-((1H-pyrazol-4-yl)methyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0523] tert-Butyl 1-((3-(4-acetamidobenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0524] tert-Butyl 1-((3-(4-carbamoylbenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate;

[0525] 4-((3-(6-((pyridin-2-ylmethyl)amino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide;

[0526] 6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid methyl ester;

[0527] tert-Butyl (5-(3-(4-methoxybenzyl)ureido)pentyl)carbamate;

[0528] tert-Butyl 6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxylate;

[0529] 1-(2-(2-(2-fluorophenyl)acetyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0530] 1-(2-(2-(2-chlorophenyl)acetyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0531] 1-(4-methoxybenzyl)-3-(2-(2-(2-methoxyphenyl)acetyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0532] 1-(4-methoxybenzyl)-3-(2-(2-(2-(trifluoromethyl)phenyl)acetyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0533] 1-(4-methoxybenzyl)-3-(2-(2-(o-tolyl)acetyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0534] 6-(3-(4-methoxybenzyl)ureido)-N-(1-phenylcyclopropyl)spiro[3.3]heptane-2-carboxamide;

[0535] 1-(4-methoxybenzyl)-3-(6-(2-phenylpyrrolidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0536] 6-(3-(4-methoxybenzyl)ureido)-N-(1-phenylethyl)spiro[3.3]heptane-2-carboxamide;

[0537] N-(2-hydroxy-1-phenylethyl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0538] 1-(4-methoxybenzyl)-3-(6-(2-phenylazetidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0539] 6-(3-(4-methoxybenzyl)ureido)-N-(pyridin-3-ylmethyl)spiro[3.3]heptane-2-carboxamide;

[0540] 6-(3-(4-methoxybenzyl)ureido)-N-(pyridin-4-ylmethyl)spiro[3.3]heptane-2-carboxamide;

[0541] N-Benzyl-6-(3-(4-methoxybenzyl)ureido)-N-methylspiro[3.3]heptane-2-carboxamide;

[0542] 1-(4-methoxybenzyl)-3-(6-((2-phenylpyrrolidin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0543] N-(1-(2-fluorophenyl)ethyl)-6-(3-(4-methoxybenzyl)ureido)-N-methylspiro[3.3]heptane-2-carboxamide;

[0544] 6-(3-(4-methoxybenzyl)ureido)-N-(2-methyl-2-(o-tolyl)propyl)spiro[3.3]heptane-2-carboxamide;

[0545] N-(2-(2-fluorophenyl)-2-methylpropyl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0546] 6-(3-(4-methoxybenzyl)ureido)-N-(pyridin-2-ylmethyl)spiro[3.3]heptane-2-carboxamide;

[0547] 1-(4-methoxybenzyl)-3-(6-(3-phenylpyrrolidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0548] 1-(4-methoxybenzyl)-3-(6-(2-(pyridin-4-yl)pyrrolidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0549] 1-(4-methoxybenzyl)-3-(6-(2-(pyridin-3-yl)pyrrolidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0550] 1-(4-methoxybenzyl)-3-(6-(3-phenylazetidine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0551] 1-(6-(4-benzoylpiperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0552] 6-(3-(4-methoxybenzyl)ureido)-N-(3-phenylcyclobutyl)spiro[3.3]heptane-2-carboxamide;

[0553] 6-(3-(4-methoxybenzyl)ureido)-N-(2-(2-methoxyphenyl)-2-methylpropyl)spiro[3.3]heptane-2-carboxamide;

[0554] 6-(3-(4-methoxybenzyl)ureido)-N-(2-methyl-2-(pyridin-2-yl)propyl)spiro[3.3]heptane-2-carboxamide;

[0555] 6-(3-(4-methoxybenzyl)ureido)-N-(2-methyl-2-(pyridin-3-yl)propyl)spiro[3.3]heptane-2-carboxamide;

[0556] N-benzyl-2-(6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)-N-methylacetamide;

[0557] N-benzyl-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0558] 6-(3-(4-methoxybenzyl)ureido)-N-phenethylspiro[3.3]heptane-2-carboxamide;

[0559] 6-(3-(4-methoxybenzyl)ureido)-N-(2-phenylpropan-2-yl)spiro[3.3]heptane-2-carboxamide;

[0560] 1-(4-methoxybenzyl)-3-(6-(1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0561] 1-(4-methoxybenzyl)-3-(6-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)spiro[3.3]hept-2-yl)urea;

[0562] 1-(6-(isoindoline-2-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0563] 1-(6-(Indoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0564] N-(2-(1H-pyrazol-4-yl)ethyl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0565] 1-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0566] N-(4-cyano-2-fluorobenzyl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0567] 6-(3-(4-methoxybenzyl)ureido)-N-(3-(pyridin-4-yl)cyclobutyl)spiro[3.3]heptane-2-carboxamide;

[0568] 6-(3-(4-methoxybenzyl)ureido)-N-methyl-N-(tetrahydrofuran-3-yl)spiro[3.3]heptane-2-carboxamide;

[0569] 6-(3-(4-methoxybenzyl)ureido)-N-(2-methyl-2-(pyridin-4-yl)propyl)spiro[3.3]heptane-2-carboxamide;

[0570] tert-Butyl 2-(3-(4-methoxybenzyl)ureido)-6-azaspiro[3.4]octane-6-carboxylate;

[0571] tert-Butyl 6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.4]octane-2-carboxylate;

[0572] 1-(4-methoxybenzyl)-3-(6-(6-methyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0573] 1-(6-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0574] 6-(3-(4-methoxybenzyl)ureido)-N-phenylspiro[3.3]heptane-2-carboxamide;

[0575] 6-(3-(4-methoxybenzyl)ureido)-N-methyl-N-phenylspiro[3.3]heptane-2-carboxamide;

[0576] N-((2-(difluoromethoxy)pyridin-4-yl)methyl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0577] N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0578] 1-(4-methoxybenzyl)-3-(6-(1,2,3,4-tetrahydro-1,6-naphthyridine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0579] N-(2,3-dihydro-1H-inden-1-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0580] N-(3-(Hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0581] N-(1-hydroxy-2,3-dihydro-1H-inden-2-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0582] N-(2,3-dihydro-2H-inden-1-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0583] 6-(3-(4-methoxybenzyl)ureido)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)spiro[3.3]heptane-2-carboxamide;

[0584] N-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0585] N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide;

[0586] 6-(3-(4-methoxybenzyl)ureido)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)spiro[3.3]heptane-2-carboxamide;

[0587] 1-(6-(6-fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0588] 1-(6-(7,8-difluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0589] 1-(6-(6-(difluoromethoxy)-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0590] 1-(4-methoxybenzyl)-3-(6-(6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0591] 1-(6-(5-fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0592] 1-(6-(7-fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0593] 1-(4-methoxybenzyl)-3-(6-(6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0594] 1-(4-methoxybenzyl)-3-(6-(7-methyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0595] 1-(4-fluorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0596] 1-(4-methoxybenzyl)-3-(6-(4-(oxetan-3-yl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0597] 1-(6-(4-(cyclopropylmethyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0598] 1-(6-(2-(Hydroxymethyl)-4-methylpiperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0599] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)benzamide;

[0600] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-phenylacetamide;

[0601] 1-(2-((2-chlorophenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0602] 1-(2-((2-chlorobenzyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0603] 1-(2-((2-chlorophenethyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0604] 1-(4-chlorobenzyl)-3-(6-(dibenzylamino)spiro[3.3]hept-2-yl)urea;

[0605] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-1-(2-chlorophenyl)methanesulfonamide;

[0606] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)benzenesulfonamide;

[0607] 1-(6-(4-isopropylpiperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0608] 1-(4-methoxybenzyl)-3-(6-(4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0609] 1-(4-methoxybenzyl)-3-(6-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0610] 1-(4-methoxybenzyl)-3-(6-(4-(pyridin-2-ylmethyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0611] 1-(6-(3-(Hydroxymethyl)-4-methylpiperazine-1-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0612] 1-(6-((5,7-difluoro-3,4-dihydroquinolin-1(2H)-yl)methyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0613] 1-(6-(Indolin-1-ylmethyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0614] 1-(6-(isoindolin-2-ylmethyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0615] 1-(2-(bicyclo[2.2.1]hept-2-ylsulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0616] Methyl 4-((6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]hept-2-yl)sulfonyl)cyclohexane-1-carboxylate;

[0617] N-(6-cyanopyridin-2-yl)-6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxamide;

[0618] 6-(3-(4-methoxybenzyl)ureido)-N-(2-methylpyrimidin-5-yl)-2-azaspiro[3.3]heptane-2-carboxamide;

[0619] 1-(6-((1H-indazol-1-yl)methyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0620] 1-(2-(3-(2-chlorophenyl)propionyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0621] tert-Butyl 3-(6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carbonyl)piperidine-1-carboxylate;

[0622] 1-(4-methoxybenzyl)-3-(2-(1,2,3,4-tetrahydronaphthalene-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0623] 1-(4-methoxybenzyl)-3-(2-(6-methylnicotinoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0624] 1-(2-isonicotinoyl-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0625] 1-(4-methoxybenzyl)-3-(2-(2-methylisonicotinoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0626] 1-(2-Benzoyl-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0627] 1-(4-methoxybenzyl)-3-(2-(2-methyl-2-phenylpropionyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0628] 1-(4-methoxybenzyl)-3-(2-(1-phenylcyclopropane-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0629] 1-(4-methoxybenzyl)-3-(2-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0630] 1-(4-methoxybenzyl)-3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0631] 1-(4-methoxybenzyl)-3-(2-(3-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0632] 1-(4-methoxybenzyl)-3-(2-(4-(trifluoromethyl)benzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0633] 1-(4-methoxybenzyl)-3-(2-(2-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0634] 1-(4-methoxybenzyl)-3-(5-phenoxypentyl)urea;

[0635] 1-(4-methoxybenzyl)-3-(6-phenoxyhexyl)urea;

[0636] tert-Butyl 2-(3-(4-chlorobenzyl)ureido)-6-azaspiro[3.4]octane-6-carboxylate;

[0637] 1-(4-methoxybenzyl)-3-(2-(2-methyl-2-(p-tolyl)propionyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0638] 1-(4-methoxybenzyl)-3-(2-(2-methyl-2-(m-tolyl)propionyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0639] 1-(2-(4-methoxybenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0640] 1-(2-(4-cyanobenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0641] 1-(2-(4-(2-hydroxypropan-2-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0642] 1-(2-(4-chlorobenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0643] 1-(4-chlorobenzyl)-3-(6-(4-methylbenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0644] 1-(4-chlorobenzyl)-3-(6-(2-methylisonicotinoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0645] 1-(4-chlorobenzyl)-3-(6-(3-methylbenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0646] 1-(4-chlorobenzyl)-3-(6-(2-methylbenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0647] 1-(4-chlorobenzyl)-3-(6-(4-methoxybenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0648] 1-(4-chlorobenzyl)-3-(6-(3-methylisonicotinoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0649] 1-(4-chlorobenzyl)-3-(6-(4-fluorobenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0650] 1-(4-chlorobenzyl)-3-(6-(3-isopropylbenzoyl)-6-azaspiro[3.4]octan-2-yl)urea;

[0651] 1-(4-chlorobenzyl)-3-(6-(pyrimidin-2-yl)-6-azaspiro[3.4]octan-2-yl)urea;

[0652] 1-(4-chlorobenzyl)-3-(6-(2-methylpyridin-4-yl)-6-azaspiro[3.4]octan-2-yl)urea;

[0653] 1-(2-(3-ethylbenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0654] 1-(2-(3-Isopropylbenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0655] 1-(2-(3-(tert-Butyl)benzoyl)-2-azaspiro[3.3]hexan-6-yl)-3-(4-methoxybenzyl)urea;

[0656] 1-(2-(3-(2-hydroxypropan-2-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0657] 1-(2-(3-methoxybenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0658] 1-(2-(3-hydroxybenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0659] 1-(2-(3-(dimethylamino)benzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0660] 1-(4-methoxybenzyl)-3-(2-(3-(pyrrolidin-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0661] 1-(4-methoxybenzyl)-3-(2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0662] Methyl 3-(6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carbonyl)benzoate;

[0663] 1-(4-chlorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea;

[0664] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)nicotinamide;

[0665] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)isonicotinamide;

[0666] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-methylisonicotinamide;

[0667] 1-(4-methoxybenzyl)-3-(2-(3-(2-oxopyrrolidin-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0668] 1-(2-(3-(1H-pyrrol-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea;

[0669] 1-(4-methoxybenzyl)-3-(2-(3-(piperidin-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0670] 1-(4-methoxybenzyl)-3-(2-(3-morpholinobenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0671] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-6-methylnicotinamide;

[0672] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-methylbenzamide;

[0673] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-3-methoxybenzamide;

[0674] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-3-(methylsulfonyl)benzamide;

[0675] 1-(4-chlorobenzyl)-3-(2-(2-phenoxyethoxy)ethyl)urea;

[0676] tert-Butyl 6-(3-(4-chlorobenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxylate;

[0677] tert-Butyl (6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)carbamate;

[0678] 1-(4-chlorobenzyl)-3-(6-(6-methylpyridin-2-yl)-6-azaspiro[3.4]octan-2-yl)urea;

[0679] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-3-hydroxybenzamide;

[0680] 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid methyl ester;

[0681] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(tetrahydrofuran-3-yl)spiro[3.3]heptane-2-carboxamide;

[0682] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-methylnicotinamide;

[0683] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-3-methylisonicotinamide;

[0684] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-4-methylnicotinamide;

[0685] 1-(4-chlorobenzyl)-3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-ylurea;

[0686] 1-(4-fluorobenzyl)-3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-ylurea;

[0687] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-hydroxybenzamide;

[0688] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-(dimethylamino)benzamide;

[0689] 1-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(pyridin-4-ylmethyl)urea;

[0690] 4-((3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)benzamide;

[0691] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-2-cyanobenzamide;

[0692] N-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)pyridine-3-sulfonamide;

[0693] 1-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-((6-oxo-1,6-dihydropyridin-3-yl)methyl)urea;

[0694] 5-((3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)picolinamide;

[0695] 1-(4-chlorobenzyl)-3-(2-((2-chlorophenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0696] 1-(4-chlorobenzyl)-3-(2-((3-chlorophenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0697] 1-(4-chlorobenzyl)-3-(2-((2-methoxyphenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0698] 1-(2-(3-(1H-pyrrol-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-chlorobenzyl)urea;

[0699] 1-(4-chlorobenzyl)-3-(2-(3-isopropylbenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0700] 1-(4-chlorobenzyl)-3-(2-(2-methyl-2-phenylpropionyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0701] 4-((3-(2-(3-(Pyrrolidin-1-yl)benzoyl)-2-azaspiro[3.3]hept-6-ylureido)methyl)benzamide;

[0702] 4-((3-(2-(5-(Pyrrolidin-1-yl)nicotinoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)benzamide;

[0703] 4-((3-(2-(4-chlorobenzoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)benzamide;

[0704] 4-((3-(2-(6-methylnicotinoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)benzamide;

[0705] 4-((3-(2-(2-methylisonicotinoyl)-2-azaspiro[3.3]hept-6-yl)ureido)methyl)benzamide;

[0706] 1-((1H-pyrazol-4-yl)methyl)-3-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)urea;

[0707] 1-(2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)-3-(oxazol-4-ylmethyl)urea;

[0708] 1-(4-methoxybenzyl)-3-(6-(4-methylpiperazine-1-carbonyl)spiro[3.3]hept-2-ylurea;

[0709] 4-(6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carbonyl)piperazine-1-carboxylic acid methyl ester;

[0710] 1-(6-(1,1-dioxythiomorpholine-4-carbonyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0711] 4-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carbonyl)piperazine-1-carboxylic acid methyl ester;

[0712] 1-(4-chlorobenzyl)-3-(6-(2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-oxoethyl)spiro[3.3]hept-2-yl)urea;

[0713] 1-(4-chlorobenzyl)-3-(6-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethylspiro[3.3]hept-2-yl)urea;

[0714] 1-(4-chlorobenzyl)-3-(6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)spiro[3.3]hept-2-yl)urea;

[0715] N-Benzyl-2-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)-N-methylpropionamide;

[0716] 1-(4-chlorobenzyl)-3-(6-((4-methyl-3-oxopiperazin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0717] 1-(4-chlorobenzyl)-3-(6-((2-(pyridin-3-yl)pyrrolidin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0718] 1-(4-chlorobenzyl)-3-(6-((2-methyl-5-oxopyrrolidin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0719] 1-(4-chlorobenzyl)-3-(6-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0720] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0721] 1-(4-chlorobenzyl)-3-(6-((3-methyl-2-oxopyrrolidin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0722] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-6-methylpicolinamide;

[0723] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-2-methylisonicotinamide;

[0724] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-1H-pyrazole-4-carboxamide;

[0725] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-N,6-dimethylnicotinamide;

[0726] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-6-methylnicotinamide;

[0727] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide;

[0728] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)cyclopentanecarboxamide;

[0729] N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)-2-oxopiperidine-4-carboxamide;

[0730] 1-(4-chlorobenzyl)-3-(6-(1-(4-methyl-3-oxopiperazin-1-yl)ethyl)spiro[3.3]hept-2-yl)urea;

[0731] 1-(4-chlorobenzyl)-3-(6-((4-methyl-2-phenylpiperazin-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0732] N-(1-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)ethyl)-6-methylnicotinamide;

[0733] 1-(4-chlorobenzyl)-3-(5-(3,4-dihydroquinolin-1(2H)-yl)-5-oxopentyl)urea;

[0734] 6-(3-(4-chlorobenzyl)ureido)-N-cyclohexylhexanamide;

[0735] 6-(3-(4-chlorobenzyl)ureido)-N-cyclopentylhexanamide;

[0736] 1-(4-chlorobenzyl)-3-(6-morpholino-6-oxohexyl)urea;

[0737] 1-(4-chlorobenzyl)-3-(6-(4-neopentylpiperazin-1-yl)-6-oxohexyl)urea;

[0738] 1-(4-chlorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-6-oxohexyl)urea;

[0739] 6-(3-(4-chlorobenzyl)ureido)-N-(o-tolyl)hexanamide;

[0740] 6-(3-(4-chlorobenzyl)ureido)-N-(pyridin-4-yl)hexanamide;

[0741] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(m-tolyl)hexanamide;

[0742] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(pyridin-4-yl)hexanamide;

[0743] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(o-tolyl)hexanamide;

[0744] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(3-methylbenzyl)hexanamide;

[0745] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-phenylhexanamide;

[0746] N-Benzyl-6-(3-(4-chlorobenzyl)ureido)-N-methylhexanamide;

[0747] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(pyridin-3-yl)hexanamide;

[0748] 6-(3-(4-chlorobenzyl)ureido)-N-methyl-N-(pyridin-2-yl)hexanamide;

[0749] 6-(3-(4-chlorobenzyl)ureido)-N-(2-fluorophenyl)hexanamide;

[0750] N-([1,1'-biphenyl]-2-yl)-6-(3-(4-chlorobenzyl)ureido)hexanamide;

[0751] 6-(3-(4-chlorobenzyl)ureido)-N-(2-fluorophenyl)-N-methylhexanamide;

[0752] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)-2-methylbenzamide;

[0753] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)-3-methylbenzamide;

[0754] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)nicotinamide;

[0755] 6-(3-(4-chlorobenzyl)ureido)-N-(6-methylpyridin-3-yl)hexanamide;

[0756] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)picolinamide;

[0757] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)-2-fluorobenzamide;

[0758] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)-6-methylnicotinamide;

[0759] N-(2-Fluorophenyl)-6-(3-(4-methoxybenzyl)ureido)-N-methylhexanamide;

[0760] N-(5-(3-(4-chlorobenzyl)ureido)pentyl)-2-(pyridin-3-yl)acetamide;

[0761] 6-(3-(4-chlorobenzyl)ureido)-N-(4-fluorophenyl)hexanamide;

[0762] 6-(3-(4-chlorobenzyl)ureido)-N-(3-fluorophenyl)hexanamide;

[0763] N-(2-Fluorophenyl)-N-methyl-6-(3-(pyridin-4-ylmethyl)ureido)hexanamide;

[0764] 6-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-fluorophenyl)-N-methylhexanamide;

[0765] N-(2-Fluorophenyl)-N-methyl-6-(3-(oxazol-5-ylmethyl)ureido)hexanamide;

[0766] 1-(4-chlorobenzyl)-3-(4-(1-nicotinoylpiperidin-4-yl)butyl)urea;

[0767] 1-(4-chlorobenzyl)-3-(4-(1-isonicotinoylpiperidin-4-yl)butyl)urea;

[0768] 1-(4-chlorobenzyl)-3-(4-(1-(2-phenylacetyl)piperidin-4-yl)butyl)urea;

[0769] 1-(4-chlorobenzyl)-3-(4-(1-pyridinylpiperidin-4-yl)butyl)urea;

[0770] 1-(4-(1-benzoylpiperidin-4-yl)butyl-1,1-d2)-3-(oxazol-5-ylmethyl)urea;

[0771] 1-(4-chlorobenzyl)-3-(4-(1-(2-(pyridin-3-yl)acetyl)piperidin-4-yl)butyl)urea;

[0772] 1-(4-chlorobenzyl)-3-(4-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)butyl)urea;

[0773] 1-(4-chlorobenzyl)-3-(4-(1-(3-methylbenzoyl)piperidin-4-yl)butyl)urea;

[0774] 1-(4-chlorobenzyl)-3-(4-(1-(2-methylbenzoyl)piperidin-4-yl)butyl)urea;

[0775] 1-(4-chlorobenzyl)-3-(4-(1-(6-methylpicolinoyl)piperidin-4-yl)butyl)urea;

[0776] 1-(4-chlorobenzyl)-3-(4-(1-(2-(6-methylpyridin-2-yl)acetyl)piperidin-4-yl)butyl)urea;

[0777] 1-(4-chlorobenzyl)-3-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)butyl)urea;

[0778] 1-(4-chlorobenzyl)-3-(4-(1-(2-oxopiperidine-4-carbonyl)piperidin-4-yl)butyl)urea;

[0779] 1-(4-chlorobenzyl)-3-(4-(1-(1-methyl-2-oxopiperidine-4-carbonyl)piperidin-4-yl)butyl)urea;

[0780] 1-(4-chlorobenzyl)-3-(4-(1-(5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)butyl)urea;

[0781] 1-(4-chlorobenzyl)-3-(4-(1-(1-methyl-5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)butyl)urea;

[0782] 1-(4-chlorobenzyl)-3-(4-(1-(oxazole-2-carbonyl)piperidin-4-yl)butyl)urea;

[0783] 1-(4-chlorobenzyl)-3-(4-(1-(isoxazole-5-carbonyl)piperidin-4-yl)butyl)urea;

[0784] 1-(4-chlorobenzyl)-3-(4-(1-(pyridin-2-yl)piperidin-4-yl)butyl)urea;

[0785] 1-(4-chlorobenzyl)-3-(4-(1-(pyridin-4-yl)piperidin-4-yl)butyl)urea;

[0786] 1-(4-chlorobenzyl)-3-(4-(1-(6-methylnicotinoyl)piperidin-4-yl)butyl)urea;

[0787] 1-(4-chlorobenzyl)-3-(4-(1-(2-(2-methylpyridin-3-yl)acetyl)piperidin-4-yl)butyl)urea;

[0788] 1-(4-chlorobenzyl)-3-(4-(1-(2-(6-methylpyridin-3-yl)acetyl)piperidin-4-yl)butyl)urea;

[0789] 1-(4-chlorobenzyl)-3-(4-(1-(1-methyl-1H-1,2,3-triazole-4-carbonyl)piperidin-4-yl)butyl)urea;

[0790] 1-(4-chlorobenzyl)-3-(4-(1-(2-(o-tolyl)acetyl)piperidin-4-yl)butylurea;

[0791] 1-(4-chlorobenzyl)-3-(4-(1-(2-(difluoromethyl)benzoyl)piperidin-4-yl)butyl)urea;

[0792] 1-(4-(1-(2-(1H-tetrazol-5-yl)benzoyl)piperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea;

[0793] 1-(4-(1-(2-(1H-pyrazol-4-yl)acetyl)piperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea;

[0794] 1-(4-(4-benzoylpiperazin-1-yl)butyl)-3-(4-chlorobenzyl)urea;

[0795] 1-(4-(1-(2H-tetrazol-5-yl)piperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea;

[0796] 1-(4-chlorobenzyl)-3-(4-(1-(2,6-dimethylbenzoyl)piperidin-4-yl)butylurea;

[0797] 1-(4-(1-(2-methylbenzoyl)piperidin-4-yl)butyl)-3-(oxazol-5-ylmethylurea;

[0798] 4-((3-(4-(1-(2-methylbenzoyl)piperidin-4-yl)butyl)ureido)methyl)benzamide;

[0799] 1-(4-methoxybenzyl)-3-(4-(1-(2-methylbenzoyl)piperidin-4-yl)butylurea;

[0800] 1-(4-(1-(2-methylbenzoyl)piperidin-4-yl)butyl)-3-(pyridin-4-ylmethylurea;

[0801] 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(oxazol-5-ylmethyl-d2)urea;

[0802] 1-(4-methoxybenzyl)-3-(6-(5-phenyl-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)urea;

[0803] 1-(4-methoxybenzyl)-3-(6-(4-phenyloxazol-2-yl)spiro[3.3]hept-2-yl)urea;

[0804] 1-(6-(Benzo[d]oxazol-2-yl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea;

[0805] 1-(4-chlorobenzyl)-3-(6-(hydroxy(phenyl)methyl)spiro[3.3]hept-2-yl)urea;

[0806] 1-(4-chlorobenzyl)-3-(6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)urea;

[0807] 1-(4-methoxybenzyl)-3-(6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)urea;

[0808] 1-(4-chlorobenzyl)-3-(6-(pyrazin-2-ylmethyl)spiro[3.3]hept-2-yl)urea;

[0809] 1-(4-methoxybenzyl)-3-(6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)urea;

[0810] 1-(4-chlorobenzyl)-3-(6-((4-cyano-1H-pyrazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0811] 1-(4-methoxybenzyl)-3-(6-(4-methylbenzyl)spiro[3.3]hept-2-yl)urea;

[0812] 1-(4-methoxybenzyl)-3-(6-(3-methylbenzyl)spiro[3.3]hept-2-yl)urea;

[0813] 1-(4-methoxybenzyl)-3-(6-(2-methylbenzyl)spiro[3.3]hept-2-yl)urea;

[0814] 1-(4-methoxybenzyl)-3-(6-((6-methylpyridin-3-yl)methyl)spiro[3.3]hept-2-yl)urea;

[0815] 1-(4-chlorobenzyl)-3-(6-(1-hydroxy-1-(6-methylpyridin-3-yl)ethyl)spiro[3.3]hept-2-yl)urea;

[0816] 1-(6-((1H-1,2,4-triazol-1-yl)methyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea;

[0817] 1-(4-chlorobenzyl)-3-(6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-yl)urea;

[0818] 1-(4-chlorobenzyl)-3-(6-(pyridin-4-yloxy)spiro[3.3]hept-2-yl)urea;

[0819] 1-(4-chlorobenzyl)-3-(6-(methylsulfonyl)spiro[3.3]hept-2-yl)urea;

[0820] 1-(4-chlorobenzyl)-3-(6-(pyridin-3-yloxy)spiro[3.3]hept-2-yl)urea;

[0821] 1-(4-methoxybenzyl)-3-(6-(pyridin-3-yloxy)spiro[3.3]hept-2-yl)urea;

[0822] 1-(4-chlorobenzyl)-3-(6-(pyridin-3-ylmethyl)spiro[3.3]hept-2-yl)urea;

[0823] 1-(4-chlorobenzyl)-3-(6-((2-methylpyridin-3-yl)methyl)spiro[3.3]hept-2-ylurea;

[0824] 1-(4-chlorobenzyl)-3-(6-((6-methylpyridin-3-yl)methyl)spiro[3.3]hept-2-ylurea;

[0825] 1-(4-chlorobenzyl)-3-(6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-yl)urea;

[0826] 1-(4-methoxybenzyl)-3-(6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-yl)urea;

[0827] 1-(4-chlorobenzyl)-3-(6-(pyridin-3-ylmethoxy)spiro[3.3]hept-2-yl)urea;

[0828] 1-(4-methoxybenzyl)-3-(6-(pyridin-3-ylmethoxy)spiro[3.3]hept-2-yl)urea;

[0829] 1-(4-chlorobenzyl)-3-(6-((phenylsulfonyl)methyl)spiro[3.3]hept-2-yl)urea;

[0830] 1-(4-chlorobenzyl)-3-(6-((pyridin-3-ylsulfonyl)methyl)spiro[3.3]hept-2-ylurea; and

[0831] 1-(6-([1,4'-bipiperidine]-1'-carbonyl)-6-azaspiro[3.4]octan-2-yl)-3-(4-chlorobenzyl)urea,

[0832] or a pharmaceutically acceptable salt of any one of the foregoing.

[0833] In some variations, any of the compounds described herein (such as compounds of Formula (I) or Formula (II) or any variation thereof) or the compounds of Table 1 can be deuterated (e.g., hydrogen atoms are replaced by 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 that used to prepare corresponding non-deuterated compounds. Other methods known in the art can also be used to replace hydrogen atoms with deuterium atoms.

[0834] Any formula given herein, such as Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK) is intended to represent compounds having the structure described by the structural formula, as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and, therefore, exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any proportion, are considered to be within the scope of the formula. Thus, any formula given 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 proportion. When a compound of Table 1 is described as having a specific stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of stereoisomers of the compound in any proportion, are also provided herein. For example, where a compound of Table 1 has a stereocenter in the "S" stereochemical configuration, enantiomers of the compound in which the stereocenter is in the "R" stereochemical configuration are also provided herein. Similarly, where a compound of Table 1 has a stereocenter in the "R" configuration, enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. In addition, if a compound of Table 1 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, if a compound of Table 1 contains a first stereocenter and a second stereocenter with "R" and "R" stereochemical configurations, respectively, stereoisomers of the compound are also provided, having a first and a second stereocenter with "S" and "S" stereochemical configurations, with "S" and "R" stereochemical configurations, and with "R" and "S" stereochemical configurations, respectively. If the compound of Table 1 contains a first stereocenter and a second stereocenter with "S" and "S" stereochemical configurations, respectively, stereoisomers of the compound are also provided, which have the first and second stereocenters with "R" and "R" stereochemical configurations, respectively, with "S" and "R" stereochemical configurations, respectively, and with "R" and "S" stereochemical configurations, respectively. If the compound of Table 1 contains a first stereocenter and a second stereocenter with "S" and "R" stereochemical configurations, respectively, stereoisomers of the compound are also provided, which have the first and second stereocenters with "R" and "S" stereochemical configurations, respectively, with "R" and "R" stereochemical configurations, respectively, and with "S" and "S" stereochemical configurations, respectively.Similarly, if a compound of Table 1 contains a first stereocenter and a second stereocenter with "R" and "S" stereochemical configurations, respectively, stereoisomers of the compound are also provided, having first and second stereocenters with "S" and "R" stereochemical configurations, "R" and "R" stereochemical configurations, and "S" and "S" stereochemical configurations, respectively. In addition, certain structures can exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any formula given herein is intended to refer to any one of the hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0835] Representative examples of the compounds detailed herein (including intermediates and final compounds) are depicted in the Tables and elsewhere herein. It should be understood that, in one aspect, any of the compounds can be used in the methods detailed herein, including, where appropriate, intermediate compounds that can be isolated and administered to an individual or subject.

[0836] As is well understood by those skilled in the art, the compounds depicted herein may exist as salts even if no salt is depicted, and it is understood that the compositions and methods provided herein include all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0837] In one variation, the compounds described herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions are provided, comprising the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any compound or form thereof described herein.

[0838] This article provides R a 、R b 、R q 、R s 、R t 、R u 、R 1 、n、Y 1 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e , G 1 、p1、p2、q1、q2、r、R 3 、R3a 、R 3b 、R 3c 、R 3d 、R 3f 、R 3g 、R 3h 、R 3i 、R 3j 、R 3k 、R 3l 、R 3m 、R 3n 、R 3p 、R 3q 、R 3r 、R 3s 、R 4 、R 5 and R 6 Any variation or embodiment can be combined with R a 、R b 、R q 、R s 、R t 、R u 、R 1 、n、Y 1 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e , G 1 、p1、p2、q1、q2、r、R 3 、R 3a 、R 3b 、R 3c 、R 3d 、R 3f 、R 3g 、R 3h 、R 3i 、R 3j 、R 3k 、R 3l 、R 3m 、R 3n 、R 3p 、R 3q 、R 3r 、R 3s 、R 4 、R 5 and R 6 Any other variant or embodiment combination is intended to the same extent as if each combination had been individually and explicitly described.

[0839] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0840] As used herein, when any variable occurs more than one time in a formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0841] Formula (II) and / or formula (I) include all subformulae thereof.

[0842] The compound names provided herein (including Table 1) are provided by ChemBioDraw Professional 15.0. It will be appreciated by those skilled in the art that various generally accepted nomenclature systems and symbols can be used to name or identify compounds. For example, common names, systematic names, or non-systematic names can be used to name or identify compounds. Generally accepted nomenclature systems and symbols in the chemical field include, for example, Chemical Abstracts Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0843] Composition

[0844] Also provided are compositions, such as pharmaceutical compositions, comprising the compounds disclosed and / or described herein and one or more additional agents, medicaments, adjuvants, carriers, excipients, and the like. Suitable drugs and medicaments include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions are provided, such as pharmaceutical compositions containing one or more compounds described herein or pharmaceutically acceptable salts thereof.

[0845] In some embodiments, a pharmaceutically acceptable composition is provided, comprising a compound of Formula (II) or Formula (I) (such as a compound of Formula (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK)), 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 to prepare the compounds described herein. The compositions described herein may include any other suitable active or inactive agent.

[0846] Any of the compositions described herein may be sterile or contain sterile components. Sterilization may be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds or conjugates.

[0847] Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0848] How to use

[0849] The compounds and compositions detailed herein, such as 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.

[0850] Without being bound by theory, it is believed that the compounds and pharmaceutical compositions disclosed herein work by regulating 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 to an individual or subject in need thereof a compound of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) or (IK) or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of 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 kidney disease, a metabolic disease, a nervous system disease or damage, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscular dystrophy in an individual or subject is provided, comprising administering to the individual or subject in need thereof a compound of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK) or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0851] Also provided herein are uses of a compound of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition mediated by NAMPT activity in a subject. In some aspects, provided are compounds or compositions as described herein for use in methods of treating the human or animal body by therapy. In some embodiments, provided herein are compounds of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in methods of treating the human or animal body by therapy. In some embodiments, provided herein are compounds of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating 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 kidney disease, a metabolic disease, a nervous system disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscular dystrophy.

[0852] Also provided herein are compositions (including pharmaceutical compositions) as described herein for treating, preventing and / or delaying the onset and / or development of the diseases described herein and other methods described herein.In certain embodiments, the composition comprises a pharmaceutical formulation in unit dosage form.

[0853] 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 human.

[0854] In many diseases, small molecule-mediated stimulation of NAMPT activity to increase NAD+ levels may have clinical benefits ( 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 diseases include, but are not limited to, heart disease, chemotherapy-induced tissue damage, kidney disease, metabolic diseases, muscle diseases, nervous system diseases and injuries, diseases caused by impaired stem cell function, as well as DNA damage and primary mitochondrial disorders. In some embodiments, the disease or condition mediated by NAMPT activity is heart disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, nervous system disease or damage, disease caused by impaired stem cell function, or DNA damage and primary mitochondrial disorders.

[0855] Heart disease. In various preclinical models of heart failure, NAD and NAMPT levels are reduced. In these models, cardiac function can be rescued by restoring NAD or overexpressing NAMPT via oral supplementation (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.

[0856] Chemotherapy-induced tissue damage. The use of chemotherapy regimens is frequently limited by toxicity to healthy tissues, and severe oxidative stress is thought to play a major role. NAD elevation has been shown to trigger a strong antioxidant response. Therefore, NAMPT activators are thought to be widely used in various chemotherapy settings to prevent reversible and irreversible secondary lesions. Examples are anthracycline and trastuzumab cardiotoxicity; cisplatin-induced renal damage; cisplatin, paclitaxel, vincristine and other agent-induced peripheral neuropathy. Neuroprotection caused by NAMPT activation can also be used to treat / prevent chemotherapy-related cognitive dysfunction ("chemo brain"), which is caused by the destruction of healthy neural tissue during active treatment and long after treatment has stopped. For example, see Zheng et al., Clin Sci (Lond). 2019, 133 (13): 1505-1521.

[0857] Kidney disease. Kidney disease is very common and is an area of ​​urgent unmet medical need. Approximately 3% of hospitalized patients are diagnosed with acute kidney injury (AKI). A portion of patients will develop chronic kidney disease that may require long-term dialysis or kidney transplantation. A key feature of renal dysfunction is reduced activity of SIRT1 and SIRT3, which is characterized by a decrease in the sirtuin substrate NAD, primarily caused by impaired de novo NAD+ synthesis. NAMPT is strongly expressed during renal injury, so the use of NAMPT-activating small molecules is considered an effective measure to prevent AKI. Similarly, renal mesangial cell hypertrophy shows depletion of NAD+, and restoration of intracellular NAD+ levels is considered effective. For example, see Poyan Mehr et al., Nat Med. 2018, Sep; 24(9): 1351-9.

[0858] Metabolic diseases. NAD+ elevation improves insulin sensitivity, dyslipidemia, and mitochondrial function in metabolic diseases and prevents / ameliorates nonalcoholic and alcoholic steatohepatitis in preclinical models. In the United States alone, more than 3 million people are diagnosed with nonalcoholic steatohepatitis each year, and it is one of the leading reasons for liver transplantation. See Guarino and Dufour, Metabolites. 2019, Sep 10; 9(9), pii:E180; Yoshino et al., Cell Metab. 2011, 14(4):528-36.

[0859] Muscle diseases. Preclinical data have shown that NAD+ enhancement strategies can alleviate skeletal muscle dysfunction in a variety of diseases, including Duchenne muscular dystrophy and age-related sarcopenia. See 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.

[0860] Neurological diseases and injuries. Supplementation of NAD via NAMPT activation has neuroprotective effects and has therapeutic benefits in preclinical models of various neurological diseases and injuries, 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.

[0861] Diseases caused by impaired stem cell function. NAD increases promote stem cell activation and hematopoiesis and can be used to accelerate the expansion of stem cell populations after stem cell transplantation. See Pi et al., Aging (Albany NY). 2019, 11(11): 3505-3522.

[0862] DNA damage disorders and primary mitochondrial disorders. NAMPT activators will also be useful in 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 manifestations for which increasing NAD via 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.

[0863] In some embodiments, a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof is provided, comprising administering to an individual or subject in need thereof a compound of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), or (IK), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, nervous system disease or damage, disease caused by impaired stem cell function, and DNA damage and primary mitochondrial disorders.

[0864] Additional applications of small molecule NAMPT activators are provided in Table 2.

[0865] Table 2

[0866]

[0867]

[0868]

[0869]

[0870] In some embodiments, the disease or condition mediated by NAMPT activity is cancer and chemotherapy-induced tissue damage, cardiovascular disease, kidney disease, chronic inflammatory and fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, nervous system disease or injury, or DNA damage disorder or primary mitochondrial disorder. In some embodiments, a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof is provided, comprising administering a compound of Formula (II), (I), (IA), (I-A1), (I-A2), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) or (IK) 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, kidney disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, nervous system disease or injury, DNA damage disorder or primary mitochondrial disorder, including any of the diseases listed in Table 2.

[0871] dose

[0872] The compounds and compositions disclosed and / or described herein are administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for a disease state). Although human dosage levels have not been optimized for the chemical entities described herein, the daily dose range is generally about 0.01 to 100 mg / kg body weight; in some embodiments, about 0.05 to 10.0 mg / kg body weight, and in some embodiments, about 0.10 to 1.4 mg / kg body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range will be about 0.7 to 7000 mg per day; in some embodiments, about 3.5 to 700.0 mg per day, and in some embodiments, about 7 to 100.0 mg per day. The amount of the chemical entity administered will depend, for example, on the subject being treated and the disease state, the severity of the ailment, the mode and schedule of administration, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg per day, and an exemplary intravenous dosage is about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound.

[0873] The daily dose is the total amount administered in a day. The daily dose can be, but is not limited to, administered daily, every other day, weekly, every two weeks, monthly, or at varying intervals. In some embodiments, the time period for administering the daily dose ranges from one day to the lifetime of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple separate doses, such as in two, three, or four separate doses. In some embodiments, the daily dose is administered in two separate doses.

[0874] The administration of the compounds and compositions disclosed and / or described herein can be via any acceptable therapeutic agent administration mode, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0875] Pharmaceutically acceptable compositions include solid, semisolid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories and aerosol forms. The compounds disclosed and / or described herein can also be administered for a long time and / or in a pulsed manner at a predetermined rate in a sustained or controlled release dosage form (e.g., a controlled release / sustained release pill, a long-acting depot injection, an osmotic pump or a transdermal (including electrotransport) patch). In some embodiments, the composition is provided in a unit dosage form suitable for a single administration of a precise dose.

[0876] 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, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitol monolaurate, triethanolamine acetate, triethanolamine oleate). Generally speaking, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95% or about 0.5% to 50% of the compounds disclosed and / or described herein by weight. The actual methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0877] In some embodiments, the composition will take the form of a pill or tablet, and thus the composition may contain one or more diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate), and / or binders (e.g., starch, gum arabic, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives) along with the compound disclosed and / or described herein. Other solid dosage forms include powders, pellets, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in gelatin capsules.

[0878] Liquid pharmaceutical compositions can be prepared, for example, by dissolving, dispersing or suspending the compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous glucose solution, glycerol, ethylene glycol, ethanol, etc.) to form a solution or suspension. Injections can be prepared into conventional forms, either as liquid solutions or suspensions, as emulsions, or into solid forms suitable for dissolving or suspending in liquids before injection. The percentage of the compound included in such parenteral compositions depends on, for example, the physical properties of the compound, the activity of the compound, and the needs of the subject. However, an active ingredient percentage of 0.01% to 10% in the solution can be employed, and if the composition is a solid that will be diluted to another concentration subsequently, it can be higher. In some embodiments, the composition will comprise approximately 0.2% to 2% of the compound disclosed and / or described herein in the solution.

[0879] Pharmaceutical compositions of the compounds disclosed and / or described herein can also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a finely divided powder for insufflation, alone or in combination with an inert carrier such as lactose. In this case, the particles of the pharmaceutical composition can have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0880] Additionally, pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional agents, medicaments, adjuvants, etc. Suitable drugs and agents include those described herein.

[0881] Reagent test kit

[0882] Also provided are articles and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles can include containers with labels. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials (such as glass or plastic). The containers can hold the pharmaceutical compositions provided herein. The label on the container can indicate that the pharmaceutical composition is used to prevent, treat, or inhibit the conditions described herein, and can also indicate instructions for in vivo or in vitro use.

[0883] In one aspect, provided herein are kits containing a compound or composition as described herein and instructions for use. The kit may contain instructions for treating cardiac disease in an individual or subject in need thereof. The kit may additionally contain any materials or equipment that can be used to administer the compound or composition, such as a vial, syringe, or IV bag. The kit may also contain sterile packaging.

[0884] combination

[0885] The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other therapies and / or therapeutic agents useful for treating the above-mentioned conditions, diseases, or disorders.

[0886] Listed implementation plans

[0887] The embodiments listed below represent aspects of the invention.

[0888] 1. A compound of formula (I):

[0889]

[0890] or a pharmaceutically acceptable salt thereof,

[0891] in:

[0892] Y 1 for And R 1 Selected from the group consisting of:

[0893] or

[0894] Y 1 for And R 1 Selected from the group consisting of:

[0895] in

[0896] R 2a and R 2b Each is independently a halogen, -O(C1-C6 alkyl), a C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and

[0897] R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl;

[0898] G 1 is CH or N;

[0899] p1 and p2 are each independently 0, 1 or 2;

[0900] q1 and q2 are each independently 1 or 2;

[0901] r is 1, 2, or 3;

[0902] n is 0 to 6;

[0903] When Y 1 for When n is 4, 5 or 6; and

[0904] When Y 1 for and when r is 1, n is 2, 3, 4, 5 or 6;

[0905] R 3 Selected from the group consisting of:

[0906] i. C1-C6 alkyl;

[0907] ii.C6-C 14 aryl;

[0908] iii. optionally substituted 5- to 18-membered heteroaryl;

[0909] iv.-NR 3a R 3b ,in

[0910] R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl);

[0911] v.-OR 3c ,in

[0912] R 3c C6-C 14 aryl;

[0913] vi.-C(O)R 3d ,in

[0914] R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; optionally substituted C6-C 14 Aryl substituted C3-C8 cycloalkyl; C3-C8 cycloalkenyl; optionally substituted C6-C 14 Aryl; optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl); optionally substituted 3- to 18-membered heterocycloalkyl; and optionally substituted 5- to 18-membered heteroaryl,

[0915] in

[0916] R 3f and R 3g Each independently selected from the group consisting of:

[0917] (a) hydrogen,

[0918] (b) optionally substituted C1-C6 alkyl,

[0919] (c)C6-C 14 Aryl,

[0920] (d) an optionally substituted 3- to 18-membered heterocycloalkyl group,

[0921] (e) optionally substituted 5- to 18-membered heteroaryl,

[0922] (f) optionally substituted C3-C 10 cycloalkyl; and

[0923] (g) optionally substituted C3-C 10 cycloalkenyl;

[0924] vii. C(O)NR 3h R 3i , C1-C6 alkyl substituted by an optionally substituted 3- to 18-membered heterocycloalkyl or an optionally substituted 5- to 18-membered heteroaryl,

[0925] where R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl);

[0926] viii.-C(O)OR 3j ,in

[0927] R 3j is hydrogen or C1-C6 alkyl;

[0928] ix.-NHC(O)R 3k ,in

[0929] R 3k is an optionally substituted C6-C 14 Aryl, optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl), or an optionally substituted 5- to 18-membered heteroaryl;

[0930] x.-NHC(O)OR 3l ,in

[0931] R 3l is hydrogen or C1-C6 alkyl;

[0932] xi.-NHSO2R 3m ,in

[0933] R 3m is an optionally substituted 5- to 18-membered heteroaryl, an optionally substituted C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), each of which is optionally substituted; and

[0934] xii.-SO2R 3n ;in

[0935] R 3n is optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 14 Aryl, or optionally substituted -(C1-C6 alkylene)-(C6-C 14 aryl);

[0936] R 4 is phenyl or -C(O)NH-CH2-phenyl;

[0937] R 5a and R 5b are independently selected from the group consisting of: hydrogen, methyl, and -NHC(O)O(C1-C6 alkyl); and

[0938] R 6 Selected from the group consisting of -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) and -C(O)-phenyl; and

[0939] in

[0940] (1) When Y 1 for When n is 0 or 1, R 1 Selected from the group consisting of: and

[0941] (2) When Y 1 for When n is 0, R 1 Selected from the group consisting of:

[0942] 2. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y is

[0943] 3. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein p1 is 1 and q1 is 1.

[0944] 4. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein p1 is 2 and q1 is 1.

[0945] 5. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein p1 is 2 and q1 is 2.

[0946] 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein p2 is 1 and q2 is 1.

[0947] 7. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein p2 is 0 and q2 is 1.

[0948] 8. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein p2 is 1 and q2 is 2.

[0949] 9. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R3 It is a C1-C6 alkyl group.

[0950] 10. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 C6-C 14 Aryl.

[0951] 11. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 18-membered heteroaryl group optionally substituted by a C1-C6 alkyl group.

[0952] 12. The compound according to embodiment 11 or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl or pyrimidinyl optionally substituted by C1-C6 alkyl.

[0953] 13. The compound according to embodiment 11 or embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0954] 14. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -NR 3a R 3b , where R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl).

[0955] 15. The compound according to embodiment 14 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0956] 16. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 OR 3c , where R 3c C6-C 14 Aryl.

[0957] 17. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)R 3d .

[0958] 18. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R3d -NR 3f R 3g , and R 3f and R 3g Each independently selected from the group consisting of:

[0959] (a) hydrogen,

[0960] (b) optionally selected from -OH, C6-C 14 C1-C6 alkyl substituted by one or more substituents from the group consisting of aryl and 5-membered to 18-membered heteroaryl, wherein C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, and CN.

[0961] (c)C6-C 14 Aryl,

[0962] (d) a 3- to 18-membered heterocycloalkyl group,

[0963] (e) a 5- to 18-membered heteroaryl group optionally substituted by methyl or CN,

[0964] (f) C3-C4 optionally substituted with one or more substituents selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 aryl and 5- to 18-membered heteroaryl; and

[0965] (g) C3-C4 optionally substituted with one or more substituents selected from the group consisting of 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 aryl and 5- to 18-membered heteroaryl.

[0966] 19. The compound according to embodiment 17 or embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0967]

[0968] 20. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d It is a C3-C8 cycloalkyl group.

[0969] 21. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d For C6-C14 Aryl-substituted C3-C8 cycloalkyl, wherein C6-C 14 The aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0970] 22. The compound according to embodiment 20 or embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0971] 23. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d It is a C3-C8 cycloalkenyl group.

[0972] 24. The compound according to embodiment 23 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0973] 24. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d is a C6-C 14 Aryl: hydroxy, halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, -C(O)O(C1-C6 alkyl), -NR 3e1 R 3e2 , -S(O)2(C1-C6 alkyl), 5- to 18-membered heteroaryl, and 3- to 18-membered heterocycloalkyl optionally substituted with oxo, wherein R 3e1 and R 3e2 Each is independently H or C1-C6 alkyl.

[0974] 25. The compound according to embodiment 24 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0975] 26. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d -(C1-C6 alkylene)-(C6-C 14 aryl): halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0976] 27. The compound according to embodiment 26 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0977] 28. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d is a 3- to 18-membered heterocycloalkyl group optionally substituted by one or more substituents selected from the group consisting of

[0978] (a) C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, C3-C 10 cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents,

[0979] (b)C6-C 14 Aryl,

[0980] (c) a 3- to 18-membered heterocycloalkyl group,

[0981] (d) -C(O)O(C1-C6 alkyl),

[0982] (e)-C(O)(C6-C 14 alkyl),

[0983] (f) halogen, and

[0984] (g) C1-C6 alkoxy optionally substituted with one or more halo substituents.

[0985] 29. The compound according to embodiment 28 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0986]

[0987] 30. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 3d is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an oxo group, and a 3- to 18-membered heterocycloalkyl group.

[0988] 31. The compound according to embodiment 30 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0989] 32. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 C(O)NR 3h R 3i Substituted C1-C6 alkyl, wherein R3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl).

[0990] 33. The compound according to embodiment 32 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0991] 34. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 is a C1-C6 alkyl substituted by a 3- to 18-membered heterocycloalkyl, wherein the 3- to 18-membered heterocycloalkyl is optionally selected from halogen and C6-C 14 The aryl group is substituted with one or more substituents.

[0992] 35. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0993] 36. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a C1-C6 alkyl group substituted by a 5- to 18-membered heteroaryl group.

[0994] 37. The compound according to embodiment 36 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0995] 38. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)OR 3j , where R 3j is hydrogen or C1-C6 alkyl.

[0996] 39. The compound according to embodiment 38 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0997] 40. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)R 3k .

[0998] 41. The compound according to embodiment 40 or a pharmaceutically acceptable salt thereof, wherein R 3k is a C6-C 14Aryl: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy, and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

[0999] 42. The compound or pharmaceutically acceptable salt thereof according to embodiment 40 or 41, wherein R 3 for

[1000] 43. The compound of embodiment 40 or a pharmaceutically acceptable salt thereof, wherein R 3k -(C1-C6 alkylene)-(C6-C 14 Aryl): C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy, and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

[1001] 44. The compound or pharmaceutically acceptable salt thereof according to embodiment 40 or 43, wherein R is

[1002] 45. The compound of embodiment 40 or a pharmaceutically acceptable salt thereof, wherein R 3k is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxy, alkoxy, and S(O)2(alkyl), where R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

[1003] 46. ​​The compound or pharmaceutically acceptable salt thereof according to embodiment 40 or 45, wherein R 3 for

[1004] 47. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)OR 3l , where R 3l is hydrogen or C1-C6 alkyl.

[1005] 48. The compound of embodiment 47 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[1006] 49. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHSO2R 3m , where R 3m is a 5- to 18-membered heteroaryl, a C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein 5- to 18-membered heteroaryl, C6-C 14 Aryl and -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted by one or more substituents selected from halo and C1-C6 alkoxy.

[1007] 50. The compound of embodiment 49 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[1008] 51. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 -SO2R 3n And R 3n C3-C 10 Cycloalkyl, C6-C 14 Aryl or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein C3-C 10 Cycloalkyl, C6-C 14 Aryl and -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted by one or more substituents selected from halo and -C(O)O(C1-C6 alkyl).

[1009] 52. The compound according to embodiment 51 or a pharmaceutically acceptable salt thereof, wherein R 3 for

[1010] 53. A compound as described in any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, wherein G 1 For CH.

[1011] 54. A compound as described in any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, wherein G 1 is N.

[1012] 55. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 for

[1013] 56. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y is

[1014] 57. The compound of embodiment 56 or a pharmaceutically acceptable salt thereof, wherein r is 1.

[1015] 58. The compound of embodiment 56 or a pharmaceutically acceptable salt thereof, wherein r is 2.

[1016] 59. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y is

[1017] 60. The compound of embodiment 59 or a pharmaceutically acceptable salt thereof, wherein R 4 It is phenyl.

[1018] 61. The compound of embodiment 59 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -C(O)NH-CH2-phenyl.

[1019] 62. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y is

[1020] 63. The compound of embodiment 62, or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from the group consisting of hydrogen, methyl and -NHC(O)O(C1-C6 alkyl).

[1021] 64. The compound of embodiment 62 or embodiment 63, or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from the group consisting of hydrogen, methyl and -NHC(O)O(C1-C6 alkyl).

[1022] 65. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 for

[1023] 66. The compound of embodiment 65 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from the group consisting of -C(O)OC(CH3)3, -NHC(O)O(C1-C6 alkyl) and -C(O)-phenyl.

[1024] 67. The compound of any one of embodiments 1-54, 56, and 58-66, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[1025] 68. The compound of any one of embodiments 1-54, 56, and 58-66, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[1026] 69. The compound of any one of embodiments 1-54 and 58-66, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[1027] 70. The compound of any one of embodiments 1-54 and 56-66, or a pharmaceutically acceptable salt thereof, wherein n is 3.

[1028] 71. The compound of any one of embodiments 1-66, or a pharmaceutically acceptable salt thereof, wherein n is 4.

[1029] 72. The compound of any one of embodiments 1-66, or a pharmaceutically acceptable salt thereof, wherein n is 5.

[1030] 73. A compound as described in any one of embodiments 1-66, or a pharmaceutically acceptable salt thereof, wherein n is 6.

[1031] 74. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for

[1032] 75. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for

[1033] 76. A compound as described in any one of embodiments 1-58 and 67-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for And R 2a Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl), wherein R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl.

[1034] 77. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[1035] 78. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for And R 2b Selected from the group consisting of: halo, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl), wherein R 2c 、R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl.

[1036] 79. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for

[1037] 80. A compound as described in any one of embodiments 1-73, or a pharmaceutically acceptable salt thereof, wherein R 1 for

[1038] 81. A compound selected from the group consisting of the compounds of Table 1 or pharmaceutically acceptable salts thereof.

[1039] 82. A pharmaceutical composition comprising a compound according to any one of embodiments 1-81 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[1040] 83. 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 of any one of embodiments 1-81 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 82.

[1041] 84. The method of embodiment 83, 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 kidney disease, a metabolic disease, a nervous system disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscular dystrophy.

[1042] 85. The method of embodiment 83, 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 syndrome, neonatal nerve damage, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, poliomyelitis, and spinal cord injury.

[1043] General synthetic methods

[1044] The compound of formula (II) or formula (I) or its any modification or embodiment or any salt in aforementioned item, will now be described by referring to the exemplary synthesis scheme and following specific examples for its general preparation below.Technical staff will recognize that, in order to obtain various compounds herein, raw material can be suitably selected so that the substituent group of final expectation will be carried to produce desired product by reaction scheme with or without suitable protection.Or, it may be necessary or desirable to adopt the suitable group that can be carried and suitably replaced by desired substituent group to replace the substituent group of final expectation by reaction scheme.In addition, those skilled in the art will recognize that protecting group can be used for protecting some functional group (amino, carboxyl or side chain group) from the impact of reaction conditions, and when appropriate, such group is removed under standard conditions.Unless otherwise noted, variable is as defined above with reference to formula (II) or formula (I).

[1045] In the case of the specific enantiomer of the desired compound, this can be accomplished using any suitable conventional procedure for separating or splitting enantiomers from corresponding enantiomeric mixtures. Therefore, for example, diastereomeric derivatives can be produced by the reaction of a mixture of enantiomers (for example, racemate and suitable chiral compound). The diastereoisomers can then be separated by any convenient means, for example, by crystallization and recovery of the desired enantiomer. In another splitting process, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, if desired, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the processes.

[1046] Chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products where it is desired to obtain a specific isomer of a compound or to otherwise purify a reaction product.

[1047] Specific non-limiting examples are provided in the Examples section below.

[1048] Example

[1049] The following examples are provided to illustrate but not to limit the compositions, uses and methods provided herein. The compounds were prepared using the general methods described above.

[1050] The following abbreviations are used throughout the examples: TEA (triethylamine), DCM (dichloromethane), (Boc)2O (di-tert-butyl dicarbonate), EA (ethyl acetate), PE (petroleum ether), DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), 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 (prop- 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 (raw material), Hex (hexane), NCS (N-chlorosuccinimide), rt (room temperature), 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).

[1051] Example A

[1052] Synthesis of Compound 168, Compound 201 and Intermediate 1.15

[1053]

[1054] Preparation of methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate (Compound 168). 1-Chloro-4-(isocyanatomethyl)benzene (6.8 g, 40.8 mmol, 1 eq) was added to a stirred solution of methyl 6-aminospiro[3.3]heptane-2-carboxylate (8.4 g, 40.8 mmol, 1 eq) in CHCl (100 mL) at room temperature. After 12 h, the solvent was removed by rotary evaporation, and the crude material was triturated in EtOH (100 mL) for 10 min, filtered, washed with EtOH (2 x 25 mL), and dried under high vacuum to afford Compound 168 (12 g, 87%) as a white solid. LRMS (APCI) m / z 337.1 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.31 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.28 (s, 2H), 4.02 (p, J = 8.0 Hz, 1H), 3.66 (s, 3H), 3.37 (s, 3H), 3.06 (p, J = 8.6 Hz, 1H), 2.49 (ddd, J = 11.8, 7.4, 5.2 Hz, 1H), 2.33 (tq, J = 8.5, 3.2, 2.5 Hz, 3H), 2.28-2.07 (m, 2H), 1.87 (ddd, J = 25.8, 11.2, 8.6 Hz, 2H).

[1055] Chiral separation of methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate. Five grams of methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate were separated by chiral SFC (Chiralpak AD-H, 30% cosolvent (EtOH containing 0.25% isopropylamine) at a rate of 70 g / min) to afford two chiral fragments as white solids: compound 201 (2.4 g, 48%) and intermediate 1.15 (2.4 g, 48%). The absolute stereochemistry of each fragment was not determined. Compound 201 eluted first from the SFC using the specified conditions, followed by intermediate 1.15.

[1056] Compound 201: LRMS (APCI) m / z 337.1 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.32 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.28 (s, 2H), 4.02 (p, J = 8.0 Hz, 1H), 3.66 (s, 3H), 3.06 (p, J = 8.5 Hz, 1H), 2.49 (ddd, J = 11.7, 7.3, 5.5 Hz, 1H), 2.39-2.28 (m, 3H), 2.28-2.10 (m, 2H), 1.87 (ddd, J = 25.9, 11.1, 8.7 Hz, 2H).

[1057] Intermediate 1.15: LRMS (APCI) m / z 337.1 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.32 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.28 (s, 2H), 4.02 (p, J = 8.0 Hz, 1H), 3.66 (s, 3H), 3.06 (p, J = 8.5 Hz, 1H), 2.49 (ddd, J = 11.6, 7.2, 5.3 Hz, 1H), 2.39-2.28 (m, 3H), 2.28-2.11 (m, 2H), 1.87 (ddd, J = 25.8, 11.0, 8.7 Hz, 2H).

[1058] Compounds 35, 8, 197, 37, 151, 152, 83, 81, 82, and 36, as well as intermediates 1.3 and 1.7, were prepared in a manner analogous to compound 168 using the reagents provided in the table below in place of methyl 6-aminospiro[3.3]heptane-2-carboxylate and 1-chloro-4-(isocyanatomethyl)benzene.

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067] Example B

[1068] Synthesis of intermediates 2.1, 2.4 and 2.5

[1069]

[1070] Preparation of 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (Intermediate 2.1). LiOH (622 mg, 25.98 mmol, 1.25 equiv) and methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate (Compound 168) (7 g, 20.78 mmol, 1 equiv) were suspended in MeOH / H₂O (50 mL / 5 mL) and heated to 60°C. After 1 hour, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation. The crude material was dissolved in H₂O / MeOH (90 mL / 10 mL) and then precipitated with 3M HCl, filtered, washed with water (3 x 20 mL), and dried under high vacuum to give the desired product 2.1 (5.2 g, 78%) as a white solid. LRMS (APCI) m / z 323.0 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.31 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.28 (s, 2H), 4.02 (p, J = 8.1 Hz, 1H), 3.02 (p, J = 8.4 Hz, 1H), 2.56-2.43 (m, 1H), 2.33 (td, J = 9.8, 8.4, 6.0 Hz, 3H), 2.29-2.11 (m, 2H), 1.87 (ddd, J = 24.6, 11.0, 8.7 Hz, 2H).

[1071] Chiral separation of 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid. Five grams of 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid were resolved by chiral SFC (Chiralpak AD-H, 30% cosolvent (EtOH containing 0.25% isopropylamine) at a rate of 70 g / min) to afford two chiral fragments as white solids: 2.4 (2.3 g, 46%) and 2.5 (2.1 g, 42%). The absolute stereochemistry of each fragment was not determined. Intermediate 2.4 eluted first from SFC using the specified conditions, followed by intermediate 2.5.

[1072] Intermediate 2.4: LRMS (APCI) m / z 323.1 (M+H). 1H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),6.40(t,J=6. 1Hz,1H),6.29(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.89(h,J=8.1Hz,1H),3.09( p, J = 6.4 Hz, 1H), 2.75 (p, J = 8.5 Hz, 1H), 2.31 (ddd, J = 10.7, 7.3, 5.2 Hz, 1H), 2.20-2.01 (m, 4H), 2.01-1.90 (m, 1H), 1.82-1.63 (m, 2H), 1.06 (d, J = 6.3 Hz, 5H). (complex isopropyl alcohol was found)

[1073] Intermediate 2.5: LRMS (APCI) m / z 323.1 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.2Hz,2H),6.36(t,J=6.1Hz,1 H),6.25(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.89(h,J=8.0Hz,1H),3.07(p,J=6.4Hz, 1H),2.78(p,J=8.5Hz,1H),2.36-2.25(m,1H),2.11(tdd,J=19.6,9.3,6.7Hz,4H),1.97( ddd,J=11.2,8.6,2.4Hz,1H),1.74(ddd,J=29.1,10.8,8.7Hz,2H),1.04(d,J=6.3Hz,5H).

[1074] Intermediates 2.2 and 2.3 were prepared in an analogous manner to Intermediate 2.1 using the reagents provided in the table below in place of methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate (Compound 168).

[1075]

[1076]

[1077]

[1078] Example C

[1079] Synthesis of intermediate 3.1

[1080]

[1081] Preparation of 1-(4-chlorobenzyl)-3-(2-azaspiro[3.3]hept-6-yl)urea (Intermediate 3.1). TFA (100 mL) was added to a stirred solution of tert-butyl 6-(3-(4-chlorobenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 1.5) (17.8 g, 46.9 mmol, 1 eq) in CHCl (200 mL) at room temperature. After 1 hour, the solvent was removed by rotary evaporation and the crude oil was azeotroped with toluene (3 x 100 mL) and dried under high vacuum. The crude oil was suspended in MeOH (250 mL) and IONAC Na-38OH was added. - Resin (50 g) was added and the reaction was stirred gently for 1 hour. The reaction was then filtered through a pad of celite, and the solvent was removed by rotary evaporation to give the product as a white solid (12.5 g, 95%). LRMS (APCI) m / z 280.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.32(d,J=8.4Hz,2H),7.26(d,J=8.5Hz,2H),4.75(s,1H),4.64(s,1H),4.29(d,J=4.3Hz,2H), 4.14(s,1H),4.03(d,J=4.8Hz,2H),2.68(dddd,J=17.8,10.3,7.7,3.0Hz,2H),2.32-2.24(m,2H),2.22-2.13(m,1H).

[1082] Intermediates 3.2, 3.3, 3.4, 3.5 and 3.6 were prepared in an analogous manner to Intermediate 3.1 using the reagents provided in the table below in place of tert-butyl 6-(3-(4-chlorobenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxylate (Compound 197).

[1083]

[1084]

[1085]

[1086]

[1087] Example D

[1088] Synthesis of intermediate 4.1

[1089] Preparation of methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methanesulfonate (Intermediate 4.1)

[1090]

[1091]

[0147] Step 1: Preparation of 3-[6-(hydroxymethyl)spiro[3.3]hept-2-yl]-1-[(4-methoxyphenyl)methyl]urea. To a solution of 6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (2.0 g, 6.28 mmol, 1.0 equiv) in DCM (20 mL) at 0°C was added triethylamine (2 equiv), followed by dropwise addition of isobutyl chloroformate. The solution was stirred at room temperature and monitored by LCMS. After 1 hour, the solution was cooled to 0°C, and the precipitate was filtered and rinsed with DCM. The crude (isobutyl carbonate)6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic anhydride was used directly in the next step (99% yield).

[1092] The above crude anhydride was dissolved in THF (20 mL) and sodium borohydride (0.475 g, 12.6 mmol, 2.0 equivalents) was added in batches at room temperature. The solution was monitored by LCMS analysis. The solution was cooled to 0 ° C, and saturated aqueous sodium carbonate solution (20 mL) was added, and the solution was vigorously stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with 30 mL of DCM. The combined organic layer was washed with brine, dried, filtered and concentrated to give the product as a white foam (1.82 g, 92% yield). LCMS-APCI (POS.) m / z: 315.0 (M + H) + 1H NMR (400MHz, DMSO-d6) δ7.15 (dd, J=8.5, 1.7Hz, 2H), 6.87 (dt, J=8.6, 2.3Hz, 2H), 6.18-5. 95(m,2H),4.40(td,J=5.4,1.3Hz,1H),4.09(d,J=5.9Hz,2H),3.91(q,J=8.1Hz,1H),3.82( td,J=9.3,7.3,2.9Hz,1H),3.31(t,J=5.8Hz,3H),2.83(q,J=6.9,4.7Hz,1H),2.79-2.71( m,1H),2.24-2.08(m,2H),2.02(t,J=9.1Hz,1H),1.87(t,J=9.9Hz,1H),1.81-1.57(m,4H).

[1093]

[1094] Step 2: Preparation of methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methanesulfonate. NEt (2.0 equiv) was added to a solution of 3-[6-(hydroxymethyl)spiro[3.3]hept-2-yl]-1-[(4-methoxyphenyl)methyl]urea (1.8 g, 5.71 mmol, 1.0 equiv) in CHCl (0.33 M). The reaction was cooled to 0°C and methanesulfonyl chloride (0.72 g, 0.31 mmol, 1.1 equiv) was added dropwise and stirred for 30 minutes. The solution was cooled to 0°C and saturated aqueous ammonium chloride was added and the solution was stirred vigorously for 10 minutes. The organic layer was separated and the aqueous layer was extracted with 10 mL of DCM. The combined organic layers were washed with brine, dried, filtered and concentrated to give the product (1.96 g, 84% yield) as a white foam. LCMS-APCI(POS.)m / z:384.0(M+H).1H NMR (400MHz, DMSO-d6) δ7.21 (dd, J=8.2, 1.6Hz, 2H), 6.94 (dt, J=8.2, 1.6Hz, 2H), 6.24- 6.00(m,2H),5.44(td,J=5.4Hz,1.3Hz,2H),4.59(td,J=5.2,1.3Hz,1H),3.91(q,J=8.1 Hz,1H),3.31(t,J=5.8Hz,3H),2.83(q,J=6.9,4.7Hz,1H),2.65(s,3H),2.79-2.71(m,1 H),2.24-2.08(m,2H),2.02(t,J=9.1Hz,1H),1.87(t,J=9.9Hz,1H),1.81-1.57(m,4H).

[1095] Example E

[1096] Synthesis of intermediate 5.1

[1097] Preparation of N-(6-aminospiro[3.3]hept-2-yl)benzamide hydrochloride (Intermediate 5.1)

[1098]

[1099] Step 1: Preparation of tert-butyl (6-benzamidospiro [3.3] hept-2-yl) carbamate. NEt (670 mg, 6.628 mmol, 3 equiv) and benzoyl chloride (341.61 mg, 2.430 mmol, 1.1 equiv) were added to a stirred solution of tert-butyl N-(6-aminospiro [3.3] hept-2-yl) carbamate (500.00 mg, 2.209 mmol, 1.0 equiv) in CHCl (5 mL) at 0°C, and the reaction was allowed to return to room temperature. After 2 hours, the reaction was quenched with HO (20 mL) and extracted with CHCl (2 x 20 mL). The organics were combined, washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give a crude product (850 mg) which was used in the next step without further purification. LRMS (APCI) m / z 275 (M+H-56).

[1100]

[1101] Step 2: Preparation of N-(6-aminospiro[3.3]hept-2-yl)benzamide hydrochloride. HCl (2.5 mL, 4 M in dioxane) was added to a stirred solution of tert-butyl N-[6-benzamidospiro[3.3]hept-2-yl]carbamate (830 mg, 2.5 mmol, 1.0 equiv) in CHCl (10 mL) at room temperature. After 1 hour, the reaction was concentrated by rotary evaporation to afford the crude product (620 mg) as a white solid, which was used without further purification. LRMS (APCI) m / z 231 (M+H).

[1102] Example F

[1103] Synthesis of intermediate 6.1

[1104] Preparation of N2-(pyridin-2-yl)spiro[3.3]heptane-2,6-diamine hydrochloride (Intermediate 6.1)

[1105]

[1106] Step 1: Preparation of tert-butyl (6-(pyridin-2-ylamino)spiro [3.3] hept-2-yl) carbamate. At room temperature, 2-aminopyridine (200 mg, 2.1 mmol, 2.0 equivalents) and TFA (243 mg, 2.1 mmol, 2 equivalents) were added to a stirred solution of tert-butyl N-[6-oxospiro [3.3] hept-2-yl] carbamate (240 mg, 1.1 mmol, 1.0 equivalents) in DCE (10 mL). After 30 minutes, NaHB (OAc) (677 mg, 3.2 mmol, 3.0 equivalents) was added and the reaction was stirred for 12 hours. The reaction was quenched with H O (20 mL) and extracted with CH Cl (2x20 mL). The organics were combined, washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the crude product as a yellow solid (380 mg), which was used in the next step without further purification. LRMS (APCI) m / z 248 (M+H-56).

[1107]

[1108] Step 2: Preparation of N2-(pyridin-2-yl)spiro[3.3]heptane-2,6-diamine hydrochloride. HCl (2.5 mL, 4 M in dioxane) was added to a stirred solution of tert-butyl N-[6-(pyridin-2-ylamino)spiro[3.3]hept-2-yl]carbamate (360 mg, 1.187 mmol, 1.0 equiv) in CHCl (5 mL) at room temperature. After 2 h, the reaction was concentrated by rotary evaporation to afford the crude product (280 mg) as a white solid, which was used without further purification. LRMS (APCI) m / z 204 (M+H).

[1109] Example G

[1110] Synthesis of intermediate 7.1

[1111] Preparation of tert-butyl ((1r,3r)-3-(benzylcarbamoyl)cyclobutyl)carbamate (Intermediate 7.1)

[1112]

[1113] Step 1: Preparation of tert-butyl ((1r,3r)-3-(benzylcarbamoyl)cyclobutyl)carbamate. EDCI (670 mg, 3.49 mmol, 1.5 equiv) was added to a stirred solution of (1r,3r)-3-[(tert-butoxycarbonyl)amino]cyclobutane-1-carboxylic acid (500.00 mg, 2.323 mmol, 1.00 equiv) in pyridine (5 mL) at room temperature. After 5 minutes, benzylamine (298.50 mg, 2.786 mmol, 1.20 equiv) was added and the reaction was stirred at room temperature for 1 hour. The reaction was then quenched with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The reaction was then quenched with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the crude product (640 mg), which was used in the next step without further purification. LRMS (APCI) m / z 249 (M+H-56).

[1114]

[1115] Step 2: Preparation of (1r,3r)-3-amino-N-benzylcyclobutane-1-carboxamide hydrochloride. HCl (2 mL, 4 M in dioxane) was added to a stirred solution of tert-butyl N-[(1r,3r)-3-(benzylcarbamoyl)cyclobutyl]carbamate (827 mg, 1.00 equiv) in CHCl (10 mL) at room temperature. After 1 hour, the reaction was concentrated by rotary evaporation to afford the crude product (640 mg) as a brown solid, which was used in the next step without further purification. LRMS (APCI) m / z 241 (M+H).

[1116] Example H

[1117] Synthesis of intermediate 8.1

[1118] Preparation of (6-amino-2-azaspiro[3.3]hept-2-yl)(p-tolyl)methanone (Intermediate 8.1)

[1119]

[1120] Step 1: Preparation of tert-butyl (2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)carbamate. HATU (6.88 g, 18.1 mmol, 1.5 eq) was added to a stirred solution of tert-butyl (2-azaspiro[3.3]hept-6-yl)carbamate hydrochloride (3 g, 12.1 mmol, 1 eq), 4-methylbenzoic acid (2.46 g, 18.1 mmol, 1.5 eq), and NEt (4.9 mL, 36.2 mmol, 3 eq) in DMF (100 mL) at room temperature. After 12 h, the reaction was poured into EtOAc (500 mL), washed with saturated sodium bicarbonate (3 x 250 mL), brine (2 x 250 mL), dried over sodium sulfate, filtered through a pad of silica gel, and the solvent removed by rotary evaporation to afford the crude product (3.6 g) as a white solid.

[1121]

[1122] Step 2: (6-Amino-2-azaspiro[3.3]hept-2-yl)(p-tolyl)methanone. TFA (25 mL) was added to a stirred solution of tert-butyl (2-(4-methylbenzoyl)-2-azaspiro[3.3]hept-6-yl)carbamate (1 g, 3.03 mmol, 1 equiv) in CHCl (50 mL) at room temperature. After 1 hour, the solvent was removed by rotary evaporation, azeotroped with toluene (3 x 50 mL), and dried under high vacuum to give the crude product as a yellow oil, which was used in the next step without further purification. LRMS (APCI) m / z 231.1 (M+H).

[1123] Example 1

[1124] Synthesis of compound 198 and intermediate 9.2

[1125]

[1126] Chiral resolution of tert-butyl (6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)carbamate (Compound 8). Racemic tert-butyl (6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)carbamate (25 g) and Compound 8 were separated by chiral SFC (Chiralpak AD-H, 20% cosolvent (EtOH containing 0.25% isopropylamine) at a rate of 80 g / min) to afford two chiral fragments as white solids: Compound 198 (9.4 g, 38%) and Intermediate 9.2 (12 g, 48%). The absolute stereochemistry of each fragment was not determined. Compound 198 eluted from the SFC first using the specified conditions, followed by Intermediate 9.2. The absolute stereochemistry was not determined. Compound 8 eluted from the SFC first using the specified conditions, followed by Intermediate 9.2.

[1127] Compound 198: LRMS (APCI) m / z 294.1 (M+H-Boc). 1 H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.04(d,J=8.0Hz,1H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.0Hz,1H),4.15( d,J=6.0Hz,2H),3.92(h,J=8.2Hz,1H),3.79(q,J=8.3Hz,1H),2.27(dp, J=18.8,6.3Hz,2H),2.19-2.00(m,2H),1.93-1.69(m,4H),1.36(s,9H).

[1128] Intermediate 9.2 LRMS (APCI) m / z 294.1 (M+H-Boc). 1 H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.04(d,J=7.8Hz,1H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.1Hz,1H),4.15(d,J=6. 0Hz, 2H), 3.92 (h, J = 7.9Hz, 1H), 3.79 (q, J = 8.2Hz, 1H), 2.27 (dp, J = 18.9, 7. 5, 6.2Hz, 2H), 2.09 (tq, J = 13.3, 6.1Hz, 2H), 1.93-1.68 (m, 4H), 1.36 (s, 9H).

[1129] Example J

[1130] Synthesis of intermediate 10.1

[1131]

[1132] Preparation of 1-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea (Intermediate 10.1). Diisobutylaluminum hydride (25% in toluene, 10.1 g, 17.8 mmol, 3 equiv) was added to a stirred solution of methyl 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylate (2.0 g, 17.8 mmol, 1 equiv) in THF (100 mL) at room temperature. After 2 hours, the reaction was quenched by the addition of MeOH (50 mL) and silica, and the solvent was removed by rotary evaporation. Purification by silica chromatography (0->10% MeOH / CHCl) gave a white solid (1.5 g, 81%). LRMS (APCI) m / z 309.1 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.14(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),6.09(t,J=5.9Hz,1H),6.0 6(d,J=8.1Hz,1H),4.40(t,J=5.2Hz,1H),4.09(d,J=5.9Hz,2H),3.91(h,J=8.2Hz,1H),3.30(dd, J=6.5,5.3Hz,2H),2.29(ddd,J=10.6,7.4,5.3Hz,1H),2.21(dt,J=16.6,8.2Hz,1H),2.16-2.08 (m,1H),2.01(td,J=9.6,8.3,3.0Hz,1H),1.87(ddd,J=11.2,8.2,3.0Hz,1H),1.79-1.60(m,4H).

[1133] Intermediate 10.2 was prepared in an analogous manner to Intermediate 10.1 using the reagents provided in the table below.

[1134]

[1135] Example K

[1136] Synthesis of intermediate 11.1

[1137]

[1138] Preparation of 1-(4-chlorobenzyl)-3-(6-formylspiro[3.3]hept-2-yl)urea (Intermediate 11.1). Dess-Martin periodinane (4.1 g, 9.72 mmol, 1 eq) was added to a stirred solution of 1-(4-chlorobenzyl)-3-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)urea (3.0 g, 9.72 mmol, 1 eq) in CHCl (100 mL) and acetonitrile (100 mL) at room temperature. After 2 h, the reaction was quenched with saturated sodium thiosulfate (100 mL) and diluted to 700 mL with saturated sodium bicarbonate and stirred vigorously for 10 min. The reaction was then extracted with CH2Cl2 (3 x 500 mL), the organic layers were combined, dried over sodium sulfate, and the solvent removed by rotary evaporation to give the crude product as a tan solid (2.5 g, 84%). LRMS (APCI) m / z 307.1 (M+H).

[1139] Example L

[1140] Synthesis of intermediates 12.1 and 12.2

[1141] 1-(6-(Aminomethyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea (Intermediate

[1142] 12.2).

[1143]

[1144] Step 1: Preparation of 1-(6-(azidomethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea. Methanesulfonyl chloride (857 mg, 7.5 mmol, 1.1 equiv) was added to a stirred solution of 1-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (2.1 g, 6.8 mmol, 1 equiv) and NEt (2.1 g, 20.4 mmol, 3 equiv) in CHCl (50 mL) at room temperature. After 2 h, the reaction was quenched with saturated sodium bicarbonate (250 mL) and extracted with CHCl (3 x 250 mL). The organics were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The crude material was suspended in DMF (8 mL), then NaN (0.66 g, 10.2 mmol, 1.5 eq) was added and the reaction heated to 70° C. for 12 hours. The reaction was cooled to room temperature, poured into EtOAc (500 mL), and washed with saturated sodium bicarbonate (3 x 400 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the desired product as a white solid (1.98 g, 87%). LRMS (APCI) m / z 334.1 (M+H).

[1145]

[1146] Step 2: Preparation of 1-(6-(aminomethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea. PtO2 (0.1 g, 0.449 mmol, 0.1 eq) and 1-(6-(azidomethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (1.5 g, 4.5 mmol, 1 eq) were suspended in MeOH (50 mL) at room temperature and stirred under H2 (80 psi) for 1 hour. The reaction was then filtered through a pad of Celite, and the solvent was removed by rotary evaporation to give the desired product (1.3 g, 98%) as a white semisolid. LRMS (APCI) m / z 308.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.31(d,J=7.8Hz,2H),7.26(d,J=7.9Hz,2H),4.29(d,J=8.7Hz,2H),4.02(t,J=8.1Hz,1H),2.64(d,J=7.0Hz,2 H),2.46(t,J=7.8Hz,1H),2.25(ddd,J=24.0,11.5,6.4Hz,3H),2.11-1.99(m,1H),1.92-1.73(m,3H),1.69(dd,J=11.1,7.4Hz,1H).

[1147] Example M

[1148] Synthesis of Intermediate 13.1 Preparation of 2-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)acetic acid (Example 13.1).

[1149]

[1150] Step 1: Preparation of ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]hept-2-ylidene)acetate. Ethyl 2-(diethoxyphosphoryl)acetate (4.9 g, 22.2 mmol, 1 eq) was added to a stirred solution of LiCl (2.26 g, 53.3 mmol, 2.4 eq) in THF (25 mL) at room temperature. After 10 minutes, DBU (7.43 g, 48.8 mmol, 2.2 eq) was added and the reaction was stirred for an additional 10 minutes. Tert-butyl (6-oxospiro[3.3]hept-2-yl)carbamate (5.0 g, 22.2 mmol, 1 eq) in THF (20 mL) was then added and the reaction was stirred for 14 hours. The reaction was concentrated by rotary evaporation, and the product (5.05 g, 77%) was isolated as a white solid by silica chromatography (0->50% EtOAc / Hex). LRMS (APCI) m / z 296.1 (M+H). 1 H NMR (400MHz, chloroform-d) δ5.62(d,J=6.8Hz,1H),4.66(s,1H),4.22-4.10(m,2H),4.05(s,1H),3.13(d,J=38.8Hz,2H ),2.84(d,J=38.1Hz,2H),2.57-2.37(m,2H),1.94(td,J=8.8,4.2Hz,2H),1.45(s,9H),1.28(t,J=6.9Hz,3H).

[1151]

[1152] Step 2: Preparation of ethyl 2-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)acetate. Ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]hept-2-ylidene)acetate (5.05 g, 17.1 mmol, 1 eq) and PtO (308 mg, 0.17 mmol, 1 eq) were suspended in MeOH (150 mL) and stirred under H (80 psi) for 1 hour. The reaction was then filtered through a pad of celite, and the solvent was removed by rotary evaporation. The crude material was suspended in CHCl (20 mL), and HCl (4 M in dioxane, 42 mL, 170.9 mmol, 10 eq) was added, and the reaction was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation and dried under high vacuum. The product was then suspended in CHCl (100 mL). NEt (3.46 g, 34.2 mmol, 2 eq) and 1-chloro-4-(isocyanatomethyl)benzene (3 g, 18.0 mmol, 1.05 eq) were added and the reaction was stirred at room temperature. After 12 hours, the reaction was concentrated by rotary evaporation, and the product (6.3 g, 98%) was isolated as a white solid by silica chromatography (0->10% MeOH / CHCl). LRMS (APCI) m / z 365.1 (M+H). 1 H NMR (400MHz, chloroform-d) δ7.31(s,2H),7.22(d,J=8.0Hz,2H),4.67(t,J=6.0Hz,1H),4.54(d,J=7.3H z,1H),4.33(d,J=5.9Hz,2H),4.11(q,J=7.1Hz,2H),4.01(q,J=7.8Hz,1H),3.51(d,J=5.1Hz,3H ),2.62-2.45(m,2H),2.37(d,J=7.9Hz,2H),2.35-2.21(m,2H),2.10(ddd,J=11.9,7.7,4.1Hz,1 H),1.77(dq,J=19.7,10.6,10.1Hz,4H),1.67(s,2H),1.30-1.20(m,3H),1.09(q,J=5.6Hz,1H).

[1153]

[1154] Step 3: Preparation of 2-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)acetic acid. Ethyl 2-(6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)acetate (6.3 g, 17.3 mmol, 1 eq) and LiOH (827 mg, 34.5 mmol, 2 eq) were suspended in MeOH / water (19 mL / 1 mL) at room temperature. After 4 h, the MeOH was removed by rotary evaporation and the crude product was diluted with water (approximately 25 mL), then precipitated by the addition of 1 M HCl (approximately 20 mL). The resulting precipitate was collected by filtration, washed with water, and dried under high vacuum to give the desired product (4.5 g, 77%) as a white solid. LRMS (APCI) m / z 337.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.39-7.15(m,4H),4.37-4.18(m,2H),4.01(d,J=8.9Hz,1H),2.49(pd,J=11.3,7.6 ,5.9Hz,2H),2.31(dq,J=36.6,6.3Hz,4H),2.10(d,J=10.4Hz,1H),1.77(ddt,J=36.3,19.2,10.0Hz,4H).

[1155] Intermediate 13.2 was prepared in an analogous manner to Intermediate 13.1 using the reagents provided in the table below.

[1156]

[1157] Example N

[1158] Synthesis of intermediate 14.1

[1159] Preparation of 1-(6-acetylspiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (Intermediate 14.1).

[1160]

[1161] Step 1: Preparation of 6-(3-(4-chlorobenzyl)ureido)-N-methoxy-N-methylspiro[3.3]heptane-2-carboxamide. HATU (6.48 g, 17.0 mmol, 1.1 equiv) was added to a stirred solution of 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (5.0 g, 15.5 mmol, 1 equiv), N,O-dimethylhydroxylamine (3 g, 31.0 mmol, 2 equiv), and NEt (6.3 g, 61.96 mmol, 4 equiv) in EtOAc (30 mL) and iPOH (10 mL) at room temperature. After 12 hours, silica was added and the solvent removed by rotary evaporation. The product (5.6 g, 98%) was isolated as a glassy solid by silica chromatography (0->10% MeOH / CHCl). LRMS (APCI) m / z 366.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2 H),4.03(p,J=8.0Hz,1H),3.69(s,3H),3.44(d,J=14.8Hz,1H),3.18(s,3H),2 .54(ddd,J=11.7,7.2,5.2Hz,1H),2.35-2.27(m,3H),2.27-2.20(m,1H),2.11 (t,J=9.8Hz,1H),1.93(dd,J=11.0,8.5Hz,1H),1.83(dd,J=11.4,8.7Hz,1H).

[1162]

[1163] Step 2: Preparation of 1-(6-acetylspiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea. MeMgBr (3 M in THF, 15.4 mL, 46.4 mmol, 3 eq) was added dropwise to a stirred solution of 6-(3-(4-chlorobenzyl)ureido)-N-methoxy-N-methylspiro[3.3]heptane-2-carboxamide (5.6 g, 15.5 mmol, 1 eq) in THF (150 mL) at 0°C. After 1 hour, the reaction was quenched with saturated sodium bicarbonate (500 mL) and extracted with CHCl (3 x 250 mL). The organics were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the desired compound as a white solid. LRMS (APCI) m / z 321. (M+H) 1H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.3Hz,2H),7.24(d,J=8.2Hz,2H),6.26(t,J=6.1Hz,1H),6.18(d,J=8.0Hz,1H),4.15(d,J=6. 0Hz,2H),3.90(q,J=8.1Hz,1H),3.15(p,J=8.6Hz,1H),2.34(ddd,J=10.6,7.3,5.3Hz,1H),2.23-1.96(m,8H),1.86-1.64(m,2H).

[1164] Example 0

[1165] Synthesis of intermediate 15.1

[1166] Preparation of 1-(6-(1-aminoethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (Intermediate 15.1)

[1167]

[1168] Step 1: Preparation of 1-(4-chlorobenzyl)-3-(6-(1-hydroxyethyl)spiro[3.3]hept-2-yl)urea. LiBH4 (1 M in THF, 468 μL, 0.468 mmol, 0.5 eq) was added to a stirred solution of 1-(6-acetylspiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (300 mg, 0.935 mmol, 1 eq) in THF (10 mL) at room temperature. After 1 hour, the reaction was quenched with MeOH (10 mL) and silica, and the solvent was removed by rotary evaporation. The product (300 mg, 99%) was then isolated by silica chromatography (0->15% MeOH / CHCl) as a white solid. LRMS (APCI) m / z 323.1 (M+H). 1 HNMR (400MHz, chloroform-d) δ7.31(d,J=8.4Hz,2H),7.23(d,J=8.3Hz,2H),4.61(s,1H ),4.50(t,J=6.4Hz,1H),4.34(d,J=5.8Hz,2H),4.02(q,J=7.9,7.3Hz,1H),3.6 5(d,J=5.8Hz,1H),3.51(d,J=5.1Hz,2H),2.56-2.43(m,1H),2.31(td,J=11.6 ,4.8Hz,1H),2.21-2.03(m,2H),1.90-1.69(m,4H),1.08(dd,J=6.2,3.0Hz,3H)

[1169]

[1170] Step 2: Preparation of 1-(6-(1-azidoethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea. DIAD (376 mg, 1.86 mmol, 1.5 equiv) was added to a stirred solution of triphenylphosphine (1.2 g, 1.86 mmol, 1.5 equiv) in THF at 0°C. After 10 minutes, DPPA (682 mg, 2.48 mmol, 2 equiv) and 1-(4-chlorobenzyl)-3-(6-(1-hydroxyethyl)spiro[3.3]hept-2-yl)urea (400 mg, 1.24 mmol, 1 equiv) were added, and the reaction was stirred for 14 hours while returning to room temperature. The solvent was removed by rotary evaporation, and the product (350 mg, 81%) was isolated as a white solid by silica chromatography (0->100% EtOAc / hexanes). LRMS (APCI) m / z 348.1 (M+H).

[1171]

[1172] Step 3: Preparation of 1-(6-(1-aminoethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea. 1-(6-(1-azidoethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (800 mg, 2.3 mmol, 1 eq) and PtO2 (52 mg, 0.23 mmol, 0.1 eq) were suspended in MeOH (25 mL) and stirred under H2 (80 psi) for 1 hour. The reaction was filtered through a pad of Celite, and the solvent was removed by rotary evaporation to give the product as a viscous semisolid (740 mg, 99%). LRMS (APCI) m / z 322.1 (M+H).

[1173] Example P

[1174] Synthesis of intermediate 16.1

[1175] Preparation of 1-(4-chlorobenzyl)-3-(6-((methylamino)methyl)spiro[3.3]hept-2-yl)urea (Intermediate 16.1)

[1176]

[1177] Step 1: Preparation of N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)formamide. Formic acid (61 mg, 1.34 mmol, 2.3 equiv) and acetic anhydride (77 mg, 0.755 mmol, 1.3 equiv) were heated to 60°C for 2 hours. The reaction was then cooled to room temperature before the addition of 1-(6-(aminomethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (200 mg, 0.581 mmol, 1 equiv) and DIPEA (300 mg, 2.32 mmol, 4 equiv). After 2 hours, the reaction was quenched with MeOH, concentrated by rotary evaporation, and dried under high vacuum. LRMS (APCI) m / z 336.2 (M+H).

[1178]

[1179] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(6-((methylamino)methyl)spiro[3.3]hept-2-yl)urea. N-((6-(3-(4-chlorobenzyl)ureido)spiro[3.3]hept-2-yl)methyl)formamide (138 mg, 0.412 mmol, 1 eq) in THF (500 μL) was added dropwise to a stirred solution of BH3 (dimethyl sulfide complex, 2 M in THF, 0.791 mL, 1.58 mmol, 4 eq) at 0°C and then allowed to return to room temperature. After 2 hours, the reaction was quenched with MeOH and concentrated by rotary evaporation. The resulting oil was suspended in HCl (4 M in dioxane, 5 mL) and concentrated by rotary evaporation. The residue was triturated with EtOAc and the resulting solid was dried under high vacuum to give the product as a white solid (163 mg, 115%). LRMS (APCI) m / z 322.2 (M+H).

[1180] Example Q

[1181] Synthesis of intermediate 17.1

[1182] Preparation of 6-((2-fluorophenyl)(methyl)amino)-6-oxohexan-1-ammonium chloride (Intermediate 17.1)

[1183]

[1184] Step 1: tert-Butyl (6-((2-fluorophenyl)(methyl)amino)-6-oxohexyl)carbamate. HATU (6.56 g, 17.2 mmol, 2 eq) was added to a stirred solution of 6-((tert-butoxycarbonyl)amino)hexanoic acid (2 g, 8.6 mmol, 1 eq), 2-fluoro-N-methylaniline (1.62 g, 12.9 mmol, 1.5 eq), and DIPEA (3.34 g, 25.9 mmol, 3 eq) in DMF (15 mL) at room temperature. After 72 h, the reaction was poured into water (200 mL) and extracted with EtOAc (3 x 75 mL). The organics were combined, washed with ammonium chloride (3 x 50 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The resulting oil was filtered through a plug of silica to afford the product as an amber oil (2.5 g, 85%). LRMS (APCI) m / z 339.1 (M+H).

[1185]

[1186] Step 2: 6-((2-Fluorophenyl)(methyl)amino)-6-oxohexan-1-aminium chloride. HCl (4 M in dioxane, 15 mL, 60 mmol, 10 equiv) was added to a stirred solution of tert-butyl (6-((2-fluorophenyl)(methyl)amino)-6-oxohexyl)carbamate (2.1 g, 6.2 mmol, 1 equiv) in MeOH (100 mL) at room temperature. After 4 h, the solvent was removed by rotary evaporation and dried under high vacuum to give the product as a white solid (1.5 g, 101%). LRMS (APCI) m / z 239.1 (M+H).

[1187] Example R

[1188] Synthesis of intermediate 18.1

[1189] Preparation of 6-((2-fluorophenyl)(methyl)amino)-6-oxohexan-1-ammonium chloride (Intermediate 18.1)

[1190]

[1191] Step 1: tert-Butyl 4-(4-isocyanatobutyl)piperidine-1-carboxylate. Triphosgene (926 mg, 3.12 mmol, 0.4 eq) was added to a vigorously stirred solution of tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate (2 g, 7.8 mmol, 1 eq) in saturated sodium bicarbonate (30 mL) and CHCl (30 mL) at 0°C. After 15 minutes, the organic layer was removed and the aqueous layer was extracted with CHCl (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, and filtered. The isocyanate solution was separated and used in the subsequent step without further purification.

[1192]

[1193] Step 2: tert-Butyl 4-(4-(3-(oxazol-5-ylmethyl)ureido)butyl)piperidine-1-carboxylate. Oxazol-5-ylmethanamine (152 mg, 1.56 mmol, 1 eq) was added to a stirred solution of tert-butyl 4-(4-isocyanatobutyl)piperidine-1-carboxylate (441 mg, 1.56 mmol, 1 eq) in CHCl (5 mL) and saturated sodium bicarbonate (3 mL) at room temperature. After 4 h, the organic layer was separated and filtered through a pad of silica, washed with 5% MeOH / CHCl (20 mL), and the solvent removed by rotary evaporation to give the crude product (459 mg, 44%), which was used without further purification. LRMS (APCI) m / z 381.2 (M+H).

[1194] Intermediates 18.2-18.5 were prepared in an analogous manner to Intermediate 18.1 using the reagents provided in the table below.

[1195]

[1196]

[1197] Example S

[1198] Synthesis of intermediate 19.1

[1199]

[1200] Preparation of methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)4-methylbenzenesulfonate (Intermediate 19.1). 4-Methylbenzenesulfonyl chloride (532 mg, 2.79 mmol, 1.25 equiv) was added to a stirred solution of 1-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea (Intermediate 10.1, 680 mg, 2.23 mmol, 1 equiv) and triethylamine (452 ​​mg, 4.47 mmol, 2 equiv) in CHCl (25 mL) at room temperature. After 12 h, the reaction was quenched with saturated sodium bicarbonate (100 mL), extracted with CHCl (3 x 100 mL), and the organics were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. LRMS (APCI) m / z 459.1 (M+H). 1 H NMR (400MHz, chloroform-d) δ7.79(d,J=8.2Hz,2H),7.36(d,J=7.8Hz,2H),7.22(d,J=8.2Hz,2H),6.91-6 .81(m,2H),4.57(t,J=5.6Hz,1H),4.47(d,J=7.4Hz,1H),4.28(d,J=5.5Hz,2H),4.00(d,J=7.0Hz ,2H),3.94(d,J=6.6Hz,2H),3.81(s,3H),2.47(s,3H),2.47-2.40(m,1H),2.27(dt,J=12.1,6.3H z,1H),2.11(ddd,J=11.7,8.4,3.4Hz,1H),1.98(td,J=10.0,8.3,2.8Hz,1H),1.80-1.71(m,4H).

[1201] Intermediate 19.2 was prepared in an analogous manner to Intermediate 19.1 using the reagents provided in the table below.

[1202]

[1203] Example T

[1204] Synthesis of intermediate 20.1

[1205] Preparation of tert-butyl 4-(4-aminobutyl-4,4-d2)piperidine-1-carboxylate (Intermediate 20.1)

[1206]

[1207] Step 1: tert-Butyl 4-(4-hydroxybutyl-4,4-d2)piperidine-1-carboxylate. LiAlD4 (4.4 mL, 1 mol / L, 1.20 equiv) was added dropwise to a solution of 4-[1-(tert-butoxycarbonyl)pyridin-4-yl]butanoic acid (1 g, 3.685 mmol, 1 equiv) in THF (15 mL) at 0°C under a nitrogen atmosphere. After stirring at 0°C under a nitrogen atmosphere for 2 hours, the reaction was determined by LCMS. The mixture was adjusted to pH 8 with KOH (aq) and filtered to remove solids. The filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product as a white oil (860 mg). LRMS (APCI) m / z 204 [M+H-56].

[1208]

[1209] Step 2: tert-Butyl 4-(4-((methylsulfonyl)oxy)butyl-4,4-d2)piperidine-1-carboxylate. Methanesulfonyl chloride (526 mg, 4.59 mmol, 1.5 equiv) and triethylamine (621 mg, 6.14 mmol, 1.99 equiv) were added to a solution of tert-butyl 4-[4-hydroxy(4,4-2H2)butyl]piperidine-1-carboxylate (800 mg, 3.084 mmol, 1 equiv) in DCM (10 mL) at 0°C. After stirring at room temperature for 2 hours, water (20 mL) was added to the resulting mixture, which was then extracted with CHCl (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the product as a yellow oil (1 g). LRMS (APCI) m / z 282 [M+H-56].

[1210]

[1211] Step 3: tert-Butyl 4-(4-(1,3-dioxoisoindolin-2-yl)butyl-4,4-d2)piperidine-1-carboxylate. 2-Potassium isoindole-1,3-dione (0.83 g, 4.48 mmol, 1.5 eq) was added to a solution of tert-butyl 4-[4-(methylsulfonyloxy)(4,4-2H2)butyl]piperidine-1-carboxylate (1.0 g, 2.96 mmol, 1 eq) in MeCN (15 mL) at room temperature. After stirring at 80°C overnight, the resulting mixture was cooled to room temperature, water (30 mL) was added, and extracted with CHCl (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (1 g) as a yellow oil. LRMS (APCI) m / z 333 [M+H-56].

[1212]

[1213] Step 4: tert-Butyl 4-(4-aminobutyl-4,4-d2)piperidine-1-carboxylate. Hydrazine monohydrate (642 mg, 13.1 mmol, 5.1 eq) was added to a solution of tert-butyl 4-[4-(1,3-dioxoisoindol-2-yl)(4,4-2H2)butyl]piperidine-1-carboxylate (1.0 g, 2.57 mmol, 1 eq) in ethanol (10 mL) at room temperature. After stirring at 80°C overnight, the mixture was cooled to room temperature and filtered to remove solids. The filtrate was concentrated under reduced pressure to give the product as a yellow semisolid (630 mg). LRMS (ES) m / z 203 [M+H-56].

[1214] Example 1

[1215] Synthesis of intermediate 21.1

[1216]

[1217] Preparation of oxazol-5-ylmethyl-d2-amine (Intermediate 21.1). Solid LiAlD4 (84 mg 2.00 mmol, 1.0 equiv) was added to a solution of oxazole-5-carbonitrile (188 mg, 2.00 mmol, 1.0 equiv) in THF (6 mL). The mixture was stirred vigorously at 23°C for 3 hours. Upon completion, Na2SO4·10H2O was carefully added to quench the reaction until gas evolution ceased. The solid was filtered off and the filtrate was concentrated to give crude oxazol-5-ylmethyl-d2-amine (90 mg, 45%), which was used without further purification. LRMS (APCI+) m / z 101.2 (M+H).

[1218] Example V

[1219] Synthesis of intermediate 22.1

[1220] Preparation of 6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-amine (Intermediate 22.1).

[1221]

[1222] Step 1: tert-Butyl (6-hydroxy-6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate. n-BuLi (2.5 M in hexanes, 1.17 mL, 2.93 mmol, 2.2 equiv) was added to a solution of diisopropylamine (303 mg, 3.00 mmol, 2.25 equiv) in THF (5 mL) at -30°C. The solution was gently warmed to -10°C over 20 minutes. The freshly prepared LDA solution was then cooled to -78°C, followed by the dropwise addition of a solution of 4-methylpyridine (273 mg, 2.93 mmol, 2.2 equiv) in THF (1 mL). Deprotonation was maintained at this temperature for 1 hour. A solution of tert-butyl (6-oxospiro[3.3]hept-2-yl)carbamate (300 mg, 1.33 mmol, 1.0 equiv) in THF (2 mL) was then added at -78 °C over 1 minute. The reaction was then allowed to warm to 23 °C over 2 hours, and the reaction was further stirred at this temperature for 1 hour. Upon completion, a half-saturated NH4Cl solution was added to quench the reaction. The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated to give crude tert-butyl (6-hydroxy-6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate. LRMS (APCI+) m / z 319.1 (M+H).

[1223]

[1224] Step 2: tert-Butyl (6-(pyridin-4-ylmethylene)spiro[3.3]hept-2-yl)carbamate. EtN (269 mg, 2.66 mmol, 2.0 equiv) and MsCl (183 mg, 1.60 mmol, 1.2 equiv) were added to a solution of crude tert-butyl (6-hydroxy-6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate (up to 1.33 mmol, 1.0 equiv) in CHCl (2 mL). The reaction was stirred at 23 °C for 2 hours. After completion, the volatiles were removed in vacuo and PhMe (1.5 mL) was added, followed by DBU (1.01 g, 6.65 mmol, 5.0 equiv). The mixture was heated at 60 °C for 14 hours. After completion, the reaction was then poured into a mixture of half-saturated brine (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine, dried (MgSO), filtered, concentrated, and purified by flash column chromatography (silica, hexanes / EtOAc) to afford tert-butyl (6-(pyridin-4-ylmethylene)spiro[3.3]hept-2-yl)carbamate (241 mg, 60% yield over 2 steps) as a colorless oil. LRMS (APCI+) m / z 301.1 (M+H).

[1225]

[1226] Step 3: tert-Butyl (6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate. Pd / C (10% weight loading, 30% mass equiv.) was added to a solution of tert-butyl (6-(pyridin-4-ylmethylene)spiro[3.3]hept-2-yl)carbamate (240 mg, 0.80 mmol, 1.0 equiv.) in THF / MeOH (6 mL, 2:1). The mixture was bubbled through H gas for 3 minutes and then stirred at 23 °C under 1 atm H atmosphere for 14 hours. Upon completion, the solid was filtered off and the filtrate was concentrated to give crude tert-butyl (6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate, which was used directly in the next step. LRMS (APCI+) m / z 303.1 (M+H)

[1227]

[1228] Step 4: 6-(Pyridin-4-ylmethyl)spiro[3.3]hept-2-amine. TFA (0.5 mL) was added to a solution of crude tert-butyl (6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)carbamate (up to 0.80 mmol) in CHCl (3 mL) at 23°C. The mixture was stirred at this temperature for 3 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-amine (Intermediate 22.1, 150 mg, 93%), which was used without further purification. LRMS (APCI+) m / z 203.1 (M+H).

[1229] Example W

[1230] Synthesis of intermediate 23.1

[1231] Preparation of 6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-amine (Intermediate 23.1).

[1232]

[1233] Step 1: tert-Butyl (6-(2-(6-methylnicotinoyl)hydrazine-1-carbonyl)spiro[3.3]hept-2-yl)carbamate. 6-Methylnicotinoylhydrazine (107 mg, 0.71 mmol, 1.0 equiv) and HATU (280 mg, 0.78 mmol, 1.1 equiv) were added to a solution of 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylic acid (180 mg, 0.71 mmol, 1.0 equiv) in DMF (2 mL), followed by DIPEA (215 mg, 2.12 mol, 3.0 equiv). The reaction was stirred at 23° C. for 14 hours. Upon completion, EtOAc (5 mL) was added. The organic phase was washed with brine, dried (MgSO), filtered, and concentrated to afford crude tert-butyl (6-(2-(6-methylnicotinoyl)hydrazine-1-carbonyl)spiro[3.3]hept-2-yl)carbamate, which was used in the next step without further purification. LRMS (APCI+) m / z 389.1 (M+H).

[1234]

[1235] Step 2: tert-Butyl (6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)carbamate. Triphenylphosphine (223 mg, 0.85 mmol, 1.2 equiv), imidazole (145 mg, 2.12 mmol, 3.0 equiv), and tetrabromomethane (259 mg, 0.78 mmol, 1.1 equiv) were added sequentially to a solution of crude tert-butyl (6-(2-(6-methylnicotinoyl)hydrazine-1-carbonyl)spiro[3.3]hept-2-yl)carbamate (0.71 mmol, 1.0 equiv) in THF (2 mL). The reaction was stirred at 23°C for 16 hours. Upon completion, a mixed solution of NaHCO₃ and Na₂S₂O₃ was added to quench the reaction. The aqueous phase was extracted with CHCl (5 mL x 3). The combined organic phases were washed with brine, dried (MgSO), filtered, concentrated, and purified by flash column chromatography (silica, CHCl / MeOH) to afford tert-butyl (6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)carbamate (148 mg, 57% over 2 steps) as a white solid. LRMS (APCI+) m / z 371.1 (M+H).

[1236]

[1237] Step 3: 6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-amine. HCl (4 M in 1,4-dioxane, 0.40 mL, 1.60 mmol, 8.0 equiv) was added to a solution of tert-butyl (6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)carbamate (74 mg, 0.20 mmol, 1.0 equiv) in CHCl (1 mL). The mixture was stirred at 23° C. for 20 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-amine (Intermediate 23.1, 52 mg, 96%) as a white waxy solid, which was used without further purification. LRMS (APCI+) m / z 271.1 (M+H).

[1238] Example X

[1239] Synthesis of intermediate 24.1

[1240] Preparation of 6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-amine (Intermediate 24.1)

[1241]

[1242] Step 1: tert-Butyl (6-(pyrimidin-2-ylmethylene)spiro[3.3]hept-2-yl)carbamate. Triphenylphosphine (787 mg, 3.00 mmol, 1.0 equiv) and toluene (2 mL) were added to a vial containing 2-(chloromethyl)pyrimidine hydrochloride (495 mg, 3.00 mmol, 1.0 equiv). The mixture was stirred at 100°C for 16 hours. The solvent was then decanted and the residue was dried to provide crude triphenyl(pyrimidin-2-yl-methyl)phosphonium chloride. DMSO (2 mL) was added to the crude ylide at 23°C, followed by sodium tert-butoxide (577 mg, 6.00 mmol, 2.0 equiv). The reaction was stirred at this temperature for 1 hour, followed by the addition of tert-butyl (6-oxospiro[3.3]hept-2-yl)carbamate (676 mg, 3.00 mmol, 1.0 equiv). The dark brown mixture was stirred at 23°C for 18 hours and then poured into a mixture of half-saturated NH4Cl solution (10 mL) and CHCl (10 mL). The layers were separated and the aqueous phase was extracted with CHCl (5 mL x 2). The combined organic phases were washed with brine, dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (silica, CHCl / MeOH) to afford tert-butyl (6-(pyrimidin-2-ylmethylene)spiro[3.3]hept-2-yl)carbamate (250 mg, 28% yield) as a light yellow gum. LRMS (APCI+) m / z 302.1 (M+H).

[1243]

[1244] Step 2: tert-Butyl (6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-yl)carbamate. To a vial was added tert-butyl (6-(pyrimidin-2-ylmethylene)spiro[3.3]hept-2-yl)carbamate (250 mg, 0.83 mmol, 1.0 equiv), piperidine (74 mg, 0.87 mmol, 1.05 equiv), formic acid (40 mg, 0.87 mmol, 1.05 equiv), Pd / C (10% weight loading, 20% mass equiv), and EtOH (3 mL). The mixture was stirred at 75° C. for 6 hours. Upon completion, the solid was filtered off and the filtrate was concentrated and purified by flash column chromatography (silica, CH2Cl2 / MeOH) to afford tert-butyl (6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-yl)carbamate (142 mg, 56% yield) as a slightly yellow gum. LRMS (APCI+) m / z 304.2 (M+H).

[1245]

[1246] Step 3: 6-(Pyrimidin-2-ylmethyl)spiro[3.3]hept-2-amine. HCl (4 M in 1,4-dioxane, 0.93 mL, 3.74 mmol, 8.0 equiv) was added to a solution of tert-butyl (6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-yl)carbamate (142 mg, 0.47 mmol, 1.0 equiv) in CHCl (1 mL). The mixture was stirred at 23°C for 20 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(pyrimidin-2-ylmethyl)spiro[3.3]hept-2-amine (Intermediate 24.1, 95 mg, 99%) as a slightly yellow gum, which was used without further purification. LRMS (APCI+) m / z 204.1 (M+H).

[1247] Example Y

[1248] Synthesis of intermediate 25.1

[1249] Preparation of 6-(pyridin-4-yloxy)spiro[3.3]hept-2-amine (Intermediate 25.1)

[1250]

[1251] Step 1: tert-Butyl (6-(pyridin-4-yloxy)spiro[3.3]hept-2-yl)carbamate. Toluene (3 mL) was added to a vial containing tert-butyl N-{6-hydroxyspiro[3.3]hept-2-yl}carbamate (227 mg, 1.00 mmol, 1.0 equiv), triphenylphosphine (393 mg, 1.50 mmol, 1.5 equiv), and 4-hydroxypyridine (142 mg, 1.50 mmol, 1.5 equiv), followed by diisopropyl azodicarboxylate (DIAD, 303 mg, 1.50 mmol, 1.5 equiv). The reaction was then stirred at 80°C for 3 hours. Upon completion, the reaction was concentrated and purified by reverse phase column chromatography (H2O (0.1% HCO2H) / MeCN (0.1% HCO2H)) to afford tert-butyl (6-(pyridin-4-yloxy)spiro[3.3]hept-2-yl)carbamate (166 mg, 54%) as a colorless oil. LRMS (APCI+) m / z 305.1 (M+H).

[1252]

[1253] Step 1: 6-(Pyridin-4-yloxy)spiro[3.3]hept-2-amine. HCl (4 M in 1,4-dioxane, 1.09 mL, 4.36 mmol, 8.0 equiv) was added to a solution of tert-butyl (6-(pyridin-4-yloxy)spiro[3.3]hept-2-yl)carbamate (166 mg, 0.545 mmol, 1.0 equiv) in CHCl (1 mL). The mixture was stirred at 23°C for 20 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(pyridin-4-yloxy)spiro[3.3]hept-2-amine (Intermediate 25.1, 110 mg, 98%) as a slightly yellow gum, which was used without further purification. LRMS (APCI+) m / z 205.1 (M+H).

[1254] Intermediate 25.2 was prepared in an analogous manner to Intermediate 25.1 using the reagents provided in the table below.

[1255]

[1256]

[1257] Example Z

[1258] Synthesis of intermediate 26.1

[1259] Preparation of 6-(methylsulfonyl)spiro[3.3]hept-2-amine (Intermediate 26.1)

[1260]

[1261] Step 1: tert-butyl (6-(methylthio) spiral [3.3] hept-2-yl) carbamate.At 23 ℃, by EtN (202mg, 2.00mmol, 2.0 equivalents) and TsCl (229mg, 1.20mmol, 1.2 equivalents) are added to N-{6-hydroxy spiral [3.3] hept-2-yl} carbamate tert-butyl ester (227mg, 1.00mmol, 1.0 equivalents) in CHCl(3mL) in solution.At 23 ℃, the mixture is stirred for 3 hours, then it is poured into half-saturated NaHCO solution.By CHCl(5mL×2) aqueous phase is extracted, and the organic phase merged is washed with salt water, dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (silica, hexane / EtOAc) to obtain the desired tosylate. Next, sodium thiomethoxide (210 mg, 3.00 mmol, 3.0 equiv) was added to a suspension of the tosylate obtained above in EtOH (3 mL). The mixture was stirred at 60°C for 18 hours. Upon completion, the reaction was quenched with a half-saturated NH4Cl solution. The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated to afford crude tert-butyl (6-(methylthio)spiro[3.3]hept-2-yl)carbamate (183 mg, 71%) as a slightly yellowish gum. LRMS (APCI+) m / z 258.1 (M+H).

[1262]

[1263] Step 2: tert-Butyl (6-(methylsulfonyl)spiro[3.3]hept-2-yl)carbamate. mCPBA (367 mg, 2.13 mmol, 3.0 equiv) was added to a solution of tert-butyl (6-(methylthio)spiro[3.3]hept-2-yl)carbamate (183 mg, 0.71 mmol, 1.0 equiv) in CHCl (3 mL) at 0°C. The reaction was then stirred at 23°C for 3 hours. Upon completion, a mixed solution of NaHCO and NaSO was added to quench the reaction. The aqueous phase was extracted with CHCl (5 mL x 3). The combined organic phases were washed with brine, dried (MgSO), filtered, and concentrated to afford crude tert-butyl (6-(methylsulfonyl)spiro[3.3]hept-2-yl)carbamate (169 mg, 83%) as a white solid, which was used without further purification. LRMS (APCI+) m / z 290.2 (M+H).

[1264]

[1265] Step 3: 6-(Methylsulfonyl)spiro[3.3]hept-2-amine. HCl (4 M in 1,4-dioxane, 1.17 mL, 4.67 mmol, 8.0 equiv) was added to a solution of tert-butyl (6-(methylsulfonyl)spiro[3.3]hept-2-yl)carbamate (169 mg, 0.584 mmol, 1.0 equiv) in CHCl (1 mL). The mixture was stirred at 23°C for 20 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(methylsulfonyl)spiro[3.3]hept-2-amine (Intermediate 26.1, 109 mg, 98%) as a slightly yellow gum, which was used without further purification. LRMS (APCI+) m / z 190.1 (M+H).

[1266] Example AA

[1267] Synthesis of intermediate 27.1

[1268] Preparation of 6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-amine (Intermediate 27.1)

[1269]

[1270] Step 1: tert-Butyl (6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-yl)carbamate. NaH (44 mg, 60% suspension in mineral oil, 1.11 mmol, 2.1 equiv) was added to a solution of tert-butyl (6-hydroxyspiro[3.3]hept-2-yl)carbamate (120 mg, 0.53 mmol, 1.0 equiv) in THF (1 mL) at 0°C. The deprotonation reaction was stirred for 1 hour at 23°C. Potassium iodide (18 mg, 0.11 mmol, 0.2 equiv) and 4-(chloromethyl)pyridine hydrochloride (91 mg, 0.55 mmol, 1.05 equiv) were then added sequentially. The reaction was stirred at 23°C for 4 hours. Upon completion, a half-saturated NH4Cl solution (5 mL) was added to quench the reaction. The aqueous phase was extracted with CHCl (3 mL x 2). The combined organic phases were washed with brine, dried (MgSO), filtered, concentrated, and purified by flash column chromatography (silica, CHCl / MeOH) to afford tert-butyl (6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-yl)carbamate (139 mg, 83% yield) as a colorless gum. LRMS (APCI+) m / z 319.1 (M+H).

[1271]

[1272] Step 2: 6-(Pyridin-4-ylmethoxy)spiro[3.3]hept-2-amine. HCl (4 M in 1,4-dioxane, 0.87 mL, 3.49 mmol, 8.0 equiv) was added to a solution of tert-butyl (6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-yl)carbamate (139 mg, 0.436 mmol, 1.0 equiv) in CHCl (1 mL). The mixture was stirred at 23°C for 20 hours. Upon completion, the volatiles were removed in vacuo to afford crude 6-(pyridin-4-ylmethoxy)spiro[3.3]hept-2-amine (Intermediate 27.1, 95 mg, 99%) as a slightly yellow gum, which was used without further purification. LRMS (APCI+) m / z 219.1 (M+H).

[1273] Intermediate 27.2 was prepared in an analogous manner to Intermediate 27.1 using the reagents provided in the table below.

[1274]

[1275] Example 1

[1276] Preparation of 1-(2-(3-(2-chlorophenyl)propionyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea (Compound 135)

[1277]

[1278] HATU (207 mg, 0.545 mmol, 1.5 eq) was added to a stirred solution of 3-(2-chlorophenyl)propanoic acid (101 mg, 0.545 mmol, 1.5 eq), 1-(4-methoxybenzyl)-3-(2-azaspiro[3.3]hept-6-yl)urea (100 mg, 0.257 mmol, 1 eq), and NEt (147 μL, 0.770 mmol, 3 eq) in DMF (1 mL) at room temperature. After 4 hours, the reaction was diluted to a total volume of 1.8 mL with MeOH, filtered through a 0.4 μm syringe filter, and the product (42 mg, 26%) was isolated as a white solid by reverse-phase HPLC (0->70% MeCN / H₂O containing 0.1% formic acid). LRMS (APCI) m / z 442 (M+H). 1H NMR(400MHz,DMSO-d6)δ7.34(dd,J=7.3,2.7Hz,1H),7.29-7.23(m,1H),7.23-7.12(m,2 H),7.07(d,J=7.4Hz,2H),6.87-6.69(m,2H),6.08(dt,J=14.0,6.1Hz,2H),4.02(d,J=5 .8Hz,2H),3.95(s,1H),3.84(d,J=12.9Hz,2H),3.77(s,1H),3.65(s,4H),2.80(t,J=7. 9Hz,2H),2.39-2.27(m,2H),2.23(q,J=7.7Hz,2H),1.86(ddt,J=12.8,9.3,5.6Hz,2H).

[1279] The compounds in the table below were prepared in a similar manner to compound 135 using the listed intermediates and reagents.

[1280]

[1281]

[1282]

[1283]

[1284]

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302]

[1303]

[1304]

[1305]

[1306]

[1307]

[1308]

[1309]

[1310]

[1311]

[1312]

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347]

[1348] Example 2

[1349] Preparation of N-benzyl-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide (Compound 68)

[1350]

[1351] Preparation of N-benzyl-6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxamide.

[1352] HATU (201 mg, 0.529 mmol, 2 eq) was added to a stirred solution of 6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (80 mg, 0.265 mmol, 1.5 eq), benzamide (57 mg, 0.529 mmol, 2 eq), and NEt (134 mg, 1.32 mmol, 5 eq) in DMF (0.5 mL) at room temperature. After 3 h, the reaction was quenched with saturated ammonium chloride and extracted with CHCl. ​​The organics were combined, dried over sodium sulfate, filtered, and the product (10 mg, 9%) was isolated as a white solid by reverse-phase HPLC (10->100% MeCN / H2O containing 0.1% formic acid). LRMS (APCI) m / z 408 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.18(t,J=6.0Hz,1H),7.31(t,J=7.4Hz,2H),7.21(d,J=7.7Hz,3H),7. 15(d,J=8.1Hz,2H),6.87(d,J=8.0Hz,2H),6.20-5.97(m,2H),4.24(d,J=5.8Hz,2H),4.10(d,J =5.7Hz,2H),3.92(h,J=8.2Hz,1H),3.72(s,3H),2.93(p,J=8.4Hz,1H),2.35(dt,J=11.9,6.2H z,1H),2.15(p,J=10.1Hz,4H),2.05-1.88(m,1H),1.80(t,J=9.7Hz,1H),1.71(t,J=9.9Hz,1H).

[1353] The compounds in the table below were prepared in a similar manner to compound 68 using the listed intermediates and reagents.

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413] Example 3

[1414] Preparation of 1-(2-((2-chlorophenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea (Compound 116)

[1415]

[1416] 1-(2-((2-chlorophenyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-3-(4-methoxybenzyl)urea. 2-Chlorobenzenesulfonyl chloride (114 mg, 0.544 mmol, 1.5 equiv) was added to a stirred solution of 1-(4-methoxybenzyl)-3-(2-azaspiro[3.3]hept-6-yl)urea (100 mg, 0.363 mmol, 1 equiv) and NEt (147 μL, 0.770 mmol, 3 equiv) in DMF (1 mL) at room temperature. After 2 h, the reaction was diluted to a total volume of 1.8 mL with MeOH, filtered through a 0.4 μm syringe filter, and the product (21 mg, 18%) was isolated as a white solid by reverse phase HPLC (0->70% MeCN / H2O containing 0.1% formic acid). LRMS (APCI) m / z 450 (M+H). 1H NMR(400MHz,DMSO-d6)δ7.97(dt,J=8.0,1.8Hz,1H),7.76-7.68(m,2H),7.59(t,J=7.4Hz,1H),7 .13(d,J=8.3Hz,2H),6.86(d,J=8.5Hz,2H),6.17(t,J=5.9Hz,1H),6.12(d,J=7.9Hz,1H),4.10( dd,J=16.2,6.9Hz,2H),3.97(s,1H),3.94(s,2H),3.87(s,1H),3.83(s,1H),3.72(s,2H),2.48- 2.38(m,1H),2.33(ddd,J=10.2,7.7,3.0Hz,2H),2.27-2.15(m,1H),1.93(td,J=8.9,3.0Hz,1H).

[1417] The compounds in the table below were prepared in a similar manner to compound 116 using the listed intermediates and reagents.

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426] Example 4

[1427] Preparation of tert-butyl 1-((3-(4-chlorobenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate (Compound 27)

[1428]

[1429] Step 1: tert-Butyl 1-((3-(4-chlorobenzyl)ureido)methyl)-6-azaspiro[2.5]octane-6-carboxylate.

[1430] Tert-butyl 1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (0.15 g, 0.62 mmol, 1.0 equiv) was added dropwise to a room temperature solution of N,N'-disuccinimidyl carbonate (0.160 mg, 0.62 mmol, 1.0 equiv) in acetonitrile (10 mL), followed by the addition of pyridine (0.06 mL, 0.62 mmol, 1.0 equiv). After 20 minutes, a solution of 4-chlorobenzylamine (88 mg, 0.62 mmol, 1.0 equiv) in acetonitrile (2 mL) was added, followed by the addition of N,N-diisopropylethylamine (0.11 mL, 1.24 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for approximately 1 hour and then concentrated to dryness. The resulting mixture was diluted with ethyl acetate (50 mL) and extracted with water (2 x 15 mL) and brine (1 x 15 mL). The organic phase was dried to a viscous oil, which was purified by reverse phase chromatography to give the desired product (148 mg, 0.36 mmol, 58.1% yield) as a white foam. LCMS-APCI (POS.) m / z: 308 (M-Boc+H) + .1H NMR (400MHz, DMSO-d6) δ7.45-7.32(m,2H),7.25(d,J=8.5Hz,2H),6.37(t,J=6.1Hz,1H),5.94(t,J=5.4Hz,1H), 4.18(d,J=6.0Hz,2H),3.43(dddd,J=19.2,12.7,6.6,3.8Hz,2H),3.17(dt,J=13.8,5.9Hz,3H),2.90(dddd,J=13 .7,8.5,5.2Hz,1H),1.51(ddd,J=12.3,10.2,6.2Hz,1H),1.40(s,9H),1.31(ddd,J=17.2,7.1,3.5Hz,2H),1.14 (ddd,J=13.1,6.5,3.3Hz,1H),0.79(tt,J=8.5,6.2Hz,1H),0.45(dd,J=8.5,4.3Hz,1H),0.16(t,J=4.8Hz,1H).

[1431] The compounds in the table below were prepared in a similar manner to compound 27 using the listed intermediates and reagents.

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449]

[1450]

[1451] Example 5

[1452] Preparation of N-(6-cyanopyridin-2-yl)-6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxamide (Compound 132)

[1453]

[1454] N-(6-Cyanopyridin-2-yl)-6-(3-(4-methoxybenzyl)ureido)-2-azaspiro[3.3]heptane-2-carboxamide. Phenyl (6-cyanopyridin-2-yl)carbamate (130 mg, 0.54 mmol, 1.5 equiv) was added to a stirred solution of 1-(4-methoxybenzyl)-3-(2-azaspiro[3.3]hept-6-yl)urea (100 mg, 0.36 mmol, 1 equiv) in DMF (1 mL) at 25°C. After 12 hours, the reaction was diluted to a total volume of 1.8 mL with MeOH, filtered through a 0.4 μm syringe filter, and the product (39 mg, 26%) was isolated as a white solid by reverse phase HPLC (0->70% MeCN / H2O containing 0.1% formic acid). 1 HNMR(400MHz,DMSO-d6)δ9.56(s,1H),8.14(dd,J=8.7,1.8Hz,1H),7.90-7.75(m,1H), 7.51(dd,J=7.3,1.8Hz,1H),7.08(d,J=7.9Hz,2H),6.83-6.76(m,2H),6.17-6.10(m,1 H),6.08(d,J=8.1Hz,1H),4.03(d,J=5.8Hz,2H),3.96(s,2H),3.86(d,J=10.2Hz,3H), 3.65(s,3H),2.36(t,J=8.8Hz,2H),1.91(t,J=9.5Hz,2H).LRMS(APCI)m / z421.1(M+H).

[1455] The compounds in the table below were prepared in a similar manner to compound 132 using the listed intermediates and reagents.

[1456]

[1457]

[1458] Example 6

[1459] Preparation of 1-(4-chlorobenzyl)-3-((2r,4s)-6-(2-methylpyridin-4-yl)-6-azaspiro[3.4]octan-2-yl)urea (Compound 171)

[1460]

[1461] 1-(4-Chlorobenzyl)-3-((2r,4s)-6-(2-methylpyridin-4-yl)-6-azaspiro[3.4]octan-2-yl)urea. 1-(4-Chlorobenzyl)-3-((2r,4s)-6-azaspiro[3.4]octan-2-yl)urea (Intermediate 3.5) (100 mg, 0.34 mmol, 1 eq), 4-fluoro-2-methylpyridine (57 mg, 0.51 mmol, 1.5 eq), and DIPEA (178 μL, 1.0 mmol, 3 eq) were suspended in isopropanol (3 mL) and heated to 150° C. in a microwave oven for 30 minutes. The solvent was then removed by rotary evaporation, and the desired product (30 mg, 23%) was isolated as a white solid by reverse-phase HPLC (0.5->95% MeCN / H 2 O containing 0.1% formic acid). LRMS (APCI) m / z 385 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.98(d,J=6.1Hz,1H),7.40-7.32(m,2H),7.30-7.24(m,2H),6.40-6.28(m,4H),4.18(d,J=6.0Hz ,2H),4.12(q,J=8.1Hz,1H),3.31(t,J=6.7Hz,3H),2.32(s,3H),2.29-2.20(m,2H),2.01(t,J=6.7Hz,2H),1.90(td,J=8.8,2.7Hz,2H).

[1462] The compounds in the table below were prepared in a similar manner to compound 171 using the listed intermediates and reagents.

[1463]

[1464]

[1465]

[1466]

[1467] Example 7

[1468] Preparation of 1-(6-((5,7-difluoro-3,4-dihydroquinolin-1(2H)-yl)methyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea (Compound 127)

[1469]

[1470] 1-(6-((5,7-difluoro-3,4-dihydroquinolin-1(2H)-yl)methyl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea. Methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methanesulfonate (Intermediate 4.1) (60 mg, 0.16 mmol, 1.0 equiv) and 5,7-difluoro-1,2,3,4-tetrahydroquinoline (21 mg, 0.19 mmol) were dissolved in DMF (0.5 mL) and potassium carbonate (1.5 equiv) was added. The reaction was stirred at 80° C. for 12 hours. The potassium carbonate was filtered off and the solution was directly purified by reverse phase HPLC on a Phenomonex Gemini 5u C18 column using 10%-100% acetonitrile in water for 30 minutes to give the desired product (18.0 mg, 24% yield) as a white foam. LCMS-APCI (POS.) m / z: 456.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.17 (dd, J=12.2, 2.9Hz, 2H), 6.99 (d, J=13.8Hz, 2H), 6. 86(dd,J=8.5,2.9Hz,2H),6.08(d,J=11.9Hz,2H),4.09(d,J=4.6Hz,2H),4.03-3 .76(m,1H),3.72(d,J=3.0Hz,3H),3.60(d,J=7.0Hz,2H),2.85(dd,J=7.4,2.4Hz ,2H),2.70(d,J=8.4Hz,2H),2.34(s,2H),2.27-1.91(m,5H),1.90-1.56(m,4H).

[1471] The compounds in the table below were prepared in a similar manner to compound 127 using the listed intermediates and reagents.

[1472]

[1473]

[1474]

[1475]

[1476] Example 8

[1477] Preparation of 1-(4-chlorobenzyl)-3-((2r,4s)-6-(2-methylpyridin-4-yl)-6-azaspiro[3.4]octan-2-yl)urea (Compound 16)

[1478]

[1479] Step 1: Phenyl (4-(1-Benzoylpiperidin-4-yl)butyl)carbamate. NEt (583 mg, 5.76 mmol, 3 equiv) and phenyl chloroformate (360.79 mg, 2.304 mmol, 1.2 equiv) were added to a stirred solution of 4-(1-Benzoylpiperidin-4-yl)butan-1-amine (prepared as previously described in "Gillig, A., Majjigapu, SR, Sordat, B. and Vogel, P. (2012), Synthesis of a C-Iminoribofuranoside Analog of the Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitor FK866. HCA, 95:34-42") (500 mg, 1.92 mmol, 1.00 equiv) in CHCl (5 mL) at 0°C and then warmed to room temperature. After 4 h, the reaction was concentrated by rotary evaporation and the product (41%) was isolated as a yellow oil by preparative TLC (PE / EtOAc 1:1). LRMS (ESI) m / z 381 (M+H).

[1480]

[1481] Step 2: 1-(4-(1-Benzoylpiperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea. NEt (119 mg, 1.2 mmol, 3.00 equiv) was added to a stirred solution of phenyl N-[4-(1-benzoylpiperidin-4-yl)butyl]carbamate (150 mg, 0.4 mmol, 1.00 equiv) and 1-(4-chlorophenyl)methanamine (167 mg, 1.18 mmol, 3.00 equiv) in CHCl (2 mL) at room temperature. After 12 h, the solvent was removed by rotary evaporation and the product (31%) was isolated as a white solid by reverse phase HPLC (30% -> 60% MeCN / H2O containing 0.1% ammonium formate). LRMS (ESI) m / z 428 (M+H). 1H NMR (300MHz, DMSO-d6) δ7.48(m,3H),7.31(m,4H),7.21(m,2H),6.30(t,J=6.1Hz,1H),5.92(t,J=5.7Hz,1H),4.46(s,1H),4.17(d ,J=6.0Hz,2H),3.55(s,1H),3.00(q,J=6.4Hz,3H),2.81(m,1H),1.70(s,2H),1.48(s,1H),1.36(s,2H),1.24(s,4H),1.06(s,2H).

[1482] The compounds in the table below were prepared in a similar manner to compound 16 using the listed intermediates and reagents.

[1483]

[1484]

[1485]

[1486]

[1487] Example 9

[1488] Preparation of 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(4-methoxybenzyl)urea (Compound 20)

[1489]

[1490] Step 1: Phenyl (4-carbamoylbenzyl)carbamate. NEt (1.6 g, 16.1 mmol, 3.0 equiv) and phenyl chloroformate (1.0 g, 5.9 mmol, 1.10 equiv) were added to a stirred solution of 4-(aminomethyl)benzamide hydrochloride (1.0 g, 5.4 mmol, 1.0 equiv) in CHCl (10 mL) at 0°C. After 2 h, the reaction was quenched with water (20 mL), extracted with CHCl (2 x 20 mL), and the organics were combined, washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the crude product (1.2 g) as a white solid, which was used in the subsequent step without further purification. LRMS (ESI) m / z 271 (M+H)

[1491]

[1492] Step 2: 1-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(4-methoxybenzyl)urea. NEt (291 mg, 2.9 mmol, 5 eq) was added to a stirred solution of 4-(1-benzoylpiperidin-4-yl)butan-1-amine (150 mg, 0.6 mmol, 1.00 eq) and phenyl N-[(4-methoxyphenyl)methyl]carbamate (518 mg, 2.0 mmol, 3.5 eq) in DMF (3 mL) at room temperature. After 12 h, the reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organics were combined, washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The product (82 mg) was then isolated as a pale yellow solid by reverse phase HPLC (30%->60% MeCN / H2O containing 0.1% ammonium formate). LRMS (ESI) m / z 424 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.49 (m, 3H), 7.42 (m, 2H), 7.23 (m, 2H), 6.88 (m, 2H), 4.60 (d, J = 13.1 Hz, 1H), 4.22 (s, 2H), 3.75 (s, 3H), 3.69 (d, J = 13.3 Hz, 1H), 3.13 (t, J = 6.8 Hz, 3H), 2.84 (d, J = 13.1 Hz, 1H), 1.83.

[1493] The compounds in the table below were prepared in a similar manner to compound 20 using the listed intermediates and reagents.

[1494]

[1495]

[1496]

[1497] Example 10

[1498] Preparation of 1-(4-methoxybenzyl)-3-(5-phenoxypentyl)urea (Compound 149)

[1499]

[1500] Step 1: 1-(5-Hydroxypentyl)-3-(4-methoxybenzyl)urea. Phenyl N-[(4-methoxyphenyl)methyl]carbamate (250 mg, 1.0 mmol, 1.00 equiv), 5-aminopentanol (120 mg, 1.2 mmol, 1.2 equiv) and NEt (295 mg, 2.9 mmol, 3 equiv) were dissolved in THF (5 mL) and heated to 65°C. After 1 hour, the reaction was cooled to room temperature, quenched with H2O (20 mL), extracted with EtOAc (2 x 20 mL), and the organics were combined and washed with saturated sodium chloride (20 mL). The organic layer was then dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the crude product (250 mg) as a white solid. LRMS (ESI) m / z 267 (M+H).

[1501]

[1502] Step 2: Pentyl 5-(3-(4-methoxybenzyl)ureido)methanesulfonate. MsCl (226 mg, 1.9 mmol, 2.50 equiv) was added to a stirred solution of 3-(5-hydroxypentyl)-1-[(4-methoxyphenyl)methyl]urea (210 mg, 0.79 mmol, 1.00 equiv) and NEt (399 mg, 3.9 mmol, 5 equiv) in CHCl (5 mL) at 0°C and then warmed to room temperature. After 1 hour, the reaction was quenched with H0 (20 mL), extracted with EtOAc (2 x 20 mL), and the organics were combined and washed with saturated sodium chloride (20 mL). The organic layer was then dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation to give the crude product (440 mg) as a white solid. LRMS (ESI) m / z 345 (M+H).

[1503]

[1504] Step 3: 1-(4-Methoxybenzyl)-3-(5-phenoxypentyl)urea. Pentyl 5-([[(4-methoxyphenyl)methyl]carbamoyl]amino)methanesulfonate (350 mg, 1.0 mmol, 1.00 equiv), KCO (351 mg, 2.5 mmol, 2.5 equiv), phenol (115 mg, 1.2 mmol, 1.2 equiv), and KI (16.9 mg, 0.10 mmol, 0.1 equiv) were suspended in DMSO (5 mL) and heated to 80°C. After 2 h, the reaction was cooled to room temperature, and the product (15 mg) was isolated as a white solid by reverse phase HPLC (50% MeCN / H2O containing 0.5% ammonium formate). LRMS (ESI) m / z 343 (M+H). 1H NMR (300MHz, DMSO-d6) δ7.32-7.21(m,2H),7.15(d,J=8.6Hz,2H),6.95-6.81(m,5H),6.16(t,J=6.2Hz,1H),5.86(s,1H ),4.11(d,J=5.8Hz,2H),3.93(t,J=6.4Hz,2H),3.71(s,3H),3.02(d,J=6.0Hz,2H),1.70(t,J=6.8Hz,2H),1.41(s,4H).

[1505] The compounds in the table below were prepared in a similar manner to compound 149 using the listed intermediates and reagents.

[1506]

[1507]

[1508] Example 11

[1509] Preparation of N-benzyl-2-(6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)-N-methylacetamide (Compound 67)

[1510]

[1511] Step 1: Preparation of (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methyl cyanide.

[1512] Methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methanesulfonate (Intermediate 4.1) (0.1 g, 0.27 mmol, 1.0 equiv) was dissolved in DMF (1 mL) and sodium cyanide (5 eq) was added. The solution was stirred overnight at 80°C and monitored by LCMS analysis. The solution was cooled to 0°C, and saturated aqueous ammonium chloride (8 mL) and EtOAc (5 mL) were added and the solution was stirred vigorously for 10 minutes. The organic layer was separated and the aqueous layer was extracted with 10 mL of EtOAc. The combined organic layers were washed with brine, dried, filtered, and concentrated to give the product as a white solid (72 mg, 87% yield). LCMS-APCI (POS.) m / z: 314.0 (M+H)+.

[1513]

[1514] Step 2: N-Benzyl-2-(6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)-N-methylacetamide.

[1515] (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl)methyl cyanide (50 mg, 0.17 mmol, 1.0 equiv) and N-methylbenzylamine (19 mg, 0.17 mmol, 1.0 equiv) were dissolved in toluene (0.5 mL) and methanesulfonic acid (16 mg, 0.17 mmol, 1.0 equiv) was added. The reaction was stirred at 110° C. for 24 hours. The solution was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate. The reaction was extracted with DCM, and the combined organic layers were dried, filtered, and concentrated. The organic phase was dried to a viscous oil and purified by reverse phase HPLC using 10%-100% acetonitrile in water on a Phenomonex Gemini 5u C18 column for 30 minutes to give the desired product (51.0 mg, 0.12 mmol, 69% yield) as a white solid. LCMS-APCI(POS.)m / z:436.0(M+H)+.1H NMR (400MHz, DMSO-d6) δ7.33(tt,J=24.0,7.5Hz,3H),7.16(dd,J=13.3,7.3Hz,4H),6.86(d,J= 8.0Hz,2H),6.22-5.97(m,2H),4.55(s,1H),4.47(s,1H),4.09(t,J=4.3Hz,2H),3.90(dq,J=15 .0,8.0Hz,1H),3.72(d,J=1.6Hz,3H),2.88(s,2H),2.78(s,2H),2.45(d,J=16.9Hz,3H),2.34( q,J=9.3,7.5Hz,1H),2.16(s,1H),2.04(dd,J=15.8,9.5Hz,1H),1.68(dh,J=37.2,9.6Hz,4H).

[1516] Example 12

[1517] Preparation of 1-(4-chlorobenzyl)-3-(6-(dibenzylamino)spiro[3.3]hept-2-yl)urea (Compound 119)

[1518]

[1519] Step 1: Preparation of 1-(4-chlorobenzyl)-3-(6-(dibenzylamino)spiro[3.3]hept-2-yl)urea.

[1520] Benzyl bromide (18 μL, 0.159 mmol, 1 eq) was added to a stirred solution of 1-(6-aminospiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (70 mg, 0.238 mmol, 1.5 eq) and DIPEA (83 μL, 0.477 mmol, 3 eq) in CHCl (2 mL) at room temperature. After 3 hours, the solvent was removed by rotary evaporation, and the product (28 mg, 40%) was isolated as a white solid by reverse-phase HPLC (5->95% MeCN / H2O containing 0.1% formic acid). LRMS (APCI) m / z 474 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 1H), 7.41-7.15 (m, 14H), 6.25 (t, J = 6.1Hz, 1H), 6.1 5(d,J=8.1Hz,1H),4.14(d,J=6.0Hz,2H),3.90(q,J=8.0Hz,1H),3.40(s,3H),3.18(d ,J=3.9Hz,1H),2.99(q,J=7.9Hz,1H),2.24(dt,J=11.3,5.8Hz,1H),2.09(dq,J=10. 0,5.2,4.5Hz,2H),1.89(dt,J=11.5,5.8Hz,1H),1.75(qd,J=13.0,11.8,9.0Hz,3H).

[1521] Example 13

[1522] Preparation of 4-(4-(6-(benzylamino)spiro[3.3]hept-2-yl)-3-oxobutyl)benzamide (Compound 24)

[1523]

[1524] Step 1: Preparation of tert-butyl (6-(4-(4-carbamoylphenyl)-2-oxobutyl)spiro[3.3]hept-2-yl)carbamate. Phenyl N-[(4-carbamoylphenyl)methyl]carbamate (657 mg, 2.4 mmol, 1.1 equiv) and NEt (671 mg, 6.6 mmol, 3.00 equiv) were added to a stirred solution of N-[6-aminospiro[3.3]hept-2-yl]carbamate (500 mg, 2.2 mmol, 1.00 equiv) in DMF (5.00 mL) and heated to 50°C. After 2 h, the reaction was cooled to room temperature and the volatiles were removed by rotary evaporation. The product was isolated as a white solid (45%) by reverse phase HPLC (60% MeCN / H2O containing 0.1% ammonium formate). LRMS (ESI) m / z 403 (M+H).

[1525]

[1526] Step 2: Preparation of 4-(4-(6-aminospiro[3.3]hept-2-yl)-3-oxobutyl)benzamide hydrochloride. HCl (10 mL, 4 M in dioxane) was added to a stirred solution of tert-butyl (6-(4-(4-carbamoylphenyl)-2-oxobutyl)spiro[3.3]hept-2-yl)carbamate (380 mg, 0.94 mmol, 1.00 equiv) in CHCl (40 mL) at room temperature. After 1 hour, the reaction was concentrated by rotary evaporation to afford the crude product (560 mg) as a white solid, which was used without further purification. LRMS (ESI) m / z 303 (M+H).

[1527]

[1528] Step 3: Preparation of 4-(4-(6-(benzylamino)spiro[3.3]hept-2-yl)-3-oxobutyl)benzamide

[1529] AcOH (29 mg, 0.54 mmol, 2 equiv) and NaHB(OAc) (103 mg, 0.54 mmol, 2.00 equiv) were added to a stirred solution of 4-[[([6-aminospiro[3.3]hept-2-yl]carbamoyl)amino]methyl]benzamide hydrochloride (82 mg, 0.27 mmol, 1.00 equiv) and benzaldehyde (29 mg, 0.27 mmol, 1.00 equiv) in CHCl (5 mL) at room temperature. After 3 h, the solvent was removed by rotary evaporation and the product (15%) was isolated as a white solid by reverse phase HPLC (15% -> 45% MeCN / H2O containing 0.1% ammonium formate). LRMS (ESI) m / z 393 (M+H). 1 H NMR (300MHz, methanol-d4) δ7.90 (s, 1H), 7.80 (d, J = 7.8Hz, 2H), 7.28 (s, 6H), 7.2 3-7.09(m,1H),6.26(s,1H),6.16(d,J=8.1Hz,1H),4.21(d,J=4.6Hz,2H), 3.92(d,J=7.9Hz,1H),3.57(s,2H),3.32(s,3H),3.11-2.92(m,1H),2.23( s,2H),2.12(s,1H),2.03(d,J=7.6Hz,1H),1.73(dt,J=20.4,10.2Hz,3H).

[1530] Example 14

[1531] Preparation of 4-((3-(6-((pyridin-2-ylmethyl)amino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide (Compound 34)

[1532]

[1533] Step 1: Preparation of 6-aminospiro[3.3]heptan-2-one hydrochloride. HCl (5 mL, 4 M in dioxane) was added to a stirred solution of tert-butyl N-[6-oxospiro[3.3]heptan-2-yl]carbamate (500 mg, 2.2 mmol, 1.00 equiv) in CHCl (5.00 mL). The reaction was then concentrated by rotary evaporation to afford the crude product (350 mg) as a white solid. LRMS (ESI) m / z 126 (M+H).

[1534]

[1535] Step 2: Preparation of 4-((3-(6-oxospiro[3.3]hept-2-yl)ureido)methyl)benzamide. N-[(4-Carbamoylphenyl)methyl]carbamate (241 mg, 0.90 mmol, 1.2 equiv) and NEt3 (300 mg, 2.97 mmol, 4 equiv) were added to a stirred solution of 6-aminospiro[3.3]hept-2-one hydrochloride (120 mg, 0.74 mmol, 1.00 equiv) in MeCN (4 mL) and heated to 65°C. After 2 h, the reaction was cooled to room temperature and concentrated by rotary evaporation to give the crude product (280 mg) as a yellow solid. LRMS (ESI) m / z 302 (M+H).

[1536]

[1537] Step 3: Preparation of 4-((3-(6-((pyridin-2-ylmethyl)amino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide. 2-Pyridinemethylamine (145 mg, 1.34 mmol, 1.5 equiv) and 4-[[([6-oxospiro[3.3]hept-2-yl]carbamoyl)amino]methyl]benzamide (270 mg, 0.90 mmol, 1.00 equiv) were dissolved in DCE (5 mL) and stirred at room temperature for 30 minutes before the addition of NaHB(OAc) (285 mg, 1.34 mmol, 1.5 equiv). After 1 hour, the reaction was concentrated by rotary evaporation, and the product (20 mg) was isolated by reverse phase HPLC (3%->15% MeCN / HO with ammonium formate) as a yellow solid. LRMS (ESI) m / z 394 (M+H). 1H NMR(400MHz,DMSO-d6)δ8.50(d,J=4.9Hz,1H),8.25(s,1H),7.91(s,1H),7.85-7.71(m ,3H),7.42(d,J=7.9Hz,1H),7.36-7.22(m,5H),6.30(t,J=6.2Hz,1H),6.21(d,J=8.0H z,1H),4.22(d,J=6.0Hz,2H),3.94(q,J=7.9Hz,1H),3.16(p,J=7.7Hz,1H),2.32-2.19 (m,2H),2.15(dt,J=11.9,6.4Hz,1H),2.06(dt,J=11.7,5.9Hz,1H),1.84-1.71(m,4H).

[1538] Example 15

[1539] Preparation of 4-((3-(6-((pyridin-2-ylmethyl)amino)spiro[3.3]hept-2-yl)ureido)methyl)benzamide (Compounds 187 and 182)

[1540]

[1541] Preparation of 1-(4-chlorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea. HATU (1.4 g, 3.7 mmol, 1.5 eq) was added to a stirred solution of 6-(3-(4-chlorobenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (Intermediate 2.1) (1 g, 0.36 mmol, 1 eq), 2-methyl-1-(piperazin-1-yl)propan-2-ol (980 mg, 6.2 mmol, 2 eq) and NEt (1.3 mL, 9.3 mmol, 3 eq) in EtOAc (50 mL) at room temperature. After 12 h, the reaction was dry loaded onto silica and the racemic product was isolated as a white solid by silica chromatography (0->15% MeOH / CH2Cl2 containing 0.1% formic acid).

[1542] Chiral separation of 1-(4-chlorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea.

[1543] A 1 g mixture of 1-(4-chlorobenzyl)-3-(6-(4-(2-hydroxy-2-methylpropyl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)urea was separated by SFC (Chiralcel OX-H column, 50% cosolvent [25% MeOH / MeCN containing 0.25% isopropylamine] at a rate of 70 g / min) to afford two isomers as white solids: compound 187 (0.32 g, 46%) and compound 182 (0.33 g, 47%). The absolute stereochemistry of each isomer was not determined and was arbitrarily assigned. Compound 187 eluted first from SFC using the specified conditions, followed by compound 182.

[1544] Compound 187: LRMS (APCI) m / z 464.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2 H),4.03(p,J=8.0Hz,1H),3.62-3.52(m,2H),3.47-3.39(m,2H),3.27(q,J=8 .6Hz,1H),2.55(ddt,J=18.0,11.5,5.1Hz,5H),2.37-2.22(m,6H),2.12(ddd ,J=11.5,8.5,3.2Hz,1H),1.87(ddd,J=36.9,11.1,8.6Hz,2H),1.21(s,6H).

[1545] Compound 182: LRMS (APCI) m / z 464.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.31(d,J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),4.28(s,2H),4.03(p,J=8.0Hz,1H),3.57(q,J=4.6Hz,2H),3.43(t,J=4.9Hz,2H), 3.27(t,J=8.6Hz,1H),2.54(ddt,J=18.2,11.7,5.0Hz,5H),2.38-2.21(m, 6H),2.21-2.07(m,1H),1.87(ddd,J=37.2,11.2,8.6Hz,2H),1.21(s,6H).

[1546] The compounds in the table below were prepared in a similar manner to compounds 187 and 182 using the listed intermediates and reagents.

[1547]

[1548]

[1549]

[1550]

[1551] Example 16

[1552] Preparation of 1-(4-chlorobenzyl)-3-(6-((4-methyl-3-oxopiperazin-1-yl)methyl)spiro[3.3]hept-2-yl)urea (Compound 238)

[1553]

[1554] 1-(4-Chlorobenzyl)-3-(6-((4-methyl-3-oxopiperazin-1-yl)methyl)spiro[3.3]hept-2-yl)urea. NaBH(OAc)3 (249 mg, 1.17 mmol, 2 equiv) was added to a stirred solution of 1-(4-chlorobenzyl)-3-(6-formylspiro[3.3]hept-2-yl)urea (Intermediate 11.1, 180 mg, 0.587 mmol, 1 equiv) and 1-methylpiperazin-2-one (134 mg, 1.17 mmol, 2 equiv) in CHCl (2 mL) at room temperature. After 12 hours, the solvent was removed by rotary evaporation, and the crude product was suspended in MeOH (3 mL), filtered through a 0.4 μm syringe filter, and the product (60 mg, 25%) was isolated as a white solid by reverse-phase HPLC (0->30% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 405.1 (M+H). 1 H NMR (400 MHz, methanol-d4) δ 7.20 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 4.16 (s, 2H), 3.90 (p, J = 8.0 Hz, 1H), 3.25 (t, J = 5.6 Hz, 2H), 2.97 (s, 2H), 2.83 (s, 3H), 2.60 (t, J = 5.7 Hz, 2H), 2.42-2.28 (m, 4H), 2.20-2.08 (m, 2H), 1.96 (ddd, J = 11.1, 7.0, 4.1 Hz, 1H), 1.81-1.73 (m, 1H), 1.73-1.57 (m, 3H).

[1555] The compounds in the table below were prepared in a similar manner to compound 238 using the listed intermediates and reagents.

[1556]

[1557]

[1558]

[1559]

[1560] Example 17

[1561] 1-(4-chlorobenzyl)-3-(6-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)spiro[3.3

[1562] Preparation of (2-heptyl)urea (Compound 242)

[1563]

[1564] 1-(4-Chlorobenzyl)-3-(6-((5-phenyl-1H-1,2,3-triazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea. 1-(6-(Azidomethyl)spiro[3.3]hept-2-yl)-3-(4-chlorobenzyl)urea (100 mg, 0.30 mmol, 1 equiv), ethynylbenzene (46 mg, 0.449 mmol, 1.5 equiv), and Cp*RuCl(cod) (11 mg, 0.03 mmol, 0.1 equiv) were suspended in THF (5 mL) and heated to 60°C. After 12 hours, the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, and the product (20 mg, 15%) was isolated as a white solid by reverse phase HPLC (5->95% MeCN / water 0.1% formic acid). LRMS (ESI) m / z 436.1 (M+H). 1 H NMR (400MHz, chloroform-d) δ7.10 (d, J = 5.5Hz, 3H), 6.99-6.92 (m, 2H), 6.88 (d, J = 10.0Hz ,5H),6.81(d,J=8.0Hz,2H),4.28(t,J=5.9Hz,1H),4.19(d,J=7.4Hz,1H),3.92(d ,J=6.5Hz,4H),3.64-3.50(m,1H),2.24(dt,J=15.3,7.5Hz,1H),2.02(dt,J=11.9 ,6.4Hz,1H),1.83(dt,J=12.1,6.4Hz,1H),1.74-1.65(m,1H),1.60-1.47(m,3H).

[1565] Example 18

[1566] Preparation of 1-(4-(1-(2H-tetrazol-5-yl)piperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea (Compound 318)

[1567]

[1568] Step 1: 1-(4-chlorobenzyl)-3-(4-(1-cyanopiperidin-4-yl)butyl)urea. CNBr (154 mg, 1.46 mmol, 1.05 equiv) was added to a stirred solution of 1-(4-chlorobenzyl)-3-(4-(piperidin-4-yl)butyl)urea (Intermediate 3.8, 500 mg, 1.39 mmol, 1 equiv) and saturated sodium bicarbonate (4.2 mL) in CHCl (10 mL) at 0°C. After 14 h, the reaction was extracted with CHCl (3 x 5 mL), and the organics were combined, dried over sodium sulfate, filtered through a pad of silica gel, and the solvent removed by rotary evaporation to give the crude product, which was used in the next step without further purification (267 mg, 55%). LRMS (ESI) m / z 349.1 (M+H).

[1569]

[1570] Step 2: 1-(4-(1-(2H-tetrazol-5-yl)piperidin-4-yl)butyl)-3-(4-chlorobenzyl)urea. 1-(4-Chlorobenzyl)-3-(4-(1-cyanopiperidin-4-yl)butyl)urea (102 mg, 0.29 mmol, 1 eq), sodium azide (21 mg, 0.322 mmol, 1.1 eq), and zinc bromide (66 mg, 0.293 mmol, 1 eq) were suspended in DMF (2 mL) and heated to 100° C. for 3 hours. The reaction was cooled to room temperature, and the product was isolated as a white solid by reverse phase HPLC (10->60% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 392.1 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),6.31(t,J=6.1Hz,1H),5.93(t,J=5.6Hz,1H),4.18(d, J=5.9Hz,2H),3.80(d,J=12.7Hz,2H),3.05-2.90(m,4H),1.71(d,J=14.1Hz,2H),1.36(t,J=7.0Hz,3H),1.32-1.07(m,7H).

[1571] Example 19

[1572] Preparation of 1-(4-methoxybenzyl)-3-(6-(5-phenyl-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)urea (Compound 325)

[1573]

[1574] 1-(4-Methoxybenzyl)-3-(6-(5-phenyl-1,3,4-oxadiazol-2-yl)spiro[3.3]hept-2-yl)urea. 6-(3-(4-Methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (200 mg, 0.628 mmol, 1 equiv) and benzohydrazide (86 mg, 0.628 mmol, 1 equiv) were suspended in phosphorus oxychloride (5 mL) and stirred at room temperature for 14 hours. The solvent was removed by rotary evaporation, and the product (17 mg, 5%) was isolated as a white solid by reverse-phase HPLC (5->95% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 419.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ8.04(d,J=8.3Hz,2H),7.59(q,J=7.5,6.5Hz,3H),7.20(d,J=8.1Hz,2H),6.88(d,J=7.1Hz,2H),4.24( s,2H),4.10(p,J=8.0Hz,1H),3.78(s,4H),2.71-2.53(m,3H),2.47(dd,J=21.5,7.2Hz,3H),1.98(dt,J=23.2,10.0Hz,2H).

[1575] Example 20

[1576] Preparation of 1-(4-methoxybenzyl)-3-(6-(4-phenyloxazol-2-yl)spiro[3.3]hept-2-yl)urea (Compound 326)

[1577]

[1578] 1-(4-Methoxybenzyl)-3-(6-(4-phenyloxazol-2-yl)spiro[3.3]hept-2-ylurea. DCC (143 mg, 0.693 mmol, 1.05 eq) was added to 6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (210 mg, 0.660 mmol, 1 eq), 2-hydroxy-1-phenylethan-1-one (90 mg, 0.660 mmol, 1 eq) and DMAP (1 mg, 0.007 mmol, 0.01 eq) in CHCl (pH 7.0) at room temperature. The crude product was suspended in toluene (50 mL), then ammonium acetate (101 mg, 1.32 mmol, 2 equiv) and AcOH (2 mL) were added, and the reaction was heated at reflux for 2 hours. The reaction was cooled to room temperature, the solvent was removed by rotary evaporation, and the product (55 mg, 20%) was isolated as a white solid by reverse phase HPLC (5->95% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 418.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ8.15(s,1H),7.73(d,J=7.7Hz,2H),7.41(t,J=7.6Hz,2H),7 .32(t,J=7.4Hz,1H),7.21(d,J=8.2Hz,2H),6.88(d,J=8.2Hz,2H),4.24(s,2H),4 .09(p,J=8.1Hz,1H),3.78(s,3H),3.61(p,J=8.6Hz,1H),2.61(dt,J=11.5,5.7Hz ,1H),2.57-2.48(m,2H),2.48-2.33(m,3H),2.04-1.95(m,1H),1.95-1.85(m,1H).

[1579] Example 21

[1580] 1-(6-(Benzo[d]oxazol-2-yl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea

[1581] Preparation of (Compound 327)

[1582]

[1583] 1-(6-(Benzo[d]oxazol-2-yl)spiro[3.3]hept-2-yl)-3-(4-methoxybenzyl)urea. DCC (136 mg, 0.660 mmol, 1.05 eq) was added to a stirred solution of 6-(3-(4-methoxybenzyl)ureido)spiro[3.3]heptane-2-carboxylic acid (200 mg, 0.628 mmol, 1 eq), 2-aminophenol (75 mg, 0.691 mmol, 1 eq) and DMAP (1 mg, 0.007 mmol, 0.01 eq) in CHCl (20 mL) at room temperature. After 14 h, the reaction was filtered through a pad of Celite and the solvent was removed by rotary evaporation. The crude material was suspended in toluene (20 mL), then 4-methylbenzenesulfonic acid (11 mg, 0.063 mmol, 0.1 eq) was added, and the reaction was heated at reflux for 2 h. The reaction was cooled to room temperature, the solvent was removed by rotary evaporation, and the product (35 mg, 14%) was isolated as a white solid by reverse phase HPLC (5->95% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 392.1 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.68-7.53(m,2H),7.41-7.32(m,2H),7.20(d,J=7.6Hz,2H),6.88(d,J=7.5Hz,2H),4. 24(s,2H),4.10(p,J=8.4,7.7Hz,1H),3.83-3.67(m,4H),2.70-2.35(m,6H),1.97(dt,J=33.1,10.0Hz,2H).

[1584] Example 22

[1585] Preparation of 1-(4-chlorobenzyl)-3-(6-(hydroxy(phenyl)methyl)spiro[3.3]hept-2-yl)urea (Compound 328)

[1586]

[1587] 1-(4-Chlorobenzyl)-3-(6-(hydroxy(phenyl)methyl)spiro[3.3]hept-2-yl)urea. Phenylmagnesium bromide (1 M in THF, 652 mL, 0.652 mmol, 2 equiv) was added to a stirred solution of 1-(4-chlorobenzyl)-3-(6-formylspiro[3.3]hept-2-yl)urea (Intermediate 11.1, 100 mg, 0.326 mmol, 1 equiv) in THF (5 mL) at 0°C. After 2 hours, the reaction was quenched with saturated ammonium chloride (50 mL) and extracted with CHCl (3 x 25 mL). The organics were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The product (13 mg, 10%) was isolated as a white solid by reverse-phase HPLC (5->95% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 385.2 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.34-6.94(m,9H),4.32(d,J=8.3Hz,1H),4.16(s,2H),3.88(dt,J=17.2,8. 3Hz,2H),2.34(dt,J=15.8,7.8Hz,2H),2.19-2.05(m,2H),1.99-1.83(m,2H),1.79-1.58(m,4H).

[1588] The compounds in the table below were prepared in a similar manner to compound 328 using the listed intermediates and reagents.

[1589]

[1590]

[1591] Example 23

[1592] Preparation of 1-(4-methoxybenzyl)-3-(6-(4-methylbenzyl)spiro[3.3]hept-2-yl)urea (Compound 334)

[1593]

[1594] 1-(4-Methoxybenzyl)-3-(6-(4-methylbenzyl)spiro[3.3]hept-2-yl)urea. Methyl (6-(3-(4-methoxybenzyl)ureido)spiro[3.3]hept-2-yl) 4-methylbenzenesulfonate (Intermediate 19.1, 100 mg, 0.218 mmol, 1 eq), 1-bromo-4-toluene (56 mg, 0.327 mmol, 1.5 eq), tetrabutylammonium iodide (121 mg, 0.327 mmol, 1.5 eq), zinc (43 mg, 0.654 mmol, 3 eq) and Ni precatalyst (e.g., Mennie, Katrina; Vara, Brandon; Levi, Samuel. Reductive sp3-sp2 Coupling Reactions Enable Late-Stage Modification of Pharmaceuticals. Organic Letters. 2020, 22, 556-559) (6 mg, 0.011 mmol, 0.05 equiv) was placed under circulating N2 for 5 minutes, then MeCN (5 mL) was added, the vial was sealed, and the reaction was heated to 90°C. After 14 hours, the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, and the product was isolated as a white solid by reverse-phase HPLC (5->95% MeCN / water containing 0.1% formic acid). LRMS (ESI) m / z 379.2 (M+H). 1 H NMR (400MHz, methanol-d4) δ7.19 (d, J = 8.2Hz, 2H), 7.06 (d, J = 7.7Hz, 2H), 7.00 (d, J = 7. 7Hz,2H),6.87(d,J=8.1Hz,2H),4.22(s,2H),4.01(p,J=8.1Hz,1H),3.78(s,3H), 2.61(d,J=7.6Hz,2H),2.41(dq,J=15.4,7.7,6.9Hz,2H),2.29(s,4H),2.15(t,J= 10.0Hz,1H),2.02-1.92(m,1H),1.81(dd,J=16.7,7.6Hz,3H),1.75-1.66(m,1H).

[1595] The compounds in the table below were prepared in a similar manner to compound 334 using the listed intermediates and reagents.

[1596]

[1597]

[1598]

[1599]

[1600]

[1601] Example 24

[1602] Preparation of 1-(4-chlorobenzyl)-3-(6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)urea (Compound 329)

[1603]

[1604] 1-(4-Chlorobenzyl)-3-(6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)urea. EtN (75 mg, 0.74 mmol, 2.0 equiv) and 1-chloro-4-(isocyanatomethyl)benzene (93 mg, 0.56 mmol, 1.5 equiv) were added to a solution of 6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-amine (Intermediate 22.1) (75 mg, 0.37 mmol, 1.0 equiv) in CHCl (1 mL) at 23°C. The reaction was stirred at this temperature for 30 minutes, then concentrated and purified by preparative HPLC (H2O (0.1% HCO2H) / MeCN (0.1% HCO2H)) to afford 1-(4-chlorobenzyl)-3-(6-(pyridin-4-ylmethyl)spiro[3.3]hept-2-yl)urea (70 mg, 51%) as a colorless oil. LRMS (APCI+) m / z 370.10 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.48 (s, 2H), 7.35 (d, J = 8.4Hz, 2H), 7.30-7.17 (m, 4H), 6.25 (t, J = 6.1Hz, 1H), 6. 17(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.90(h,J=8.1Hz,1H),2.68(dd,J=7.6,1.8Hz,2H),2.40(p,J =7.9Hz,1H),2.30(ddd,J=10.8,7.3,5.2Hz,1H),2.17(ddd,J=12.1,7.3,5.2Hz,1H),2.09(ddd,J=11.3, 7.7,3.9Hz,1H),1.93(ddd,J=11.6,7.7,4.0Hz,1H),1.75(q,J=9.0Hz,3H),1.68(dd,J=11.2,8.2Hz,1H).

[1605] The compounds in the table below were prepared in a similar manner to compound 329 using the listed intermediates and reagents.

[1606]

[1607]

[1608]

[1609]

[1610]

[1611]

[1612]

[1613]

[1614] Example 25

[1615] Preparation of 1-(4-chlorobenzyl)-3-(6-((4-cyano-1H-pyrazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea (Compound 333)

[1616]

[1617] 1-(4-Chlorobenzyl)-3-(6-((4-cyano-1H-pyrazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea. EtN (118 mg, 1.17 mmol, 3.0 equiv) and MsCl (89 mg, 0.777 mmol, 2.0 equiv) were added sequentially to a solution of 1-(4-chlorobenzyl)-3-(6-(hydroxymethyl)spiro[3.3]hept-2-yl)urea (Intermediate 10.1, 120 mg, 0.389 mmol, 1.0 equiv) in CHCl (2 mL). The mixture was stirred at 23°C for 3 hours and then poured into a half-saturated NaHCO solution. The aqueous phase was extracted with CHCl (5 mL x 2), and the combined organic phases were washed with brine, dried (MgSO), filtered, and concentrated to provide the crude mesylate, which was used without further purification. Next, KCO (107 mg, 0.777 mmol, 2.0 equiv) and 1H-pyrazole-4-carbonitrile (72 mg, 0.777 mmol, 2.0 equiv) were added to a solution of the thus obtained mesylate (up to 0.389 mmol) in DMF (1 mL). The reaction was heated at 80°C for 3 hours. Upon completion, the reaction was directly subjected to preparative HPLC (H2O (0.1% HClOH) / MeCN (0.1% HClOH)) to afford 1-(4-chlorobenzyl)-3-(6-((4-cyano-1H-pyrazol-1-yl)methyl)spiro[3.3]hept-2-yl)urea (61 mg, 40% over 2 steps) as a white solid. LRMS (APCI+) m / z 384.15 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.04(s,1H),7.36(d,J=8.4Hz,2H),7.24(d,J=8.2Hz,2H),6.25(t, J=6.1Hz,1H),6.17(d,J=8.0Hz,1H),4.15(d,J=6.7Hz,4H),3.90(h,J=8.2Hz,1H),2.60(hept,J=7.7Hz, 1H),2.31(ddd,J=10.7,7.3,5.1Hz,1H),2.16(ddd,J=12.1,7.4,5.2Hz,1H),2.07(ddd,J=11.3,7.9,3.5 Hz,1H),1.92(ddd,J=11.5,7.9,3.4Hz,1H),1.80(dd,J=11.3,8.2Hz,2H),1.74(dd,J=11.3,8.4Hz,2H).

[1618] The compounds in the table below were prepared in a similar manner to compound 333 using the listed intermediates and reagents.

[1619]

[1620]

[1621]

[1622] Biological Example 1

[1623] NMN fluorescence biochemistry and NAD cell assays

[1624] A. Human Recombinase Assay

[1625] The ability of the compounds described herein to stimulate nicotinamide mononucleotide (NMN) synthesis by the enzyme NAMPT was determined. The human recombinant enzyme assay uses recombinant enzyme and substrate in a buffered, cell-free system to measure compound activation of enzyme activity. Assay conditions closely mimic the cellular environment. Dose responses were measured using an assay that detects nicotinamide mononucleotide formation. All experiments were performed in a 384-well format. Generally, 0.5 μL of DMSO containing varying concentrations of test compound was mixed with 10 μL of enzyme reagent solution. The enzyme reaction was initiated by adding 10 μL of a solution containing substrate. 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 incubation at ambient temperature for 60 minutes, 10 μL of 20% acetophenone in DMSO was added, followed by 10 μL of 2M KOH and 40 μL of formic acid. After incubation at ambient temperature for 40 minutes, the fluorescence of the plate was read using an EnVision microplate reader (excitation / emission = 355 nm / 460 nm). The potency measurements of the compounds were quantified and expressed as AC 1.4 (Compound concentrations that produced 40% higher activity than basal and EC 50 (Compound concentration that produces half-maximal activation). Table A shows the AC of the tested compounds. 1.4 and EC 50 data.

[1626] Table A

[1627]

[1628]

[1629]

[1630]

[1631]

[1632]

[1633]

[1634] ND = Not Determined

[1635] B. Cellular NAD+ regulation assay.

[1636] The compounds described herein were also tested for their ability to stimulate endogenous NAMPT in a native cellular environment in a cellular NAD+ modulation assay, which measures the ability of a compound to modulate cellular NAD levels. Compounds that penetrate cells and activate the catalytic activity of endogenous NAMPT are expected to increase NAD levels.

[1637] Neuroblastoma SH-SY5Y cells were grown in a 1:1 mixture of Eagle's Minimum Essential Medium and F12 medium with 10% fetal bovine serum at 37°C in a humidified incubator with an atmosphere of 95% air and 5% CO2. 20 μL of SH-SY5Y cells in medium with 0.1% fetal bovine serum were plated at a density of 5000 cells / well in 384-well Corning TM BioCoat TM The assay was started in a Poly-D-Lysine multiwell plate. The plate was incubated for 5 hours in a 37°C incubator. Compounds in DMSO were added to the plate in a volume of 120 nL using a Labcyte Echo Liquid Handler. 5 μL of a 1.5 uM doxorubicin solution in assay medium was added to each well. The plate was then incubated for 40 hours. 30 μL of a reading solution containing 0.2 U / mL diaphorase, 40 uM resazurin, 10 uM FMN, 0.8 U / mL alcohol dehydrogenase, 3% ethanol, 0.4 mg / mL bovine serum albumin, 0.2% Triton X-100, 30 mM EDTA in 100 mM Tris-HCl, pH 8.4 was used. After incubation for 60 minutes at ambient temperature, the fluorescence of the plate was read using an EnVision microplate reader (excitation / emission = 540 nm / 590 nm). Table B shows the AC of the tested compounds. 0.3 and EC 50 data.

[1638] Table B

[1639]

[1640]

[1641] ND = Not Determined

[1642] 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 were individually incorporated by reference.

[1643] It should be understood that although the disclosure provided herein has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not to limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure belongs.

Claims

1. A compound of formula (II): or a pharmaceutically acceptable salt thereof, in: n is 0; Y 1 for And R 1 Selected from the group consisting of: in R 2a and R 2b Each is independently halogen, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and R 2c , R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl; G 1 for CH; p1 is 1 or 2, and p2 is 1; q1 is 1 or 2, and q2 is 1; and R 3 Selected from the group consisting of: i. unsubstituted C1-C6 alkyl; ii.C6-C 14 Aryl; iii. Optionally one or more R a A 5- to 18-membered heteroaryl group substituted with a substituent, wherein R a C1-C6 alkyl, C6-C 14 aryl or 5- to 18-membered heteroaryl, wherein R a The 5- to 18-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl substituents; i v.-NR 3a R 3b ,in R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 -(C1-C6 alkylene)-(5- to 18-membered heteroaryl); v.-OR 3c ,in R 3c C6-C 14 Aryl, 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl); vi.-C(O)R 3d ,in R 3d Selected from the group consisting of: -NR 3f R 3g ; C3-C8 cycloalkyl; C6-C 14 Aryl-substituted C3-C8 cycloalkyl, wherein the C6-C 14 The aryl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; C3-C8 cycloalkenyl; C6-C 14 Aryl: hydroxy, halide, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, -C(O)O(C1-C6 alkyl), -NR 3e1 R 3e2 , -S(O)2(C1-C6 alkyl), 5- to 18-membered heteroaryl, and 3- to 18-membered heterocycloalkyl optionally substituted with oxo, wherein R 3e1 and R 3e2 Each independently is H or C1-C6 alkyl; -(C1-C6 alkylene)-(C6-C 14 Aryl): halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; A 3- to 18-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from the group consisting of: (a) C1-C6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of hydroxyl, halogen, C3-C 10 cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents, (b)C6-C 14 Aryl, (c) a 3- to 18-membered heterocycloalkyl group, (d) -C(O)O(C1-C6 alkyl), (e)-C(O)(C6-C 14 aryl), (f) halogen, (g) C1-C6 alkoxy optionally substituted by one or more halo substituents, and (h) oxo; and a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an oxo group, and a 3- to 18-membered heterocycloalkyl group, in R 3f and R 3g Each independently selected from the group consisting of: (a) hydrogen, (b) is optionally independently selected from -OH, C6-C 14 A C1-C6 alkyl group substituted with one or more substituents from the group consisting of an aryl group and a 5- to 18-membered heteroaryl group, wherein the C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are each independently unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy and CN, (c)C6-C 14 Aryl, (d) a 3- to 18-membered heterocycloalkyl group, (e) a 5- to 18-membered heteroaryl group optionally substituted by methyl or CN, (f) C3-C4 optionally substituted by one or more substituents independently selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 Aryl and 5- to 18-membered heteroaryl; and (g) C3-C4 optionally substituted by one or more substituents independently selected from the group consisting of: 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 Aryl and 5- to 18-membered heteroaryl; vii. C1-C6 alkyl substituted with one or more of the following substituents: -OH, -C(O)NR 3h R 3i 、C6-C 14 Aryl, wherein the C6-C 14 Aryl is optionally substituted with one or more independently selected C1-C6 alkyl substituents, 3- to 18-membered heterocycloalkyl, wherein the 3- to 18-membered heterocycloalkyl is optionally independently selected from halo, oxo, C1-C6 alkyl, C6-C 14 aryl and one or more substituents of 5- to 18-membered heteroaryl, 5- to 18-membered heteroaryl, wherein the 5- to 18-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, C6-C 14 Aryl or cyano substituted, -N(R 3p )-C(O)R 3q 、-S(O)2-R 3r or -C(O)-R 3s , in R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl), R 3p is H or C1-C6 alkyl, R 3q is C3-C8 cycloalkyl, 3- to 18-membered heterocycloalkyl optionally substituted with one or more independently selected oxo substituents, or 5- to 18-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, R 3r C6-C 14 aryl or 5- to 18-membered heteroaryl, and R 3s is a 3- to 18-membered heterocycloalkyl group optionally substituted with one or more independently selected C1-C6 alkyl substituents, wherein the C1-C6 alkyl group is independently optionally substituted with one or more -OH; viii.-C(O)OR 3j ,in R 3j is hydrogen or C1-C6 alkyl; i x.-NHC(O)R 3k ,in R 3k is a C6-C 14 Aryl: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 each independently hydrogen or C1-C6 alkyl, optionally substituted by one or more substituents independently selected from the group consisting of: -(C1-C6 alkylene)-(C6-C 14 Aryl): C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 are each independently hydrogen or C1-C6 alkyl, or a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl; x.-NHC(O)OR 3l ,in R 3l is hydrogen or C1-C6 alkyl; xi.-NHSO2R 3m ,in R 3m is a 5- to 18-membered heteroaryl, a C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein the 5- to 18-membered heteroaryl, the C6-C 14 The aryl group and the -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkoxy; and xii.-SO2R 3n ;in R 3n C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein R 3n The C3-C 10 Cycloalkyl, the C6-C 14 The aryl group and the -(C1-C6 alkylene)-(C6-C 14 aryl) are each independently optionally substituted by one or more substituents independently selected from halo and -C(O)O(C1-C6 alkyl).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p1 is 1 and q1 is 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p1 is 2 and q1 is 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein p1 is 2 and q1 is 2.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 It is an unsubstituted C1-C6 alkyl group.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 C6-C 14 Aryl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 is optionally replaced by one or more R a A 5- to 18-membered heteroaryl group substituted with a substituent, wherein R a C1-C6 alkyl, C6-C 14 aryl or 5- to 18-membered heteroaryl, wherein R a The 5- to 18-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl substituents.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally replaced by one or more R a Substituents: substituted pyridyl, pyrimidinyl, 1,3,4-oxadiazolyl, oxazolyl or benzo[d]oxazolyl.

9. The compound according to claim 7 or claim 8, or a pharmaceutically acceptable salt thereof, wherein R 3 for 10. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 For-NR 3a R 3b , where R 3a and R 3b Each independently selected from the group consisting of: hydrogen, C6-C 14 Aryl, 5- to 18-membered heteroaryl, -(C1-C6 alkylene)-(C6-C 14 aryl) and -(C1-C6 alkylene)-(5- to 18-membered heteroaryl).

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 for 12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 OR 3c , where R 3c C6-C 14 aryl, 5- to 18-membered heteroaryl, or -(C1-C6 alkylene)-(5- to 18-membered heteroaryl).

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 -C(O)R 3d .

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d For-NR 3f R 3g , and R 3f and R 3g Each independently selected from the group consisting of: (a) hydrogen, (b) is optionally independently selected from -OH, C6-C 14 A C1-C6 alkyl group substituted with one or more substituents from the group consisting of an aryl group and a 5- to 18-membered heteroaryl group, wherein the C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are each independently unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy and CN, (c)C6-C 14 Aryl, (d) a 3- to 18-membered heterocycloalkyl group, (e) a 5- to 18-membered heteroaryl group optionally substituted by methyl or CN, (f) C3-C4 optionally substituted by one or more substituents independently selected from the group consisting of 10 Cycloalkyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 Aryl and 5- to 18-membered heteroaryl; and (g) C3-C4 optionally substituted by one or more substituents independently selected from the group consisting of: 10 Cycloalkenyl: halogen, hydroxy, C1-C6 alkyl optionally substituted by hydroxy, C6-C 14 Aryl and 5- to 18-membered heteroaryl.

15. The compound according to claim 13 or claim 14, or a pharmaceutically acceptable salt thereof, wherein R 3 for 16. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d It is a C3-C8 cycloalkyl group.

17. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d For C6-C 14 Aryl-substituted C3-C8 cycloalkyl, wherein the C6-C 14 The aryl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 3 for 19. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d It is a C3-C8 cycloalkenyl group.

20. A compound of formula (II): or a pharmaceutically acceptable salt thereof, in: n is 0; Y 1 for And R 1 Selected from the group consisting of: in R 2a and R 2b Each is independently halogen, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d or -N(R 2e )C(O)(C1-C6 alkyl); and R 2c , R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl; G 1 for CH; p1 is 1 or 2, and p2 is 1; q1 is 1 or 2, and q2 is 1; And R 3 for 21. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d is a C6-C 14 Aryl: hydroxy, halide, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C1-C6 alkylene)-OH, -C(O)O(C1-C6 alkyl), -NR 3e1 R 3e2 , -S(O)2(C1-C6 alkyl), 5- to 18-membered heteroaryl, and 3- to 18-membered heterocycloalkyl optionally substituted with oxo, wherein R 3e1 and R 3e2 Each is independently H or C1-C6 alkyl.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 3 for 23. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d -(C1-C6 alkylene)-(C6-C 14 Aryl): halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 3 for 25. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d is a 3- to 18-membered heterocycloalkyl group optionally substituted by one or more substituents independently selected from the group consisting of: (a) C1-C6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of hydroxyl, halogen, C3-C 10 cycloalkyl and 5- to 18-membered heteroaryl optionally substituted with one or more C1-C6 alkyl substituents, (b)C6-C 14 Aryl, (c) a 3- to 18-membered heterocycloalkyl group, (d) -C(O)O(C1-C6 alkyl), (e)-C(O)(C6-C 14 aryl), (f) halogen, (g) C1-C6 alkoxy optionally substituted by one or more halo substituents, and (h) Oxo group.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 3 for 27. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3d is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an oxo group, and a 3- to 18-membered heterocycloalkyl group.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 3 for 29. A compound as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 C(O)NR 3h R 3i Substituted C1-C6 alkyl, wherein R 3h and R 3i Each independently selected from C1-C6 alkyl and -(C1-C6 alkylene)-(C6-C 14 aryl).

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 3 for 31. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 is a C1-C6 alkyl substituted by a 3- to 18-membered heterocycloalkyl, wherein the 3- to 18-membered heterocycloalkyl is optionally independently selected from halo, oxo, C1-C6 alkyl, C6-C 14 The aryl group and the 5- to 18-membered heteroaryl group are substituted with one or more substituents.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 3 for 33. A compound as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 is a C1-C6 alkyl group, wherein R 3 The C1-C6 alkyl (i) is substituted by a 5- to 18-membered heteroaryl, wherein the 5- to 18-membered heteroaryl is optionally substituted by one or more C1-C6 alkyl, C6-C 14 aryl or cyano, and (ii) is optionally substituted with one or more -OH.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 for 35. A compound as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)OR 3j , where R 3j It is hydrogen or C1-C6 alkyl.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 3 for 37. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)R 3k .

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 3k is a C6-C 14 Aryl: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

39. A compound as claimed in claim 37 or claim 38, or a pharmaceutically acceptable salt thereof, wherein R 3 for 40. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 3k -(C1-C6 alkylene)-(C6-C 14 Aryl): C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

41. A compound as claimed in claim 37 or claim 40, or a pharmaceutically acceptable salt thereof, wherein R 3 for 42. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 3k is a 5- to 18-membered heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of: C1-C6 alkyl, cyano, -NR 3k1 R 3k2 , hydroxyl, C1-C6 alkoxy, and S(O)2(C1-C6 alkyl), wherein R 3k1 and R 3k2 Each is independently hydrogen or C1-C6 alkyl.

43. A compound as claimed in claim 37 or claim 42, or a pharmaceutically acceptable salt thereof, wherein R 3 for 44. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)OR 3l , where R 3l It is hydrogen or C1-C6 alkyl.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R 3 for 46. ​​A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 -NHSO2R 3m , where R 3m is a 5- to 18-membered heteroaryl, a C6-C 14 Aryl, or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein the 5- to 18-membered heteroaryl, the C6-C 14 The aryl group and the -(C1-C6 alkylene)-(C6-C 14 aryl) are each optionally substituted by one or more substituents independently selected from halo and C1-C6 alkoxy.

47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R 3 for 48. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 SO2R 3n And R 3n C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl or -(C1-C6 alkylene)-(C6-C 14 aryl), wherein R 3n The C3-C 10 Cycloalkyl, the C6-C 14 The aryl group and the -(C1-C6 alkylene)-(C6-C 14 aryl) are each independently optionally substituted by one or more substituents independently selected from halo and -C(O)O(C1-C6 alkyl).

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 3 for 50. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 For one or more -N(R 3p )-C(O)R 3q Substituted C1-C6 alkyl, wherein R 3p is H or C1-C6 alkyl, and R 3q is (i) C3-C8 cycloalkyl, (ii) 3- to 18-membered heterocycloalkyl optionally substituted with one or more independently selected oxo substituents, or (iii) 5- to 18-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 3 for 52. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 For one or more -S(O)2-R 3r Substituted C1-C6 alkyl, wherein R 3r C6-C 14 Aryl or 5- to 18-membered heteroaryl.

53. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein R 3 for 54. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 For one or more -C(O)-R 3s Substituted C1-C6 alkyl, wherein R 3s is a 3- to 18-membered heterocycloalkyl group optionally substituted with one or more independently selected C1-C6 alkyl substituents, wherein said C1-C6 alkyl group is independently optionally substituted with one or more -OH groups.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 3 for 56. A compound as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 is a C1-C6 alkyl group, wherein R 3 The C1-C6 alkyl (i) is replaced by one or more independently selected C6-C 14 The aryl substituent is substituted with 14 The aryl group is optionally substituted with one or more independently selected C1-C6 alkyl substituents, and (ii) is optionally substituted with one or more -OH.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein R 3 for 58. A compound as described in any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein R 1 for 59. A compound as described in any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein R 1 for 60. A compound as described in any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 1 for And R 2a Selected from the group consisting of: halogen, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl), wherein R 2c , R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl.

61. A compound as described in any one of claims 1-57 and 60, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

62. A compound as described in any one of claims 1-57, 60 and 61, or a pharmaceutically acceptable salt thereof, wherein R 1 for 63. A compound as described in any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 1 for And R 2b Selected from the group consisting of: halogen, -O(C1-C6 alkyl), C1-C6 alkyl substituted with -OH, -C(O)NR 2c R 2d and -N(R 2e )C(O)(C1-C6 alkyl), wherein R 2c , R 2d and R 2e Each is independently hydrogen or C1-C6 alkyl.

64. A compound as described in any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein R 1 for 65. A compound as described in any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein R 1 for 66. A compound selected from the following compounds or pharmaceutically acceptable salts thereof 67. A pharmaceutical composition comprising a compound according to any one of claims 1-66 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

68. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 66, or a pharmaceutical composition as described in claim 67, in the preparation of a medicament for treating a disease or disorder mediated by NAMPT activity in a subject in need thereof.

69. The use of claim 68, wherein the disease or disorder is selected from the group consisting of cancer, hyperproliferative diseases or disorders, inflammatory diseases or disorders, metabolic disorders, cardiac diseases or disorders, chemotherapy-induced tissue damage, kidney disease, metabolic diseases, nervous system diseases or damage, neurodegenerative disorders or diseases, diseases caused by impaired stem cell function, diseases caused by DNA damage, primary mitochondrial disorders, or muscle diseases and muscular dystrophy.

70. The method of claim 68, wherein the disease or illness 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 syndrome, neonatal nerve damage, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, poliomyelitis, and spinal cord injury.

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