NAMPT Modulators

Abstract

Provided is a compound of formula (II): TIFF2023512786000744.tif4288 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and p are as defined herein. Also provided are pharmaceutically acceptable compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of formula (II) or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 971,838, filed February 7, 2020, the disclosure of which is incorporated herein by reference in its entirety.

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

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

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

[0005] Over 200 enzymes use either NAD+ or NADP+ as coenzymes, and enzyme function is not limited to energy metabolism. It is now recognized that NAD+ plays a role in regulating diverse functions such as mitochondrial function, respiratory capacity, and biogenesis, mitochondrial nuclear signaling, and more. In addition, it controls cell signaling, gene expression, DNA repair, hematopoiesis, immune function, endoplasmic reticulum stress (unfolded protein response), and autophagy. In addition, NAD is anti-inflammatory and is the precursor of NADPH, the major source of reducing power to combat oxidative stress. A growing body of literature indicates that increasing NAD levels is an effective strategy to prevent or ameliorate a wide variety of disease conditions (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13).

[0006] Levels of NAD+ and NADP+ related enzymes play important roles in normal physiological function and are altered under various disease and stress conditions, including aging. Cellular NAD+ levels decline during aging, metabolic and inflammatory diseases, ischemia / reperfusion injury, and other conditions in humans (Massudi et al., PLoS ONE. 2012, 7(7):e42357) and animals (Yang et al., Cell. 2007, 130(6):1095-107; Braidy et al. PLoS One. 2011, 26; 6(4):e19194; Peek et al. Science. 2013, 342(6158):1243417; Ghosh et al., J Neurosci. 2012, 32(17):5821-32), suggesting that regulation of cellular NAD+ levels influences the rate and severity of decline and deterioration of bodily functions. Increasing cellular NAD+ concentrations may therefore be beneficial in the context of aging and age-related diseases. The cellular NAD+ pool is controlled by the balance between the activity of NAD+ synthesis and consumption enzymes. In mammals, NAD+ is synthesized from various dietary sources, including one or more of its major 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) from Trp via the de novo biosynthetic pathway or the kynurenine pathway, (ii) from NA in the Preiss-Handler pathway, and (iii) from NAM, NR, and NMN in the salvage pathway (Verdin et al., Science. 2015, 350(6265):1208-13). Among these, the main NAD+ biosynthetic pathway includes the synthesis step of nicotinamide mononucleotide (NMN) using nicotinamide and 5'-phosphoribosylpyrophosphate by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), which is important in determining life span and response to various stresses (Fulco et al, Dev Cell. 2008,14(5):661-73; Imai, Curr Pharm Des. 2009,15(1):20-8; Revollo et al., J Biol Chem. 2004,279(49):50754-63; Revollo et al., Cell Metab. 2007,Nov;6(5):363-75; van der Veer et al., J Biol Chem. 2007,282(15):10841-5; Yang et al. al., Cell. 2007, 130(6):1095-107). Thus, increasing the rate of NAMPT catalysis by small molecule activators would be an effective strategy to increase NAD levels and thereby address a wide range of pathologies. These include cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscular disease, neurological disease and injury, diseases caused by stem cell dysfunction, as well as DNA damage and primary mitochondrial disorders. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Stromland et al., Biochem Soc Trans. 2019, 47(1): 119-130 [Non-Patent Document 2] Ralto et al., Nat Rev Nephrol. 2019 [Non-Patent Document 3] Fang et al., Trends Mol Med. 2017, 23(10): 899-916 [Non-Patent Document 4] Yoshino et al., Cell Metab. 2011, 14(4): 528-36 [Non-Patent Document 5] Yang and Sauve, Biochim Biophys Acta. 2016, 1864: 1787-1800 [Non-Patent Document 6] Verdin, Science. 2015, 350(6265): 1208-13 [Non-Patent Document 7] Massudi et al., PLoS ONE. 2012, 7(7): e42357 [Non-Patent Document 8] Yang et al., Cell. 2007, 130(6): 1095-107 [Non-Patent Document 9] Braidy et al., PLoS One. 2011, 26; 6(4): e19194 [Non-Patent Document 10] Peek et al., Science. 2013, 342(6158): 1243417 [Non-Patent Document 11] Ghosh et al., J Neurosci. 2012, 32(17): 5821-32 [Summary of the Invention] [Means for Solving the Problems]

[0008] In one aspect, provided herein is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is halo or methoxy; R 6 is hydrogen or halo; and p is 0 or 1, If p is 1, R 2 is hydrogen or C 1 -C 6 Alkyl or Z 4 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 but a)Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c)Z 3 (CR c R d ) m NR e -, d) Z 4 S(O) 2 (CH 2 ) n -, e)Z 5 OC(O)-, f)NR f R g C(O)-, g) one or more independently selected C 1 -C 6 Alkyl or C 3 -C 6 5-10 membered heteroaryl optionally substituted with cycloalkyl substituents; h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, -C 1 -C 6 Alkyl (one or more independently selected R y -C optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, a 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo, one or more independently selected halo, or -C 1 -C 6 5-6 membered heteroaryl and C optionally substituted with alkyl substituents 3 - 6 a 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from cycloalkyl; i)Z 6 S(O) 2 N(R s )-, j)Z 7 N(R t )S(O) 2 -,or k)Z 8 -O-(CH 2 ) q - in which R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C 1 -C 6alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R g together with the nitrogen to which they are attached, are 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R h is independently -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, or C 6 -C 12 aryl, optionally substituted with one or more independently selected halo substituents; Each R xare independently halo, -OH, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3-6 membered heterocycloalkyl or heterocycloalkenyl, and 5-6 membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r , C 6 -C 12 independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R j , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; R s is hydrogen or C 1 -C 6 is alkyl; R t is hydrogen or C 1 -C 6 is alkyl; m is 0 or 1; n is 0, 1, or 2, and q is 0 or 1; Z 1 and Z 5 are each independently R z and; Z 2 and Z 3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, a 5- to 6-membered heteroaryl, and C 1 -C 6 selected from the group consisting of alkyl; Z 7 is C 6 -C 12 is aryl; Z 8 is 5-6 membered heteroaryl and C 3 -C 6 chloroalkyl; and R z is selected from the group consisting of: a) -OH, -CN, C 3 -C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl. 1 -C 6 alkyl, where C 6 -C 12 Aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl are each independently optionally selected from halo, C 1 -C 6 Alkyl, and C 1 -C 6 substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5-10 membered heteroaryl). 3 -C 6 cycloalkyl, wherein the 5- or 10-membered heteroaryl is optionally selected from one or more independently selected C 1 -C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R w -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 and R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are independently halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12aryl, and 5-6 membered heteroaryl; u and R v are each independently hydrogen or C 1 -C 6 alkyl, 3-10 membered heterocycloalkyl or heterocycloalkenyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 5-10 membered heteroaryl optionally substituted with alkyl substituents; and R 5 is hydrogen, halo, or R b together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring, provided that (1)R 4 Z 1 NR a In the case of C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH and -CH 2 - other than thiofuran; (2)R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] other than; and (3) the compound of formula (II) is not a compound of Table 1X; and If p is 0, R 4 teeth l) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that contains exactly two ring heteroatoms, both of which are nitrogen atoms, and the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6and optionally further substituted with one or more oxo substituents; m) the 3-6 membered heterocycloalkyl or heterocycloalkenyl contains exactly one ring heteroatom which is an oxygen atom, and the 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo or -C 1 -C 6 substituted with alkyl substituents; n) one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally further comprising one or more independently selected oxo or -C 1 -C 6 3- to 6-membered heterocycloalkyl or heterocycloalkynyl, substituted with alkyl substituents; o) a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein the 5-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituents; p) a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other of which is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl is optionally selected from one or more independently selected oxo, C 1 -C 6 Alkenyl, or -S(O) 2 -(C 1 -C 6 alkenyl) substituents, q) a 5-membered heteroaryl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein the 5-membered heteroaryl is substituted with exactly one methyl substituent; r) a 5-membered heteroaryl containing exactly two ring heteroatoms, both of which are nitrogen atoms, the 5-membered heteroaryl being substituted with one or more methyl substituents; s) a 6-membered heteroaryl containing one or two ring heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is [ka] Other than t)Z 9 -S(O) 2 -, u)Z 10 -S(O) 2 -NH-, v)Z 11 -C(O)-NH-, w)Z 12 -CH 2 -O-, x)Z 13 -O-, y)Z 14 -C(H)(C 1 -C 6ア Ru(Cl)-NH-C(O)-, z) [ka] or aa) [ka] where Z 9 is cyclopropyl, C 6 -C 12 Aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl (one or more independently selected R A optionally substituted with a substituent group), -NH(C 1 -C 6ア Ru(Cl), -NH 2 (One or more independently selected R B substituted with a substituent), and C 1 -C 6Alkyl (optionally one or more independently selected R C substituted with a substituent, provided that Z 9 but [ka] other than unsubstituted methyl, or unsubstituted ethyl, where: R A But -C 1 -C 6 alkyl or -CN; and R B However, (i)-C 1 -C 6 alkyl-(5-10 membered heteroaryl), or (ii) one or more independently selected C 6 -C 12 is a 5-10 membered heteroaryl optionally substituted with aryl; and R C is a 3-8 membered heterocycloalkyl or heterocycloalkenyl; Z 10 is one or more independently selected C 6 -C 12 C substituted with aryl substituents 1 -C 6 is alkyl; Z 11 is substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl substituents; 3 -C 10 Cycloalkyl and C 1- C 6 alkyl, with the proviso that Z 11 When is cyclopropyl, R 1 is other than methoxy; Z 12 is C 6 -C 12 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, C substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl substituents; 1-C 6 alkyl, and -C(O)-(3-10 membered heterocycloalkyl or heterocycloalkenyl); Z 13 represents one or more independently selected -C(O)-NH(C 1 -C 6 is a 5- to 10-membered heteroaryl substituted with an alkyl) substituent; and Z 14 is one or more independently selected C 1 -C 6 is a 5-10 membered heteroaryl optionally substituted with alkyl substituents; and R 5 is hydrogen.

[0009] In another aspect, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: R 1 is halo or methoxy; R 2 is hydrogen or C 1 -C 6 Alkyl or Z 4 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 teeth a)Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c)Z 3 (CR c R d ) m NR e -, d) Z4 S(O) 2 (CH 2 ) n -, e)Z 5 OC(O)-, f)NR f R g C(O)-, g) one or more independently selected C 1 -C 6 a 5-10 membered heteroaryl optionally substituted with alkyl substituents; or h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, one or more independently selected R y -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 a 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5-6 membered heteroaryl optionally substituted with alkyl substituents; R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C 1 -C 6alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R g together with the nitrogen to which they are attached, represent halo, -OH, -CN, oxo, one or more independently selected R x -C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R h is independently -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, or C 6 -C 12 aryl, optionally substituted with one or more independently selected halo substituents; Each R x is halo, -OH, -C 3 -C 6Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r , C 6 -C 12 independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; each Rj , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; m is 0 or 1; and n is 0, 1 or 2; R 5 is hydrogen or R b and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; Z 1 and Z 5 are each independently R z and; Z 2 and Z 3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and R z is selected from the group consisting of: a) -OH, -CN, C 3-C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl. 1 -C 6 Alkyl, where C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently halo, C 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C optionally substituted with 5- to 10-membered heteroaryl 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy 3 -C 6 The cycloalkyl and 5- or 10-membered heteroaryl are optionally selected from one or more independently selected C 1 ~C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R w -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 and R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are independently halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12 aryl, and 5-6 membered heteroaryl; u and R v are each independently hydrogen or C 1 -C 6 is alkyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 5-10 membered heteroaryl optionally substituted with alkyl substituents; In the formula (1)R 4 Z 1 NR a C(O)-, and Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH and -CH 2 - other than thiofuran; (2)R 4is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] other than; and (3) The compound of formula (I) is a compound, or a pharma- ceutically acceptable salt thereof, which is not a compound of Table 1X.

[0010] In another aspect, provided herein is a compound of formula (IG): [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined for formula (II) or any variation or embodiment thereof.

[0011] In another aspect, provided herein is a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R a , and Z 1 is as defined for formula (II) or any variation or embodiment thereof.

[0012] In another aspect, provided herein is a compound of formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R5 , R b , and Z 2 is as defined for formula (II) or any variation or embodiment thereof.

[0013] In another aspect, provided herein is a compound of formula (IC): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d , R e , m, and Z 3 is as defined for formula (II) or any variation or embodiment thereof.

[0014] In another aspect, provided herein is a compound of formula (ID): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n, and Z 4 is as defined for formula (II) or any variation or embodiment thereof.

[0015] In another aspect, provided herein is a compound of formula (IE): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and Z 5 is as defined for formula (II) or any variation or embodiment thereof.

[0016] In another aspect, provided herein is a compound of formula (IF): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R f , and R g is as described above for formula (II) or any variation or embodiment thereof.

[0017] In another aspect, provided herein is a compound of formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 4 , and R 6 is as described above for formula (II) or any variation or embodiment thereof.

[0018] In a further aspect, provided herein is a pharmaceutical composition comprising at least one compound of formula (II), (IG), (I), (IA), (IB), (IC), (ID), (IE), (IF), or (II-A), e.g., the compounds of Table 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally further comprising a pharma- ceutically acceptable excipient.

[0019] In another aspect, provided herein is a method for 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), (IG), (I), (IA), (IB), (IC), (ID), (IE), (IF), or (II-A), e.g., a compound of Table 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of formula (II), (IG), (I), (IA), (IB), (IC), (ID), (IE), (IF), or (II-A). In some embodiments, the disease or condition is selected from the group consisting of cancer, hyperproliferative disease or condition, inflammatory disease or condition, metabolic disorder, cardiac disease or condition, chemotherapy-induced tissue damage, renal disease, metabolic disease, neurological disease or damage, neurodegenerative disorder or disease, disease caused by stem cell dysfunction, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder. In some embodiments, the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

[0020] Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through the practice of the disclosure.

[0021] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are hereby incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description definition As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used dictates otherwise.

[0023] Throughout this application, unless the context dictates otherwise, references to compounds of formula (II) include all subgroups, including all substructures, subgenera, preferences, embodiments, examples and specific compounds of formula (II) as defined herein, such as formulas (I), (IG), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), as defined and / or described herein. Compounds of formula (II) and subgroups thereof, such as compounds of formula (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4) References to (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) 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) and subgroups thereof, such as formulae (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) include polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof.In some embodiments, references to compounds of formula (II) and subgroups thereof, such as formulae (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to compounds of formula (II) and subgroups thereof, such as formulae (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) include isomers, tautomers, and / or oxides thereof. In some embodiments, references to compounds of formula (II) and subgroups thereof, such as formulae (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) include solvates thereof. Similarly, a reference to a "salt" includes a solvate of a salt of the compound.

[0024] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6Alkyl includes both straight and branched chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, it is intended that all branched and straight chain versions having that number of carbons are included; thus, for example, "propyl" includes n-propyl and isopropyl. "Butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0025] If a range of values ​​is specified (for example, C 1~6 alkyl), each value within that range, and all ranges therebetween. For example, "C 1-6 "Alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 Contains alkyl.

[0026] "Alkyl" refers to an unsaturated branched or straight chain alkyl group having the indicated number of carbon atoms (e.g., 2-8, or 2-6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0027] "Alkynyl" refers to an unsubstituted branched or straight chain alkyl group having the indicated 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).

[0028] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cyclopropyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, caged, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). Additionally, when a polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon, one ring of the polycyclic cycloalkyl group can be aromatic. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (a portion of which is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while a 1,2,3,4-tetrahydronaphthalen-5-yl group (a portion of which is attached to the parent structure through an aromatic carbon atom) is not considered to be a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are provided below.

[0029] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6-12 or 6-10 carbon atoms. An aryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other examples, a polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom of the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein a portion of the aryl group is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, but a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein a portion of the aryl group is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (wherein a portion thereof is attached to the parent structure via an aromatic carbon atom) is considered an aryl group, but a 1,2,3,4-tetrahydroquinolin-1-yl group (wherein a portion thereof is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, the aryl is phenyl or naphthyl. In some cases, the aryl is phenyl. Additional examples of aryl groups that include an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0030] "Heteroaryl" refers to an aromatic ring containing the indicated number of atoms (e.g., 5-12, or 5-10 membered heteroaryl) composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. A heteroaryl group does not include adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise indicated, a heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom, as valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0031] 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, triazole (e.g., 1,2,4-triazole, 1,3,5-triazine), and tetrazine.

[0032] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[4,3-b]pyridine, 1H-pyrazolo ... ]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4 -b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

[0033] In other examples, polycyclic heteroaryl groups may contain non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom of an aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein a portion of the group is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein a portion of the group is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.

[0034] "Heterocycloalkyl" refers to a non-aromatic fully saturated ring having the indicated number of atoms (e.g., 3-10, or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4) selected from N, O, S, with the remaining ring atoms being carbon. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Examples of spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (wherein a portion of the group is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, but a 1,2,3,4-tetrahydroquinolin-8-yl group (wherein a portion of the group is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.

[0035] "Heterocycloalkenyl" refers to a non-aromatic ring having the indicated number of atoms (e.g., 3-10, or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and having at least one double bond obtained by removing one hydrogen atom from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro)-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (wherein a portion of the group is attached to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, but a 1,2-tetrahydroquinolin-8-yl group (wherein a portion of the group is attached to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

[0036] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl. , 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydro 4,5,6,7-tetrahydro-4H-pyrrolo[3,4-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, Benz[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnoline-4(3H)-one, pyrimidin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)- 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 an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group is determined by the atom to which it is attached to the parent structure.

[0037] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0038] Unless otherwise indicated, the disclosed compounds and / or compounds 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 may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise indicated, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, the compound is intended to include both the E and Z isomers. When a compound described herein contains a moiety capable of tautomerization, unless otherwise indicated, the compound is intended to include all possible tautomers.

[0039] "Protecting group" has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound so that a chemical reaction can be selectively carried out at an otherwise unprotected reactive site, and so that the group can be easily removed after the selective reaction is complete. A variety of protecting groups have been disclosed, for example, in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" comprises at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0040] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound is a salt that retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed 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-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma- ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0041] When the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying the solution of the acid salt.On the other hand, when the compound is a free base, the addition salt, particularly the pharma- ceutical 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 the conventional procedure for preparing an acid addition salt from a basic compound (see Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).Those skilled in the art will be aware of various synthetic methods that can be used to prepare pharma- ceutical acceptable addition salts.

[0042] A "solvate" is formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohol (e.g., ethanol). Solvates include hydrates having any ratio of a compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0043] The term "substituted" means that the particular group or moiety has one or more substituents, including but not limited to, alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term "unsubstituted" means that the specified group does not bear any substituents. When the term "substituted" is used to describe a structural system, it is meant that the substitution occurs at any valence-tolerant position on the system. When a group or moiety has multiple substituents, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety has 1-5 substituents. In some embodiments, the substituted group or moiety bears five substituents. In some embodiments, the substituted group or moiety bears two substituents. In some embodiments, the substituted group or moiety bears three substituents. In some embodiments, the substituted group or moiety bears four substituents. In some embodiments, the substituted group or moiety bears five substituents.

[0044] "Optional" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group that includes one or more substituents, one of ordinary skill in the art will understand that such groups are not intended to introduce any substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0045] The compounds disclosed and / or described herein may be, for example, 2 H, 3 H, 11 C. 13 C and / or 14The compound may be an enriched isotopic form, enriched in C content. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms may be made, for example, by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled Compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0046] The term "pharmaceutical acceptable carrier" or "pharmaceutical 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 pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients may also be incorporated into the pharmaceutical compositions.

[0047] The terms "patient," "individual," and "subject" refer to an animal, such as a mammal, bird, or fish. In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient or subject is a human, e.g., a human who has been or will be the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0048] 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 compound described herein, compared to activity in the absence of the chemical compound. The change may be an increase in activity or a decrease in activity, and may result from a direct interaction of the chemical compound with the target, or from an interaction of the chemical compound with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical compound may increase or decrease a target activity, for example, by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by increasing or decreasing (directly or indirectly) the amount of the target present in a cell or organism.

[0049] The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound disclosed and / or described herein that, when administered to a patient in need of such treatment, is sufficient to affect therapy, as defined herein. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to the modulation of nicotinamide phosphoribosyltransferase (NAMPT). The therapeutically effective amount varies, for example, depending on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the method of administration, all of which can be readily determined by one skilled in the art. A therapeutically effective amount can be ascertained experimentally, for example, by analyzing blood levels of the chemical, or theoretically, by calculating bioavailability.

[0050] "Treatment" (and related terms such as "treat", "treat", "treating", "treating") includes one or more of the following: preventing a disease or disorder (i.e., not allowing the onset of clinical symptoms of the disease or disorder to occur; inhibiting a disease or disorder; delaying or arresting the onset of clinical symptoms of the disease or disorder; and / or ameliorating the disease or disorder (i.e., causing a reduction or regression of clinical symptoms). The term encompasses situations in which the disease or disorder is already experienced by the patient, as well as situations in which the disease or disorder is not currently experienced but is expected to occur. The term encompasses both complete and partial reduction or prevention of the condition or disorder, as well as complete or partial reduction of clinical symptoms of the disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, aid in the management of the disease or disorder, or reduce or eliminate the disease or disorder. When used in a prophylactic manner, the compounds disclosed and / or described herein may prevent a disease or disorder from developing or reduce the extent of a disease or disorder that may develop.

[0051] compound The compounds and their salts (such as pharma- ceutically acceptable salts) are described in detail herein, including in the brief summary and the appended claims. Also provided are the uses of all compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, optical isomers, diastereomers and mixtures thereof in any ratio, including racemic mixtures, salts and solvates of the compounds described herein, as well as methods for making such compounds. Any compound described herein may also be referred to as a drug.

[0052] In one embodiment, provided is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is halo or methoxy; R 6 is hydrogen or halo; and p is 0 or 1, where If p is 1, R 2 is hydrogen or C 1 -C 6 Alkyl or Z 4 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 but a)Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c)Z 3 (CR c R d ) m NR e -, d) Z 4 S(O) 2 (CH2 ) n -, e)Z 5 OC(O)-, f)NR f R g C(O)-, g) one or more independently selected C 1 -C 6 Alkyl or C 3 -C 6 5-10 membered heteroaryl optionally substituted with cycloalkyl substituents h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, -C 1 -C 6 Alkyl (one or more independently selected R y -C optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, a 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo, one or more independently selected halo, or -C 1 -C 6 5-6 membered heteroaryl optionally substituted with alkyl substituents, and C 3 - 6 a 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl; i)Z 6 S(O) 2 N(R s )-, j)Z 7 N(Rt )S(O) 2 -,or k)Z 8 -O-(CH 2 ) q -;where R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C 1 -C 6 alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R g together with the nitrogen to which they are attached, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which may be selected from the group consisting of halo, -OH, -CN, oxo, and one or more independently selected R x -C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n, forming a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R h are independent, -C 1 -C 6 Alkyl, -OC 1 -C 6 C optionally substituted with alkyl, or one or more independently selected halo substituents 6 -C 12 is aryl; Each R x is halo, -OH, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r , C 6 -C 12 independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R j , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; R s is hydrogen or -C 1 -C 6 is alkyl; R t is hydrogen or -C 1 -C 6is alkyl; m is 0 or 1; n is 0, 1, or 2; and q is 0 or 1; Z 1 and Z 5 are each independently R z and; Z 2 and Z3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, a 5- to 6-membered heteroaryl, and C 1 -C 6 selected from the group consisting of alkyl; Z 7 is C 6 -C 12 is aryl; Z 8 is 5-6 membered heteroaryl and C 3 ~C 6 cycloalkyl; and R z is selected from the group consisting of: a) -OH, -CN, C 3 -C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl. 1 -C 6 Alkyl, where C 6 -C 12Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently halo, C 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C optionally substituted with 5- to 10-membered heteroaryl 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy 3 -C 6 The cycloalkyl and 5- or 10-membered heteroaryl are optionally selected from one or more independently selected C 1 ~C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R w -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C1 -C 6 and R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are independently halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12 aryl, and 5-6 membered heteroaryl; u and R v are each independently hydrogen or C 1 -C 6 is alkyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 5-10 membered heteroaryl optionally substituted with alkyl substituents; and R 5 is hydrogen, halo, or R b and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring, provided that: (1)R 4 Z 1 NR a In the case of C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH and -CH 2 - other than thiofuran; (2)R 4 However, 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] other than; and (3) the compound of formula (II) is not a compound of Table 1X; and If p is 0, R 4 teeth, l) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that contains exactly two ring heteroatoms, both of which are nitrogen atoms, and the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 and optionally further substituted with one or more oxo substituents; m) the 3-6 membered heterocycloalkyl or heterocycloalkenyl contains exactly one ring heteroatom which is an oxygen atom, and the 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo or -C 1 -C 6 substituted with alkyl substituents; n) one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally further comprising one or more independently selected oxo or -C 1 -C 6 3-6 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl substituents; o) a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other an oxygen atom, wherein the 5-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituents; p) a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other of which is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituents; q) a 5-membered heteroaryl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein said 5-membered heteroaryl is substituted with exactly one methyl substituent; r) a 5-membered heteroaryl containing exactly two ring heteroatoms, both of which are nitrogen atoms, said 5-membered heteroaryl being substituted with one or more methyl substituents; s) a 6-membered heteroaryl containing one or two ring heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is [ka] Other than t)Z 9 -S(O) 2 -, u)Z 10 -S(O) 2 -NH-, v)Z 11 -C(O)-NH-, w)Z 12 -CH 2 -O-, x)Z 13 -O-, y)Z 14 -C(H)(C 1 -C 6 alkyl)-NH-C(O)-, z) [ka] or aa) [ka] where Z 9 is cyclopropyl, C 6 -C 12 Aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl (one or more independently selected R A optionally substituted with a substituent group), -NH(C 1 -C 6ア Ru(Cl), -NH 2 (One or more independently selected R B substituted with a substituent), and C 1 -C 6 Alkyl (optionally one or more independently selected R C substituted with a substituent, provided that Z 9 but [ka] other than unsubstituted methyl, or unsubstituted ethyl, where: R A -C 1 -C 6 alkyl or -CN; and R B (i)-C 1 -C 6 alkyl-(5-10 membered heteroaryl), or (ii) one or more independently selected C 6 -C 12 is a 5-10 membered heteroaryl optionally substituted with aryl; and R C is a 3-8 membered heterocycloalkyl or heterocycloalkenyl; Z 10 is one or more independently selected C 6 -C 12 C substituted with aryl substituents 1 -C 6 is alkyl; Z 11is substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl substituents; 3 -C 10 Cycloalkyl and C 1 -C 6 alkyl, with the proviso that Z 11 If is cyclopropyl, then R 1 is other than methoxy; Z 12 is C 6 -C 12 C substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents; 1 -C 6 alkyl, and -C(O)-(3-10 membered heterocycloalkyl or heterocycloalkenyl); Z 13 represents one or more independently selected -C(O)-NH(C 1 -C 6 is a 5-10 membered heteroaryl substituted with an alkyl) substituent; and Z 14 is one or more independently selected C 1 -C 6 is a 5-10 membered heteroaryl optionally substituted with alkyl substituents; and R 5 is hydrogen.

[0053] In one embodiment, provided is a compound of formula (IG): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is halo or methoxy; R 2 is hydrogen or C 1 -C 6Alkyl or Z 4 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 but a)Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c)Z 3 (CR c R d ) m NR e -, d) Z 4 S(O) 2 (CH 2 ) n -, e)Z 5 OC(O)-, f)NR f R g C(O)-, g) one or more independently selected C 1 -C 6 Alkyl or C 3 -C 6 5-10 membered heteroaryl optionally substituted with cycloalkyl substituents; h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, -C 1 -C 6 Alkyl (one or more independently selected R y -C optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, a 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo, one or more independently selected halo, or -C 1 -C 6 5-6 membered heteroaryl optionally substituted with alkyl substituents, and C 3 -C 6 cycloalkyl; i)Z 6 S(O) 2 N(R s )-, j)Z 7 N(R t )S(O) 2 -,or k)Z 8 -O-(CH 2 ) q -where; R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C 1 -C 6 alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R gtogether with the nitrogen to which they are attached, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which may be selected from the group consisting of halo, -OH, -CN, oxo, and one or more independently selected R x -C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , forming a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R h are independent, -C 1 -C 6 Alkyl, -OC 1 -C 6 C optionally substituted with alkyl, or one or more independently selected halo substituents 6 -C 12 is aryl; Each R x is halo, -OH, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r , C 6 -C 12independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R j , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; R s is hydrogen or -C 1 -C 6 is alkyl; R t is hydrogen or -C 1 -C 6 is alkyl; m is 0 or 1; n is 0, 1 or 2; q is 0 or 1; Z 2 and Z 3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, a 5- to 6-membered heteroaryl, and C 1 -C 6 selected from the group consisting of alkyl; Z 7 is C 6 -C 12 is aryl; Z 8 is 5-6 membered heteroaryl and C 3 ~C 6 cycloalkyl; R z is selected from the group consisting of: a) C 1 -C6 Alkyl, -OH, -CN, C 3 -C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 Optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl, wherein C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently halo, C 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- to 10-membered heteroaryl); 3 -C 6 cycloalkyl, wherein the 5- or 10-membered heteroaryl is selected from one or more independently selected C 1 ~C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, -C 1 -C 6 Alkyl (one or more independently selected R w -C optionally substituted with one or more independently selected halo substituents; 1 -C 6Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 and R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12 aryl, and 5-6 membered heteroaryl; and wherein R u and R v are each independently hydrogen or C 1 -C 6 is alkyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 5-10 membered heteroaryl optionally substituted with alkyl substituents; R 5 is hydrogen, halo, or R b and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and R 6 is hydrogen or halo, Z 1 and Z 5 are each independently R z where: (1)R 4 Z 1 NR a C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH and -CH 2 Other than thiofuran; (2)R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] other than; and (3) The compound of formula (IG) is not a compound of Table 1X.

[0054] In one embodiment, provided is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: R 1 is halo or methoxy; R 2 is hydrogen or C 1 -C 6 Alkyl or Z 4 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 but a) Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c) Z 3 (CR c R d ) m NRe -, d) Z 4 S(O) 2 (CH 2 ) n -, e) Z 5 OC(O)-, f) NR f R g C(O)-, g) One or more independently selected C 1 -C 6 a 5-10 membered heteroaryl optionally substituted with alkyl substituents; or h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, each selected from halo, oxo, -OH, -CN, one or more independently selected R y -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 a 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of: R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C1 -C 6 alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R g together with the nitrogen to which they are attached, represent halo, -OH, -CN, oxo, one or more independently selected R x -C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R h is independent -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, or C 6 -C 12 aryl, optionally substituted with one or more independently selected halo substituents; Each R x is halo, -OH, -C 3-C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r , C 6 -C 12 independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R j , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; m is 0 or 1; and n is 0, 1 or 2; R 5 is hydrogen or R b and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; Z 1 and Z 5 are each independently R z and; Z 2 and Z 3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and R z is selected from the group consisting of: a) C1 -C 6 Alkyl, -OH, -CN, C 3 -C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 Optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl, wherein C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently halo, C 1 -C 6 Alkyl, and C 1 -C 6 independently optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- to 10-membered heteroaryl); 3 -C 6 cycloalkyl, wherein the 5- or 10-membered heteroaryl is selected from one or more independently selected C 1 ~C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R w -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 and R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are independently halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12 aryl, and 5-6 membered heteroaryl; u and R v are each independently hydrogen or C 1 -C 6 is alkyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 A 5-10 membered heteroaryl optionally substituted with alkyl substituents.

[0055] In some embodiments of Formula (II), Formula (IG), Formula (IG) or Formula (I), (1) R 4 Z 1 NR a In the case of C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2OH and -CH 2 - other than thiofuran; (2) R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] and (3) the compound of Formula (II), Formula (IG), or Formula (I) is not a compound of Table 1X. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0056] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 1 is halo. For example, in some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In another embodiment, R 1 is iodine.

[0057] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 1 is methoxy.

[0058] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 2 is hydrogen. In some embodiments, R 2 is C 1 -C6 For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0059] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 3 is hydrogen. In some embodiments, R 3 is C 1 -C 6 For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0060] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 5 is hydrogen. In some embodiments, R b If present, R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, R 5 is halo. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodine.

[0061] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 6 is hydrogen. In some embodiments of Formula (II), Formula (IG), or Formula (I), R 6 In some embodiments of Formula (II), Formula (IG), or Formula (I), R 6 In some embodiments of Formula (II), Formula (IG), or Formula (I), R 6 In some embodiments of Formula (II), Formula (IG), or Formula (I), R6 is bromo. In some embodiments of Formula (II), Formula (IG), or Formula (I), R 6 is iodine.

[0062] In some embodiments of the compound of formula (II), p is 1. In some embodiments of the compound of formula (II), p is 1 and the compound is of formula (IG). In other embodiments of the compound of formula (II), p is 1 and the compound is of formula (I).

[0063] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is Z 1 NR a C(O)-, Z 2 C(O)NR b -, Z 3 (CR c R d ) m NR e -, Z 4 S(O) 2 (CH 2 ) n -, Z 5 OC(O)- and NR f R g In some embodiments, R 4 is Z 1 NR a C(O)- or NR f R g In some embodiments, R 4 is Z 1 NR a C(O)- or Z 2 C(O)NR b -It is.

[0064] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R3 , R a , and Z 1 is as defined for formula (II), formula (IG), or formula (I), or any variations or embodiments thereof.

[0065] In some embodiments, the compound has formula (I-A1), (I-A2), (I-A3), or (I-A4): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R a , and Z 1 is as defined for formula (II), formula (IG), formula (I), or formula (IA), or any variation or embodiment thereof.

[0066] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), R a is hydrogen. In some embodiments, R a is C 1 -C 6 For example, in some embodiments, R a is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0067] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 is R z In some embodiments, Z 1 is selected from the group consisting of: -OH, C 3 -C 6 Cycloalkyl, C 6 -C 12 C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl. 1 -C 6alkyl, where C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently selected from the group consisting of C 1 -C 6 Alkyl and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- or 10-membered heteroaryl); 3 -C 6 Cycloalkyl, where 5- or 10-membered heteroaryl is C 1 -C 6 is optionally further substituted with alkyl; and -C 1 -C 6 Alkyl and -C(O)OC 1 -C 6 and wherein the -C is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 1 -C 6 Alkyl is C 6 -C 12 The aryl is optionally substituted.

[0068] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 is C 1 -C 6 In some embodiments, Z is alkyl. 1 is unsubstituted C 1 -C 6 In some embodiments, Z is alkyl. 1 -OH, C 3 -C6 Cycloalkyl, C 6 -C 12 C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, and 5-10 membered heteroaryl. 1 -C 6 alkyl, where C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently selected from the group consisting of C 1 -C 6 Alkyl and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy.

[0069] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 But, C 3 -C 6 In some embodiments, Z is cycloalkyl. 1 is unsubstituted C 3 -C 6 In some embodiments, Z is cycloalkyl. 1 is C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 C substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- or 10-membered heteroaryl); 3 -C 6 Cycloalkyl, where 5- or 10-membered heteroaryl is C 1 -C 6 In some embodiments, Z is optionally further substituted with alkyl. 1 is optionally substituted with one or more groups independently selected from methoxy, ethoxy, and phenyl; 3 -C 6In some embodiments, Z is cycloalkyl. 1 is optionally substituted with 5- or 10-membered heteroaryl; 1 -C 6 C optionally substituted with alkoxy 3- C 6 cycloalkyl, where the 5- or 10-membered heteroaryl is optionally selected from C 1 -C 6 Alkyl (e.g. [ka] In some embodiments, Z 1 is C 3 -C 6 In some embodiments, Z is cycloalkyl (optionally substituted phenyl). 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- or 10-membered heteroaryl), where the 5- or 10-membered heteroaryl is C 1 -C 6 It is optionally further substituted with alkyl.

[0070] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 is a 3-10 membered heterocycloalkyl or heterocycloalkenyl. 1 is a 3-10 membered heterocycloalkyl or heterocycloalkenyl containing one or more heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, Z 1 is a 3-6 membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z1 is C 1 -C 6 Alkyl and -C(O)OC 1 -C 6 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 1 -C 6 Alkyl is C 6 -C 12 In some embodiments, Z is optionally substituted with aryl. 1 teeth, [ka] and each of them is -C 1 -C 6 Alkyl and -C(O)OC 1 -C 6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 1 -C 6 Alkyl is C 6 -C 12 The aryl is optionally substituted.

[0071] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 is C 1 -C 6 In certain embodiments, Z is alkyl. 1 is ethyl. In some embodiments, Z 1 is ethyl, [ka] is selected from the group consisting of:

[0072] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1 , R 2 , R 3 , R 5 , R b , and Z 2 is as defined for formula (II), formula (IG), or formula (I), or any variation or embodiment thereof.

[0073] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), R b is hydrogen. In some embodiments, R b is C 1 -C 6 For example, in some embodiments, R b is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), R 5 is hydrogen. In other embodiments, R b is R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments of Formula (II) or Formula (IG), R 5 is halo. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodine.

[0074] In some embodiments, the compound is of formula (I-B1), (I-B2), or (I-B3): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and Z 2is as defined in formula (II), formula (IG), formula (I), or formula (IB), or any variations or embodiments thereof.

[0075] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is hydrogen. In some embodiments, Z 2 is R z In some embodiments, Z 2 is selected from the group consisting of C 3 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl. 1 -C 6 Alkyl; C 1 -C 6 Alkyl and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy 3 -C 6 Cycloalkyl; C 1 -C 6 Alkoxy; One or more independently selected -C 1 -C 6 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl substituents; C 6 -C 12 Aryl; and One or more independently selected C 1 -C 6 A 5-10 membered heteroaryl optionally substituted with alkyl substituents.

[0076] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is C 3 -C 6C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl. 1 -C 6 In some embodiments, Z is alkyl. 2 are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, respectively, C 3 -C 6 It is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl.

[0077] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is C 1 -C 6 Alkyl and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy 3 -C 6 In some embodiments, Z is cycloalkyl. 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, respectively, C 1 -C 6 Alkyl and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy.

[0078] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is C 1 -C 6 In some embodiments, Z is alkoxy. 2 is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy.

[0079] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and is one or more independently selected -C 1 -C 6 In some embodiments, Z is optionally substituted with an alkyl substituent. 2 is one or more independently selected -C 1 -C 6 In some embodiments, Z is a 4-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl substituents. 2 can be one or more -C 1 -C 6 an azetidinyl group optionally substituted with an alkyl substituent, or one or more independently selected -C 1 -C 6 A tetrahydrofuranyl group optionally substituted with an alkyl substituent. In some embodiments, Z 2 teeth [ka] , each of which is one or more independently selected -C 1 -C 6 In some embodiments, Z is optionally substituted with an alkyl substituent. 2 teeth, [ka] In some embodiments, Z 2 teeth, [ka] It is. In some embodiments, Z 2 teeth [ka] each optionally containing one or more independently selected -C 1 -C 6 In some embodiments, Z is substituted with an alkyl substituent. 2 teeth [ka] and optionally one or more independently selected -C 1 -C 6 In some embodiments, Z is substituted with an alkyl substituent. 2 teeth, [ka] It is.

[0080] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is C 6 -C 12 For example, in some embodiments, Z 2 is phenyl or naphthyl.

[0081] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), Z 2 is one or more independently selected C 1 -C 6 In some embodiments, Z is a 5-10 membered heteroaryl optionally substituted with an alkyl substituent. 2 is one or more independently selected -C 1 -C 6 In some embodiments, Z is a 5-6 membered heteroaryl optionally substituted with an alkyl substituent. 2 is one or more independently selected -C 1 -C 6 A pyridyl group optionally substituted with an alkyl substituent. In some embodiments, Z 2 is a pyridyl group optionally substituted with methyl, ethyl, or isopropyl. 2 is a pyridyl group substituted with methyl. 2 is a pyridyl group substituted with isopropyl. 2 teeth, [ka] In some embodiments, Z is selected from the group consisting of 2 teeth, [ka] It is.

[0082] In some embodiments, Z 2 is ethyl, [ka] is selected from the group consisting of:

[0083] In some embodiments, Z teeth, [ka] It is.

[0084] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (IC): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d , R e , m, and Z 3 is as defined in formula (IG) or formula (I), or any variations or embodiments thereof.

[0085] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), m is 0. In other embodiments, m is 1. In some embodiments of Formula (IG), Formula (I), or Formula (IC), R c is hydrogen. In other embodiments, R c is C 1 -C 6In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), R d is hydrogen. In other embodiments, R d is C 1 -C 6 In some embodiments, R c and R d together with the carbon to which they are attached, C 3 -C 6 Forms a cycloalkyl.

[0086] In some embodiments, the compound is of formula (I-C1), (I-C2), (I-C3), or (I-C4): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R e , and Z 3 is as defined in formula (II), formula (IG), formula (I), or formula (IC), or any variations or embodiments thereof.

[0087] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), R e is hydrogen. In other embodiments, R e is C 1 -C 6 It is an alkyl.

[0088] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), Z 3 is hydrogen. In some embodiments, Z 3 is R z In some embodiments, Z 3 is C 3 -C 6 Cycloalkyl; optionally -C 1 -C 6 3-10 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl or oxo; C6 -C 12 Aryl; one or more independently selected C 1 -C 6 In some embodiments, Z is selected from the group consisting of 5-10 membered heteroaryl optionally substituted with alkyl substituents. 3 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally 1 -C 6 In some embodiments, Z is substituted with alkyl or oxo. 3 teeth, [ka] In some embodiments, Z is selected from the group consisting of 3 teeth, [ka] It is.

[0089] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (ID): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n, and Z 4 is as defined in formula (II), formula (IG) or formula (I) or any variation or embodiment thereof.

[0090] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (ID), n is 0. In some embodiments, n is 1. In other embodiments, n is 2.

[0091] In some embodiments, the compound is a compound of formula (I-D1) or (I-D2): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and Z 4 is as defined in formula (IG), formula (I), or formula (ID), or any variation or embodiment thereof.

[0092] In some embodiments, the compound is a compound of formula (I-D3), (I-D4), (I-D5), (I-D6) or (I-D7): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is as defined in formula (II), formula (IG), formula (I) or formula (ID), or any variations or embodiments thereof.

[0093] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (ID), Z 4 is hydrogen. In some embodiments, Z 4 is R z In another embodiment, Z 4 is C 1 -C 6 For example, in some embodiments, Z 4 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 4 is R 2 and together with the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring. [ka] is selected from the group consisting of:

[0094] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (IE): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and Z 5 is as defined for formula (II), formula (IG), formula (I) or any variation or embodiment thereof.

[0095] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IE), Z 5 is C 1 -C 6 For example, in some embodiments, Z 5 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 5 is ethyl.

[0096] In another embodiment, the compound of formula (II), formula (IG), or formula (I) may be a compound of formula (IF): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R f , and R g is as defined for formula (II), formula (IG), or formula (I), or any variations or embodiments thereof.

[0097] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g together with the nitrogen to which they are attached, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, including halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1-C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl.

[0098] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g together with the nitrogen to which they are attached, a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, including halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3-6 membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of 3-6 membered heterocycloalkyl or heterocycloalkenyl, and 5-6 membered heteroaryl. In some embodiments, R f and R g together with the nitrogen to which they are attached, a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl selected from the group consisting of azetidyl, pyrrolizinyl, and piperidinyl, each of which is halo, -OH, -CN, oxo, -C1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3-6 membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of 3-6 membered heterocycloalkyl or heterocycloalkenyl, and 5-6 membered heteroaryl. In some embodiments, [ka] and are halo, -OH, -CN, oxo, and -C 1 -C 6 Alkyl (one or more independently selected Rx optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl. f and R g along with the nitrogen to which they are attached, -C 1 -C 6Forms a 5-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl, where -C 1 -C 6 The alkyl is optionally substituted with -OH. In some embodiments, R f and R g together with the nitrogen to which they are attached, -C 1 -C 6 Forms pyrrolidinyl optionally substituted with alkyl, where -C 1 -C 6 The alkyl is optionally substituted with -OH. In some embodiments, [ka] It is.

[0099] In embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g together with the nitrogen to which they are attached, a 6- to 10-membered heterocycloalkyl or heterocycloalkenyl, including halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl. In some embodiments, R f and R gtogether with the nitrogen to which they are attached form a bicyclic 6-10 membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments, R f and R g together with the nitrogen to which they are attached, [ka] each of which is halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of: f and R g together with the nitrogen to which they are attached form a bridged 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments, [ka] -C, each of which is selected from the group consisting of halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1-C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl.

[0100] In some embodiments, R f and R g together with the nitrogen to which they are attached form a spirocyclic 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments, [ka] each of which is selected from the group consisting of halo, -OH, -CN, oxo, -C 1 -C 6 Alkyl (one or more independently selected R x optionally substituted with a substituent group, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl.

[0101] In some embodiments, [ka] [ka] is selected from the group consisting of:

[0102] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is one or more independently selected C 1 -C 6 In some embodiments, R is a 5- to 10-membered heteroaryl optionally substituted with an alkyl substituent. 4 is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxa and wherein each is selected from the group consisting of pyrazolyl, benzoxadiazolyl, benzothiophenyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, and imidazothiazolyl, each of which is selected from the group consisting of pyrazolothiazolyl ... 1 -C 6 Optionally substituted with alkyl substituents. In some embodiments, R 4 is one or more independently selected -C 1 -C 6 In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with an alkyl substituent. 4 is pyrazolyl, pyridinyl, or oxadiazole, each of which is selected from one or more independently selected C 1 -C 6 In certain embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0103] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is a 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R y -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 In some embodiments, R is a 3-10 membered heterocycloalkyl or heterocycloalkane optionally substituted with one or more substituents independently selected from the group consisting of 5-6 membered heteroaryl optionally substituted with alkyl substituents. 4 -S(O) 2 -C 1 -C 6 Alkyl or -C 1 -C 6 In some embodiments, R is a 4-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl (optionally substituted with -OH). 4 -S(O) 2 -C 1 -C 6Alkyl or -C 1 -C 6 In some embodiments, R is an azetidinyl or piperazinyl optionally substituted with alkyl (optionally substituted with -OH). 4 -S(O) 2 -C 1 -C 6 In some embodiments, R is azetidinyl optionally substituted with alkyl. 4 -S(O) 2 CH 3 In some embodiments, R is azetidinyl substituted with 4 Optionally, -C 1 -C 6 In certain embodiments, R is piperazinyl substituted with alkyl (optionally substituted with -OH). 4 is -CH 2 C(CH 3 ) 2 Piperazinyl optionally substituted with OH.

[0104] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 teeth, [ka] [ka] [ka] is selected from the group consisting of:

[0105] In some embodiments, R 4 teeth, [ka] [ka] In some embodiments, R 4 teeth [ka] In some embodiments, R 4 teeth, [ka] It is.

[0106] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is Z 6 S(O) 2 N(R s In some embodiments, Z 6 is a 5-6 membered heterocycloalkyl or heterocycloalkenyl. 6 is 5-6 membered heteroaryl. In some embodiments, Z 6 is C 1 -C 6 In some embodiments, Z is alkyl. 6 is methyl. In some of the foregoing embodiments, R s is hydrogen. In other embodiments, R s is C 1 -C 6 In yet another embodiment, R s is methyl. In some embodiments, R 4 teeth, [ka] It is.

[0107] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is Z 7 N(R t )S(O) 2 In some embodiments, Z 7 is C 6 -C 12 In some embodiments, Z is aryl. 7 is phenyl. In some embodiments, R tis hydrogen. In other embodiments, R t is C 1 -C 6 In yet another embodiment, R t is methyl. In some embodiments, R 4 -S(O) 2 -NH-phenyl.

[0108] In some embodiments of Formula (II), Formula (IG), or Formula (I), R 4 is Z 8 -O-(CH 2 ) q In some embodiments, q is 0, such that R 4 Z 8 In other embodiments, q is 1, such that R 4 Z 8 -O-(CH 2 In some of the foregoing embodiments, Z 8 is 5-6 membered heteroaryl. In some embodiments, Z 8 In other of the foregoing embodiments, Z is pyridinyl. 8 is C 3 -C 6 In one embodiment, Z is cycloalkyl. 8 is cyclopentyl. In some embodiments, R 4 teeth, [ka] It is.

[0109] In some embodiments of Formula (II), p is 0. In some embodiments of Formula (II), p is 0 and the compound is a compound of Formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is halo or methoxy; R 4 teeth l) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that contains exactly two ring heteroatoms, both of which are nitrogen atoms, and the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 substituted with alkyl substituents and optionally further substituted with one or more oxo substituents; m) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly one ring heteroatom which is an oxygen atom, said 3- to 6-membered heterocycloalkyl or heterocycloalkenyl being selected from one or more independently selected oxo or -C 1 -C 6 Optionally substituted with alkyl substituents; n) one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally further comprising one or more independently selected oxo or -C 1 -C 6 3-6 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl substituents; o) a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, said 5-membered heterocycloalkyl or heterocycloalkenyl being selected from one or more independently selected oxo, -C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 5-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with alkyl) substituents; p) a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other of which is a nitrogen atom, said 6-membered heterocycloalkyl or heterocycloalkenyl being selected from one or more independently selected oxo, -C 1 -C 6Alkyl, or -S(O) 2 -(C 1 -C 6ア a 6-membered heterocycloalkyl or heterocycloalkenyl, q) a 5-membered heteroaryl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, said 5-membered heteroaryl being substituted with exactly one methyl substituent; r) a 5-membered heteroaryl containing exactly two ring heteroatoms, both of which are nitrogen atoms, said 5-membered heteroaryl being substituted with one or more methyl substituents; s) a 6-membered heteroaryl containing one or two ring heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is [ka] a 6-membered heteroaryl other than t)Z 9 -S(O) 2 -, u)Z 10 -S(O) 2 -NH-, v)Z 11 -C(O)-NH-, w)Z 12 -CH 2 -O-, x)Z 13 -O-, y)Z 14 -C(H)(C 1 -C 6 alkyl)-NH-C(O)-, z) [ka] or aa) [ka] where Z 9 is cyclopropyl, C6 -C 12 aryl, one or more independently selected R A 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with substituents, -NH(C 1 -C 6 alkyl), one or more independently selected R B Substituted with -NH 2 and one or more independently selected R C C substituted with a substituent 1 -C 6 alkyl, with the proviso that Z 9 teeth, [ka] , unsubstituted methyl, or unsubstituted ethyl, where: R A -C 1 -C 6 alkyl or -CN; and R B (i)-C 1 -C 6 alkyl-(5-10 membered heteroaryl), or (ii) one or more independently selected C 6 -C 12 is a 5-10 membered heteroaryl optionally substituted with aryl; and R C is a 3-8 membered heterocycloalkyl or heterocycloalkenyl; Z 10 is one or more independently selected C 6 -C 12 C substituted with aryl substituents 1 -C 6 is alkyl; Z 11 When is cyclopropyl, R 1 is other than methoxy, 11 is substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl substituents; 3 -C 10Cycloalkyl and C 1 -C 6 selected from the group consisting of alkyl; Z 12 is C 6 -C 12 C substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents; 1 -C 6 and -C(O)-(3-10 membered heterocycloalkyl or heterocycloalkenyl); Z 13 represents one or more independently selected -C(O)-NH(C 1 -C 6 is a 5-10 membered heteroaryl substituted with an alkyl) substituent; and Z 14 is one or more independently selected C 1 -C 6 is a 5-10 membered heteroaryl optionally substituted with alkyl substituents; R 6 is hydrogen or halo.

[0110] In some embodiments of Formula (II) or Formula (II-A), R 4 is selected from the group consisting of: a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 a 3-6 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl substituents and optionally further substituted with one or more oxo substituents; a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly one ring heteroatom which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally selected from one or more independently selected oxo or -C 1 -C 6 3-6 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl substituents; 3-6 membered heterocycloalkyl or heterocycloalkenyl, each of which is selected from one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally one or more independently selected oxo or -C 1 -C 6 3-6 membered heterocycloalkyl or heterocycloalkenyl, further substituted with alkyl substituents; a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, said 5-membered heterocycloalkyl or heterocycloalkenyl optionally containing one or more independently selected oxo, -C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 5-membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl) substituents, and a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, -C 1 -C 6 Alkyl, or -S(O) 2 -(C 1 -C 6 A 6-membered heterocycloalkyl or heterocycloalkenyl substituted with an alkyl) substituent.

[0111] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 In some embodiments, R is substituted with an alkyl substituent and optionally further substituted with one or more oxo substituents. 4 is a 5-6 membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-6 membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 It is substituted with alkyl substituents and optionally further substituted with one or more oxo substituents.

[0112] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that contains exactly one ring heteroatom that is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally selected from one or more independently selected oxo or -C 1 -C 6 In some embodiments, R 4 is a 5-6 membered heterocycloalkyl or heterocycloalkenyl containing exactly one ring heteroatom which is an oxygen atom, wherein the 5-6 membered heterocycloalkyl or heterocycloalkenyl is optionally selected from one or more independently selected oxo or -C 1 -C 6 It is substituted with alkyl substituents.

[0113] In some embodiments of Formula (II) or Formula (II-A), R 4is a 3-6 membered heterocycloalkyl or heterocycloalkenyl, which is one or more independently selected -S(O) 2 -C 1 -C 6 substituted with alkyl substituents, optionally with one or more independently selected oxo or -C 1 -C 6ア In some embodiments, R 4 is a 5-6 membered heterocycloalkyl or heterocycloalkenyl, having one or more independently selected -S(O) 2 -C 1 -C 6 substituted with alkyl substituents, optionally with one or more independently selected oxo or -C 1 -C 6 It is further substituted with alkyl substituents.

[0114] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, -C 1 -C 6ア Rukill, or -S(O) 2 -(C 1 -C 6ア is substituted with an alkyl) substituent.

[0115] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl optionally contains one or more independently selected oxo, -C 1 -C 6 Alkyl, or -S(O) 2 -(C 1-C 6 Alkyl) substituents.

[0116] In some embodiments of Formula (II) or Formula (II-A), R 4 teeth, [ka] is selected from the group consisting of:

[0117] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, both of which are nitrogen atoms, and the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is selected from one or more independently selected -C 1 -C 6 and optionally further substituted with one or more independently selected oxo substituents, or a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, which 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C 1 -C 6 Alkyl, or -S(O) 2- (C 1 -C 6 In some embodiments, R 4 teeth, [ka] It is.

[0118] In some embodiments of Formula (II) or Formula (II-A), R 4 is selected from the group consisting of: a 5-membered heteroaryl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein said 5-membered heteroaryl is substituted with exactly one methyl substituent; a 5-membered heteroaryl containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents; and a 6-membered heteroaryl containing one or two ring heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is [ka] A 6-membered heteroaryl other than.

[0119] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 5-membered heteroaryl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein the 5-membered heteroaryl is substituted with exactly one methyl substituent. 4 is a 5-membered heteroaryl containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents. 4 is a 6-membered heteroaryl containing one or two ring heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is [ka] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0120] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 9 -S(O) 2 -, Z 10 -S(O) 2 -NH-, Z 11 -C(O)-NH-, Z 12 -CH 2 -O-, Z 13 -O-, Z 14 -C(H)(C 1 -C 6 alkyl)-NH-C(O)-, [ka] It is.

[0121] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 9 -S(O) 2 In some embodiments, the compound of formula (II) or formula (II-A) is a compound of formula (II-A1): [ka] or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments of Formula (II), Formula (II-A), or Formula (II-A1), Z 9 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected R A Optionally substituted with substituents, except that Z 9 teeth [ka] In some embodiments, Z 9 is one or more independently selected R A Optionally substituted 5-6 membered heterocycloalkyl or heterocycloalkenyl, provided that Z 9 but [ka] In some embodiments, R A is methyl or -CN. In some embodiments, Z 9 is an unsubstituted 3-10 membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 9 is an unsubstituted 5-6 membered heterocycloalkyl or heterocycloalkenyl.

[0123] In some embodiments, Z 9 is one or more independently selected R C C optionally substituted with a substituent 1 -C 6 alkyl, provided that Z 9 is other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is one or more independently selected R C C optionally substituted with a substituent 1 -C 3 alkyl, provided that Z 9 is other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is unsubstituted C 3 -C 6 In some embodiments, Z is alkyl. 9 is unsubstituted propyl. In some embodiments, Z 9 is optionally substituted with one or more independently selected 3-8 membered heterocycloalkyl or heterocycloalkenyl; 1 -C 6 In some embodiments, Z is alkyl. 9 is optionally substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl; 1 -C 6 It is an alkyl.

[0124] In some embodiments, Z 9 is -NH(C1 -C 6 In some embodiments, Z 9 -NH(CH 3 In some embodiments, Z 9 is one or more independently selected R B Substituted with -NH 2 In some embodiments, Z 9 Ha-NH 2 and one or more independently selected -C 1 -C 6 In some embodiments, Z is substituted with alkyl-(5-10 membered heteroaryl). 9 is one or more independently selected -C 1 -C 6 -NH substituted with alkyl-(5-6 membered heteroaryl) 2 In some embodiments, Z 9 is one or more independently selected -C 1 -C 6 Alkylpyridinyl substituted -NH 2 In another embodiment, Z 9 is one or more independently selected C 6 -C 12 In another embodiment, Z is a 5-10 membered heteroaryl optionally substituted with aryl. 9 is a 5-6 membered heteroaryl optionally substituted with one or more phenyl.

[0125] In one embodiment, Z 9 is cyclopropyl. In some embodiments, Z 9 is C 6 -C 12 In some embodiments, Z is aryl. 9 is phenyl.

[0126] In some embodiments, Z 9 teeth, [ka] is selected from the group consisting of:

[0127] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 10 -S(O) 2 In some embodiments, Z 10 is C substituted with one or more phenyl substituents 1 -C 6 In some embodiments, Z is alkyl. 10 teeth, [ka] It is.

[0128] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 11 In some embodiments, Z 11 When is cyclopropyl, R 1 is other than methoxy, 11 But, C 3 -C 10 In some embodiments, Z is cycloalkyl. 11 is substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl substituents; 1 -C 6 In some embodiments, Z is alkyl. 11 is substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents. 1 -C 6 In some embodiments, Z is alkyl. 11 teeth, [ka] It is.

[0129] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 12 -CH2 In some embodiments, Z 12 is C 6 -C 12 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl or heterocycloalkenyl, C 1 -C 6 In some embodiments, Z is selected from the group consisting of alkyl (substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl or 5-10 membered heteroaryl substituents), and -C(O)-(3-10 membered heterocycloalkyl or heterocycloalkenyl). 12 is C 6 -C 12 In some embodiments, Z is aryl. 12 is 5-10 membered heteroaryl. In some embodiments, Z 12 is 5-6 membered heteroaryl. In some embodiments, Z 12 is a 3-10 membered heterocycloalkyl or heterocycloalkenyl. In another embodiment, Z 12 is a 5-6 membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 12 is C 1 -C 6 alkyl (substituted with one or more independently selected 3-10 membered heterocycloalkyl or heterocycloalkenyl or 5-10 membered heteroaryl substituents). In some embodiments, Z 12 is a C substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 6-membered heteroaryl substituents; 1 -C 6 In some embodiments, Z is alkyl. 12 is -C(O)-(3-10 membered heterocycloalkyl or heterocycloalkenyl). In another embodiment, Z 12 is -C(O)-(5-6 membered heterocycloalkyl or heterocycloalkenyl). 12teeth, [ka] is selected from the group consisting of:

[0130] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 13 In some embodiments, Z 13 represents one or more independently selected -C(O)-NH(C 1 -C 6 In some embodiments, Z is a 5-6 membered heteroaryl substituted with an alkyl) substituent. 13 represents one or more independently selected -C(O)-NH(C 1 -C 6 In some embodiments, Z is a pyridinyl substituted with an alkyl) substituent. 13 teeth [ka] It is.

[0131] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 14 -C(H)(C 1 -C 6 In some embodiments, R 4 is Z 14 -C(H)(CH 3 )-NH-C(O)-. In some embodiments, Z 14 is one or more independently selected C 1 -C 6 In some embodiments, Z is a 5-6 membered heteroaryl optionally substituted with an alkyl substituent. 14 is one or more independently selected C 1 -C 6 In some embodiments of Formula (II) or Formula (II-A), R is pyridinyl optionally substituted with an alkyl substituent. 4 teeth [ka] It is.

[0132] In some embodiments of Formula (II) or Formula (II-A), R 4 teeth, [ka] In another embodiment, R 4 teeth [ka] It is.

[0133] In some embodiments of Formula (II), or any variation thereof, including Formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), R 1 is halo. For example, in some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In other embodiments, R 1 is iodo. In some embodiments, R 1 In some embodiments of Formula (II), or any variation thereof, including Formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), and (IF), R 1is hydrogen. In some embodiments, R 2 is C 1 -C 6 For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of Formula (II), or any variation thereof, including Formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), and (IF), R 3 is hydrogen. In some embodiments, R 3 is C 1 -C 6 For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0134] In some embodiments of Formula (II), or any variation thereof, including Formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), and (IF), R 2 and R 3 Each is hydrogen. In some embodiments, R 2 is C 1 -C 6 is alkyl, R 3 is hydrogen. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, and R 3is hydrogen. In certain embodiments, R 2 is methyl, R 3 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is C 1 -C 6 For example, in some embodiments, R 2 is hydrogen and R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 2 is hydrogen and R 3 is methyl.

[0135] In some embodiments, provided herein are compounds set forth in Table 1 and salts thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

Table 2-79

Table 2-80

Table 2-81

Table 2-82

Table 2-83

Table 2-84

Table 2-85

Table 2-86

Table 2-87

Table 2-88

Table 2-89

Table 2-90

Table 2-91

Table 2-92

Table 2-93

Table 2-94

Table 2-95

Table 2-96

Table 2-97

Table 2-98

Table 2-99

Table 2-100

Table 2-101

Table 2-102

Table 2-103

Table 2-104

Table 2-105

Table 2-106

Table 2-107

Table 2-108

Table 2-109

Table 2-110

Table 2-111

Table 2-112

[0136] In some variations, the compounds of formula (II), (I), (IG), (I)(IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), or any variation thereof, or in Table 1, may be deuterated (e.g., replacing a hydrogen atom with a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Other methods known in the art may also be used to replace hydrogen atoms with deuterium atoms.

[0137] Any formula described herein, such as formula (II), (IG), (I)(IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), is intended to represent a compound having the structure depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula provided herein may have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomers, one or more diastereomeric forms, one or more atropisomers, and mixtures thereof in any ratio. Where a compound of Table 1 is depicted in a particular stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of stereoisomers of the compound in any ratio, are also provided herein. For example, where a compound of Table 1 has a stereocenter in the "S" stereochemical configuration, enantiomers of the compound where that 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 where that stereocenter is in the "S" stereochemical configuration are also provided herein. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. Additionally, where a compound of Table 1 has more than one stereocenter, any enantiomer or diastereomer of the compound is also provided. For example, if a compound in Table 1 contains a first and a second stereocenter having "R" and "R" stereochemical configurations, respectively, then also provided are stereoisomers of the compound having the first and second stereocenters having "S" and "S" stereochemical configurations, respectively, "S" and "R" stereochemical configurations, respectively, and "R" and "S" stereochemical configurations, respectively.Where a compound of Table 1 contains a first and a second stereocenter having "S" and "S" stereochemical configurations, respectively, stereoisomers of the compound are also provided that have the first and second stereocenters having "R" and "R" stereochemical configurations, respectively, "S" and "R" stereochemical configurations, respectively, and "R" and "S" stereochemical configurations, respectively. Where a compound of Table 1 contains a first and a second stereocenter having "S" and "R" stereochemical configurations, respectively, stereoisomers of the compound are also provided that have the first and second stereocenters having "R" and "S" stereochemical configurations, respectively, "R" and "R" stereochemical configurations, respectively, and "S" and "S" stereochemical configurations, respectively. Similarly, where a compound in Table 1 contains a first and a second stereocenter having "R" and "S" stereochemical configurations, respectively, stereoisomers of the compound having the first and second stereocenters having "S" and "R" stereochemical configurations, respectively, "R" and "R" stereochemical configurations, respectively, and "S" and "S" stereochemical configurations, respectively, are also provided. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), as a tautomer, or as an atropisomer. Furthermore, any formula given herein is intended to refer to any one of the hydrates, solvates, and amorphous and polymorphic forms of such a compound, and mixtures thereof, even if such forms are not explicitly described. In some embodiments, the solvent is water and the solvate is a hydrate.

[0138] Representative examples of compounds detailed herein, including intermediates and final compounds, are set forth in the Tables and elsewhere herein. In one aspect, it is understood that any compound may be used in the methods detailed herein, including intermediate compounds, which, where applicable, may be isolated and administered to an individual or subject.

[0139] The compounds provided herein may exist as salts even when no salt is provided, and it is understood that the compositions and methods provided herein encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds, as would be well understood by one of ordinary skill in the art. In some embodiments, the salts of the compounds provided herein are pharma- ceutically acceptable salts.

[0140] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions are provided that include the compounds in substantially pure form. In another variation, pharmaceutical compositions are provided that include the compounds detailed herein and a pharma- ceutically acceptable carrier. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms detailed herein.

[0141] R as provided herein 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , R a , R b , R c , R d , R e , R f , R g , R h , R j , R k , R m , R n , R o , R p , Rq , R r , R s , R t , R x , R y , R z , R A , R B , R C Any variation or embodiment of m, n, p, and q may be represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , R a , R b , R c , R d , R e , R f , R g , R h , R j , R k , R m , R n , R o , R p , R q , R r , R s , R t , R x , R y , R z , R A , R B , R C , m, n, p, and q may be combined with any and all other variations or embodiments of m, n, p, and q just as if each combination were individually and specifically set forth.

[0142] Other embodiments will become apparent to those skilled in the art from the following detailed description.

[0143] As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence.

[0144] Formula (II) includes all subformulas thereof. For example, formula (II) includes compounds of formulae (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1).

[0145] As shown in Table 1 and Examples 1-16, the names of compounds 1-552 provided herein are provided by ChemInnovations' Chem 4d software version 7.5.0.0. The names of intermediates 1.1-10.0 shown in Examples A-MM are provided by ChemBioDraw Professional 15.0. Those skilled in the art will appreciate that compounds may be named or identified using a variety of commonly recognized naming systems and symbols. By way of example, compounds may be named or identified by common names, systematic names, or non-systematic names. Nomenclature systems and symbols commonly recognized in the field of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).

[0146] composition Compositions, such as pharmaceutical compositions, are also provided that include the compounds disclosed and / or described herein, as well as one or more additional medicinal agents, drugs, adjuvants, carriers, excipients, and the like. Suitable pharmaceutical agents and drugs include those described herein. In some embodiments, the pharmaceutical composition includes a pharma- ceutically acceptable excipient or adjuvant, as well as at least one chemical entity as described herein. Examples of pharma- ceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, are provided that include one or more compounds described herein, or pharma- ceutically acceptable salts thereof.

[0147] In some embodiments, provided is a pharma- ceutically acceptable composition comprising a compound of formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition may include a synthetic intermediate that may be used in the preparation of a compound described herein. The compositions described herein may include any other suitable active or inactive agents.

[0148] Any of the compositions described herein may be sterile or may contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds or conjugates.

[0149] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0150] How to use The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any of the formulas provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein.

[0151] Without being bound by theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by modulating nicotinamide phosphoribosyltransferase (NAMPT). In some embodiments, the compounds and pharmaceutical compositions disclosed herein are activators of NAMPT. In some embodiments, provided is a method of 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), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or Table 1, or a pharma- ceutically 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 renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle wasting disorder in an individual or subject, comprising administering to an individual or subject in need thereof a compound represented by formula (II): , (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutical acceptable salt thereof.

[0152] Also provided herein is the use of a compound of formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by NAMPT activity in a subject. In some embodiments, a compound or composition described herein is provided for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein is a compound of Formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutical acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein is a compound of formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutical 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 renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle wasting disorder.

[0153] Also provided herein are compositions (including pharmaceutical formulations) as described herein for use in treating, preventing, and / or delaying the onset of, and / or the onset of, the diseases described herein and other methods described herein. In certain embodiments, the compositions include formulations present in unit dosage form.

[0154] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, rabbit, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.

[0155] There are many conditions in which small molecule-mediated stimulation of NAMPT activity to boost NAD+ levels may be clinically beneficial (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13). These conditions include, but are not limited to, cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscle disease, neurological disease and damage, disease caused by stem cell dysfunction, and DNA damage and primary mitochondrial disorders. In some embodiments, the disease or condition mediated by NAMPT activity is cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscle disease, neurological disease or damage, disease caused by stem cell dysfunction, or DNA damage and primary mitochondrial disorders.

[0156] 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 via oral supplementation or overexpression of NAMPT (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 using small molecule activators to compensate for reduced protein levels is a promising strategy to treat various forms of heart failure.

[0157] Chemotherapy-induced tissue damage. The use of chemotherapy regimens is often limited by toxicity to healthy tissues, with severe oxidative stress thought to play a major role. NAD boosting has been shown to induce a strong antioxidant response. Thus, NAMPT activators are believed to be widely useful in preventing reversible and irreversible secondary pathologies in various chemotherapy settings. Examples include anthracycline and trastuzumab cardiotoxicity, cisplatin-induced nephropathy, and peripheral neuropathy induced by cisplatin, paclitaxel, vincristine, and other drugs. Neuroprotection by NAMPT activation is also useful to treat / prevent chemotherapy-associated cognition ("chemo brain") caused by the destruction of healthy neural tissue during active treatment and long after treatment is discontinued. See, e.g., Zheng et al., Clin Sci (Lond). 2019, 133(13):1505-1521.

[0158] Kidney Disease. Kidney disease is a highly prevalent and urgent area of ​​unmet medical need. Approximately 3% of hospitalized patients are diagnosed with acute kidney injury (AKI). A subset of patients progresses to chronic kidney disease that may require long-term dialysis or kidney transplantation. A key feature of renal dysfunction is the decreased activity of SIRT1 and SIRT3, characterized by a decrease in the sirtuin substrate NAD, mainly due to impaired de novo NAD synthesis. Since NAMPT is strongly expressed during renal injury, small molecule activation of NAMPT is considered an effective means of preventing AKI. Similarly, renal mesangial cell hypertrophy indicates NAD depletion, and restoration of intracellular NAD levels is considered effective. See, e.g., Poyan Mehr et al., Nat Med. 2018, Sep; 24(9): 1351-9.

[0159] Metabolic Disease. NAD+ boosting improves insulin sensitivity, dyslipidemia, and mitochondrial function in metabolic disease and protects against / ameliorates nonalcoholic and alcoholic steatohepatitis in preclinical models. Nonalcoholic steatohepatitis is diagnosed in over 3 million people annually in the United States alone and is one of the leading causes of liver transplants. See Guarino and Dufour,Metabolites.2019,Sep 10;9(9),pii:E180;Yoshino et al.,Cell Metab.2011,14(4):528-36.

[0160] Muscle diseases. Preclinical data suggests that NAD+ boosting strategies may alleviate skeletal muscle dysfunction in many conditions, such as 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.

[0161] Neurological Disease and Injury. Replenishing NAD through NAMPT activation is neuroprotective and of therapeutic benefit in a wide range of preclinical models of neurological disease and injury, including age-related cognitive decline, glaucoma, ischemic stroke, and ALS. See Johnson et al., NPJ Aging Mech Dis. 2018, 4:10; Harlan et al., J Biol Chem. 2016, 291(20):10836-46; Zhao et al., Stroke. 2015, Jul; 46(7):1966-74; Williams et al., Front Neurosci. 2017, Apr 25; 11:232.

[0162] Diseases caused by impaired stem cell function. NAD boosting is useful for promoting stem cell activation and hematopoiesis, and for promoting the expansion of stem cell populations after stem cell transplantation. See Pi et al., Aging (Albany NY). 2019, 11(11):3505-3522.

[0163] DNA Damage Disorders and Primary Mitochondrial Disorders. NAMPT activators are also useful for treating DNA damage disorders associated with accelerated aging phenotypes such as xeroderma pigmentosum, Cockayne syndrome, and ataxia telangiectasia. Similarly, there are several primary mitochondrial disorders with common symptoms and signs, for which NAD boosting via NAMPT activation may be an appropriate 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.

[0164] In some embodiments, there is provided a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to a subject a compound of formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-D8), (I-D9), (I-D10), (I-D11), (I-D12), (I-D13), (I-D14), (I-D15), (I-D16), (I-D17), (I-D18), (I-D19), (I-D20), (I-D21), (I-D22), (I-D23), (I-D24), (I-D25), (I-D26), (I-D27), (I-D28), (I-D29), (I-D30), (I-D31), (I-D32), (I-D33), (I-D34), (I-D35), (I-D36), (I-D37), (I-D38), (I-D39), (I-D41), (I-D39 ... The present invention relates to a method for treating a disease or condition comprising administering a compound of formula (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutically acceptable salt thereof, to an individual or subject in need thereof, wherein the disease or condition is selected from the group consisting of cardiac disease, chemotherapy-induced tissue damage, renal disease, metabolic disease, muscular disease, neurological disease and damage, diseases caused by stem cell dysfunction, and DNA damage and primary mitochondrial disorders.

[0165] Additional uses of small molecule NAMPT activators are listed in Table 2. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0166] In some embodiments, the disease or condition mediated by NAMPT activity is cancer and chemotherapy induced tissue damage, cardiovascular disease, renal disease, chronic inflammatory and fibrotic disease, vascular disease, metabolic dysfunction, muscular disease, neurological 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 to the individual or subject in need thereof a compound of formula (II), (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), or (II-A), or a compound of Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or condition is cancer or chemotherapy induced tissue damage, cardiovascular disease, renal disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscular disease, neurological disease or injury, DNA damage disorder or primary mitochondrial disorder, such as any of the diseases listed in Table 2.

[0167] transparency Membrane permeability is an important property of small molecule drug design, especially for compounds with intracellular targets, since their efficacy depends heavily on their ability to cross membranes. The efficacy of a drug may depend on the ability of the drug to reach its intended site of action. Drug absorption is the movement of a drug into the bloodstream. Many factors affect this process, including the physicochemical properties of the drug, the formulation, and the route of administration. Generally, for oral treatment, the drug needs to be introduced into the blood via the intestinal route. For other routes, such as intravenous therapy, intramuscular injection, and enteral feeding, absorption is easier for the blood. Whatever the route of administration, the drug needs to be dissolved and absorbed to have a therapeutic effect. By adjusting factors that affect absorption, the pharmacokinetic (PK) profile of a drug may be altered. The permeability of a drug through biological membranes is an important factor that affects absorption and distribution. This is because if a drug wants to reach the systemic circulation, it must first pass through several semipermeable cell membranes. Drugs may pass through cell membranes by passive diffusion, facilitated passive diffusion, active transport, and pinocytosis. The physicochemical properties of the drug (such as size and lipophilicity) and membrane-based efflux mechanisms can lead to reduced permeability.

[0168] For orally administered drugs, most absorption occurs in the small intestine. Thus, drugs that are poorly absorbed by the small intestine and / or that actively efflux from the small intestine will be unlikely to actually reach their intended site of action. This low likelihood of reaching the intended site of action will result in a significant reduction in drug efficacy, necessitating significantly higher and potentially unrealistic doses compared to those predicted by in vitro on-target potency assays. Conversely, drugs that are easily absorbed and / or have a low amount of active efflux from the small intestine may require a lower dose to be administered than a similar or even more "potent" drug that is poorly absorbed. Thus, the ability of a drug to be absorbed by efflux occurring in the small intestine and the amount of efflux occurring in the small intestine are important considerations for the development of orally administered drugs.

[0169] There are various in vitro methods to assess the permeability of drugs and predict their in vivo absorption. One such method is the Caco-2 permeability assay. The Caco-2 cell line is derived from a human colon carcinoma and has many characteristics similar to intestinal epithelial cells. The Caco-2 permeability assay is a good method to investigate human intestinal permeability and drug efflux. Monolayers of the Caco-2 cell line are recognized as an accurate in vitro model of human small intestinal drug absorption. Even though the cell line is isolated from a human colon adenocarcinoma, differentiated Caco-2 cells resemble enterocytes (small intestinal absorptive cells) in that Caco-2 cells form functional tight junctions, apical and basolateral domains, and a brush border cytoskeleton. The Caco-2 permeability assay measures the transport rate of compounds through Caco-2 cells, evaluating transport in both directions. The in vitro apparent permeability (P) of drugs to Caco-2 cells in the apical to basolateral direction is aap ) has been shown to correlate with in vivo oral absorption in humans, both in that drugs with low Caco-2 cell permeability have low intestinal drug absorption in vivo, and in that drugs with high or complete Caco-2 cell permeability have high intestinal drug absorption in vivo (Artursson, et al., Biochem Biophys Res Comm, 1991,3(29):880-885). Typically, a drug that is completely absorbed in vivo is about 1×10 -6 Poorly absorbed drugs with a permeability coefficient greater than cm / sec have a permeability coefficient less than 1×10 −7 cm / sec in the apical to basolateral direction of Caco-2 cells.

[0170] Additionally, Caco-2 cells have been used to identify and quantify the level of active efflux of drugs. Active efflux of drugs is defined as the basolateral to apical P aap and P in the apical to basolateral direction. aap Typically, the lower the ratio, the greater the ability of the drug to reach its intended site of action, and the greater the ability of the drug to reach its intended site of action, the greater the potential efficacy of the drug.

[0171] The compounds provided herein are suitable for oral administration, as measured by their permeability properties evaluated by Caco-2 cell model.The compounds described herein have been demonstrated to have improved permeability, as described in Biological Example 2 herein.

[0172] Dosage Doses of the compounds and compositions disclosed and / or described herein are administered at therapeutically effective doses, e.g., at doses sufficient to provide treatment of a medical condition. Human dosage levels have not yet been optimized for the chemical entities described herein, but generally, daily doses range from about 0.01 to 100 mg / kg body weight; in some embodiments, from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg body weight. Thus, when administered to a 70 kg person, in some embodiments, the dosage range is from about 0.7 to 7000 mg per day; in some embodiments, from about 3.5 to 700.0 mg per day, and in some embodiments, from about 7 to 100.0 mg per day. The dosage of the compound depends, for example, on the subject and disease state being treated, the severity of the affliction, the method and schedule of administration, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous dosage range is from about 5 mg to about 500 mg per day, depending on the pharmacokinetics of each compound.

[0173] A daily dose is the total amount administered in one day. A daily dose may be administered daily, every other day, weekly, biweekly, monthly, or at various intervals, but is not limited to this. In some embodiments, a daily dose is administered for a period ranging from one day to the lifespan of a subject. In some embodiments, a daily dose is administered once a day. In some embodiments, a daily dose is administered in multiple divided doses, such as 2, 3, or 4 divided doses. In some embodiments, a daily dose is administered in two divided doses.

[0174] Administration of the compounds and compositions disclosed and / or described herein may be via any accepted mode of administration of a therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or ocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0175] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein may be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release tablets, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for extended periods of time and / or for pulse administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0176] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical compositions may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). In general, depending on the intended mode of administration, the pharmaceutical compositions contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight, of the compounds disclosed and / or described herein. Actual methods for preparing such dosage forms will be known, or apparent, to those skilled in the art: see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0177] In some embodiments, the composition takes the form of a tablet or pill, and thus the composition may include one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in gelatin capsules.

[0178] Liquid pharma- ceutically administrable compositions may be prepared, for example, by dissolving, dispersing, or suspending the compound disclosed and / or described herein and any pharmaceutical excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables may be in conventional forms, either as solutions or suspensions in liquid, or as emulsions, in solid form preparations suitable for solution or suspension in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient from 0.01% to 10% in solution can be used, and may be higher if the composition is a solid that is subsequently diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of the compound disclosed and / or described herein in solution.

[0179] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as aerosols or solutions for nebulizers or as microfine powders for insufflation, either alone or in combination with inert carriers such as lactose.In such cases, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0180] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein as well as one or more additional agents, drugs, adjuvants, etc. Suitable pharmaceutical agents and drugs include those described herein.

[0181] kit Also provided are articles of manufacture and kits that include any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials, such as glass or plastic. The containers may hold the pharmaceutical compositions provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit a condition described herein, and may also indicate directions for either in vivo or in vitro use. In one aspect, provided herein is a kit comprising the compound or composition described herein and instructions for use.The kit may also include instructions for use in treating cardiac disease in an individual or subject in need thereof.The kit may additionally include any material or device that can be used to administer the compound or composition, such as a vial, syringe, or IV bag.The kit may also include a sterile package.

[0182] Combination (use together) The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0183] Enumerated Embodiments The following enumerated embodiments are representative of some aspects of the present invention.

[0184] 1. Compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: R 1 is halo or methoxy; R 2 is hydrogen or C 1 -C 6 Alkyl or Z 4and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring. R 3 is hydrogen or C 1 -C 6 is alkyl; R 4 but a)Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c)Z 3 (CR c R d ) m NR e -, d) Z 4 S(O) 2 (CH 2 ) n -, e)Z 5 OC(O)-, f)NR f R g C(O)-, g) optionally, one or more independently selected C 1 -C 6 a 5-10 membered heteroaryl substituted with an alkyl substituent; or h) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, -OH, -CN, one or more independently selected R y -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 and 5-6 membered heteroaryl optionally substituted with alkyl substituents; R a and R e are each independently hydrogen or C 1 -C 6 is alkyl; R b is hydrogen or C 1 -C 6 alkyl or R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d are each independently hydrogen or C 1 -C 6 alkyl or R c and R d together with the carbon to which they are attached, C 3 -C 6 Forming a cycloalkyl; R f and R g together with the nitrogen to which they are attached, represent halo, -OH, -CN, oxo, one or more independently selected R x -C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R nforming a 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3-6 membered heterocycloalkyl or heterocycloalkenyl and 5-6 membered heteroaryl; Each R h is independent -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, or C 6 -C 12 aryl (optionally substituted with one or more independently selected halo substituents); Each R x is halo, -OH, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R y are halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR q R r ,C 6 -C 12 independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R j , R k , R m , R n , R o , R p , R q , and R r are independently hydrogen or C 1 -C 6 is alkyl; m is 0 or 1; and n is 0, 1 or 2; R 5 is hydrogen or R band together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; Z 1 and Z 5 are each independently R z and; Z 2 and Z 3 are each independently hydrogen or R z and; Z 4 is hydrogen or R z or R 2 and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and R z is selected from the group consisting of: a) C 1 -C 6 Alkyl, -OH, -CN, C 3 -C 6 Cycloalkyl, -NHC 1 -C 6 Alkyl, C 6 -C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently halo, C 1 -C 6 Alkyl, and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C 3 -C 6 Cycloalkyl, C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- or 10-membered heteroaryl), wherein said 5- or 10-membered heteroaryl is optionally substituted with one or more independently selected C 1 -C 6 optionally further substituted with alkyl; c) C 1 -C 6 Alkoxy; d) 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R w -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 wherein each R is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; w are independently halo, -OH, -CN, -C 1 -C 6 Alkoxy, -C(O)NR u R v , C 6 -C 12 aryl, and 5-6 membered heteroaryl; u and R vare each independently hydrogen or C 1 -C 6 is alkyl; e) C 6 -C 12 Aryl; and f) one or more independently selected C 1 -C 6 5-10 membered heteroaryl optionally substituted with alkyl substituents; In the formula (1)R 4 Z 1 NR a C(O)-, then Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH and -CH 2 - other than thiofuran; (2)R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, [ka] other than; and (3) The compound of formula (I) is not a compound of Table 1X, or a pharma- ceutically acceptable salt thereof.

[0185] 2.R 1 is halo, or a pharma- ceutically acceptable salt thereof.

[0186] 3.R 1 The compound of embodiment 1 or embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein is Cl.

[0187] 4.R 1 is methoxy, or a pharma- ceutically acceptable salt thereof.

[0188] 5.R 2 The compound according to any one of embodiments 1-4, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0189] 6.R 2 But, C 1 -C 6 The compound according to any one of embodiments 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R is 0 or 1.

[0190] 7.R 3 The compound according to any one of embodiments 1-6, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0191] 8.R 3 But, C 1 -C 6 The compound according to any one of embodiments 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0192] 9. The compound according to any one of embodiments 1 to 6, wherein the compound of formula (I) is a compound of formula (IA) or a pharma- ceutically acceptable salt thereof: [ka]

[0193] 10.R a The compound according to any one of embodiments 1-9, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0194] 11.R a But, C 1 -C 6 The compound of any one of embodiments 1-9, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0195] 12. A compound according to any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of: C 1 -C 6 Alkyl, -OH, C 3 -C 6 Cycloalkyl, C 6 -C 12aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently C 1 -C 6 Alkyl and C 1 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; C 3 -C 6 Cycloalkyl, C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, optionally substituted with 5- or 10-membered heteroaryl, wherein said 5- or 10-membered heteroaryl is optionally C 1 -C 6 further substituted with alkyl; and -C 1 -C 6 Alkyl and -C(O)OC 1 -C 6 and wherein the -C is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 1 -C 6 Alkyl is optionally C 6 -C 12 The above 3-10 membered heterocycloalkyl or heterocycloalkenyl substituted by aryl.

[0196] 13. A compound according to any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein Z 1 But ethyl, [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0197] 14. The compound according to embodiment 1, wherein the compound of formula (I) is a compound of formula (IB) or a pharma- ceutically acceptable salt thereof: [ka]

[0198] 15.R b The compound according to any one of embodiments 1-8 and 14, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0199] 16.R b But, C 1 -C 6 The compound according to any one of embodiments 1 to 8 and 14, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0200] 17.R b R 5 and together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring, or a pharma- ceutically acceptable salt thereof.

[0201] 18.Z 2 The compound according to any one of embodiments 1-8 and 14-17, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0202] 19. A compound according to any one of embodiments 1 to 8 and 14 to 17, or a pharma- ceutically acceptable salt thereof, wherein Z 2 but, C 3 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl. 1 -C 6 Alkyl; C 1 -C 6 Alkyl and C 1 -C 6 C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy 3 -C 6 Cycloalkyl; C 1 -C 6 Alkoxy; Optionally, one or more -C 1 -C 6 3-10 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl substituents; C 6 -C 12 Aryl; and Optionally, one or more independently selected C 1 -C 6 and 5-10 membered heteroaryl substituted with an alkyl substituent, or a pharma- ceutically acceptable salt thereof.

[0203] 20.Z 2 One or more -C 1 -C 6 The compound of embodiment 19, or a pharma- ceutically acceptable salt thereof, wherein R is 5-6 membered heteroaryl optionally substituted with an alkyl substituent.

[0204] 21.Z 2 One or more -C 1 -C 6 The compound according to embodiment 20, or a pharma- ceutically acceptable salt thereof, wherein the pyridyl group is optionally substituted with an alkyl substituent.

[0205] 22. A compound according to any one of embodiments 1 to 8 and 14 to 17, or a pharma- ceutically acceptable salt thereof, wherein Z 2 But ethyl, [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0206] 23.Z 2 but [ka] or a pharma- ceutically acceptable salt thereof.

[0207] 24. The compound according to embodiment 1, wherein said compound of formula (I) is a compound of formula (IC) or a pharma- ceutically acceptable salt thereof: [ka]

[0208] 25. The compound according to any one of embodiments 1 to 8 and 24, wherein m is 1, or a pharma- ceutically acceptable salt thereof.

[0209] 26. The compound according to any one of embodiments 1 to 8 and 24, wherein m is 0, or a pharma- ceutically acceptable salt thereof.

[0210] 27.R c The compound according to any one of embodiments 1-8 and 24-25, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0211] 28.R c But, C 1 -C 6 26. The compound according to any one of embodiments 1-8 and 24-25, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0212] 29.R d The compound according to any one of embodiments 1-8, 24-25, and 27-28, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0213] 30.R d But, C 1 -C 6The compound according to any one of embodiments 1-8, 24-25, and 27-28, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0214] 31.R c and R d together with the carbon to which they are attached, C 3 -C 6 The compound according to any one of embodiments 1-8 and 24-25, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

[0215] 32.R e The compound according to any one of embodiments 1-8 and 24-31, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0216] 33.R e But, C 1 -C 6 The compound according to any one of embodiments 1-8 and 24-31, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0217] 34.Z 3 The compound according to any one of embodiments 1-8 and 24-33, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0218] 35. A compound according to any one of embodiments 1 to 8 and 24 to 33, or a pharma- ceutically acceptable salt thereof, wherein Z 3 but, C 3 -C 6 Cycloalkyl; Optionally -C 1 -C 6 3-10 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl; C 6 -C 12 Aryl; and One or more independently selected C 1 -C 6The compound or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 5-10 membered heteroaryl optionally substituted with an alkyl substituent.

[0219] 36.Z 3 but, [ka] The compound according to any one of embodiments 1 to 8 and 24 to 33, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof. 37. The compound according to embodiment 1, wherein the compound of formula (I) is a compound of formula (ID), or a pharma- ceutically acceptable salt thereof: [ka]

[0220] 38. The compound according to any one of embodiments 1-8 and 37, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

[0221] 39. The compound according to any one of embodiments 1-8 and 37, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

[0222] 40. The compound according to any one of embodiments 1 to 8 and 37, wherein n is 2, or a pharma- ceutically acceptable salt thereof.

[0223] 41.Z 4 is hydrogen or R z or a pharma- ceutically acceptable salt thereof.

[0224] 42.Z 4 But, C 1 -C 6 The compound according to any one of embodiments 1-8 and 37-40, wherein R is alkyl, or a pharma- ceutically acceptable salt thereof.

[0225] 43.Z 4 R2 and together with the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring, or a pharma- ceutically acceptable salt thereof.

[0226] 44. [ka] The compound of embodiment 43, selected from the group consisting of:

[0227] 45. The compound according to embodiment 1, wherein the compound of formula (I) is a compound of formula (IE) or a pharma- ceutically acceptable salt thereof: [ka]

[0228] 46.Z 5 But, C 1 -C 6 The compound according to any one of embodiments 1-8 and 45, wherein R is alkyl, or a pharma- ceutically acceptable salt thereof.

[0229] 47.Z 5 The compound according to any one of embodiments 1-8 and 45, wherein is ethyl, or a pharma- ceutically acceptable salt thereof.

[0230] 48. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IF) or a pharma- ceutically acceptable salt thereof: [ka]

[0231] 49. A compound according to any one of claims 1 to 8 and 48, or a pharma- ceutically acceptable salt thereof, wherein R f and R g together with the nitrogen to which they are attached, represent halo, -OH, -CN, oxo, one or more independently selected R x-C optionally substituted with a substituent 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, forming a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of:

[0232] 50.R f and R g together with the nitrogen to which they are attached, optionally -C 1 -C 6 wherein said -C forms a 5-6 membered heterocycloalkyl or heterocycloalkenyl substituted with 1 -C 6 50. The compound of claim 49, or a pharma- ceutically acceptable salt thereof, wherein said alkyl is optionally substituted with -OH.

[0233] 51. A compound according to any one of embodiments 1 to 8 and 48 to 49, or a pharma- ceutically acceptable salt thereof, [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0234] 52. [ka] or a pharma- ceutically acceptable salt thereof.

[0235] 53.R 4 but one or more independently selected C 1 -C 6 The compound according to any one of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein R is 5-10 membered heteroaryl optionally substituted with an alkyl substituent.

[0236] 54.R 4 but, [ka] 54. The compound according to any one of embodiments 1-8 and 53, selected from the group consisting of:

[0237] 55. A compound according to any one of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein R 4 is a 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, -OH, -CN, and one or more independently selected R y -C optionally substituted with a substituent 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 1 -C 6 Alkoxy, -C(O)OC 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents; 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C1 -C 6 and 5-6 membered heteroaryl optionally substituted with alkyl substituents, and the 3-10 membered heterocycloalkyl or heterocycloaryl optionally substituted with one or more substituents independently selected from the group consisting of:

[0238] 56.R 4 But S(O) 2 -C 1 -C 6 Alkyl or -C 1 -C 6 The compound according to embodiment 55, which is a 4-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl (optionally substituted with -OH), or a pharma- ceutically acceptable salt thereof.

[0239] 57.R 4 but, [ka] [ka] 56. The compound according to any one of embodiments 1-8 and 55, selected from the group consisting of:

[0240] 58.R 4 but [ka] or a pharma- ceutically acceptable salt thereof.

[0241] 59. A compound selected from the group consisting of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0242] 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1-59, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0243] 61. A method for treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0244] 62. The method of embodiment 61, wherein the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a renal disease, a metabolic disease, a neurological disease or damage, a neurodegenerative disorder or disease, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle wasting disorder.

[0245] 63. The method of embodiment 61, wherein the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, polio (poliovirus infection), and spinal cord injury.

[0246] General synthesis method The compounds of formula (II), (IG), (I)(IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) are illustrated by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples. Those skilled in the art will recognize that to obtain the various compounds herein, starting materials may be appropriately selected such that the final desired substituents are carried through the reaction scheme with or without appropriate protection to produce the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group which can be carried through the reaction scheme and optionally replaced with the desired substituent. Additionally, those skilled in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from the reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as defined above with reference to Formulas (II), (IG), (I)(IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1).

[0247] When it is desired to obtain a particular enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reaction of a mixture of enantiomers, for example a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, for example by crystallization, and the desired enantiomer is recovered. In another separation process, chiral high performance liquid chromatography can be used to separate the racemate. Alternatively, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described, if necessary.

[0248] Chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0249] A general method for preparing the compounds described herein is shown in the following exemplary method. The variable groups of the schemes provided herein are defined as for formula (II), (IG), (I)(IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0250] In some embodiments, compounds provided herein can be synthesized according to Schemes A1, A2, or A3. Scheme A1 [ka] Scheme A2 [ka] Scheme A3 [ka] Here, R 1 , R 2 , R 3 , R 4 , and R 5 is as defined for formula (II) or any variation thereof detailed herein.

[0251] In certain embodiments, compounds provided herein can be synthesized according to Schemes A1a, A2a, or A3a: Scheme A1a [ka] Scheme A2a [ka] Scheme A3a [ka] In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is as defined for formula (II) or any variation thereof detailed herein.

[0252] In some embodiments, compounds provided herein can be synthesized according to Scheme B1 or B2: Scheme B1 [ka] Scheme B2 [ka] In the formula, R 1 , R 2 , R3 , R 5 , R a , R g , R f , and Z 1 is as defined in formula (II) or any variation thereof as detailed herein.

[0253] In certain embodiments, compounds provided herein can be synthesized according to Schemes B1a or B2a: Scheme B1a [ka] Scheme B2a [ka] In the formula, R 1 , R 2 , R 3 , R 5 , R a , R g , R f , and Z 1 is as defined in formula (II) or any variation thereof as detailed herein.

[0254] In some embodiments, compounds provided herein can be synthesized according to Schemes C1 or C2: Scheme C1 [ka] Scheme C2 [ka] wherein R 1 , R 2 , R 3 , R 5 , R b , R c , R e , Z 2 and Z 3is as defined for formula (II) or any variation thereof detailed herein, and PG is a suitable protecting group.

[0255] In certain embodiments, compounds provided herein can be synthesized according to Schemes C1a or C2a: Scheme C1a [ka] Scheme C2a [ka] In the formula, R 1 , R 2 , R 3 , R 5 , R b , R c , R e , Z 2 and Z 3 is as defined in formula (II) or any variation thereof as detailed herein.

[0256] In some embodiments, compounds provided herein may be synthesized according to Scheme D1: Scheme D1 [ka] In the formula, R 1 , R 5 , R c , R d , m, and Z 3 is as defined in formula (II) or any variation thereof detailed herein, and PG is a suitable protecting group.

[0257] In certain embodiments, compounds provided herein can be synthesized according to Scheme D1a: [ka] In the formula, R 1 , R 5 , R c, R d , m, and Z 3 is as defined in formula (II) or any variation thereof as detailed herein.

[0258] In some embodiments, compounds provided herein can be synthesized according to Scheme E1: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any variation thereof as detailed herein.

[0259] In certain embodiments, compounds provided herein can be synthesized according to Scheme E1a: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any variation thereof as detailed herein.

[0260] In some embodiments, compounds provided herein can be synthesized according to Scheme F1: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any variation thereof as detailed herein.

[0261] In certain embodiments, compounds provided herein can be synthesized according to Scheme F1a: [ka] In the formula, R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any variation thereof as detailed herein.

[0262] Specific non-limiting examples are described in the Examples section below. EXAMPLES

[0263] The following examples are provided to illustrate, but not limit, the compositions, uses, and methods provided herein. Compounds are prepared using the general methods described above.

[0264] The following abbreviations are used throughout the examples: TEA (triethylamine), DCM (dichloromethane), (Boc). 2 O (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 (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh 3(triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), rt (room temperature), DCE (dichloroethane), FA (formic acid), CHCl 3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equivalent (equivalent), and DSC (bis(2,5-dioxopyrroliether-yl)carbonate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0265] Example A Synthesis of intermediates 1.1, 1.2, 1.3 and 1.4. Step 1: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (intermediate 1-a): [ka] To a solution of ethyl 2-(4-aminophenyl)acetate (27.46 g, 153.2 mmol) in DCM (20 mL) at 20° C., 4-methoxybenzyl isocyanate (25.0 g, 153.2 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 4 h, then methanol (10 mL) was added and cooled to 0° C. After 1 h at 0° C., the slurry was filtered to give intermediate 1-a (26.7 g, 78.0 mmol, 50.9% yield) as an off-white solid. LCMS-APCI (POS.) m / z: 343.1 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ 8.50(s,1H), 7.38-7.30(m,2H), 7.27-7.19(m,2H), 7.15-7.07(m,2H), 6.94-6.85(m,2H), 6.52(t,J=5. 9Hz,1H), 4.22(d,J=5.4Hz,2H), 4.06(q,J=7.1Hz,2H), 3.73(s,3H), 3.55(s,2H), 1.17(t,J=7.1Hz,3H).

[0266] Step 2: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (Intermediate 1.1): [ka] To a solution of intermediate 1-a (26.5 g, 77.5 mmol) in 1,4 dioxane (400 mL) at 20° C., 4N LiOH (234.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h, then methanol (50 mL) was added. The pH of the mixture was adjusted to pH 1-2 using 6N aqueous HCl at 0° C. After 1 h at 0° C., the slurry was filtered to give 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (20.2 g, 64.3 mmol, 82.9% yield) as an off-white solid. LCMS-APCI (POS.) m / z: 315.0 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ 12.22(s,1H), 8.47(s,1H), 7.33(d,J=8.0Hz,2H), 7.23(d,J=8.1Hz,2H), 7.11(d,J=8.1Hz,2H), 6.9 0(d,J=8.1Hz,2H), 6.50(t,J=6.0Hz,1H), 4.22(d,J=5.7Hz,2H), 3.74(d,J=1.3Hz,3H), 3.46(s,2H).

[0267] Intermediates 1.2 and 1.3 were prepared in a similar manner to Intermediate 1.1 using the reagents shown in the table below in place of 4-methoxybenzyl isocyanate. [Table 4]

[0268] Example B Synthesis of Intermediates 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7 Step 1: Preparation of tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)phenyl)-ethyl)carbamate (Intermediate 2-a): [ka] To a solution of (S)-[1-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.0 g, 22.7 mmol) in DCM (20 mL) at 20° C. was added 4-methoxybenzyl isocyanate (14.4 g, 34.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 4 h, then methanol (10 mL) was added and cooled to 0° C. After 1 h at 0° C., the slurry was filtered to give tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)-phenyl)ethyl)carbamate (1.2 g, 6.3 mmol, 28% yield) as an off-white solid. LCMS-APCI (POS.) m / z: 400.1 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ 8.43(s,1H), 7.36-7.19(m,4H), 7.14(d,J=8.2Hz,2H), 6.89(d,J=8.2Hz,2H), 6.48(t,J=5.9Hz,1 H), 4.53(p,J=7.3Hz,1H), 4.21(d,J=5.7Hz,2H), 3.73(s,3H), 1.37(s,9H), 1.27(d,J=7.0Hz,3H).

[0269] Step 2: Preparation of (S)-1-(4-(1-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (Intermediate 2.1): [ka] Intermediate 2-a (34.7 g, 86.9 mmol) was dissolved in dichloromethane and cooled to 0° C. in an ice bath. Hydrogen chloride (4 N in 1,4-dioxane, 174 mL, 695 mmol) was added dropwise using a syringe and the resulting mixture was stirred at 0° C. for 5 min, after which the ice bath was removed. The reaction was stirred at room temperature for 45 min and the progress of the reaction was monitored by LC / MS. It was quenched with triethylamine (28 mL) and the resulting mixture was concentrated in vacuo to give a white solid. The solid was purified by elution with saturated NaHCO 3 The solution was partitioned between DCM. The phases were separated and the aqueous phase was extracted with additional DCM. The organic extracts were combined and washed with Na 2 SO4 Drying at 40° C. and concentration under reduced pressure gave (S)-1-(4-(1-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (6.18 g, 18.28 mmol, 90% yield) as a viscous, nearly colorless oil. The purity was estimated to be 70%. LCMS-APCI (POS.) m / z: 300.1 (M+H)+. 1 H NMR (400MHz, DMSO-d 6 )δ 9.14(s,1H), 8.40(d,J=5.3Hz,3H), 7.45(d,J=8.3Hz,2H), 7.36(d,J=8.3Hz,2H), 7.23(d,J=8.2Hz, 2H), 6.89(d,J=8.2Hz,3H), 4.29(p,J=6.1Hz,1H), 4.22(s,2H), 3.73(s,3H), 1.49(d,J=6.7Hz,3H).

[0270] Intermediates 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7 were prepared in a similar manner to Intermediate 2.1 using the reagents shown in the table below in place of 4-methoxy benzyl isocyanate. [Table 5-1] [Table 5-2]

[0271] Example C Synthesis of Intermediates 3.1, 3.2, and 3.3 Step 1: Preparation of methyl 4-(3-(4-methoxybenzyl)ureido)benzoate (intermediate 3-a): [ka] To a suspension of methyl 4-isocyanatobenzoate (10.0 g, 56.4 mmol) in methylene chloride (56.4 mL, 1 M) was added (4-methoxyphenyl)methanamine (7.74 g, 56.4 mmol) dropwise at 0° C. The reaction was gradually warmed to room temperature and stirred at room temperature for 60 min, and the progress of the reaction was monitored by LC / MS. The reaction became homogeneous followed by white solid precipitation. The solution was then filtered and the filter cake was washed with excess methylene chloride and dried to give crude intermediate 3-a (17.4 g, 55.2 mmol, 98% yield) as an off-white solid setup. LCMS-APCI (POS.) m / z: 315.2 (M+H)+. 1H NMR(400MHz,DMSO-d6)δ 8.96(s,1H), 7.85(d,J=8.6Hz,2H), 7.54(d,J=8.8Hz,2H), 7.24(d,J=8.5Hz,2H), 6.90( d,J=8.5Hz,2H), 6.71(t,J=5.9Hz,1H), 4.25(d,J=5.7Hz,2H), 3.73(s,3H), 3.81(s,3H).

[0272] Step 2: Preparation of 1-(4-(hydroxymethyl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 3-b): [ka] To a dry flask was added intermediate 3-a (16.0 g, 50.9 mmol) in 120 mL of dry methylene chloride and the suspension was cooled to 0° C. Then, 1 M DIBAL (126 mL, 126 mmol) in methylene chloride was added dropwise over 45 min and the reaction was stirred at 0° C. for an additional 30 min. The homogeneous solution was allowed to warm to room temperature and then stirred for 4 h. The solution was then cooled to 0° C. and quenched dropwise with MeOH (100 mL) and after the exotherm had subsided, 300 mL of methylene chloride and 200 mL of sodium hydroxide solution (1 M) were added and the mixture was stirred for an additional 60 min at room temperature. The organic layer was then separated and the aqueous layer was extracted with (5:1 methylene chloride-isopropanol, 300 mL) The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give intermediate 3-b as a white solid (14.2 g, 49.8 mmol, 99% yield). The crude product was subjected to the next oxidation step for further purification. LCMS-APCI (POS.) m / z: 287.2 (M+H)+. 1 H NMR (400MHz, DMSO-d 6 )δ 8.61(s,1H), 7.35(d,J=8.0Hz,2H), 7.24(d,J=8.2Hz,2H), 7.17(d,J=8.1Hz,2H), 6.90(d,J=8.2Hz,2H), 6.61(t,J=5.9Hz,1H), 5.02(t,J=5.7Hz,1H), 4.40(d,J=5.5Hz,2H), 4.22(d,J=5.7Hz,2H), 3.74(s,3H).

[0273] Step 3: Preparation of 1-(4-formylphenyl)-3-(4-methoxybenzyl)urea (Intermediate 3.1): [ka] To a suspension of intermediate 3-b (14.0 g, 48.8 mmol) in methylene chloride-isopropanol (20:1, 250 mL, 0.2 M) was added manganese dioxide (44.2 g, 508 mmol) at room temperature. The resulting suspension was allowed to stir at room temperature for 12 h. The solution was filtered through a celite pad. The filter cake was washed with isopropanol and the mother liquor was concentrated to give intermediate 3.1 (13.2 g, 46.5 mmol) as a pale yellow solid setup. LCMS-APCI (POS.) m / z: 285.2 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ 9.81(s,1H), 9.15(s,1H), 7.78(dd,J=8.6,2,7Hz,2H), 7.62(dd,J=8.6,2,7Hz,2H), 7.24(dd,J=8.5, 2,8Hz,2H), 6.90(dd,J=8.6,2,7Hz,2H), 6.87-6.77(m,1H), 4.43(dd,J=8.5,2,8Hz,2H), 3.74(s,3H).

[0274] Intermediates 3.2 and 3.3 were prepared in a similar manner to Intermediate 2.1 using the reagents shown in the table below in place of (4-methoxyphenyl)methanamine. [Table 6]

[0275] Example D Synthesis of Intermediates 4.1 and 4.2 Step 1: Preparation of phenyl(4-chlorobenzyl)carbamate (intermediate 4.1): [ka] To a solution of 1-(4-chlorophenyl)methanamine (2.00 g, 14.124 mmol, 1.00 equiv) in THF (30 mL) was added phenylcarboxylochloridate (2.43 g, 15.537 mmol, 1.1 equiv) and K 2 CO 3(2.93 g, 21.186 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 3 h, filtered to remove solids, and the filtrate was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 3.6 g of phenyl N-[(4-chlorophenyl)methyl]carbamate (95%) as a white solid. LRMS (ES) m / z 262 [M+H].

[0276] Intermediate 4.2 was prepared in a similar manner to Intermediate 4.1 using (4-methoxyphenyl)methanamine instead of (4-chlorophenyl)methanamine. [Table 7]

[0277] Example E Synthesis of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0) Step 1: Preparation of 1-((methylsulfonyl)methyl)-4-nitrobenzene (intermediate 5-a): [ka] To a solution of 1-(bromomethyl)-4-nitrobenzene (1 g, 4.629 mmol, 1 equiv.) in DMF (10 mL) was added sodium methanesulfinate (712 mg, 6.975 mmol, 1.51 equiv.). The resulting mixture was stirred at 65° C. for 0.5 h, cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and anhydrous Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, 1 g of 1-(methanesulfonylmethyl)-4-nitrobenzene was obtained as a yellow solid. (No LCMS signal, H-NMR confirmed). 1H NMR (300 MHz, DMSO-d6) δ 8.34-8.23 (m, 2H), 7.76-7.65 (m, 2H), 4.73 (s, 2H), 2.99 (s, 3H).

[0278] Step 2: Preparation of 1-(1-(methylsulfonyl)ethyl)-4-nitrobenzene (intermediate 5-b): [ka] To a solution of 1-(methanesulfonylmethyl)-4-nitrobenzene (850 mg, 3.949 mmol, 1 equiv) in DMF (10 mL) was added t-BuOK (531 mg, 4.732 mmol, 1.20 equiv). After stirring at room temperature for 1 h, iodomethane (560 mg, 3.945 mmol, 1.00 equiv) was added to the mixture. The resulting mixture was stirred at room temperature for 1 h and water (20 mL) was added. The mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and diluted with anhydrous Na 2 SO 4 Drying at 400 rpm and concentrating under reduced pressure gave 950 mg of 1-(1-methanesulfonylmethyl)-4-nitrobenzene as a yellow oil. No LCMS signal. H-NMR analysis showed it to be the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.23 (m, 2H), 7.79-7.67 (m, 2H), 4.82 (q, J = 7.1 Hz, 1H), 2.91 (s, 3H), 1.69 (d, J = 7.1 Hz, 3H).

[0279] Step 3: Preparation of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0): [ka] To a solution of 1-(1-methanesulfonylethyl)-4-nitrobenzene (950 mg, 4.144 mmol, 1 equiv) in methanol (10 mL) was added Pd / C (467 mg, 50% w / w). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 1 h, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 700 mg of 4-(1-methanesulfonylethyl)aniline as a yellow oil. LRMS (ES) m / z 200 [M+H].

[0280] Example F 3-(4-aminophenyl)thietane 1,1-dioxide trifluoroacetate Synthesis of (Intermediate 6.0) Step 1: Preparation of diethyl 2-(4-nitrophenyl)malonate (intermediate 6-a): [ka] A solution of 1-bromo-4-nitrobenzene (5 g, 24.752 mmol, 1 equiv.) in DMSO (50 mL) was treated with 1,3-diethylpropanedioate (12 g, 74.921 mmol, 3.03 equiv.), CuI (473 mg, 2.484 mmol, 0.10 equiv.), L-proline (572 mg, 4.968 mmol, 0.20 equiv.) and K 2 CO 3 (13.7 g, 99.128 mmol, 4.00 equiv.) was added. The mixture was stirred at 90° C. for 2 days under nitrogen atmosphere, cooled to room temperature, water (100 mL) was added, and extracted twice with EtOAc (100 mL). The combined organic layers were washed twice with brine (100 mL) and diluted with anhydrous Na 2 SO 4 Dry at 40° C., concentrate under reduced pressure, and purify by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 4.7 g of 1,3-diethyl 2-(4-nitrophenyl)propanedioate as a yellow oil. LRMS (ES) m / z 282 (M+H).

[0281] Step 2: Preparation of diethyl 2-(4-aminophenyl)malonate (intermediate 6-b): [ka] To a solution of 1,3-diethyl 2-(4-nitrophenyl)propanedioate (2.2 g, 7.822 mmol, 1 equiv) in ethanol (25 mL) was added Pd / C (1.10 g, 50% w / w). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 h, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 1.9 g of 1,3-diethyl 2-(4-aminophenyl)propanedioate (96.67%) as a yellow oil. LRMS (ES) m / z 252 [M+H].

[0282] Step 3: Preparation of diethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)malonate (Intermediate 6-c): [ka] To a solution of 1,3-diethyl 2-(4-aminophenyl)propanedioate (1 g, 3.96 mmol, 1 equiv.) in THF (10 mL) was added di-tert-butyl dicarbonate (2.6 g, 11.4 mmol, 2.9 equiv.). The resulting mixture was stirred at room temperature for 2 h, water (30 mL) was added, and the mixture was diluted with CH 2 Cl 2 (30 mL) twice. The combined organic layers were washed twice with brine (30 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1 g of 1,3-diethyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanedioate as an off-white solid. LRMS (ES) m / z 296 [M+H-56].

[0283] Step 4: Preparation of tert-butyl (4-(1,3-dihydroxypropan-2-yl)phenyl)carbamate (Intermediate 6-d): [ka] A solution of 1,3-diethyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanedioate (1 g, 2.846 mmol, 1 equiv.) in ethanol (20 mL) was added to NaBH 4 (1.08 g, 28.547 mmol, 10.03 equiv.) was added. The resulting mixture was stirred at room temperature overnight and NH 4 The mixture was quenched with Cl. water (10 mL) at 0° C. and concentrated in vacuo to remove EtOH. The mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography. 2 Cl 2 Elution with 20:1 hexane / MeOH gave 720 mg of tert-butyl N-[4-(1,3-dihydroxypropan-2-yl)phenyl]carbamate (94.64%) as an off-white solid; LRMS (ES) m / z 212 [M+H-56].

[0284] Step 5: Preparation of 2-(4-((tert-butoxycarbonyl)amino)phenyl)propane-1,3-diyl dimethanesulfonate (Intermediate 6-e): [ka] To a solution of tert-butyl N-[4-(1,3-dihydroxypropan-2-yl)phenyl]carbamate (670 mg, 2.506 mmol, 1 equiv) in DCM (10 mL) was added methanesulfonyl chloride (715 mg, 6.242 mmol, 2.49 equiv) and TEA (760 mg, 7.511 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 2 h and poured into water (20 mL). The aqueous layer was diluted with CH 2 Cl 2(20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1.2 g of tert-butyl N-[4-[2-(methanesulfonyloxy)-1-[(methanesulfonyloxy)methyl]ethyl]phenyl]carbamate as a yellow solid. LRMS (ES) m / z 368 [M+H-56].

[0285] Step 6: Preparation of tert-butyl (4-(thietan-3-yl)phenyl)carbamate (intermediate 6-f): [ka] A solution of tert-butyl N-[4-[2-(methanesulfonyloxy)-1-[(methanesulfonyloxy)methyl]ethyl]phenyl]carbamate (1.1 g, 2.597 mmol, 1 equiv.) in DMF (10 mL) was added to Na at room temperature. 2 S (122 mg, 1.564 mmol, 0.60 equiv) was added. The resulting mixture was stirred at 100° C. for 5 h. The solution was then cooled to room temperature and poured into water (20 mL). The aqueous layer was extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EtOAc (5:1) to give 270 mg of tert-butyl N-[4-(thietan-3-yl)phenyl]carbamate (39.17%) as a yellow solid. LRMS (ES) m / z 210 [M+H-56].

[0286] Step 7: Preparation of tert-butyl (4-(1,1-dioxidothietan-3-yl)phenyl)carbamate (Intermediate 6-g): [ka] To a solution of tert-butyl N-[4-(thietan-3-yl)phenyl]carbamate (250 mg, 0.942 mmol, 1 equiv.) in DCM (3 mL) was added m-CPBA (485 mg, 2.811 mmol, 2.98 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 2 h and water (20 mL) was added. The resulting mixture was subjected to CH 2 Cl 2 (20 mL) twice. The combined organic layers were extracted with Na 2 S 2 O 4 (10 mL), NaHCO 3 (10 mL), washed twice with brine (20 mL), and then washed with anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 290 mg of tert-butyl N-[4-(1,1-dioxo-1lambda 6-thietan-3-yl)phenyl]carbamate as a yellow oil. LRMS (ES) m / z 242 [M+H-56].

[0287] Step 8: Preparation of 3-(4-aminophenyl)thietane 1,1-dioxide trifluoroacetate (Intermediate 6.0): [ka] To a solution of tert-butyl N-[4-(1,1-dioxo-1 lambda 6-thietan-3-yl)phenyl]carbamate (290 mg, 0.975 mmol, 1 equiv) in DCM (3 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 190 mg of 3-(4-aminophenyl)thietane 1,1-dioxide trifluoroacetate as a brown solid. LRMS (ES) m / z 298 [M+H].

[0288] Example G Synthesis of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0) Step 1: Preparation of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (intermediate 7-a): [ka] To a solution of tetrahydrothiophene 1,1-dioxide (2 g, 16.643 mmol, 1.00 equiv) in THF (20.00 mL) at −20° C., LiHMDS (25.00 mL, 25.000 mmol, 1.50 equiv) was added dropwise over a period of 20 min under a nitrogen atmosphere. After stirring at room temperature under a nitrogen atmosphere for 0.5 h, the mixture was treated with ZnCl 2 (3.35 g, 24.575 mmol, 1.48 equiv.) was added. The mixture was stirred at room temperature for 1 h. To the above mixture, 1-bromo-4-nitrobenzene (2.35 g, 11.650 mmol, 0.70 equiv.), Pd(OAc) 2 (187.00 mg, 0.833 mmol, 0.05 equiv.) and X-Phos (795.00 mg, 1.668 mmol, 0.10 equiv.) were added. The mixture was stirred at 65° C. for 12 h under nitrogen atmosphere, cooled to room temperature and diluted with NH 4 Quench with aqueous Cl (20 mL) and HCl (1 mol / L, 5 mL), and then add CH 2 Cl 2 (50 mL) twice. The combined organic layers were washed twice with brine (50 mL) and anhydrous Na 2 SO 4 It was dried at 40° C., concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 1.1 g of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (27.40%) as a brown solid. No LCMS signal.

[0289] Step 2: Preparation of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0): [ka] To a solution of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (1.10 g, 4.559 mmol, 1.00 equiv) in methanol (11 mL) was added Pd / C (550.00 mg, 50% w / w). The resulting mixture was stirred under hydrogen atmosphere overnight at room temperature, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 800 mg of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (83.05%) as a yellow solid. LRMS (ES) m / z 212 [M+H].

[0290] Example H Synthesis of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate (Intermediate 8.0) Step 1: Preparation of tert-butyl (4-iodophenyl)carbamate (Intermediate 8-a): [ka] To a solution of 4-iodoaniline (1 g, 4.566 mmol, 1 equiv) in MeOH (20 mL) was added (Boc) 2 2 g (0.009 mmol, 2.01 equiv) and TEA (2 mL) were added. The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, concentrated in vacuo, and water (50 mL) was added. The mixture was extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (30:1) to give 650 mg of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 44.61%) as an off-white solid. LRMS (ES) m / z 264 [M+H-56].

[0291] Step 2: Preparation of tert-butyl (4-(1,1-dioxido-2,5-dihydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-b): [ka] To a solution of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 2.037 mmol, 1 equiv.) in toluene (10 mL) was added 2,5-dihydro-1 lambda 6-thiophene-1,1-dione (264 mg, 2.234 mmol, 1.10 equiv.), Pd(OAc)2 (91 mg, 0.405 mmol, 0.20 equiv.), TBABr (654 mg, 2.029 mmol, 1.00 equiv.) and TEA (410 mg, 4.052 mmol, 1.99 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 days, stirred at 80° C. for 3 h, cooled to room temperature and water (20 mL) was added. The mixture was extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL) and diluted with anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 430 mg of tert-butyl N-[4-(1,1-dioxo-2,5-dihydro-1lambda-6-thiophen-3-yl)phenyl]carbamate (68.24%) as a brown solid. LRMS (ES) m / z 254 [M+H-56].

[0292] Step 3: Preparation of tert-butyl (4-(1,1-dioxidotetrahydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-c): [ka] To a solution of tert-butyl N-[4-(1,1-dioxo-2,5-dihydro-1lambda 6-thiophen-3-yl)phenyl]carbamate (430 mg, 1.390 mmol, 1 equiv) in methanol (10 mL) was added Pd / C (215 mg, 50% w / w). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 1 h, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 390 mg of tert-butyl N-[4-(1,1-dioxo-1lambda 6-thiolan-3-yl)phenyl]carbamate (90.11%) as a brown solid. LRMS (ES) m / z 256 [M+H].

[0293] Step 4: Preparation of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate (Intermediate 8.0): [ka] To a solution of tert-butyl N-[4-(1,1-dioxo-1-lambda 6-thiolan-3-yl)phenyl]carbamate (390 mg, 1.252 mmol, 1 equiv.) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, diluted with water (10 mL), and purified by HPLC with NaCl. 2 CO 3 The pH was adjusted to 8 with aqueous solution. The aqueous layer was extracted twice with EA (10 mL). The combined organic layers were washed twice with brine (10 mL) and 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 260 mg of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate as a brown oil. LRMS (ES) m / z 212 [M+H].

[0294] Example I Synthesis of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0) Step 1: Preparation of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (Intermediate 9-a): [ka] To a solution of LDA (8.5 mL, 17.0 mmol, 1.10 equiv) in THF (20 mL) at -78°C was added a solution of thian-4-one (1.8 g, 15.493 mmol, 1 equiv) in THF (5 mL) dropwise over 10 min under argon atmosphere. After stirring at room temperature for 0.5 h under argon atmosphere, to the mixture at -78°C was added a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (6.09 g, 17.047 mmol, 1.10 equiv) in THF (10 mL) dropwise over 10 min. The resulting mixture was stirred at room temperature under argon atmosphere for 0.5 h, quenched with water (100 mL) at 0°C, and extracted twice with EtOAc (200 mL). The combined organic layers were washed twice with brine (100 mL) and anhydrous NaCl was added. 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (99:1) to give 2.5 g of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate as a yellow oil. LRMS (ES) m / z 249 [M+H].

[0295] Step 2: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (Intermediate 9-b): [ka] Dioxane (20 mL) and H 2 To a solution of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (2.4 g, 9.668 mmol, 1 equiv.) in 2O (10 mL), (4-nitrophenyl)boronic acid (1.94 g, 11.602 mmol, 1.20 equiv.), Pd(dppf)Cl 2 CH 2 Cl 2 (1.58 g, 1.934 mmol, 0.20 equiv.) and K 2 CO 3(2.66 g, 19.34 mmol, 2 equiv.) was added. The resulting mixture was stirred at 85° C. for 3 h under nitrogen atmosphere, cooled to room temperature, and water (200 mL) was added. The mixture was extracted twice with EtOAc (200 mL). The combined organic layers were washed twice with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 1 g of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (46.74%) as a yellow solid. LRMS (ES) m / z 222 [M+H].

[0296] Step 3: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (intermediate 9-c): [ka] To a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (700 mg, 3.164 mmol, 1 equiv.) in DCM (15 mL) was added m-CPBA (1.6 g, 9.5 mmol, 3 equiv.) at −78° C. The resulting mixture was stirred at room temperature for 3 h and poured into water (20 mL). The aqueous layer was diluted with CH 2 Cl 2 (30 mL) twice. The combined organic layers were washed with Na 2 SO 3 (10mL of aqueous solution), NaHCO 3( aq. 10 mL), washed twice with brine (20 mL), and then washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give 650 mg of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide as a yellow solid. LRMS (ES) m / z 254 [M+H].

[0297] Step 4: Preparation of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0): [ka] To a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (650 mg, 2.559 mmol, 1 equiv) in methanol (8 mL) and THF (8 mL) was added Pd / C (325 mg, 50% w / w). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 400 mg of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide as a brown solid. LRMS (ES) m / z 226 [M+H].

[0298] Example J Synthesis of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10.0) Step 1: Preparation of ethyl (Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (Intermediate 10-a): [ka] A solution of 1-(4-nitrophenyl)ethan-1-one (2 g, 12.110 mmol, 1 equiv.) in AcOH (6 mL) and toluene (40 mL) was treated with ethyl 2-cyanoacetate (1.37 g, 12.111 mmol, 1.00 equiv.) and NH 4 OAc (187 mg, 2.426 mmol, 0.20 equiv.) was added. The resulting mixture was stirred at 110° C. overnight, cooled to room temperature, and poured into water (50 mL). The resulting mixture was extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1.7 g of ethyl (Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (53.94%) as a yellow solid. LRMS (ES) m / z 261 (M+H).

[0299] Step 2: Preparation of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (Intermediate 10-b): [ka] To a solution of NaOEt (2 g, 6.176 mmol, 1.00 equiv, 21%) in EtOH (30 mL) was added dropwise over 5 min at 0° C. 2-cyanoacetamide (517 mg, 6.149 mmol, 1.00 equiv). After stirring for 15 min at room temperature, ethyl (2Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (1.6 g, 6.148 mmol, 1 equiv) was added. The resulting reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and the mixture was acidified to pH 1 with HCl (aq. 4 mol / L, ca. 5 mL). The precipitated solid was collected by filtration and dried under reduced pressure to give 1.2 g of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (65.44%) as a yellow solid. No LCMS signal. H-NMR confirmation. 1H NMR (400MHz, DMSO-d6) δ 12.43(s,1H), 8.42-8.34(m,3H), 8.02-7.94(m,2H), 5.43(s,2H), 1.76(s,3H).

[0300] Step 3: Preparation of 3-methyl-3-(4-nitrophenyl)pentanedioic acid (Intermediate 10-c): [ka] To a solution of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (1.1 g, 3.688 mmol, 1 equiv.) in HO (9 mL) at 0° C. was added sulfuric acid (9 mL) and AcOH (6 mL) dropwise over 15 min. The resulting mixture was stirred at 100° C. for 2 days, cooled to room temperature, diluted with ice-cold water (30 mL), and extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (50 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure to give 1.2 g of 3-methyl-3-(4-nitrophenyl)pentanedioic acid as a brown semi-solid. LRMS (ES) m / z 268 (M+H).

[0301] Step 4: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (Intermediate 10-d): [ka] To a solution of 3-methyl-3-(4-nitrophenyl)pentanedioic acid (1.1 g, 4.1 mmol, 1 equiv.) in THF (10 mL) at 0 °C was added BH 3 -THF (1 mol / L in THF, 41 mL, 41 mmol, 10 equiv.) was added dropwise over 15 min. The resulting mixture was stirred at 70° C. for 1.5 h, cooled to room temperature, quenched with water (30 mL) at 0° C., and extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL) and diluted with anhydrous Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, 720 mg of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (82.06%) was obtained as a brown oil. LRMS (ES) m / z 240 (M+H).

[0302] Step 5: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diyl dimethanesulfonate (Intermediate 10-e): [ka] To a solution of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (720 mg, 3.009 mmol, 1 equiv) in DCM (10 mL) at 0° C. was added TEA (912 mg, 9.013 mmol, 3.00 equiv) and methanesulfonyl chloride (859 mg, 7.500 mmol, 2.49 equiv) dropwise. The resulting mixture was stirred at room temperature for 2 h and poured into water (10 mL). The aqueous layer was diluted with CH 2 Cl 2 (10 mL) twice. The combined organic layers were washed twice with brine (10 mL) and anhydrous Na2 SO 4 It was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 410 mg of 5-(methanesulfonyloxy)-3-methyl-3-(4-nitrophenyl)pentyl methanesulfonate (34.46%) as a yellow oil. LRMS (ES) m / z 396 (M+H).

[0303] Step 6: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (Intermediate 10-f): [ka] To a solution of 5-(methanesulfonyloxy)-3-methyl-3-(4-nitrophenyl)pentyl methanesulfonate (410 mg, 1.037 mmol, 1 equiv) in ACN (5 mL) was added Na 2 S (49.33 mg, 0.632 mmol, 0.61 equiv) was added. The resulting mixture was stirred at 80° C. overnight under nitrogen atmosphere, cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The residue was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 130 mg of 4-(4-nitrophenyl)tetrahydro-2H-thiopyran (52.83%) as a yellow solid. LRMS (ES) m / z 238 (M+H).

[0304] Step 7: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10-g): [ka] To a solution of 4-methyl-4-(4-nitrophenyl)thiane (130 mg, 0.548 mmol, 1 equiv.) in DCM (3 mL) was added m-CPBA (283 mg, 1.640 mmol, 2.99 equiv.). The resulting mixture was stirred at room temperature for 2 h and poured into water (10 mL). The aqueous layer was diluted with CH 2 Cl 2 (10 mL) twice. The combined organic layers were washed with Na 2 S 2 O 4 (5 mL), washed twice with brine (10 mL), and then washed with anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 170 mg of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide as a yellow solid. LRMS (ES) m / z 270 (M+H).

[0305] Step 8: Preparation of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10.0): [ka] To a solution of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (170 mg, 0.631 mmol, 1 equiv) in methanol (3 mL) was added Pd / C (85 mg, 50% w / w). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 1.5 h, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 100 mg of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (66.19%) as a brown oil. LRMS (ES) m / z 240 (M+H).

[0306] Example K Synthesis of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 11.1-11.15) Preparation of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediate 11-a): [ka] LiHMDS (22.2 mL, 22.2 mmol, 1.1 equiv, 1 M in THF) was added to a stirred solution of 3-methylpyrrolidin-2-one (8.7 g, 20.2 mmol, 1 equiv) in THF (20 mL) at 0° C. After 1 h, benzyl bromide (27 g, 125 mmol, 1.25 equiv) in THF (20 mL) was added and the reaction was allowed to warm to room temperature over 12 h. The reaction was dry loaded onto silica and the product was isolated by silica chromatography (0->100% EtOAc / Hex) as a reddish solid (24.1 g, 72%). LC / MS (APCI) m / z: 235.1 [M+H]. 1 H NMR(400MHz,chloroform-d)δ 8.17(d,J=8.8Hz,2H), 7.38(d,J=8.4Hz,2H), 4.61-4.43(m,2H), 3.21(dd,J=8.2,5.4Hz,2H), 2.55(t,J=8.1Hz,1H), 2.33-2.19(m,1H), 1.64(dq,J=12.2,8.6Hz,1H), 1.23(d,J=7.1Hz,3H).

[0307] Intermediates 11.2-11.15 were prepared in a similar manner to Intermediate 11.1. [Table 8-1] [Table 8-2] [Table 8-3]

[0308] Example L 5-Methyl-1-(4-nitrobenzyl)pyrrolidin-2-one Synthesis of (Intermediate 12.1-12.2) Preparation of 5-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediate 12): [ka] Sodium triacetoxyborohydride (11 g, 53 mmol, 2 equiv.) was added to a stirred solution of (4-nitrophenyl)methanamine hydrochloride (5 g, 26.5 mmol, 1 equiv.), ethyl 4-oxopentanoate (4.2 g, 29.2 mmol, 1.1 equiv.), and triethylamine (3.6 mL, 26.5 mmol, 1 equiv.) in DCM (200 mL) at room temperature. After 14 h, the reaction was dry loaded onto silica and the product was isolated by silica chromatography as a white solid (5 g, 81%). LC / MS (APCI) m / z: 235.1 [M+H]. 1 H NMR (400MHz, Kururform-d)δ 8.20(d,J=8.3Hz,2H), 7.43(d,J=8.3Hz,2H), 4.90(d,J=15.6Hz,1H), 4.25(d,J=15.6Hz,1H), 3.58(h,J=6.3Hz,1H), 2.50(dt d,J=34.1,17.1,9.5Hz,2H), 2.23(ddd,J=13.3,11.0,6.8Hz,1H), 1.67(ddt,J=13.2,9.3,6.8Hz,1H), 1.18(d,J=6.2Hz,3H).

[0309] Intermediate 12.2 was prepared in a similar manner as Intermediate 12.1. [Table 9]

[0310] Example M Synthesis of 1-(4-aminobenzyl)-3-methylpyrrolidone-2-one (Intermediate 13.1-13.X) Preparation of 1-(4-aminobenzyl)-3-methylpyrrolidone-2-one (Intermediate 13.1): [ka] 3-Methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (3 g, 12.8 mmol, 1 equiv.) and PtO 2 (0.29 g, 1.28 mmol, 0.1 equiv.) 2(80 psi) for 1 h. The reaction was filtered through a pad of Celite, the solvent was removed by rotary evaporation, and dried under high vacuum to give the product as a reddish solid (2.6 g, 99%). LC / MS (APCI) m / z: 205.2 [M+H].

[0311] Intermediates 13.2-13.36 were prepared in a similar manner to Intermediate 13.1. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7]

[0312] Example N Synthesis of 4-methyl-1-(4-nitrobenzyl)piperazin-2-one (Intermediates 14.1-14.6) Step 1: Preparation of 1-(4-nitrobenzyl)piperazin-2-one hydrochloride (intermediate 14-a): [ka] tert-Butyl 4-(4-nitrobenzyl)-3-oxopiperazine-1-carboxylate (Intermediate 11.2, 24.1 g, 71.9 mmol, 1 equiv.) was suspended in 4 M HCl in dioxane (180 mL, 719 mmol, 10 equiv.) at room temperature. After 2 h, the solvent was removed by rotary evaporation and dried under high vacuum to give the desired product as a white solid (19.5 g, 99.9%). LCMS-APCI (POS.) m / z: 236.1 (M+H). + .

[0313] Step 2: Preparation of 4-methyl-1-(4-nitrobenzyl)piperazin-2-one (Intermediate 14.1): [ka] Formaldehyde (17.47 g, 215.3 mmol, 3 equiv., 37% in water) and AcOH (12.9 mL, 215.3 mmol, 3 equiv.) were added to a stirred suspension of 1-(4-nitrobenzyl)piperazin-2-one hydrochloride (19.5 g, 71.8 mmol, 1 equiv.) in MeOH (800 mL) at room temperature. After 10 min the reaction became homogenous, followed by addition of NaCNBH 3 (9.9 g, 157.9 mmol, 2.2 equiv.) was added and the reaction was allowed to warm to room temperature. After 3 h, the total volume was reduced to approximately 400 mL by rotary evaporation, quenched with saturated sodium bicarbonate (1 L), extracted with DCM (3x750 mL), the organics were combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The oily yellow product was then crystallized overnight under high vacuum to give the product as pale yellow crystals (17 g, 95%). LCMS-APCI (POS.) m / z: 250.1 (M+H) + . 1 H NMR (400MHz, chloroform-d) δ 8.11(d,J=8.7Hz,2H), 7.35(d,J=8.7Hz,2H), 4.62(s,2H), 3.25-3.18(m,2H), 3.14(s,2H), 2.63-2.53(m,2H), 2.28(s,3H).

[0314] Intermediates 14.2-14.6 were prepared in a similar manner to Intermediate 14.1. [Table 11]

[0315] Example O Synthesis of 4-((azetidin-1-ylsulfonyl)methyl)anilines (Intermediates 15.1-15.4) Step 1: Preparation of 1-((4-nitrobenzyl)sulfonyl)azetidine (intermediate 15-a): [ka] (4-Nitrophenyl)methanesulfonyl chloride (500 mg, 2.12 mmol, 1 equiv) was added to a stirred solution of azetidine (121 mg, 2.12 mmol, 1 equiv) and diisoproylethylamine (1.1 mL, 6.4 mmol, 3 equiv) in DCM (5 mL) at room temperature. After 1 h, the reaction was washed with saturated sodium bicarbonate (5 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The crude material was separated by silica chromatography (0->3% MeOH / DCM) to give 1-((4-nitrobenzyl)sulfonyl)azetidine (110 mg, 20%). LCMS-APCI (negative) m / z: 255.2 (MH). - . 1 H NMR (400MHz, DMSO-d 6 )δ 8.27(d,J=8.8Hz,1H), 7.72(d,J=8.8Hz,1H), 4.73(s,1H), 3.89(t,J=7.7Hz,2H), 2.19(p,J=7.7Hz,1H).

[0316] Step 2: Preparation of 4-((azetidin-1-ylsulfonyl)methyl)aniline (Intermediate 15.1): [ka] 1-((4-Nitrobenzyl)sulfonyl)azetidine (110 mg, 0.43 mmol, 1 equiv) and PtO2 (5 mg, 0.022 mmol, 0.05 equiv) were suspended in MeOH (5 mL) and then stirred under H2 for 12 h. The reaction was filtered through a 0.45 μm PTFE syringe filter and the solvent was removed by rotary evaporation to give the product (90 mg, 93%). LCMS-APCI (POS.) m / z: 227.2 (M+H). + .

[0317] Intermediates 15.2-15.4 were prepared in a similar manner as Intermediate 15.1. [Table 12]

[0318] Example P Synthesis of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (Intermediate 16) Step 1: Preparation of phenyl(4-chlorobenzyl)carbamate (intermediate 16-a): [ka] 1-(4-chlorophenyl)methanamine (10.00 g, 70.621 mmol, 1 equiv.) and NEt 3 To a stirred solution of (10.72 g, 105.9 mmol, 1.5 equiv) in THF (100 mL) at 0° C., phenyl chloroformate (12.16 g, 77.6 mmol, 1.1 equiv) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 3 h, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give 17.76 g (91.38%) of phenyl (4-chlorobenzyl)carbamate as a pink solid. LCMS-APCI (POS.) m / z: 362 (M+H). + .

[0319] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (Intermediate 16-b): [ka] To a stirred solution of phenyl(4-chlorobenzyl)carbamate (7.80 g, 29.8 mmol, 1.2 equiv.) and 4-aminobenzaldehyde (3.00 g, 24.8 mmol, 1 equiv.) in i-PrOH (30.00 mL) was added diisopropylethylamine (16.00 g, 123.8 mmol, 5 equiv.). The resulting mixture was stirred at 90° C. overnight, cooled to room temperature, water (100 mL) was added, and extracted twice with EtOAc (100 mL). The combined organic layers were washed twice with brine (100 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C., concentrating under reduced pressure and purifying by silica gel column chromatography eluting with PE / EtOAc (2:1) gave 2.04 g (27%) of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea as a yellow solid. LCMS-APCI (POS.) m / z: 289 (M+H). + .

[0320] Step 3: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16-c): [ka] To a stirred solution of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (2 g, 6.9 mmol, 1 equiv) in EtOH (40 mL) at 0 °C was added NaBH 4 (390 mg, 10.4 mmol, 1.5 equiv)) was added. The resulting mixture was stirred at room temperature for 2 h, quenched by addition of water (50 mL) at 0° C., and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with water (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2.08 g of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea as a yellow solid. LCMS-APCI (POS.) m / z: 291 (M+H). + .

[0321] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16): [ka] To a stirred solution of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (2 g, 6.9 mmol, 1 equiv) in DCM (20 mL) at 0 °C was added SOC1 2 (1.65 g, 13.9 mmol, 2 equiv.) was added. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 2.2 g of 1-[4-(chloromethyl)phenyl]-3-[(4-chlorophenyl)methyl]urea as a brown solid. LCMS-APCI(POS.) m / z: 309(M+H). + .

[0322] Example Q Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (Intermediates 17.1-17.6) [ka] To a stirred mixture of 3-[(4-chlorophenyl)methyl]-1-(4-formylphenyl)urea (Intermediate 3.2, 300.00 mg, 1.039 mmol, 1.00 equiv.) and 3-aminotetrahydrothiophene 1,1-dioxide (168.55 mg, 1.247 mmol, 1.2 equiv.) in DCE (10 mL) was added STAB (440.43 mg, 2.078 mmol, 2 equiv.) at 0° C. The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, and purified by C18 column chromatography eluting with water (0.05% NH4HCO3):ACN (2:1) to give 240 mg of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidetetrahydrothiophen-3-yl)amino)methyl)phenyl)urea (56.63%) as a white solid. LCMS-APCI(POS.) m / z: 408(M+H) + .

[0323] Intermediates 17.2-17.6 were prepared in a similar manner to Intermediate 17.1. [Table 13-1] [Table 13-2]

[0324] Example R Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (Intermediates 18.1-18.2) [ka] To a stirred mixture of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (120.00 mg, 0.294 mmol, 1.00 equiv) and formaldehyde (53.00 mg, 1.765 mmol, 6 equiv) in DCE (4.00 mL) at 0 °C was added STAB (124.70 mg, 0.588 mmol, 2 equiv) and AcOH (35.33 mg, 0.588 mmol, 2 equiv). After stirring at room temperature for 2 h, the above mixture was added with additional formaldehyde (53.00 mg, 1.765 mmol, 6 equiv) and STAB (124.70 mg, 0.588 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight and then diluted with NH 3 H 2 The pH was adjusted to 10 with 2 mL of O and extracted twice with DCM (10 mL). The combined organic layers were washed twice with water (10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by Prep-HPLC under the following conditions (column: XBridge Prep OBD C 18Column, 30*150mm 5um; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 26B to 56B in 9 min; 254nm; Obtained 50mg of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (40.28%) as a white solid. LCMS-APCI(POS.)m / z: 422(M+H) + .

[0325] Intermediate 18.2 was prepared in a similar manner to Intermediate 18.1. [Table 14]

[0326] Example S Synthesis of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19) Step 1: Preparation of 2-amino-1-(4-nitrophenyl)ethan-1-one hydrochloride (intermediate 19-a): [ka] To a solution of 2-amino-1-(4-bromophenyl)ethanone (100.00 g, 467.154 mmol, 1.00 equiv) in DCM (1.20 L) was added hexamethylenetetramine (85.00 g, 607.143 mmol, 1.30 equiv). The resulting mixture was stirred at room temperature for 2 h. The precipitated solid was collected by filtration and diluted with CH 2 Cl 2 (500 mL). To the residue was added HCl (200.00 mL, 6 mol / L) and EtOH (1.00 L). The resulting mixture was stirred at room temperature for 3 h and allowed to stand overnight. The precipitated solid was collected by filtration, washed with hexanes (500 mL) and concentrated under vacuum to give 140 g of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (crude) as a pale yellow solid. LCMS-APCI (POS.) m / z: 181 (M+H) + .

[0327] Step 2: Preparation of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19): [ka] To a solution of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (140.00 g, 646.293 mmol, 1.00 equiv) in DCM (1.60 L) was added H 2 K in O (700.00 mL) 2 CO 3 (179.00 g, 1295.173 mmol, 2.00 equiv.) and di-tert-butyl dicarbonate (169.00 g, 774.345 mmol, 1.20 equiv.) were added. The resulting mixture was stirred at room temperature for 3 h and then cooled to 5° C. 2 Cl 2 (1 L) twice. The combined organic layers were washed twice with brine (1 L) and anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 176 g of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (crude product) as a brown oil. LCMS-APCI (POS.) m / z: 225 (M+H-56). + .

[0328] Example T Synthesis of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20) Step 1: Preparation of methyl (2-((tert-butoxycarbonyl)amino)-1-(4-nitrophenyl)ethyl)glycinate (Intermediate 20-a): [ka] A solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (14.00 g, 49.950 mmol, 1.00 equiv.) and methyl 2-aminoacetate hydrochloride (12.61 g, 100.400 mmol, 2.01 equiv.) in MeOH (200.00 mL) was stirred at room temperature for 30 min. Then, the above mixture obtained at 0° C. was added with NaBH 3 CN (6.22 g, 98.901 mmol, 1.98 equiv) was added. The resulting mixture was stirred at 70 °C overnight, cooled to room temperature, adjusted to pH 8 with saturated NH4.H2O (aq), and extracted twice with EtOAc (200 mL). The combined organic layers were washed twice with water (200 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 17 g (crude) of methyl 2-([2-[(tert-butoxycarbonyl)amino]-1-(4-nitrophenyl)ethyl]amino)acetate as a brown oil. LCMS-APCI(POS.) m / z: 354(M+H) + .

[0329] Step 2: Preparation of 2-((2-methoxy-2-oxoethyl)amino)-2-(4-nitrophenyl)ethane-1-aminium 2,2,2-trifluoroacetate (Intermediate 20-b): [ka] To a stirred solution of methyl 2-([2-[(tert-butoxycarbonyl)amino]-1-(4-nitrophenyl)ethyl]amino)acetate (17.00 g, 48.108 mmol, 1.00 equiv) in DCM (200.00 mL) was added TFA (40.00 mL, 188.483 mmol, 20.18 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give 7 g (crude) of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate TFA salt as a brown oil. LCMS-APCI (POS.) m / z: 254 (M+H) + .

[0330] Step 3: Preparation of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20): [ka] NH in MeOH (70.00 mL) 3 A solution of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate TFA salt (7.0 g, 27.640 mmol, 1.00 equiv) in (g) was stirred at 70° C. for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by trituration with EtOAc (100 mL). The precipitated solid was collected by filtration, washed twice with EtOAc (100 mL), and concentrated under reduced pressure to give 2 g (32.71%) of 5-(4-nitrophenyl)piperazin-2-one as a brown solid. LCMS-APCI (POS.) m / z: 222 (M+H) + .

[0331] Example U Synthesis of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21) Step 1: Preparation of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21-a): [ka] To a stirred solution of 5-(4-nitrophenyl)piperazin-2-one (500.00 mg, 2.260 mmol, 1.00 equiv) in DCM (10.00 mL) (Boc) 2 O (1479.87 mg, 6.781 mmol, 3 equiv.) and TEA (914.85 mg, 9.041 mmol, 4 equiv.) were added. The resulting mixture was stirred at room temperature overnight, water (10 mL) was added, and extracted twice with DCM (10 mL). The combined organic layers were washed twice with brine (10 mL) and diluted with anhydrous Na 2 SO 4Drying at 40° C., concentrating under reduced pressure, and purifying by silica gel column chromatography eluting with PE / EtOAc (3:2) afforded 380 mg (52.32%) of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate as a yellow oil. LCMS-APCI (POS.) m / z: 322 (M+H) + .

[0332] Step 2: Preparation of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 20): [ka] To a stirred solution of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (350.00 mg, 1.089 mmol, 1.00 equiv) in DMF (8.0 mL) was added CH 3 I (463.81 mg, 3.268 mmol, 3 equiv.) and Cs 2 CO 3 (1419.55 mg, 4.357 mmol, 4 equiv.) was added. The resulting mixture was stirred at room temperature for 2 h, filtered to remove solids, concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EtOAc (5:2) to give 230 mg (62.97%) of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate as a yellow oil. LCMS-APCI(POS.) m / z: 336(M+H). + .

[0333] Example V Synthesis of 4-methyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 22) Preparation of 4-methyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 22): [ka] To a stirred solution of 5-(4-nitrophenyl)piperazin-2-one (600.00 mg, 2.712 mmol, 1.00 equiv) in MeOH (10.00 mL) was added HCHO (813.68 mg, 27.120 mmol, 10.00 equiv), NaBH 3 CN (340.89 mg, 5.425 mmol, 2 equiv.) and AcOH (530.00 mg, 8.826 mmol, 3.25 equiv.) were added. The resulting mixture was stirred at room temperature for 5 h, concentrated under reduced pressure and purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give 800 mg of 4-methyl-5-(4-nitrophenyl)piperazin-2-one as a yellow solid. LCMS-APCI (POS.) m / z: 236 (M+H). + .

[0334] Example W Synthesis of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 23) Preparation of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 23): [ka] To a stirred solution of 5-(4-nitrophenyl)piperazin-2-one (500.00 mg, 2.260 mmol, 1.00 equiv) in DMF (10.00 mL) was added NaH (361.60 mg, 9.041 mmol, 4.0 equiv, 60%) at 0 °C. After stirring at 0 °C for 30 min, the resulting mixture was diluted with CH 3 I (962.45 mg, 6.781 mmol, 3.00 equiv) was added. The resulting mixture was stirred at room temperature overnight and purified by C18 column chromatography eluted with water (0.05% NH4HCO3) / ACN=(4:1) to give 390 mg (69.22%) of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one as a brown solid. LCMS-APCI(POS.) m / z: 250(M+H). + .

[0335] Example X Synthesis of 1,4-dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24) Step 1: Preparation of tert-butyl (2-amino-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 24-a): [ka] To a solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (20.00 g, 71.357 mmol, 1.00 equiv) in MeOH (400.00 mL) at 0 °C was added NH 4 OAc (14.00 g, 181.624 mmol, 2.55 equiv.) and NaBH 3 CN (110.00 g, 1750.422 mmol, 24.53 equiv.) was added. The resulting mixture was stirred at 70° C. overnight, cooled to room temperature and diluted with saturated NH 3 H 2 Adjust pH to 8 with CH 2 Cl 2 (1 L) twice. The combined organic layers were washed twice with brine (1 L) and 2 SO 4 Drying at 40° C., concentrating under reduced pressure, and purifying by silica gel column chromatography eluting with MeOH / EtOAc (1:20) gave 6.7 g of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (33.38%) as a brown oil and 2.8 g of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate as a brown solid. LCMS-APCI(POS.) m / z: 226 (M+H-56). + .

[0336] Step 2: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (intermediate 24-b): [ka] To a solution of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (4.60 g, 16.371 mmol, 1.00 equiv) in DCM (40 mL) was added HCl (gas) in 1,4-dioxane (30.00 mL). The resulting mixture was stirred at room temperature for 3 h, the pH was adjusted to 13-14 with NaOH (aq), and extracted twice with DCM:MeOH (10:1, 50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, 2.3 g of 1-(4-nitrophenyl)ethane-1,2-diamine was obtained as a pale brown solid. LCMS-APCI(POS.) m / z: 182(M+H) + .

[0337] Step 3: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (Intermediate 24-c): [ka] To a solution of 1-(4-nitrophenyl)ethane-1,2-diamine (2.60 g, 14.349 mmol, 1.00 equiv) in ACN (26.00 mL), 2 CO 3( To the resulting mixture were added EtOH (4.00 mL). After stirring at room temperature overnight, the resulting mixture was stirred at 80° C. for 3 h, cooled to room temperature, and filtered to remove solids. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give 2.2 g of 6-(4-nitrophenyl)piperazin-2-one (69.31%) as a brown solid. LCMS-APCI(POS.) m / z: 222(M+H) + .

[0338] Step 4: Preparation of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 24-d): [ka] To a solution of 6-(4-nitrophenyl)piperazin-2-one (1.00 g, 4.520 mmol, 1.00 equiv) and TEA (914.00 mg, 9.033 mmol, 2.00 equiv) in DCM (10.00 mL) was added di-tert-butyl dicarbonate (1.18 g, 5.407 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 2 h and extracted twice with DCM (20 mL). The combined organic layers were washed twice with brine (20 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 1.1 g of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (crude) as a yellow semi-solid. LCMS-APCI (POS.) m / z: 266 (M+H-56). + .

[0339] Step 5: Preparation of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 24-e): [ka] To a solution of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (1.10 g, 3.423 mmol, 1.00 equiv) in DMF (25.00 mL) was added Cs 2 CO 3 (2.20 g, 6.752 mmol, 1.97 equiv) and methyl iodide (534.48 mg, 3.766 mmol, 1.10 equiv) were added. The resulting mixture was stirred at room temperature for 2 h and extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EtOAc (1:4) to give 530 mg of tert-butyl-4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (46.17%) as a yellow semi-solid. LCMS-APCI (POS.) m / z: 300 (M+H-56). + .

[0340] Step 6: Preparation of 1-methyl-6-(4-nitrophenyl)piperazin-2-one hydrochloride (intermediate 24-f): [ka] To a solution of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (530.00 mg, 1.580 mmol, 1.00 equiv) in DCM (8.00 mL) was added HCl (gas) in 1,4-dioxane (2.00 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 550 mg (crude) of 1-methyl-6-(4-nitrophenyl)piperazin-2-one hydrochloride as an orange semi-solid. LCMS-APCI (POS.) m / z: 236 (M+H). + .

[0341] Step 7: 1,4-Dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24): [ka] To a solution of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (530.00 mg, 1.580 mmol, 1.00 equiv) in DCM (8.00 mL) was added HCl (gas) in 1,4-dioxane (2.00 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 550 mg (crude) of 1-methyl-6-(4-nitrophenyl)piperazin-2-one hydrochloride as an orange semi-solid. LCMS-APCI (POS.) m / z: 250 (M+H). +.

[0342] Example Y Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one (Intermediate 25.1-25.2) Preparation of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one (Intermediate 25.1): [ka] To a solution of 2-fluoro-4-nitrobenzaldehyde (200.00 mg, 1.183 mmol, 1.00 equiv) in MeOH (5.00 mL) was added 1-methylpiperazin-2-one (202.00 mg, 1.770 mmol, 1.50 equiv). After stirring at room temperature for 30 min, the mixture was treated with AcOH (142.00 mg, 2.365 mmol, 2.00 equiv) and NaBH 3 CN (151.00 mg, 2.403 mmol, 2.03 equiv) was added. The resulting mixture was stirred at room temperature overnight and then diluted with NH 3 .H 2 The mixture was adjusted to pH 8 with 2H2O, concentrated in vacuo, and purified by C18 column chromatography and diluted with water (0.05% NH 4 HCO 3 ) / ACN (2:1) to give 80 mg of 4-[(2-fluoro-4-nitrophenyl)methyl]-1-methylpiperazin-2-one (25.31%) as a yellow oil. LCMS-APCI (POS.) m / z: 268 (M+H) + .

[0343] Intermediate 25.2 was prepared in the same manner as Intermediate 25.1. [Table 15]

[0344] Example Z Synthesis of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazin-2-one (Intermediate 26) Step 1: Preparation of tert-butyl methyl (2-((1-(4-nitrophenyl)ethyl)amino)ethyl)carbamate (Intermediate 26-a): [ka] A stirred solution of PNAP (2.27 g, 13.774 mmol, 1.2 equiv.) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.00 g, 11.478 mmol, 1.00 equiv.) in MeOH (30 mL) was added to NaBH 3 CN (1.44 g, 22.956 mmol, 2 equiv.) and AcOH (1.38 g, 22.956 mmol, 2 equiv.) were added. The resulting mixture was stirred at room temperature overnight and saturated NH 4 .H 2 The pH was adjusted to 8 with 2H2O (aq) and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with water (50 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C., concentrating under reduced pressure, and purifying by silica gel column chromatography using PE / EtOAc (2:3) gave 2.8 g (75.43%) of tert-butyl N-methyl-N-(2-[[1-(4-nitrophenyl)ethyl]amino]ethyl)carbamate as a pale yellow oil. LCMS-APCI(POS.) m / z: 268 (M+H-56). + .

[0345] Step 2: Preparation of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)acetamido)ethyl)(methyl)carbamate (Intermediate 24-b): [ka] To a stirred solution of PNAP (2.27 g, 13.774 mmol, 1.2 equiv.) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.00 g, 11.478 mmol, 1.00 equiv.) in MeOH (30 mL) at 0 °C was added NaBH 3CN (1.44 g, 22.956 mmol, 2 equiv.) and AcOH (1.38 g, 22.956 mmol, 2 equiv.) were added. The resulting mixture was stirred at room temperature overnight and saturated NH 4 .H 2 The mixture was adjusted to pH 8 with 0 (aq) and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with water (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluted with PE / EtOAc (2:3) to give 2.8 g (75.43%) of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)acetamido)ethyl)(methyl)carbamate as a pale yellow oil. LCMS-APCI (POS.) m / z: 400 (M+H). + .

[0346] Step 3: Preparation of 2-chloro-N-(2-(methylamino)ethyl)-N-(1-(4-nitrophenyl)ethyl)acetamide hydrochloride (Intermediate 26-c): [ka] To a stirred solution of tert-butyl N-(2-[2-chloro-N-[1-(4-nitrophenyl)ethyl]acetamido]ethyl)-N-methylcarbamate (3.00 g, 7.502 mmol, 1.00 equiv) in DCM (30.00 mL) was added HCl (gas) in 1,4-dioxane (30.00 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give 3.1 g of 2-chloro-N-[2-(methylamino)ethyl]-N-[1-(4-nitrophenyl)ethyl]acetamide hydrochloride as a pale yellow solid. LCMS-APCI(POS.) m / z: 300 (M+H) + .

[0347] Step 4: Preparation of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazin-2-one (Intermediate 26): [ka] To a stirred solution of 2-chloro-N-[2-(methylamino)ethyl]-N-[1-(4-nitrophenyl)ethyl]acetamide hydrochloride (3.10 g, 10.342 mmol, 1.00 equiv) in ACN (50.00 mL) was added K 2 CO 3 (7.15 g, 51.735 mmol, 5.00 equiv.) was added. The resulting mixture was stirred at 80° C. for 1 h, cooled to room temperature, and filtered to remove solids. The filtrate was concentrated under reduced pressure to give 1.69 g of 4-methyl-1-[1-(4-nitrophenyl)ethyl]piperazin-2-one as a yellow oil. LCMS-APCI (POS.) m / z: 264 (M+H). + .

[0348] Example AA Synthesis of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)urea (Intermediates 27.1-27.4) Step 1: Preparation of phenyl(4-formylphenyl)carbamate (intermediate 27-a): [ka] To a stirred solution of 4-aminobenzaldehyde (2.00 g, 16.510 mmol, 1.00 equiv) in THF (40.00 mL) at 0 °C was added K 2 CO 3 (4.56 g, 32.994 mmol, 2.00 equiv.) and phenyl chloroformate (3.87 g, 24.717 mmol, 1.50 equiv.) were added dropwise over 10 min. The resulting mixture was stirred at room temperature for 1 h and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL), dried over anhydrous MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1.9 g of phenyl N-(4-formylphenyl)carbamate (84.41%) as a yellow color. LCMS-APCI(POS.) m / z: 242(M+H) + .

[0349] Step 2: Preparation of phenyl(4-(((2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (Intermediate 27-b): [ka] To a stirred solution of phenyl N-(4-formylphenyl)carbamate (600.00 mg, 2.487 mmol, 1.00 equiv) in DCE (10.00 mL) was added 3-aminopyrrolidin-2-one (508.00 mg, 5.074 mmol, 2.04 equiv), STAB (1056.00 mg, 4.983 mmol, 2.00 equiv) and AcOH (299.00 mg, 4.979 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature overnight and extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography to give CH. 2 Cl 2 / MeOH (12:1) to give 415 mg of phenyl N-(4-[[(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)carbamate (46.87%) as an off-white foam. LCMS-APCI (POS.) m / z: 326 (M+H). + .

[0350] Step 3: Preparation of phenyl(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (Intermediate 27-c): [ka] To a stirred solution of phenyl N-(4-[[(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)carbamate (400.00 mg, 1.229 mmol, 1.00 equiv) in MeOH (8.00 mL, 197.591 mmol, 160.72 equiv) was added paraformaldehyde (369.00 mg, 4.096 mmol, 3.33 equiv) and NaBH 3CN (155.00 mg, 2.467 mmol, 2.01 equiv) was added. The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure and purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give 380 mg of phenyl(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (79.65%) as an off-white solid. LCMS-APCI(POS.) m / z: 340(M+H). + .

[0351] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)urea (Intermediate 27): [ka] To a stirred solution of phenyl N-(4-[[methyl(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)carbamate (100.00 mg, 0.295 mmol, 1.00 equiv) in THF (2.00 mL, 24.686 mmol, 83.78 equiv) was added TEA (149.00 mg, 1.472 mmol, 5.00 equiv) and 1-(4-chlorophenyl)methanamine (62.40 mg, 0.441 mmol, 1.50 equiv). The resulting mixture was stirred at 60° C. overnight, concentrated under reduced pressure, and purified by preparative HPLC (2#SHIMADZU (HPLC-01)) with the following conditions: column, XBridge Prep OBD C 18 Column, 30*150mm 5um; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3.H2O) and Mobile phase B: ACN (from 25% phase B up to 55% in 8 min); Detector, uv254nm. Obtained 60mg of 3-[(4-chlorophenyl)methyl]-1-(4-[[methyl(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)urea (52.64%) as a white solid. LCMS-APCI(POS.) m / z: 387(M+H)+.

[0352] Intermediates 27.2-27.4 were prepared in a similar manner to Intermediate 27.1. [Table 16]

[0353] Example BB Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 28) Step 1: Preparation of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 28-a): [ka] A solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (5.00 g, 17.839 mmol, 1.00 equiv) in EtOH (100.00 mL) was added to NaBH 4 (1.02 g, 26.961 mmol, 1.51 equiv) was added. The resulting mixture was stirred at room temperature under nitrogen for 1 h, concentrated under reduced pressure, and extracted a third time with EtOAc (50 mL). The combined organic layers were washed a third time with brine (50 mL) and anhydrous Na 2 SO 4 It was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EtOAc (4:1) to give 1.2 g of tert-butyl N-[2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate as a yellow solid. LCMS-APCI(POS.) m / z: 227 (M+H-56). + .

[0354] Step 2: Preparation of 2-amino-1-(4-nitrophenyl)ethan-1-ol hydrochloride (intermediate 28-b): [ka] To a solution of tert-butyl N-[2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (2.10 g, 7.439 mmol, 1.0 equiv) in DCM (22.0 mL) was added HCl (gas) in 1,4-dioxane (5.50 mL, 96.346 mmol, 12.95 equiv). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere and concentrated under reduced pressure to give 1.9 g of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride as an orange solid. LCMS-APCI (POS.) m / z: 183 (M+H). + .

[0355] Step 3: Preparation of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 28): [ka] To a solution of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride (800.00 mg, 3.659 mmol, 1.00 equiv) and TEA (1.59 g, 15.713 mmol, 4.29 equiv) in THF (10.00 mL) at 0° C. was added triphosgene (309.00 mg, 1.041 mmol, 0.28 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h, quenched with MeOH (30 mL) at 0° C., and concentrated under reduced pressure to give 700 mg of 5-(4-nitrophenyl)-1,3-oxazolidin-2-one as a red solid. LCMS-APCI (POS.) m / z: 209 (M+H). + .

[0356] Example CC 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one Synthesis of (Intermediate 29) Preparation of 3-methyl-5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 29): [ka] To a stirred solution of 5-(4-nitrophenyl)-1,3-oxazolidin-2-one (980.00 mg, 4.708 mmol, 1.00 equiv) in DMF (20.00 mL) was added Cs 2 CO 3 (6.13 g, 18.814 mmol, 4.00 equiv.) and CH 3 I (736.00 mg, 5.185 mmol, 1.10 equiv) was added. The resulting mixture was stirred at room temperature for 4 h and extracted a third time with EtOAc (50 mL). The combined organic layers were washed a third time with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluted with PE / EtOAc (3:2) to give 330 mg of 3-methyl-5-(4-nitrophenyl)-1,3-oxazolidin-2-one as a yellow solid. LCMS-APCI (POS.) m / z: 223 (M+H). + .

[0357] Example DD Synthesis of 5-(4-nitrophenyl)oxazolidin-2-ones (intermediates 30.1-30.2) Step 1: Preparation of methyl 4-oxo-4-(pyridin-3-yl)butanoate (Intermediate 30-a): [ka] To a solution of 3-pyridinecarboxaldehyde (5.00 g, 46.7 mmol, 1.00 equiv) and methyl chloride (4.80 g, 56.0 mmol, 1.20 equiv) in EtOH (50 mL) was added Et 3 N (9.40 g, 93 mmol, 2.00 equiv.) and 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride (1.26 g, 4.67 mmol, 0.10 equiv.) were added under nitrogen atmosphere. The resulting mixture was stirred at 50° C. overnight under nitrogen atmosphere, cooled to room temperature, concentrated under reduced pressure, and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4Drying at 40° C., concentrating under reduced pressure, and purifying by silica gel column chromatography eluting with PE / EtOAc (4:1) gave 2.19 g of methyl 4-oxo-4-(pyridin-3-yl)butanoate as a yellow solid. LCMS-APCI (POS.) m / z: 194 (M+H) + .

[0358] Step 2: Preparation of 1-(4-nitrobenzyl)-5-(pyridin-3-yl)pyrrolidin-2-one (Intermediate 30.1): [ka] To a solution of methyl 4-oxo-4-(pyridin-3-yl)butanoate (1.72 g, 8.9 mmol, 1.00 equiv) and p-nitrobenzylamine (2.00 g, 10.688 mmol, 1.20 equiv) in MeOH (20.00 mL) at 0 °C was added NaBH 3 CN (2.80 g, 17.8 mmol, 2.0 equiv) and AcOH (2.67 g, 17.8 mmol, 2.00 equiv) were added. The resulting mixture was stirred at 70° C. for 2 days, cooled to room temperature, concentrated under reduced pressure, and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C., concentrating under reduced pressure, and purifying by silica gel column chromatography eluting with EtOAc gave 1 g of 1-[(4-nitrophenyl)methyl]-5-(pyridin-3-yl)pyrrolidin-2-one as a pale yellow oil. LCMS-APCI(POS.) m / z: 298(M+H) + .

[0359] Intermediate 30.2 was prepared in a similar manner to Intermediate 30.1. [Table 17]

[0360] Example EE Synthesis of 1-(1-(4-nitrophenyl)ethyl)piperidin-2-one (Intermediate 31) [ka] To a stirred mixture of methyl 5-aminopentanoate hydrochloride (1.00 g, 0.60 mmol, 1.00 equiv.) and PNAP (1.300 g, 0.79 mmol, 1.32 equiv.) in DCE (10.00 mL) was added STAB (2.500 g, 1.18 mmol, 1.98 equiv.) and AcOH (700 mg, 1.17 mmol, 1.95 equiv.). The resulting mixture was stirred at room temperature for 2 days and saturated NaHCO 3 The pH was adjusted to 8 with (aqueous) and extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (1:8) to give 1 g of 1-[1-(4-nitrophenyl)ethyl]piperidin-2-one (67.52%) as a yellow solid. LCMS-APCI (POS.) m / z: 249 (M+H). + .

[0361] Example FF Synthesis of 1-(4-(1,1-dioxidothiomorpholin-3-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 32) Step 1: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)thio)ethyl)carbamate (Intermediate 32-a): [ka] To a stirred solution of 2-bromo-1-(4-nitrophenyl)ethanone (8.00 g, 32.781 mmol, 1.00 equiv.) and DIEA (8.47 g, 65.562 mmol, 2.00 equiv.) in ACN (80.00 mL) at 0° C. was added NaI (1.47 g, 9.834 mmol, 0.30 equiv.) and 2-bromo-1-(4-nitrophenyl)ethanone (8.00 g, 32.781 mmol, 1.00 equiv.). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was determined by LCMS. Water (200 mL) was added and the mixture was adjusted to pH 7 with HCl (aq.) and extracted three times with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 8.9 g of tert-butyl N-(2-[[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl]ethyl)carbamate (79.76%) as a yellow solid. LCMS-APCI(POS.) m / z: 285 (M+H-56). + .

[0362] Step 2: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-b): [ka] To a stirred mixture of tert-butyl N-(2-{[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl}ethyl)carbamate (8.9 g, 26.092 mmol / L 1 eq.) in DCM (100 mL) was added m-CPBA (22.586 g, 130.419 mmol / L, 5 eq.). The resulting mixture was stirred at room temperature overnight, water (100 mL) was added, and extracted three times with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EA (4:1) to give 7 g of tert-butyl N-{2-[2-(4-nitrophenyl)-2-oxoethanesulfonyl]ethyl}carbamate as a pale yellow solid. LCMS-APCI(POS.) m / z: 317 (M+H-56). + .

[0363] Step 3: Preparation of tert-butyl (2-((2-(4-aminophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-c): [ka] To a stirred mixture of tert-butyl N-{2-[2-(4-nitrophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (7 g, 18.761 mmol / L, 1 equiv.) in EtOH (80 mL) was added iron (4.2 g, 75.061 mmol / L, 4 equiv.) and NH 4 Cl (6.9 g, 131.327 mmol / L, 7 equiv.) 2 A solution of 2,4-dimethylformamide (DMSO) was added to the mixture. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain CH 2 Cl 2 / MeOH (50:1) to give 5.3 g of tert-butyl N-{2-[2-(4-aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (77.69%) as a pale yellow solid. LCMS-APCI (POS.) m / z: 287 (M+H-56). + .

[0364] Step 4: Preparation of tert-butyl (2-((2-oxo-2-(4-((phenoxycarbonyl)amino)phenyl)ethyl)sulfonyl)ethyl)carbamate (Intermediate 32-d): [ka] To a solution of tert-butyl N-{2-[2-(4-aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (3 g, 8.761 mmol, 1.00 equiv) in THF (30 mL) at 0° C. was added phenyl chloroformate (2.05 g, 13.093 mmol, 1.49 equiv) dropwise over 10 min. The resulting mixture was stirred at room temperature for 2 h, then gradually warmed to 80° C., stirred at 80° C. overnight, cooled to room temperature, concentrated under reduced pressure, purified by trituration with hexanes:EA=10:1 (30 mL), and concentrated under reduced pressure to give 3.7 g of phenyl N-[4-(2-{2-[(tert-butoxycarbonyl)amino]ethanesulfonyl}acetyl)phenyl]carbamate (91.31%) as a brown solid. LCMS-APCI(POS.)m / z:407(M+H-56) + .

[0365] Step 5: Preparation of tert-butyl (2-((2-(4-(3-(4-methoxybenzyl)ureido)phenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-e): [ka] To a solution of phenyl N-[4-(2-{2-[(tert-butoxycarbonyl)amino]ethanesulfonyl}acetyl)phenyl]carbamate (1.1 g, 2.378 mmol, 1.00 equiv.) in i-PrOH (11 mL) was added 4-methoxy-benzylmethanamine (0.4 g, 2.916 mmol, 1.23 equiv.) and DIEA (0.9 g, 6.964 mmol, 2.93 equiv.). The resulting mixture was stirred at 80° C. for 4 h, cooled to room temperature, and purified by trituration with PE:EA=8:1 (15 mL) and concentrated under reduced pressure to give 1.38 g of tert-butyl N-(2-{2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-2-oxoethanesulfonyl}ethyl)carbamate (crude) as a brown solid. LCMS-APCI(POS.)m / z:450(M+H-56) + .

[0366] Step 6: Preparation of 1-(4-(1,1-dioxidothiomorpholin-3-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 32): [ka] To a solution of tert-butyl N-(2-{2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-2-oxoethanesulfonyl}ethyl)carbamate (1.28 g, 2.532 mmol, 1.00 equiv) in DCM (12 mL) was added HCl (gas) in 1,4-dioxane (3 mL, 4 mol / L). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure and diluted with NaBH 3 CN (0.32 g, 5.092 mmol, 2.01 equiv) and MeOH (12 mL) were added. The above resulting mixture was stirred at room temperature for 2 h, water (30 mL) was added, and extracted three times with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 ml) and diluted with anhydrous Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, 1.1 g (crude) of 1-[4-(1,1-dioxo-1lambda 6-thiomorpholin-3-yl)phenyl]-3-[(4-methoxyphenyl)methyl]urea was obtained as a brown solid. The crude product (500 mg) was purified by preparative HPLC under the following conditions: (2#SHIMADZU(HPLC-01)): Column, YMC-Actus Triart C 18 ExRS, 30*150 mm, 5μm; mobile phase, water (10mmol / L NH4HCO3+0.1%NH3.H2O) and ACN (15% ACN to 45% in 10 min); detector, UV 254nm, 210nm gave 230mg of 1-[4-(1,1-dioxo-1lambda 6-thiomorpholin-3-yl)phenyl]-3-[(4-methoxyphenyl)methyl]urea as a white solid. LCMS-APCI(POS.)m / z:390(M+H) + .

[0367] Example GG Synthesis of 1-(4-(1,1-dioxidothiomorpholin-2-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 33) Step 1: Preparation of methyl 2-bromo-2-(4-nitrophenyl)acetate (intermediate 33-a): [ka] CCl 4 To a stirred solution of methyl 2-(4-nitrophenyl)acetate (5 g, 25.618 mmol, 1.00 equiv.) and AIBN (0.21 g, 1.281 mmol, 0.05 equiv.) in (50 mL) was added NBS (6.84 g, 38.427 mmol, 1.5 equiv.). The resulting mixture was stirred at 80° C. overnight, cooled to room temperature, added water (100 mL), and extracted twice with CHCl (50 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and purified by HPLC. 18 Purification by column chromatography eluting with water (0.05%, NH4HCO3) / ACN (1:1) gave 4.1 g (58.39%) of methyl 2-bromo-2-(4-nitrophenyl)acetate as a yellow oil. LCMS-APCI (POS.) m / z: 274 (M+H). + . 1 H NMR (300MHz, DMSO-d 6 )δ 8.34-8.19(m,2H), 7.89-7.78(m,2H), 6.17(s,1H), 3.76(s,3H).

[0368] Step 2: Preparation of 2-(4-nitrophenyl)thiomorpholin-3-one (intermediate 33-b): [ka] To a stirred solution of methyl 2-bromo-2-(4-nitrophenyl)acetate (3 g, 10.946 mmol, 1.00 equiv) in EtOH (30 mL) was added cysteamine hydrochloride (1.37 g, 12.041 mmol, 1.1 equiv) and K 2 CO 3(3.33 g, 24.081 mmol, 2.2 equiv) was added. The resulting mixture was stirred at room temperature overnight, water (50 mL) was added and extracted twice with EA (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluted with PE / EA (1:9) to give 1.4 g 53.68% of 2-(4-nitrophenyl)thiomorpholin-3-one as a yellow solid. LCMS-APCI (POS.) m / z: 239 (M+H) + .

[0369] Step 3: Preparation of 2-(4-nitrophenyl)thiomorpholine (Intermediate 33-c): [ka] To a stirred solution of 2-(4-nitrophenyl)thiomorpholin-3-one (1.4 g, 5.876 mmol, 1.00 equiv) in THF (15 mL) was added BH 3 -Me 2 S (2.94 mL, 29.380 mmol, 5 equiv, 2 mol / L) was added. The resulting mixture was stirred at 60° C. for 1 h, concentrated under reduced pressure, and the residue was added with HCl (15 mL, 4N) and stirred at 60° C. for an additional 30 min. The mixture was diluted with saturated NaHCO 3 (aqueous solution), adjust the pH to 8, concentrate under reduced pressure, and 18 The mixture was purified by column chromatography and diluted with water (0.05% NH 4 HCO 3 ) / ACN (2:1) to give 590 mg (44.77%) of 2-(4-nitrophenyl)thiomorpholine as a red oil. LCMS-APCI (POS.) m / z: 225 (M+H) + .

[0370] Step 4: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (Intermediate 33-d): [ka] To a stirred solution of 2-(4-nitrophenyl)thiomorpholine (590 mg, 2.631 mmol, 1.00 equiv) and TEA (798.58 mg, 7.893 mmol, 3 equiv) in DCM (6 mL) (Boc) 2 O (1148.26 mg, 5.262 mmol, 2 equiv.) was added. The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, and purified by silica gel column chromatography eluted with PE / EA (3:1) to give 400 mg (46.87%) of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 8.33-8.17(m,2H), 7.77-7.66(m,2H), 7.71-7.54(m,1H), 6.92(s,1H), 4.34-4 .09(m,3H), 3.20(ddd,J=13.6,10.1,3.2Hz,1H), 2.88-2.72(m,1H), 2.77-2.6 5(m,1H), 2.45(s,1H), 1.74-1.57(m,1H), 1.57-1.45(m,1H), 1.43(s,2H), 1.4 0(s,8H), 1.29(s,2H), 1.25(d,J=6.4Hz,3H), 1.15(s,1H), 0.99-0.76(m,2H).

[0371] Step 5: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-e): [ka] To a stirred solution of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (400 mg, 1.233 mmol, 1.00 equiv) in DCM (10 mL) was added m-CPBA (1063.91 mg, 6.165 mmol, 5 equiv). The resulting mixture was stirred at room temperature overnight and diluted with saturated Na 2 SO 3 (aq) (20 mL) was added and extracted twice with EtOAc (20 mL). The combined organic layers were washed with saturated NaHCO 3(aq) (20 mL) and twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 420 mg of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylic acid 1,1-dioxide as a yellow solid. LCMS-APCI (POS.) m / z: 357 (M+H). + .

[0372] Step 6: Preparation of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-f): [ka] To a stirred solution of tert-butyl 2-(4-nitrophenyl)-1,1-dioxo-1 lambda 6-thiomorpholine-4-carboxylate (420 mg, 1.178 mmol, 1.00 equiv) in i-PrOH (5 mL) was added Pd / C (10% Pd, 50% wet with water, 210 mg). The resulting mixture was stirred under H2 at room temperature for 2 h, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 380 mg of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI (POS.) m / z: 327 (M+H). + .

[0373] Step 7: Preparation of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-g): [ka] To a stirred solution of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (420 mg, 1.178 mmol, 1.00 equiv) in i-PrOH (5 mL) was added Pd / C (10% Pd, 50% wet with water, 210 mg). The resulting mixture was diluted with H 2The mixture was stirred under reduced pressure at room temperature for 2 hours, filtered to remove solids, and the filtrate was concentrated under reduced pressure to give 380 mg of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 327(M+H). + .

[0374] Step 8: Preparation of 1-(4-(1,1-dioxidothiomorpholin-2-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 33): [ka] To a stirred solution of tert-butyl 2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-1,1-dioxo-1lambda 6-thiomorpholine-4-carboxylate (93 mg, 0.190 mmol, 1.00 equiv) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (0.5 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, purified by C18 column chromatography, and purified in water (0.05% NH 4 HCO 3 ) / ACN (4:1) to give 45 mg (60.83%) of 3-[4-(1,1-dioxo-1 lambda 6-thiomorpholin-2-yl)phenyl]-1-[(4-methoxyphenyl)methyl]urea as a white solid. LCMS-APCI (POS.) m / z: 390 (M+H) + .

[0375] Example HH Synthesis of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediate 34.1-34.2) Preparation of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediate 34): [ka] To a stirred mixture of methyl[(4-nitrophenyl)methyl]amine (500 mg, 3.009 mmol, 1.00 equiv) and TEA (456 mg, 4.506 mmol, 1.50 equiv) in DCM (4 mL) was added acetic anhydride (307 mg, 3.007 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for 2 h and extracted twice with EtOAc (10 mL). The combined organic layers were washed twice with brine (10 mL) and diluted with anhydrous NaCl. 2 SO 4 and concentrated under reduced pressure to give 630 mg of N-methyl-N-[(4-nitrophenyl)methyl]acetamide as a brown solid. LCMS-APCI (POS.) m / z: 208 (M+H) + .

[0376] Intermediate 30.2 was prepared in the same manner as Intermediate 30.1. [Table 18]

[0377] Example II Synthesis of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (Intermediate 35): Step 1: Preparation of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 35-a): [ka] To a solution of 1-[tert-butoxy(hydroxy)methyl]pyrrolidin-3-one (5 g, 26.704 mmol, 1.00 equiv.) in THF (50 mL) at -78°C, LiHMDS (53.8 mL, 1 mol / L in THF, 2 equiv.) was added dropwise over 30 min under nitrogen atmosphere. After stirring at -78°C for 1 h under nitrogen atmosphere, 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (10.5 g, 29.392 mmol, 1.10 equiv.) was added to the solution at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 2 h under nitrogen atmosphere. The product had no LCMS signal as determined by TLC. The reaction at 0°C was quenched with water (50 mL) and extracted a third time with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL) and anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 16 g of tert-butyl 3-(trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-1-carboxylate (crude) as a brown oil.

[0378] Step 2: Preparation of tert-butyl 3-(4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 35-b): [ka] To a solution of tert-butyl 3-(trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-1-carboxylate (8 g, 12.607 mmol, 1.00 equiv.) and 4-nitrophenylboronic acid (2.5 g, 14.976 mmol, 1.19 equiv.) in dioxane (40 mL at room temperature) was added Pd(dppf)Cl 2 (0.9g, 1.230mmol, 0.10 equivalent) and K 2 CO 3 (3.5g, 25.325mmol, 2.01eq) of H 2A solution of 1000 ml of tert-butyl 3-(4-nitrophenyl)-2,5-dihydropyrrole-1-carboxylate (65.57%) was added under nitrogen atmosphere. The resulting mixture was stirred at 80° C. overnight under nitrogen atmosphere. The reaction was determined by LCMS. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography, eluted with PE / EA (6:1) to give 2.4 g of tert-butyl 3-(4-nitrophenyl)-2,5-dihydropyrrole-1-carboxylate (65.57%) as a yellow solid. LCMS-APCI(POS.) m / z: 234 (M+H-56) + .

[0379] Step 3: Preparation of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (Intermediate 35-c): [ka] To a solution of tert-butyl 3-(4-nitrophenyl)-2,5-dihydropyrrole-1-carboxylate (2.3 g, 7.922 mmol, 1.00 equiv.) in methanol (20 mL) was added Pd / C (10% Pd, 50% wet with water, 2.3 g) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was determined by LCMS. The resulting mixture was filtered to remove solids and concentrated under reduced pressure to give 1.96 g of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate as a brown color. LCMS-APCI (POS.) m / z: 206 (M+H-56) + .

[0380] Step 4: Preparation of tert-butyl 3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (Intermediate 35-d): [ka] To a solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (600 mg, 2.287 mmol, 1.00 equiv) in i-PrOH (6 mL) was added phenyl N-[(4-chlorophenyl)methyl]carbamate (896.6 mg, 3.426 mmol, 1.50 equiv) and DIEA (590.8 mg, 4.571 mmol, 2.00 equiv) at room temperature. The mixture was stirred at 80° C. overnight, cooled to room temperature and purified by silica gel column chromatography eluted with PE / EA (2:1) to give 450 mg of tert-butyl 3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (45.76%) as a yellow semi-solid. LCMS-APCI (POS.) m / z: 347 (M+H-56). + .

[0381] Step 5: Preparation of 1-(4-chlorobenzyl)-3-(4-(pyrrolidin-3-yl)phenyl)urea (Intermediate 35-e): [ka] To a solution of tert-butyl 3-[4-({[(4-chlorophenyl)methyl]carbamoyl}amino)phenyl]pyrrolidine-1-carboxylate (400 mg, 0.930 mmol, 1.00 equiv) in DCM (4 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was determined by LCMS. The resulting mixture was adjusted to pH 10 and purified with CH for a third time. 2 Cl 2 (10 mL). The combined organic layers were washed twice with brine (10 mL) and extracted with anhydrous Na 2 SO 4 Drying at 40° C. and concentration under reduced pressure gave 300 mg of 1-[(4-chlorophenyl)methyl]-3-[4-(pyrrolidin-3-yl)phenyl]urea as a brown semi-solid. LCMS-APCI(POS.) m / z: 330(M+H) + .

[0382] Step 6: Preparation of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (Intermediate 35): [ka] To a solution of 1-[(4-chlorophenyl)methyl]-3-[4-(pyrrolidin-3-yl)phenyl]urea (280 mg, 0.849 mmol, 1.00 equiv) and TEA (171.80 mg, 1.698 mmol, 2.00 equiv) in DCM (4 mL) was added MsCl (116.69 mg, 1.019 mmol, 1.2 equiv) at 0° C. The resulting mixture was stirred at room temperature for 4 h and then cooled to 5° C. with 5% CO. 2 Cl 2 (10 mL). The combined organic layers were washed twice with brine (10 mL) and extracted a third time with anhydrous Na 2 SO 4 The mixture was dried at 40° C., concentrated under reduced pressure, and purified by preparative HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH 4 HCO 3 ) and ACN (30% ACN up to 60% in 8 min); detector, UV 254 nm, 210 nm, this gave 230 mg of 1-[(4-chlorophenyl)methyl]-3-[4-(1-methanesulfonylpyrrolidin-3-yl)phenyl]urea (66.42%) as a brown solid. LCMS-APCI(POS.) m / z: 408(M+H) + .

[0383] Intermediate 35.2 was prepared in a similar manner to Intermediate 35.1. [Table 19]

[0384] Example JJ Synthesis of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36): Step 1: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid (intermediate 36-a): [ka] To a stirred mixture of sulfanilic acid (2 g, 11.548 mmol, 1.00 equiv.) and DIEA (14.91 g, 115.364 mmol, 9.99 equiv.) in isopropyl alcohol (20 mL) was added phenyl N-[(4-chlorophenyl)methyl]carbamate (3.62 g, 13.832 mmol, 1.20 equiv.). The resulting mixture was stirred at 80 °C overnight, cooled to room temperature, and then cooled to C. 18 The mixture was purified by column chromatography and diluted with water (0.05% NH 4 HCO 3 ) / ACN (20:1) to give 3.7 g of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid as a brown solid. LC / MS (APCI) m / z: 341 [M+H].

[0385] Step 2: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36): [ka] A solution of 4-({[(4-chlorophenyl)methyl]carbamoyl}amino)benzenesulfonic acid (3.5 g, 10.271 mmol, 1.00 equiv) in thionyl chloride (35 mL) was stirred at 60° C. for 30 min under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give 3.8 g of 4-({[(4-chlorophenyl)methyl]carbamoyl}amino)benzenesulfonyl chloride as a yellow oil. LC / MS (APCI) m / z: 359 [M+H].

[0386] Example KK Synthesis of 4-(2-oxaspiro[3.5]nonan-7-yl)aniline (intermediate 37): Step 1: Preparation of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (intermediate 37-a): [ka] A flame-dried flask was charged with diisopropylamine (318 mg, 3.14 mmol, 1.1 equiv) and THF (6 mL). After cooling to -30°C, a solution of n-BuLi (1.32 mL, 3.13 mmol, 1.09 equiv) was added dropwise and the mixture was allowed to warm slowly to -10°C over 15 min. It was then cooled to -78°C before a solution of 2-oxaspiro[3.5]nonan-7-one (400 mg, 2.85 mmol, 1.0 equiv) in THF was added dropwise. The deprotonation was maintained at -78°C for 15 min and then removed from the bath for an additional 15 min. The flask was then re-cooled to -78°C and PhNTf 2 (1.12 g, 3.14 mmol, 1.1 equiv) in THF was slowly added and the reaction was again kept at -78 °C for 15 min and outside the bath for 1 h. Upon completion, half-saturated NH 4 Cl solution was added and the aqueous phase was extracted with EtOAc (50 mL* 3). The combined organic phase was dried (MgSO 4 ), filtered and concentrated to give the crude vinyl triflate which was used directly in the next step. LCMS-ESI (POS.) m / z: 273.1 (M+H) + .

[0387] Step 2: Preparation of 7-(4-nitrophenyl)-2-oxaspiro[3.5]non-6-ene (intermediate 37-b). [ka] Dioxane / H 2 A solution of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.85 mmol, 1.0 equiv.) and (4-nitrophenyl)boronic acid (714 mg, 4.28 mmol, 1.5 equiv.) in 2H2O (10 mL, 3:1) was stirred at 4°C for 1 h at 25°C for 30 min at 25°C. 2 After bubbling for 10 minutes at 1000K, 2 CO 3 (794 mg, 5.71 mmol, 2.0 equiv.) and Pd(dppf)Cl 2(209 mg, 0.285 mmol, 0.1 equiv) was added. The mixture was stirred at 75 °C for 15 h. Upon completion, half-saturated NH 4 Cl solution was added and the aqueous phase was extracted with EtOAc (10 mL* 2). The combined organic phase was dried (MgSO 4 ), filtered, concentrated and purified by flash column chromatography (silica, hexane / EtOAc=20 / 1->3 / 1) to give the desired product as a yellowish waxy solid (512 mg, 73%). LCMS-ESI(POS.) m / z: 246.1(M+H) + . 1 H NMR(400MHz,Chloroform-d)δ 8.16(d,J=8.9Hz,2H), 7.49(d,J=8.8Hz,2H), 6.24(tt,J=3.8,1.6Hz,1H), 4.53(d,J=5.8Hz,2H),4. 47(d,J=5.8Hz,2H), 2.61(dt,J=4.4,2.5Hz,2H), 2.52(tq,J=6.4,2.1Hz,2H), 2.10(t,J=6.3Hz,2H).

[0388] Step 3: Preparation of 4-(2-oxaspiro[3.5]nonan-7-yl)aniline (Intermediate 37): [ka] To a solution of 7-(4-nitrophenyl)-2-oxaspiro[3.5]non-6-ene (110 mg, 0.448, 1.0 equiv.) in THF (6 mL) was added Pd / C (33 mg, 10% wet, 30% mass equiv.). 2 The mixture was then incubated at 23° C. for 14 h. 2 Stirred under atmosphere. Upon completion, the solid was filtered off and the filtrate was concentrated to give the aniline (90 mg, 93%). LCMS-ESI (POS.) m / z: 218.1 (M+H). + .

[0389] Example LL Synthesis of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38): Step 1: Preparation of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38): [ka] CH 2 Cl 2 To a solution of 2-(4-aminophenyl)ethan-1-ol (1.37 g, 10.0 mmol, 1.0 equiv) in 10 mL of ethyl acetate was added p-chlorobenzyl isocyanate (1.70 g, 10.2 mmol, 1.02 equiv) slowly at 0 °C. The mixture was stirred vigorously at 23 °C for 1 h. Upon completion, the precipitate was filtered and washed with cold CH 2 Cl 2 (10 mL) and Et 2 Washing with O (10 mL) gave 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (2.8 g, 92%) as an off-white solid. LCMS-ESI (POS.) m / z: 305.10 (M+H). + . 1 H NMR (400MHz, DMSO-d 6 )δ 8.47(s,1H), 7.39(d,J=8.4Hz,2H), 7.32(d,J=8.4Hz,2H), 7.29(d,J=8.4Hz,2H), 7.06(d,J=8.2Hz,2H), 6.59(t,J=6.0Hz,1H), 4.58(s,1H), 4.27(d,J=6.0Hz,2H), 3.54(t,J=7.2Hz,2H), 2.63(t,J=7.2Hz,2H).

[0390] Example MM Synthesis of 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39): Preparation of 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39): [ka] THF / CH 2 Cl 2To a solution of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38, 500 mg, 1.64 mmol, 1.0 equiv) in 1:20 sulphuric acid (20 mL, 1:1), PPh 3 (516 mg, 1.97 mmol, 1.2 equiv) and imidazole (167 mg, 2.46 mmol, 2.0 equiv) were added. N-bromosuccinimide (350 mg, 1.97 mmol, 1.2 equiv) was then added at 0° C. The reaction solution was stirred at 23° C. for 1 h. Upon completion, NaHCO 3 and Na 2 S 2 O 3 The reaction was quenched by adding a mixture of 2 Cl 2 (5 mL). The combined organic phase was washed with brine and dried (MgSO 4 ), filtered, concentrated and purified by column chromatography (silica, hexane / EtOAc, 20:1->0:1) to give 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (200 mg, 33%) as a white solid. LCMS-ESI (POS.) m / z: 367.00 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ 8.55(s,1H), 7.39(d,J=8.5Hz,2H), 7.33(d,J=5.6Hz,2H), 7.31(d,J=5.6Hz,2H), 7.13(d,J=8.5H) z,2H), 6.63(t,J=6.0Hz,1H), 4.28(d,J=6.0Hz,2H), 3.67(t,J=7.3Hz,2H), 3.03(t,J=7.3Hz,2H).

[0391] Example 1 Synthesis of ethyl 2-[4-({[(4-methoxyphenyl)methyl]amino}carbonylamino)phenyl]acetate (Compound 331) [ka] To a solution of ethyl 2-(4-aminophenyl)acetate (27.46 g, 153.2 mmol) in DCM (20 mL) at 20° C., 4-methoxybenzyl isocyanate (25.0 g, 153.2 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 4 h, then methanol (10 mL) was added and cooled to 0° C. After 1 h at 0° C., the slurry was filtered to give the desired product (26.7 g, 78.0 mmol, 50.9% yield) as an off-white solid. LCMS-APCI (POS.) m / z: 343.1 (M+H)+. 1H NMR(400MHz,DMSO-d6)δ 8.50(s,1H), 7.38-7.30(m,2H), 7.27-7.19(m,2H), 7.15-7.07(m,2H), 6.94-6.85(m,2H), 6.52(t,J=5. 9Hz,1H), 4.22(d,J=5.4Hz,2H), 4.06(q,J=7.1Hz,2H), 3.73(s,3H), 3.55(s,2H), 1.17(t,J=7.1Hz,3H).

[0392] The compounds in the following table were prepared in a similar manner to compound 331 using the intermediates and reagents listed. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8]

Table 20-9

Table 20-10

Table 20-11

Table 20-12

Table 20-13

Table 20-14

Table 20-15

Table 20-16

Table 20-17

Table 20-18

Table 20-19

Table 20-20

Table 20-21

Table 20-22

Table 20-23

Table 20-24

Table 20-25

[0393] Example 2 ({4-[2-(3,3-difluoroazetidyl)-2-oxoethyl]phenyl}amino)-N-[(4-methoxyphenyl)methyl]carboxamide (Compound 320) [ka] To a room temperature solution of intermediate 1.1 (100 mg, 0.318 mmol, 1.0 equiv), 3,3-difluoroazetidine (59 mg, 0.636 mmol, 2.0 equiv) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (181 mg, 0.275 mmol, 1.5 equiv) in dimethylformamide (6 mL) was added N,N-diisopropylethylamine (0.006 mL, 0.03 mmol, 0.1 equiv). The resulting mixture was stirred at room temperature for 9 h. The reaction mixture was diluted with water (0.5 mL) and extracted with ethyl acetate (2 x 1 mL). The organic phase was dried to a viscous oil, which was purified by reverse phase HPLC with 10% to 100% acetonitrile in water run on a Phenomonex Gemini 5u C18 column over 30 min to give compound 320 (37.0 mg, 0.095 mmol, 29.9% yield) as a white foam. LCMS-APCI (POS.) m / z: 390.0 (M+H)+. 1H NMR(400MHz,DMSO-d6)δ 8.46(s,1H), 7.37-7.29(m,2H), 7.27-7.18(m,2H), 7.12-7.04(m,2H), 6.94-6.85(m ,2H), 6.49(t,J=5.9Hz,1H), 4.61(t,J=12.5Hz,2H), 4.33-4.18(m,4H), 3.73(s,3H).

[0394] The compounds in the following table were prepared in a similar manner to compound 320 using the intermediates and reagents listed. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5]

Table 21-6

Table 21-7

Table 21-8

Table 21-9

Table 21-10

Table 21-11

Table 21-12

Table 21-13

Table 21-14

Table 21-15

Table 21-16

Table 21-17

Table 21-18

Table 21-19

Table 21-20

Table 21-21

Table 21-22

Table 21-23

Table 21-24

Table 21-25

Table 21-26

Table 21-27

Table 21-28

Table 21-29

Table 21-30

Table 21-31

Table 21-32

Table 21-33

Table 21-34

Table 21-35

Table 21-36

Table 21-37

Table 21-38

Table 21-39

Table 21-40

Table 21-41

Table 21-42

Table 21-43

Table 21-44

Table 21-45

Table 21-46

Table 21-47

Table 21-48

Table 21-49

Table 21-50

Table 21-51

Table 21-52

Table 21-53

Claims

1. Compound of formula (II): 【Chemical 259】 or a pharma- ceutically acceptable salt thereof, R １ is halo or methoxy; R ６ is hydrogen or halo; p is 1; R ２ is hydrogen or C １ -C ６ alkyl or Z ４ and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R ３ is hydrogen or C １ -C ６ is alkyl; R ４ teeth a) 3-10 membered heterocycloalkyl or heterocycloalkenyl, including halo, oxo, —OH, —CN, —C １ -C ６ Alkyl (one or more independently selected R ｙ substituents), optionally substituted with one or more independently selected halo substituents; １ -C ６ Alkoxy, -C(O)OC １ -C ６ Alkyl, -C(O)C １ -C ６ Alkyl, -S(O) ２ -C １ -C ６ Alkyl, C ６ -C １２ Aryl (optionally substituted with one or more independently selected halo substituents), 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo, one or more independently selected halo or -C １ -C ６ Alkyl substituents, and C ３ -C ６ said 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected substituents selected from the group consisting of: 5-6 membered heteroaryl optionally substituted with cycloalkyl; b)NR ｆ R ｇ C(O)-、 c)Z １ NR ａ C(O)-、 d)Z ２ C(O)NR ｂ -、 e)Z ３ (CR ｃ R ｄ ) ｍ NR ｅ -、 f)Z ４ S(O) ２ (CH ２ ) ｎ -、 g)Z ５ OC(O)-、 h) one or more independently selected C １ -C ６ Alkyl or C ３ -C ６ 5-10 membered heteroaryl optionally substituted with cycloalkyl substituents; i)Z ６ S(O) ２ N(R ｓ )-、 j) Z ７ N (R ｔ ) S (O) ２ -,or k) Z ８ -O-(CH ２ ) ｑ -wherein R ａ and R ｅ are each independently hydrogen or C １ -C ６ is alkyl; R ｂ is hydrogen or C １ -C ６ alkyl or R ５ and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R ｃ and R ｄ are each independently hydrogen or C １ -C ６ alkyl or R ｃ and R ｄ together with the carbon to which they are attached, C ３ -C ６ Forming a cycloalkyl; R ｆ and R ｇ together with the nitrogen to which they are attached, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which may be selected from halo, —OH, —CN, oxo, one or more independently selected R ｘ -C optionally substituted with a substituent １ -C ６ Alkyl, -C ３ -C ６ Cycloalkyl, -C １ -C ６ Alkoxy, -C(O)R ｈ , -NHC(O)OC １ -C ６ Alkyl, -NR ｊ R ｋ , -C(O)NR ｍ R ｎ , a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R ｈ is independently -C １ -C ６ Alkyl, —O—C １ -C ６ Alkyl, or C ６ -C １２ aryl (optionally substituted with one or more independently selected halo substituents); Each R ｘ is halo, -OH, -C ３ -C ６ Cycloalkyl, -C １ -C ６ Alkoxy, -NR ｏ R ｐ , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; Each R ｙ is halo, -OH, -CN, -C １ -C ６ Alkoxy, -C(O)NR ｑ R ｒ , C ６ -C １２ independently selected from the group consisting of aryl, and 5-6 membered heteroaryl; Each R ｊ , R ｋ , R ｍ , R ｎ , R ｏ , R ｐ , R ｑ , and R ｒ are independently hydrogen or C １ -C ６ is alkyl; R ｓ is hydrogen or -C １ -C ６ is alkyl; R ｔ is hydrogen or -C １ -C ６ is alkyl; m is 0 or 1; n is 0, 1, or 2, and q is 0 or 1; Z １ and Z ５ Each independently represents R ｚ and Z ２ and Z ３ are each independently hydrogen or R ｚ and Z ４ is hydrogen, or R ｚ or R ２ and together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z ６ is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, a 5- to 6-membered heteroaryl, and １ -C ６ selected from the group consisting of alkyl; Z ７ is C ６ -C １２ is aryl; Z ８ is a 5- to 6-membered heteroaryl and C ３ -C ６ cycloalkyl; and R ｚ is selected from the group consisting of: a) -OH, -CN, C ３ -C ６ Cycloalkyl, -NHC １ -C ６ Alkyl, C ６ -C １２ C optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl. １ -C ６ alkyl, wherein said C ６ -C １２ Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently selected from halo, C １ -C ６ Alkyl, and C １ -C ６ optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; b) C ６ -C １２ Aryl, C １ -C ６ Alkyl, and C １ -C ６ C optionally substituted with one or more substituents independently selected from the group consisting of alkoxy (optionally substituted with 5- or 10-membered heteroaryl); ３ -C ６ cycloalkyl, wherein the 5- or 10-membered heteroaryl is one or more independently selected C １ -C ６ optionally further substituted with alkyl; c) C １ -C ６ Alkoxy; d) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which is selected from the group consisting of halo, oxo, —OH, —CN, and one or more independently selected R ｗ -C optionally substituted with a substituent １ -C ６ alkyl, optionally substituted with one or more independently selected halo substituents, １ -C ６ Alkoxy, -C(O)OC １ -C ６ Alkyl, -C(O)C １ -C ６ Alkyl, -S(O) ２ -C １ -C ６ alkyl, optionally substituted with one or more independently selected halo substituents; ６ -C １２ aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C １ -C ６ a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with alkyl substituents; ｗ are independently halo, —OH, —CN, —C １ -C ６ Alkoxy, -C(O)NR ｕ R ｖ , C ６ -C １２ aryl, and 5-6 membered heteroaryl; ｕ and R ｖ are each independently hydrogen or C １ -C ６ is alkyl; e) C ６ -C １２ Aryl; and f) one or more independently selected C １ -C ６ 5-10 membered heteroaryl optionally substituted with alkyl substituents; and R ５ is hydrogen, halo, or R ｂ together with the intervening atoms form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring, provided that (1) R ４ But, Z １ N.R. ａ In the case of C(O)-, Z １ is methyl, unsubstituted cyclopropyl, -C(CH ３ ) ２ CH ２ OH and -CH ２ - other than thiofuran; (2) R ４ is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, 【Chemistry 260】 other than; and (3) The compound of formula (II) 【Chemistry 308】 【Chemistry 309】 isn't it, The compound or a pharma- ceutically acceptable salt thereof.

2. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is Cl.

3. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is methoxy.

4. R ２ and R ３ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein each is hydrogen.

5. A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, comprising R ４ is a 3-10 membered heterocycloalkyl or heterocycloalkenyl, which is selected from halo, oxo, —OH, —CN, one or more independently selected R ｙ -C optionally substituted with a substituent １ -C ６ alkyl, optionally substituted with one or more independently selected halo substituents, １ -C ６ Alkoxy, -C(O)OC １ -C ６ Alkyl, -C(O)C １ -C ６ Alkyl, -S(O) ２ -C １ -C ６ alkyl, optionally substituted with one or more independently selected halo substituents; ６ -C １２ aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C １ -C ６ and 5-6 membered heteroaryl optionally substituted with alkyl substituents.

6. R ４ but, 【Chemical 269】 The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. R ４ but 【Chemistry 270】 7. The compound of claim 6, which is: or a pharma- ceutically acceptable salt thereof.

8. 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (IA): 【Chemistry 271】 or a pharma- ceutically acceptable salt thereof.

9. 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (IB): 【Chemical 273】 or a pharma- ceutically acceptable salt thereof.

10. 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (IC): 【Chemical 276】 or a pharma- ceutically acceptable salt thereof.

11. 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (ID): 【Chemical 278】 or a pharma- ceutically acceptable salt thereof.

12. 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (IE): 【Chemistry 280】 or a pharma- ceutically acceptable salt thereof.

13. 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound of formula (IF): 【Chemistry 281】 or a pharma- ceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 4 and 13, or a pharma- ceutically acceptable salt thereof, comprising R ｆ and R ｇ together with the nitrogen to which they are attached, represent halo, —OH, —CN, oxo, one or more independently selected R ｘ -C optionally substituted with a substituent １ -C ６ Alkyl, -C ３ -C ６ Cycloalkyl, -C １ -C ６ Alkoxy, -C(O)R ｈ , -NHC(O)OC １ -C ６ Alkyl, -NR ｊ R ｋ , -C(O)NR ｍ R ｎ , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, forming a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of: 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

15. R ｆ and R ｇ together with the nitrogen to which they are attached, optionally -C １ -C ６ 5-6 membered heterocycloalkyl or heterocycloalkenyl substituted with alkyl, wherein said -C １ -C ６ 15. The compound of any one of claims 1 to 4, 13, and 14, or a pharma- ceutically acceptable salt thereof, wherein alkyl is optionally substituted with -OH.

16. A compound according to any one of claims 1 to 4 and 13 to 15, or a pharma- ceutically acceptable salt thereof, 【Chemistry 282-1】 【Chemistry 282-2】 【Chemistry 282-3】 or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

17. 【Chemical 283】 17. The compound according to any one of claims 1 to 4 and 13 to 16, which is: or a pharma- ceutically acceptable salt thereof.

18. 【Chemical 310】 【Chemistry 311】 【Chemistry 312】 【Chemistry 313】 【Chemistry 314】 【Chemistry 315】 【Chemistry 316】 【Chemistry 317】 【Chemistry 318】 【Chemical 319】 【Chemistry 320】 【Chemistry 321】 【Chemistry 322】 【Chemical 323】 【Chemical 324】 【Chemistry 325】 【Chemical 326】 【Chemical 327】 【Chemical 328】 【Chemical 329】 【Chemistry 330】 【Chemistry 331】 【Chemical 332】 【Chemical 333】 【Chemical 334】 【Chemical 335】 【Chemical 336】 【Chemical 337】 【Chemical 338】 【Chemical 339】 【Chemistry 340】 【Chemical 341】 【Chemical 342】 【Chemical 343】 【Chemical 344】 【Chemical 345】 【Chemical 346】 【Chemical 347】 【Chemical 348】 【Chemical 349】 【Chemistry 350】 【Chemistry 351】 【Chemical 352】 【Chemical Formula 353】 【Chemical 354】 【Chemistry 355】 【Chemical 356】 【Chemical 357】 【Chemical 358】 【Chemical 359】 【Hua360】 【Chemistry 361】 【Chemical 362】 【Chemistry 363】 【Hua364】 【Chemistry 365】 【Chemistry 366】 【Chemical 367】 【Chemistry 368】 【Chemical 369】 【Hua370】 【Chemical 371】 【Chemical 372】 【Chemical 373】 【Chemical 374】 【Chemical 375】 【Chemical 376】 【Chemical 377】 【Chemical 378】 【Chemical 379】 【Hua380】 【Chemistry 381】 【Chemical 382】 【Chemical 383】 【Chemical Formula 384】 【Chemistry 385】 【Chemistry 386】 【Chemical 387】 【Chemistry 388】 【Chemical 389】 【Chemical 390】 【Chemical Formula 391】 【Chemical 392】 【Chemical 393】 【Chemical 394】 【Chemical 395】 【Chemical 396】 【Chemical 397】 【Chemical 398】 【Chemical 399】 【Chemical 400】 【Chemistry 401】 【Chemistry 402】 【Chemistry 403】 【Chemistry 404】 【Chemistry 405】 【Chemistry 406】 【Chemistry 407】 【Chemistry 408】 【Chemistry 409】 【Chemistry 410】 【Chemistry 411】 【Chemistry 412】 【Chemistry 413】 A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

19. The compound is 【Chemistry 305】 20. The compound of claim 18, which is: or a pharma- ceutically acceptable salt thereof.

20. The compound is 【Chemistry 306】 20. The compound of claim 18, which is: or a pharma- ceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 for use in treating a disease or condition mediated by NAMPT activity in a subject in need thereof.

23. 23. The pharmaceutical composition for use according to claim 22, 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, heart failure, heart failure with preserved ejection fraction, chemotherapy induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, a muscle disease or muscle wasting disorder, obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

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