NAMPT modulators

Abstract

Provided are compounds of Formula (II) 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 is a pharmaceutically acceptable composition 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

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 971,838, filed on February 7, 2020, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

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

[0004] The present disclosure relates to the use of modulators of nicotinamide phosphoribosyltransferase (NAMPT) and its derivatives, as well as enhancers or inducers of NAMPT expression, NAMPT activity, or NAMPT-mediated signaling for preventing or treating various pathological conditions.

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

[0006] More than 200 enzymes use NAD+ or NADP+ as coenzymes, and enzymatic functions are not limited to energy metabolism. It is now understood that NAD+ plays a role in regulating diverse functions, including mitochondrial function, respiratory capacity and biogenesis, mitochondrial-nuclear signaling. In addition, NAD+ controls cell signaling, gene expression, DNA repair, hematopoiesis, immune function, unfolded protein response, and autophagy. In addition, NAD is anti-inflammatory and is a precursor to NADPH, which is the main source of reducing power to combat oxidative stress. A large amount of literature indicates that increasing NAD levels is an effective strategy to prevent or improve a wide range of disease states ( Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10): 899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864: 1787-1800; Verdin, Science. 2015, 350(6265): 1208-13).

[0007] The levels of NAD+and NADP+-related enzymes play an important role in normal physiology and are altered under various disease and stress conditions, including aging. Cellular NAD+levels decrease during aging, metabolic disease, inflammatory disease, during ischemia / reperfusion injury, and in other conditions in humans (Massudi et al., PLoS ONE. 2012, 7(7):e42357) and animals (Yang et al., Cell. 2007, 130(6): 1095-107; Braidy et al. PLoS One. 2011, 26; 6(4):e19194; Peek et al. Science. 2013, 342(6158): 1243417; Ghosh et al., J Neurosci. 2012, 32(17): 5821-32), suggesting that modulation of cellular NAD+levels influences the rate and severity of physical functional decline and deterioration. Thus, an increase in cellular NAD+concentration can be beneficial in the context of aging and age-related diseases.

[0008] The cellular NAD+pool is controlled by the balance between NAD+synthetase and the activity of consuming enzymes. In mammals, NAD+is synthesized from a variety of dietary sources that contain one or more of the main precursors of NAD+, including: tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide (NAM). Based on the bioavailability of NAD+precursors, there are three NAD+synthesis pathways in cells: (i) synthesis from Trp via the de novo biosynthesis pathway or the kynurenine pathway, (ii) synthesis from NA in the Preiss-Handler pathway, and (iii) synthesis from NAM, NR, and NMN in the salvage pathway (Verdin et al., Science. 2015, 350(6265): 1208-13). Among these pathways, the main NAD+biosynthesis pathway involves the following step: synthesis of nicotinamide mononucleotide (NMN) from nicotinamide and 5'-phosphoribosyl-pyrophosphate by the rate-limiting enzyme nicotinamide phosphoribosyl-transferase (NAMPT), which is critical for determining lifespan 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., Cell. 2007, 130(6): 1095-107). Thus, increasing the catalytic rate of NAMPT by small molecule activators would be an effective strategy to increase NAD+levels and thereby treat a wide range of disease states. These disease states include cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease and injury, diseases resulting from impaired stem cell function, and DNA damage and primary mitochondrial disorders. SUMMARY

[0009] In one aspect, provided herein is a compound of Formula (II):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] R 1 is halogen or methoxy;

[0013] R 6is hydrogen or halogen; and

[0014] p is 0 or 1, wherein

[0015] when p is 1,

[0016] R 2 is hydrogen or C1-C6alkyl, or, together with Z 4 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0017] R 3 is hydrogen or C1-C6alkyl;

[0018] R 4 is

[0019] a) Z 1 NR a C(O)-,

[0020] b) Z 2 C(O)NR b -,

[0021] c) Z 3 (CR c R d ) m NR e -,

[0022] d) Z 4 S(O)2(CH2) n -,

[0023] e) Z 5 OC(O)-,

[0024] f) NR f R g C(O)-,

[0025] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl or C3-C6cycloalkyl substituents,

[0026] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected R y substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C 12aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more oxo, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halo or -C1-C6alkyl substituents, and C3-C6cycloalkyl,

[0027] i) Z 6 S(O)2N(R s )-,

[0028] j) Z 7 N(R t )S(O)2- or

[0029] k) Z 8 -O-(CH2) q -; wherein

[0030] R a and R e are each independently hydrogen or C1-C6alkyl;

[0031] R b is hydrogen or C1-C6alkyl, or taken together with R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0032] R c and R d are each independently hydrogen or C1-C6alkyl, or R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl;

[0033] R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected substituents selected from the group consisting of halo, -OH, -CN, oxo, -C1-C6alkyl optionally substituted with one or more independently selected R x substituents, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl;

[0034] each R h is independently -C1-C6alkyl, -O-C1-C6alkyl, or C6-C 12 aryl optionally substituted with one or more independently selected halo substituents;

[0035] each R x is independently selected from the group consisting of halogen, -OH, -C3-C6cycloalkyl, -Ci-C6alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0036] each R y is independently selected from the group consisting of halogen, -OH, -CN, -Ci-C6alkoxy, -C(O)NR q R r , C6-C 12 aryl and 5- to 6-membered heteroaryl;

[0037] each R j , R k , R m , R n , R o , R p , R q and R r are independently hydrogen or Ci-C6alkyl;

[0038] R s is hydrogen or -Ci-C6alkyl;

[0039] R t is hydrogen or -Ci-C6alkyl;

[0040] m is 0 or 1 ;

[0041] n is 0, 1 or 2; and

[0042] q is 0 or 1 ;

[0043] Z 1 and Z 5 are each independently R z ;

[0044] Z 2 and Z 3 are each independently hydrogen or R z ;

[0045] Z 4 is hydrogen or R z , or together with R 2 and the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0046] Z 6 is selected from the group consisting of 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, 5- to 6-membered heteroaryl and Ci-C6alkyl;

[0047] Z7 C6-C 12 aryl;

[0048] Z 8 is selected from the group consisting of 5- to 6-membered heteroaryl and C3-C6 cycloalkyl, and

[0049] R z Selected from the group consisting of:

[0050] a) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 aryl, 3 to 10 membered heterocycloalkyl or heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein the C6-C 12 The aryl group, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy;

[0051] b) C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of: C6-C6 cycloalkyl optionally substituted with 5- or 10-membered heteroaryl 12 Aryl, C1-C6 alkyl and C1-C6 alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyl groups;

[0052] c) C1-C6 alkoxy;

[0053] d) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R w -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; wherein each R w independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v 、C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and Rv Each is independently hydrogen or C1-C6 alkyl;

[0054] e)C6-C 12 aryl; and

[0055] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; and

[0056] R 5 is hydrogen, halogen, or b and the intervening atoms together form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring, provided that

[0057] (1) When R 4 Z 1 NR a When C(O)-, Z 1 other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiophene;

[0058] (2)R 4 Not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furylmethyl)piperazinyl, and

[0059] (3) The compound of formula (II) is not a compound of Table 1X; and

[0060] When p is 0, R 4 for

[0061] l) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is substituted with one or more independently selected -C1-C6 alkyl substituents and is optionally further substituted with one or more oxo substituents,

[0062] m) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing exactly one ring heteroatom which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is optionally substituted with one or more independently selected oxo or -C1-C6 alkyl substituents,

[0063] n) 3 to 6 membered heterocycloalkyl or heterocycloalkenyl substituted with one or more independently selected -S(O)2-C1-C6 alkyl substituents and optionally further substituted with one or more independently selected oxo or -C1-C6 alkyl substituents,

[0064] o) 5-membered heterocycloalkyl or heterocycloalkenyl which exactly comprises two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, C1-C6alkyl or -S(O)2-(C1-C6alkyl) substituents,

[0065] p) 6-membered heterocycloalkyl or heterocycloalkenyl which exactly comprises two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, C1-C6alkyl or -S(O)2-(C1-C6alkyl) substituents,

[0066] q) 5-membered heteroaryl which exactly comprises two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heteroaryl is exactly substituted with one methyl substituent,

[0067] r) 5-membered heteroaryl which exactly comprises two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents,

[0068] s) 6-membered heteroaryl which comprises one or two ring heteroatoms and is optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is not

[0069] t) Z 9 -S(O)2-,

[0070] u) Z 10 -S(O)2-NH-,

[0071] v) Z 11 -C(O)-NH-,

[0072] w) Z 12 -CH2-O-,

[0073] x) Z 13 -O-,

[0074] y) Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,

[0075] z) or

[0076] aa) wherein

[0077] Z 9 is selected from the group consisting of cyclopropyl, C6-C 12 aryl, optionally substituted with one or more independently selected RA 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituted with one or more independently selected R B -NH2substituted with one or more independently selected R C C1-C6alkyl substituted with one or more independently selected R 9 is not unsubstituted methyl or unsubstituted ethyl, wherein:

[0078] R A is -C1-C6alkyl or -CN; and

[0079] R B is (i) -C1-C6alkyl-(5- to 10-membered heteroaryl), or (ii) optionally substituted with one or more independently selected C6-C 12 aryl-substituted 5- to 10-membered heteroaryl; and

[0080] R C is 3- to 8-membered heterocycloalkyl or heterocycloalkenyl;

[0081] Z 10 is 5- to 10-membered heteroaryl substituted with one or more independently selected C6-C 12 C1-C6alkyl substituted with one or more independently selected aryl substituents;

[0082] Z 11 is selected from the group consisting of C3-C 10 cycloalkyl and C1-C6alkyl, provided that when Z 11 is cyclopropyl, then R 1 is not methoxy;

[0083] Z 12 is selected from the group consisting of C6-C 12 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, C1-C6alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents, and -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl);

[0084] Z 13 is 5- to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6alkyl) substituents; and

[0085] Z 14 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; and

[0086] R5 is hydrogen.

[0087] In another aspect, provided herein is a compound of Formula (I):

[0088]

[0089] or a pharmaceutically acceptable salt thereof,

[0090] wherein:

[0091] R 1 is halogen or methoxy;

[0092] R 2 is hydrogen or C1-C6 alkyl, or, together with Z 4 and the intervening atoms, forms a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring

[0093] R 3 is hydrogen or C1-C6 alkyl;

[0094] R 4 is

[0095] a) Z 1 NR a C(O)-,

[0096] b) Z 2 C(O)NR b -,

[0097] c) Z 3 (CR c R d ) m NR e -,

[0098] d) Z 4 S(O)2(CH2) n -,

[0099] e) Z 5 OC(O)-,

[0100] f) NR f R g C(O)-,

[0101] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, or

[0102] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y-C1-C6alkyl substituted with one or more independently selected halo substituents, -C1-C6alkoxy substituted with one or more independently selected halo substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein

[0103] R a and R e each independently is hydrogen or C1-C6alkyl;

[0104] R b is hydrogen or C1-C6alkyl, or taken together with R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0105] R c and R d each independently is hydrogen or C1-C6alkyl, or R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl;

[0106] R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -CN, oxo, C1-C6alkyl, -O-C1-C6alkyl, -C(O)R x -C1-C6alkyl substituted with one or more independently selected halo substituents, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h -NHC(O)OC1-C6alkyl, -NR j R k -C(O)NR m R n 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl;

[0107] each R h independently is -C1-C6alkyl optionally substituted with one or more independently selected halo substituents, -O-C1-C6alkyl, or C6-C10aryl; 12 aryl;

[0108] each R x is independently selected from the group consisting of halo, -OH, -C3-C6cycloalkyl, -C1-C6alkoxy, -NR o R p, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0109] Each R y independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r 、C6-C 12 Aryl and 5- to 6-membered heteroaryl;

[0110] Each R j 、R k 、R m 、R n 、R o 、R p 、R q and R r are independently hydrogen or C1-C6 alkyl;

[0111] m is 0 or 1; and

[0112] n is 0, 1, or 2;

[0113] R 5 is hydrogen, or with R b and the intervening atoms together form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0114] Z 1 and Z 5 Each independently is R z ;

[0115] Z 2 and Z 3 are each independently hydrogen or R z ;

[0116] Z 4 is hydrogen or R z , or with R 2 and the intervening atoms are taken together to form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring; and

[0117] R z Selected from the group consisting of:

[0118] a) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 aryl, 3 to 10 membered heterocycloalkyl or heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein the C6-C 12each instance of aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl is independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkyl, -C1-C6alkoxy, -C(O)NR

[0119] b) C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C6-C10aryl optionally substituted with 5- or 10-membered heteroaryl, C1-C6alkyl optionally substituted with 5- or 10-membered heteroaryl, and C1-C6alkoxy optionally substituted with 5- or 10-membered heteroaryl; 12 aryl, C1-C6alkyl, and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6alkyl groups;

[0120] c) C1-C6alkoxy;

[0121] d) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected halogen substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)NR w substituted with one or more independently selected halogen substituents, -C(O)NR 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR u R v , C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and R v each independently is hydrogen or C1-C6alkyl;

[0122] e) C6-C 12 aryl; and

[0123] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents,

[0124] wherein (1) when R 4 is Z 1 NR a C(O)-, Z 1 is not methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiophene;

[0125] (2) R4 is not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridinylpiperazinyl, 4- (furanylmethyl)piperazinyl, and

[0126] (3) the compound of Formula (I) is not a compound of Table XI.

[0127] In another aspect, provided herein is a compound of Formula (I-G):

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined for Formula (II) or any variation or embodiment thereof.

[0130] In another aspect, provided herein is a compound of Formula (I-A):

[0131]

[0132] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R a , and Z 1 are as defined for Formula (II) or any variation or embodiment thereof.

[0133] In another aspect, provided herein is a compound of Formula (I-B):

[0134]

[0135] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 5 , R b , and Z 2 are as defined for Formula (II) or any variation or embodiment thereof.

[0136] In another aspect, provided herein is a compound of Formula (I-C):

[0137]

[0138] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , Rd , R e , m and Z 3 as defined for formula (II), or any variation or embodiment thereof.

[0139] In another aspect, provided herein is a compound of formula (I-D):

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n and Z 4 as defined for formula (II), or any variation or embodiment thereof.

[0142] In another aspect, provided herein is a compound of formula (I-E):

[0143]

[0144] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and Z 5 as defined for formula (II), or any variation or embodiment thereof.

[0145] In another aspect, provided herein is a compound of formula (I-F):

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R f and R g as defined for formula (II), or any variation or embodiment thereof.

[0148] In another aspect, provided herein is a compound of formula (II-A):

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 and R 6 as defined for formula (II), or any variation or embodiment thereof.

[0151] In yet another aspect, provided herein are pharmaceutical compositions comprising at least one compound of Formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A), such as a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally further comprising a pharmaceutically acceptable excipient.

[0152] In another aspect, provided herein is a method of treating a disease or disorder mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound of Formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A), such as a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A). In some embodiments, the disease or disorder is selected from the group consisting of cancer, a hyperproliferative disease or disorder, an inflammatory disease or disorder, a metabolic disorder, a heart disease or disorder, chemotherapy-induced tissue damage, a kidney disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle atrophy. In some embodiments, the disease or disorder is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal neurological injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, neurological injury, poliomyelitis (polio), and spinal cord injury.

[0153] Additional embodiments, features, and advantages of the present disclosure will be apparent from the detailed description that follows and will be better understood by reference to the detailed description when considered in conjunction with the accompanying drawings.

[0154] The disclosures of the publications (including patents) cited in this specification are hereby incorporated by reference. DETAILED DESCRIPTION

[0156] DEFINITIONS

[0157] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0158] Throughout this application, unless otherwise indicated, a reference to a compound of Formula (II) includes all subgroups of Formula (II) as defined herein, such as Formula (I), (I-G), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), including all substructures, subgroups, preferences, embodiments, examples, and specific compounds defined and / or described herein. A reference to a compound of Formula (II) and subgroups thereof, such as Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), includes 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, a reference to a compound of Formula (II) and subgroups thereof, such as Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof.In some embodiments, reference to a compound of Formula (II), and subgroups thereof, such as Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), includes polymorphs, solvates, and / or co-crystals thereof. In some embodiments, reference to a compound of Formula (II), and subgroups thereof, such as Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), includes isomers, tautomers, and / or oxides thereof. In some embodiments, reference to a compound of Formula (II), and subgroups thereof, such as Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), includes solvates thereof. Similarly, the term“salt” includes solvates of salts of compounds.

[0159] “Alkyl” encompasses straight-chain and branched-chain alkyl groups 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, a Ci-6alkyl group can be a straight chain or branched chain alkyl group having from 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. 1-6 Alkyl encompasses straight-chain and branched-chain alkyl groups of 1 to 6 carbon atoms. When naming an alkyl residue having a specified number of carbons, all branched and straight chain versions of that number of carbons are intended to be encompassed; thus, for example, “propyl” includes n-propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0160] When a range of values is given (for example C 1-6 Each value within a range and all intermediate ranges included. For example, "C 1-6 alkyl" includes Ci, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 and C 1-2 alkyl.

[0161] "Alkenyl" refers to an unsaturated 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 double bond. The group can be in the cis- or trans- configuration (Z or E configuration) about the double bond(s). Alkenyl 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-1 -yl, but-2-en-2-yl, but-1,3-dien-1 -yl, but-1,3-dien-2-yl).

[0162] "Alkynyl" refers to an unsaturated 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).

[0163] "Cycloalkyl" indicates non-aromatic, fully saturated carbocyclic rings having the specified 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 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, clathrate, and spirocyclic groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). Additionally, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of cycloalkyl groups fused to aromatic rings are described below.

[0164] "Aryl" indicates aromatic carbocyclic rings having the specified number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups can 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 cases, a polycyclic aryl group can include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, as defined herein, the term "aryl" does not encompass or overlap with "heteroaryl," regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl. Additional examples of aryl groups comprising aromatic carbocyclic rings fused to non-aromatic rings are described below.

[0165] "Heteroaryl" indicates an aromatic ring containing the specified number of atoms (e.g., 5- to 12-membered or 5- to 10-membered heteroaryl), which consists of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms are carbon. Heteroaryl does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 1. Unless otherwise indicated, a heteroaryl group can be bound to the parent structure by a carbon or nitrogen atom, as valency allows. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl.

[0166] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0167] 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-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, furano[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furano[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furano[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]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, naphthridine (e.g., 1,8-naphthridine, 1,7-naphthridine, 1,6-naphthridine, 1,5-naphthridine, 2,7-naphthridine, 2,6-naphthridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0168] In other instances, polycyclic heteroaryl groups can include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is to be considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (where the moiety is bound to the parent structure via a non-aromatic carbon atom) is not to be considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0169] “Heterocycloalkyl” indicates a non-aromatic, fully saturated ring having the specified number of atoms (e.g., 3- to 10-membered or 3- to 7-membered heterocycloalkyl), consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon. Heterocycloalkyl groups can 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. Additionally, one ring of a polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is to be considered a heterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is not to be considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl ring fused to an aromatic ring are described below.

[0170] "Heterocycloalkenyl" indicates a non-aromatic ring having the specified number of atoms (e.g., 3- to 10-membered or 3- to 7-membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms are carbon, and wherein at least one double bond is obtained by removal of one hydrogen molecule from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl group. Heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuryl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothienyl (e.g., 2,3-dihydrothienyl, 2,5-dihydrothienyl), dihydropyrrolyl (e.g., 2,3-dihydro-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-lH-imidazolyl, 4,5-dihydro-lH-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, one ring of a polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2-dihydroquinolin-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups composed of a heterocycloalkenyl fused to an aromatic ring are described below.

[0171] 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-lH-indenyl, 1,2,3,4-tetrahydronaphthyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzo furanyl, 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]isothiophenyl, 2,3-dihydrobenzo[d]isothiophenyl, 2,3-dihydrobenzo[d]thiophenyl, 5,6-dihydro-4H-cyclopenta[d]thiophenyl, 4,5,6,7-tetrahydrobenzo[d]thiophenyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiophenyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-l-one, l,2-dihydroindazol-3-one, lH-benzo[d]imidazol-2(3H)-one, benzo furan-2(3H)-one, benzo furan-3(2H)-one, isobenzo furan-l(3H)-one, benzo[c]isoxazol-3(lH)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-l(3H)-one, benzo[c]isothiophen-3(lH)-one, benzo[d]isothiophen-3(2H)-one, benzo[d]thiophen-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, l,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(lH,3H)-dione, quinoxalin-2(lH)-one, quinoxalin-2,3(lH,4H)-dione, cinnolin-4(3H)-one, pyridin-2(lH)-one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, lH-pyrrolo[3,2-b]pyridin-2(3H)-one, lH-pyrrolo[3,2-c]pyridin-2(3H)-one, lH-pyrrolo[2,3-c]pyridin-2(3H)-one, lH-pyrrolo[2,3-b]pyridin-2(3H)-one, l,2-dihydropyrazolo[3,4-d]thiazol-3-one, and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one.As discussed herein, whether a ring is to be considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group is determined by the atom(s) that bind the moiety to the parent structure.

[0172] "Halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0173] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso isomers, and other stereoisomeric forms, including mixtures thereof in racemic scale, in optically pure form, and in intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, these compounds are intended to comprise both E and Z isomers. When the compounds described herein contain moieties that are capable of existing in tautomeric forms, and unless otherwise specified, the compounds are intended to include all possible tautomers.

[0174] "Protecting group" has its conventional meaning associated with it in organic synthesis, i.e., a group that is selectively blocking one or more reactive sites in a multifunctional compound so that a chemical reaction can be carried out selectively at another unprotected reactive site, and so that the group can be readily removed after the selective reaction is complete. A wide variety of protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, "hydroxyl protected forms" contain at least one hydroxyl group protected by a hydroxyl protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0175] The term "pharmaceutically acceptable salt" refers to a salt of any of the compounds herein that is known to be nontoxic and generally used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness and is biologically or otherwise pharmaceutically desirable. 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 acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases 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, propylamine, and ethanolamine. In some embodiments, a pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium, and magnesium salts.

[0176] If a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an acid addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, particularly a pharmaceutically acceptable acid addition salt (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those of skill will recognize various synthetic methodologies that can be used to prepare pharmaceutically acceptable acid addition salts.

[0177] A "solvate" is formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0178] The term "substituted" means that the specified group or moiety bears one or more substituents, including but not limited to substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halogen, hydroxy, nitro, carboxy, sulfhydryl, sulfanylalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonamido, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term "unsubstituted" means that the specified group bears no substituents. Where the term "substituted" is used to describe a structural system, substitution is intended to occur at any valency permitted position on the system. Where a group or moiety bears more than one substituent, it is understood that the substituents can be the same or different from each other. In some embodiments, a substituted group or moiety bears one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0179] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" encompasses "alkyl" as defined herein and "substituted alkyl." Those skilled in the art will appreciate that with respect to any group containing one or more substituents, such group does not intend to introduce any substitution or substitution pattern that is not practically and / or inherently stable. It will also be appreciated that where a group or moiety is optionally substituted, the disclosure includes embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0180] The compounds disclosed and / or described herein can be in an isotopically enriched form, e.g., enriched 2 H, 3 H, 11 C, 13 C and / or 14C content. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy of the compounds disclosed and / or described herein and increase the duration of action of these compounds. Deuterium-substituted compounds can be synthesized using various methods such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0181] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical composition is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0182] The terms "patient," "individual," and "subject" refer to an animal, such as a mammal, a bird, or a fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, for example, a human who has been or will be the object of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be applicable to both human therapy and veterinary applications.

[0183] As used herein, the term "treatment" refers to the ability to modulate nicotinamide phosphoribosyltransferase (NAMPT). As used herein, "modulate" refers to a change in activity, directly or indirectly, in response to the presence of a chemical entity as described herein, relative to the activity in the absence of the chemical entity. The change can be an increase in activity or a decrease in activity, and can be due to a direct interaction of the chemical entity with the target, or due to an interaction of the chemical entity with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical entity can increase or decrease the activity of a target, e.g., by directly binding to the target, by (directly or indirectly) causing another factor to increase or decrease the activity of the target, or by (directly or indirectly) increasing or decreasing the amount of the target present in a cell or organism.

[0184] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein, as defined herein, sufficient to effect a treatment when administered to a patient in need of treatment. A therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation of nicotinamide phosphoribosyltransferase (NAMPT). The therapeutically effective amount will vary depending on, for example, the subject and disease state being treated, the subject's body mass and age, the severity of the disease state, the particular compound, the dosing regimen to be followed, the time of administration, the mode of administration, all of which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount can be determined experimentally, e.g., by assaying blood concentrations of the chemical entity, or theoretically, by calculating bioavailability.

[0185] "Treatment" (and related terms, such as "treat," "treating," "in treatment") includes one or more of preventing a disease or condition (i.e., causing the clinical symptoms of the disease or condition not to develop); inhibiting a disease or condition; slowing or arresting the development of clinical symptoms of a disease or condition; and / or relieving a disease or condition (i.e., causing regression or remission of clinical symptoms). The term encompasses instances in which the patient is experiencing the disease or condition, as well as instances in which the patient is not currently experiencing but is expected to develop the disease or condition. The term encompasses complete and partial reduction or prevention of a condition or disease, and complete or partial reduction of clinical symptoms of a disease or condition. Thus, the compounds described and / or disclosed herein can prevent an existing disease or condition from worsening, help manage the disease or condition, or reduce or eliminate the disease or condition. When used prophylactically, the compounds disclosed and / or described herein can prevent the development of a disease or condition, or reduce the extent of a disease or condition that can develop.

[0186] Compounds

[0187] Compounds and salts (such as pharmaceutically acceptable salts) thereof are described in detail herein, including the Summary and the appended claims. Uses of all compounds described herein are also provided, including any and all stereoisomers of the compounds described herein, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and any mixture thereof in any ratio (including racemic mixtures), salts, and solvates, as well as methods of making such compounds. Any compound described herein can also be referred to as a drug.

[0188] In one aspect, a compound of Formula (II) is provided:

[0189]

[0190] or a pharmaceutically acceptable salt thereof, wherein:

[0191] R 1 is halogen or methoxy;

[0192] R 6 is hydrogen or halogen; and

[0193] p is 0 or 1, wherein

[0194] when p is 1,

[0195] R 2 is hydrogen or Ci-C6alkyl, or together with Z 4 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0196] R 3 is hydrogen or Ci-C6alkyl;

[0197] R 4 is

[0198] a) Z 1 NR a C(O)-,

[0199] b) Z 2 C(O)NR b -,

[0200] c) Z 3 (CR c R d ) m NR e -,

[0201] d) Z 4 S(O)2(CH2) n -,

[0202] e) Z 5 OC(O)-,

[0203] f) NR f R g C(O)-,

[0204] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl or C3-C6cycloalkyl substituents,

[0205] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected R y substituents, -C1-C6alkyl optionally substituted with one or more independently selected halogen substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo substituents, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halogen or -C1-C6alkyl substituents, and C3-C6cycloalkyl, 12 substituents, -C1-C6alkyl optionally substituted with one or more independently selected halogen substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo substituents, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halogen or -C1-C6alkyl substituents, and C3-C6cycloalkyl,

[0206] i) Z 6 S(O)2N(R s )-,

[0207] j) Z 7 N(R t )S(O)2-,

[0208] k) Z 8 -O-(CH2) q -; wherein

[0209] R a and R e are each independently hydrogen or C1-C6alkyl;

[0210] R b is hydrogen or C1-C6alkyl, or R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0211] R c and R d are each independently hydrogen or C1-C6alkyl, or R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl;

[0212] R f and R gtogether with the nitrogen to which it is attached, form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R x substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0213] each R h is independently -C1-C6alkyl, -O-C1-C6alkyl or C6-C 12 aryl optionally substituted with one or more independently selected halogen substituents;

[0214] each R x is independently selected from the group consisting of halogen, -OH, -C3-C6cycloalkyl, -C1-C6alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0215] each R y is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR q R r , C6-C 12 aryl and 5- to 6-membered heteroaryl;

[0216] each R j , R k , R m , R n , R o , R p , R q and R r are independently hydrogen or C1-C6alkyl;

[0217] R s is hydrogen or -C1-C6alkyl;

[0218] R t is hydrogen or -C1-C6alkyl;

[0219] m is 0 or 1;

[0220] n is 0, 1 or 2; and

[0221] q is 0 or 1;

[0222] Z 1 and Z 5 each independently is R z ;

[0223] Z 2 and Z 3 each independently is hydrogen or R z ;

[0224] Z 4 is hydrogen or R z , or together with R 2 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0225] Z 6 is selected from the group consisting of 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, 5- to 6-membered heteroaryl, and C1-C6alkyl;

[0226] Z 7 is C6-C 12 aryl;

[0227] Z 8 is selected from the group consisting of 5- to 6-membered heteroaryl and C3-C6cycloalkyl, and

[0228] R z is selected from the group consisting of:

[0229] a) C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CN, C3-C6cycloalkyl, -NHC1-C6alkyl, C6-C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein the C6-C 12 aryl, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and the 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, and C1-C6alkoxy;

[0230] b) C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C6-C 12 aryl optionally substituted with a 5- or 10-membered heteroaryl, C1-C6alkyl, and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6alkyl groups;

[0231] c) C1-C6alkoxy;

[0232] d) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl, -C1-C6alkoxy, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w -C1-C6alkyl, -C1-C6alkoxy, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR u R v , C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and R v each independently is hydrogen or C1-C6alkyl;

[0233] e) C6-C 12 aryl; and

[0234] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; and

[0235] R 5 is hydrogen, halogen, or together with R b and the intervening atoms forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring, provided that

[0236] (1) when R 4 is Z 1 NR a C(O)-, Z 1 is not methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiophene;

[0237] (2) R 4 is not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridinylpiperazinyl, 4-(furanylmethyl)piperazinyl, and

[0238] (3) the compound of Formula (II) is not a compound of Table IX; and

[0239] when p is 0, R 4 is

[0240] l) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which exactly contains two ring heteroatoms, which are both nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -Ci-C6-alkyl substituents and is optionally further substituted with one or more oxo substituents,

[0241] m) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which exactly contains one ring heteroatom, which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6-alkyl substituents,

[0242] n) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which is substituted with one or more independently selected -S(0)2-Ci-C6-alkyl substituents and is optionally further substituted with one or more independently selected oxo or -Ci-C6-alkyl substituents,

[0243] o) 5-membered heterocycloalkyl or heterocycloalkenyl which exactly contains two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, Ci-C6-alkyl or -S(0)2-(Ci-C6-alkyl) substituents,

[0244] p) 6-membered heterocycloalkyl or heterocycloalkenyl which exactly contains two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, Ci-C6-alkyl or -S(0)2-(Ci-C6-alkyl) substituents,

[0245] q) 5-membered heteroaryl which exactly contains two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heteroaryl is exactly substituted with one methyl substituent,

[0246] r) 5-membered heteroaryl which exactly contains two ring heteroatoms, which are both nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents,

[0247] s) 6-membered heteroaryl which contains one or two ring heteroatoms and is optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is not

[0248] t) Z 9 -S(O)2-,

[0249] u) Z 10 -S(O)2-NH-,

[0250] v) Z 11 -C(O)-NH-,

[0251] w)Z 12 -CH2-O-,

[0252] x)Z 13 -O-,

[0253] y)Z 14 -C(H)(C1-C6 alkyl)-NH-C(O)-,

[0254] z) or

[0255] aa) in

[0256] Z 9 Selected from the group consisting of: cyclopropyl, C6-C 12 Aryl, optionally substituted with one or more independently selected R A substituted 3 to 10 membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6 alkyl), one or more independently selected R B -NH2 substituted with a substituent, and optionally with one or more independently selected R C Substituent-substituted C1-C6 alkyl, provided that Z 9 Not for Unsubstituted methyl or unsubstituted ethyl, wherein:

[0257] R A is -C1-C6 alkyl or -CN; and

[0258] R B is (i) -C1-C6 alkyl-(5- to 10-membered heteroaryl), or (ii) optionally substituted with one or more independently selected C6-C 12 aryl-substituted 5- to 10-membered heteroaryl; and

[0259] R C is a 3- to 8-membered heterocycloalkyl or heterocycloalkenyl group;

[0260] Z 10 is one or more independently selected C6-C 12 C1-C6 alkyl substituted with an aryl substituent;

[0261] Z 11 Selected from the group consisting of: C3-C5 substituted with one or more independently selected 3 to 10 membered heterocycloalkyl or heterocycloalkenyl substituents 10 Cycloalkyl and C1-C6 alkyl, provided that when Z 11 When it is cyclopropyl, R 1 Not methoxy;

[0262] Z 12 Selected from the group consisting of: C6-C 12 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, C1-C6 alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents, and -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl);

[0263] Z 13 is a 5- to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents; and

[0264] Z 14 is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected C1-C6 alkyl substituents; and

[0265] R 5 For hydrogen.

[0266] In one aspect, compounds of formula (IG) are provided:

[0267]

[0268] or a pharmaceutically acceptable salt thereof, wherein:

[0269] R 1 is halogen or methoxy;

[0270] R 2 is hydrogen or C1-C6 alkyl, or with Z 4 and the intervening atoms together form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0271] R 3 is hydrogen or C1-C6 alkyl;

[0272] R 4 for

[0273] a)Z 1 NR a C(O)-,

[0274] b)Z 2 C(O)NR b -,

[0275] c)Z 3 (CR c R d ) m NR e -,

[0276] d)Z 4 S(O)2(CH2)n

[0277] e) Z 5 OC(O)-,

[0278] f) NR f R g C(O)-,

[0279] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl or C3-C6cycloalkyl substituents,

[0280] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected R y substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo substituents, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halogen or -C1-C6alkyl substituents, and C3-C6cycloalkyl, 12 substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo substituents, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halogen or -C1-C6alkyl substituents, and C3-C6cycloalkyl,

[0281] i) Z 6 S(O)2N(R s )-,

[0282] j) Z 7 N(R t )S(O)2-,

[0283] k) Z 8 -O-(CH2) q -; wherein

[0284] R a and R e are each independently hydrogen or C1-C6alkyl;

[0285] R b is hydrogen or C1-C6alkyl, or together with R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0286] R c and R d are each independently hydrogen or C1-C6alkyl, or R c and R d ​together with the carbon to which it is attached form a C3-C6cycloalkyl;

[0287] R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R x -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h -NHC(O)OC1-C6alkyl, -NR j R k -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0288] each R h is independently -C1-C6alkyl, -O-C1-C6alkyl or C6-C 12 aryl optionally substituted with one or more independently selected halogen substituents;

[0289] each R x is independently selected from the group consisting of halogen, -OH, -C3-C6cycloalkyl, -C1-C6alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0290] each R y is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR q R r , C6-C 12 aryl and 5- to 6-membered heteroaryl;

[0291] each R j , R k , R m , R n , R o , R p , R q and R r are independently hydrogen or C1-C6alkyl;

[0292] R s is hydrogen or -C1-C6alkyl;

[0293] R t is hydrogen or -C1-C6alkyl;

[0294] m is 0 or 1 ;

[0295] n is 0, 1 or 2;

[0296] q is 0 or 1 ;

[0297] Z 2 and Z 3 each independently is hydrogen or R z ;

[0298] Z 4 is hydrogen or R z , or together with R 2 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0299] Z 6 is selected from the group consisting of 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, 5- to 6-membered heteroaryl and C1-C6alkyl;

[0300] Z 7 is C6-C 12 aryl;

[0301] Z 8 is selected from the group consisting of 5- to 6-membered heteroaryl and C3-C6cycloalkyl, and

[0302] R z is selected from the group consisting of:

[0303] a) C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CN, C3-C6cycloalkyl, -NHC1-C6alkyl, C6-C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl and 5- to 10-membered heteroaryl, wherein the C6-C 12 aryl, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl and the 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl and C1-C6alkoxy;

[0304] b) C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C6-C 12 aryl optionally substituted with a 5- or 10-membered heteroaryl, C1-C6alkyl and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6alkyl groups;

[0305] c) C1-C6alkoxy;

[0306] d) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl, -C1-C6alkoxy, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w -C1-C6alkyl, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR u R v , C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and R v each independently is hydrogen or C1-C6alkyl;

[0307] e) C6-C 12 aryl; and

[0308] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents;

[0309] R 5 is hydrogen, halogen, or together with R b and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and

[0310] R 6 is hydrogen or halogen, Z 1 and Z 5 each independently is R z , provided that

[0311] (1) when R 4 is Z 1 NR a C(O)-, Z 1 is not methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiophene;

[0312] (2) R 4 is not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridinylpiperazinyl, 4-(furanylmethyl)piperazinyl, and

[0313] (3) the compound of Formula (I-G) is not a compound of Table IX.

[0314] In one aspect, a compound of Formula (I) is provided:

[0315]

[0316] or a pharmaceutically acceptable salt thereof,

[0317] wherein:

[0318] R 1 is halogen or methoxy;

[0319] R 2 is hydrogen or Ci-C6alkyl, or, together with Z 4 and the intervening atoms, forms a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring;

[0320] R 3 is hydrogen or Ci-C6alkyl;

[0321] R 4 is

[0322] a) Z 1 NR a C(O)-,

[0323] b) Z 2 C(O)NR b -,

[0324] c) Z 3 (CR c R d ) m NR e -,

[0325] d) Z 4 S(O)2(CH2) n -,

[0326] e) Z 5 OC(O)-,

[0327] f) NR f R g C(O)-,

[0328] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected Ci-C6alkyl substituents, or

[0329] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y-C1-C6alkyl substituted with one or more independently selected halo substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halo substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein

[0330] R a and R e each independently is hydrogen or C1-C6alkyl;

[0331] R b is hydrogen or C1-C6alkyl, or, together with R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0332] R c and R d each independently is hydrogen or C1-C6alkyl, or R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl;

[0333] R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -CN, oxo, C1-C6alkyl optionally substituted with one or more independently selected R x -C1-C6alkyl substituted with one or more independently selected halo substituents, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl;

[0334] each R h independently is -C1-C6alkyl optionally substituted with one or more independently selected halo substituents, -O-C1-C6alkyl, or C6-C 12 aryl;

[0335] each R x is independently selected from the group consisting of halo, -OH, -C3-C6cycloalkyl, -C1-C6alkoxy, -NR o R p, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0336] Each R y independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r 、C6-C 12 Aryl and 5- to 6-membered heteroaryl;

[0337] Each R j 、R k 、R m 、R n 、R o 、R p 、R q and R r are independently hydrogen or C1-C6 alkyl;

[0338] m is 0 or 1; and

[0339] n is 0, 1, or 2;

[0340] R 5 is hydrogen, or with R b and the intervening atoms together form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0341] Z 1 and Z 5 Each independently is R z ;

[0342] Z 2 and Z 3 are each independently hydrogen or R z ;

[0343] Z 4 is hydrogen or R z , or with R 2 and the intervening atoms are taken together to form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring; and

[0344] R z Selected from the group consisting of:

[0345] a) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 aryl, 3 to 10 membered heterocycloalkyl or heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein the C6-C 12The aryl group, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy;

[0346] b) C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of: C6-C6 cycloalkyl optionally substituted with 5- or 10-membered heteroaryl 12 Aryl, C1-C6 alkyl and C1-C6 alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyl groups;

[0347] c) C1-C6 alkoxy;

[0348] d) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R w -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; wherein each R w independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v 、C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0349] e)C6-C 12 aryl; and

[0350] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0351] In some embodiments of Formula (II), Formula (IG), or Formula (I), (1) when R 4 Z 1 NR a When C(O)-, Z 1 is not methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, or -CH2-thiophene; (2) R4 is not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridinylpiperazinyl, 4- (furanylmethyl)piperazinyl, and (3) the compound of Formula (II), Formula (I-G), or Formula (I) is not a compound of Table IX.

[0352] Table IX:

[0353]

[0354]

[0355]

[0356] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 1 is halogen. For example, in some embodiments, R 1 is fluorine. In some embodiments, R 1 is chlorine. In some embodiments, R 1 is bromine. In other embodiments, R 1 is iodine.

[0357] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 1 is methoxy.

[0358] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 2 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.

[0359] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl. For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.

[0360] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 5 is hydrogen. In some embodiments, R b is, if present, taken together with R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, R 5 is halogen. In some embodiments, R 5fluoro. In some embodiments, R 5 chloro. In some embodiments, R 5 bromo. In some embodiments, R 5 iodo.

[0361] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 hydrogen. In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 halo. In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 fluoro. In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 chloro. In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 bromo. In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 6 iodo.

[0362] 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 has Formula (I-G). In other embodiments of the compound of Formula (II), p is 1 and the compound has Formula (I).

[0363] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is selected from the group consisting of 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(CH2) n -, Z 5 OC(O)-, and NR f R g C(O)-. In some embodiments, R 4 is Z 1 NR a C(O)- or NR f R g C(O)-. In some embodiments, R 4 is Z 1 NR a C(O)- or Z 2 C(O)NR b -.

[0364] In another aspect, the compound of formula (II), formula (IG), or formula (I) is a compound of formula (IA):

[0365]

[0366] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R a and Z 1 As defined for Formula (II), Formula (IG) or Formula (I), or any variation or embodiment thereof.

[0367] In some embodiments, the compound is a compound of Formula (I-A1), (I-A2), (I-A3), or (I-A4):

[0368]

[0369]

[0370] or a pharmaceutically acceptable salt thereof, wherein R 1 、R a and Z 1 As defined for Formula (II), Formula (IG), Formula (I) or Formula (IA) or any variation or embodiment thereof.

[0371] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), R a In some embodiments, R a is a C1-C6 alkyl group. For example, in some embodiments, R a is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0372] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 R z In some embodiments, Z 1 Selected from the group consisting of:

[0373] C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: -OH, C3-C6 cycloalkyl, C6-C 12 aryl, 3 to 10 membered heterocycloalkyl or heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein the C6-C 12The aryl group, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy;

[0374] C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of: C6-C6 cycloalkyl optionally substituted with 5- or 10-membered heteroaryl 12 Aryl, C1-C6 alkyl and C1-C6 alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with C1-C6 alkyl; and

[0375] A 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of: -C1-C6 alkyl and -C(O)OC1-C6 alkyl, wherein the -C1-C6 alkyl group is optionally substituted with C6-C 12 Aryl substitution.

[0376] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 In some embodiments, Z 1 is an unsubstituted C1-C6 alkyl. 1 is a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of: -OH, C3-C6 cycloalkyl, C6-C 12 aryl, 3 to 10 membered heterocycloalkyl or heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein the C6-C 12 The aryl group, the 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group, and the 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy.

[0377] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IA), Z 1 is a C3-C6 cycloalkyl group. 1 is an unsubstituted C3-C6 cycloalkyl. 1 is a C3-C6 cycloalkyl group substituted with one or more substituents independently selected from the group consisting of: a C6-C6 cycloalkyl group optionally substituted with a 5- or 10-membered heteroaryl group 12 aryl, C1-C6 alkyl and C1-C6 alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with C1-C6 alkyl. 1C3-C6cycloalkyl optionally substituted with one or more groups independently selected from methoxy, ethoxy, and phenyl. In some embodiments, Z 1 C3-C6cycloalkyl optionally substituted with C1-C6alkoxy optionally substituted with 5- or 10-membered heteroaryl, wherein the 5- or 10-membered heteroaryl is optionally further substituted with C1-C6alkyl (e.g. C3-C6cycloalkyl optionally substituted with one or more groups independently selected from methoxy, ethoxy, and phenyl. In some embodiments, Z 1 C3-C6cycloalkyl optionally substituted with one or more groups independently selected from methoxy, ethoxy, and phenyl. In some embodiments, Z 1 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents independently selected from the group consisting of C6-C 12 aryl, C1-C6alkyl, and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with C1-C6alkyl.

[0378] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), Z 1 3- to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 3- to 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 3- to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of -C1-C6alkyl and -C(O)OC1-C6alkyl, wherein the -C1-C6alkyl is optionally substituted with C6-C 12 aryl. In some embodiments, Z 1 each optionally substituted with one or more substituents independently selected from the group consisting of -C1-C6alkyl and -C(O)OC1-C6alkyl, wherein the -C1-C6alkyl is optionally substituted with C6-C 12 aryl.

[0379] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), Z 1 C1-C6alkyl. In certain embodiments, Z 1 ethyl. In some embodiments, Z 1 ethyl, and ​

[0380] In another aspect, the compound of Formula (II), Formula (I-G), or Formula (I) is a compound of Formula (I-B):

[0381]

[0382] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 5 , R b , and Z 2 are as defined for Formula (II), Formula (I-G), or Formula (I), or any variation or embodiment thereof. 1 2 3 5 b 2 are as defined for Formula (II), Formula (I-G), or Formula (I), or any variation or embodiment thereof.

[0383] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), R b is hydrogen. In some embodiments, R b is C1-C6 alkyl. For example, in some embodiments, R b is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), R 5 is hydrogen. In other embodiments, R b and R 5 together with the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments of Formula (II) or Formula (I-G), R 5 is halogen. In some embodiments, R 5 is fluorine. In some embodiments, R 5 is chlorine. In some embodiments, R 5 is bromine. In some embodiments, R 5 is iodine.

[0384] In some embodiments, the compound is a compound of Formula (I-B1), (I-B2), or (I-B3):

[0385]

[0386]

[0387] or a pharmaceutically acceptable salt thereof, wherein R 1 , and Z 2 are as defined for Formula (II), Formula (I-G), Formula (I), or Formula (I-B), or any variation or embodiment thereof.

[0388] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2is hydrogen. In some embodiments, Z 2 is R z is hydrogen. In some embodiments, Z 2 is selected from the group consisting of:

[0389] C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl and 5- to 10-membered heteroaryl;

[0390] C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy;

[0391] C1-C6alkoxy;

[0392] 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C1-C6alkyl substituents;

[0393] C6-C 12 aryl; and

[0394] 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0395] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl and 5- to 10-membered heteroaryl. In some embodiments, Z 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl, each optionally substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl and 5- to 10-membered heteroaryl.

[0396] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy. In some embodiments, Z 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy.

[0397] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is C1-C6alkoxy. In some embodiments, Z 2methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy.

[0398] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more independently selected -Ci-C6alkyl substituents.

[0399] In some embodiments, Z 2 is a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is an azetidinyl group optionally substituted with one or more -Ci-C6alkyl substituents or a tetrahydrofuryl group optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is each optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is In some embodiments, Z 2 is In some embodiments, Z 2 is each optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is

[0400] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is a C6-Ci2aryl group. For example, in some embodiments, Z 12 is a C6-Ci2aryl group. For example, in some embodiments, Z 2 is a phenyl or naphthyl group.

[0401] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 is a 5- to 6-membered heteroaryl group optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2pyridinyl optionally substituted with one or more independently selected -Ci-C6alkyl substituents. In some embodiments, Z 2 pyridinyl optionally substituted with methyl, ethyl, or isopropyl. In some embodiments, Z 2 pyridinyl substituted with methyl. In other embodiments, Z 2 pyridinyl substituted with isopropyl. In some embodiments, Z 2 is selected from the group consisting of: In some embodiments, Z 2 is

[0402] In some embodiments, Z 2 is selected from the group consisting of: ethyl,

[0403] In some embodiments, Z 2 is

[0404] In another aspect, the compound of Formula (II), Formula (I-G), or Formula (I) is a compound of Formula (I-C):

[0405]

[0406] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d , R e , m, and Z 3 are as defined for Formula (I-G) or Formula (I), or any variation or embodiment thereof.

[0407] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-C), m is 0. In other embodiments, m is 1. In some embodiments of Formula (I-G), Formula (I), or Formula (I-C), R c is hydrogen. In other embodiments, R c is Ci-C6alkyl. In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-C), R d is hydrogen. In other embodiments, R d is Ci-C6alkyl. In some embodiments, R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl.

[0408] In some embodiments, the compound is of formula (I-C1), (I-C2), (I-C3), or (I-C4):

[0409]

[0410] or a pharmaceutically acceptable salt thereof, wherein R 1 、R e and Z 3 As defined for Formula (II), Formula (IG), Formula (I), or Formula (IC), or any variation or embodiment thereof.

[0411] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), R e In other embodiments, R e It is a C1-C6 alkyl group.

[0412] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), Z 3 In some embodiments, Z 3 R z In some embodiments, Z 3 Selected from the group consisting of: C3-C6 cycloalkyl; 3 to 10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C1-C6 alkyl or oxo; C6-C 12 and 5 to 10 membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, Z 3 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with -C1-C6 alkyl or oxo. 3 Selected from the group consisting of: In some embodiments, Z 3 for

[0413] In another aspect, the compound of formula (II), formula (IG), or formula (I) is a compound of formula (ID):

[0414]

[0415] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 , n and Z 4 As defined for Formula (II), Formula (IG) or Formula (I), or any variation or embodiment thereof.

[0416] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-D), n is 0. In some embodiments, n is 1. In other embodiments, n is 2.

[0417] In some embodiments, the compound is a compound of formula (I-D1) or (I-D2):

[0418]

[0419] or a pharmaceutically acceptable salt thereof, wherein R 1 and Z 4 are as defined for formula (II), formula (I-G), formula (I), or formula (I-D), or any variation or embodiment thereof.

[0420] In some embodiments, the compound is a compound of formula (I-D3), (I-D4), (I-D5), (I-D6), or (I-D7):

[0421]

[0422]

[0423] or a pharmaceutically acceptable salt thereof, wherein R 1 are as defined for formula (II), formula (I-G), formula (I), or formula (I-D), or any variation or embodiment thereof.

[0424] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-D), Z 4 is hydrogen. In some embodiments, Z 4 is R z . In other embodiments, Z 4 is C1-C6 alkyl. For example, in some embodiments, Z 4 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In some embodiments, Z 4 together with R 2 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, is selected from the group consisting of:

[0425] In another aspect, the compound of formula (II), formula (I-G), or formula (I) is a compound of formula (IE):

[0426]

[0427] or a pharmaceutically acceptable salt thereof, wherein R 1 , R2 、R 3 and Z 5 As defined for Formula (II), Formula (IG), Formula (I), or any variation or embodiment thereof.

[0428] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IE), Z 5 is a C1-C6 alkyl group. For example, in some embodiments, Z 5 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. 5 For ethyl.

[0429] In another aspect, the compound of formula (II), formula (IG), or formula (I) is a compound of formula (IF):

[0430]

[0431] or a salt thereof, wherein R 1 、R 2 、R 3 、R f and R g As defined for Formula (II), Formula (IG) or Formula (I), or any variation or embodiment thereof.

[0432] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g Together with the nitrogen to which it is attached, it forms a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected R x Substituent-substituted -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R h 、-NHC(O)OC1-C6 alkyl、-NR j R k 、-C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl.

[0433] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g Together with the nitrogen to which it is attached, it forms a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected Rx -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h -NHC(O)OC1-C6alkyl, -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 g , together with the nitrogen to which they are attached, form a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R x -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h -NHC(O)OC1-C6alkyl, -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, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R x -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)R h -NHC(O)OC1-C6alkyl, -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 g , together with the nitrogen to which they are attached, form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C1-C6alkyl, wherein the -C1-C6alkyl is optionally substituted with -OH. In some embodiments, R f and R g , together with the nitrogen to which they are attached, form a pyrrolidinyl optionally substituted with -C1-C6alkyl, wherein the -C1-C6alkyl is optionally substituted with -OH. In some embodiments, ​​

[0434] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g Together with the nitrogen to which it is attached, it forms a 6- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected R x Substituent-substituted -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R h 、-NHC(O)OC1-C6 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 g Together with the nitrogen to which it is attached, they form a bicyclic 6- to 10-membered heterocycloalkyl or heterocycloalkenyl group. For example, in some embodiments, R f and R g Together with the nitrogen to which it is attached, it forms Each is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected R x Substituent-substituted -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R h 、-NHC(O)OC1-C6 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 g Together with the nitrogen to which it is attached, it forms a bridged 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments, Selected from the group consisting of: Each is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected R x Substituent-substituted -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R h 、-NHC(O)OC1-C6 alkyl、-NR j R k 、-C(O)NRm R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl.

[0435] 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, is selected from the group consisting of: each is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)Ra, -C(O)ORa, -C(O)NRaRa, -NRaC(O)Ra, -NRaRa, -NRaC(O)ORa, -NRaC(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -ORa, -CN, -NO2, -NRaC(O)ORa, -NRaS(O)2Ra, -OC(O)NRaRa, -OC(O)Ra, -Si(Ra)3, -NRaC(N-CN)NRaRa, and -N=C(NRa)NRaRa. x substituted -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, -C(O)Ra, -C(O)ORa, -C(O)NRaRa, -NRaC(O)Ra, -NRaRa, -NRaC(O)ORa, -NRaC(O)NRaRa, -S(O)2Ra, -S(O)2NRaRa, -ORa, -CN, -NO2, -NRaC(O)ORa, -NRaS(O)2Ra, -OC(O)NRaRa, -OC(O)Ra, -Si(Ra)3, -NRaC(N-CN)NRaRa, and -N=C(NRa)NRaRa. h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl.

[0436] In some embodiments, is selected from the group consisting of:

[0437]

[0438] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents. In some embodiments, R 4is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzoxadiazolyl, benzothienyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furanopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, and imidazothiazolyl, each optionally substituted with one or more independently selected C1-C6alkyl substituents. In some embodiments, R 4 is a 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents. In some embodiments, R 4 is pyrazolyl, pyridyl, or oxadiazole, each optionally substituted with one or more independently selected C1-C6alkyl substituents. In certain embodiments, R 4 is selected from the group consisting of:

[0439] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected R y substituents, -C1-C6alkyl optionally substituted with one or more independently selected halogen substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents. 12 substituents, -C1-C6alkyl optionally substituted with one or more independently selected halogen substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0440] In some embodiments, R 4 is a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -S(O)2-C1-C6alkyl or -C1-C6alkyl optionally substituted with -OH. In some embodiments, R 4azetidinyl or piperazinyl optionally substituted with -S(0)2-Ci-C6alkyl or -Ci-C6alkyl optionally substituted with -OH. In some embodiments, R 4 azetidinyl optionally substituted with -S(0)2-Ci-C6alkyl. In some embodiments, R 4 azetidinyl substituted with -S(0)2CH3.

[0441] In some embodiments, R 4 piperazinyl optionally substituted with -Ci-C6alkyl optionally substituted with -OH. In certain embodiments, R 4 piperazinyl optionally substituted with -CH2C(CH3)2OH.

[0442] In some embodiments of formula (II), formula (I-G), or formula (I), R 4 is selected from the group consisting of:

[0443]

[0444]

[0445] In some embodiments, R 4 is selected from the group consisting of:

[0446] In some embodiments, R 4 is In some embodiments, R 4 is

[0447] In some embodiments of formula (II), formula (I-G), or formula (I), R 4 is Z 6 S(0)2N(R s )-. In some embodiments, Z 6 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl. In other embodiments, Z 6 is 5- to 6-membered heteroaryl. In some embodiments, Z 6 is Ci-C6alkyl. In some embodiments, Z 6 is methyl. In some of the foregoing embodiments, R s is hydrogen. In other embodiments, R s is Ci-C6alkyl. In other embodiments, R s is methyl. In some embodiments, R 4 is

[0448] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is Z 7 N(R t )S(O)2-. In some embodiments, Z 7 is C6-C 12 aryl. In some embodiments, Z 7 is phenyl. In some embodiments, R t is hydrogen. In other embodiments, R t is C1-C6alkyl. In other embodiments, R t is methyl. In some embodiments, R 4 is -S(O)2-NH-phenyl.

[0449] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is Z 8 -O-(CH2) q -. In some embodiments, q is 0, and R 4 is Z 8 -O-. In other embodiments, q is 1, and R 4 is Z 8 -O-(CH2)-. In some of the foregoing embodiments, Z 8 is 5- to 6- membered heteroaryl. In some embodiments, Z 8 is pyridyl. In other of the foregoing embodiments, Z 8 is C3-C6cycloalkyl. In some embodiments, Z 8 is cyclopentyl. In some embodiments, R 4

[0450] In some embodiments of Formula (II), p is 0. In some embodiments of Formula (II), p is 0, and the compound has Formula (II-A):

[0451]

[0452] or a pharmaceutically acceptable salt thereof, wherein:

[0453] R 1 is halogen or methoxy;

[0454] R 4 is

[0455] ​l) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which contains exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -Ci-C6alkyl substituents and is optionally further substituted with one or more oxo substituents,

[0456] m) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which contains exactly one ring heteroatom, which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6alkyl substituents,

[0457] n) 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which is substituted with one or more independently selected -S(0)2-Ci-C6alkyl substituents and is optionally further substituted with one or more independently selected oxo or -Ci-C6alkyl substituents,

[0458] o) 5-membered heterocycloalkyl or heterocycloalkenyl which contains 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 is optionally substituted with one or more independently selected oxo, -Ci-C6alkyl or -S(0)2-(Ci-C6alkyl) substituents,

[0459] p) 6-membered heterocycloalkyl or heterocycloalkenyl which contains 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 is optionally substituted with one or more independently selected oxo, -Ci-C6alkyl or -S(0)2-(Ci-C6alkyl) substituents,

[0460] q) 5-membered heteroaryl which contains exactly two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the 5-membered heteroaryl is exactly substituted with one methyl substituent,

[0461] r) 5-membered heteroaryl which contains exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents,

[0462] s) 6-membered heteroaryl which contains one or two ring heteroatoms and is optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is not

[0463] t) Z 9 -S(0)2-,

[0464] u) Z 10 -S(0)2-NH-,

[0465] v) Z 11-C(O)-NH-,

[0466] w)Z 12 -CH2-O-,

[0467] x)Z 13 -O-,

[0468] y)Z 14 -C(H)(C1-C6 alkyl)-NH-C(O)-,

[0469] z) or

[0470] aa) in

[0471] Z 9 Selected from the group consisting of: cyclopropyl, C6-C 12 Aryl, optionally substituted with one or more independently selected R A substituted 3 to 10 membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6 alkyl), one or more independently selected R B -NH2 substituted with a substituent, and optionally with one or more independently selected R C Substituent-substituted C1-C6 alkyl, provided that Z 9 Not for Unsubstituted methyl or unsubstituted ethyl, wherein:

[0472] R A is -C1-C6 alkyl or -CN; and

[0473] R B is (i) -C1-C6 alkyl-(5- to 10-membered heteroaryl), or (ii) optionally substituted with one or more independently selected C6-C 12 aryl-substituted 5- to 10-membered heteroaryl; and

[0474] R C is a 3- to 8-membered heterocycloalkyl or heterocycloalkenyl group;

[0475] Z 10 is one or more independently selected C6-C 12 C1-C6 alkyl substituted with an aryl substituent;

[0476] Z 11 Selected from the group consisting of: C3-C5 substituted with one or more independently selected 3 to 10 membered heterocycloalkyl or heterocycloalkenyl substituents 10 Cycloalkyl and C1-C6 alkyl, provided that when Z 11 When it is cyclopropyl, R 1 Not methoxy;

[0477] Z 12 is selected from the group consisting of C6-C 12 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, C1-C6alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents, and -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl);

[0478] Z 13 is 5- to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6alkyl) substituents; and

[0479] Z 14 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; and

[0480] R 6 is hydrogen or halogen.

[0481] In some embodiments of Formula (II) or Formula (II-A), R 4 is selected from the group consisting of:

[0482] 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that specifically includes two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C1-C6alkyl substituents and is optionally further substituted with one or more oxo substituents,

[0483] 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that specifically includes one ring heteroatom, which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -C1-C6alkyl substituents,

[0484] 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that is substituted with one or more independently selected -S(O)2-C1-C6alkyl substituents and is optionally further substituted with one or more independently selected oxo or -C1-C6alkyl substituents,

[0485] 5-membered heterocycloalkyl or heterocycloalkenyl that specifically includes 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 is optionally substituted with one or more independently selected oxo, -C1-C6alkyl or -S(O)2-(C1-C6alkyl) substituents, and

[0486] 6-membered heterocycloalkyl or heterocycloalkenyl that includes 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 substituted with one or more independently selected oxo, -Ci-C6alkyl, or -S(0)2-(Ci-C6alkyl) substituents.

[0487] In some embodiments of Formula (II) or Formula (II-A), R 4 is 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that includes exactly one ring heteroatom, which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6alkyl substituents. In some embodiments, R 4 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl that includes exactly one ring heteroatom, which is an oxygen atom, wherein the 5- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6alkyl substituents.

[0488] In some embodiments of Formula (II) or Formula (II-A), R 4 is 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that includes exactly one ring heteroatom, which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6alkyl substituents. In some embodiments, R 4 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl that includes exactly one ring heteroatom, which is an oxygen atom, wherein the 5- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -Ci-C6alkyl substituents.

[0489] In some embodiments of Formula (II) or Formula (II-A), R 4 is 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that is substituted with one or more independently selected -S(0)2-Ci-C6alkyl substituents and is optionally further substituted with one or more independently selected oxo or -Ci-C6alkyl substituents. In some embodiments, R 4 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl that is substituted with one or more independently selected -S(0)2-Ci-C6alkyl substituents and is optionally further substituted with one or more independently selected oxo or -Ci-C6alkyl substituents.

[0490] In some embodiments of Formula (II) or Formula (II-A), R 4is a 5-membered heterocycloalkyl or heterocycloalkenyl group that specifically contains 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 group is optionally substituted with one or more independently selected oxo, -Ci-C6alkyl, or -S(0)2-(Ci-C6alkyl) substituents.

[0491] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 6-membered heterocycloalkyl or heterocycloalkenyl group that specifically contains 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 group is optionally substituted with one or more independently selected oxo, -Ci-C6alkyl, or -S(0)2-(Ci-C6alkyl) substituents.

[0492] In some embodiments of Formula (II) or Formula (II-A), R 4 is selected from the group consisting of:

[0493] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group that specifically contains two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is substituted with one or more independently selected -Ci-C6alkyl substituents and is optionally further substituted with one or more independently selected oxo substituents; or a 6-membered heterocycloalkyl or heterocycloalkenyl group that specifically contains 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 group is optionally substituted with one or more independently selected oxo, -Ci-C6alkyl, or -S(0)2-(Ci-C6alkyl) substituents. In some embodiments, R 4 is

[0494] In some embodiments of Formula (II) or Formula (II-A), R 4 is selected from the group consisting of:

[0495] a 5-membered heteroaryl group that specifically contains two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, wherein the 5-membered heteroaryl group is specifically substituted with one methyl substituent,

[0496] a 5-membered heteroaryl group that specifically contains two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl group is substituted with one or more methyl substituents, and

[0497] a 6-membered heteroaryl group that contains one or two ring heteroatoms and is optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl group is not

[0498] In some embodiments of Formula (II) or Formula (II-A), R 4 is a 5-membered heteroaryl group that includes 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 group is substituted with exactly one methyl substituent. In other embodiments, R 4 is a 5-membered heteroaryl group that includes exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 5-membered heteroaryl group is substituted with one or more methyl substituents. In other embodiments, R 4 is a 6-membered heteroaryl group that includes one or two ring heteroatoms and is optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl group is not In some embodiments, R 4 is selected from the group consisting of:

[0499] 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 -CH2-O-, Z 13 -O-, Z 14 -C(H)(C1-C6 alkyl)-NH-C(O)-,

[0500]

[0501] 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):

[0502]

[0503] or a pharmaceutically acceptable salt thereof.

[0504] In some embodiments of Formula (II), Formula (II-A), or Formula (II-A1), Z 9 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group that is optionally substituted with one or more independently selected R A substituents, provided that Z 9 is not In some embodiments, Z 9 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group that is optionally substituted with one or more independently selected R A5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituted with one or more independently selected Rsubstituents, provided that Z is not 9 is not In some embodiments, R A is methyl or -CN. In some embodiments, Z 9 is unsubstituted 3- to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 9 is unsubstituted 5- to 6-membered heterocycloalkyl or heterocycloalkenyl.

[0505] In some embodiments, Z 9 is optionally substituted with one or more independently selected R C substituted with one or more independently selected Rsubstituents, provided that Z is not 9 is not unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is optionally substituted with one or more independently selected R C substituted with one or more independently selected Rsubstituents, provided that Z is not 9 is not unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is unsubstituted C3-C6alkyl. In some embodiments, Z 9 is unsubstituted propyl. In some embodiments, Z 9 is C1-C6alkyl optionally substituted with one or more independently selected 3- to 8-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 9 is C1-C6alkyl optionally substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl.

[0506] In some embodiments, Z 9 is -NH(C1-C6alkyl). In some embodiments, Z 9 is -NH(CH3). In some embodiments, Z 9 is substituted with one or more independently selected R B substituted with one or more independently selected Rsubstituents. In some embodiments, Z 9 is substituted with one or more independently selected -C1-C6alkyl-(5- to 10-membered heteroaryl). In some embodiments, Z 9 is substituted with one or more independently selected -C1-C6alkyl-(5- to 6-membered heteroaryl). In some embodiments, Z 9 is substituted with one or more independently selected -C1-C6alkyl-pyridyl. In other embodiments, Z 9 is optionally substituted with one or more independently selected C6-C 12aryl-substituted 5- to 10-membered heteroaryl. In other embodiments, Z 9 is a 5- to 6-membered heteroaryl optionally substituted with one or more phenyl groups.

[0507] In some embodiments, Z 9 is cyclopropyl. In some embodiments, Z 9 is C6-C 12 aryl. In some embodiments, Z 9 is phenyl.

[0508] In some embodiments, Z 9 is selected from the group consisting of:

[0509] In some embodiments of formula (II) or formula (II-A), R 4 is Z 10 -S(O)2-NH-. In some embodiments, Z 10 is C1-C6 alkyl substituted with one or more phenyl substituents. In some embodiments, Z 10 is

[0510] In some embodiments of formula (II) or formula (II-A), R 4 is Z 11 -C(O)-NH-. In some embodiments, Z 11 is C3-C 10 cycloalkyl, provided that when Z 11 is cyclopropyl, then R 1 is not methoxy. In some embodiments, Z 11 is C1-C6 alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents. In some embodiments, Z 11 is C1-C6 alkyl substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents.

[0511] In some embodiments, Z 11 is

[0512] In some embodiments of formula (II) or formula (II-A), R 4 is Z 12 -CH2-O-. In some embodiments, Z 12 is selected from the group consisting of: C6-C 12aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, C1-C6alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents, and -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl). In some embodiments, Z 12 is C6-C 12 aryl. In some embodiments, Z 12 is 5- to 10-membered heteroaryl. In some embodiments, Z 12 is 5- to 6-membered heteroaryl. In some embodiments, Z 12 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl. In other embodiments, Z 12 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 12 is C1-C6alkyl substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents. In some embodiments, Z 12 is C1-C6alkyl substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 6-membered heteroaryl substituents. In some embodiments, Z 12 is -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl). In other embodiments, Z 12 is -C(O)-(5- to 6-membered heterocycloalkyl or heterocycloalkenyl). In some embodiments, Z 12 is selected from the group consisting of:

[0513] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 13 -O-. In some embodiments, Z 13 is 5- to 6-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6alkyl) substituents. In some embodiments, Z 13 is pyridyl substituted with one or more independently selected -C(O)-NH(C1-C6alkyl) substituents. In some embodiments, Z 13

[0514] In some embodiments of Formula (II) or Formula (II-A), R 4 is Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-. In some embodiments, R 4 is Z 14 ​-C(H)(CH3)-NH-C(O)-. In some embodiments, Z 14 is a 5- to 6-membered heteroaryl group optionally substituted with one or more independently selected C1-C6alkyl substituents. In some embodiments, Z 14 is a pyridyl group optionally substituted with one or more independently selected C1-C6alkyl substituents. In some embodiments of Formula (II) or Formula (II-A), R 4 is

[0515] In some embodiments of Formula (II) or Formula (II-A), R 4 is In other embodiments, R 4 is

[0516] In some embodiments of Formula (II) or any variation thereof, including Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), R 1 is halogen. 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 is methoxy. In some embodiments of Formula (II) or any variation thereof, including Formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), and (I-F), R 2 is hydrogen. In some embodiments, R 2 is C1-C6alkyl. For example, in some embodiments, R 2is hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl. For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.

[0517] In some embodiments of formula (II), or any variation thereof, including formula (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), and (I-F), R 2 and R 3 are each hydrogen. In some embodiments, R 2 is C1-C6 alkyl and R 3 is hydrogen. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl, and R 3 is hydrogen. In certain embodiments, R 2 is methyl and R 3 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is C1-C6 alkyl. For example, in some embodiments, R 2 is hydrogen, and R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or t-butyl. In certain embodiments, R 2 is hydrogen

[0518] and R 3 is methyl.

[0519] In some embodiments, provided herein are the compounds described in Table 1, and salts thereof.

[0520] Table 1.

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] In some variations, any of the compounds described herein, such as the compounds of Formula (II), (I), (I-G), (I) (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), or any variations thereof, the compounds of Table 1 can be deuterated (e.g., hydrogen atoms replaced with deuterium atoms). In some of these variations, the compounds are deuterated at a single site. In other variations, the compounds are deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner analogous to the preparation of the corresponding non-deuterated compounds. Other methods known in the art can also be used to replace hydrogen atoms with deuterium atoms.

[0593] Any formula given herein is intended to represent compounds having the structure depicted by the formula, as well as certain variations or forms. In particular, compounds of any formula given herein can have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in all ratios, are intended to be embraced within the scope of the formula. Thus, any formula given herein is intended to represent both the racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof in all ratios. Where a compound of Table 1 is depicted in a particular stereochemical configuration, any alternative stereochemical configuration of the compound is also provided herein, as well as mixtures of the compound stereoisomers in any ratio. For example, where a compound of Table 1 has a stereocenter in the "S" stereochemical configuration, the enantiomer of the compound is also provided herein, with the stereocenter in the "R" stereochemical configuration. Likewise, where a compound of Table 1 has a stereocenter in the "R" configuration, the enantiomer of the compound is also provided herein, in the "S" stereochemical configuration. Mixtures of the compound having the "S" and "R" stereochemical configurations are also provided. Additionally, if a compound of Table 1 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, if a compound of Table 1 contains a first stereocenter and a second stereocenter having the "R" and "R" stereochemical configurations, respectively, the compound stereoisomers having the first stereocenter and the second stereocenter in the "S" and "S" stereochemical configurations, respectively, the "S" and "R" stereochemical configurations, respectively, and the "R" and "S" stereochemical configurations, respectively, are also provided. If a compound of Table 1 contains a first stereocenter and a second stereocenter having the "S" and "S" stereochemical configurations, respectively, the compound stereoisomers having the first stereocenter and the second stereocenter in the "R" and "R" stereochemical configurations, respectively, the "S" and "R" stereochemical configurations, respectively, and the "R" and "S" stereochemical configurations, respectively, are also provided.If a compound of Table 1 contains a first stereocenter and a second stereocenter having "S" and "R" stereochemistry, respectively, then stereoisomers of the compound having "R" and "S" stereochemistry at the first and second stereocenters, respectively, are also provided. Similarly, if a compound of Table 1 contains a first stereocenter and a second stereocenter having "R" and "S" stereochemistry, respectively, then stereoisomers of the compound having "S" and "R" stereochemistry at the first and second stereocenters, respectively, are also provided. In addition, certain structures can exist in geometric isomeric (i.e., cis and trans isomers), tautomeric, or atropisomeric forms. In addition, any formula given herein is intended to represent also any hydrate, solvate, amorphous and polymorphic forms, and mixtures thereof, of such compounds, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0594] Representative examples of the compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It will be appreciated that in one aspect, any of the compounds can be used in the methods detailed herein, including, where applicable, intermediate compounds that can be isolated and administered to a person or subject.

[0595] The compounds depicted herein can be in salt form, even if a salt is not depicted, and it will be appreciated that the compositions and methods provided herein encompass all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms of the compounds, as will be well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0596] In one variation, the compounds herein are synthetic compounds prepared for administration to a person or subject. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier are provided. 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 detailed herein or forms thereof.

[0597] The R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 , Z 3 , Z4 , 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 , 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 in any variation or embodiment can be combined with 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 , 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 , Rm , 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 , each other variation or embodiment combination of m, n, p, and q as if each combination had been individually and specifically described.

[0598] Other embodiments will be apparent to those skilled in the art from consideration of the specification and practice of the application.

[0599] As used herein, when any variable occurs more than one time in a chemical formula, its definition in each occurrence is independent of its definition at every other occurrence.

[0600] Formula (II) includes all subformulae thereof. For example, Formula (II) includes compounds of Formulae (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1).

[0601] As shown in Table 1 and Examples 1-16, the names of the compounds 1-552 provided herein were provided by ChemInnovation’s Chem 4d software version 7.5.0.0. The names of the intermediates 1.1-10.0 as shown in Example A-MM were provided by ChemBioDraw Professional 15.0. Those skilled in the art will appreciate that compounds can be named or identified using a variety of commonly accepted naming systems and symbols. For example, compounds can be named or identified using common names, systematic or non-systematic names. Commonly accepted naming systems and symbols in the chemical art include, for example, the Chemical Abstract Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0602] Compositions

[0603] Also provided are compositions, such as pharmaceutical compositions, comprising a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal agents and pharmaceutical agents include those described herein. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, are provided that contain one or more compounds described herein, or pharmaceutically acceptable salts thereof.

[0604] In some embodiments, a pharmaceutically acceptable composition is provided that comprises a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition can contain synthetic intermediates useful in the preparation of the compounds described herein. The compositions described herein can contain any other suitable active or non-active agents.

[0605] Any of the compositions described herein can be sterile or contain sterile components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein can contain one or more substantially pure compounds or conjugates.

[0606] Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or disorder described herein.

[0607] Methods of use

[0608] The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any of the formulae provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in methods of administration and treatment as provided herein.

[0609] Without being bound by theory, it is believed that the compounds and pharmaceutical compositions disclosed herein act by modulating nicotinamide phosphoribosyltransferase (NAMPT). In some embodiments, the compounds and pharmaceutical compositions disclosed herein are activators of NAMPT. In some embodiments, there is provided a method of treating a disease or disorder mediated by NAMPT activity in a person or subject, the method comprising administering to a person or subject in need thereof a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a method of treating cancer, a hyperproliferative disease or disorder, an inflammatory disease or disorder, a metabolic disorder, a cardiac disease or disorder, chemotherapy-induced tissue damage, a kidney disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle atrophy in a person or subject, the method comprising administering to a person or subject in need thereof a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0610] Also provided herein is the use of a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder mediated by NAMPT activity in a subject. In some aspects, provided herein is a compound or composition as described herein 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), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically 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), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder mediated by NAMPT activity. In some embodiments, the disease or disorder is selected from the group consisting of a cancer, a hyperproliferative disease or disorder, an inflammatory disease or disorder, a metabolic disorder, a cardiac disease or disorder, a chemotherapy-induced tissue damage, a kidney disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle atrophy.

[0611] Also provided herein are compositions (including pharmaceutical compositions) as described herein for use in treating, preventing, and / or delaying the onset and / or development of a disease described herein and for use in other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation present in a unit dosage form.

[0612] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, rabbit, pig, sheep, horse, dairy cow, or human. In some embodiments, the subject is a human.

[0613] There are numerous conditions in which small molecule-mediated stimulation of NAMPT activity that would increase NAD+levels would be potentially clinically beneficial (Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13). These conditions include, but are not limited to, cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease and injury, diseases resulting from impaired stem cell function, and DNA damage and primary mitochondrial disorders. In some embodiments, the disease or condition mediated by NAMPT activity is cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease or injury, diseases resulting from impaired stem cell function, or DNA damage and primary mitochondrial disorders.

[0614] Cardiac disease. NAD, as well as NAMPT levels, are reduced in various preclinical models of heart failure. In these models, cardiac function can be rescued by restoring NAD through 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). Thus, increasing the catalytic efficiency of NAMPT with a small molecule activator to compensate for reduced protein levels is a promising strategy for treating various forms of heart failure.

[0615] Chemotherapy-induced tissue damage. Frequently used chemotherapy regimens are limited by toxicity to healthy tissues and severe oxidative stress is believed to play a major role. It has been shown that increasing NAD triggers a strong antioxidant response. Therefore, NAMPT activators are widely considered suitable for use in various settings of chemotherapy to prevent reversible and irreversible secondary lesions. Examples are anthracycline and trastuzumab cardiotoxicity, cisplatin-induced kidney damage, peripheral neuropathy induced by cisplatin, paclitaxel, vincristine and other agents. Neuroprotection by NAMPT activation is also suitable for the treatment / prevention of chemotherapy-related cognitive (“chemobrain”) caused by destruction of healthy nerve tissue during active treatment and for a long time after treatment has been stopped. See, for example, Zheng et al., Clin Sci (Lond). 2019, 133(13): 1505-1521.

[0616] Kidney disease. Kidney disease is highly prevalent and is an area with a pressing unmet medical need. Acute kidney injury (AKI) is diagnosed in about 3% of hospitalized patients. A small group of patients will progress to chronic kidney disease, which can require long-term dialysis or kidney transplantation. A key feature of kidney dysfunction is reduced activity of SIRT1 and SIRT3, characterized by a decrease in the sirtuin substrate NAD, mainly due to impaired de novo NAD+synthesis. NAMPT is stably expressed during kidney injury, whereby small molecule activation of NAMPT should be considered an effective measure to prevent AKI. Similarly, renal mesangial cell hypertrophy exhibits NAD+depletion, and restoration of intracellular NAD+levels should be considered effective. See, for example, Poyan Mehr et al., Nat Med. 2018 Sep;24(9): 1351-9.

[0617] Metabolic disease. Increasing NAD+improves insulin sensitivity, dyslipidemia, mitochondrial function and defends / improves non-alcoholic and alcoholic steatohepatitis in preclinical models of metabolic disease. More than 30 million people are diagnosed with non-alcoholic steatohepatitis in the United States each year and it is one of the main reasons for liver transplantation. See, Guarino and Dufour, Metabolites. 2019 Sep 10;9(9), pii: E180; Yoshino et al., Cell Metab. 2011, 14(4):528-36.

[0618] Muscle disease. Preclinical data have shown that strategies to increase NAD+ can reduce skeletal muscle dysfunction in a number of conditions, including Duchenne's muscular dystrophy and age-related muscle loss. 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.

[0619] Neurological diseases and injuries. Supplementation of NAD via NAMPT activation is neuroprotective and has therapeutic benefit in a wide range of preclinical models of neurological diseases and injuries, including age-related cognitive decline, glaucoma, ischemic stroke, and ALS. See Johnson et al., NPJ Aging Mech Dis. 2018, 4: 10; Harlan et al., J Biol Chem. 2016, 291(20): 10836-46; Zhao et al., Stroke. 2015 Jul; 46(7): 1966-74; Williams et al., Front Neurosci. 2017 Apr 25; 11: 232.

[0620] Diseases caused by impaired stem cell function. Increasing NAD promotes stem cell activation and hematopoiesis and is useful to accelerate expansion of stem cell populations following stem cell transplantation. See Pi et al., Aging (Albany NY). 2019, 11(11): 3505-3522.

[0621] DNA damage disorders and primary mitochondrial disorders. NAMPT activators will also be useful to treat DNA damage disorders associated with accelerated aging phenotypes, such as xeroderma pigmentosum, Cockayne syndrome, and ataxia telangiectasia. Similarly, there are several primary mitochondrial disorders that share common symptoms and manifestations for which increasing NAD via NAMPT activation can 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.

[0622] In some embodiments, there is provided a method of treating a disease or disorder mediated by NAMPT activity in a subject in need thereof, the method comprising administering to a person or subject in need thereof a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of cardiac disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease and injury, diseases resulting from impaired stem cell function, and DNA damage and primary mitochondrial disorders.

[0623] Additional applications of small molecule NAMPT activators are provided in Table 2.

[0624] Table 2

[0625]

[0626]

[0627]

[0628] In some embodiments, the disease or disorder mediated by NAMPT activity is cancer and chemotherapy-induced tissue damage, cardiovascular disease, kidney disease, chronic inflammatory and fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, neurological disease or injury, or a DNA damage disorder or primary mitochondrial disorder. In some embodiments, there is provided a method of treating a disease or disorder mediated by NAMPT activity in a subject in need thereof, the method comprising administering to a person or subject in need thereof a compound of Formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is cancer or chemotherapy-induced tissue damage, cardiovascular disease, kidney disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, neurological disease or injury, a DNA damage disorder or primary mitochondrial disorder, including any of the diseases listed in Table 2.

[0629] Permeability

[0630] Membrane permeability is a key property in the design of small molecule drugs, especially for compounds with intracellular targets, as the efficacy of these compounds is highly dependent on their ability to cross membranes. The efficacy of a drug can depend on the ability of the drug to reach the intended site of action. Drug absorption is the movement of a drug into the bloodstream. Many factors influence this process, including the physicochemical properties of the drug, the formulation, and the route of administration. In general, for oral therapy, the drug needs to be introduced into the blood via the path of the gut. For other routes, such as intravenous therapy, intramuscular injection, and enteral nutrition, absorption is more direct to the bloodstream. Regardless of the route of administration, the drug must dissolve and be absorbed to achieve a therapeutic effect. By modulating the factors that influence absorption, the pharmacokinetic (PK) properties of a drug can be changed. The permeability of a drug across biological membranes is a key factor that influences absorption and distribution. This is because if a drug is to reach the systemic circulation, it needs to first cross several semipermeable cell membranes. Drugs can cross cell membranes by passive diffusion, facilitated passive diffusion, active transport, and pinocytosis. The physicochemical properties of a drug, such as size and lipophilicity, as well as membrane-based efflux mechanisms, can result in poor permeability.

[0631] For orally administered drugs, most absorption occurs in the small intestine. Thus, drugs that are poorly absorbed by the small intestine and / or actively effluxed from the small intestine have a lower likelihood of actually reaching the intended site of action. This lower likelihood of reaching the intended site of action will thus greatly diminish the efficacy of the drug, requiring significantly higher and potentially impractical doses compared to the dose that would be expected by in vitro on-target potency assays. Conversely, drugs that are readily absorbed and / or effluxed from the small intestine in reduced amounts will likely require lower doses to be administered than similar or even more "potent" drugs that are poorly absorbed. Thus, the ability of a drug to be absorbed by the small intestine and the amount of efflux that occurs within the small intestine are important considerations in the development of any orally administered drug.

[0632] There are a wide variety of in vitro methods to assess the permeability of a drug and to predict the in vivo absorption of a drug. 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 way to study human intestinal permeability and drug efflux. Monolayers of the Caco-2 cell line have been accepted as an accurate in vitro model of human small intestinal drug absorption. Even though the cell line is isolated from a human colon adenocarcinoma, the differentiated Caco-2 cells resemble intestinal cells (small intestinal absorptive cells) in that they form functional tight junctions, apical and basolateral domains, and a brush border cytoskeleton. The Caco-2 permeability assay measures the rate of transport of a compound across the Caco-2 cells and assesses transport in both directions. It has been shown that the in vitro apparent permeability of a drug for Caco-2 cells in the apical to basolateral direction (PappAB) correlates with in vivo oral absorption in humans, in that drugs with poor Caco-2 cell permeability have poor small intestinal drug absorption in vivo, and drugs with high or complete Caco-2 cell permeability have high small intestinal drug absorption in vivo (Artursson et al., Biochem Biophys Res Comm, 1991, 3(29):880-885). Typically, in Caco-2 cells in the apical to basolateral direction, drugs that are completely absorbed in vivo have a permeability coefficient greater than 1 x 10-6cm / s, and drugs that are poorly absorbed have a permeability coefficient less than 1 x 10-7cm / s. aap ) correlates with in vivo oral absorption in humans, in that drugs with poor Caco-2 cell permeability have poor small intestinal drug absorption in vivo, and drugs with high or complete Caco-2 cell permeability have high small intestinal drug absorption in vivo (Artursson et al., Biochem Biophys Res Comm, 1991, 3(29):880-885). Typically, in Caco-2 cells in the apical to basolateral direction, drugs that are completely absorbed in vivo have a permeability coefficient greater than 1 x 10 -6 cm / s, and drugs that are poorly absorbed have a permeability coefficient less than 1 x 10-7cm / s.

[0633] In addition, Caco-2 cells have been used to identify and quantify the level of active efflux of a drug. The active efflux of a drug can be determined by calculating the ratio of P aap in the basolateral to apical direction to P aap in the apical to basolateral direction. Typically, the lower the ratio, the higher the ability of the drug to reach the intended site of action; and the higher the ability of the drug to reach the intended site of action, the greater the potential efficacy of the drug.

[0634] The compounds provided herein are suitable for oral administration, as measured by the permeability profile of the compounds as evaluated by the Caco-2 cell model. As described in Biological Example 2 herein, the compounds described herein have been demonstrated to have improved permeability.

[0635] Dose

[0636] The compounds and compositions disclosed and / or described herein are administered at therapeutically effective doses, e.g., doses sufficient to provide treatment for a disease state. While human dosage levels have not been optimized for the chemical entities described herein, generally, daily dosages are in the range of about 0.01 to 100 mg / kg body weight; in some embodiments, about 0.05 to 10.0 mg / kg body weight; and in some embodiments, about 0.10 to 1.4 mg / kg body weight. Thus, for administration to a 70 kg person, the dosage range would be, in some embodiments, about 0.7 to 7000 mg / day; in some embodiments, about 3.5 to 700.0 mg / day; and in some embodiments, about 7 to 100.0 mg / day. The amount of chemical entity administered will depend on, for example, the subject and disease state being treated, the severity of the affliction, the manner and timing of administration, and the judgment of the prescribing physician. By way of example, exemplary dosage ranges for oral administration are about 5 mg to about 500 mg / day, and exemplary intravenous administration dosages are about 5 mg to about 500 mg / day, each depending on the compound pharmacokinetics.

[0637] A daily dose is the total amount administered in a day. A daily dose can be administered daily, every other day, weekly, every 2 weeks, every month, or at varying intervals, without limitation. In some embodiments, a daily dose is administered for a period ranging from one day to the subject’s entire life. In some embodiments, a daily dose is administered once per day. In some embodiments, a daily dose is administered in multiple divided doses, such as in 2, 3, or 4 divided doses. In some embodiments, a daily dose is administered in 2 divided doses.

[0638] Administration of the compounds and compositions disclosed and / or described herein can be via any accepted modes of administration for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, a compound or composition is administered orally or intravenously. In some embodiments, a compound or composition disclosed and / or described herein is administered orally.

[0639] 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 can also be administered in sustained or controlled release dosage form (e.g., controlled / sustained release pellets, depot injection, osmotic pump, or transdermal (including electrotransport) patch form) for extended periods of time and / or pulsed dosing at a predetermined rate. In some embodiments, the compositions are provided in unit dosage form suitable for single administration precise dosages.

[0640] The compounds disclosed and / or described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate. If desired, pharmaceutical compositions can also contain minor amounts of nontoxic 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). Typically, the pharmaceutical compositions will contain from about 0.005% to 95% or from about 0.5% to 50% by weight of the compounds disclosed and / or described herein, depending on the type of disorder or conditions treated. Actual methods for preparing such dosage forms are known, or will be apparent in light of this disclosure, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0641] In some embodiments, the compositions will be in the form of a pill or tablet, and the composition can thus contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders, pellets, solutions or suspensions encapsulated in gelatin capsules.

[0642] Pharmaceutically acceptable liquid compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier, such as water, saline, aqueous right glucose, glycerol, glycols, ethanol, or the like, to form a solution or suspension. Injectable solutions can be prepared in conventional forms, either as liquid solutions or suspensions, emulsions, or solid forms suitable for dissolving or suspending in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient in solution ranging from 0.01 to 10% can be used, and the percentage can be even higher if the composition is a solid that will be subsequently diluted to another concentration. In some embodiments, the composition will comprise about 0.2 to 2% of a compound disclosed and / or described herein in solution.

[0643] Pharmaceutical compositions of the compounds disclosed and / or described herein can also be administered to the respiratory tract in the form of an aerosol or solution for a nebulizer or as a fine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition will have diameters of less than 50 microns, or in some embodiments less than 10 microns.

[0644] Additionally, the pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal agents and pharmaceutical agents include those described herein.

[0645] Kits

[0646] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture can comprise a container having a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. The container can hold a pharmaceutical composition provided herein. The label on the container can indicate that the pharmaceutical composition is used for preventing, treating, or inhibiting a disorder described herein, and can also indicate directions for in vivo or in vitro use.

[0647] In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits can contain instructions for treating a heart disease in a person or subject in need thereof. The kits can additionally contain any materials or equipment that can be used to administer the compound or composition, such as a vial, syringe, or IV bag. The kits can also contain sterile packaging.

[0648] Combinations

[0649] The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned conditions, diseases, or disorders.

[0650] Embodiments

[0651] The following enumerated embodiments represent some aspects of the present invention.

[0652] 1. A compound of Formula (I):

[0653]

[0654] or a pharmaceutically acceptable salt thereof,

[0655] wherein:

[0656] R 1 is halogen or methoxy;

[0657] R 2 is hydrogen or Ci-C6alkyl, or together with Z 4 and the intervening atoms form a 4-6 membered heterocycloalkyl or heterocycloalkenyl ring

[0658] R 3 is hydrogen or Ci-C6alkyl;

[0659] R 4 is

[0660] a) Z 1 NR a C(O)-,

[0661] b) Z 2 C(O)NR b -,

[0662] c) Z 3 (CR c R d ) m NR e -,

[0663] d) Z 4 S(O)2(CH2) n -,

[0664] e) Z 5 OC(O)-,

[0665] f) NR f R g C(O)-,

[0666] g) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected Ci-C6alkyl substituents, or

[0667] h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, -NR y substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, -NR 12 aryl, 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 C1-C6alkyl;

[0668] R a and R e each independently is hydrogen or C1-C6alkyl;

[0669] R b is hydrogen or C1-C6alkyl, or R 5 and the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0670] R c and R d each independently is hydrogen or C1-C6alkyl, or R c and R d together with the carbon to which they are attached form a C3-C6cycloalkyl;

[0671] R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, -NR x substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, -NR h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl;

[0672] each R h independently is -C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -O-C1-C6alkyl, or C6-C 12 aryl;

[0673] each Rx independently selected from the group consisting of halogen, -OH, -C3-C6cycloalkyl, -Ci-C6alkoxy, -NR o R p , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl;

[0674] each R y is independently selected from the group consisting of halogen, -OH, -CN, -Ci-C6alkoxy, -C(O)NR q R r , C6-C 12 aryl and 5- to 6-membered heteroaryl;

[0675] each R j , R k , R m , R n , R o , R p , R q and R r are independently hydrogen or Ci-C6alkyl;

[0676] m is 0 or 1 ; and

[0677] n is 0, 1 or 2;

[0678] R 5 is hydrogen, or together with R b and the intervening atoms forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0679] Z 1 and Z 5 are each independently R z ;

[0680] Z 2 and Z 3 are each independently hydrogen or R z ;

[0681] Z 4 is hydrogen or R z , or together with R 2 and the intervening atoms forms a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; and

[0682] R z is selected from the group consisting of:

[0683] a) Ci-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, -CN, C3-C6cycloalkyl, -NHCi-C6alkyl, C6-C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl and 5- to 10-membered heteroaryl, wherein the C6-C12 each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, and C1-C6alkoxy;

[0684] b) C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C6-C10aryl optionally substituted with 5- or 10-membered heteroaryl, 12 aryl, C1-C6alkyl, and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6alkyl groups;

[0685] c) C1-C6alkoxy;

[0686] d) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, C6-C10aryl optionally substituted with one or more independently selected R w substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C10aryl optionally substituted with one or more independently selected halogen substituents, 5- to 10-membered heteroaryl optionally substituted with one or more independently selected halogen substituents, 3- to 6-membered heterocycloalkyl optionally substituted with one or more independently selected halogen substituents, and 3- to 6-membered heterocycloalkenyl optionally substituted with one or more independently selected halogen substituents; 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents; wherein each R w is independently selected from the group consisting of halogen, -OH, -CN, -C1-C6alkoxy, -C(O)NR u R v , C6-C 12 aryl and 5- to 6-membered heteroaryl; and wherein R u and R v each independently is hydrogen or C1-C6alkyl;

[0687] e) C6-C 12 aryl; and

[0688] f) 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents,

[0689] wherein (1) when R 4 is Z 1 NR a C(O)-, Z 1 is not methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiophene;

[0690] (2) R 4 is not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4- (furanylmethyl)piperazinyl, and

[0691] (3) the compound of Formula (I) is not a compound of Table IX.

[0692] 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen.

[0693] 3. The compound of Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.

[0694] 4. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy.

[0695] 5. The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, R 2 is hydrogen.

[0696] 6. The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, R 2 is C1-C6 alkyl.

[0697] 7. The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, R 3 is hydrogen.

[0698] 8. The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, R 3 is C1-C6 alkyl.

[0699] 9. The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-A):

[0700]

[0701] 10. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R a is hydrogen.

[0702] 11. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R a is C1-C6 alkyl.

[0703] 12. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of:

[0704] C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, C3-C6cycloalkyl, C6-C10aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein the C3-C6cycloalkyl, C6-C10aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more substituents independently selected from the group consisting of -OH, C1-C6alkyl, and C1-C6alkoxy; 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein the C6-C10aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy; 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein the C6-C10aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy;

[0705] C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C6-C10aryl optionally substituted with 5- or 10-membered heteroaryl, wherein the C6-C10aryl is optionally further substituted with C1-C6alkyl; 12 aryl, C1-C6alkyl and C1-C6alkoxy, wherein the 5- or 10-membered heteroaryl is optionally further substituted with C1-C6alkyl; and

[0706] 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of -C1-C6alkyl and -C(O)OC1-C6alkyl, wherein the -C1-C6alkyl is optionally substituted with C6-C10aryl; 12 aryl.

[0707] 13. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of ethyl,

[0708] 14. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-B):

[0709]

[0710] 15. The compound of any one of embodiments 1-8 and 14, or a pharmaceutically acceptable salt thereof, wherein R b is hydrogen.

[0711] 16. The compound of any one of embodiments 1-8 and 14, or a pharmaceutically acceptable salt thereof, wherein R b is C1-C6alkyl.

[0712] 17. The compound of any one of embodiments 1-8 and 14, or a pharmaceutically acceptable salt thereof, wherein R b and R 5 together with the intervening atoms form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring.

[0713] 18. The compound of any one of embodiments 1-8 and 14-17, or a pharmaceutically acceptable salt thereof, wherein Z 2 is hydrogen.

[0714] 19. The compound of any one of embodiments 1-8 and 14-17, or a pharmaceutically acceptable salt thereof, wherein Z 2 is selected from the group consisting of:

[0715] C1-C6alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl and 5- to 10-membered heteroaryl;

[0716] C3-C6cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6alkyl and C1-C6alkoxy;

[0717] C1-C6alkoxy;

[0718] 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more -C1-C6alkyl substituents;

[0719] C6-C 12 aryl; and

[0720] 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0721] 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein Z 2 is 5- to 6-membered heteroaryl optionally substituted with one or more -C1-C6alkyl substituents.

[0722] 21. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein Z 2 is pyridinyl optionally substituted with one or more -C1-C6alkyl substituents.

[0723] 22. The compound of any one of embodiments 1-8 and 14-17, or a pharmaceutically acceptable salt thereof, wherein Z 2 is selected from the group consisting of ethyl,

[0724] 23. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein Z 2 is

[0725] 24. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-C):

[0726]

[0727] 25. The compound of any one of embodiments 1-8 and 24, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0728] 26. The compound of any one of embodiments 1-8 and 24, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0729] 27. The compound of any one of embodiments 1-8 and 24-25, or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen.

[0730] 28. The compound of any one of embodiments 1-8 and 24-25, or a pharmaceutically acceptable salt thereof, wherein R c is C1-C6alkyl.

[0731] 29. The compound of any one of embodiments 1-8, 24-25, and 27-28, or a pharmaceutically acceptable salt thereof, wherein R d is hydrogen.

[0732] 30. The compound of any one of embodiments 1-8, 24-25, and 27-28, or a pharmaceutically acceptable salt thereof, wherein R d is C1-C6alkyl.

[0733] 31. The compound of any one of embodiments 1-8 and 24-25, or a pharmaceutically acceptable salt thereof, wherein R c and R d together with the carbon to which they are attached form C3-C6cycloalkyl.

[0734] 32. The compound of any one of embodiments 1-8 and 24-31, or a pharmaceutically acceptable salt thereof, wherein R e is hydrogen.

[0735] 33. The compound of any one of embodiments 1-8 and 24-31, or a pharmaceutically acceptable salt thereof, wherein R e is C1-C6alkyl.

[0736] 34. The compound of any one of embodiments 1-8 and 24-33, or a pharmaceutically acceptable salt thereof, wherein Z 3 is hydrogen.

[0737] 35. The compound of any one of embodiments 1-8 and 24-33, or a pharmaceutically acceptable salt thereof, wherein Z 3 is selected from the group consisting of:

[0738] C3-C6cycloalkyl;

[0739] 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C1-C6alkyl;

[0740] C6-C 12 aryl; and

[0741] 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0742] 36. The compound of any one of embodiments 1-8 and 24-33, or a pharmaceutically acceptable salt thereof, wherein Z 3 is selected from the group consisting of:

[0743] 37. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-D):

[0744]

[0745] 38. The compound of any one of embodiments 1-8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0746] 39. The compound of any one of embodiments 1-8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0747] 40. The compound of any one of embodiments 1-8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0748] 41. The compound of any one of embodiments 1-8 and 37-40, or a pharmaceutically acceptable salt thereof, wherein Z 4 is hydrogen or R z .

[0749] 42. The compound of any one of embodiments 1-8 and 37-40, or a pharmaceutically acceptable salt thereof, wherein Z 4 is C1-C6alkyl.

[0750] 43. The compound of any one of embodiments 1-8 and 37-40, or a pharmaceutically acceptable salt thereof, wherein Z 4 and R 2 together with the intervening atoms form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring.

[0751] 44. The compound of embodiment 43, wherein is selected from the group consisting of:

[0752] 45. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IE):

[0753]

[0754] 46. ​​The compound of any one of embodiments 1-8 and 45, or a pharmaceutically acceptable salt thereof, wherein Z 5 It is a C1-C6 alkyl group.

[0755] 47. The compound of any one of embodiments 1-8 and 45, or a pharmaceutically acceptable salt thereof, wherein Z 5 For ethyl.

[0756] 48. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IF):

[0757]

[0758] 49. The compound of any one of embodiments 1-8 and 48, or a pharmaceutically acceptable salt thereof, wherein R f and R g Together with the nitrogen to which it is attached, it forms a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, optionally substituted with one or more independently selected R x Substituent-substituted -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R h 、-NHC(O)OC1-C6 alkyl、-NR j R k 、-C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl and 5- to 6-membered heteroaryl.

[0759] 50. The compound of embodiment 49, or a pharmaceutically acceptable salt thereof, wherein R f and R g Together with the nitrogen to which it is attached, it forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with -C1-C6 alkyl, wherein the -C1-C6 alkyl group is optionally substituted with -OH.

[0760] 51. The compound of any one of embodiments 1-8 and 48-49, or a pharmaceutically acceptable salt thereof, wherein Selected from the group consisting of:

[0761]

[0762] 52. The compound of embodiment 51, or a pharmaceutically acceptable salt thereof, wherein

[0763] 53. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0764] 54. The compound of any one of embodiments 1-8 and 53, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

[0765] 55. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, -C1-C6alkyl optionally substituted with one or more independently selected R y substituents, -C1-C6alkoxy optionally substituted with one or more independently selected halogen substituents, -C(O)OC1-C6alkyl, -C(O)C1-C6alkyl, -S(O)2-C1-C6alkyl, C6-C 12 aryl optionally substituted with one or more independently selected halogen substituents, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6alkyl substituents.

[0766] 56. The compound of embodiment 55, or a pharmaceutically acceptable salt thereof, wherein R 4 is 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -S(O)2-C1-C6alkyl or -C1-C6alkyl optionally substituted with -OH.

[0767] 57. The compound of any one of embodiments 1-8 and 55, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

[0768] 58. The compound of embodiment 57, or a pharmaceutically acceptable salt thereof, wherein R 4

[0769] ​​59. A compound selected from the group consisting of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0770] 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1-59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0771] 61. A method of treating a disease or disorder mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject a compound according to any one of embodiments 1-59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 60.

[0772] 62. The method of embodiment 61, wherein the disease or disorder is selected from the group consisting of a cancer, a hyperproliferative disease or disorder, an inflammatory disease or disorder, a metabolic disorder, a cardiac disease or disorder, a chemotherapy-induced tissue damage, a kidney disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease resulting from impaired stem cell function, a disease resulting from DNA damage, a primary mitochondrial disorder, or a muscle disease or muscle atrophy.

[0773] 63. The method of embodiment 61, wherein the disease or disorder 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 neurological injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, neurological injury, poliomyelitis (polio), and spinal cord injury.

[0774] General Synthetic Methods

[0775] Compounds of formula (II), (I-G), (I) (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1) will now be described by reference to the illustrative synthetic schemes below for their general preparation and the specific examples that follow. The skilled person will recognize that, in order to obtain the various compounds herein, the starting materials can be appropriately chosen so that the ultimately desired substituents are either protected or unprotected throughout the entire reaction scheme, where appropriate. Alternatively, it can be necessary or desirable to employ suitable protecting groups for intermediate substituents, which can be removed at a convenient subsequent time in the synthesis. In addition, one skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxyl, or side chain groups) from reaction conditions, and such groups are removed under standard conditions, where appropriate. Unless otherwise specified, the variables are as defined above with respect to formula (II), (I-G), (I) (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1).

[0776] Where 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 the enantiomers. Thus, for example, a mixture of enantiomers (e.g. a racemate) can be reacted with an appropriate chiral compound to produce diastereomeric derivatives. The diastereomeric derivatives can then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered. In another resolution procedure, racemates can be separated by chiral high-performance liquid chromatography. Alternatively, where necessary, particular enantiomers can be obtained by using an appropriate chiral intermediate in one of the procedures described.

[0777] Where it is desired to obtain a particular isomer of a compound or to otherwise purify the reaction products, chromatography, recrystallization, and other conventional separation procedures can also be used on the intermediates or final products.

[0778] General methods for preparing the compounds described herein are depicted in the methods exemplified below. The variable groups in the schemes provided herein are as defined for Formula (II), (I-G), (I) (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), or any variation thereof. Other compounds described herein can be prepared by analogous methods.

[0779] In some embodiments, the compounds provided herein can be synthesized according to Scheme Al, A2, or A3.

[0780] Scheme Al

[0781]

[0782] Scheme A2

[0783]

[0784] Scheme A3

[0785]

[0786] wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined for Formula (II) or any variation thereof detailed herein.

[0787] In certain embodiments, the compounds provided herein can be synthesized according to Scheme Al a, A2a, or A3a:

[0788] Scheme Al a

[0789]

[0790] Scheme A2a

[0791]

[0792] Scheme A3a

[0793]

[0794] wherein R 1 , R 2 , R 3R 4 R 5 as defined for Formula (II) or any variation thereof detailed herein.

[0795] In some embodiments, the compounds provided herein can be synthesized according to Scheme B1 or B2:

[0796] Scheme B1

[0797]

[0798] Scheme B2

[0799]

[0800] wherein R 1 R 2 R 3 R 5 R a R g R f and Z 1 as defined for Formula (II) or any variation thereof detailed herein.

[0801] In certain embodiments, the compounds provided herein can be synthesized according to Scheme B1a or B2a:

[0802] Scheme B1a

[0803]

[0804] Scheme B2a

[0805]

[0806] wherein R 1 R 2 R 3 R 5 R a R g R f and Z 1 as defined for Formula (II) or any variation thereof detailed herein.

[0807] In some embodiments, the compounds provided herein can be synthesized according to Scheme C1 or C2:

[0808] Scheme C1

[0809]

[0810] Scheme C2

[0811]

[0812] where R 1 、R 2 、R 3 、R 5 、R b 、R c 、R e , Z 2 and Z 3 is as defined herein for Formula (II) or any variation thereof, and PG is a suitable protecting group.

[0813] In certain embodiments, the compounds provided herein can be synthesized according to Scheme C1a or C2a:

[0814] Plan C1a

[0815]

[0816] Plan C2a

[0817]

[0818] where R 1 、R 2 、R 3 、R 5 、R b 、R c 、R e , Z 2 and Z 3 As defined herein for Formula (II) or any variation thereof.

[0819] In some embodiments, the compounds provided herein can be synthesized according to Scheme D1:

[0820] Plan D1

[0821]

[0822] where R 1 、R 5 、R c 、R d , m and Z 3 is as defined herein for Formula (II) or any variation thereof, and PG is a suitable protecting group.

[0823] In certain embodiments, the compounds provided herein can be synthesized according to Scheme D1a:

[0824] Plan D1a

[0825]

[0826] where R 1 、R5 、R c 、R d , m and Z 3 As defined herein for Formula (II) or any variation thereof.

[0827] In some embodiments, the compounds provided herein can be synthesized according to Scheme E1:

[0828] Plan E1

[0829]

[0830] where R 1 、R 2 、R 3 、R 5 , n and Z 4 As defined herein for Formula (II) or any variation thereof.

[0831] In certain embodiments, the compounds provided herein can be synthesized according to Scheme E1a:

[0832] Plan E1a

[0833]

[0834] where R 1 、R 2 、R 3 、R 5 , n and Z 4 As defined herein for Formula (II) or any variation thereof.

[0835] In some embodiments, the compounds provided herein can be synthesized according to Scheme F1:

[0836] Plan F1

[0837]

[0838] where R 1 、R 2 、R 3 、R 5 , n and Z 4 As defined herein for Formula (II) or any variation thereof.

[0839] In certain embodiments, the compounds provided herein can be synthesized according to Scheme F1a:

[0840] Plan F1a

[0841]

[0842] where R 1R 2 R 3 R 5 n and Z 4 as defined for Formula (II) or any variation thereof detailed herein.

[0843] Specific non-limiting examples are provided in the Examples section below. Examples

[0844] The following examples are provided to illustrate, but not limit, the compositions, uses, and methods provided herein. Compounds were prepared using the general methods described above.

[0845] The following abbreviations are used throughout the examples: TEA (triethylamine), DCM (dichloromethane), (Boc)20 (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 (diphenyl phosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh3 (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), r.t. (room temperature), DCE (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equiv (equivalents), and DSC (bis(2,5-dioxopyrrolidin-1-yl) carbonate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0846] Example A

[0847] Synthesis of intermediates 1.1, 1.2, 1.3, and 1.4.

[0848] Step 1: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (Intermediate 1-a):

[0849]

[0850] To a solution of ethyl 2-(4-aminophenyl)acetate (27.46 g, 153.2 mmol) in DCM (20 mL) was added 4-methoxybenzyl isocyanate (25.0 g, 153.2 mmol) dropwise at 20 °C. 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 (positive) m / z: 343.1 (M+H) + .1H NMR (400 MHz, 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 = 5.9 Hz, 1H), 4.22 (d, J = 5.4 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.55 (s, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0851] Step 2: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (Intermediate 1.1):

[0852]

[0853] To a solution of intermediate 1-a (26.5 g, 77.5 mmol) in 1,4 dioxane (400 mL) was added 4 N LiOH (234.0 mmol) dropwise at 20 °C. 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 6 N aqueous HC1 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 (positive) m / z: 315.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.47 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.50 (t, J = 6.0 Hz, 1H), 4.22 (d, J = 5.7 Hz, 2H), 3.74 (d, J = 1.3 Hz, 3H), 3.46 (s, 2H).

[0854] Intermediates 1.2 and 1.3 were prepared in a similar manner as Intermediate 1.1 using the reagents provided in the table below in place of isocyanate 4-methoxybenzyl ester.

[0855]

[0856]

[0857] Example B

[0858] Synthesis of Intermediates 2.1, 2.2, 2.3, 2.4, 2.5, 2.6 and 2.7

[0859] Step 1: Preparation of (S)-(l-(4-(3-(4-methoxybenzyl)ureido)phenyl)-ethyl)carbamic acid tert-butyl ester (Intermediate 2-a):

[0860]

[0861] To a solution of (S)-[l-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.0 g, 22.7 mmol) in DCM (20 mL) was added dropwise isocyanate 4-methoxybenzyl ester (14.4 g, 34.0 mmol) at 20 C. The resulting mixture was stirred at room temperature for 4 hours, then methanol (10 mL) was added and cooled to 0 C. After 1 hour at 0 C, the slurry was filtered to give (S)-(l-(4-(3-(4-methoxybenzyl)ureido)-phenyl)ethyl)carbamic acid tert-butyl ester (1.2 g, 6.3 mmol, 28% yield) as an off-white solid. LCMS-APCI (positive) m / z: 400.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.36 - 7.19 (m, 4H), 7.14 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.48 (t, J = 5.9 Hz, 1H), 4.53 (p, J = 7.3 Hz, 1H), 4.21 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H), 1.37 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H).

[0862] Step 2: Preparation of (S)-l-(4-(l-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (Intermediate 2.1):

[0863]

[0864] Intermediate 2-a (34.7 g, 86.9 mmol) was dissolved in dichloromethane and cooled to 0 °C with 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 minutes before the ice bath was removed. The reaction was stirred at room temperature for 45 minutes and the reaction progress was monitored with 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 partitioned between saturated NaHC03solution and DCM. The layers were separated and the aqueous phase was extracted again with DCM. The organic extracts were combined, dried over Na2S04and concentrated under reduced pressure to give (S)-1-(4-(1- aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride as a viscous, nearly colorless oil (6.18 g, 18.28 mmol, 90% yield). The purity was estimated to be 70%. LCMS-APCI (positive) m / z: 300.1 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.40 (d, J = 5.3 Hz, 3H), 7.45 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 3H), 4.29 (p, J = 6.1 Hz, 1H), 4.22 (s, 2H), 3.73 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H).

[0865] In a similar manner to Intermediate 2.1, Intermediates 2.2, 2.3, 2.4, 2.5, 2.6 and 2.7 were prepared using the reagents provided in the table below in place of isocyanate 4-methoxybenzyl ester.

[0866]

[0867]

[0868] Example C

[0869] Synthesis of Intermediates 3.1, 3.2 and 3.3

[0870] Step 1: Preparation of methyl 4-(3-(4-methoxybenzyl)ureido)benzoate (Intermediate 3-a):

[0871]

[0872] To a suspension of methyl 4-isocyanatobenzoate (10.0 g, 56.4 mmol) in dichloromethane (56.4 mL, 1 M) was added (4-methoxyphenyl)methanamine (7.74 g, 56.4 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at room temperature for 60 minutes and the reaction progress was monitored with LC / MS. The reaction became homogenous followed by precipitation of a white solid. The solution was then filtered and the filter cake was washed with excess dichloromethane and dried to yield crude intermediate 3-a (17.4 g, 55.2 mmol, 98% yield) as an off-white solid upon solidification. LCMS-APCI (positive) m / z: 315.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.71 (t, J = 5.9 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H), 3.81 (s, 3H).

[0873] Step 2: Preparation of 1-(4-(hydroxymethyl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 3-b):

[0874]

[0875] To a dry flask was added 120 mL of dry dichloromethane containing intermediate 3-a (16.0 g, 50.9 mmol) and the suspension was cooled to 0 °C. Thereafter, 1 M DIBAL in dichloromethane (126 mL, 126 mmol) was added dropwise over 45 minutes and the reaction was stirred for an additional 30 minutes at 0 °C. The homogenous solution was allowed to warm to room temperature followed by stirring for 4 hours. The solution was then cooled to 0 °C and quenched dropwise with MeOH (100 mL) and after the exotherm had subsided, 300 mL of dichloromethane and 200 mL of sodium hydroxide solution (1 M) were added and the mixture was stirred for an additional 60 minutes at room temperature. The organic layer was then separated and the aqueous layer was extracted with (5:1 dichloromethane-isopropanol, 300 mL). The combined organic layers were washed with brine and dried over magnesium sulfate, filtered and evaporated to yield intermediate 3-b (14.2 g, 49.8 mmol, 99% yield) as a white solid. The crude product was carried through to the following oxidation stage without further purification. LCMS-APCI (positive) m / z: 287.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.61 (t, J = 5.9 Hz, 1H), 5.02 (t, J = 5.7 Hz, 1H), 4.40 (d, J = 5.5 Hz, 2H), 4.22 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H).

[0876] Step 3: Preparation of l-(4-formylphenyl)-3-(4-methoxybenzyl)urea (Intermediate 3.1):

[0877]

[0878] To a suspension of Intermediate 3-b (14.0 g, 48.8 mmol) in dichloromethane- isopropanol (20: 1, 250 mL, 0.2 M) was added manganese dioxide (44.2 g, 508 mmol) at room temperature. The resulting suspension was stirred at room temperature for 12 h. The solution was then filtered through celite. 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 light yellow solid upon solidification. LCMS-APCI (positive) m / z: 285.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.15 (s, 1H), 7.78 (dd, J = 8.6, 2,7 Hz, 2H), 7.62 (dd, J = 8.6, 2,7 Hz, 2H), 7.24 (dd, J = 8.5, 2,8 Hz, 2H), 6.90 (dd, J = 8.6, 2,7 Hz, 2H), 6.87 - 6.77 (m, 1H), 4.43 (dd, J = 8.5, 2,8 Hz, 2H), 3.74 (s, 3H).

[0879] Intermediates 3.2 and 3.3 were prepared in a similar manner to Intermediate 2.1 using the reagents provided in the table below in place of (4-methoxyphenyl)methanamine.

[0880]

[0881] Example D

[0882] Synthesis of Intermediates 4.1 and 4.2

[0883] Step 1: Preparation of phenyl (4-chlorobenzyl)carbamate (Intermediate 4.1):

[0884]

[0885] To a solution of 1-(4-chlorophenyl)methanamine (2.00 g, 14.124 mmol, 1.00 equiv) in THF (30 mL) was added phenyl chloroformate (2.43 g, 15.537 mmol, 1.1 equiv) and K2CO3(2.93 g, 21.186 mmol, 1.5 equiv). 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 eluted with PE / EtOAc (5:1) to give 3.6 g of N-[(4-chlorophenyl)methyl] carbamic acid phenyl ester (95%) as a white solid. LRMS (ES) m / z 262 [M+H].

[0886] Intermediate 4.2 was prepared in a similar manner to Intermediate 4.1, using (4- methoxyphenyl)methanamine instead of (4-chlorophenyl)methanamine.

[0887]

[0888] Example E

[0889] Synthesis of 4-(1-(methylsulfonyl)ethyl)aniline

[0890] (Intermediate 5.0)

[0891] Step 1: Preparation of 1-((methylsulfonyl)methyl)-4-nitrobenzene (Intermediate 5-a):

[0892]

[0893] 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 with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 1 g of 1-(methanesulfonylmethyl)-4-nitrobenzene 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).

[0894] Step 2: Preparation of 1-(1-(methylsulfonyl)ethyl)-4-nitrobenzene (Intermediate 5-b):

[0895]

[0896] To a solution of 1-(methanesulfonylmethyl)-4-nitrobenzene (850 mg, 3.949 mmol, 1 eq) in DMF (10 mL) was added t-BuOK (531 mg, 4.732 mmol, 1.20 eq). After stirring at room temperature for 1 h, to the mixture was added iodomethane (560 mg, 3.945 mmol, 1.00 eq). The resulting mixture was stirred at room temperature for 1 h, and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 950 mg of 1-(1-methanesulfonyl ethyl)-4-nitrobenzene as a yellow oil. No LCMS signal. H-NMR analysis indicated it was 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).

[0897] Step 3: Preparation of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0):

[0898]

[0899] To a solution of 1-(1-methanesulfonyl ethyl)-4-nitrobenzene (950 mg, 4.144 mmol, 1 eq) in methanol (10 mL) was added Pd / C (467 mg, 50% w / w). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 h, filtered to remove the solids and the filtrate was concentrated under reduced pressure to give 700 mg of 4-(1-methanesulfonyl ethyl)aniline as a yellow oil. LRMS (ES) m / z 200 [M+H].

[0900] Example F

[0901] Synthesis of 3-(4-aminophenyl)thietine 1,1-dioxide trifluoroacetate salt

[0902] (Intermediate 6.0)

[0903] Step 1: Preparation of 2-(4-nitrophenyl)propanedioic acid diethyl ester (Intermediate 6-a):

[0904]

[0905] To a solution of 1-bromo-4-nitrobenzene (5 g, 24.752 mmol, 1 eq) in DMSO (50 mL) was added malonic acid 1,3-diethyl ester (12 g, 74.921 mmol, 3.03 eq), CuI (473 mg, 2.484 mmol, 0.10 eq), L-proline (572 mg, 4.968 mmol, 0.20 eq) and K2CO3 (13.7 g, 99.128 mmol, 4.00 eq). The mixture was stirred at 90 °C under nitrogen atmosphere for 2 days, cooled to room temperature, added water (100 mL) and extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 4.7 g of 2-(4-nitrophenyl)propanoic acid 1,3-diethyl ester as a yellow oil. LRMS (ES) m / z 282 (M+H).

[0906] Step 2: Preparation of 2-(4-aminophenyl)propanoic acid diethyl ester (Intermediate 6-b):

[0907]

[0908] To a solution of 2-(4-nitrophenyl)propanoic acid 1,3-diethyl ester (2.2 g, 7.822 mmol, 1 eq) 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 the solids and the filtrate was concentrated under reduced pressure to give 1.9 g of 2-(4-aminophenyl)propanoic acid 1,3-diethyl ester (96.67%) as a yellow oil. LRMS (ES) m / z 252 [M+H].

[0909] Step 3: Preparation of 2-(4-((tert-butoxycarbonyl)amino)phenyl)propanoic acid diethyl ester (Intermediate 6-c):

[0910]

[0911] To a solution of 2-(4-aminophenyl)malonic acid 1,3-diethyl ester (1 g, 3.96 mmol, 1 eq) in THF (10 mL) was added di-tert-butyl dicarbonate (2.6 g, 11.4 mmol, 2.9 eq). The resulting mixture was stirred at room temperature for 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2(30 mL) twice. The combined organic layers were washed with brine (30 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1 g of tert-butyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanoate as an off-white solid. LRMS (ES) m / z 296 [M+H-56].

[0912] Step 4: Preparation of tert-butyl (4-(1,3-dihydroxypropan-2-yl)phenyl)carbamate (Intermediate 6-d):

[0913]

[0914] To a solution of tert-butyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanoate (1 g, 2.846 mmol, 1 eq) in ethanol (20 mL) was added NaBH4(1.08 g, 28.547 mmol, 10.03 eq). The resulting mixture was stirred at room temperature overnight, quenched with aqueous NH4Cl solution (10 mL) at 0 °C, concentrated under vacuum to remove EtOH. The mixture was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20:1) to give 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].

[0915] Step 5: Preparation of dimethane sulfonic acid 2-(4-((tert-butoxy carbonyl)amino)phenyl)propane-1,3-diyl ester (Intermediate 6-e):

[0916]

[0917] To a solution of tert-butyl N-[4-(1,3-dihydroxypropan-2-yl)phenyl]carbamate (670 mg, 2.506 mmol, 1 eq) in DCM (10 mL) was added methanesulfonyl chloride (715 mg, 6.242 mmol, 2.49 eq) and TEA (760 mg, 7.511 mmol, 3.00 eq). The resulting mixture was stirred at room temperature for 2 h and poured into water (20 mL). The aqueous layer was extracted twice with CHCl (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous NaSO, 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].

[0918] Step 6: Preparation of tert-butyl (4-(thietan-3-yl)phenyl)carbamate (Intermediate 6-f):

[0919]

[0920] To 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 NaS (122 mg, 1.564 mmol, 0.60 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 5 hours. 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 NaSO, concentrated under reduced pressure, and purified by silica gel column chromatography eluting 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].

[0921] Step 7: Preparation of tert-butyl (4-(1,1-dioxothietane-3-yl)phenyl)carbamate (Intermediate 6-g):

[0922]

[0923] To a solution of tert-butyl N-[4-(thiacyclobutan-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 extracted with CH2Cl2(20 mL) twice. The combined organic layers were washed with Na2S2O4(10 mL), NaHCO3(10 mL) and washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 290 mg of tert-butyl N-[4-(1,1-dioxo-1 λ6-thiacyclobutan-3-yl)phenyl]carbamate as yellow oil. LRMS (ES) m / z 242 [M+H-56].

[0924] Step 8: Preparation of 3-(4-aminophenyl)thiacyclobutane 1,1-dioxide trifluoroacetate salt (Intermediate 6.0):

[0925]

[0926] To a solution of tert-butyl N-[4-(1,1-dioxo-1 λ6-thiacyclobutan-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, concentrated under reduced pressure to give 190 mg of 3-(4-aminophenyl)thiacyclobutane 1,1-dioxide trifluoroacetate salt as brown solid. LRMS (ES) m / z 298 [M+H].

[0927] Example G

[0928] Synthesis of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide

[0929] (Intermediate 7.0)

[0930] Step 1 : Preparation of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7-a):

[0931]

[0932] To a solution of tetrahydrothiophene 1,1-dioxide (2 g, 16.643 mmol, 1.00 equiv) in THF (20.00 mL) was added LiHMDS (25.00 mL, 25.000 mmol, 1.50 equiv) dropwise at -20 °C over a period of 20 min. After stirring at room temperature under nitrogen atmosphere for 0.5 h, to the mixture was added ZnCl2(3.35 g, 24.575 mmol, 1.48 equiv) at -20 °C. The mixture was stirred at room temperature for 1 h. To the above mixture was added 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). The mixture was stirred at 65 °C under nitrogen atmosphere for 12 h, cooled to room temperature, quenched with aqueous NH4Cl (20 mL) and HCl (1 mol / L, 5 mL) and extracted with CH2Cl2(50 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, 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.

[0933] Step 2: Preparation of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0):

[0934]

[0935] 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 at room temperature under hydrogen atmosphere overnight, filtered to remove the 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].

[0936] Example H

[0937] Synthesis of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate salt

[0938] (Intermediate 8.0)

[0939] Step 1: Preparation of tert-butyl (4-iodophenyl)carbamate (Intermediate 8-a):

[0940]

[0941] To a solution of 4-iodoaniline (1 g, 4.566 mmol, 1 eq) in MeOH (20 mL) was added (Boc)20 (2 g, 0.009 mmol, 2.01 eq) and TEA (2 mL). The resulting mixture was stirred at 50 °C overnight, cooled to room temperature, concentrated in vacuo, added water (50 mL). The mixture was extracted with EtOAc (50 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure, purified by silica gel column chromatography eluted with PE / EtOAc (30:1) to give 650 mg of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 44.61%) as off-white solid. LRMS (ES) m / z 264 [M+H-56].

[0942] Step 2: Preparation of tert-butyl (4-(1,1-dioxo-2,5-dihydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-b):

[0943]

[0944] To a solution of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 2.037 mmol, 1 eq) in toluene (10 mL) was added 2,5-dihydro-1λ6-thiophene-1,1-dione (264 mg, 2.234 mmol, 1.10 eq), Pd(OAc)2 (91 mg, 0.405 mmol, 0.20 eq), TBABr (654 mg, 2.029 mmol, 1.00 eq) and TEA (410 mg, 4.052 mmol, 1.99 eq). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 days and at 80 °C for 3 hours, cooled to room temperature, added water (20 mL). The mixture was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine (30 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure, purified by silica gel column chromatography eluted with PE / EtOAc (3:2) to give 430 mg of tert-butyl N-[4-(1,1-dioxo-2,5-dihydro-1λ6-thiophen-3-yl)phenyl]carbamate (68.24%) as brown solid. LRMS (ES) m / z 254 [M+H-56].

[0945] Step 3: Preparation of tert-butyl (4-(1,1-dioxotetrahydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-c):

[0946]

[0947] To a solution of tert-butyl N-[4-(l,l-dioxo-2,5-dihydro-l lambda6-thiophen-3- yl)phenyl]carbamate (430 mg, 1.390 mmol, 1 eq) 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-(l,l-dioxo-l lambda6-thioldidene-3-yl)phenyl]carbamate as a brown solid (90.11%). LRMS (ES) m / z 256 [M+H].

[0948] Step 4: Preparation of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate (Intermediate 8.0):

[0949]

[0950] To a solution of tert-butyl N-[4-(l,l-dioxo-2,5-dihydro-l lambda6-thiophen-3- yl)phenyl]carbamate (430 mg, 1.390 mmol, 1 eq) 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-(l,l-dioxo-l lambda6-thioldidene-3-yl)phenyl]carbamate as a brown solid (90.11%). LRMS (ES) m / z 256 [M+H].

[0951] Example I

[0952] Synthesis of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0953] (Intermediate 9.0)

[0954] Step 1: Preparation of trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4- yl ester (Intermediate 9-a):

[0955]

[0956] To a solution of LDA (8.5 mL, 17.0 mmol, 1.10 equiv) in THF (20 mL) was added a solution of thioxan-4-one (1.8 g, 15.493 mmol, 1 equiv) in THF (5 mL) dropwise over a period of 10 min at -78 °C under an argon atmosphere. After stirring at room temperature for 0.5 h under an argon atmosphere, a solution of 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonmethane sulfonamide (6.09 g, 17.047 mmol, 1.10 equiv) in THF (10 mL) was added dropwise over a period of 10 min at -78 °C. The resulting mixture was stirred at room temperature for 0.5 h under an argon atmosphere, quenched with water (100 mL) at 0 °C and extracted with EtOAc (200 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, 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].

[0957] Step 2: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (Intermediate 9-b):

[0958]

[0959] To a solution of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (2.4 g, 9.668 mmol, 1 equiv) in dioxane (20 mL) and H2O (10 mL) was added (4-nitrophenyl)boronic acid (1.94 g, 11.602 mmol, 1.20 equiv), Pd(dppf)Cl2CH2Cl2(1.58 g, 1.934 mmol, 0.20 equiv) and K2CO3(2.66 g, 19.34 mmol, 2 equiv). The resulting mixture was stirred at 85 °C for 3 h under a nitrogen atmosphere, cooled to room temperature and water (200 mL) was added. The resulting mixture was extracted with EtOAc (200 mL) twice. The combined organic layers were washed with brine (200 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, 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 as a yellow solid (46.74 %). LRMS (ES) m / z 222 [M+H].

[0960] Step 3: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (Intermediate 9-c):

[0961]

[0962] To a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (700 mg, 3.164 mmol, 1 eq) in DCM (15 mL) was added m-CPBA (1.6 g, 9.5 mmol, 3 eq) at -78 °C. The resulting mixture was stirred at room temperature for 3 h, poured into water (20 mL). The aqueous layer was extracted with CH2Cl2(30 mL) twice. The combined organic layers were washed with Na2SO3(10 mL aqueous solution), NaHCO3(10 mL aqueous solution) and washed with brine (20 mL) twice, dried over anhydrous Na2SO4, 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].

[0963] Step 4: Preparation of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0):

[0964]

[0965] To a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (650 mg, 2.559 mmol, 1 eq) in methanol (8 mL) and THF (8 mL) was added Pd / C (325 mg, 50% w / w). The resulting mixture was stirred at room temperature under hydrogen atmosphere overnight, filtered to remove the 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].

[0966] Example J

[0967] Synthesis of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide

[0968] (Intermediate 10.0)

[0969] Step 1: Preparation of (Z)-ethyl 2-cyano-3-(4-nitrophenyl)but-2-enoate (Intermediate 10-a):

[0970]

[0971] To a solution of 1-(4-nitrophenyl)ethan-1-one (2 g, 12.110 mmol, 1 eq) in AcOH (6 mL) and toluene (40 mL) was added ethyl 2-cyanoacetate (1.37 g, 12.111 mmol, 1.00 eq) and NH4OAc (187 mg, 2.426 mmol, 0.20 eq). The resulting mixture was stirred at 110 °C overnight, cooled to room temperature, and poured into water (50 mL). The resulting mixture was extracted with EtOAc (50 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1.7 g of (Z)-ethyl 2-cyano-3-(4-nitrophenyl)but-2-enoate (53.94%) as a yellow solid. LRMS (ES) m / z 261 (M+H).

[0972] Step 2: Preparation of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5- dicarbonitrile (Intermediate 10-b):

[0973]

[0974] To a solution of NaOEt (2 g, 6.176 mmol, 1.00 eq, 21%) in EtOH (30 mL) was added 2-cyanoacetamide (517 mg, 6.149 mmol, 1.00 eq) dropwise over a period of 5 min at 0 °C. After stirring at room temperature for 15 min, (2Z)-ethyl 2-cyano-3-(4-nitrophenyl)but-2-enoate (1.6 g, 6.148 mmol, 1 eq) was added. The resulting mixture was stirred at room temperature for 4 h, concentrated under reduced pressure. The residue was dissolved in water (20 mL) and the mixture was acidified to pH 1 with HCl (4 mol / L aqueous solution, ~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 confirmed.1H NMR (400 MHz, 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).

[0975] Step 3: Preparation of 3-methyl-3-(4-nitrophenyl)pentanedioic acid (Intermediate 10-c):

[0976]

[0977] To a solution of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (1.1 g, 3.688 mmol, 1 eq) in H2O (9 mL) was added sulfuric acid (9 mL) and AcOH (6 mL) dropwise over a period of 15 min at 0 °C. The resulting mixture was stirred at 100 °C for 2 days, cooled to room temperature, diluted with ice-cold water (30 mL) and extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 1.2 g of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol as a brownish semi-solid. LRMS (ES) m / z 268 (M+H).

[0978] Step 4: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (Intermediate 10-d):

[0979]

[0980] To a solution of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (1.1 g, 4.1 mmol, 1 eq) in THF (10 mL) was added BH3-THF (1 mol / L in THF, 41 mL, 41 mmol, 10 eq) dropwise over a period of 15 min at 0 °C. 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 with EtOAc (30 mL) twice. The combined organic layers were washed with brine (30 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 720 mg of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (82.06%) as a brownish oil. LRMS (ES) m / z 240 (M+H).

[0981] Step 5: Preparation of dimethanesulfonic acid 3-methyl-3-(4-nitrophenyl)pentane-1,5-diyl ester (Intermediate 10-e):

[0982]

[0983] To a solution of 3-methyl-3-(4-nitrophenyl)pentane-l,5-diol (720 mg, 3.009 mmol, 1 eq) in DCM (10 mL) was added TEA (912 mg, 9.013 mmol, 3.00 eq) and methanesulfonyl chloride (859 mg, 7.500 mmol, 2.49 eq) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h, poured into water (10 mL). The aqueous layer was extracted with CH2Cl2(10 mL) twice. The combined organic layers were washed with brine (10 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 410 mg of methanesulfonic acid 5-(methanesulfonyloxy)-3-methyl-3-(4-nitrophenyl)pentyl ester (34.46%) as yellow oil. LRMS (ES) m / z 396 (M+H).

[0984] Step 6: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (Intermediate 10-f):

[0985]

[0986] To a solution of methanesulfonic acid 5-(methanesulfonyloxy)-3-methyl-3-(4- nitrophenyl)pentyl ester (410 mg, 1.037 mmol, 1 eq) in ACN (5 mL) was added Na2S (49.33 mg, 0.632 mmol, 0.61 eq). The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight, cooled to room temperature, added water (20 mL). The mixture was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give 130 mg of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (52.83%) as yellow oil. LRMS (ES) m / z 238 (M+H).

[0987] Step 7: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1- dioxide (Intermediate 10-g):

[0988]

[0989] To a solution of 4-methyl-4-(4-nitrophenyl)thiacyclohexane (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, poured into water (10 mL). The aqueous layer was extracted with CH2Cl2(10 mL) twice. The combined organic layers were washed with Na2S2O4(5 mL) and washed with brine (10 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 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).

[0990] Step 8: Preparation of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1- dioxide (Intermediate 10.0):

[0991]

[0992] 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 at room temperature under hydrogen atmosphere for 1.5 h, filtered to remove the solids and the filtrate was concentrated under reduced pressure to give 100 mg of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (66.19%) as a brown oil. LRMS (ES) m / z 240 (M+H).

[0993] Example K

[0994] Synthesis of 3-methyl-l-(4-nitrobenzyl)pyrrolidin-2-one

[0995] (Intermediate 11.1-11.15)

[0996] Preparation of 3-methyl-l-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 11-a):

[0997]

[0998] LiHMDS (22.2 mL, 22.2 mmol, 1.1 eq, 1 M in THF) was added to a stirred solution of 3-methylpyrrolidin-2-one (8.7 g, 20.2 mmol, 1 eq) in THF (20 mL) at 0 °C. After 1 h, benzyl bromide (27 g, 125 mmol, 1.25 eq) in THF (20 mL) was added and the reaction was allowed to return 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 light red solid (24.1 g, 72%). LC / MS (APCI) m / z: 235.1 [M+H]. 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.61 - 4.43 (m, 2H), 3.21 (dd, J = 8.2, 5.4 Hz, 2H), 2.55 (t, J = 8.1 Hz, 1H), 2.33 - 2.19 (m, 1H), 1.64 (dq, J = 12.2, 8.6 Hz, 1H), 1.23 (d, J = 7.1 Hz, 3H).

[0999] Intermediates 11.2-11.15 were prepared in a similar manner to Intermediate 11.1

[1000]

[1001]

[1002]

[1003] Example L

[1004] Synthesis of 5-methyl-l-(4-nitrobenzyl)pyrrolidin-2-one

[1005] (Intermediates 12.1-12.2)

[1006] Preparation of 5-methyl-l-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 12):

[1007]

[1008] Sodium triacetoxyborohydride (11 g, 53 mmol, 2 eq) was added to a stirred solution of (4-nitrophenyl)methanamine hydrochloride (5 g, 26.5 mmol, 1 eq), ethyl 4-oxopentanoate (4.2 g, 29.2 mmol, 1.1 eq) and triethylamine (3.6 mL, 26.5 mmol, 1 eq) 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 HNMR (400 MHz, chloroform-d) δ 8.20 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.90 (d, J = 15.6 Hz, 1H), 4.25 (d, J = 15.6 Hz, 1H), 3.58 (h, J = 6.3 Hz, 1H), 2.50 (dtd, J = 34.1, 17.1, 9.5 Hz, 2H), 2.23 (ddd, J = 13.3, 11.0, 6.8 Hz, 1H), 1.67 (ddt, J = 13.2, 9.3, 6.8 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H).

[1009] Intermediate 12.2 was prepared in a similar manner to Intermediate 12.1

[1010]

[1011]

[1012] Example M

[1013] Synthesis of 1-(4-aminobenzyl)-3-methylpyrrolidin-2-one

[1014] (Intemidate 13.1-13.X)

[1015] Preparation of 1-(4-aminobenzyl)-3-methylpyrrolidin-2-one (Intermediate 13.1):

[1016]

[1017] 3-methyl-l-(4-nitrobenzyl)pyrrolidin-2-one (3 g, 12.8 mmol, 1 eq) and Pt02(0.29 g, 1.28 mmol, 0.1 eq) were stirred under H2(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 light red solid (2.6 g, 99%). LC / MS (APCI) m / z: 205.2 [M+H].

[1018] Intermediates 13.2-13.36 were prepared in a similar manner as Intermediate 13.1

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025] Example N

[1026] Synthesis of 4-methyl-l-(4-nitrobenzyl)piperazin-2-one

[1027] (Intermediates 14.1-14.6)

[1028] Step 1: Preparation of l-(4-nitrobenzyl)piperazin-2-one hydrochloride (Intermediate 14-a):

[1029]

[1030] tert-Butyl 4-(4-nitrobenzyl)-3-oxopiperazine-l-carboxylate (Intermediate 11.2, 24.1 g, 71.9 mmol, 1 equiv) was suspended in 4M HC1 in dioxane (180 mL, 719 mmol, 10 equiv) at room temperature. After 2 hours, 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 (positive) m / z: 236.1 (M+H) + .

[1031] Step 2: Preparation of 4-methyl-l-(4-nitrobenzyl)piperazin-2-one (Intermediate 14.1):

[1032]

[1033] Formaldehyde (17.47 g, 215.3 mmol, 3 eq, 37% in water) and AcOH (12.9 mL, 215.3 mmol, 3 eq) were added to a stirring suspension of l-(4-nitrobenzyl)piperazin-2-one hydrochloride (19.5 g, 71.8 mmol, 1 eq) in MeOH (800 mL) at room temperature. After 10 min, the reaction became homogeneous and was then cooled to 0 °C, then NaCNBH3(9.9 g, 157.9 mmol, 2.2 eq) was added and the reaction was allowed to warm to room temperature. After 3 h, the total volume was reduced to ~400 mL by rotary evaporation, quenched with saturated sodium bicarbonate (1 L), extracted with DCM (3 x 750 mL), the organics were combined, dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The oily yellow product was then crystallized under high vacuum overnight to give the product as light yellow crystals (17 g, 95%). LCMS-APCI (positive) m / z: 250.1 (M+H) + . 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 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).

[1034] Intermediates 14.2-14.6 were prepared in a similar manner to Intermediate 14.1

[1035]

[1036]

[1037] Example O

[1038] Synthesis of 4-((azetidin-l-ylsulfonyl)methyl)aniline

[1039] (Intermediates 15.1-15.4)

[1040] Step 1: Preparation of l-((4-nitrobenzyl)sulfonyl)azetidine (Intermediate 15-a):

[1041]

[1042] (4-nitrophenyl)methanesulfonyl chloride (500 mg, 2.12 mmol, 1 equiv) was added to a stirring solution of azetidine (121 mg, 2.12 mmol, 1 equiv) and diisopropylethylamine (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 resolved by silica chromatography (0->3% MeOH / DCM) to give 1-((4-nitrobenzyl)sulfonyl)azetidine (110 mg, 20%). LCMS-APCI (negative) m / z: 255.2 (M-H) - . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.73 (s, 1H), 3.89 (t, J = 7.7 Hz, 2H), 2.19 (p, J = 7.7 Hz, 1H).

[1043] Step 2: Preparation of 4-((azetidin-l-ylsulfonyl)methyl)aniline (Intermediate 15.1):

[1044]

[1045] l-((4-nitrobenzyl)sulfonyl)azetidine (110 mg, 0.43 mmol, 1 equiv) and Pt02(5 mg, 0.022 mmol, 0.05 equiv) were suspended in MeOH (5 mL) and then stirred under H2for 12 h. The reaction was filtered through a 0.45 pm PTFE syringe filter and the solvent removed by rotary evaporation to give the product (90 mg, 93%). LCMS-APCI (positive) m / z: 227.2 (M+H) + .

[1046] Intermediates 15.2-15.4 were prepared in a similar manner to Intermediate 15.1

[1047]

[1048]

[1049] Example P

[1050] Synthesis of l-(4-chlorobenzyl)-3-(4-formylphenyl)urea

[1051] (Intermediate 16)

[1052] Step 1: Preparation of phenyl (4-chlorobenzyl)carbamate (Intermediate 16-a):

[1053]

[1054] To a stirred solution of 1-(4-chlorophenyl)methanamine (10.00 g, 70.621 mmol, 1 eq) and NEt3(10.72 g, 105.9 mmol, 1.5 eq) in THF (100 mL) was added phenyl chloroformate (12.16 g, 77.6 mmol, 1.1 eq) dropwise at 0 °C over a period of 15 min. The resulting mixture was stirred at room temperature for 3 h, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to afford 17.76 g (91.38%) of (4-chlorobenzyl)phenylcarbamate as a pink solid. LCMS-APCI (positive) m / z: 362 (M+H) + .

[1055] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (Intermediate 16-b):

[1056]

[1057] To a stirred solution of (4-chlorobenzyl)phenylcarbamate (7.80 g, 29.8 mmol, 1.2 eq) and 4-aminobenzaldehyde (3.00 g, 24.8 mmol, 1 eq) in i-PrOH (30.00 mL) was added diisopropylethylamine (16.00 g, 123.8 mmol, 5 eq). The resulting mixture was stirred at 90 °C overnight, cooled down to room temperature, water (100 mL) was added and extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to afford 2.04 g (27%) of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea as a yellow solid. LCMS-APCI (positive) m / z: 289 (M+H) + .

[1058] Step 3: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16-c):

[1059]

[1060] To a stirred solution of 1 -(4-chlorobenzyl)-3-(4-formylphenyl)urea (2 g, 6.9 mmol, 1 eq) in EtOH (40 mL) was added NaBH4(390 mg, 10.4 mmol, 1.5 eq) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, quenched by the addition of water (50 mL) at 0 °C and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with water (50 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure to give 2.08 g of 1 -(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea as a yellow solid. LCMS-APCI (positive) m / z: 291 (M+H) + .

[1061] Step 4: Preparation of 1 -(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16):

[1062]

[1063] To a stirred solution of 1 -(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (2 g, 6.9 mmol, 1 eq) in DCM (20 mL) was added SOCl2(1.65 g, 13.9 mmol, 2 eq) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, 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 (positive) m / z: 309 (M+H) + .

[1064] Example Q

[1065] Synthesis of 1 -(4-chlorobenzyl)-3-(4-(((1,1 -dioxotetrahydrothiophen-3- yl)(methyl)amino)methyl)phenyl)urea

[1066] (Intermediate 17.1 -17.6)

[1067]

[1068] To a stirred mixture of 3-[(4-chlorophenyl)methyl]-l-(4-formylphenyl)urea (Intermediate 3.2, 300.00 mg, 1.039 mmol, 1.00 eq) and 3- aminotetrahydrothiophene 1,1-dioxide (168.55 mg, 1.247 mmol, 1.2 eq) in DCE (10 mL) was added STAB (440.43 mg, 2.078 mmol, 2 eq) 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 afford 240 mg of l-(4-chlorobenzyl)-3-(4-(((l,l-dioxotetrahydrothiophen-3-yl)amino)methyl)phenyl)urea (56.63%) as a white solid. LCMS-APCI (Positive) m / z: 408 (M+H) + .

[1069] Intermediates 17.2-17.6 were prepared in a similar manner as Intermediate 17.1

[1070]

[1071]

[1072] Example R

[1073] Synthesis of l-(4-chlorobenzyl)-3-(4-(((l,l-dioxotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea

[1074] (Intermediates 18.1-18.2)

[1075]

[1076] To a stirred mixture of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxotetrahydrothiophen-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, to the above mixture was added 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, the pH was adjusted to 10 with NH3H2O (2 mL), and extracted with DCM (10 mL) twice. The combined organic layers were washed with water (10 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by prep-HPLC with the following conditions (column: XBridge Prep OBD C 18 column, 30*150mm 5um; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26B to 56B in 9 min; 254 nm) to give 50 mg of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (40.28%) as a white solid. LCMS-APCI (positive) m / z: 422 (M+H) + .

[1077] Intermediate 18.2 was prepared in a similar manner as Intermediate 18.1

[1078]

[1079]

[1080] Example S

[1081] Synthesis of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19)

[1082] Step 1: Preparation of 2-amino-1-(4-nitrophenyl)ethan-1-one hydrochloride (Intermediate 19-a):

[1083]

[1084] To a solution of 2-amino-l-(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 washed with CH2Cl2(500 mL). To the residue was added HC1 (200.00 mL, 6 mol / L) and EtOH (1.00 L). The resulting mixture was stirred at room temperature for 3 h, left overnight. The precipitated solid was collected by filtration and washed with hexane (500 mL), concentrated in vacuo to give 140 g of 2-amino-l-(4-nitrophenyl)ethanone hydrochloride (crude) as a light yellow solid. LCMS-APCI (positive) m / z: 181 (M+H) + .

[1085] Step 2: Preparation of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19):

[1086]

[1087] To a solution of 2-amino-l-(4-nitrophenyl)ethanone hydrochloride (140.00 g, 646.293 mmol, 1.00 equiv) in DCM (1.60 L) was added a solution of K2CO3(179.00 g, 1295.173 mmol, 2.00 equiv) in H2O (700.00 mL) and di-tert-butyl dicarbonate (169.00 g, 774.345 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 3 h and extracted with CH2Cl2(1 L) twice. The combined organic layers were washed with brine (1 L) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 176 g of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (crude) as a brown oil. LCMS-APCI (positive) m / z: 225 (M+H-56) + .

[1088] Example T

[1089] Synthesis of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20)

[1090] Step 1: Preparation of methyl (2-((tert-butoxycarbonyl)amino)-l-(4-nitrophenyl)ethyl)glycinate (Intermediate 20-a):

[1091]

[1092] 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 to the above resulting mixture was added NaBH3CN (6.22 g, 98.901 mmol, 1.98 equiv) at 0 °C. The resulting mixture was stirred at 70 °C overnight, cooled to room temperature, adjusted to pH 8 with saturated NH4.H2O (aq.) and extracted with EtOAc (200 mL) twice. The combined organic layers were washed with water (200 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 17 g (crude) of methyl 2-([2-[(tert-butoxycarbonyl)amino]-1-(4-nitrophenyl)ethyl]amino)acetate as a brown oil. LCMS-APCI (positive) m / z: 354 (M+H) + .

[1093] Step 2: Preparation of 2-((2-methoxy-2-oxoethyl)amino)-2-(4-nitrophenyl)ethan-1- aminium 2,2,2-trifluoroacetate (Intermediate 20-b):

[1094]

[1095] 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, concentrated under reduced pressure to give 7 g (crude) of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate trifluoroacetate as a brown oil. LCMS-APCI (positive) m / z: 254 (M+H) + .

[1096] Step 3: Preparation of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20):

[1097]

[1098] A solution of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate trifluoroacetate salt (7.00 g, 27.640 mmol, 1.00 equiv) in MeOH (70.00 mL) containing NH3(g) was stirred at 70 °C for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure, purified by trituration with EtOAc (100 mL). The precipitated solid was collected by filtration and washed with EtOAc (100 mL) twice, concentrated under reduced pressure to give 2 g (32.71%) of 5-(4-nitrophenyl)piperazin-2-one as a brown solid. LCMS-APCI (positive) m / z: 222 (M+H) + .

[1099] Example U

[1100] Synthesis of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate

[1101] (Intermediate 21)

[1102] Step 1: Preparation of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21-a):

[1103]

[1104] 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) was added (Boc)20 (1479.87 mg, 6.781 mmol, 3 equiv) and TEA (914.85 mg, 9.041 mmol, 4 equiv). The resulting mixture was stirred at room temperature overnight, water (10 mL) was added and extracted with DCM (10 mL) twice. The combined organic layers were washed with brine (10 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 380 mg (52.32%) of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate as a yellow oil. LCMS-APCI (positive) m / z: 322 (M+H) + .

[1105] Step 2: Preparation of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 20):

[1106]

[1107] 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 (8.00 mL) was added CH3I (463.81 mg, 3.268 mmol, 3 equiv) and Cs2CO3(1419.55 mg, 4.357 mmol, 4 equiv). The resulting mixture was stirred at room temperature for 2 h, filtered to remove solids, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography eluting 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 (positive) m / z: 336 (M+H) + .

[1108] Example V

[1109] Synthesis of 4-methyl-5-(4-nitrophenyl)piperazin-2-one

[1110] (Intermediate 22)

[1111] Preparation of 4-methyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 22):

[1112]

[1113] 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), NaBH3CN (340.89 mg, 5.425 mmol, 2 equiv) and AcOH (530.00 mg, 8.826 mmol, 3.25 equiv). 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 (positive) m / z: 236 (M+H) + .

[1114] Example W

[1115] Synthesis of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one

[1116] (Intermediate 23)

[1117] Preparation of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 23):

[1118]

[1119] 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, 4.00 equiv, 60%) at 0 °C. After stirring at 0 °C for 30 min, CH3I (962.45 mg, 6.781 mmol, 3.00 equiv) was added to the resulting mixture at 0 °C. 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 (Positive) m / z: 250 (M+H) + .

[1120] Example X

[1121] Synthesis of 1,4-dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24)

[1122] Step 1: Preparation of tert-butyl (2-amino-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 24-a):

[1123]

[1124] 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) was added NH4OAc (14.00 g, 181.624 mmol, 2.55 equiv) and NaBH3CN (110.00 g, 1750.422 mmol, 24.53 equiv) at 0 °C. The resulting mixture was stirred at 70 °C overnight, cooled to room temperature, adjusted to pH 8 with saturated NH3H2O, extracted with CH2Cl2(1 L) twice. The combined organic layers were washed with brine (1 L) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography eluted with MeOH / EtOAc (1:20) to give 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 (Positive) m / z: 226 (M+H-56) + .

[1125] Step 2: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (Intermediate 24-b):

[1126]

[1127] 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 HC1 (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 with DCM:MeOH (10:1, 50 mL) twice. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure to give 2.3 g of 1-(4-nitrophenyl)ethane-1,2-diamine as a light brown oil. LCMS-APCI (positive) m / z: 182 (M+H) + .

[1128] Step 3: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (Intermediate 24-c):

[1129]

[1130] 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) was added K2C03(5.95 g, 43.052 mmol, 3.00 equiv) and ethyl chloroacetate (1.76 g, 14.349 mmol, 1.00 equiv). After stirring at room temperature overnight, EtOH (4.00 mL) was added to the resulting mixture. The resulting mixture was stirred at 80 °C for 3 h, cooled to room temperature, and filtered to remove the solids. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with DCM / MeOH (10:1) to give 2.2 g of 6-(4-nitrophenyl)piperazin-2-one as a brown solid (69.31%). LCMS-APCI (positive) m / z: 222 (M+H) + .

[1131] Step 4: Preparation of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 24-d):

[1132]

[1133] 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 with DCM (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 1.1 g of 3-(4-nitrophenyl)-5-oxopiperazine-1 -carboxylic acid tert-butyl ester (crude) as a yellow semi-solid. LCMS-APCI (positive) m / z: 266 (M+H-56) + .

[1134] Step 5: Preparation of 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1 -carboxylic acid tert-butyl ester (Intermediate 24-e):

[1135]

[1136] To a solution of 3-(4-nitrophenyl)-5-oxopiperazine-1 -carboxylic acid tert-butyl ester (1.10 g, 3.423 mmol, 1.00 equiv) in DMF (25.00 mL) was added Cs2CO3(2.20 g, 6.752 mmol, 1.97 equiv) and iodomethane (534.48 mg, 3.766 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 2 h, extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine (30 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, eluted with PE / EtOAc (1:4) to give 530 mg of 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1 -carboxylic acid tert-butyl ester (46.17%) as a yellow semi-solid. LCMS-APCI (positive) m / z: 300 (M+H-56) + .

[1137] Step 6: Preparation of 1-methyl-6-(4-nitrophenyl)piperazin-2-one hydrochloride (Intermediate 24-f):

[1138]

[1139] 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 HC1 (gas) in 1,4-dioxane (2.00 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 2 h, 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 (positive) m / z: 236 (M+H) + .

[1140] Step 7: Preparation of 1,4-dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24):

[1141]

[1142] 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 HC1 (gas) in 1,4-dioxane (2.00 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 2 h, 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 (positive) m / z: 236 (M+H) + .

[1143] Example Y

[1144] Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1 -methylpiperazin-2-one

[1145] (Intermediate 25.1 - 25.2)

[1146] Preparation of 4-(2-fluoro-4-nitrobenzyl)-1 -methylpiperazin-2-one (Intermediate 25.1):

[1147]

[1148] 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, AcOH (142.00 mg, 2.365 mmol, 2.00 equiv) and NaBH3CN (151.00 mg, 2.403 mmol, 2.03 equiv) were added to the mixture. The resulting mixture was stirred at room temperature overnight, adjusted to pH 8 with NH3.H2O, concentrated in vacuo, and purified by C18 column chromatography eluting with water (0.05% NH4HCO3) / ACN (2:1) to afford 80 mg of 4-[(2-fluoro-4-nitrophenyl)methyl]-1-methylpiperazin-2-one as a yellow oil (25.31%). LCMS-APCI (positive) m / z: 268 (M+H) + .

[1149] Intermediate 25.2 was prepared in a similar manner to Intermediate 25.1

[1150]

[1151] Example Z

[1152] Synthesis of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazin-2-one (Intermediate 26)

[1153] Step 1: Preparation of tert-butyl methyl(2-((1-(4-nitrophenyl)ethyl)amino)ethyl)carbamate (Intermediate 26-a):

[1154]

[1155] To a stirred solution of PNAP (2.27 g, 13.774 mmol, 1.2 eq) and tert-butyl N-(2- aminoethyl)-N-methylcarbamate (2.00 g, 11.478 mmol, 1.00 eq) in MeOH (30 mL) was added NaBH3CN (1.44 g, 22.956 mmol, 2 eq) and AcOH (1.38 g, 22.956 mmol, 2 eq) at 0 °C. The resulting mixture was stirred at room temperature overnight, adjusted to pH 8 with saturated NH4.H2O (aq), and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with water (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to afford 2.8 g (75.43%) of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)amidino)ethyl)(methyl)carbamate as a light yellow oil. LCMS-APCI (positive) m / z: 400 (M+H) + .

[1156] Step 2: Preparation of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)amidino)ethyl)(methyl)carbamate (Intermediate 24-b):

[1157]

[1158] To a stirred solution of PNAP (2.27 g, 13.774 mmol, 1.2 eq) and tert-butyl N-(2- aminoethyl)-N-methylcarbamate (2.00 g, 11.478 mmol, 1.00 eq) in MeOH (30 mL) was added NaBH3CN (1.44 g, 22.956 mmol, 2 eq) and AcOH (1.38 g, 22.956 mmol, 2 eq) at 0 °C. The resulting mixture was stirred at room temperature overnight, adjusted to pH 8 with saturated NH4.H2O (aq), and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with water (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to afford 2.8 g (75.43%) of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)amidino)ethyl)(methyl)carbamate as a light yellow oil. LCMS-APCI (positive) m / z: 400 (M+H) + .

[1159] Step 3: Preparation of 2-chloro-N-(2-(methylamino)ethyl)-N-(1-(4-nitrophenyl)ethyl)acetamide hydrochloride (Intermediate 26-c):

[1160]

[1161] To a stirred solution of tert-butyl N-(2-[2-chloro-N-[l-(4-nitrophenyl)ethyl]acetamido]ethyl)-N- methylcarbamate (3.00 g, 7.502 mmol, 1.00 equiv) in DCM (30.00 mL) was added HC1 (gas) in 1,4-dioxane (30.00 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated under reduced pressure to give 3.1 g of 2-chloro-N-[2-(methylamino)ethyl]-N-[l-(4-nitrophenyl)ethyl]acetamide hydrochloride as a light yellow solid. LCMS-APCI (positive) m / z: 300 (M+H) + .

[1162] Step 4: Preparation of 4-methyl-l-(l-(4-nitrophenyl)ethyl)piperazin-2-one (Intermediate 26):

[1163]

[1164] To a stirred solution of 2-chloro-N-[2-(methylamino)ethyl]-N-[l-(4-nitrophenyl)ethyl]acetamide hydrochloride (3.10 g, 10.342 mmol, 1.00 equiv) in ACN (50.00 mL) was added K2CO3 (7.15 g, 51.735 mmol, 5.00 equiv). The resulting mixture was stirred at 80 °C for 1 h, cooled to room temperature, filtered to remove the solids. The filtrate was concentrated under reduced pressure to give 1.69 g of 4-methyl-l-[l-(4-nitrophenyl)ethyl]piperazin-2-one as a yellow oil. LCMS-APCI (positive) m / z: 264 (M+H) + .

[1165] Example AA

[1166] Synthesis of l-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3- yl)amino)methyl)phenyl)urea (Intermediate 27.1-27.4)

[1167] Step 1: Preparation of phenyl (4-formylphenyl)carbamate (Intermediate 27-a):

[1168]

[1169] To a stirred solution of 4-aminobenzaldehyde (2.00 g, 16.510 mmol, 1.00 equiv) in THF (40.00 mL) was added a solution of K2CO3 (4.56 g, 32.994 mmol, 2.00 equiv) in H2O (10.00 mL) and phenyl chloroformate (3.87 g, 24.717 mmol, 1.50 equiv) dropwise over a period of 10 min at 0 °C. The resulting mixture was stirred at room temperature for 1 h, extracted with EtOAc (50 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to afford 1.9 g of N-(4-formylphenyl)phenylcarbamate (84.41%) as yellow solid. LCMS-APCI (Positive) m / z: 242 (M+H) + .

[1170] Step 2: Preparation of (4-(((2-oxopyrrolidin-3-yl)amino)methyl)phenyl)phenylcarbamate (Intermediate 27-b):

[1171]

[1172] To a stirred solution of N-(4-formylphenyl)phenylcarbamate (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 with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous MgSO4, concentrated under reduced pressure, purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to afford 415 mg of N-(4-[[(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)phenylcarbamate (46.87%) as off-white foam. LCMS-APCI (Positive) m / z: 326 (M+H) + .

[1173] Step 3: Preparation of (4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)phenylcarbamate (Intermediate 27-c):

[1174]

[1175] 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 NaBH3CN (155.00 mg, 2.467 mmol, 2.01 equiv). The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 380 mg of phenyl (4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (79.65%) as off-white solid. LCMS-APCI (Positive) m / z: 340 (M+H) + .

[1176] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3- yl)amino)methyl)phenyl)urea (Intermediate 27):

[1177]

[1178] 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 NaBH3CN (155.00 mg, 2.467 mmol, 2.01 equiv). The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 380 mg of phenyl (4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (79.65%) as off-white solid. LCMS-APCI (Positive) m / z: 340 (M+H) 18 column, XBridge Prep OBD C18, 19*150mm 5um; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O) and mobile phase B: ACN (25% phase B rise to 55% in 8 min); detector, uv 254 nm, afforded 60 mg of 3-[(4-chlorophenyl)methyl]-1-(4-[[methyl(2-oxopyrrolidin-3- yl)amino]methyl]phenyl)urea (52.64%) as white solid. LCMS-APCI (Positive) m / z: 387 (M+H)+.

[1179] Intermediates 27.2-27.4 were prepared in a similar manner as Intermediate 27.1

[1180]

[1181]

[1182] Example BB

[1183] Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 28)

[1184] Step 1: Preparation of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 28-a):

[1185]

[1186] To 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 NaBH4(1.02 g, 26.961 mmol, 1.51 equiv) at 0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h, concentrated under reduced pressure, and extracted with EtOAc (50 mL) for three times. The combined organic layers were washed with brine (50 mL) for three times, dried over anhydrous Na2SO4, 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 (positive) m / z: 227 (M+H-56) + .

[1187] Step 2: Preparation of 2-amino-1-(4-nitrophenyl)ethan-1-ol hydrochloride (Intermediate 28-b):

[1188]

[1189] To a solution of tert-butyl N-[2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (2.10 g, 7.439 mmol, 1.00 equiv) in DCM (22.00 mL) was added HC1 (gas) in 1,4-dioxane (5.50 mL, 96.346 mmol, 12.95 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure to give 1.9 g of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride as an orange solid. LCMS-APCI (positive) m / z: 183 (M+H) + .

[1190] Step 3: Preparation of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 28):

[1191]

[1192] 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 Cs2CO3(6.13 g, 18.814 mmol, 4.00 equiv) and CH3I (736.00 mg, 5.185 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 4 h and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with brine (50 mL) three times, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting 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 (Positive) m / z: 223 (M+H) + .

[1193] Example CC

[1194] Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one

[1195] (Intermediate 29)

[1196] Preparation of 3-methyl-5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 29):

[1197]

[1198] 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 Cs2CO3(6.13 g, 18.814 mmol, 4.00 equiv) and CH3I (736.00 mg, 5.185 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 4 h and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with brine (50 mL) three times, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting 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 (Positive) m / z: 223 (M+H) + .

[1199] Example DD

[1200] Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 30.1-30.2)

[1201] Step 1: Preparation of methyl 4-oxo-4-(pyridin-3-yl)butanoate (Intermediate 30-a):

[1202]

[1203] To a solution of 3-pyridinecarboxaldehyde (5.00 g, 46.7 mmol, 1.00 equiv) and methyl acrylate (4.80 g, 56.0 mmol, 1.20 equiv) in EtOH (50 mL) was added Et3N (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) under nitrogen atmosphere. The resulting mixture was stirred at 50 °C under nitrogen atmosphere overnight, cooled down to room temperature, concentrated under reduced pressure, and extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give 2.19 g of methyl 4-oxo-4-(pyridin-3-yl)butanoate as a yellow solid. LCMS-APCI (positive) m / z: 194 (M+H) + .

[1204] Step 2: Preparation of 1-(4-nitrobenzyl)-5-(pyridin-3-yl)pyrrolidin-2-one (Intermediate 30.1):

[1205]

[1206] 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) was added NaBH3CN (2.80 g, 17.8 mmol, 2.00 equiv) and AcOH (2.67 g, 17.8 mmol, 2.00 equiv) at 0 °C. The resulting mixture was stirred at 70 °C for two days, cooled down to room temperature, concentrated under reduced pressure, and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with EtOAc to give 1 g of 1-[(4-nitrophenyl)methyl]-5-(pyridin-3-yl)pyrrolidin-2-one as a light yellow oil. LCMS-APCI (positive) m / z: 298 (M+H) + .

[1207] Intermediate 30.2 was prepared in a similar manner as Intermediate 30.1

[1208]

[1209]

[1210] Example EE

[1211] Synthesis of 1-(1-(4-nitrophenyl)ethyl)piperidin-2-one

[1212] (Intermediate 31)

[1213]

[1214] 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, adjusted to pH 8 with saturated NaHC03(aq), and extracted with EtOAc (20 mL) twice. The combined organic layers were washed with brine (20 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure, and purified by silica gel column chromatography eluted 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 (positive) m / z: 249 (M+H) + .

[1215] Example FF

[1216] Synthesis of 1-(4-(1,1-dioxidothiomorpholin-3-yl)phenyl)-3-(4- methoxybenzyl)urea (Intermediate 32)

[1217] Step 1: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)thio)ethyl)carbamate (Intermediate 32-a):

[1218]

[1219] To a stirred solution of 2-bromo-l-(4-nitrophenyl)ethanone (8.00 g, 32.781 mmol, 1.00 eq) and DIEA (8.47 g, 65.562 mmol, 2.00 eq) in ACN (80.00 mL) was added Nal (1.47 g, 9.834 mmol, 0.30 eq) and 2-bromo-l-(4-nitrophenyl)ethanone (8.00 g, 32.781 mmol, 1.00 eq) at 0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was checked by LCMS. Water (200 mL) was added and the mixture was adjusted to pH 7 with HC1 (aq.) and extracted with EtOAc (200 mL) thrice. The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2S04, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (20: 1) to afford 8.9 g of tert-butyl N-(2-[[2-(4-nitrophenyl)-2- oxoethyl]thio]ethyl)carbamate (79.76%) as a yellow solid. LCMS-APCI (Positive) m / z: 285 (M+H-56) + .

[1220] Step 2: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-b):

[1221]

[1222] To a stirred mixture of tert-butyl N-(2-{[2-(4-nitrophenyl)-2-oxoethyl]thio}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 with EtOAc (200 mL) thrice. The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2S04, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EA (4: 1) to afford 7 g of tert-butyl N-{2-[2-(4-nitrophenyl)-2-oxoethanesulfonyl]ethyl}carbamate as a light yellow solid. LCMS-APCI (Positive) m / z: 317 (M+H-56) + .

[1223] Step 3: Preparation of tert-butyl (2-((2-(4-aminophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-c):

[1224]

[1225] To a stirred mixture of tert-butyl N-{2-[2-(4-nitrophenyl)-2- oxoethanesulfonyl]ethyl}carbamate (7 g, 18.761 mmol / L, 1 eq) in EtOH (80 mL) was added iron (4.2 g, 75.061 mmol / L, 4 eq), and a solution of NH4Cl (6.9 g, 131.327 mmol / L, 7 eq) in H2O (16 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight, concentrated under reduced pressure, purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (50:1) to afford 5.3 g of tert-butyl N-{2-[2-(4- aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (77.69%) as a light yellow solid. LCMS-APCI (positive) m / z: 287 (M+H-56) + .

[1226] Step 4: Preparation of tert-butyl (2-((2-oxo-2-(4-((phenoxycarbonyl)amino)phenyl)ethyl) sulfonyl)ethyl)carbamate (Intermediate 32-d):

[1227]

[1228] To a solution of tert-butyl N-{2-[2-(4-aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (3 g, 8.761 mmol, 1.00 eq) in THF (30 mL) was added phenyl chloroformate (2.05 g, 13.093 mmol, 1.49 eq) dropwise at 0 °C over a period of 10 min. The resulting mixture was stirred at room temperature for 2 h, then gradually warmed to 80 °C and stirred at 80 °C overnight, cooled to room temperature, concentrated under reduced pressure, purified by wet grinding with hexane:EA = 10:1 (30 mL) and concentrated under reduced pressure to afford 3.7 g of phenyl N-[4-(2-{2-[(tert-butoxy carbonyl)amino]ethanesulfonyl}acetyl)phenyl]carbamate (91.31%) as a brown solid. LCMS-APCI (positive) m / z: 407 (M+H-56) + .

[1229] Step 5: Preparation of tert-butyl (2-((2-(4-(3-(4-methoxybenzyl)ureido)phenyl)-2- oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-e):

[1230]

[1231] 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-benzylamine (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 wet grinding 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 (positive) m / z: 450 (M+H-56) + .

[1232] Step 6: Preparation of 1-(4-(1,1-dioxothiomorpholin-3-yl)phenyl)-3-(4- methoxybenzyl)urea (Intermediate 32):

[1233]

[1234] 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 HC1 (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, NaBH3CN (0.32 g, 5.092 mmol, 2.01 equiv) and MeOH (12 mL) were added. The resulting mixture was stirred at room temperature for 2 h, water (30 mL) was added and extracted with EtOAc (20 mL) three times. The combined organic layers were washed with brine (20 ml) twice, dried over anhydrous Na2S04, concentrated under reduced pressure to give 1.1 g (crude) of 1-[4-(1,1-dioxo-1l6-thiomorpholin-3-yl)phenyl]-3-[(4- methoxyphenyl)methyl]urea as a brown solid. The crude product (500 mg) was purified by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, YMC-Actus Triart C 18ExRS, 30*150 mm, 5 pm; mobile phase, water (10 mmol / L NH4HCO3+0.1% NH3.H2O) and ACN (15% ACN up to 45% in 10 min); detector UV 254 nm, 210 nm, to give 230 mg of l-[4-(l,l-dioxo-lA6-thiomorpholin-3-yl)phenyl]-3-[(4- methoxyphenyl)methyl]urea as a white solid. LCMS-APCI (positive) m / z: 390 (M+H) + .

[1235] Example GG

[1236] Synthesis of l-(4-(l,l-dioxothiomorpholin-2-yl)phenyl)-3-(4- methoxybenzyl)urea (Intermediate 33)

[1237] Step 1: Preparation of methyl 2-bromo-2-(4-nitrophenyl)acetate (Intermediate 33-a):

[1238]

[1239] To a stirred solution of methyl 2-(4-nitrophenyl)acetate (5 g, 25.618 mmol, 1.00 eq) and AIBN (0.21 g, 1.281 mmol, 0.05 eq) in CC14(50 mL) was added NBS (6.84 g, 38.427 mmol, 1.5 eq). The resulting mixture was stirred at 80 °C overnight, cooled to room temperature, water (100 mL) was added and extracted with CH2Cl2(50 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure and purified by column chromatography with water (0.05% NH4HCO3) / ACN (1:1) to elute, to give 4.1 g (58.39%) of methyl 2-bromo-2-(4-nitrophenyl)acetate as a yellow oil. LCMS-APCI (positive) m / z: 274 (M+H) 18 . + . 1 H NMR (300 MHz, DMSO-d6) δ 8.34 - 8.19 (m, 2H), 7.89 - 7.78 (m, 2H), 6.17 (s, 1H), 3.76 (s, 3H).

[1240] Step 2: Preparation of 2-(4-nitrophenyl)thiomorpholine-3-one (Intermediate 33-b):

[1241]

[1242] To a stirred solution of methyl 2-bromo-2-(4-nitrophenyl)acetate (3 g, 10.946 mmol, 1.00 eq) in EtOH (30 mL) was added cysteamine hydrochloride (1.37 g, 12.041 mmol, 1.1 eq) and K2CO3(3.33 g, 24.081 mmol, 2.2 eq). The resulting mixture was stirred at room temperature overnight, water (50 mL) was added and extracted with EA (100 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EA (1:9) to afford 1.4 g 53.68% of 2-(4-nitrophenyl)thiomorpholin-3-one as a yellow solid. LCMS-APCI (positive) m / z: 239 (M+H) + .

[1243] Step 3: Preparation of 2-(4-nitrophenyl)thiomorpholine (Intermediate 33-c):

[1244]

[1245] To a stirred solution of 2-(4-nitrophenyl)thiomorpholin-3-one (1.4 g, 5.876 mmol, 1.00 eq) in THF (15 mL) was added BH3-Me2S (2.94 mL, 29.380 mmol, 5 eq, 2 mol / L). The resulting mixture was stirred at 60 °C for 1 h, concentrated under reduced pressure, to the residue was added HCl (15 mL, 4 N) and stirred at 60 °C for another 30 min. The mixture was adjusted to pH 8 with saturated NaHCO3(aq), concentrated under reduced pressure, purified by C 18 column chromatography eluting with water (0.05% NH4HCO3) / ACN (2:1) to afford 590 mg (44.77%) of 2-(4-nitrophenyl)thiomorpholine as a red oil. LCMS-APCI (positive) m / z: 225 (M+H) + .

[1246] Step 4: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (Intermediate 33-d):

[1247]

[1248] 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) was added (Boc)20 (1148.26 mg, 5.262 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, purified by silica gel column chromatography eluted with PE / EA (3:1) to afford 400 mg (46.87%) of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) 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, 3.2 Hz, 1H), 2.88 - 2.72 (m, 1H), 2.77 - 2.65 (m, 1H), 2.45 (s, 1H), 1.74 - 1.57 (m, 1H), 1.57 - 1.45 (m, 1H), 1.43 (s, 2H), 1.40 (s, 8H), 1.29 (s, 2H), 1.25 (d, J = 6.4 Hz, 3H), 1.15 (s, 1H), 0.99 - 0.76 (m, 2H).

[1249] Step 5: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-e):

[1250]

[1251] 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, saturated Na2S03(aq) (20 mL) was added and extracted with EtOAc (20 mL) twice. The combined organic layers were washed with saturated NaHC03(aq) (20 mL) and brine (20 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure to afford 420 mg of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI (positive) m / z: 357 (M+H) + .

[1252] Step 6: Preparation of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-f):

[1253]

[1254] To a stirred solution of tert-butyl 2-(4-nitrophenyl)-1,1-dioxo-1λ6-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 at room temperature under H for 2 h, filtered to remove the 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 (positive) m / z: 327 (M+H) + .

[1255] Step 7: Preparation of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-g):

[1256]

[1257] 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 stirred at room temperature under H for 2 h, filtered to remove the 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 (positive) m / z: 327 (M+H) + .

[1258] Step 8: Preparation of 1-(4-(1,1-dioxothiomorpholin-2-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 33):

[1259]

[1260] To a stirred solution of tert-butyl 2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-1,1-dioxo-1λ-thiomorpholine-4-carboxylate (93 mg, 0.190 mmol, 1.00 equiv) in DCM (1 mL) was added HCl (g) in 1,4-dioxane (0.5 mL, 4 mol / L). The resulting mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified by C18 column chromatography eluting with water (0.05% NH4HCO3) / ACN (4:1) to afford 45 mg (60.83%) of 3-[4-(1,1-dioxo-1λ-thiomorpholin-2-yl)phenyl]-1-[(4-methoxyphenyl)methyl]urea as a white solid. LCMS-APCI (positive) m / z: 390 (M+H) + .

[1261] Example HH

[1262] Synthesis of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediates 34.1-34.2)

[1263] Preparation of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediate 34):

[1264]

[1265] 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 hours and extracted twice with EtOAc (10 mL). The combined organic layers were washed twice with brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 630 mg of N-methyl-N-[(4-nitrophenyl)methyl]acetamide as a brown solid. LCMS-APCI (positive) m / z: 208 (M+H) + .

[1266] Intermediate 30.2 was prepared in a similar manner to Intermediate 30.1

[1267]

[1268] Example II

[1269] Synthesis of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (Intermediate 35):

[1270] Step 1: Preparation of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H- pyrrole-1-carboxylate (Intermediate 35-a):

[1271]

[1272] To a solution of 1-[tert-butoxy(hydroxy)methyl]pyrrolidin-3-one (5 g, 26.704 mmol, 1.00 equiv) in THF (50 mL) was added LiHMDS (53.8 mL, 1 mol / L in THF, 2 equiv) dropwise at -78 °C under nitrogen atmosphere over a period of 30 min. After stirring at -78 °C under nitrogen atmosphere for 1 h, 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonmethane sulfonamide (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 under nitrogen atmosphere for 2 h. No LCMS signal was observed for the product by TLC. The reaction was quenched with water (50 mL) at 0 °C and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na2SO4, concentrated under reduced pressure to give 16 g of tert-butyl 3-(trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-1- carboxylate (crude) as brown oil.

[1273] Step 2: Preparation of tert-butyl 3-(4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 35-b):

[1274]

[1275] 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) was added Pd(dppf)Cl2(0.9 g, 1.230 mmol, 0.10 equiv), and a solution of K2CO3(3.5 g, 25.325 mmol, 2.01 equiv) in H2O (10 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. 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 yellow solid. LCMS-APCI (positive) m / z: 234 (M+H-56) + .

[1276] Step 3: Preparation of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (Intermediate 35-c):

[1277]

[1278] 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 a hydrogen atmosphere. The reaction was confirmed by LCMS. The resulting mixture was filtered to remove the 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 (positive) m / z: 206 (M+H-56) + .

[1279] Step 4: Preparation of tert-butyl 3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (Intermediate 35-d):

[1280]

[1281] 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 eluting 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 semisolid. LCMS-APCI (positive) m / z: 347 (M+H-56) + .

[1282] Step 5: Preparation of 1-(4-chlorobenzyl)-3-(4-(pyrrolidin-3-yl)phenyl)urea (Intermediate 35-e):

[1283]

[1284] 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 pH value of the resulting mixture was adjusted to 10, and extracted with CH2CI2(10 mL) three times. The combined organic layer was washed with brine (10 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure to give 300 mg of 1 -[(4-chlorophenyl)methyl]-3-[4-(pyrrolidin-3-yl)phenyl]urea as a brown semi-solid. LCMS-APCI (positive) m / z: 330 (M+H) + .

[1285] Step 6: Preparation of 1 -(4-chlorobenzyl)-3-(4-(1 -(methylsulfonyl)pyrrolidin-3- yl)phenyl)urea (Intermediate 35):

[1286]

[1287] 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 MsCI (116.69 mg, 1.019 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, and extracted with CH2CI2(10 mL) three times. The combined organic layer was washed with brine (10 mL) twice, dried over anhydrous Na2S04, concentrated under reduced pressure, purified by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01 ): Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HC03) and ACN (30% ACN up to 60% in 8 min); detector, UV 254 nm, 210 nm, to give 230 mg of 1 -[(4-chlorophenyl)methyl]-3-[4-(1 -methylsulfonylpyrrolidin-3- yl)phenyl]urea (66.42%) as a brown solid. LCMS-APCI (positive) m / z: 408 (M+H) + .

[1288] Intermediate 35.2 was prepared in a similar manner as Intermediate 35.1

[1289]

[1290]

[1291] Example JJ

[1292] Synthesis of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36):

[1293] Step 1: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid (Intermediate 36-a):

[1294]

[1295] To a stirred mixture of p-aminobenzenesulfonic acid (2 g, 11.548 mmol, 1.00 equiv) and DIEA (14.91 g, 115.364 mmol, 9.99 equiv) in isopropanol (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 purified by column chromatography eluting with water (0.05% NH4HCO3) / 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]. 18 Column chromatography purification eluting with water (0.05% NH4HCO3) / 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].

[1296] Step 2: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36):

[1297]

[1298] 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].

[1299] Example KK

[1300] Synthesis of 4-(2-oxaspiro[3.5]non-7-yl)aniline (Intermediate 37):

[1301] Step 1: Preparation of trifluoromethanesulfonic acid 2-oxaspiro[3.5]non-6-en-7-yl ester (Intermediate 37-a):

[1302]

[1303] A flame-dried flask was charged with diisopropylamine (318 mg, 3.14 mmol, 1.1 eq) and THF (6 mL). After cooling to -30 °C, a solution of n-BuLi (1.32 mL, 3.13 mmol, 1.09 eq) was added dropwise and the mixture was slowly warmed 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 eq) in THF was added dropwise. The deprotonation was maintained at -78 °C for 15 min before being removed from the bath for another 15 min. The flask was then cooled to -78 °C again, a solution of PhNTf2 in THF (1.12 g, 3.14 mmol, 1.1 eq) was added slowly and the reaction was maintained at -78 °C for another 15 min and in the external bath for 1 h. Upon completion, a half-saturated NH4Cl solution was added and the aqueous phase was extracted with EtOAc (50 mL*3). The combined organic phases were dried (MgSO4), 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) + .

[1304] Step 2: Preparation of 7-(4-nitrophenyl)-2-oxaspiro[3.5]non-6-ene (Intermediate 37-b):

[1305]

[1306] A solution of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.85 mmol, 1.0 eq) and (4-nitrophenyl)boronic acid (714 mg, 4.28 mmol, 1.5 eq) in dioxane / H2O (10 mL, 3:1) was bubbled with N2for 10 min before K2CO3(794 mg, 5.71 mmol, 2.0 eq) and Pd(dppf)Cl2(209 mg, 0.285 mmol, 0.1 eq) were added. The mixture was stirred at 75 °C for 15 h. Upon completion, a half-saturated NH4Cl solution was added and the aqueous phase was extracted with EtOAc (10 mL*2). The combined organic phases were dried (MgSO4), 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) + . 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 6.24 (tt, J = 3.8, 1.6 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 5.8 Hz, 2H), 2.61 (dt, J = 4.4, 2.5 Hz, 2H), 2.52 (tq, J = 6.4, 2.1 Hz, 2H), 2.10 (t, J = 6.3 Hz, 2H).

[1307] Step 3: Preparation of 4-(2-oxaspiro[3.5]non-7-yl)aniline (Intermediate 37):

[1308]

[1309] To a solution of 7-(4-nitrophenyl)-2-oxaspiro[3.5]non-6-ene (110 mg, 0.448, 1.0 eq) in THF (6 mL) was added Pd / C (33 mg, 10% w / w, 30% mass eq). Bubbling H2was continued for 3 min. The mixture was stirred at 23 °C under H2atmosphere for 14 h. Upon completion, the solids were filtered off and the filtrate was concentrated to give aniline (90 mg, 93%). LCMS-ESI (positive) m / z: 218.1 (M+H) + .

[1310] Example LL

[1311] Synthesis of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38):

[1312] Step 1: Preparation of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38):

[1313]

[1314] To a solution of 2-(4-aminophenyl)ethan-1-ol (1.37 g, 10.0 mmol, 1.0 eq) in CH2Cl2(20 mL) was added p-chlorobenzyl isocyanate (1.70 g, 10.2 mmol, 1.02 eq) slowly at 0 °C. The mixture was then stirred vigorously at 23 °C for 1 h. Upon completion, the precipitate was filtered and washed with cold CH2Cl2(10 mL) and Et2O (10 mL) to give 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (2.8 g, 92%) as an off-white solid. LCMS-ESI (positive) m / z: 305.10 (M+H) + . 1HNMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.59 (t, J = 6.0 Hz, 1H), 4.58 (s, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H).

[1315] Example MM

[1316] Synthesis of 1 -(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39):

[1317] Preparation of 1 -(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39):

[1318]

[1319] To a solution of 1 -(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38, 500 mg, 1.64 mmol, 1.0 equiv) in THF / CH2CI2(20 mL, 1 :1 ) was added PPh3(516 mg, 1.97 mmol, 1.2 equiv) and imidazole (167 mg, 2.46 mmol, 2.0 equiv). Then N-bromosuccinimide (350 mg, 1.97 mmol, 1.2 equiv) was added at 0 °C. The reaction was stirred at 23 °C for 1 h. Upon completion, a mixture solution of NaHC03and Na2S203was added to quench the reaction. The aqueous phase was extracted with CH2CI2(5 mL). The combined organic phase was washed with brine, dried (MgS04), 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 (positive) m / z: 367.00 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.39(d,J=8.5Hz,2H),7.33(d,J=5.6Hz,2H),7.31(d,J=5.6Hz,2H),7.1 3(d,J=8.5Hz,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).

[1320] Example 1

[1321] Synthesis of ethyl 2-[4-({[(4-methoxyphenyl)methyl]amino}carbonylamino)phenyl]acetate (Compound 331)

[1322]

[1323] To a solution of ethyl 2-(4-aminophenyl)acetate (27.46 g, 153.2 mmol) in DCM (20 mL) was added 4-methoxybenzyl isocyanate (25.0 g, 153.2 mmol) dropwise at 20°C. The resulting mixture was stirred at room temperature for 4 hours, then methanol (10 mL) was added and cooled to 0°C. After 1 hour 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 (positive) m / z: 343.1 (M+H)+. 1H NMR(400MHz,DMSO-d6)δ8.50(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).

[1324] The compounds in the following table were prepared in a similar manner to compound 331 using the intermediates and reagents listed.

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347]

[1348]

[1349]

[1350]

[1351]

[1352]

[1353]

[1354] Example 2

[1355] Synthesis of ( {4-[2-(3,3-difluoroazetidinyl)-2-oxoethyl]phenyl} amino)-N- [(4- methoxyphenyl)methyl]formamide (Compound 320)

[1356]

[1357] To a room temperature solution of Intermediate 1.1 (100 mg, 0.318 mmol, 1.0 eq), 3,3-difluoroazetidine (59 mg, 0.636 mmol, 2.0 eq) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (181 mg, 0.275 mmol, 1.5 eq) in dimethylformamide (6 mL) was added N,N-diisopropylethylamine (0.006 mL, 0.03 mmol, 0.1 eq). The resulting mixture was stirred at room temperature for about 9 hours. The resulting 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, purified by reverse phase HPLC with a Phenomonex Gemini 5u C18 column, eluting with 10-100% acetonitrile in water over 30 minutes to give Compound 320 (37.0 mg, 0.095 mmol, 29.9% yield) as a white foam. LCMS-APCI (positive) m / z: 390.0 (M+H)+.1H NMR (400 MHz, 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 = 5.9 Hz, 1H), 4.61 (t, J = 12.5 Hz, 2H), 4.33-4.18 (m, 4H), 3.73 (s, 3H).

[1358] The compounds in the following table were prepared in a similar manner to Compound 320, using the intermediates and reagents listed.

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414]

[1415]

[1416] Example 3

[1417] Synthesis of N-{4-[(cyclobutylcarbonylamino)methyl]phenyl}{[(4- methoxyphenyl)methyl]amino}formamide (Compound 221)

[1418]

[1419] A scintillation vial was charged with cyclobutane carboxylic acid (42 mg, 0.63 mmol, 1.0 equiv) and O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (320 mg, 0.84 mmol, 2.0 equiv) in dimethylformamide (2 mL). N,N-diisopropylethylamine (37 μL, 0.21 mmol, 0.5 equiv) was added. 1-(4- (aminomethyl)phenyl)-3-(4-methoxybenzyl)urea (180 mg, 0.63 mmol, 1.5 equiv) was added and the resulting mixture was stirred at room temperature for about 30 minutes. The resulting reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 8 mL). The organic phase was dried to a viscous oil and purified by reverse phase HPLC with a 30 minute gradient of 10% to 100% acetonitrile in water on a Phenomonex Gemini 5u C18 column to give the desired product as a white solid (38.0 mg, 0.10 mmol, 25% yield). LCMS-APCI (positive) m / z: 368.15 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.48 (t, J = 6.0 Hz, 1H), 4.18 (dd, J = 22.4, 5.9 Hz, 4H), 3.74 (d, J = 1.5 Hz, 3H), 3.04 (p, J = 8.6 Hz, 1H), 2.14 (p, J = 9.4 Hz, 2H), 2.02 (d, J = 9.4 Hz, 2H), 1.88 (q, J = 9.1 Hz, 1H), 1.76 (d, J = 10.0 Hz, 2H).

[1420] The compounds in the following table were prepared in a similar manner to Compound 221 using the intermediates and reagents listed.

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449]

[1450]

[1451]

[1452] Example 4

[1453] Synthesis of 1 -(4-((4-(2-hydroxy-2-methylpropyl)piperazin-1 -yl)methyl)phenyl)-3- (4-methoxybenzyl)urea (Compound 242)

[1454]

[1455] To a solution of amine and Intermediate 3.1 (100 mg, 0.35 mmol) and 2-methyl-1 -(piperazin-1 -yl)propan-2-ol (82 mg, 0.52 mmol) in DCE (2 mL) and pyridine (0.2 mL) preheated at 70 °C for 15 min and then cooled to room temperature was added sodium triacetoxyborohydride (1 12 mg, 0.52 mmol) and the solution was stirred at 50 °C for 12 h. The solution was cooled to room temperature and saturated aqueous sodium carbonate (3.0 mL) was added and the solution was stirred vigorously for 10 min. The organic layer was separated and the aqueous layer was extracted with 5 mL of DCM. The combined organic layers were washed with brine, dried, filtered and concentrated. The crude material was purified by reverse phase HPLC with a 30 min gradient of 10-100% acetonitrile in water on a Phenomonex Gemini 5u C18 column to give 1 -(4-((4-(2-hydroxy-2-methylpropyl)piperazin-1 -yl)methyl)phenyl)-3-(4- methoxybenzyl)urea (82 mg, 0.19 mmol) as a viscous yellowish oil. LCMS-APCI (positive) m / z: 427.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.50 (t, J = 5.9 Hz, 2H), 4.22 (d, J = 5.8 Hz, 2H), ...

Claims

1. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 is chlorine, fluorine or methoxy; R 6 is hydrogen; and p is 0 or 1, where When p is 1, R 2 is hydrogen; R 3 is hydrogen; R 4 for g) 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents, or h) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo groups containing 1 to 4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl optionally substituted with one or more independently selected halogen or -C1-C6 alkyl substituents containing 1 to 4 heteroatoms selected from N, O, and S, and C3-C6 cycloalkyl; wherein Each R y independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r 、C6-C 12 Aryl and 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S; and Each R q and R r are independently hydrogen or C1-C6 alkyl; and R 5 is hydrogen; and When p is 0, R 4 is 1) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is substituted with one or more independently selected -C1-C6 alkyl substituents and is optionally further substituted with one or more oxo substituents, and R 5 is hydrogen, provided that for the compound of formula (II) (1)R 4 Not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furylmethyl)piperazinyl, and (2) The compound of formula (II) is not 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is chlorine or fluorine.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a methoxy group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (IG): or a pharmaceutically acceptable salt thereof, wherein: R 1 is chlorine, fluorine or methoxy; R 2 is hydrogen; R 3 is hydrogen; R 4 for g) 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents, or h) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo containing 1 to 4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more independently selected halogen or -C1-C6 alkyl substituents, and C3-C6 cycloalkyl; in Each R y independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r 、C6-C 12 aryl and 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S; Each R q and R r are independently hydrogen or C1-C6 alkyl; R 5 is hydrogen; and R 6 is hydrogen, the prerequisite is (1)R 4 Not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furylmethyl)piperazinyl, and (2) The compound of formula (IG) is not 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is chlorine, fluorine or methoxy; R 2 is hydrogen; R 3 is hydrogen; R 4 for g) 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more independently selected C1-C6 alkyl substituents, or h) a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing 1 to 4 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S optionally substituted with one or more independently selected C1-C6 alkyl substituents; wherein Each R y independently selected from the group consisting of: halogen, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r 、C6-C 12 aryl and 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S; Each R q and R r are independently hydrogen or C1-C6 alkyl; R 5 is hydrogen; in (1)R 4 Not 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furylmethyl)piperazinyl, and (2) The compound of formula (I) is not or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OH, -CN, optionally substituted with one or more independently selected R y -C1-C6 alkyl, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, C1-C6 alkyl, -C ... 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing 1 to 4 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S optionally substituted with one or more independently selected C1-C6 alkyl substituents.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted by one or more independently selected oxo, -S(O)2-C1-C6 alkyl or -C1-C6 alkyl optionally substituted with -OH.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of:

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 4 for 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with one or more independently selected C1-C6 alkyl substituents.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of:

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-A): or a pharmaceutically acceptable salt thereof, wherein: R 1 is chlorine, fluorine or methoxy; R 4 is 1) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is substituted with one or more independently selected -C1-C6 alkyl substituents and is optionally further substituted with one or more oxo substituents, and R 6 is hydrogen, provided that for the compound of formula (II-A) R 4 Not 4-methylpiperazinyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 for: A 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group containing exactly two ring heteroatoms, both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl group is substituted with one or more independently selected -C1-C6 alkyl substituents and is optionally further substituted with one or more oxo substituents.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of:

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 for 18. A compound selected from: or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 22. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for treating a disease or condition mediated by NAMPT activity.

24. The method of claim 23, wherein the disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy-induced tissue damage, a kidney disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, a disease caused by impaired stem cell function, a disease caused by DNA damage, a primary mitochondrial disorder, a muscle disease, and muscular dystrophy.

25. The method of claim 24, wherein the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, heart failure, heart failure with preserved ejection fraction, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve damage, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve injury, polio, and spinal cord injury.

26. The use according to claim 25, wherein the disease or condition is heart failure with preserved ejection fraction.

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