NAMPT regulator

Abstract

A compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R1, R2, R3, R4, R5, R6 and p are as defined herein. Additionally, a pharmaceutically acceptable composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided. Additionally, a method of using a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided. [Chemical Formula (II)]

Description

Technology Field

[0001] The present invention provides phenylurea compounds, pharmaceutical compositions comprising such compounds, and methods for treating various diseases and pathological conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT) with such compounds.

[0002] This application carries priority to U.S. Provisional Patent Application No. 62 / 971,838 filed on February 7, 2020, the disclosures of which are incorporated herein by reference in their entirety. Background Technology

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

[0004] Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme (enzyme cofactor) involved in fundamental biological processes of both catabolic and anabolic metabolism. As a coenzyme, NAD acts as a universal electron carrier, associated with many oxidases (generally dehydrogenases) involved in energy metabolism. NAD exists in cells in oxidized (NAD+ and NADP+) and reduced (NADH and NADPH) states, serving as a chemical agent to capture and transfer free energy during the oxidative processes of catabolism or to provide small energy packets for the production of macromolecules in anabolism. NADH, generated from the oxidation of carbohydrates, lipids, and amino acids, provides a reduction equivalent to the electron transport chain in mitochondria, ultimately inducing ATP synthesis through oxidative phosphorylation.

[0005] Over 200 enzymes utilize NAD+ or NADP+ as coenzymes, and their functions are not limited to energy metabolism. It is now recognized that NAD+ plays a role in regulating various functions, including mitochondrial function, respiratory capacity and biosynthesis, and mitochondrial-nuclear signaling. Furthermore, it controls cell signaling, gene expression, DNA repair, hematopoiesis, immune function, unfolded protein responses, and autophagy. Additionally, NAD is an anti-inflammatory agent and a precursor to NADPH, which is a major source of reducing power for combating oxidative stress. According to the literature, increasing NAD levels is an effective strategy for preventing or improving various disease states (Strømland et al. Biochem Soc Trans . 2019, 47(1): 119-130; Ralto et al. Nat Rev Nephrol . 2019; Fang et al. Trends Mol Med . 2017, 23(10): 899-916; Yoshino et al. Cell Metab . 2011,14(4): 528-36; Yang and Sauve's Biochim Biophys Acta . 2016, 1864: 1787-1800; Verdin, Science . 2015, 350(6265): 1208-13).

[0006] 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 are affected during aging, metabolic diseases, inflammatory diseases, ischemic / reperfusion injury, and 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 NeurosciIn other pathological conditions, levels are reduced (*. 2012, 32(17): 5821-32), suggesting that the regulation of cellular NAD+ levels affects the rate and severity of decline and deterioration of bodily functions. Therefore, an increase in cellular NAD+ concentration may be beneficial in the context of aging and age-related diseases.

[0007] The cellular NAD+ pool is regulated by the balance between the activities of NAD+ synthesizing and consuming enzymes. In mammals, NAD+ is synthesized from various dietary sources, including one or more of its major precursors, such as tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide (NAM). Depending on the bioavailability of the precursors, there are three pathways for synthesizing NAD+ in cells: (i) from Trp via the novel biosynthetic pathway or the kynurenine pathway, (ii) from NA via the Preiss-Handler pathway, and (iii) from NAM, NR, and NMN via the recovery pathway (Verdin et al. Science . 2015, 350(6265): 1208-13). The dominant NAD+ biosynthetic pathway among these involves a step of synthesizing nicotinamide mononucleotide (NMN) using nicotinamide and 5'-phosphoribosyl-pyrophosphate by nicotinamide phosphoribosyl-transferase (NAMPT), a rate-limiting enzyme important for determining lifespan and response to various stresses (Fulco et al. Dev Cell . 2008, 14(5): 661-73; Imai's Curr Pharm Des . 2009, 15(1):20-8; Revollo et al. J Biol Chem . 2004, 279(49):50754-63; Revollo et al. Cell Metab . 2007, Nov; 6(5): 363-75; van der Veer et al. J Biol Chem. 2007, 282(15): 10841-5; Yang et al. Cell. 2007, 130(6):1095-107). Therefore, increasing the catalytic rate of NAMPT by small molecule activators will raise NAD levels and thus be an effective strategy to address a wide range of disease states. These include heart disease, tissue damage caused by chemotherapy, kidney disease, metabolic disease, muscle disease, neurological disease and damage, diseases caused by impaired stem cell function, and DNA damage and primary mitochondrial disorders. The problem to be solved

[0008] The present invention provides phenylurea compounds, pharmaceutical compositions comprising such compounds, and a method for treating various diseases and pathological conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT) with such compounds. means of solving the problem

[0009] In this regard, the present invention provides a compound of the following formula (II) or a pharmaceutically acceptable salt thereof, and

[0010] [Chemical Formula (II)]

[0011]

[0012] Here, R 1 It is a halo or methoxy;

[0013] R 6 It is hydrogen or a halo;

[0014] p is 0 or 1, and

[0015] Here, when p is 1,

[0016] R 2 is hydrogen or a C1-C6 alkyl, or Z 4 and together with intervening atoms, to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0017] R 3 It is hydrogen or C1-C6 alkyl;

[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 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents,

[0026] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12Aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxos, 5 to 6-membered heteroaryls optionally substituted with one or more independently selected halo or -C1-C6 alkyl substituents, and 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyls,

[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 - and;

[0030] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0031] R b is hydrogen or a C1-C6 alkyl or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0032] R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0033] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h, -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0034] Each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0035] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryl;

[0036] Each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0037] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0038] R s is hydrogen or -C1-C6 alkyl;

[0039] R tis hydrogen or -C1-C6 alkyl;

[0040] m is 0 or 1, and;

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

[0042] q is 0 or 1, and;

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

[0044] Z 2 and Z 3 Each independently hydrogen or R z is;

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

[0046] Z 6 It is selected from the group consisting of 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, 5 to 6-membered heteroaryl and C1-C6 alkyl;

[0047] Z 7 C6-C 12 Ariligo;

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

[0049] R z is selected from the group consisting of the following:

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

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

[0052] c) C1-C6 alkoxy;

[0053] d) Halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

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

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

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

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

[0058] (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

[0059]

[0060] and

[0061]

[0062] It is something other than that;

[0063] (3) The compound of chemical formula (II) is not a compound of Table 1X;

[0064] When p is 0, R 4 Is,

[0065] l) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents,

[0066] m) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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-C6 alkyl substituents,

[0067] n) 3 to 6-membered heterocycloalkyl or heterocycloalkenyl substituted with one or more independently selected -S(O)2-C1-C6 alkyl substituents, optionally further substituted with one or more independently selected oxo or -C1-C6 alkyl substituents,

[0068] o) a pentoecycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentoecycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents,

[0069] p) a hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents,

[0070] q) a pentagonal aryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal aryl is substituted with exactly one methyl substituent,

[0071] r) a pentagonal heteroaryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal heteroaryl is substituted with one or more methyl substituents,

[0072] s) a 6-membered heteroaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is,

[0073]

[0074] and

[0075]

[0076] It is something other than,

[0077] t) Z 9 -S(O)2-,

[0078] u) Z 10 -S(O)2-NH-,

[0079] v) Z 11 -C(O)-NH-,

[0080] w) Z 12 -CH2-O-,

[0081] x) Z 13 -O-,

[0082] y) Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,

[0083] z)

[0084]

[0085] or

[0086] aa)

[0087]

[0088] And,

[0089] Here, Z 9 is cyclopropyl, C6-C 12 Aryl, one or more independently selected R A 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6alkyl), optionally substituted with a substituent, one or more independently selected R B -NH2 substituted with a substituent and one or more independently selected R CSelected from the group consisting of C1-C6 alkyls optionally substituted with a substituent, except Z 9 Is,

[0090]

[0091] It is other than unsubstituted methyl or unsubstituted ethyl, and

[0092] Here, R A is -C1-C6 alkyl or -CN;

[0093] R B is (i) -C1-C6 alkyl-(5 to 10-membered heteroaryl), or (ii) one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl group;

[0094] R C is a 3 to 8-membered heterocycloalkyl or heterocycloalkenyl;

[0095] Z 10 is one or more independently selected C6-C 12 It is a C1-C6 alkyl substituted with an aryl substituent;

[0096] Z 11 C3-C substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents 10 Selected from the group consisting of cycloalkyl and C1-C6alkyl, provided that Z 11 When this is a cycloprofile, R 1 It is something other than methoxy;

[0097] Z 12 is C6-C 12Selected from the group consisting of 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);

[0098] Z 13 is a 5 to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents;

[0099] Z 14 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0100] R 5 is hydrogen.

[0101] In another aspect, the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, and

[0102] [Chemical Formula (I)]

[0103]

[0104] Here, R 1 It is a halo or methoxy;

[0105] R 2 is hydrogen or a C1-C6 alkyl or Z 4 and together with intervening atoms, to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring, and

[0106] R 3 It is hydrogen or C1-C6 alkyl;

[0107] R 4 Is,

[0108] a) Z 1 NR a C(O)-,

[0109] b) Z2 C(O)NR b -,

[0110] c) Z 3 (CR c R d ) m NR e -,

[0111] d) Z 4 S(O)2(CH2) n -,

[0112] e) Z 5 OC(O)-,

[0113] f) NR f R g C(O)-,

[0114] g) a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, or

[0115] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 It is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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;

[0116] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0117] R b is hydrogen or a C1-C6 alkyl or R 5and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0118] R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0119] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0120] Each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0121] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0122] Each R yis a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0123] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0124] m is 0 or 1, and;

[0125] n is 0, 1, or 2, and;

[0126] R 5 is hydrogen or R b and together with intervening atoms, to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0127] Z 1 and Z 5 are each independently R z And;

[0128] Z 2 and Z 3 Each independently hydrogen or R z is;

[0129] Z 4 is hydrogen or R z or R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0130] R z is selected from the group consisting of the following:

[0131] a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy;

[0132] b) C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls;

[0133] c) C1-C6 alkoxy;

[0134] d) Halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v, C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0135] e) C6-C 12 Aryl; and

[0136] f) 5 to 10 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents,

[0137] Here, (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiofuran;

[0138] (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

[0139]

[0140] and

[0141]

[0142] It is something other than that,

[0143] (3) The compound of chemical formula (I) is not a compound of Table 1X.

[0144] In another aspect, the present invention provides a compound of the following chemical formula (IG) or a pharmaceutically acceptable salt thereof, and

[0145] [Chemical Formula (IG)]

[0146]

[0147] Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6is as defined in formula (II) or any variation or embodiment thereof.

[0148] In another aspect, the present invention provides a compound of the following formula (IA) or a pharmaceutically acceptable salt thereof, and

[0149] [Chemical Formula (IA)]

[0150]

[0151] Here, R 1 , R 2 , R 3 , R a and Z 1 is as defined in formula (II) or any variation or embodiment thereof.

[0152] In another aspect, the present invention provides a compound of the following formula (IB) or a pharmaceutically acceptable salt thereof, and

[0153] [Chemical Formula (IB)]

[0154]

[0155] Here, R 1 , R 2 , R 3 , R 5 , R b and Z 2 is as defined in formula (II) or any variation or embodiment thereof.

[0156] In another aspect, the present invention provides a compound of the following chemical formula (IC) or a pharmaceutically acceptable salt thereof, and

[0157] [Chemical Formula (IC)]

[0158]

[0159] Here, R 1 , R 2 , R 3 , R c , R d , R e , m and Z 3is as defined in formula (II) or any variation or embodiment thereof.

[0160] In another aspect, the present invention provides a compound of the following formula (ID) or a pharmaceutically acceptable salt thereof, and

[0161] [Chemical Formula (ID)]

[0162]

[0163] Here, R 1 , R 2 , R 3 , n and Z 4 is as defined in formula (II) or any variation or embodiment thereof.

[0164] In another aspect, the present invention provides a compound of the following formula (IE) or a pharmaceutically acceptable salt thereof, and

[0165] [Chemical Formula (IE)]

[0166]

[0167] Here, R 1 , R 2 , R 3 and Z 5 is as defined in formula (II) or any variation or embodiment thereof.

[0168] In another aspect, the present invention provides a compound of the formula (IF) or a pharmaceutically acceptable salt thereof, and

[0169] [Chemical Formula (IF)]

[0170]

[0171] Here, R 1 , R 2 , R 3 , R f and R g is as defined in formula (II) or any variation or embodiment thereof.

[0172] In another aspect, the present invention provides a compound of the following formula (II-A) or a pharmaceutically acceptable salt thereof, and

[0173] [Chemical Formula (II-A)]

[0174]

[0175] Here, R 1 , R 4 and R 6 is as defined in formula (II) or any variation or embodiment thereof.

[0176] In a further aspect, a pharmaceutical composition is provided herein comprising at least one compound of formulas (II), (IG), (I), (IA), (IB), (IC), (ID), (IE), (IF), 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 above, and optionally further comprising a pharmaceutically acceptable excipient.

[0177] In another aspect, a method for treating a disease or pathological condition mediated by NAMPT activity in a subject requiring treatment is provided herein, comprising the step of administering to a subject an effective amount of at least one compound of formula (II), formula (IG), formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (IF), or formula (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), formula (IG), formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (IF), or formula (II-A). In some embodiments, the disease or pathology is selected from the group consisting of cancer, hyperproliferative disease or pathology, inflammatory disease or pathology, metabolic disorder, heart disease or pathology, tissue damage due to chemotherapy, kidney disease, metabolic disease, neurological disease or damage, neurodegenerative disorder or disease, disease due to impaired stem cell function, disease due to DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder. In some embodiments, the disease or pathology 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-Barré syndrome, neurological injury, polio (poliomyelitis), and spinal cord injury.

[0178] Further embodiments, features, and advantages of the present invention will become apparent from the following detailed description and the practice of the present invention.

[0179] For the sake of brevity, the disclosures of publications cited herein, including patents, are incorporated herein by reference. Specific details for implementing the invention

[0180] definition

[0181] As used in this specification, the following words and phrases are generally intended to have the meanings described below, except where otherwise indicated by the context in which they are used.

[0182] Throughout this application, unless the context otherwise indicates, references to compounds of formula (II) include all subgroups of formula (II) defined herein, such as formula (I), formula (IG), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), and include all substructures, subgenuses, preferences, embodiments, examples, and specific compounds defined and / or described herein. Compounds of formula (II) and their subgroups, e.g., formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), and formula (II-A1), references to compounds of formulas (II-A1) include their ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, cocrystalline forms, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or includes a protected form.In some embodiments, references to compounds of formula (II) and their subgroups, such as formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1), include their polymorphs, solvates, cocrystalline isomers, tautomers, and / or oxides. In some embodiments, references to the compounds of formula (II) and their subgroups, such as formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A) and (II-A1), include their polymorphs, solvates, and / or co-crystals.In some embodiments, references to compounds of formula (II) and their subgroups, such as formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), and formula (II-A1), include their isomers, tautomers, and / or oxides. In some embodiments, references to the compounds of formula (II) and their subgroups, e.g., formulas (IG), (I), (IA), (I-A1), (I-A2), (I-A3), (I-A4), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C1), (I-C2), (I-C3), (I-C4), (ID), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (IE), (IF), (II-A), and (II-A1) include their solvates. Similarly, the term “salt” includes the solvates of the salts of the compounds.

[0183] "Alkyl" comprises straight and branched carbon chains having an indicated number of carbon atoms, for example, 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, it is intended to include all branched and straight-chain versions having that number of carbons; thus, for example, “propyl” includes n-propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0184] When a range of values ​​is given (e.g., C 1-6 alkyl), includes all intermediate ranges as well as each value within the range. For example, "C 1-6 "Alkyl" is C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 and C 1-2 It contains alkyl.

[0185] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having an 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 may be in a cis or trans configuration (Z or E configuration) with respect to the double bond(s). The alkenyl group includes, but is 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, buta-1,3-diene-1-yl, buta-1,3-diene-2-yl).

[0186] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having an indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. The alkynyl group includes, but is not limited to, ethinyl, propynyl (e.g., prop-1-in-1-yl, prop-2-in-1-yl) and butynyl (e.g., but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl).

[0187] "Cycloalkyl" represents a non-aromatic, fully saturated carbocyclic ring having an indicated number of cyclic carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6. The cycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as crosslinked, caged, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). Additionally, if a polycyclic cycloalkyl group is bonded to the parent structure through a non-aromatic carbon, one ring of the polycyclic cycloalkyl group may be aromatic. For example, the 1,2,3,4-tetrahydronaphthalene-1-yl group (wherein the moiety is bonded to the matrix structure through a non-aromatic carbon atom) is a cycloalkyl group, whereas the 1,2,3,4-tetrahydronaphthalene-5-yl group (wherein the moiety is bonded to the matrix structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0188] "Aryl" indicates an aromatic carbocyclic ring having an indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, where the polycyclic aryl group is bonded to the parent structure through an atom of the aromatic ring, the polycyclic aryl group may include a non-aromatic ring fused to the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalene-5-yl group (where the moiety is bonded to the parent structure through an aromatic carbon atom) is considered an aryl group, whereas the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the moiety is bonded to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, the 1,2,3,4-tetrahydroquinoline-8-yl group (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, whereas the 1,2,3,4-tetrahydroquinoline-1-yl group (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of the attachment point (e.g., both quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some cases, the aryl is phenyl or naphthyl. In certain cases, the aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.

[0189] "Heteroaryl" represents an aromatic ring containing an indicated number of atoms (e.g., 5 to 12, or 5 to 10 heteroaryls) composed 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 carbons. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 or less. Unless otherwise indicated, the heteroaryl group may be bonded to the parent structure by carbon or nitrogen atoms as long as the valence allows. For example, "pyridyl" contains 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" contains 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0190] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazol, 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, isothiazol, 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.

[0191] 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, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, Oxazolo[4,5-b]pyridine, Isoxazolo[4,5-b]pyridine, [1,2,3]Oxadiazolo[4,5-b]pyridine, Furo[2,3-c]pyridine, Oxazolo[5,4-c]pyridine, Isoxazolo[5,4-c]pyridine, [1,2,3]Oxadiazolo[5,4-c]pyridine, Furo[3,2-c]pyridine, Oxazolo[4,5-c]pyridine, Isoxazolo[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,Includes [5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazololine, quinoxaline, phthalazine, naphthiridine (e.g., 1,8-naphthiridine, 1,7-naphthiridine, 1,6-naphthiridine, 1,5-naphthiridine, 2,7-naphthiridine, 2,6-naphthiridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

[0192] In other cases, where a polycyclic heteroaryl group is bonded to a matrix structure through an atom of an aromatic ring, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl group (wherein the moiety is bonded to the matrix structure through an aromatic carbon atom) is considered a heteroaryl group, whereas a 4,5,6,7-tetrahydrobenzo[d]thiazole-5-yl group (wherein the moiety is bonded to the matrix structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0193] "Heterocycloalkyl" represents a non-aromatic, fully saturated ring having an indicated number of atoms, composed 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 carbons (e.g., 3 to 10, or 3 to 7 heterocycloalkyl). The heterocycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolinidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomophorinyl. Examples include thiomophorin S-oxide and thiomophorin 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, when a polycyclic heterocycloalkyl group is bonded to a parent structure through a non-aromatic carbon or nitrogen atom, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl). For example, a 1,2,3,4-tetrahydroquinoline-1-yl group (where the moiety is bonded to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, whereas a 1,2,3,4-tetrahydroquinoline-8-yl group (where the moiety is bonded to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of heterocycloalkyl groups fused to an aromatic ring are described below.

[0194] "Heterocycloalkenyl" represents a non-aromatic ring having at least one double bond induced by removing one molecule of hydrogen from an adjacent carbon atom, an adjacent nitrogen atom, or an adjacent carbon and nitrogen atom of the corresponding heterocycloalkyl, having an indicated number of atoms (e.g., 3 to 10, or 3 to 7 heterocycloalkyl) composed 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 carbons. The heterocycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrryl (e.g., 2,3-dihydro-1H-pyrryl, 2,5-dihydro-1H-pyrryl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl), It includes 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, when a polycyclic heterocycloalkenyl group is bonded to the parent structure through a non-aromatic carbon or nitrogen atom, one ring of the polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl).For example, a 1,2-dihydroquinoline-1-yl group (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, whereas a 1,2-dihydroquinoline-8-yl group (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of heterocycloalkenyl groups fused to an aromatic ring are described below.

[0195] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl. 2,3-Dihydrobenzo[d]isoxazolyl, 2,3-Dihydrobenzo[d]oxazolyl, 2,3-Dihydrobenzo[b]thiophenyl, 1,3-Dihydrobenzo[c]thiophenyl, 1,3-Dihydrobenzo[c]isothiazolyl, 2,3-Dihydrobenzo[d]isothiazolyl, 2,3-Dihydrobenzo[d]thiazolyl, 5,6-Dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, Isoindolin-1-one, 1,2-dihydroindazole-3-one, 1H-benzo[d]imidazole-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazole-3(1H)-one, benzo[d]isoxazole-3(2H)-one, benzo[d]oxazole-2(3H)-one, benzo[b]thiophene-2(3H)-one, benzo[b]thiophene-3(2H)-one, benzo[c]thiophene-1(3H)-one, benzo[c]isothiazole-3(1H)-one, benzo[d]isothiazole-3(2H)-one, benzo[d]thiazole-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazole-6-one, 1,2-dihydropyrrolo[3,4-d]thiazole-3-one, quinoline-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxaline-2(1H)-one, quinoxaline-2,3(1H,4H)-dione,It includes cinnoline-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazine-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazole[3,4-d]thiazole-3-one and 4,5-dihydropyrrolo[3,4-d]thiazole-6-one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group is determined by the atoms to which the moiety is bonded to the parent structure.

[0196] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0197] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso-isomers, and other stereoisomer forms, including racemic mixtures, optically pure forms, and mixtures of intermediates thereof. Enantiomers, diastereomers, meso-isomers, and other stereoisomer forms may be prepared using chiral synthones or chiral reagents, or digested using conventional techniques. Unless otherwise specified, if the compounds disclosed and / or described herein contain olefin double bonds or other geometrically asymmetric centers, the compounds are intended to include both E and Z isomers. When the compounds described herein contain moiety capable of tautomerization, the compounds are intended to include all possible tautomers unless otherwise specified.

[0198] In organic synthesis, a "protecting group" refers to a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to proceed selectively at other unprotected reactive sites, and which can be easily removed after the selective reaction is complete. Various protecting groups are, for example, those of TH Greene and PGM Wuts. Protective Groups in Organic Synthesis This is disclosed in , Third Edition, John Wiley & Sons, New York (1999). For example, the “hydroxy protected form” contains at least one hydroxyl group protected by a hydroxy protecting group. Similarly, amines and other reactive groups may be similarly protected.

[0199] The term “pharmaceuticalally acceptable salt” refers to a salt of any compound that is known to be nontoxic and is commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological efficacy of the compound described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include Berge et al.’s Pharmaceutical Salts, J. Pharmaceutical SciencesThis can be found in , January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts may be formed from inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvate, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts may be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0200] If the compound described herein is obtained as an acid addition salt, the free base may be obtained by basicizing the solution of the salt. Conversely, if the compound is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the usual procedure for preparing an acid addition salt from a base compound (e.g., Pharmaceutical Salts by Berge et al. J. Pharmaceutical Sciences(See , January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to produce pharmaceutically acceptable addition salts.

[0201] "Solvents" are formed by the interaction between a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvents include hydrates having any ratio of the compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0202] The term "substituted" means that a specific group or moiety has one or more substituents, including but not limited to alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, etc. The term "unsubstituted" means that a specific group does not have substituents. When the term "substituted" is used to describe a structural system, substitution means that any atom in the system occurs at an allowed position. When a group or moiety has one or more substituents, it is understood that the substituents may be identical or different from one another. In some embodiments, the substituted group or moiety has one to five substituents. In some embodiments, the substituted group or moiety has one substituent. In some embodiments, the substituted group or moiety has two substituents. In some embodiments, the substituted group or moiety has three substituents. In some embodiments, the substituted group or moiety has four substituents. In some embodiments, the substituted group or moiety has five substituents.

[0203] “Optional” or “opportunistically” means that an event or situation described below may or may not occur, and the description includes cases where the event or situation occurs and cases where it does not occur. For example, “opportunistically substituted alkyl” includes both “alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that with respect to any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is stereoimpractical, synthetically unfeasible, and / or inherently unstable. Where a group or moiety is optionally substituted, it will be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0204] The compounds disclosed and / or described herein are in concentrated isotopic forms, e.g. 2 H, 3 H, 11 C, 13 C and / or 14 The content of C may be in a concentrated form. In one embodiment, the compound contains at least one deuterium atom. Such a deuterated form may be prepared, for example, by the procedures described in U.S. Patents No. 5,846,514 and No. 6,334,997. Such a deuterated compound may improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds are described in Dean, D.’s *Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development*. Curr. Pharm. Des. , 2000; 6(10); The Synthesis of Radiolabeled Compounds via Organometallic Intermediates by Kabalka, G. et al. Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem. It can be synthesized using various methods such as those described in , 1981, 64(1-2), 9-32.

[0205] The terms "pharmaceuticalally acceptable carrier" or "pharmaceutically acceptable excipient" include any solvent, dispersion medium, coating agent, antimicrobial and antifungal agent, isotonic agent, absorption retardant, etc. The use of such media and formulations for pharmaceutically active substances is well known in the art. Their use in pharmaceutical compositions is considered except where any conventional media or formulation is incompatible with the active ingredient. A co-active ingredient may also be incorporated into the pharmaceutical composition.

[0206] The terms “patient,” “individual,” and “subject” refer to animals such as mammals, birds, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient or subject is a human, for example, a human who is or will be the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein may be useful for both human therapy and veterinary applications.

[0207] As used herein, the term “therapeutic” refers to the ability to modulate nicotinamide phosphoribosyltransferase (NAMPT). As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical as described herein, compared to activity in the absence of the chemical. The change may be an increase or decrease in activity, which may result from a direct interaction between the chemical and the target, or from an interaction between the chemical and one or more other factors, which in turn affect the activity of the target. For example, the presence of the chemical may increase or decrease target activity by, for example, directly binding to the target, causing other factors (directly or indirectly) to increase or decrease target activity, or by increasing or decreasing the amount of the target present in the cell or organism (directly or indirectly).

[0208] The terms “therapeutic effective dose” or “effective dose” refer to an amount of the compound disclosed and / or described herein that is sufficient to produce a therapeutic effect as defined herein when administered to a patient requiring such treatment. The therapeutic effective dose of the compound may be an amount sufficient to treat a disease responsive to the regulation of nicotinamide phosphoribosyltransferase (NAMPT). The therapeutic effective dose depends, for example, on the subject and the disease state being treated, the subject’s body weight and age, the severity of the disease state, the specific compound, the regimen to be followed, the timing of administration, and the manner of administration, all of which can be readily determined by a person skilled in the art. The therapeutic effective dose may be confirmed experimentally, for example by analyzing the blood concentration of the chemical, or theoretically by calculating bioavailability.

[0209] “Treatment” (and related terms, e.g., “treat,” “treated,” “treating”) includes one or more of the following: prevention of disease or disorder (i.e., preventing the onset of clinical symptoms of disease or disorder); suppression of disease or disorder; delaying or preventing the onset of clinical symptoms of disease or disorder; and / or alleviation of disease or disorder (i.e., alleviation of clinical symptoms or inducing regression). This term includes situations in which the disease or disorder is already experienced by the patient, as well as situations in which the disease or disorder is not currently experienced but is expected to occur. This term includes both the complete and partial reduction or prevention of the condition or disorder and the complete or partial reduction of clinical symptoms of the disease or disorder. Accordingly, the compounds described and / or disclosed herein may prevent the exacerbation of an existing disease or disorder, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder. When used in a prophylactic manner, the compounds disclosed and / or described herein may prevent the onset of a disease or disorder or reduce the degree of a disease or disorder that may develop.

[0210] compound

[0211] Compounds and their salts (e.g., pharmaceutically acceptable salts) are described in detail herein, including a brief summary and the appended claims. Additionally, methods for preparing all compounds described herein, as well as the uses of all and any stereoisomers including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any proportion including racemic mixtures, salts and solvates of the compounds described herein, are provided. Any compounds described herein may also be referred to as drugs.

[0212] In one aspect, a compound of the following formula (II) or a pharmaceutically acceptable salt thereof is provided, and

[0213] [Chemical Formula (II)]

[0214]

[0215] Here, R 1 It is a halo or methoxy;

[0216] R 6 It is hydrogen or a halo;

[0217] p is 0 or 1, and

[0218] Here, when p is 1,

[0219] R 2 is hydrogen or a C1-C6 alkyl, or Z 4 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0220] R 3 It is hydrogen or C1-C6 alkyl;

[0221] R 4 Is,

[0222] a) Z 1 NR a C(O)-,

[0223] b) Z 2 C(O)NR b -,

[0224] c) Z 3 (CR c R d ) m NR e -,

[0225] d) Z 4 S(O)2(CH2) n -,

[0226] e) Z 5 OC(O)-,

[0227] f) NR f R g C(O)-,

[0228] g) 5 to 10 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents,

[0229] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 Aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxos, 5 to 6-membered heteroaryls optionally substituted with one or more independently selected halo or -C1-C6 alkyl substituents, and 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyls,

[0230] i) Z 6 S(O)2N(R s )-,

[0231] j) Z 7 N(R t )S(O)2-, or

[0232] k) Z 8 -O-(CH2) q - and;

[0233] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0234] R b is hydrogen or a C1-C6 alkyl or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0235] R c and Rd Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0236] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0237] Each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0238] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0239] Each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0240] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0241] R s is hydrogen or -C1-C6 alkyl;

[0242] R t is hydrogen or -C1-C6 alkyl;

[0243] m is 0 or 1, and;

[0244] n is 0, 1, or 2, and;

[0245] q is 0 or 1, and;

[0246] Z 1 and Z 5 are each independently R z And;

[0247] Z 2 and Z 3 Each independently hydrogen or R z is;

[0248] Z 4 is hydrogen or R z Or, R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0249] Z 6 is selected from the group consisting of 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, 5 to 6-membered heteroaryl and C1-C6 alkyl;

[0250] Z 7 C6-C 12 Ariligo;

[0251] Z 8is selected from the group consisting of 5 to 6-membered heteroaryls and C3-C6 cycloalkyls, and

[0252] R z is selected from the group consisting of the following:

[0253] a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy;

[0254] b) C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls;

[0255] c) C1-C6 alkoxy;

[0256] d) Halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 123 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 Silver halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0257] e) C6-C 12 Aryl; and

[0258] f) a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0259] R 5 is hydrogen, halo, or R b and together with intervening atoms, to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring, provided,

[0260] (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 ...is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiofuran;

[0261] (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

[0262]

[0263] and

[0264]

[0265] It is something other than that;

[0266] (3) The compound of chemical formula (II) is not a compound of Table 1X;

[0267] When p is 0, R 4 Is,

[0268] l) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents,

[0269] m) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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-C6 alkyl substituents,

[0270] n) 3 to 6-membered heterocycloalkyl or heterocycloalkenyl substituted with one or more independently selected -S(O)2-C1-C6 alkyl substituents, optionally further substituted with one or more independently selected oxo or -C1-C6 alkyl substituents,

[0271] o) a pentoecious heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentoecious heterocycloalkyl or heterocycloalkenyl comprises one or more independently selected oxos, C1-C6 alkyls , or optionally substituted with -S(O)2-(C1-C6 alkyl) substituents,

[0272] p) a hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is one or more independently selected oxos, C1-C6 alkyls , or optionally substituted with -S(O)2-(C1-C6 alkyl) substituents,

[0273] q) a pentagonal aryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal aryl is substituted with exactly one methyl substituent,

[0274] r) a pentagonal heteroaryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal heteroaryl is substituted with one or more methyl substituents,

[0275] s) a 6-membered heteroaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is,

[0276]

[0277] or

[0278]

[0279] It is something other than,

[0280] t) Z 9 -S(O)2-,

[0281] u) Z 10 -S(O)2-NH-,

[0282] v) Z 11 -C(O)-NH-,

[0283] w) Z 12 -CH2-O-,

[0284] x) Z 13 -O-,

[0285] y) Z 14-C(H)(C1-C6alkyl)-NH-C(O)-,

[0286] z)

[0287]

[0288] or

[0289] aa)

[0290]

[0291] And,

[0292] Here, Z 9 is cyclopropyl, C6-C 12 Aryl, one or more independently selected R A 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6alkyl), optionally substituted with a substituent, one or more independently selected R B -NH2 substituted with a substituent and one or more independently selected R C Selected from the group consisting of C1-C6 alkyls optionally substituted with a substituent, except Z 9 Is,

[0293]

[0294] It is something other than unsubstituted methyl or unsubstituted ethyl,

[0295] Here, R A is -C1-C6 alkyl or -CN;

[0296] R B is (i) -C1-C6 alkyl-(5 to 10-membered heteroaryl), or (ii) one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl group;

[0297] R C is a 3 to 8-membered heterocycloalkyl or heterocycloalkenyl;

[0298] Z 10 is one or more independently selected C6-C 12 It is a C1-C6 alkyl substituted with an aryl substituent;

[0299] Z 11 C3-C 10 Selected from the group consisting of cycloalkyl and C1-C6 alkyl substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents, provided that Z 11 If this is a cycloprofile, R 1 It is something other than methoxy;

[0300] Z 12 is C6-C 12 Selected from the group consisting of 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);

[0301] Z 13 is a 5 to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents;

[0302] Z 14 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0303] R 5 is hydrogen.

[0304] In one aspect, a compound of the following chemical formula (IG) or a pharmaceutically acceptable salt thereof is provided, and

[0305] [Chemical Formula (IG)]

[0306]

[0307] Here, R 1 It is a halo or methoxy;

[0308] R 2 is hydrogen or a C1-C6 alkyl or Z4 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0309] R 3 is hydrogen or C1-C6 alkyl;

[0310] R 4 Is,

[0311] a) Z 1 NR a C(O)-,

[0312] b) Z 2 C(O)NR b -,

[0313] c) Z 3 (CR c R d ) m NR e -,

[0314] d) Z 4 S(O)2(CH2) n -,

[0315] e) Z 5 OC(O)-,

[0316] f) NR f R g C(O)-,

[0317] g) 5 to 10 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents,

[0318] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12Aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxos, 5 to 6-membered heteroaryls optionally substituted with one or more independently selected halo or -C1-C6 alkyl substituents, and 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyls,

[0319] i) Z 6 S(O)2N(R s )-,

[0320] j) Z 7 N(R t )S(O)2-, or

[0321] k) Z 8 -O-(CH2) q - and;

[0322] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0323] R b is hydrogen or a C1-C6 alkyl, or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0324] R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0325] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h, -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0326] Each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0327] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryl;

[0328] Each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0329] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0330] R s is hydrogen or -C1-C6 alkyl;

[0331] R t is hydrogen or -C1-C6 alkyl;

[0332] m is 0 or 1, and;

[0333] n is 0, 1, or 2, and;

[0334] q is 0 or 1, and;

[0335] Z 2 and Z 3 Each independently hydrogen or R z And;

[0336] Z 4 is hydrogen or R z or R 2 and together with intervening atoms, to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0337] Z 6 is selected from the group consisting of 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, 5 to 6-membered heteroaryl and C1-C6 alkyl;

[0338] Z 7 C6-C 12 Aril is;

[0339] Z 8 It is selected from the group consisting of 5 to 6-membered heteroaryls and C3-C6 cycloalkyls, and

[0340] R z is selected from the group consisting of the following:

[0341] a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy;

[0342] b) C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls;

[0343] c) C1-C6 alkoxy;

[0344] d) Halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0345] e) C6-C 12 Aryl; and

[0346] f) a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0347] R 5 is hydrogen, halogen, or R b and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0348] R 6 It is hydrogen or a halo, and Z 1 and Z 5 are each independently R z And, however,

[0349] (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiofuran;

[0350] (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl,

[0351]

[0352] and

[0353]

[0354] It is something other than that;

[0355] (3) Compounds of chemical formula (IG) are not compounds of Table 1X.

[0356] In one aspect, a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof is provided, and

[0357] [Chemical Formula (I)]

[0358]

[0359] Here, R 1 It is a halo or methoxy;

[0360] R 2 is hydrogen or a C1-C6 alkyl, or Z 4 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0361] R 3 It is hydrogen or C1-C6 alkyl;

[0362] R 4 Is,

[0363] a) Z 1 NR a C(O)-,

[0364] b) Z 2 C(O)NR b -,

[0365] c) Z 3 (CR c R d ) m NR e -,

[0366] d) Z 4 S(O)2(CH2) n -,

[0367] e) Z 5 OC(O)-,

[0368] f) NR f R g C(O)-,

[0369] g) a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, or

[0370] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12It is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0371] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0372] R b is hydrogen or a C1-C6 alkyl or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0373] R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0374] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0375] Each R his independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0376] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0377] Each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0378] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0379] m is 0 or 1, and;

[0380] n is 0, 1, or 2, and;

[0381] R 5 is hydrogen or R b and together with intervening atoms, to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0382] Z 1 and Z 5 are each independently R z And;

[0383] Z 2 and Z 3 Each independently hydrogen or R z is;

[0384] Z 4 is hydrogen or R z or R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0385] R z is selected from the group consisting of the following:

[0386] a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy;

[0387] b) C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls;

[0388] c) C1-C6 alkoxy;

[0389] d) Halo, oxo, -OH, -CN, one or more independently selected R w-C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0390] e) C6-C 12 Aryl; and

[0391] f) 5 to 10 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0392] In some embodiments of formula (II), formula (IG), or formula (I), (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH and -CH2-thiofuran; (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

[0393]

[0394] and

[0395]

[0396] Other than that; (3) Compounds of formula (II), formula (IG), or formula (I) are not compounds of Table 1X.

[0397]

[0398]

[0399]

[0400]

[0401] In some embodiments of formula (II), formula (IG), or formula (I), R 1 It is a halo. For example, in some embodiments, R 1 is a fluoro. In some embodiments, R 1 It is chloro. In some embodiments, R 1 It is bromo. In another embodiment, R 1 It is iodine.

[0402] In some embodiments of formula (II), formula (IG), or formula (I), R 1 It is methoxy.

[0403] In some embodiments of formula (II), formula (IG), or formula (I), R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0404] In some embodiments of formula (II), formula (IG), or formula (I), R 3 is hydrogen. In some embodiments, R 3 is a C1-C6 alkyl. For example, in some embodiments, R 3It is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0405] In some embodiments of formula (II), formula (IG), or formula (I), R 5 is hydrogen. In some embodiments, R b If exists, R 5 and together with intervening atoms, it forms a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, R 5 is a halo. In some embodiments, R 5 is a fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodine.

[0406] In some embodiments of formula (II), formula (IG), or formula (I), R 6 is hydrogen. In formula (II), formula (IG), or some embodiment of formula (I), R 6 is a halo. In some embodiments of formula (II), formula (IG), or formula (I), R 6 is a fluoro. In formula (II), formula (IG), or some embodiment of formula (I), R 6 is chloro. In formula (II), formula (IG), or some embodiment of formula (I), R 6 is bromo. In formula (II), formula (IG), or some embodiment of formula (I), R 6 It is iodine.

[0407] In some embodiments of the compound of formula (II), p is 1. In some embodiments of the compound of formula (II), p is 1, and the compound is of formula (IG). In other embodiments of the compound of formula (II), p is 1, and the compound is of formula (I).

[0408] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is Z 1 NR a C(O)-, Z 2 C(O)NR b -, Z 3 (CR c R d ) m NR e -, Z 4 S(O)2(CH2) n -, Z 5 OC(O)- and NR f R g It is selected from the group consisting of C(O)-. In some embodiments, R 4 is Z 1 NR a C(O)- or NR f R g C(O)- is. In some embodiments, R 4 is Z 1 NR a C(O)- or Z 2 C(O)NR b -am.

[0409] In another aspect, the compound of formula (II), formula (IG), or formula (I) is the compound of formula (IA) below or a pharmaceutically acceptable salt thereof, and

[0410] [Chemical Formula (IA)]

[0411]

[0412] Here, R 1 , R 2 , R 3 , R a and Z 1is as defined in formula (II), formula (IG), or formula (I), or any variation or embodiment thereof.

[0413] In some embodiments, the compound is a compound of the following formula (I-A1), formula (I-A2), formula (I-A3), or formula (I-A4) or a pharmaceutically acceptable salt thereof, and

[0414] [Chemical Formula (I-A1)]

[0415]

[0416] [Chemical Formula (I-A2)]

[0417]

[0418] [Chemical Formula (I-A3)]

[0419]

[0420] [Chemical Formula (I-A4)]

[0421]

[0422] Here, R 1 , R a and Z 1 is as defined for formula (II), formula (IG), formula (I), or formula (IA), or any variation or embodiment thereof.

[0423] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), R a is hydrogen. In some embodiments, R a is a C1-C6 alkyl. For example, in some embodiments, R a is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0424] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), Z 1 is R zis. In some embodiments, Z 1 It is selected from the group consisting of the following.

[0425] -OH, C3-C6 cycloalkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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-C6 alkyl and C1-C6 alkoxy;

[0426] C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with a C1-C6 alkyl;

[0427] 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 C6-C 12 Arbitrarily substituted with Arillo.

[0428] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), Z 1 is a C1-C6 alkyl. In some embodiments, Z 1 is an unsubstituted C1-C6 alkyl. In some embodiments, Z 1 -OH, C3-C6 cycloalkyl, C6-C 12It is a C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl and 5 to 10-membered heteroaryl are each independently substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy.

[0429] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), Z 1 is a C3-C6 cycloalkyl. In some embodiments, Z 1 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, Z 1 C6-C 12 It is a C3-C6 cycloalkyl substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with a C1-C6 alkyl. In some embodiments, Z 1 is a C3-C6 cycloalkyl optionally substituted with one or more groups independently selected from methoxy, ethoxy, and phenyl. In some embodiments, Z 1 is a C3-C6 cycloalkyl optionally substituted with a C1-C6 alkoxy optionally substituted with a 5- or 10-membered heteroaryl, wherein the 5- or 10-membered heteroaryl is optionally further substituted with a C1-C6 alkyl (e.g.,

[0430]

[0431] ). In some embodiments, Z 1 is a C3-C6 cycloalkyl optionally substituted with phenyl. In some embodiments, Z 1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is C6-C 12 It is optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with a C1-C6 alkyl.

[0432] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), Z 1 is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 is a 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 is a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 is a 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 C6-C 12 Aryl is arbitrarily substituted. In some embodiments, Z 1 silver

[0433]

[0434] or

[0435]

[0436] Each is 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 is C6-C 12 Arillo is arbitrarily substituted.

[0437] In some embodiments of formula (II), formula (IG), formula (I), or formula (IA), Z 1 is a C1-C6 alkyl. In certain embodiments, Z 1 It is ethyl. In some embodiments, Z 1 ethyl,

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445] and

[0446]

[0447] It is selected from a group consisting of.

[0448] In another aspect, the compound of formula (II), formula (IG), or formula (I) is the compound of formula (IB) or its pharmaceutically acceptable salt, and

[0449] [Chemical Formula (IB)]

[0450]

[0451] Here, R 1 , R 2 , R 3 , R 5 , R b and Z 2 is as defined for formula (II), formula (IG), or formula (I), or any variation or embodiment thereof.

[0452] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Rb is hydrogen. In some embodiments, R b is a C1-C6 alkyl. For example, in some embodiments, R b is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IB), R 5 is hydrogen. In another embodiment, R b is R 5 and together with intervening atoms, it forms a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments of formula (II) or formula (IG), R 5 is a halo. In some embodiments, R 5 is a fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodine.

[0453] In some embodiments, the compound is a compound of the following formula (I-B1), formula (I-B2), or formula (I-B3) or a pharmaceutically acceptable salt thereof, and

[0454] [Chemical Formula (I-B1)]

[0455]

[0456] [Chemical formula (I-B2)]

[0457]

[0458] [Chemical Formula (I-B3)]

[0459]

[0460] Here, R 1 and Z 2 is as defined for formula (II), formula (IG), formula (I), or formula (IB), or any variation or embodiment thereof.

[0461] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is hydrogen. In some embodiments, Z 2 is R z is. In some embodiments, Z 2 is selected from the group consisting of the following.

[0462] C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl and 5 to 10-membered heteroaryls;

[0463] C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy;

[0464] C1-C6 alkoxy;

[0465] 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C1-C6 alkyl substituents;

[0466] C6-C 12 Aryl; and

[0467] 5 to 10-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0468] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is a C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl and 5 to 10-membered heteroaryls. In some embodiments, Z 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl and 5 to 10 heteroaryls.

[0469] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is a C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy. In some embodiments, Z 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy.

[0470] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is a C1-C6 alkoxy. In some embodiments, Z 2 is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy.

[0471] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 is a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 is an azetidinyl group optionally substituted with one or more -C1-C6 alkyl substituents or a tetrahydrofuranyl group optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 Is

[0472]

[0473]

[0474] or

[0475]

[0476] and each is optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 Is

[0477]

[0478] is. In some embodiments, Z 2 Is

[0479]

[0480] is. In some embodiments, Z 2 Is

[0481]

[0482]

[0483] or

[0484]

[0485] and each is optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 is optionally substituted with one or more independently selected -C1-C6 alkyl substituents

[0486]

[0487] is. In some embodiments, Z 2 Is

[0488]

[0489] am.

[0490] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is C6-C 12 It is Aryl. For example, in some embodiments, Z 2 is phenyl or naphthyl.

[0491] In some embodiments of formula (II), formula (IG), formula (I), or formula (IB), Z 2 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, Z 2 is a 5 to 6-membered heteroaryl optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 is a pyridyl group optionally substituted with one or more independently selected -C1-C6 alkyl substituents. In some embodiments, Z 2 is a pyridyl group optionally substituted with methyl, ethyl, or isopropyl. In some embodiments, Z 2 is a methyl-substituted pyridyl group. In another embodiment, Z 2 is a pyridyl group substituted with isopropyl. In some embodiments, Z 2 Is

[0492]

[0493]

[0494] and

[0495]

[0496] It is selected from the group consisting of. In some embodiments, Z 2 Is

[0497]

[0498] am.

[0499] In some embodiments, Z 2 is ethyl,

[0500]

[0501]

[0502] and

[0503]

[0504]

[0505]

[0506]

[0507]

[0508] and

[0509]

[0510] It is selected from a group consisting of.

[0511] In some embodiments, Z 2 Is

[0512]

[0513] or

[0514]

[0515] am.

[0516] In another aspect, the compound of formula (II), formula (IG), or formula (I) is the compound of formula (IC) below or a pharmaceutically acceptable salt thereof, and

[0517] [Chemical Formula (IC)]

[0518]

[0519] Here, R 1 , R 2 , R 3 , R c , R d , R e , m and Z 3 is as defined for the chemical formula (IG) or chemical formula (I), or any variation or embodiment thereof.

[0520] In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IC), m is 0. In other embodiments, m is 1. In some embodiments of Formula (IG), Formula (I), or Formula (IC), R c is hydrogen. In another embodiment, Rc is a C1-C6 alkyl. In some embodiments of formula (II), formula (IG), formula (I), or formula (IC), R d is hydrogen. In another embodiment, R d is a C1-C6 alkyl. In some embodiments, R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached.

[0521] In some embodiments, the compound is a compound of the following formula (I-C1), formula (I-C2), formula (I-C3), or formula (I-C4) or a pharmaceutically acceptable salt thereof, and

[0522] [Chemical Formula (I-C1)]

[0523]

[0524] [Chemical formula (I-C2)]

[0525]

[0526] [Chemical formula (I-C3)]

[0527]

[0528] [Chemical formula (I-C4)]

[0529]

[0530] Here, R 1 , R e and Z 3 is as defined for formula (II), formula (IG), formula (I), or formula (IC), or any variation or embodiment thereof.

[0531] In some embodiments of formula (II), formula (IG), formula (I), or formula (IC), R e is hydrogen. In another embodiment, R e is a C1-C6 alkyl.

[0532] In some embodiments of formula (II), formula (IG), formula (I), or formula (IC), Z 3 It is hydrogen. In some embodiments, Z 3 is R z is. In some embodiments, Z 3 C3-C6 cycloalkyl; 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C1-C6 alkyl or oxo; C6-C 12 Selected from the group consisting of aryls; and 5 to 10 heteroaryls 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 optionally substituted with a -C1-C6 alkyl or oxo. In some embodiments, Z 3 silver

[0533]

[0534]

[0535]

[0536] and

[0537]

[0538] It is selected from the group consisting of. In some embodiments, Z 3 silver

[0539]

[0540] am.

[0541] In another aspect, the compound of formula (II), formula (IG), or formula (I) is the compound of formula (ID) below or this pharmaceutically acceptable salt, and

[0542] [Chemical Formula (ID)]

[0543]

[0544] Here, R 1 , R 2, R 3 , n and Z 4 is as defined for formula (II), formula (IG) or formula (I) or any variation or embodiment thereof.

[0545] In some embodiments of formula (II), formula (IG), formula (I), or formula (ID), n is 0. In some embodiments, n is 1. In other embodiments, n is 2.

[0546] In some embodiments, the compound is a compound of the following formula (I-D1) or formula (I-D2) or a pharmaceutically acceptable salt thereof, and

[0547] [Chemical Formula (I-D1)]

[0548]

[0549] [Chemical Formula (I-D2)]

[0550]

[0551] Here, R 1 and Z 4 is as defined for the chemical formula (IG), chemical formula (I), or chemical formula (ID), or any variation or embodiment thereof.

[0552] In some embodiments, the compound is a compound of the following formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6) or formula (I-D7) or a pharmaceutically acceptable salt thereof, and

[0553] [Chemical Formula (I-D3)]

[0554]

[0555] [Chemical Formula (I-D4)]

[0556]

[0557] [Chemical Formula (I-D5)]

[0558]

[0559] [Chemical Formula (I-D6)]

[0560]

[0561] [Chemical Formula (I-D7)]

[0562]

[0563] Here, R 1 is as defined for formula (II), formula (IG), formula (I), or formula (ID), or any variation or embodiment thereof.

[0564] In some embodiments of formula (II), formula (IG), formula (I), or formula (ID), Z 4 is hydrogen. In some embodiments, Z 4 is R z is. In another embodiment, Z 4 is a C1-C6 alkyl. For example, in some embodiments, Z 4 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, Z 4 is R 2 and together with intervening atoms, it forms a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments,

[0565]

[0566] Is

[0567]

[0568]

[0569] and

[0570]

[0571] It is selected from a group consisting of.

[0572] In another aspect, the compound of formula (II), formula (IG), or formula (I) is the compound of formula (IE) below or a pharmaceutically acceptable salt thereof, and

[0573] [Chemical Formula (IE)]

[0574]

[0575] Here, R 1 , R 2 , R 3 and Z 5 is as defined for formula (II), formula (IG), formula (I), or any variation or embodiment thereof.

[0576] In some embodiments of formula (II), formula (IG), formula (I), or formula (IE), Z 5 is a C1-C6 alkyl. For example, in some embodiments, Z 5 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, Z 5 is ethyl.

[0577] In another aspect, the compound of formula (II), formula (IG), or formula (I) is a compound of formula (IF) or a salt thereof, and

[0578] [Chemical Formula (IF)]

[0579]

[0580] Here, R 1 , R 2 , R 3 , R f and R g is as defined for formula (II), formula (IG), or formula (I), or any variation or embodiment thereof.

[0581] In some embodiments of formula (II), formula (IG), formula (I), or formula (IF), R f and Rg together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n It forms a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryl.

[0582] In some embodiments of formula (II), formula (IG), formula (I), or formula (IF), R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forms a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. In some embodiments, R f and R gThey form a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl selected from the group consisting of azetidinyl, pyrrolinidinyl, and piperidinyl together with the nitrogen to which they are attached, each comprising a halo, -OH, -CN, oxo, and one or more independently selected Rs. x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. In some embodiments,

[0583]

[0584] Is

[0585]

[0586]

[0587] or

[0588]

[0589] and each is a halo, -OH, -CN, oxo, one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with a substituent h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. In some embodiments, R f and R gis formed with the nitrogen to which they are attached a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with a -C1-C6 alkyl, wherein the -C1-C6 alkyl is optionally substituted with -OH. In some embodiments, R f and R g They form a pyrrolinidinyl optionally substituted with a -C1-C6 alkyl group together with the nitrogen to which they are attached, wherein the -C1-C6 alkyl group is optionally substituted with -OH. In some embodiments,

[0590]

[0591] Is

[0592]

[0593] is. In some embodiments of Formula (II), Formula (IG), Formula (I), or Formula (IF), R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forms a 6 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. In some embodiments, R f and R g They form a bicyclic 6 to 10-membered heterocycloalkyl or heterocycloalkenyl with the nitrogen to which they are attached. For example, in some embodiments, R f and R gtogether with the nitrogen to which they are attached

[0594]

[0595] or

[0596]

[0597] Forming, each comprising a halo, -OH, -CN, oxo, and one or more independently selected Rs x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. In some embodiments, R f and R g They form 6 to 10-membered heterocycloalkyl or heterocycloalkenyl groups crosslinked with the nitrogen to which they are attached. For example, in some embodiments,

[0598]

[0599] Is

[0600]

[0601] and

[0602]

[0603] Selected from the group consisting of, each comprising a halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m Rn It is optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryls.

[0604] In some embodiments, R f and R g They form spirocyclic 6 to 10-membered heterocycloalkyl or heterocycloalkenyl groups together with the nitrogen to which they are attached. For example, in some embodiments

[0605]

[0606] Is

[0607]

[0608]

[0609] and

[0610]

[0611] Selected from the group consisting of, each comprising a halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n It is optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryl.

[0612] In some embodiments,

[0613]

[0614] is selected from the group consisting of the following.

[0615]

[0616]

[0617]

[0618] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 4 is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naftiridinyl, benzoxazolyl, benzothiazoyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetrazoyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazoyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazoyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzoxadiazoyl, benzothiophenyl, benzisothiazolyl, benzothiadiazoyl, pyrrolopyridinyl, pyrazolopyridinyl, Selected from the group consisting of imidazopyridinyl, triazolopyridinyl, propyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, and imidazothiazolyl, each optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 4 is a 5 to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 4 is pyrazolyl, pyridinyl, or oxadiazole, each optionally substituted with one or more independently selected C1-C6 alkyl substituents. In certain embodiments, R 4 Is

[0619]

[0620] and

[0621]

[0622] It is selected from a group consisting of.

[0623] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is a halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 It is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of an aryl, a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and a 5 to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, R 4 is a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -S(O)2-C1-C6 alkyl or -C1-C6 alkyl optionally substituted with -OH. In some embodiments, R 4 is azetidinyl or piperazinyl optionally substituted with -S(O)2-C1-C6 alkyl or -C1-C6 alkyl optionally substituted with -OH. In some embodiments, R 4 is azetidinyl optionally substituted with -S(O)2-C1-C6 alkyl. In some embodiments, R 4 is azetidinyl substituted with -S(O)2CH3. In some embodiments, R 4 is a piperazinyl optionally substituted with a -C1-C6 alkyl group optionally substituted with an -OH group. In certain embodiments, R 4is piperazinyl optionally substituted with -CH2C(CH3)2OH.

[0624] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is selected from the group consisting of the following.

[0625]

[0626]

[0627]

[0628]

[0629]

[0630] and

[0631]

[0632] In some embodiments, R 4 is selected from the group consisting of the following.

[0633]

[0634]

[0635]

[0636]

[0637] and

[0638]

[0639] In some embodiments, R 4 Is

[0640]

[0641] or

[0642]

[0643] is. In some embodiments, R 4 Is

[0644]

[0645] or

[0646]

[0647] am.

[0648] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is Z 6 S(O)2N(R s )-is. In some embodiments, Z 6 is a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl. In another embodiment, Z 6 It is a 5 to 6-membered heteroaryl. In some embodiments, Z 6 is a C1-C6 alkyl. In some embodiments, Z 6 It is methyl. In some of the above embodiments, R s is hydrogen. In another embodiment, R s is a C1-C6 alkyl. In another embodiment, R s is methyl. In some embodiments, R 4 Is

[0649]

[0650]

[0651] or

[0652]

[0653] am.

[0654] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is Z 7 N(R t )S(O)2- is. In some embodiments, Z 7 C6-C 12 It is Aril. In some embodiments, Z 7 is phenyl. In some embodiments, R t It is hydrogen. In another embodiment, R t is a C1-C6 alkyl. In another embodiment, R tis methyl. In some embodiments, R 4 is -S(O)2-NH-phenyl.

[0655] In some embodiments of formula (II), formula (IG), or formula (I), R 4 is Z 8 -O-(CH2) q -is. In some embodiments, q is 0, and therefore R 4 is Z 8 It is -O-. In another embodiment, q is 1, and therefore R 4 is Z 8 -O-(CH2)- is. In some of the above embodiments, Z 8 It is a 5 to 6-membered heteroaryl. In some embodiments, Z 8 It is pyridinyl. In the other embodiment above, Z 8 is a C3-C6 cycloalkyl. In some embodiments, Z 8 It is cyclopentyl. In some embodiments, R 4 Is

[0656]

[0657] or

[0658]

[0659] am.

[0660] In some embodiments of formula (II), p is 0. In some embodiments of formula (II), p is 0 and the compound is a compound of formula (II-A) or a pharmaceutically acceptable salt thereof, and

[0661] [Chemical Formula (II-A)]

[0662]

[0663] Here, R 1 It is a halo or methoxy;

[0664] R 4 Is,

[0665] l) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents,

[0666] m) 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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-C6 alkyl substituents,

[0667] 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,

[0668] o) a pentoecycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentoecycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents,

[0669] p) a hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents,

[0670] q) a pentagonal aryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal aryl is substituted with exactly one methyl substituent,

[0671] r) a pentagonal aryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal aryl is substituted with one or more methyl substituents,

[0672] s) a 6-membered heteroaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is,

[0673]

[0674] or

[0675]

[0676] It is something other than,

[0677] t) Z 9 -S(O)2-,

[0678] u) Z 10 -S(O)2-NH-,

[0679] v) Z 11 -C(O)-NH-,

[0680] w) Z 12 -CH2-O-,

[0681] x) Z 13 -O-,

[0682] y) Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,

[0683] z)

[0684]

[0685] or

[0686] aa)

[0687]

[0688] And,

[0689] Here, Z 9 is cyclopropyl, C6-C 12 Aryl, one or more independently selected R A 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6alkyl), optionally substituted with a substituent, one or more independently selected R B -NH2 substituted with a substituent and one or more independently selected R C Selected from the group consisting of C1-C6 alkyls optionally substituted with a substituent, except Z 9 Is

[0690]

[0691] It is something other than unsubstituted methyl or unsubstituted ethyl, and

[0692] Here, R A is -C1-C6 alkyl or -CN;

[0693] R B is (i) -C1-C6 alkyl-(5 to 10-membered heteroaryl), or (ii) one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl group;

[0694] R C is a 3 to 8-membered heterocycloalkyl or heterocycloalkenyl;

[0695] Z 10 is one or more independently selected C6-C 12 It is a C1-C6 alkyl substituted with an aryl substituent;

[0696] Z 11 C3-C 10 Selected from the group consisting of cycloalkyl and C1-C6 alkyl substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents, provided that Z 11 When this is a cycloprofile, R 1 It is something other than methoxy;

[0697] Z12 is C6-C 12 Selected from the group consisting of 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);

[0698] Z 13 is a 5 to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents;

[0699] Z 14 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0700] R 6 It is hydrogen or halo.

[0701] In some embodiments of formula (II) or formula (II-A), R 4 is selected from the group consisting of the following.

[0702] 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents,

[0703] 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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-C6 alkyl substituents,

[0704] 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,

[0705] 5-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents, and

[0706] A hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents.

[0707] In some embodiments of formula (II) or formula (II-A), R 4 is a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents. In some embodiments, R 4 is a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the 5 to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C1-C6 alkyl substituents and optionally further substituted with one or more oxo substituents.

[0708] In some embodiments of formula (II) or formula (II-A), R 4 is a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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-C6 alkyl substituents. In some embodiments, R 4 is a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic 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 -C1-C6 alkyl substituents.

[0709] In some embodiments of formula (II) or formula (II-A), R 4 is a 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. In some embodiments, R 4 is a 5 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.

[0710] In some embodiments of formula (II) or formula (II-A), R 4is a pentoecycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentoecycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6alkyl, or -S(O)2-(C1-C6alkyl) substituents.

[0711] In some embodiments of formula (II) or formula (II-A), R 4 It is a hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents.

[0712] In some embodiments of formula (II) or formula (II-A), R 4 is selected from the group consisting of the following.

[0713]

[0714]

[0715]

[0716] and

[0717]

[0718] In some embodiments of formula (II) or formula (II-A), R 4is a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more independently selected oxo substituents, or a 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents. In some embodiments, R 4 Is

[0719]

[0720] or

[0721]

[0722] am.

[0723] In some embodiments of formula (II) or formula (II-A), R 4 is selected from the group consisting of the following.

[0724] A pentagonal heteroaryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal heteroaryl is substituted with exactly one methyl substituent,

[0725] A pentagonal heteroaryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal heteroaryl is substituted with one or more methyl substituents, and

[0726] A six-membered heteroaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the six-membered heteroaryl is

[0727]

[0728] or

[0729]

[0730] It is something other than that.

[0731] In some embodiments of formula (II) or formula (II-A), R 4 is a pentagonal heteroaryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal heteroaryl is substituted with exactly one methyl substituent. In another embodiment, R 4 is a pentagonal heteroaryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal heteroaryl is substituted with one or more methyl substituents. In another embodiment, R 4 is a 6-membered heteroaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is

[0732]

[0733] or

[0734]

[0735] It is something other than. In some embodiments, R 4 Is

[0736]

[0737] and

[0738]

[0739] It is selected from a group consisting of.

[0740] 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-, Z12 -CH2-O-, Z 13 -O-, Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,

[0741]

[0742] or

[0743]

[0744] am.

[0745] 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 the compound of formula (II-A1) or a pharmaceutically acceptable salt thereof.

[0746] [Chemical Formula (II-A1)]

[0747]

[0748] In some embodiments of formula (II), formula (II-A), or formula (II-A1), Z 9 is one or more independently selected R A It is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with a substituent, wherein Z 9 Is

[0749]

[0750] It is something other than. In some embodiments, Z 9 is one or more independently selected R A It is a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with a substituent, wherein Z 9 Is

[0751]

[0752] It is something other than. In some embodiments, R A is methyl or -CN. In some embodiments, Z9 is an unsubstituted 3 to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 9 is an unsubstituted 5 to 6-membered heterocycloalkyl or heterocycloalkenyl.

[0753] In some embodiments, Z 9 is one or more independently selected R C C1-C6 alkyl optionally substituted with a substituent, except Z 9 is something other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is one or more independently selected R C It is a C1-C3 alkyl optionally substituted with a substituent, except Z 9 is something other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is an unsubstituted C3-C6 alkyl. In some embodiments, Z 9 is an unsubstituted profile. In some embodiments, Z 9 is a C1-C6 alkyl optionally substituted with one or more independently selected 3 to 8-membered heterocycloalkyl or heterocycloalkenyl groups. In some embodiments, Z 9 is a C1-C6 alkyl optionally substituted with one or more independently selected 5 to 6-membered heterocycloalkyl or heterocycloalkenyl groups.

[0754] In some embodiments, Z 9 is -NH(C1-C6 alkyl). In some embodiments, Z 9 is -NH(CH3). In some embodiments, Z 9 is one or more independently selected R B It is -NH2 substituted with a substituent. In some embodiments, Z 9 is an -NH2 substituted with one or more independently selected -C1-C6 alkyl-(5 to 10-membered heteroaryls). In some embodiments, Z 9is -NH2 substituted with one or more independently selected -C1-C6 alkyl-(5 to 6-membered heteroaryls). In some embodiments, Z 9 is one or more independently selected -C1-C6 alkyl-pyridinyl substituted -NH2. In another embodiment, Z 9 is one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl. In another embodiment, Z 9 is a 5 to 6-membered heteroaryl optionally substituted with one or more phenyl groups.

[0755] In some embodiments, Z 9 is cyclopropyl. In some embodiments, Z 9 is C6-C 12 It is an aryl. In some embodiments, Z 9 is phenyl.

[0756] In some embodiments, Z 9 Is

[0757]

[0758]

[0759]

[0760]

[0761]

[0762] and

[0763]

[0764] It is selected from a group consisting of.

[0765] In some embodiments of formula (II) or formula (II-A), R 4 is Z 10 -S(O)2-NH- is. In some embodiments, Z 10 is a C1-C6 alkyl substituted with one or more phenyl substituents. In some embodiments, Z 10 silver

[0766]

[0767] am.

[0768] In some embodiments of formula (II) or formula (II-A), R 4 is Z 11 -C(O)-NH- is. In some embodiments, Z 11 C3-C 10 It is cycloalkyl, provided that Z 11 When this is a cycloprofile, R 1 It is something other than methoxy. In some embodiments, Z 11 is a C1-C6 alkyl substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents. In some embodiments, Z 11 is a C1-C6 alkyl substituted with one or more independently selected 5 to 6-membered heterocycloalkyl or heterocycloalkenyl substituents. In some embodiments, Z 11 silver

[0769]

[0770] or

[0771]

[0772] am.

[0773] In some embodiments of formula (II) or formula (II-A), R 4 is Z 12 It is -CH2-O-. In some embodiments, Z 12 is C6-C 12 Selected from the group consisting of 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). In some embodiments, Z12 is C6-C 12 It is Aril. In some embodiments, Z 12 is a 5 to 10-membered heteroaryl. In some embodiments, Z 12 is a 5 to 6-membered heteroaryl. In some embodiments, Z 12 is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl. In another embodiment, Z 12 is a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 12 is a 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. In some embodiments, Z 12 is a C1-C6 alkyl 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 another embodiment, Z 12 is -C(O)-(5 to 6-membered heterocycloalkyl or heterocycloalkenyl). In some embodiments, Z 12 Is

[0774]

[0775]

[0776] and

[0777]

[0778] It is selected from a group consisting of.

[0779] In some embodiments of formula (II) or formula (II-A), R 4 is Z 13 -O- is. In some embodiments, Z 13is a 5 to 6-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents. In some embodiments, Z 13 is a pyridinyl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents. In some embodiments, Z 13 silver

[0780]

[0781] am.

[0782] 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 optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments, Z 14 is a pyridinyl optionally substituted with one or more independently selected C1-C6 alkyl substituents. In some embodiments of Formula (II) or Formula (II-A), R 4 Is

[0783]

[0784] or

[0785]

[0786] am.

[0787] In some embodiments of formula (II) or formula (II-A), R 4 Is

[0788]

[0789] is. In another embodiment, R 4 Is

[0790]

[0791] am.

[0792] In some embodiments of any variation thereof including formula (II), or formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A) and formula (II-A1), R 1 It is a halo. For example, in some embodiments, R 1 is a fluoro. In some embodiments, R 1 It is chloro. In some embodiments, R 1 It is bromo. In another embodiment, R 1 It is iodine. In some embodiments, R 1 is methoxy. In some embodiments of any variation thereof including formula (II), or formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE) and formula (IF), R 2 is hydrogen. In some embodiments, R 2is a C1-C6 alkyl. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of any variation thereof including formula (II), or formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE) and formula (IF), R 3 is hydrogen. In some embodiments, R 3 is a C1-C6 alkyl. For example, in some embodiments, R 3 It is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0793] In some embodiments of any variation thereof including formula (II), or formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE) and formula (IF), R 2 and R 3Each is hydrogen. In some embodiments, R 2 is a 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 tert-butyl, and R 3 is hydrogen. In a specific embodiment, R 2 is methyl, and R 3 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is a 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 tert-butyl. In certain embodiments, R 2 is hydrogen and R 3 It is methyl.

[0794] In some embodiments, the compounds and salts thereof listed in Table 1 are provided herein.

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899] In some variations, any of the compounds described herein, such as Formula (II), Formula (I), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A) and Formula (II-A1), or any variations thereof, or the compounds of Table 1 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterinated at multiple sites. The deuterinated compound can be prepared from the deuterinated starting material in a manner similar to the preparation of the corresponding non-deuterinated compound. Hydrogen atoms can also be replaced with deuterium atoms using other methods known in the art.

[0900] Any formula provided herein, such as formula (II), formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), and formula (II-A1), are intended to represent compounds having specific variations or forms as well as structures depicted by structural formulas. In particular, compounds of any formula provided herein may have an asymmetric center and thus may exist in different enantiomer or diastereomer forms. All optical isomers and stereoisomers of a compound of a general formula, and mixtures thereof in any proportion, are considered to be within the scope of the formula. Accordingly, any formula provided herein is intended to represent a racemic mixture, one or more enantiomer forms, one or more diastereomer forms, one or more rotationally hindered isomer forms, and mixtures thereof in any proportion. Where a compound of Table 1 is depicted in a specific stereochemical arrangement, any alternative stereochemical arrangement of the compound, as well as mixtures of stereoisomers of the compound in any proportion, are also provided herein. For example, if a compound of Table 1 has a stereocenter in the "S" stereochemical arrangement, enantiomers of the compound in which the stereocenter is in the "R" stereochemical arrangement are also provided herein. Similarly, when a compound of Table 1 has a stereocenter in the "R" arrangement, enantiomers of the compound in the "S" stereochemical arrangement are also provided herein.In addition, a mixture of compounds having both "S" and "R" stereochemical arrangements is provided. In addition, if the compounds of Table 1 have two or more stereocenters, any enantiomer or diastereomer of the compounds is also provided. For example, if the compounds of Table 1 contain a first stereocenter and a second stereocenter having "R" and "R" stereochemical arrangements, respectively, stereoisomers of compounds having first and second stereocenters having "S" and "S" stereochemical arrangements, respectively, and "S" and "R" stereochemical arrangements, respectively, are also provided. Where the compounds of Table 1 each contain a first stereocenter and a second stereocenter having "S" and "S" stereochemical arrangements, stereoisomers of the compounds having "R" and "R" stereochemical arrangements, "S" and "R" stereochemical arrangements, and first and second stereocenters having "R" and "S" stereochemical arrangements, are also provided. Where the compounds of Table 1 each contain a first stereocenter and a second stereocenter having "S" and "R" stereochemical arrangements, stereoisomers of the compounds having "R" and "S" stereochemical arrangements, "R" and "R" stereochemical arrangements, and first and second stereocenters having "S" and "S" stereochemical arrangements, are also provided. Similarly, where the compounds of Table 1 contain a first stereocenter and a second stereocenter having "R" and "S" stereochemical arrangements, respectively, stereoisomers of compounds having first and second stereocenters having "S" and "R" stereochemical arrangements, respectively, and "S" and "S" stereochemical arrangements, respectively are also provided. Additionally, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or rotationally hindered isomers.Additionally, any chemical formula provided herein is intended to refer to any one of the hydrates, solvates, amorphous and polymorphic forms of such compounds, and mixtures thereof, even if the form is not explicitly listed. In some embodiments, the solvent is water and the solvate is the hydrate.

[0901] Representative examples of compounds described in detail herein, including intermediates and final compounds, are shown in the table and elsewhere in this application. In one aspect, it is understood that any compound comprising an intermediate compound that, where applicable, can be isolated and administered to an individual or subject may be used in the method described herein.

[0902] The compounds described herein may exist as salts even if the salt is not described, and the compositions and methods provided herein are understood to include all salts and solvates of the compounds described herein, as well as non-salt and non-solvate forms of the compounds, as is well understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0903] In one variation, the compound of the present invention is a synthetic compound prepared for administration to an individual or subject. In another variation, a composition containing the compound in a substantially pure form is provided. In yet another variation, a pharmaceutical composition comprising the compound described herein and a pharmaceutically acceptable carrier is provided. In another variation, a method for administering the compound is provided. The purified form, the pharmaceutical composition, and the method for administering the compound are suitable for any of the compounds or forms thereof described herein.

[0904] R provided to this institution 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 , Z3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , R a , R b , R c , R d , R e , R f , R g , R h , R j , R k , R m , R n , R o , R p , R q , R r , R s , R t , R x , R y , R z , R A , R B , R C Any variation or embodiment of , m, n, p, and q is R as if each combination were described individually and specifically. 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 , Rc , 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 Each of , m, n, p, and q can be combined with different variations or embodiments.

[0905] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0906] As used herein, where any variable occurs one or more times in a chemical formula, the definition for each case is independent of the definition for all other cases.

[0907] Chemical formula (II) includes all of its sub-chemical formulas. For example, chemical formula (II) includes compounds of chemical formula (IG), chemical formula (I), chemical formula (IA), chemical formula (I-A1), chemical formula (I-A2), chemical formula (I-A3), chemical formula (I-A4), chemical formula (IB), chemical formula (I-B1), chemical formula (I-B2), chemical formula (I-B3), chemical formula (IC), chemical formula (I-C1), chemical formula (I-C2), chemical formula (I-C3), chemical formula (I-C4), chemical formula (ID), chemical formula (I-D1), chemical formula (I-D2), chemical formula (I-D3), chemical formula (I-D4), chemical formula (I-D5), chemical formula (I-D6), chemical formula (I-D7), chemical formula (IE), chemical formula (IF), chemical formula (II-A), and chemical formula (II-A1).

[0908] As shown in Table 1 and Examples 1 through 16, the names of Compounds 1 through 552 provided herein are provided by ChemInnovation's Chem 4d software version 7.5.0.0. The names of Intermediates 1.1 through 10.0 shown in Examples A through MM are provided by ChemBioDraw Professional 15.0. Those skilled in the art will understand that compounds may be named or identified using various commonly recognized naming systems and symbols. For example, compounds may be named or identified by generic names, phylogenetic names, or non-phylogenetic names. Naming systems and symbols commonly recognized in the field of chemistry include, for example, the Chemical Abstract Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0909] composition

[0910] Additionally, compositions such as pharmaceutical compositions comprising the compounds disclosed and / or described herein and one or more additional medicinal formulations, pharmaceutical formulations, adjuvants, carriers, excipients, etc. Suitable medicinal and pharmaceutical formulations include those described herein. In some embodiments, the pharmaceutical composition comprises pharmaceutically acceptable excipients or adjuvants as described herein and at least one chemical substance. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions such as pharmaceutical compositions containing one or more compounds described herein or pharmaceutically acceptable salts thereof are provided.

[0911] In some embodiments, a pharmaceutically acceptable composition is provided comprising a compound of formula (II), formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain a synthetic intermediate that can be used in the preparation of the compound described herein. The composition described herein may contain any other suitable active or inactive agent.

[0912] Any composition described herein may be sterilized or may contain a sterilized component. Sterilization may be achieved by methods known in the art. Any composition described herein may contain one or more substantially pure compounds or conjugates.

[0913] Additionally, a packaged pharmaceutical composition is provided, comprising a pharmaceutical composition as described herein and instructions for using the composition for the treatment of a patient suffering from the disease or condition described herein.

[0914] How to use

[0915] Compounds and compositions described herein, such as compounds of any of the formulas provided herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients, may be used in methods of administration and treatment as provided herein.

[0916] Without being bound by theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by regulating nicotinamide phosphoribosyltransferase (NAMPT). In some embodiments, the compounds and pharmaceutical compositions disclosed herein are activators of NAMPT. In some embodiments, a method for treating a disease or pathological condition mediated by NAMPT activity in an individual or subject is provided, comprising the step of administering to an individual or subject in need of treatment a compound of formula (II), formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.In some embodiments, the method comprises the step of administering to an individual or subject requiring treatment a compound of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject requiring treatment for cancer, hyperproliferative disease or condition, inflammatory disease or condition, metabolic disorder, heart disease or condition, tissue damage caused by chemotherapy, A method for treating kidney disease, metabolic disease, neurological disease or injury, neurodegenerative disorder or disease, disease caused by impaired stem cell function, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder is provided.

[0917] In addition, the present invention provides the use of compounds of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), or compounds of Table 1, or pharmaceutically acceptable salts thereof, in the manufacture of medicines for the treatment of diseases or pathological conditions mediated by NAMPT activity in subjects. In some aspects, compounds or compositions as described herein are provided for use in methods of treating a human or animal body by therapy. In some embodiments, compounds of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in a method of treating a human or animal body by therapy.In some embodiments, compounds of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), or compounds of Table 1, or pharmaceutically acceptable salts thereof, are provided herein for use in treating diseases or pathological conditions mediated by NAMPT activity. In some embodiments, the disease or pathology is selected from the group consisting of cancer, hyperproliferative disease or pathology, inflammatory disease or pathology, metabolic disorder, heart disease or pathology, tissue damage caused by chemotherapy, kidney disease, metabolic disease, nervous system disease or injury, neurodegenerative disorder or disease, disease caused by impaired stem cell function, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder.

[0918] Additionally, compositions as described herein (including pharmaceutical compositions) are provided for treating, preventing, and / or delaying the onset and / or development of the diseases described herein and / or for use in other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation present in a unit dosage form.

[0919] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, rabbit, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.

[0920] There are numerous pathological conditions where small molecule-mediated stimulation of NAMPT activity that increases NAD+ levels could potentially be clinically beneficial (Strømland et al. Biochem Soc Trans . 2019, 47(1):119-130; Ralto et al. Nat Rev Nephrol . 2019; Fang et al. Trends Mol Med . 2017, 23(10): 899-916; Yoshino et al. Cell Metab . 2011, 14(4): 528-36; Yang and Sauve's Biochim Biophys Acta . 2016, 1864:1787-1800; Verdin's Science . 2015, 350(6265): 1208-13). These pathological conditions include, but are not limited to, heart disease, tissue damage due to chemotherapy, kidney disease, metabolic disease, muscle disease, neurological disease and injury, disease due to impaired stem cell function, and DNA damage and primary mitochondrial disorder. In some embodiments, the disease or pathological condition mediated by NAMPT activity is heart disease, tissue damage due to chemotherapy, kidney disease, metabolic disease, muscle disease, neurological disease or injury, disease due to impaired stem cell function, or DNA damage and primary mitochondrial disorder.

[0921] Heart disease: NAD and NAMPT levels are reduced in various preclinical models of heart failure. In these models, cardiac function can be restored through oral supplementation of NAD or through the overexpression of NAMPT (Diguet et al. Circulation . 2018, 137: 2256-2273; Zheng et al. Clin Sci(Lond) . 2019, 133(13): 1505-1521; Smyrnias et al. J Am Coll Cardiol . 2019, 73(14): 1795-1806). Therefore, increasing the catalytic efficiency of NAMPT with small molecule activators to compensate for reduced protein levels is a promising strategy for treating various forms of heart failure.

[0922] Tissue damage caused by chemotherapy: The use of chemotherapy is often limited due to toxicity to healthy tissues, and severe oxidative stress is thought to play a significant role. NAD boosting has been shown to induce potent antioxidant responses. Therefore, NAMPT activators are considered widely useful in various chemotherapy settings for preventing reversible and irreversible secondary pathologies. Examples include anthracycline and trastuzumab cardiotoxicity, cisplatin-induced renal injury, and peripheral neuropathy induced by cisplatin, paclitaxel, vincristine, and other agents. Neuroprotection by NAMPT activation is also useful for treating or preventing chemotherapy-related cognition ("chemo brain") caused by the destruction of healthy nerve tissue during active treatment and for a long period after discontinuation of treatment. For example, Zheng et al. Clin Sci (Lond) See . 2019, 133(13):1505-1521.

[0923] Kidney disease: Renal disease is a highly prevalent field with urgent unmet medical needs. Acute renal injury (AKI) is diagnosed in approximately 3% of hospitalized patients. Some patients will progress to chronic renal disease requiring long-term dialysis or a kidney transplant. A key feature of renal dysfunction is the reduced activity of SIRT1 and SIRT3, characterized by a decrease in sirtuin substrate NAD due to impaired new NAD+ synthesis. Since NAMPT is strongly expressed during renal injury, small molecule activation using NAMPT is considered an effective means of preventing AKI. Similarly, renal mesangial cell hypertrophy indicates NAD+ depletion, and the restoration of intracellular NAD+ levels is considered effective. For example, Poyan Mehr et al. Nat Med See . 2018, Sep; 24(9): 1351-9.

[0924] Metabolic diseases:NAD+ boosting improves insulin sensitivity, dyslipidemia, and mitochondrial function in metabolic diseases, and prevents or improves non-alcoholic and alcoholic steatohepatitis in preclinical models. In the United States alone, over 3 million people are diagnosed with non-alcoholic steatohepatitis annually, and it is one of the leading causes of liver transplantation. Guarino and Dufour's Metabolites . 2019, Sep 10; 9(9), pii: E180; Yoshino et al. Cell Metab See . 2011, 14(4): 528-36.

[0925] Muscle disease: Preclinical data suggested that NAD+ boosting strategies can alleviate skeletal muscle dysfunction in various pathologies, including Duchenne muscular dystrophy and age-related sarcopenia. Zhang et al. Clin Sci (Lond) . 2019, 133(13): 1505-1521; Mohamed et al. Aging (Albany NY) . 2014, 6(10): 820-34; Ryu et al. Sci Transl Med . 2016, 8(361): 361ra139 See.

[0926] Neurological Disorders and Injuries: NAD supplementation via NAMPT activation is neuroprotective and has therapeutic benefits in a wide range of preclinical models of neurological diseases and injuries, including age-related cognitive decline, glaucoma, ischemic stroke, and ALS. 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 See . 2017, Apr 25; 11: 232.

[0927] Diseases caused by impaired stem cell function: NAD boosting is useful for promoting stem cell activation and hematopoiesis, and for accelerating the expansion of stem cell populations after stem cell transplantation. Pi et al. Aging (Albany NY) See . 2019, 11(11): 3505-3522.

[0928] DNA Damage Disorders and Primary Mitochondrial Disorders: NAMPT activators would also be useful in the treatment of DNA damage disorders associated with accelerated aging phenotypes, such as xeropigmentation, cocaine syndrome, and telangiectasia. Similarly, there are several primary mitochondrial disorders with shared symptoms and indications for which NAD boosting via NAMPT activation could be an appropriate therapeutic intervention. 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 See . 2014, 19(6): 1042-9.

[0929] In some embodiments, a method for treating a disease or pathological condition mediated by NAMPT activity in a subject requiring treatment is provided, comprising the step of administering to an individual or subject requiring treatment a compound of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual or subject requiring treatment, wherein the disease or pathological condition is a heart disease, tissues resulting from chemotherapy. It is selected from a group consisting of injury, kidney disease, metabolic disease, muscle disease, nervous system disease and injury, disease due to impaired stem cell function, and DNA damage and primary mitochondrial disorder.

[0930] Additional applications of small molecule NAMPT activators are provided in Table 2.

[0931]

[0932]

[0933]

[0934] In some embodiments, the disease or pathological condition mediated by NAMPT activity is tissue damage caused by cancer and chemotherapy, cardiovascular disease, renal disease, chronic inflammation and fibrosis, vascular disease, metabolic dysfunction, muscle disease, nervous system disease or injury, or DNA damage disorder or primary mitochondrial disorder. In some embodiments, a method for treating a disease or pathological condition mediated by NAMPT activity in a subject requiring treatment is provided, comprising the step of administering to an individual or subject requiring treatment a compound of formula (II), formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or pathological condition is tissue damage caused by cancer or chemotherapy, including any of the diseases listed in Table 2, cardiovascular disease, kidney disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, nervous system disease or injury, DNA damage disorder or primary mitochondrial disorder.

[0935] Permeability

[0936] Membrane permeability is a key characteristic in small molecule drug design, particularly for compounds with intracellular targets, as their efficacy depends heavily on their ability to cross membranes. Drug efficacy can vary depending on the drug's ability to reach its intended site of action. Drug absorption is the movement of a drug into the bloodstream. Many factors, including the drug's physicochemical properties, formulation, and route of administration, influence this process. Generally, oral drugs must enter the bloodstream via the intestinal route. For other routes, such as intravenous therapy, intramuscular injection, and enteral nutrition, absorption is more direct to the blood. Regardless of the route of administration, the drug must be dissolved and absorbed to achieve a therapeutic effect. The pharmacokinetic (PK) profile of a drug can be altered by adjusting the factors affecting absorption. The permeability of a drug through biological membranes is a key factor influencing absorption and distribution. This is because a drug must first pass through several semipermeable cell membranes to reach the systemic circulation. Drugs can cross cell membranes via passive diffusion, facilitated passive diffusion, active transport, and pinocytosis. Permeability may be reduced due to the physicochemical properties of the drug (e.g., size and lipophilicity) and membrane-based efflux mechanisms.

[0937] For orally administered drugs, most absorption occurs in the small intestine. Therefore, drugs that are poorly absorbed and / or actively excreted in the small intestine are unlikely to actually reach their intended site of action. Because of this low likelihood of reaching the intended site, the drug's efficacy is significantly reduced, requiring a dose that is considerably higher and potentially unrealistic compared to the dose expected by in vitro target efficacy testing. Conversely, drugs that are easily absorbed and / or have reduced active excretion from the small intestine will require lower doses than similar or much more "potent" drugs that are poorly absorbed. Therefore, the drug's absorption capacity and the excretion occurring within the small intestine are important considerations in the development of orally administered drugs.

[0938] There are various in vitro methods to evaluate drug permeability and predict their in vivo absorption. One such method is the Caco-2 permeability assay. The Caco-2 cell line is derived from human colon cancer and possesses many characteristics similar to intestinal epithelial cells. The Caco-2 permeability assay is a good method for investigating human intestinal permeability and drug efflux. Monolayers of the Caco-2 cell line have been recognized as an accurate in vitro model of drug absorption in the human small intestine. Although the cell line was isolated from human colon adenocarcinoma, differentiated Caco-2 cells are similar to intestinal cells (small intestinal absorption cells) in that they form functional tight junctions, apical and basolateral domains, and a brush-boundary cytoskeleton. The Caco-2 permeability assay measures the transport rate of compounds through Caco-2 cells and evaluates bidirectional transport. In the sense that drugs with poor Caco-2 cell permeability have poor absorption in the small intestine, and drugs with high or perfect Caco-2 cell permeability have high absorption in the small intestine, the in vitro apparent permeability (P) of a drug from the apex to the basolateral direction to Caco-2 cells aap ) was shown to correlate with oral absorption in humans (Artursson et al., Biochem Biophys Res Comm, 1991, 3(29): 880-885). Generally, drugs that are completely absorbed in vivo have a permeability coefficient of 1 x 10⁻¹⁰ from the apex to the basolateral direction in Caco-2 cells. -6 Drugs that are greater than cm / second and poorly absorbed have a permeability coefficient of 1 x 10⁻⁶ -7 It is less than cm / second.

[0939] Additionally, Caco-2 cells were used to confirm and quantify the level of active efflux for the drug. The active efflux of the drug is P from the basal lateral direction toward the apex. aap and P from the vertex in the direction of the base-outer aapIt can be determined by calculating the ratio. Generally, the lower the ratio, the greater the drug's ability to reach the intended site of action, and the greater the drug's ability to reach the intended site of action, the greater the drug's potential efficacy.

[0940] The compounds provided herein are suitable for oral administration as measured by permeability characteristics evaluated by a Caco-2 cell model. The compounds described herein have been proven to have improved permeability as described in Biological Example 2 of the present invention.

[0941] Dosage

[0942] The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dose, for example, a dose sufficient to provide treatment for a diseased condition. Human dosage levels have not yet been optimized for the chemicals described herein, but generally, the daily dose is 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 person weighing 70 kg, in some embodiments, the dosage range is about 0.7 to 7000 mg per day; in some embodiments, about 3.5 to 700.0 mg per day; and in some embodiments, about 7 to 100.0 mg per day. The amount of chemical administered depends, for example, on the subject being treated and the diseased condition, the severity of pain, the method and schedule of administration, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg per day, and an exemplary intravenous dosage is about 5 mg to about 500 mg per day, each according to the pharmacokinetics of the compound.

[0943] The daily dose is the total amount administered per day. The daily dose may be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, but is not limited thereto. In some embodiments, the daily dose is administered for a period ranging from one day to the lifespan of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered as multiple divided doses, e.g., 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered as two divided doses.

[0944] The compounds and compositions disclosed and / or described herein may be administered via any mode of administration permitted 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, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0945] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol administration forms, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. Compounds disclosed and / or described herein may also be administered in sustained-release or controlled-release administration forms for extended periods (e.g., controlled / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electro-transport) patches) and / or pulsed administration at a predetermined rate. In some embodiments, compositions are provided in unit administration forms suitable for a single administration of an accurate dose.

[0946] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate), such as humectants, emulsifiers, solubilizers, pH buffers, etc. Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50% by weight, of the compounds disclosed and / or described herein. The actual method of manufacturing such a dosage form will be known to or obvious to those skilled in the art, for example, Remington's Pharmaceutical Sciences See Mack Publishing Company, Easton, Pennsylvania.

[0947] In some embodiments, the composition will take the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) together with the compounds disclosed and / or described herein. Other solid dosage forms include a powder, slurry, solution, or suspension (e.g., propylene carbonate, vegetable oil, or triglyceride) encapsulated in a gelatin capsule.

[0948] A liquid pharmaceutically administerable composition may be prepared, for example, by dissolving, dispersing, or suspending the compound disclosed and / or described herein and any pharmaceutical additive in a carrier (e.g., water, saline solution, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. The injectable formulation may be prepared in a liquid solution or suspension, an emulsion, or in a conventional form such as a solid suitable for dissolving or suspending in a liquid prior to injection. The percentage of the compound contained in such parenteral compositions varies, for example, depending on the physical properties of the compound, the activity of the compound, and the needs of the target. However, a percentage of the active ingredient in the solution of 0.01% to 10% may be used, and may be higher if the composition is a solid to be subsequently diluted to a different concentration. In some embodiments, the composition will contain about 0.2% to 2% of the compound disclosed and / or described herein in the solution.

[0949] Pharmaceutical compositions of compounds disclosed and / or described herein may also be administered into the airway as a nebulizer aerosol or solution, or as a fine powder for inhalation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0950] Additionally, the pharmaceutical composition may include the compounds disclosed and / or described herein and one or more additional medicinal preparations, pharmaceutical preparations, adjuvants, etc. Suitable medicinal and pharmaceutical preparations include those described herein.

[0951] Kit

[0952] Additionally, manufacturing articles and kits containing any of the compounds or pharmaceutical compositions provided herein are provided. The manufacturing article may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from various materials, such as glass or plastic. The container may contain the pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or suppress the pathological conditions described herein, and may also indicate instructions for in vivo or in vitro use.

[0953] In one aspect, a kit containing the compound or composition described herein and instructions for use is provided herein. The kit may include instructions for use in the treatment of heart disease in an individual or subject requiring treatment. The kit may further include any material or equipment that can be used for administering the compound or composition, such as a vial, syringe, or IV bag. The kit may also include sterile packaging.

[0954] mixture

[0955] The compounds and compositions described or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful for the treatment of the aforementioned disorders, diseases, or conditions.

[0956] Enumerated embodiments

[0957] The following embodiments represent some aspects of the present invention.

[0958] 1. A compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof,

[0959] [Chemical Formula (I)]

[0960]

[0961] Here, R 1 It is a halo or methoxy;

[0962] R 2 is hydrogen or a C1-C6 alkyl or Z 4 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0963] R 3 It is hydrogen or C1-C6 alkyl;

[0964] R 4 Is,

[0965] a) Z 1 NR a C(O)-,

[0966] b) Z 2 C(O)NR b -,

[0967] c) Z 3 (CR c R d ) m NR e -,

[0968] d) Z 4 S(O)2(CH2) n -,

[0969] e) Z 5 OC(O)-,

[0970] f) NR f R g C(O)-,

[0971] g) a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, or

[0972] h) Halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12It is a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 6-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0973] Here, R a and R e Each is independently hydrogen or C1-C6 alkyl;

[0974] R b is hydrogen or a C1-C6 alkyl or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0975] R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d They form a C3-C6 cycloalkyl group together with the carbon to which they are attached;

[0976] R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0977] Each Rh is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aril is;

[0978] Each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl;

[0979] Each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls;

[0980] Each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl;

[0981] m is 0 or 1, and;

[0982] n is 0, 1, or 2, and;

[0983] R 5 is hydrogen or R b and together with intervening atoms, to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0984] Z 1 and Z 5 are each independently R z And;

[0985] Z 2 and Z 3 Each independently hydrogen or R zis;

[0986] Z 4 is hydrogen or R z or R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring;

[0987] R z is selected from the group consisting of the following:

[0988] a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy;

[0989] b) C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls;

[0990] c) C1-C6 alkoxy;

[0991] d) Halo, oxo, -OH, -CN, one or more independently selected R w-C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v Each is independently hydrogen or C1-C6 alkyl;

[0992] e) C6-C 12 Aryl; and

[0993] f) 5 to 10 heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents,

[0994] Here, (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH, and -CH2-thiofuran;

[0995] (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

[0996]

[0997] and

[0998]

[0999] It is something other than that,

[1000] (3) A compound of chemical formula (I) that is not a compound of Table 1X or a pharmaceutically acceptable salt thereof.

[1001] 2. In Embodiment 1, R 1 This haloin compound or its pharmaceutically acceptable salt.

[1002] 3. In Embodiment 1 or Embodiment 2, R 1 This Cl compound or its pharmaceutically acceptable salt.

[1003] 4. In Embodiment 1, R 1 This methoxyin compound or its pharmaceutically acceptable salt.

[1004] 5. In any one of embodiments 1 to 4, R 2 A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1005] 6. In any one of embodiments 1 to 4, R 2 A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1006] 7. In any one of embodiments 1 to 6, R 3 This hydrogen compound or its pharmaceutically acceptable salt.

[1007] 8. In any one of embodiments 1 to 6, R 3 A compound that is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1008] 9. In any one of embodiments 1 to 6, a compound in which the compound of formula (I) is a compound of the following formula (IA) or a pharmaceutically acceptable salt thereof:

[1009] [Chemical Formula (IA)]

[1010]

[1011] 10. In any one of embodiments 1 to 9, R a A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1012] 11. In any one of embodiments 1 to 9, R a A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1013] 12. In any one of embodiments 1 to 11, Z 1 A compound selected from the following group or a pharmaceutically acceptable salt thereof.

[1014] -OH, C3-C6 cycloalkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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-C6 alkyl and C1-C6 alkoxy;

[1015] C6-C 12 A C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with a C1-C6 alkyl.

[1016] 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 C6-C 12Arbitrarily substituted with Arillo.

[1017] 13. In any one of embodiments 1 to 11, Z 1 ethyl,

[1018]

[1019]

[1020]

[1021] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[1022] 14. In Embodiment 1, the compound of formula (I) is a compound of formula (IB) or a pharmaceutically acceptable salt thereof.

[1023] [Chemical Formula (IB)]

[1024]

[1025] 15. In any one of embodiments 1 to 8 and 14, R b A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1026] 16. In any one of embodiments 1 to 8 and 14, R b A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1027] 17. In any one of embodiments 1 to 8 and 14, R b Ga R 5 and a compound that takes together with an intervening atom to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring, or a pharmaceutically acceptable salt thereof.

[1028] 18. In any one of embodiments 1 to 8 and 14 to 17, Z 2 A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1029] 19. In any one of embodiments 1 to 8 and 14 to 17, Z 2 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[1030] C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl and 5 to 10-membered heteroaryls;

[1031] C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy;

[1032] C1-C6 alkoxy;

[1033] 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more -C1-C6 alkyl substituents;

[1034] C6-C 12 Aryl; and

[1035] 5 to 10-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[1036] 20. In embodiment 19, Z 2 A compound that is a 5 to 6-membered heteroaryl optionally substituted with one or more -C1-C6 alkyl substituents, or a pharmaceutically acceptable salt thereof.

[1037] 21. In embodiment 20, Z 2 A pyridyl-based compound optionally substituted with one or more -C1-C6 alkyl substituents or a pharmaceutically acceptable salt thereof.

[1038] 22. In any one of embodiments 1 to 8 and 14 to 17, Z 2 ethyl,

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045] and

[1046]

[1047] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[1048] 23. In embodiment 22, Z 2 go

[1049]

[1050] Phosphorus compound or pharmaceutically acceptable salt thereof.

[1051] 24. In Embodiment 1, the compound of formula (I) is a compound of formula (IC) below, or a pharmaceutically acceptable salt thereof.

[1052] [Chemical Formula (IC)]

[1053]

[1054] 25. In any one of embodiments 1 to 8 and 24, a compound in which m is 1 or a pharmaceutically acceptable salt thereof.

[1055] 26. In any one of embodiments 1 to 8 and 24, a compound in which m is 0 or a pharmaceutically acceptable salt thereof.

[1056] 27. In any one of embodiments 1 to 8 and 24 to 25, R c A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1057] 28. In any one of embodiments 1 to 8 and 24 to 25, R cA compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1058] 29. In any one of embodiments 1 to 8, 24 to 25 and 27 to 28, R d A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1059] 30. In any one of embodiments 1 to 8, 24 to 25 and 27 to 28, R d A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1060] 31. In any one of embodiments 1 to 8 and 24 to 25, R c and R d A compound that forms a C3-C6 cycloalkyl group together with the carbon to which it is attached, or a pharmaceutically acceptable salt thereof.

[1061] 32. In any one of embodiments 1 to 8 and 24 to 31, R e A compound in which hydrogen is present or a pharmaceutically acceptable salt thereof.

[1062] 33. In any one of embodiments 1 to 8 and 24 to 31, R e A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1063] 34. In any one of embodiments 1 to 8 and 24 to 33, Z 3 This hydrogen compound or its pharmaceutically acceptable salt.

[1064] 35. In any one of embodiments 1 to 8 and 24 to 33, Z 3 A compound selected from the following group or a pharmaceutically acceptable salt thereof.

[1065] C3-C6 cycloalkyl;

[1066] 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C1-C6 alkyl;

[1067] C6-C 12 Aryl; and

[1068] 5 to 10-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[1069] 36. In any one of embodiments 1 to 8 and 24 to 33, Z 3 this

[1070]

[1071]

[1072] and

[1073]

[1074] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[1075] 37. In Embodiment 1, a compound in which the compound of formula (I) is a compound of formula (ID) below, or a pharmaceutically acceptable salt thereof.

[1076] [Chemical Formula (ID)]

[1077]

[1078] 38. In any one of embodiments 1 to 8 and 37, a compound in which n is 0 or a pharmaceutically acceptable salt thereof.

[1079] 39. In any one of embodiments 1 to 8 and 37, a compound in which n is 1 or a pharmaceutically acceptable salt thereof.

[1080] 40. In any one of embodiments 1 to 8 and 37, a compound in which n is 2 or a pharmaceutically acceptable salt thereof.

[1081] 41. In any one of embodiments 1 to 8 and 37 to 40, Z4 hydrogen or R z Phosphorus compound or pharmaceutically acceptable salt thereof.

[1082] 42. In any one of embodiments 1 to 8 and 37 to 40, Z 4 A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1083] 43. In any one of embodiments 1 to 8 and 37 to 40, Z 4 Ga R 2 and a compound that takes together with an intervening atom to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring, or a pharmaceutically acceptable salt thereof.

[1084] 44. In embodiment 43,

[1085]

[1086] go

[1087]

[1088]

[1089] and

[1090]

[1091] A compound selected from the group consisting of

[1092] 45. In Embodiment 1, a compound in which the compound of formula (I) is a compound of formula (IE) below, or a pharmaceutically acceptable salt thereof.

[1093] [Chemical Formula (IE)]

[1094]

[1095] 46. ​​In any one of embodiments 1 to 8 and 45, Z 5 A compound in which α is a C1-C6 alkyl or a pharmaceutically acceptable salt thereof.

[1096] 47. In any one of embodiments 1 to 8 and 45, Z 5 A compound that is ethyl or a pharmaceutically acceptable salt thereof.

[1097] 48. In claim 1, a compound in which the compound of formula (I) is a compound of formula (IF) below, or a pharmaceutically acceptable salt thereof.

[1098] [Chemical Formula (IF)]

[1099]

[1100] 49. In any one of paragraphs 1 through 8 and 48, R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n A compound forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[1101] 50. In Paragraph 49, R f and R g A compound or pharmaceutically acceptable salt thereof in which the -C1-C6 alkyl is optionally substituted with a nitrogen to which they are attached, and the -C1-C6 alkyl is optionally substituted with an -OH.

[1102] 51. In any one of embodiments 1 to 8 and 48 to 49,

[1103]

[1104] A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[1105]

[1106]

[1107]

[1108] and

[1109]

[1110] 52. In embodiment 51,

[1111]

[1112] go

[1113]

[1114] Phosphorus compound or pharmaceutically acceptable salt thereof.

[1115] 53. In any one of embodiments 1 to 8, R 4 A compound that is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents, or a pharmaceutically acceptable salt thereof.

[1116] 54. In any one of embodiments 1 to 8 and 53, R 4 go

[1117]

[1118]

[1119] and

[1120]

[1121] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[1122] 55. In any one of embodiments 1 to 8, R4 halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 A compound that is a aryl, a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5 to 6-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl substituents, or a pharmaceutically acceptable salt thereof.

[1123] 56. In embodiment 55, R 4 A compound that is a -S(O)2-C1-C6 alkyl or a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -OH or -C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[1124] 57. In any one of embodiments 1 to 8 and 55, R 4 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[1125]

[1126]

[1127]

[1128]

[1129] and

[1130]

[1131] 58. In embodiment 57, R 4 go

[1132]

[1133] or

[1134]

[1135] Phosphorus compound or pharmaceutically acceptable salt thereof.

[1136] 59. A compound selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[1137] 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[1138] 61. A method for treating a disease or pathological condition mediated by NAMPT activity in a subject requiring treatment, comprising the step of administering to a subject a compound of any one of embodiments 1 to 59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 60.

[1139] 62. The method of embodiment 61, wherein the disease or pathological condition is selected from the group consisting of cancer, hyperproliferative disease or pathological condition, inflammatory disease or pathological condition, metabolic disorder, heart disease or pathological condition, tissue damage caused by chemotherapy, kidney disease, metabolic disease, nervous system disease or injury, neurodegenerative disorder or disease, disease caused by impaired stem cell function, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder.

[1140] 63. The method of embodiment 61, wherein the disease or pathological condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal neurological injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, neurological injury, polio (poliomyelitis), and spinal cord injury.

[1141] General synthesis method

[1142] Compounds of Formula (II), Formula (IG), Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B2), Formula (I-B3), Formula (IC), Formula (I-C1), Formula (I-C2), Formula (I-C3), Formula (I-C4), Formula (ID), Formula (I-D1), Formula (I-D2), Formula (I-D3), Formula (I-D4), Formula (I-D5), Formula (I-D6), Formula (I-D7), Formula (IE), Formula (IF), Formula (II-A), and Formula (II-A1) will now be described with reference to the exemplary synthesis schemes for general preparation below and the subsequent specific examples. Those skilled in the art will recognize that to obtain the various compounds of the present invention, starting materials can be appropriately selected and carried out through a reaction scheme with or without appropriate protection of the desired substituent to ultimately obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group that can be carried out via the reaction scheme and appropriately replaced with the desired substituent instead of the ultimately desired substituent. In addition, those skilled in the art will recognize that a protecting group may be used to protect a specific functional group (amino, carboxyl, or side chain group) from reaction conditions, and that such a group is removed under standard conditions at an appropriate time.Unless otherwise specified, variables are as defined above with reference to Chemical Formula (II), Chemical Formula (IG), Chemical Formula (I), Chemical Formula (IA), Chemical Formula (I-A1), Chemical Formula (I-A2), Chemical Formula (I-A3), Chemical Formula (I-A4), Chemical Formula (IB), Chemical Formula (I-B1), Chemical Formula (I-B2), Chemical Formula (I-B3), Chemical Formula (IC), Chemical Formula (I-C1), Chemical Formula (I-C2), Chemical Formula (I-C3), Chemical Formula (I-C4), Chemical Formula (ID), Chemical Formula (I-D1), Chemical Formula (I-D2), Chemical Formula (I-D3), Chemical Formula (I-D4), Chemical Formula (I-D5), Chemical Formula (I-D6), Chemical Formula (I-D7), Chemical Formula (IE), Chemical Formula (IF), Chemical Formula (II-A), and Chemical Formula (II-A1).

[1143] If it is desirable to obtain a specific enantiomer of a compound, this can be achieved from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or decomposing enantiomers. Thus, for example, a diastereomer derivative can be produced by the reaction of a mixture of enantiomers, e.g., a racemic mixture, with a suitable chiral compound. The diastereomer is then separated by any convenient means, e.g., crystallization, and the desired enantiomer can be recovered. As another decomposition process, the racemic mixture can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, a specific enantiomer can be obtained using a suitable chiral intermediate in one of the described processes.

[1144] Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or final products if it is desirable to obtain specific isomers of a compound or otherwise purify the reaction product.

[1145] A general method for preparing the compounds described herein is illustrated in the method exemplified below. In the reaction schemes provided herein, variable groups are defined for formula (II), formula (IG), formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (I-A3), formula (I-A4), formula (IB), formula (I-B1), formula (I-B2), formula (I-B3), formula (IC), formula (I-C1), formula (I-C2), formula (I-C3), formula (I-C4), formula (ID), formula (I-D1), formula (I-D2), formula (I-D3), formula (I-D4), formula (I-D5), formula (I-D6), formula (I-D7), formula (IE), formula (IF), formula (II-A), formula (II-A1), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[1146] In some embodiments, the compound provided herein may be synthesized according to reaction formula A1, reaction formula A2, or reaction formula A3.

[1147] Reaction Equation A1

[1148]

[1149] Reaction Equation A2

[1150]

[1151] Reaction Equation A3

[1152]

[1153] Here, R 1 , R 2 , R 3 , R 4 and R 5 is as defined for formula (II) or any variation thereof described in detail herein.

[1154] In certain embodiments, the compounds provided herein may be synthesized according to reaction formula A1a, reaction formula A2a, or reaction formula A3a.

[1155] Reaction formula A1a

[1156]

[1157] Reaction formula A2a

[1158]

[1159] Reaction formula A3a

[1160]

[1161] Here, R 1 , R 2 , R 3 , R 4 and R 5 is as defined for formula (II) or any variation thereof described in detail herein.

[1162] In some embodiments, the compound provided herein may be synthesized according to reaction formula B1 or reaction formula B2.

[1163] Reaction Equation B1

[1164]

[1165] Reaction Equation B2

[1166]

[1167] Here, R 1 , R 2 , R 3 , R 5 , R a , R g , R f and Z 1 is as defined for the formula (II) or any variation thereof described in detail herein.

[1168] In certain embodiments, the compound provided herein may be synthesized according to reaction formula B1a or reaction formula B2a.

[1169] Reaction equation B1a

[1170]

[1171] Reaction equation B2a

[1172]

[1173] Here, R 1 , R 2 , R 3 , R 5 , R a , R g , R f and Z 1 is as defined for the formula (II) or any variation thereof described in detail herein.

[1174] In some embodiments, the compound provided herein may be synthesized according to reaction formula C1 or reaction formula C2.

[1175] Reaction equation C1

[1176]

[1177] Reaction equation C2

[1178]

[1179] Here, R 1 , R 2 , R 3 , R 5 , R b , R c , R e , Z 2 and Z 3 is as defined for formula (II) or any variation thereof described in detail herein, and PG is a suitable protecting group.

[1180] In certain embodiments, the compound provided herein may be synthesized according to reaction formula C1a or reaction formula C2a.

[1181] Reaction equation C1a

[1182]

[1183] Reaction formula C2a

[1184]

[1185] Here, R 1 , R 2 , R 3 , R 5 , R b , R c , R e , Z 2 and Z 3 is as defined for the formula (II) or any variation thereof described in detail herein.

[1186] In some embodiments, the compound provided herein can be synthesized according to reaction scheme D1.

[1187] Reaction Equation D1

[1188]

[1189] Here, R 1 , R 5 , R c , R d , m and Z 3 is as defined for formula (II) or any variation thereof described in detail herein, and PG is a suitable protecting group.

[1190] In certain embodiments, the compound provided herein can be synthesized according to reaction formula D1a.

[1191] Reaction equation D1a

[1192]

[1193] Here, R 1 , R 5 , R c , R d , m and Z 3 is as defined for the formula (II) or any variation thereof described in detail herein.

[1194] In some embodiments, the compound provided herein can be synthesized according to reaction formula E1.

[1195] Equation E1

[1196]

[1197] Here, R 1 , R 2 , R 3 , R 5 , n and Z 4 is as defined for formula (II) or any variation thereof described in detail herein.

[1198] In certain embodiments, the compound provided herein can be synthesized according to reaction formula E1a.

[1199] Equation E1a

[1200]

[1201] Here, R 1 , R 2 , R 3 , R 5 , n and Z 4 is as defined for formula (II) or any variation thereof described in detail herein.

[1202] In some embodiments, the compound provided herein can be synthesized according to reaction formula F1.

[1203] Reaction Equation F1

[1204]

[1205] Here, R 1 , R 2 , R 3 , R 5 , n and Z 4 is as defined for formula (II) or any variation thereof described in detail herein.

[1206] In certain embodiments, the compound provided herein can be synthesized according to reaction formula F1a.

[1207] Reaction equation F1a

[1208]

[1209] Here, R 1 , R 2 , R 3 , R 5 , n and Z 4 is as defined for formula (II) or any variation thereof described in detail herein.

[1210] Specific, non-limiting examples are provided in the Examples section below.

[1211] Examples

[1212] The following examples are provided to illustrate the compositions, uses, and methods provided herein, but are not limited thereto. Compounds are prepared using the general methods described above.

[1213] The following abbreviations are used throughout the examples. TEA (triethylamine), DCM (dichloromethane), (Boc)2O (di-tert-butyl decarbonate), EA (ethyl acetate), PE (petroleum ether), DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropane-2-amine), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undeth-7-en), THF (tetrahydrofuran), PPh3 (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), rt (room temperature), DCE (dichloroethane), FA (formic acid), CHCl3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equiv (equivalent), DSC (bis(2,5-dioxopyrrolidine-1-yl) carbonate) and HBTU (O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[1214] Example A

[1215] Synthesis of intermediates 1.1, 1.2, 1.3, and 1.4.

[1216] Step 1: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (intermediate 1-a).

[1217]

[1218] 4-methoxybenzyl isocyanate (25.0 g, 153.2 mmol) was added dropwise at 20°C to a solution of ethyl 2-(4-aminophenyl)acetate (27.46 g, 153.2 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 4 hours, after which methanol (10 mL) was added and the mixture was cooled to 0°C. After 1 hour at 0°C, the slurry was filtered to yield intermediate 1-a (26.7 g, 78.0 mmol, 50.9% yield) as an off-white solid. LCMS-APCI(POS.) m / z: 343.1(M+H) + . 1HNMR (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).

[1219] Step 2: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (intermediate 1.1).

[1220]

[1221] 4N LiOH (234.0 mmol) was added dropwise at 20°C to a solution of intermediate 1-a (26.5 g, 77.5 mmol) in 1,4-dioxane (400 mL). The resulting mixture was stirred at room temperature for 2 hours, after which methanol (50 mL) was added. The pH of the mixture was adjusted to pH 1 to 2 using aqueous 6N HCl at 0°C. After 1 hour at 0°C, the slurry was filtered to yield 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (20.2 g, 64.3 mmol, 82.9% yield) as an off-white solid. LCMS-APCI(POS.) m / z: 315.0(M+H) + . 1 HNMR(400MHz, DMSO- d6) δ12.22(s, 1H), 8.47(s, 1H), 7.33(d, J =8.0Hz, 2H), 7.23(d, J =8.1Hz, 2H), 7.11(d, J =8.1Hz, 2H), 6.90(d, J =8.1Hz, 2H), 6.50(t, J =6.0Hz, 1H), 4.22(d, J =5.7Hz, 2H), 3.74(d, J =1.3Hz, 3H), 3.46(s, 2H).

[1222] Intermediates 1.2 and 1.3 were prepared in a manner similar to intermediate 1.1 using the reagents provided in the table below instead of 4-methoxybenzyl isocyanate.

[1223]

[1224] Example B

[1225] Synthesis of Intermediates 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7

[1226] Step 1: Preparation of tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)phenyl)-ethyl)carbamate (intermediate 2-a)

[1227]

[1228] (S)-[1-(4-amino-phenyl)-ethyl]-carbamic acid in DCM (20 mL) tert4-methoxybenzyl isocyanate (14.4 g, 34.0 mmol) was added dropwise to a solution of β-butyl ester (2.0 g, 22.7 mmol) at 20 °C. The resulting mixture was stirred at room temperature for 4 hours, after which methanol (10 mL) was added and the mixture was cooled to 0 °C. After 1 hour at 0 °C, the slurry was filtered to yield tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)-phenyl)ethyl)carbamate (1.2 g, 6.3 mmol, 28% yield) as a grayish-white solid. LCMS-APCI(POS.) m / z: 400.1 (M+H) + . 1 HNMR(400MHz, DMSO- d 6) δ8.43(s, 1H), 7.36-7.19(m, 4H), 7.14(d, J =8.2Hz, 2H), 6.89(d, J =8.2Hz, 2H), 6.48(t, J =5.9Hz, 1H), 4.53(p, J =7.3Hz, 1H), 4.21(d, J =5.7Hz, 2H), 3.73(s, 3H), 1.37(s, 9H), 1.27(d, J =7.0Hz, 3H).

[1229] Step 2: Preparation of (S)-1-(4-(1-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (Intermediate 2.1)

[1230]

[1231] Intermediate 2-a (34.7 g, 86.9 mmol) was dissolved in dichloromethane and cooled to 0°C using an ice bath. Hydrogen chloride (4N in 1,4-dioxane, 174 mL, 695 mmol) was added dropwise using a needle, and the resulting mixture was stirred at 0°C for 5 minutes, after which the ice bath was removed. The reaction mixture was stirred at room temperature for 45 minutes, and the reaction progress was monitored by LC / MS. The mixture was quenched with triethylamine (28 mL), and the resulting mixture was concentrated under vacuum to yield a white solid. The solid was distributed between a saturated NaHCO3 solution and DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure to yield (S)-1-(4-(1-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (6.18 g, 18.28 mmol, 90% yield) as a viscous, nearly colorless oil. The purity was estimated to be 70%. LCMS-APCI(POS.) m / z: 300.1(M+H)+. 1 HNMR(400MHz, DMSO- d 6)δ9.14(s, 1H), 8.40(d, J =5.3Hz, 3H), 7.45(d, J =8.3Hz, 2H), 7.36(d, J =8.3Hz, 2H), 7.23(d, J =8.2Hz, 2H), 6.89(d, J =8.2Hz, 3H), 4.29(p, J =6.1Hz, 1H), 4.22(s, 2H), 3.73(s, 3H), 1.49(d, J =6.7Hz, 3H).

[1232] Intermediates 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7 were prepared in a manner similar to intermediate 2.1 using the reagents provided in the table below instead of 4-methoxybenzyl isocyanate.

[1233]

[1234]

[1235] Example C

[1236] Synthesis of Intermediates 3.1, 3.2, and 3.3

[1237] Step 1: Preparation of methyl 4-(3-(4-methoxybenzyl)ureido)benzoate (intermediate 3-a)

[1238]

[1239] (4-methoxyphenyl)methaneamine (7.74 g, 56.4 mmol) was added dropwise at 0°C to a suspension of methyl 4-isocyanatobenzoate (10.0 g, 56.4 mmol) in methylene chloride (56.4 mL, 1 M). The reaction mixture was slowly heated to room temperature and stirred for 60 minutes at room temperature, and the reaction progress was monitored by LC / MS. The reaction became homogeneous and was followed by a white solid precipitate. Subsequently, the solution was filtered, the filter cake was washed with an excess of methylene chloride, and dried to obtain crude intermediate 3-a (17.4 g, 55.2 mmol, 98% yield) as a grayish-white solid set. LCMS-APCI(POS.) m / z: 315.2(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ8.96(s, 1H), 7.85(d, J=8.6Hz, 2H), 7.54(d, J=8.8Hz, 2H), 7.24(d, J=8.5Hz, 2H), 6.90(d, J=8.5Hz, 2H), 6.71(t, J=5.9Hz, 1H), 4.25(d, J=5.7Hz, 2H), 3.73(s, 3H), 3.81(s, 3H).

[1240] Step 2: Preparation of 1-(4-(hydroxymethyl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 3-b)

[1241]

[1242] Intermediate 3-a (16.0 g, 50.9 mmol) in 120 mL of dry methylene chloride was added to a dry flask, and the suspension was cooled to 0°C. Next, 1 M DIBAL was added dropwise over 45 minutes in 126 mL of methylene chloride (126 mmol), and the reaction mixture was stirred at 0°C for an additional 30 minutes. The homogeneous solution was heated to room temperature and stirred for 4 hours. Subsequently, the solution was cooled to 0°C and quenched by adding MeOH (100 mL) dropwise. After the exothermic reaction subsided, 300 mL of methylene chloride and 200 mL of sodium hydroxide solution (1 M) were added, and the mixture was stirred at room temperature for an additional 60 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with (5:1 methylene chloride-isopropanol, 300 mL). The combined organic layer was washed with brine, dried with magnesium sulfate, filtered, and evaporated to produce intermediate 3-b as a white solid (14.2 g, 49.8 mmol, 99% yield). The crude product was taken through the following oxidation step with further purification. LCMS-APCI(POS.) m / z: 287.2(M+H)+. 1 HNMR(400MHz, DMSO- d 6) δ8.61(s, 1H), 7.35(d, J =8.0Hz, 2H), 7.24(d, J =8.2Hz, 2H), 7.17(d, J =8.1Hz, 2H), 6.90(d, J =8.2Hz, 2H), 6.61(t, J =5.9Hz, 1H), 5.02(t, J =5.7Hz, 1H), 4.40(d, J =5.5Hz, 2H), 4.22(d, J =5.7Hz, 2H), 3.74(s, 3H).

[1243] Step 3: Preparation of 1-(4-formylphenyl)-3-(4-methoxybenzyl)urea (Intermediate 3.1)

[1244]

[1245] Manganese dioxide (44.2 g, 508 mmol) was added at room temperature to a suspension of intermediate 3-b (14.0 g, 48.8 mmol) in methylene chloride-isopropanol (20:1, 250 mL, 0.2 M). The resulting suspension was stirred at room temperature for 12 hours. Subsequently, the solution was filtered over Celite. The filter cake was washed with isopronaol, and the mother liquor was concentrated to yield intermediate 3.1 (13.2 g, 46.5 mmol) as a pale yellow solid set. LCMS-APCI(POS.) m / z: 285.2(M+H) + . 1 HNMR(400MHz, DMSO- d 6) δ9.81(s, 1H), 9.15(s, 1H), 7.78(dd, J =8.6, 2,7Hz, 2H), 7.62(dd, J =8.6, 2,7Hz, 2H), 7.24(dd, J =8.5, 2,8Hz, 2H), 6.90(dd, J =8.6, 2,7Hz, 2H), 6.87-6.77(m, 1H), 4.43(dd, J =8.5, 2,8Hz, 2H), 3.74(s, 3H).

[1246] Intermediate 3.2 and intermediate 3.3 were prepared in a manner similar to intermediate 2.1 using the reagents provided in the table below instead of (4-methoxyphenyl)methaneamine.

[1247]

[1248] Example D

[1249] Synthesis of Intermediates 4.1 and 4.2

[1250] Step 1: Preparation of phenyl (4-chlorobenzyl)carbamate (intermediate 4.1)

[1251]

[1252] Phenyl carbonochloridate (2.43 g, 15.537 mmol, 1.1 equivalents) and K2CO3 (2.93 g, 21.186 mmol, 1.5 equivalents) were added to a solution of 1-(4-chlorophenyl)methaneamine (2.00 g, 14.124 mmol, 1.00 equivalents) in THF (30 mL). The resulting mixture was stirred at room temperature for 3 hours, filtered to remove the solid, concentrated the filtrate, purified by silica gel column chromatography, and eluted with PE / EtOAc (5:1) to obtain 3.6 g of phenyl N-[(4-chlorophenyl)methyl]carbamate (95%) as a white solid. LRMS (ES) m / z 262 [M+H].

[1253] Intermediate 4.2 was prepared in a manner similar to intermediate 4.1 using (4-methoxyphenyl)methaneamine instead of (4-chlorophenyl)methaneamine.

[1254]

[1255] Example E

[1256] Synthesis of 4-(1-(methylsulfonyl)ethyl)aniline (intermediate 5.0)

[1257] Step 1: Preparation of 1-((methylsulfonyl)methyl)-4-nitrobenzene (intermediate 5-a)

[1258]

[1259] Sodium methanesulfinate (712 mg, 6.975 mmol, 1.51 equivalents) was added to a solution of 1-(bromomethyl)-4-nitrobenzene (1 g, 4.629 mmol, 1 equivalent) in DMF (10 mL). The resulting mixture was stirred at 65 °C for 0.5 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain 1 g of 1-(methanesulfonylmethyl)-4-nitrobenzene as a yellow solid (no LCMS signal, confirmed by H-NMR). 1H NMR (300MHz, DMSO-d6) δ8.34-8.23(m, 2H), 7.76-7.65(m, 2H), 4.73(s, 2H), 2.99(s, 3H).

[1260] Step 2: Preparation of 1-(1-(methylsulfonyl)ethyl)-4-nitrobenzene (intermediate 5-b)

[1261]

[1262] t-BuOK (531 mg, 4.732 mmol, 1.20 equivalents) was added to a solution of 1-(methanesulfonylmethyl)-4-nitrobenzene (850 mg, 3.949 mmol, 1 equivalent) in DMF (10 mL). After stirring at room temperature for 1 hour, iodomethane (560 mg, 3.945 mmol, 1.00 equivalents) was added to the mixture. The resulting mixture was stirred at room temperature for 1 hour, and water (20 mL) was added. The mixture was extracted twice with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 950 mg of 1-(1-methanesulfonylethyl)-4-nitrobenzene as a yellow oil. No LCMS signal. H-NMR analysis indicated that 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).

[1263] Step 3: Preparation of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0)

[1264]

[1265] Pd / C (467 mg, 50% w / w) was added to a solution of 1-(1-methanesulfonylethyl)-4-nitrobenzene (950 mg, 4.144 mmol, 1 equivalent) in methanol (10 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 700 mg of 4-(1-methanesulfonylethyl)aniline as a yellow oil. LRMS(ES) m / z 200 [M+H].

[1266] Example F

[1267] Synthesis of 3-(4-aminophenyl)tiethane 1,1-dioxide trifluoroacetate salt (Intermediate 6.0)

[1268] Step 1: Preparation of diethyl 2-(4-nitrophenyl)malonate (intermediate 6-a)

[1269]

[1270] 1,3-diethylpropanedioate (12g, 74.921mmol, 3.03 equivalents), CuI (473mg, 2.484mmol, 0.10 equivalents), L-proline (572mg, 4.968mmol, 0.20 equivalents), and K2CO3 (13.7g, 99.128mmol, 4.00 equivalents) were added to a solution of 1-bromo-4-nitrobenzene (5g, 24.752mmol, 1 equivalent) in DMSO (50mL). The mixture was stirred under a nitrogen atmosphere at 90°C for 2 days, cooled to room temperature, water (100mL) was added, and the mixture was extracted twice with EtOAc (100mL). The combined organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (20:1) to obtain 4.7 g of 1,3-diethyl 2-(4-nitrophenyl)propanedioate as a yellow oil. LRMS (ES) m / z 282 (M+H).

[1271] Step 2: Preparation of diethyl 2-(4-aminophenyl)malonate (intermediate 6-b)

[1272]

[1273] Pd / C (1.10 g, 50% w / w) was added to a solution of 1,3-diethyl 2-(4-nitrophenyl)propanedioate (2.2 g, 7.822 mmol, 1 equivalent) in ethanol (25 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 1.9 g of 1,3-diethyl 2-(4-aminophenyl)propanedioate (96.67%) as a yellow oil. LRMS (ES) m / z 252 [M+H].

[1274] Step 3: Preparation of diethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)malonate (intermediate 6-c)

[1275]

[1276] Di-tert-butyl dicarbonate (2.6 g, 11.4 mmol, 2.9 equivalents) was added to a solution of 1,3-diethyl 2-(4-aminophenyl)propanedioate (1 g, 3.96 mmol, 1 equivalent) in THF (10 mL). The resulting mixture was stirred at room temperature for 2 hours, water (30 mL) was added, and the mixture was extracted twice with CH2Cl2 (30 mL). The combined organic layer was washed twice with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (10:1) to obtain 1 g of 1,3-diethyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanedioate as a grayish-white solid. LRMS(ES) m / z 296[M+H-56].

[1277] Step 4: Preparation of tert-butyl (4-(1,3-dihydroxypropane-2-yl)phenyl)carbamate (intermediate 6-d)

[1278]

[1279] NaBH4 (1.08 g, 28.547 mmol, 10.03 equivalents) was added to a solution of 1,3-diethyl 2-(4-[[(tert-butoxy)carbonyl]amino]phenyl)propanedioate (1 g, 2.846 mmol, 1 equivalent) in ethanol (20 mL). The resulting mixture was stirred overnight at room temperature, quenched with NH4Cl aq (10 mL) at 0°C, and concentrated under vacuum to remove EtOH. The mixture was extracted twice with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with CH2Cl2 / MeOH (20:1) to obtain 720 mg of tert-butyl N-[4-(1,3-dihydroxypropane-2-yl)phenyl]carbamate (94.64%) as a grayish-white solid. LRMS(ES) m / z 212 [M+H-56].

[1280] Step 5: Preparation of 2-(4-((tert-butoxycarbonyl)amino)phenyl)propane-1,3-diyl dimethanesulfonate (intermediate 6-e)

[1281]

[1282] Methanesulfonyl chloride (715 mg, 6.242 mmol, 2.49 equivalents) and TEA (760 mg, 7.511 mmol, 3.00 equivalents) were added to a solution of tert-butyl N-[4-(1,3-dihydroxypropane-2-yl)phenyl]carbamate (670 mg, 2.506 mmol, 1 equivalent) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours and poured into water (20 mL). The aqueous layer was extracted twice with CH2Cl2 (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 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].

[1283] Step 6: Preparation of tert-butyl (4-(tiethane-3-yl)phenyl)carbamate (intermediate 6-f)

[1284]

[1285] Na2S (122 mg, 1.564 mmol, 0.60 equivalents) was added at room temperature to a solution of tert-butyl N-[4-[2-(methanesulfonyloxy)-1-[(methanesulfonyloxy)methyl]ethyl]phenyl]carbamate (1.1 g, 2.597 mmol, 1 equivalent) in DMF (10 mL). 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 layer was washed twice with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (5:1) to obtain 270 mg of tert-butyl N-[4-(tiethane-3-yl)phenyl]carbamate (39.17%) as a yellow solid. LRMS(ES) m / z 210 [M+H-56].

[1286] Step 7: Preparation of tert-butyl (4-(1,1-deoxydotiethane-3-yl)phenyl)carbamate (6 g intermediate)

[1287]

[1288] m-CPBA (485 mg, 2.811 mmol, 2.98 equivalents) was added to a solution of tert-butyl N-[4-(tiethane-3-yl)phenyl]carbamate (250 mg, 0.942 mmol, 1 equivalent) in DCM (3 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and water (20 mL) was added. The resulting mixture was extracted twice with CH2Cl2 (20 mL). The combined organic layer was washed with Na2S2O4 (10 mL), NaHCO3 (10 mL), and brine (20 mL) twice, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 290 mg of tert-butyl N-[4-(1,1-dioxo-1lambda6-tiethane-3-yl)phenyl]carbamate as a yellow oil. LRMS(ES) m / z 242 [M+H-56].

[1289] Step 8: Preparation of 3-(4-aminophenyl)tiethane 1,1-dioxide trifluoroacetate salt (Intermediate 6.0)

[1290]

[1291] tert-butyl in DCM (3 mL) N TFA (0.5 mL) was added to a solution of -[4-(1,1-dioxo-1lambda6-tiethane-3-yl)phenyl]carbamate (290 mg, 0.975 mmol, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 190 mg of 3-(4-aminophenyl)tiethane 1,1-dioxide trifluoroacetate salt as a brown solid. LRMS (ES) m / z 298 [M+H].

[1292] Example G

[1293] Synthesis of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0)

[1294] Step 1: Preparation of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (intermediate 7-a)

[1295]

[1296] LiHMDS (25.00 mL, 25.000 mmol, 1.50 equivalents) was added dropwise to a solution of tetrahydrothiophene 1,1-dioxide (2 g, 16.643 mmol, 1.00 equivalents) in THF (20.00 mL) over a period of 20 minutes under a nitrogen atmosphere at -20°C. After stirring under a nitrogen atmosphere at room temperature for 0.5 hours, ZnCl2 (3.35 g, 24.575 mmol, 1.48 equivalents) was added to the mixture at -20°C. The mixture was stirred at room temperature for 1 hour. 1-bromo-4-nitrobenzene (2.35 g, 11.650 mmol, 0.70 equivalents), Pd(OAc)2 (187.00 mg, 0.833 mmol, 0.05 equivalents) and X-Phos (795.00 mg, 1.668 mmol, 0.10 equivalents) were added to the above mixture. The mixture was stirred under a nitrogen atmosphere at 65°C for 12 hours, cooled to room temperature, quenched with aqueous NH4Cl (20 mL) and HCl (1 mol / L, 5 mL), and extracted twice with CH2Cl2 (50 mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 1.1 g of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (27.40%) as a brown solid. No LCMS signal.

[1297] Step 2: Preparation of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0)

[1298]

[1299] Pd / C (550.00 mg, 50% w / w) was added to a solution of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (1.10 g, 4.559 mmol, 1.00 equivalent) in methanol (11 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 800 mg of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (83.05%) as a yellow solid. LRMS(ES) m / z 212 [M+H].

[1300] Example H

[1301] Synthesis of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate salt (Intermediate 8.0)

[1302] Step 1: Preparation of tert-butyl(4-iodophenyl)carbamate (intermediate 8-a)

[1303]

[1304] (Boc)2O (2g, 0.009mmol, 2.01 equivalents) and TEA (2mL) were added to a solution of 4-iodoaniline (1g, 4.566mmol, 1 equivalent) in MeOH (20mL). The resulting mixture was stirred overnight at 50°C, cooled to room temperature, concentrated under vacuum, and water (50mL) was added. The mixture was extracted twice with EtOAc (50mL). The combined organic layer was washed twice with brine (50mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (30:1) to obtain 650mg of tert-butyl N-(4-iodophenyl)carbamate (650mg, 44.61%) as a grayish-white solid. LRMS(ES) m / z 264[M+H-56].

[1305] Step 2: Preparation of tert-butyl(4-(1,1-deoxydo-2,5-dihydrothiophene-3-yl)phenyl)carbamate (intermediate 8-b)

[1306]

[1307] 2,5-dihydro-1-lambda6-thiophene-1,1-dione (264 mg, 2.234 mmol, 1.10 equivalents), Pd(OAc)2 (91 mg, 0.405 mmol, 0.20 equivalents), TBABr (654 mg, 2.029 mmol, 1.00 equivalents), and TEA (410 mg, 4.052 mmol, 1.99 equivalents) were added to a solution of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 2.037 mmol, 1 equivalent) in toluene (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 days and at 80°C for 3 hours, cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with EtOAc (30 mL). The combined organic layer was washed twice with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 430 mg of tert-butyl N-[4-(1,1-dioxo-2,5-dihydro-1lambda6-thiophene-3-yl)phenyl]carbamate (68.24%) as a brown solid. LRMS (ES) m / z 254 [M+H-56].

[1308] Step 3: Preparation of tert-butyl (4-(1,1-dioxydotetrahydrothiophene-3-yl)phenyl)carbamate (intermediate 8-c)

[1309]

[1310] Pd / C (215 mg, 50% w / w) was added to a solution of tert-butyl N-[4-(1,1-dioxo-2,5-dihydro-1lambda6-thiophene-3-yl)phenyl]carbamate (430 mg, 1.390 mmol, 1 equivalent) in methanol (10 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 390 mg of tert-butyl N-[4-(1,1-dioxo-1lambda6-thiolan-3-yl)phenyl]carbamate (90.11%) as a brown solid. LRMS(ES) m / z 256 [M+H].

[1311] Step 4: Preparation of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate salt (Intermediate 8.0)

[1312]

[1313] TFA (1 mL) was added to a solution of tert-butyl N-[4-(1,1-dioxo-1-lambda6-thiolan-3-yl)phenyl]carbamate (390 mg, 1.252 mmol, 1 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, diluted with water (10 mL), and the pH adjusted to 8 using aqueous Na2CO3. The aqueous layer was extracted twice with EA (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain 260 mg of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate salt as a brown oil. LRMS(ES) m / z 212 [M+H].

[1314] Example I

[1315] Synthesis of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0)

[1316] Step 1: Preparation of 3,6-Dihydro-2H-thiopyran-4-yl Trifluoromethanesulfonate (Intermediate 9-a)

[1317]

[1318] To a solution of LDA (8.5 mL, 17.0 mmol, 1.10 equivalents) in THF (5 mL) at -78°C, a solution of thian-4-one (1.8 g, 15.493 mmol, 1 equivalent) was added dropwise over a period of 10 minutes under an argon atmosphere. After stirring under an argon atmosphere at room temperature for 0.5 hours, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (6.09 g, 17.047 mmol, 1.10 equivalents) in THF (10 mL) at -78°C was added dropwise to the mixture over a period of 10 minutes. The resulting mixture was stirred under an argon atmosphere at room temperature for 0.5 hours, quenched with water (100 mL) at 0°C, and extracted twice with EtOAc (200 mL). The combined organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (99:1) to obtain 2.5 g of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate as a yellow oil. LRMS(ES) m / z 249 [M+H].

[1319] Step 2: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (intermediate 9-b)

[1320]

[1321] (4-nitrophenyl)boronic acid (1.94 g, 11.602 mmol, 1.20 equivalents), Pd(dppf)Cl2CH2Cl2 (1.58 g, 1.934 mmol, 0.20 equivalents), and K2CO3 (2.66 g, 19.34 mmol, 2 equivalents) were added to a solution of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (2.4 g, 9.668 mmol, 1 equivalent) in dioxane (20 mL) and H2O (10 mL). The resulting mixture was stirred under a nitrogen atmosphere at 85°C for 3 hours, cooled to room temperature, and water (200 mL) was added. The resulting mixture was extracted twice with EtOAc (200 mL). The combined organic layer was washed twice with brine (200 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (20:1) to obtain 1 g of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (46.74%) as a yellow solid. LRMS(ES) m / z 222 [M+H].

[1322] Step 3: Preparation of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (intermediate 9-c)

[1323]

[1324] m-CPBA (1.6 g, 9.5 mmol, 3 equivalents) was added at -78°C to a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (700 mg, 3.164 mmol, 1 equivalent) in DCM (15 mL). The resulting mixture was stirred at room temperature for 3 hours and poured into water (20 mL). The aqueous layer was extracted twice with CH2Cl2 (30 mL). The combined organic phase was washed with Na2SO3 (aq. 10 mL), NaHCO3 (aq. 10 mL), and brine (20 mL) twice, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain 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].

[1325] Step 4: Preparation of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0)

[1326]

[1327] Pd / C (325 mg, 50% w / w) was added to a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (650 mg, 2.559 mmol, 1 equivalent) in methanol (8 mL) and THF (8 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 400 mg of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide as a brown solid. LRMS(ES) m / z 226 [M+H].

[1328] Example J

[1329] Synthesis of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (intermediate 10.0)

[1330] Step 1: Preparation of ethyl (Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (intermediate 10-a)

[1331]

[1332] Ethyl 2-cyanoacetate (1.37 g, 12.111 mmol, 1.00 equivalent) and NH4OAc (187 mg, 2.426 mmol, 0.20 equivalent) were added to a solution of 1-(4-nitrophenyl)ethane-1-one (2 g, 12.110 mmol, 1 equivalent) in AcOH (6 mL) and toluene (40 mL). The resulting mixture was stirred overnight at 110 °C, cooled to room temperature, and poured into water (50 mL). The resulting mixture was extracted twice with EtOAc (50 mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (10:1) to obtain 1.7 g of ethyl (Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (53.94%) as a yellow solid. LRMS(ES) m / z 261 (M+H).

[1333] Step 2: Preparation of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (intermediate 10-b)

[1334]

[1335] 2-cyanoacetamide (517 mg, 6.149 mmol, 1.00 equivalent) was added dropwise over a period of 5 minutes at 0°C to a solution of NaOEt (2 g, 6.176 mmol, 1.00 equivalent, 21%) in EtOH (30 mL). After stirring for 15 minutes at room temperature, ethyl (2Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (1.6 g, 6.148 mmol, 1 equivalent) was added. The resulting mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and the mixture was acidified to pH 1 using HCl (aq. 4 mol / L, ~5 mL). The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.2 g of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (65.44%) as a yellow solid. No LCMS signal. 1H-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).

[1336] Step 3: Preparation of 3-methyl-3-(4-nitrophenyl)pentanedioid acid (intermediate 10-c)

[1337]

[1338] Sulfuric acid (9 mL) and AcOH (6 mL) were added dropwise over a period of 15 minutes at 0°C to a solution of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (1.1 g, 3.688 mmol, 1 equivalent) in H2O (9 mL). The resulting mixture was stirred at 100°C for 2 days, cooled to room temperature, diluted with ice-cold water (30 mL), and extracted twice with EtOAc (30 mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 1.2 g of brown semi-solid 3-methyl-3-(4-nitrophenyl)pentanedioid acid. LRMS(ES) m / z 268 (M+H).

[1339] Step 4: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (intermediate 10-d)

[1340]

[1341] BH3-THF (1 mol / L in THF, 41 mL, 41 mmol, 10 equivalents) was added dropwise over a period of 15 minutes at 0°C to a solution of 3-methyl-3-(4-nitrophenyl)pentanediic acid (1.1 g, 4.1 mmol, 1 equivalent) in THF (10 mL). The resulting mixture was stirred at 70°C for 1.5 hours, cooled to room temperature, quenched with water (30 mL) at 0°C, and extracted twice with EtOAc (30 mL). The combined organic layer was washed twice with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 720 mg of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (82.06%) as a brown oil. LRMS(ES) m / z 240(M+H).

[1342] Step 5: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diyl dimethanesulfonate (intermediate 10-e)

[1343]

[1344] TEA (912 mg, 9.013 mmol, 3.00 equivalents) and methanesulfonyl chloride (859 mg, 7.500 mmol, 2.49 equivalents) were added dropwise to a solution of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diol (720 mg, 3.009 mmol, 1 equivalent) in DCM (10 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours and poured into water (10 mL). The aqueous layer was extracted twice with CH2Cl2 (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 410 mg of 5-(methanesulfonyloxy)-3-methyl-3-(4-nitrophenyl)pentyl methanesulfonate (34.46%) as a yellow oil. LRMS(ES) m / z 396 (M+H).

[1345] Step 6: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (intermediate 10-f)

[1346]

[1347] Na2S (49.33 mg, 0.632 mmol, 0.61 equivalents) was added to a solution of 5-(methanesulfonyloxy)-3-methyl-3-(4-nitrophenyl)pentyl methanesulfonate (410 mg, 1.037 mmol, 1 equivalent) in ACN (5 mL). The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere, cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (20:1) to obtain 130 mg of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (52.83%) as a yellow oil. LRMS(ES) m / z 238 (M+H).

[1348] Step 7: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (intermediate 10-g)

[1349]

[1350] m-CPBA (283 mg, 1.640 mmol, 2.99 equivalents) was added to a solution of 4-methyl-4-(4-nitrophenyl)thiane (130 mg, 0.548 mmol, 1 equivalent) in DCM (3 mL). The resulting mixture was stirred at room temperature for 2 hours and poured into water (10 mL). The aqueous phase was extracted twice with CH2Cl2 (10 mL). The combined organic phase was washed with Na2S2O4 (5 mL) and brine (10 mL) twice, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 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).

[1351] Step 8: Preparation of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (intermediate 10.0)

[1352]

[1353] Pd / C (85 mg, 50% w / w) was added to a solution of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (170 mg, 0.631 mmol, 1 equivalent) in methanol (3 mL). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 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).

[1354] Example K

[1355] Synthesis of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediate 11.1-intermediate 11.15)

[1356] Preparation of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediate 11-a)

[1357]

[1358] LiHMDS (22.2 mL, 22.2 mmol, 1.1 equivalents, 1 M in THF) was added at 0 °C to a stirred solution of 3-methylpyrrolidin-2-one (8.7 g, 20.2 mmol, 1 equivalent) in THF (20 mL). After 1 hour, benzyl bromide (27 g, 125 mmol, 1.25 equivalents) in THF (20 mL) was added, and the reaction was allowed to return to room temperature over 12 hours. The reaction mixture was dry-loaded onto silica, and the product was isolated as a reddish solid (24.1 g, 72%) by silica chromatography (0->100% EtOAc / Hex). LC / MS (APCI) m / z: 235.1 [M+H]. 1 HNMR(400MHz, chloroform- d ) δ8.17(d, J =8.8Hz, 2H), 7.38(d, J =8.4Hz, 2H), 4.61-4.43(m, 2H), 3.21(dd, J =8.2, 5.4Hz, 2H), 2.55(t, J =8.1Hz, 1H), 2.33-2.19(m, 1H), 1.64(dq, J =12.2, 8.6Hz, 1H), 1.23(d, J =7.1Hz, 3H).

[1359] Intermediates 11.2 to 11.15 were prepared in a manner similar to intermediate 11.1.

[1360]

[1361]

[1362]

[1363] Example L

[1364] Synthesis of 5-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediates 12.1-12.2)

[1365] Preparation of 5-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (intermediate 12)

[1366]

[1367] Sodium triacetoxyborohydride (11 g, 53 mmol, 2 equivalents) was added at room temperature to a stirred solution of (4-nitrophenyl)methaneamine hydrochloride (5 g, 26.5 mmol, 1 equivalent), ethyl 4-oxopentanoate (4.2 g, 29.2 mmol, 1.1 equivalents), and triethylamine (3.6 mL, 26.5 mmol, 1 equivalent) in DCM (200 mL). After 14 hours, the reaction mixture was dry-loaded onto silica, and the product was isolated as a white solid (5 g, 81%) by silica chromatography. LC / MS (APCI) m / z: 235.1 [M+H]. 1 HNMR(400MHz, chloroform- d ) δ8.20(d, J =8.3Hz, 2H), 7.43(d, J =8.3Hz, 2H), 4.90(d, J =15.6Hz, 1H), 4.25(d, J =15.6Hz, 1H), 3.58(h, J =6.3Hz, 1H), 2.50(dtd, J =34.1, 17.1, 9.5Hz, 2H), 2.23(ddd, J =13.3, 11.0, 6.8Hz, 1H), 1.67(ddt, J =13.2, 9.3, 6.8Hz, 1H), 1.18(d, J =6.2Hz, 3H).

[1368] Intermediate 12.2 was prepared in a manner similar to intermediate 12.1.

[1369]

[1370] Example M

[1371] Synthesis of 1-(4-aminobenzyl)-3-methylpyrrolidine-2-one (intermediate 13.1 to intermediate 13.X)

[1372] Preparation of 1-(4-aminobenzyl)-3-methylpyrrolidine-2-one (intermediate 13.1)

[1373]

[1374] 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (3 g, 12.8 mmol, 1 equivalent) and PtO2 (0.29 g, 1.28 mmol, 0.1 equivalent) were stirred for 1 hour under H2 (80 psi). The reaction mixture was filtered through a Celite pad, the solvent was removed by rotary evaporation, and the product was dried under high vacuum to obtain a reddish solid (2.6 g, 99%). LC / MS (APCI) m / z: 205.2 [M+H].

[1375] Intermediates 13.2 to 13.36 were prepared in a manner similar to intermediate 13.1.

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382] Example N

[1383] Synthesis of 4-methyl-1-(4-nitrobenzyl)piperazine-2-one (intermediates 14.1 to 14.6)

[1384] Step 1: Preparation of 1-(4-nitrobenzyl)piperazine-2-one hydrochloride (intermediate 14-a)

[1385]

[1386] Tert-butyl 4-(4-nitrobenzyl)-3-oxopiperazine-1-carboxylate (intermediate 11.2 g, 24.1 g, 71.9 mmol, 1 equivalent) was suspended in 4 M HCl in 180 mL of dioxane (719 mmol, 10 equivalents) at room temperature. After 2 hours, the solvent was removed by rotary evaporation and dried under high vacuum to obtain the desired product as a white solid (19.5 g, 99.9%). LCMS-APCI(POS.) m / z: 236.1(M+H) + .

[1387] Step 2: Preparation of 4-methyl-1-(4-nitrobenzyl)piperazine-2-one (Intermediate 14.1)

[1388]

[1389] Formaldehyde (17.47 g, 215.3 mmol, 3 equivalents, 37% in water) and AcOH (12.9 mL, 215.3 mmol, 3 equivalents) were added at room temperature to a stirred suspension of 1-(4-nitrobenzyl)piperazine-2-one hydrochloride (19.5 g, 71.8 mmol, 1 equivalent) in MeOH (800 mL). After 10 minutes, the reaction became homogeneous, and then it was cooled to 0°C, NaCNBH3 (9.9 g, 157.9 mmol, 2.2 equivalents) was added, and the reaction mixture was heated to room temperature. After 3 hours, the total volume was reduced to approximately 400 mL by rotary evaporation, quenched with saturated sodium bicarbonate (1 L), extracted with DCM (3 x 750 mL), the organic matter was combined, dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The oily yellow product was crystallized overnight under high vacuum to obtain a pale yellow crystalline product (17 g, 95%). LCMS-APCI(POS.) m / z: 250.1(M+H) + . 1 HNMR(400MHz, chloroform- d ) δ8.11(d, J =8.7Hz, 2H), 7.35(d, J=8.7Hz, 2H), 4.62(s, 2H), 3.25-3.18(m, 2H), 3.14(s, 2H), 2.63-2.53(m, 2H), 2.28(s, 3H).

[1390] Intermediates 14.2 to 14.6 were prepared in a manner similar to intermediate 14.1.

[1391]

[1392] Example O

[1393] Synthesis of 4-((azetidine-1-ylsulfonyl)methyl)aniline (intermediates 15.1 to 15.4)

[1394] Step 1: Preparation of 1-((4-nitrobenzyl)sulfonyl)azetidine (intermediate 15-a)

[1395]

[1396] (4-nitrophenyl)methanesulfonyl chloride (500 mg, 2.12 mmol, 1 equivalent) was added at room temperature to a stirred solution of azetadine (121 mg, 2.12 mmol, 1 equivalent) and diisoproylethylamine (1.1 mL, 6.4 mmol, 3 equivalents) in DCM (5 mL). After 1 hour, the reaction mixture was washed with saturated sodium bicarbonate (5 mL), dried over sodium sulfate, filtered, and the solvent removed by rotary evaporation. The crude material was separated by silica chromatography (0->3% MeOH / DCM) to obtain 1-((4-nitrobenzyl)sulfonyl)azetadine (110 mg, 20%). LCMS-APCI (Neg.) m / z: 255.2 (MH) - . 1 HNMR(400MHz, DMSO- d 6) δ8.27(d, J =8.8Hz, 1H), 7.72(d, J =8.8Hz, 1H), 4.73(s, 1H), 3.89(t, J =7.7Hz, 2H), 2.19(p, J =7.7Hz, 1H).

[1397] Step 2: Preparation of 4-((azetidine-1-ilsulfonyl)methyl)aniline (Intermediate 15.1)

[1398]

[1399] 1-((4-nitrobenzyl)sulfonyl)azetidine (110 mg, 0.43 mmol, 1 equivalent) and PtO2 (5 mg, 0.022 mmol, 0.05 equivalents) were suspended in 5 mL of MeOH and stirred under H2 for 12 hours. The reaction mixture was filtered through a 0.45 μm PTFE syringe filter, and the solvent was removed by rotary evaporation to obtain the product (90 mg, 93%). LCMS-APCI(POS.) m / z: 227.2 (M+H) + .

[1400] Intermediates 15.2 to 15.4 were prepared in a manner similar to intermediate 15.1.

[1401]

[1402] Example P

[1403] Synthesis of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (intermediate 16)

[1404] Step 1: Preparation of phenyl (4-chlorobenzyl)carbamate (intermediate 16-a)

[1405]

[1406] Phenyl chloroformate (12.16 g, 77.6 mmol, 1.1 equivalents) was added dropwise over a period of 15 minutes at 0°C to a stirred solution of 1-(4-chlorophenyl)methaneamine (10.00 g, 70.621 mmol, 1 equivalent) and NEt3 (10.72 g, 105.9 mmol, 1.5 equivalents) in THF (100 mL). The resulting mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (4:1) to obtain 17.76 g (91.38%) of phenyl(4-chlorobenzyl)carbamate as a pink solid. LCMS-APCI(POS.) m / z: 362(M+H) + .

[1407] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (intermediate 16-b)

[1408]

[1409] Diisopropylethylamine (16.00g, 123.8mmol, 5 equivalents) was added to a stirred solution of phenyl(4-chlorobenzyl)carbamate (7.80g, 29.8mmol, 1.2 equivalents) and 4-aminobenzaldehyde (3.00g, 24.8mmol, 1 equivalent) in i-PrOH (30.00mL). The resulting mixture was stirred overnight at 90°C, cooled to room temperature, water (100mL) was added, and extracted twice with EtOAc (100mL). The combined organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (2:1) to obtain 2.04 g (27%) of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea as a yellow solid. LCMS-APCI(POS.) m / z: 289(M+H) + .

[1410] Step 3: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (intermediate 16-c)

[1411]

[1412] NaBH4 (390 mg, 10.4 mmol, 1.5 equivalents) was added at 0°C to a stirred solution of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (2 g, 6.9 mmol, 1 equivalent) in EtOH (40 mL). The resulting mixture was stirred at room temperature for 2 hours, quenched with water (50 mL) added at 0°C, and extracted twice with EtOAc (50 mL). The combined organic layer was washed twice with water (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 2.08 g of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea as a yellow solid. LCMS-APCI(POS.) m / z: 291(M+H) + .

[1413] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (intermediate 16)

[1414]

[1415] SOCl2 (1.65 g, 13.9 mmol, 2 equivalents) was added at 0°C to a stirred solution of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (2 g, 6.9 mmol, 1 equivalent) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 2.2 g of 1-[4-(chloromethyl)phenyl]-3-[(4-chlorophenyl)methyl]urea as a brown solid. LCMS-APCI(POS.) m / z: 309(M+H) + .

[1416] Example Q

[1417] Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-deoxydotetrahydrothiophene-3-yl)(methyl)amino)methyl)phenyl)urea (intermediates 17.1 to 17.6)

[1418]

[1419] STAB (440.43 mg, 2.078 mmol, 2 equivalents) was added at 0°C to a stirred mixture of 3-[(4-chlorophenyl)methyl]-1-(4-formylphenyl)urea (intermediate 3.2, 300.00 mg, 1.039 mmol, 1.00 equivalents) and 3-aminotetrahydrothiophene 1,1-dioxide (168.55 mg, 1.247 mmol, 1.2 equivalents) in DCE (10 mL). The resulting mixture was stirred overnight at room temperature, concentrated under reduced pressure, purified by C18 column chromatography, and eluted with water (0.05% NH4HCO3):ACN (2:1) to obtain 240 mg of 1-(4-chlorobenzyl)-3-(4-(((1,1-deoxydotetrahydrothiophene-3-yl)amino)methyl)phenyl)urea (56.63%) as a white solid. LCMS-APCI(POS.) m / z: 408(M+H) + .

[1420] Intermediates 17.2 to 17.6 were prepared in a manner similar to intermediate 17.1.

[1421]

[1422] Example R

[1423] Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-deoxydotetrahydrothiophene-3-yl)(methyl)amino)methyl)phenyl)urea (intermediates 18.1 to 18.2)

[1424]

[1425] STAB (124.70 mg, 0.588 mmol, 2 equivalents) and AcOH (35.33 mg, 0.588 mmol, 2 equivalents) were added at 0°C to a stirred mixture of 1-(4-chlorobenzyl)-3-(4-(((1,1-deoxydotetrahydrothiophene-3-yl)(methyl)amino)methyl)phenyl)urea (120.00 mg, 0.294 mmol, 1.00 equivalents) and formaldehyde (53.00 mg, 1.765 mmol, 6 equivalents) in DCE (4.00 mL). After stirring at room temperature for 2 hours, additional formaldehyde (53.00 mg, 1.765 mmol, 6 equivalents) and STAB (124.70 mg, 0.588 mmol, 2 equivalents) were added to the mixture. The resulting mixture was stirred overnight at room temperature, the pH was adjusted to 10 using NH3H2O ​​(2 mL), and the mixture was extracted twice with DCM (10 mL). The combined organic layer was washed twice with water (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and extracted by preparative HPLC under the following conditions (Column XBridge Prep OBD C 18 Column, 30*150 mm 5 µm; Mobile phase A: water (10 mMOL / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26 B to 56 B at 9 min; 50 mg of 1-(4-chlorobenzyl)-3-(4-(((1,1-deoxydotetrahydrothiophene-3-yl)(methyl)amino)methyl)phenyl)urea (40.28%) was obtained as a white solid by purification at 254 nm. LCMS-APCI(POS.) m / z: 422 (M+H) + .

[1426] Intermediate 18.2 was prepared in a manner similar to intermediate 18.1.

[1427]

[1428] Example S

[1429] Synthesis of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (intermediate 19)

[1430] Step 1: Preparation of 2-amino-1-(4-nitrophenyl)ethane-1-one hydrochloride (intermediate 19-a)

[1431]

[1432] Hexamethylenetetramine (85.00 g, 607.143 mmol, 1.30 equivalents) was added to a solution of 2-amino-1-(4-bromophenyl)ethanol (100.00 g, 467.154 mmol, 1.00 equivalents) in DCM (1.20 L). The resulting mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with CH2Cl2 (500 mL). HCl (200.00 mL, 6 mol / L) and EtOH (1.00 L) were added to the residue. The resulting mixture was stirred at room temperature for 3 hours and left overnight. The precipitated solid was collected by filtration, washed with hexane (500 mL), and concentrated under vacuum to obtain 140 g of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride (crude) as a light brown solid. LCMS-APCI(POS.) m / z: 181(M+H) + .

[1433] Step 2: Preparation of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19)

[1434]

[1435] To a solution of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride (140.00 g, 646.293 mmol, 1.00 equivalent) in DCM (1.60 L), a solution of K2CO3 (179.00 g, 1295.173 mmol, 2.00 equivalent) in H2O (700.00 mL) and di-tert-butyl dicarbonate (169.00 g, 774.345 mmol, 1.20 equivalent) were added. The resulting mixture was stirred at room temperature for 3 hours and extracted twice with CH2Cl2 (1 L). The combined organic layer was washed twice with brine (1 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 176 g of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (crude) as a brown oil. LCMS-APCI(POS.) m / z: 225(M+H-56) + .

[1436] Example T

[1437] Synthesis of 5-(4-nitrophenyl)piperazine-2-one (intermediate 20)

[1438] Step 1: Preparation of methyl (2-((tert-butoxycarbonyl)amino)-1-(4-nitrophenyl)ethyl)glycinate (intermediate 20-a)

[1439]

[1440] A solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl] carbamate (14.00 g, 49.950 mmol, 1.00 equivalent) and methyl 2-aminoacetate hydrochloride (12.61 g, 100.400 mmol, 2.01 equivalent) in MeOH (200.00 mL) was stirred at room temperature for 30 minutes. Subsequently, NaBH3CN (6.22 g, 98.901 mmol, 1.98 equivalent) was added to the resulting mixture at 0°C. The resulting mixture was stirred overnight at 70°C, cooled to room temperature, adjusted to pH 8 using saturated NH4H2O (aq.), and extracted twice with EtOAc (200 mL). The combined organic phase was washed twice with water (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 17 g (crude) of methyl 2-([2-[(tert-butoxycarbonyl)amino]-1-(4-nitrophenyl)ethyl]amino)acetate as a brown oil. LCMS-APCI(POS.) m / z: 354(M+H) + .

[1441] Step 2: Preparation of 2-((2-methoxy-2-oxoethyl)amino)-2-(4-nitrophenyl)ethane-1-aminium 2,2,2-trifluoroacetate (intermediate 20-b)

[1442]

[1443] TFA (40.00 mL, 188.483 mmol, 20.18 equivalents) was added at room temperature 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 equivalents) in DCM (200.00 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain 7 g (crude) of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate TFA salt as a brown oil. LCMS-APCI(POS.) m / z: 254(M+H) + .

[1444] Step 3: Preparation of 5-(4-nitrophenyl)piperazine-2-one (intermediate 20)

[1445]

[1446] A solution of methyl 2-[[2-amino-1-(4-nitrophenyl)ethyl]amino]acetate TFA salt (7.00 g, 27.640 mmol, 1.00 equivalent) in NH3 (g) in MeOH (70.00 mL) was stirred at 70°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by grinding with EtOAc (100 mL). The precipitated solid was collected by filtration, washed twice with EtOAc (100 mL), and concentrated under reduced pressure to obtain 2 g (32.71%) of 5-(4-nitrophenyl)piperazine-2-one as a brown solid. LCMS-APCI(POS.) m / z: 222 (M+H) + .

[1447] Example U

[1448] Synthesis of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (intermediate 21)

[1449] Step 1: Preparation of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (intermediate 21-a)

[1450]

[1451] (Boc)2O (1479.87 mg, 6.781 mmol, 3 equivalents) and TEA (914.85 mg, 9.041 mmol, 4 equivalents) were added to a stirred solution of 5-(4-nitrophenyl)piperazine-2-one (500.00 mg, 2.260 mmol, 1.00 equivalent) in DCM (10.00 mL). The resulting mixture was stirred overnight at room temperature, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 380 mg (52.32%) of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate as a yellow oil. LCMS-APCI(POS.) m / z: 322(M+H) + .

[1452] Step 2: Preparation of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21)

[1453]

[1454] CH3I (463.81 mg, 3.268 mmol, 3 equivalents) and Cs2CO3 (1419.55 mg, 4.357 mmol, 4 equivalents) were added to a stirred solution of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (350.00 mg, 1.089 mmol, 1.00 equivalents) in DMF (8.00 mL). The resulting mixture was stirred at room temperature for 2 hours, filtered to remove the solid, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (5:2) to obtain 230 mg (62.97%) of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate as a yellow oil. LCMS-APCI(POS.) m / z: 336(M+H) + .

[1455] Example V

[1456] Synthesis of 4-methyl-5-(4-nitrophenyl)piperazine-2-one (intermediate 22)

[1457] Preparation of 4-methyl-5-(4-nitrophenyl)piperazine-2-one (intermediate 22)

[1458]

[1459] HCHO (813.68 mg, 27.120 mmol, 10.00 equivalents), NaBH3CN (340.89 mg, 5.425 mmol, 2 equivalents), and AcOH (530.00 mg, 8.826 mmol, 3.25 equivalents) were added to a stirred solution of 5-(4-nitrophenyl)piperazine-2-one (600.00 mg, 2.712 mmol, 1.00 equivalents) in MeOH (10.00 mL). The resulting mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with DCM / MeOH (20:1) to obtain 800 mg of 4-methyl-5-(4-nitrophenyl)piperazine-2-one as a yellow solid. LCMS-APCI(POS.) m / z: 236(M+H) + .

[1460] Example W

[1461] Synthesis of 1,4-dimethyl-5-(4-nitrophenyl)piperazine-2-one (intermediate 23)

[1462] Preparation of 1,4-dimethyl-5-(4-nitrophenyl)piperazine-2-one (intermediate 23)

[1463]

[1464] NaH (361.60 mg, 9.041 mmol, 4.00 equivalents, 60%) was added at 0°C to a stirred solution of 5-(4-nitrophenyl)piperazine-2-one (500.00 mg, 2.260 mmol, 1.00 equivalents) in DMF (10.00 mL). After stirring for 30 minutes at 0°C, CH3I (962.45 mg, 6.781 mmol, 3.00 equivalents) was added to the resulting mixture at 0°C. The resulting mixture was stirred overnight at room temperature, purified by C18 column chromatography, and eluted with water (0.05% NH4HCO3) / ACN (4:1) to obtain 390 mg (69.22%) of 1,4-dimethyl-5-(4-nitrophenyl)piperazine-2-one as a brown solid. LCMS-APCI(POS.) m / z: 250(M+H) + .

[1465] Example X

[1466] Synthesis of 1,4-dimethyl-6-(4-nitrophenyl)piperazine-2-one (intermediate 24)

[1467] Step 1: Preparation of tert-butyl(2-amino-2-(4-nitrophenyl)ethyl)carbamate (intermediate 24-a)

[1468]

[1469] NH4OAc (14.00g, 181.624 mmol, 2.55 equivalents) and NaBH3CN (110.00g, 1750.422 mmol, 24.53 equivalents) were added at 0°C to a solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (20.00g, 71.357 mmol, 1.00 equivalents) in MeOH (400.00 mL). The resulting mixture was stirred overnight at 70°C, cooled to room temperature, adjusted to pH 8 using saturated NH3H2O, and extracted twice with CH2Cl2 (1 L). The combined organic layer was washed twice with brine (1 L), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with MeOH / EtOAc (1:20) to obtain 6.7 g of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (33.38%) as a brown oil and 2.8 g of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate as a brown solid. LCMS-APCI(POS.) m / z: 226(M+H-56) + .

[1470] Step 2: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (intermediate 24-b)

[1471]

[1472] Gaseous HCl in 1,4-dioxane (30.00 mL) was added to a solution of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (4.60 g, 16.371 mmol, 1.00 equivalent) in DCM (40 mL). The resulting mixture was stirred at room temperature for 3 hours, the pH was adjusted to 13–14 with NaOH (aq), and the mixture was extracted twice with DCM:MeOH (10:1, 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 2.3 g of 1-(4-nitrophenyl)ethane-1,2-diamine as a light brown oil. LCMS-APCI(POS.) m / z: 182 (M+H)+ .

[1473] Step 3: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (intermediate 24-c)

[1474]

[1475] K2CO3 (5.95g, 43.052mmol, 3.00 equivalents) and ethyl chloroacetate (1.76g, 14.349mmol, 1.00 equivalents) were added to a solution of 1-(4-nitrophenyl)ethane-1,2-diamine (2.60g, 14.349mmol, 1.00 equivalents) in ACN (26.00mL). After stirring overnight at room temperature, EtOH (4.00mL) was added to the resulting mixture. The resulting mixture was stirred at 80°C for 3 hours, cooled to room temperature, and filtered to remove the solid. The filtered solution was concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with DCM / MeOH (10:1) to obtain 2.2 g of 6-(4-nitrophenyl)piperazine-2-one (69.31%) as a brown solid. LCMS-APCI(POS.) m / z: 222(M+H) + .

[1476] Step 4: Preparation of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (intermediate 24-d)

[1477]

[1478] Di-tert-butyl dicarbonate (1.18 g, 5.407 mmol, 1.20 equivalents) was added to a solution of 6-(4-nitrophenyl)piperazine-2-one (1.00 g, 4.520 mmol, 1.00 equivalents) and TEA (914.00 mg, 9.033 mmol, 2.00 equivalents) in DCM (10.00 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted twice with DCM (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 1.1 g of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (crude) as a yellow semi-solid. LCMS-APCI(POS.) m / z: 266 (M+H-56) + .

[1479] Step 5: Preparation of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (intermediate 24-e)

[1480]

[1481] Cs2CO3 (2.20g, 6.752mmol, 1.97 equivalents) and methyl iodide (534.48mg, 3.766mmol, 1.10 equivalents) were added to a solution of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (1.10g, 3.423mmol, 1.00 equivalents) in DMF (25.00mL). The resulting mixture was stirred at room temperature for 2 hours and extracted twice with EtOAc (30mL). The combined organic layer was washed twice with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (1:4) to obtain 530 mg of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (46.17%) as a yellow semi-solid. LCMS-APCI(POS.) m / z: 300(M+H-56) + .

[1482] Step 6: Preparation of 1-methyl-6-(4-nitrophenyl)piperazine-2-one hydrochloride (intermediate 24-f)

[1483]

[1484] Gaseous HCl in 1,4-dioxane (2.00 mL, 4 mol / L) was added to a solution of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (530.00 mg, 1.580 mmol, 1.00 equivalent) in DCM (8.00 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 550 mg (crude) of 1-methyl-6-(4-nitrophenyl)piperazine-2-one hydrochloride as an orange semi-solid. LCMS-APCI(POS.) m / z: 236(M+H) + .

[1485] Step 7: Preparation of 1,4-dimethyl-6-(4-nitrophenyl)piperazine-2-one (intermediate 24)

[1486]

[1487] Gaseous HCl in 1,4-dioxane (2.00 mL, 4 mol / L) was added to a solution of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (530.00 mg, 1.580 mmol, 1.00 equivalent) in DCM (8.00 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 550 mg (crude) of 1-methyl-6-(4-nitrophenyl)piperazine-2-one hydrochloride as an orange semi-solid. LCMS-APCI(POS.) m / z: 250 (M+H) + .

[1488] Example Y

[1489] Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazine-2-one (intermediate 25.1 to intermediate 25.2)

[1490] Preparation of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazine-2-one (intermediate 25.1)

[1491]

[1492] 1-methylpiperazine-2-one (202.00 mg, 1.770 mmol, 1.50 equivalents) was added to a solution of 2-fluoro-4-nitrobenzaldehyde (200.00 mg, 1.183 mmol, 1.00 equivalents) in MeOH (5.00 mL). After stirring at room temperature for 30 minutes, AcOH (142.00 mg, 2.365 mmol, 2.00 equivalents) and NaBH3CN (151.00 mg, 2.403 mmol, 2.03 equivalents) were added to the mixture. The resulting mixture was stirred overnight at room temperature, pH adjusted with NH3H2O, concentrated under vacuum, purified by C18 column chromatography, and eluted with water (0.05% NH4HCO3) / ACN (2:1) to obtain 80 mg of 4-[(2-fluoro-4-nitrophenyl)methyl]-1-methylpiperazine-2-one (25.31%) as a yellow oil. LCMS-APCI(POS.) m / z: 268(M+H) + .

[1493] Intermediate 25.2 was prepared in a manner similar to intermediate 25.1.

[1494]

[1495] Example Z

[1496] Synthesis of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazine-2-one (intermediate 26)

[1497] Step 1: Preparation of tert-butylmethyl(2-((1-(4-nitrophenyl)ethyl)amino)ethyl)carbamate (intermediate 26-a)

[1498]

[1499] NaBH3CN (1.44g, 22.956mmol, 2 equivalents) and AcOH (1.38g, 22.956mmol, 2 equivalents) were added at 0°C to a stirred solution of PNAP (2.27g, 13.774mmol, 1.2 equivalents) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.00g, 11.478mmol, 1.00 equivalents) in MeOH (30mL). The resulting mixture was stirred overnight at room temperature, adjusted to pH 8 using saturated NH4H2O (aq.), and extracted twice with EtOAc (50mL). The combined organic phase was washed twice with water (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (2:3) to obtain 2.8 g (75.43%) of tert-butyl N-methyl-N-(2-[[1-(4-nitrophenyl)ethyl]amino]ethyl)carbamate as a pale yellow oil. LCMS-APCI(POS.) m / z: 268(M+H-56) + .

[1500] Step 2: Preparation of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)acetamido)ethyl)(methyl)carbamate (intermediate 24-b)

[1501]

[1502] NaBH3CN (1.44g, 22.956mmol, 2 equivalents) and AcOH (1.38g, 22.956mmol, 2 equivalents) were added at 0°C to a stirred solution of PNAP (2.27g, 13.774mmol, 1.2 equivalents) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.00g, 11.478mmol, 1.00 equivalents) in MeOH (30mL). The resulting mixture was stirred overnight at room temperature, adjusted to pH 8 using saturated NH4H2O (aq.), and extracted twice with EtOAc (50mL). The combined organic phase was washed twice with water (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (2:3) to obtain 2.8 g (75.43%) of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)acetamido)ethyl)(methyl)carbamate) as a pale yellow oil. LCMS-APCI(POS.) m / z: 400(M+H) + .

[1503] Step 3: Preparation of 2-chloro-N-(2-(methylamino)ethyl)-N-(1-(4-nitrophenyl)ethyl) acetamide hydrochloride (intermediate 26-c)

[1504]

[1505] Gaseous HCl in 1,4-dioxane (30.00 mL) was added to a stirred solution of tert-butyl N-(2-[2-chloro-N-[1-(4-nitrophenyl)ethyl]acetamido]ethyl)-N-methylcarbamate (3.00 g, 7.502 mmol, 1.00 equivalent) in DCM (30.00 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain 3.1 g of 2-chloro-N-[2-(methylamino)ethyl]-N-[1-(4-nitrophenyl)ethyl]acetamide hydrogen chloride as a light brown solid. LCMS-APCI(POS.) m / z: 300(M+H) + .

[1506] Step 4: Preparation of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazine-2-one (intermediate 26)

[1507]

[1508] K2CO3 (7.15 g, 51.735 mmol, 5.00 equivalents) was added to a stirred solution of 2-chloro-N-[2-(methylamino)ethyl]-N-[1-(4-nitrophenyl)ethyl]acetamide hydrogen chloride (3.10 g, 10.342 mmol, 1.00 equivalents) in ACN (50.00 mL). The resulting mixture was stirred at 80°C for 1 hour, cooled to room temperature, and filtered to remove the solid. The filtered solution was concentrated under reduced pressure to obtain 1.69 g of 4-methyl-1-[1-(4-nitrophenyl)ethyl]piperazine-2-one as a yellow oil. LCMS-APCI(POS.) m / z: 264(M+H) + .

[1509] Example AA

[1510] Synthesis of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidine-3-yl)amino)methyl)phenyl)urea (intermediate 27.1-intermediate 27.4)

[1511] Step 1: Preparation of phenyl(4-formylphenyl)carbamate (intermediate 27-a)

[1512]

[1513] To a stirred solution of 4-aminobenzaldehyde (2.00 g, 16.510 mmol, 1.00 equivalent) in THF (40.00 mL), a solution of K2CO3 (4.56 g, 32.994 mmol, 2.00 equivalent) in H2O (10.00 mL) at 0°C and phenyl chloroformate (3.87 g, 24.717 mmol, 1.50 equivalent) were added dropwise over a period of 10 minutes. The resulting mixture was stirred at room temperature for 1 hour and extracted twice with EtOAc (50 mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous MgSO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (10:1) to obtain 1.9 g of phenyl N-(4-formylphenyl)carbamate (84.41%) in yellow. LCMS-APCI(POS.) m / z: 242(M+H) + .

[1514] Step 2: Preparation of phenyl(4-(((2-oxopyrrolidine-3-yl)amino)methyl)phenyl)carbamate (intermediate 27-b)

[1515]

[1516] 3-aminopyrrolidine-2-one (508.00 mg, 5.074 mmol, 2.04 equivalents), STAB (1056.00 mg, 4.983 mmol, 2.00 equivalents), and AcOH (299.00 mg, 4.979 mmol, 2.00 equivalents) were added to a stirred solution of phenyl N-(4-formylphenyl)carbamate (600.00 mg, 2.487 mmol, 1.00 equivalents) in DCE (10.00 mL). The resulting mixture was stirred overnight at room temperature and extracted twice with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous MgSO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with CH2Cl2 / MeOH (12:1) to obtain 415 mg of phenyl N-(4-[[(2-oxopyrrolidine-3-yl)amino]methyl]phenyl)carbamate (46.87%) as a grayish-white foam. LCMS-APCI(POS.) m / z: 326(M+H) + .

[1517] Step 3: Preparation of phenyl(4-((methyl(2-oxopyrrolidine-3-yl)amino)methyl)phenyl)carbamate (intermediate 27-c)

[1518]

[1519] Paraformaldehyde (369.00 mg, 4.096 mmol, 3.33 equivalents) and NaBH3CN (155.00 mg, 2.467 mmol, 2.01 equivalents) were added to a stirred solution of phenyl N-(4-[[(2-oxopyrrolidine-3-yl)amino]methyl]phenyl)carbamate (400.00 mg, 1.229 mmol, 1.00 equivalents) in MeOH (8.00 mL, 197.591 mmol, 160.72 equivalents). The resulting mixture was stirred overnight at room temperature, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (1:1) to obtain 380 mg of phenyl (4-((methyl(2-oxopyrrolidine-3-yl)amino)methyl)phenyl)carbamate (79.65%) as a grayish-white solid. LCMS-APCI(POS.) m / z: 340 (M+H)+ .

[1520] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidine-3-yl)amino)methyl)phenyl)urea (intermediate 27)

[1521]

[1522] TEA (149.00 mg, 1.472 mmol, 5.00 equivalents) and 1-(4-chlorophenyl)methaneamine (62.40 mg, 0.441 mmol, 1.50 equivalents) were added to a stirred solution of phenyl N-(4-[[methyl(2-oxopyrrolidine-3-yl)amino]methyl]phenyl)carbamate (100.00 mg, 0.295 mmol, 1.00 equivalents) in THF (2.00 mL, 24.686 mmol, 83.78 equivalents). The resulting mixture was stirred overnight at 60°C, concentrated under reduced pressure, and preparatively analyzed by HPLC under the following conditions (2#SHIMADZU(HPLC-01)): Column, XBridge Prep OBD C 18 Column, 30*150 mm 5 µm; Mobile phase A: water (10 mMOL / L NH4HCO3 + 0.1% NH3H2O) and Mobile phase B: ACN (25% of Phase B to 55% in 8 min); Detector, UV 254 nm. Purified to obtain 60 mg of 3-[(4-chlorophenyl)methyl]-1-(4-[[methyl(2-oxopyrrolidine-3-yl)amino]methyl]phenyl)urea (52.64%) as a white solid. LCMS-APCI(POS.) m / z: 387(M+H)+.

[1523] Intermediates 27.2 to 27.4 were prepared in a manner similar to intermediate 27.1.

[1524]

[1525] Example BB

[1526] Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (intermediate 28)

[1527] Step 1: Preparation of tert-butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate (intermediate 28-a)

[1528]

[1529] NaBH4 (1.02 g, 26.961 mmol, 1.51 equivalents) was added at 0°C to a solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (5.00 g, 17.839 mmol, 1.00 equivalents) in EtOH (100.00 mL). The resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere, concentrated under reduced pressure, and extracted three times with EtOAc (50 mL). The combined organic layer was washed three times with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (4:1) to obtain 1.2 g of tert-butyl N-[2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate as a yellow solid. LCMS-APCI(POS.) m / z: 227(M+H-56) + .

[1530] Step 2: Preparation of 2-amino-1-(4-nitrophenyl)ethane-1-ol hydrochloride (intermediate 28-b)

[1531]

[1532] Gaseous HCl in 1,4-dioxane (5.50 mL, 96.346 mmol, 12.95 equivalents) was added to a solution of tert-butyl N-[2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (2.10 g, 7.439 mmol, 1.00 equivalents) in DCM (22.00 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and concentrated under reduced pressure to obtain 1.9 g of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride as an orange solid. LCMS-APCI(POS.) m / z: 183(M+H) + .

[1533] Step 3: Preparation of 5-(4-nitrophenyl)oxazolidin-2-one (intermediate 28)

[1534]

[1535] Triphosgene (309.00 mg, 1.041 mmol, 0.28 equivalents) was added at 0°C to a solution of 2-amino-1-(4-nitrophenyl)ethanol hydrochloride (800.00 mg, 3.659 mmol, 1.00 equivalents) and TEA (1.59 g, 15.713 mmol, 4.29 equivalents) in THF (10.00 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours, quenched with MeOH (30 mL) at 0°C, and concentrated under reduced pressure to obtain 700 mg of 5-(4-nitrophenyl)-1,3-oxazolidin-2-one as a red solid. LCMS-APCI(POS.) m / z: 209(M+H) + .

[1536] Example CC

[1537] Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazine-2-one (intermediate 29)

[1538] Preparation of 3-methyl-5-(4-nitrophenyl)oxazolidin-2-one (intermediate 29)

[1539]

[1540] Cs2CO3 (6.13g, 18.814mmol, 4.00 equivalents) and CH3I (736.00mg, 5.185mmol, 1.10 equivalents) were added to a stirred solution of 5-(4-nitrophenyl)-1,3-oxazolidin-2-one (980.00mg, 4.708mmol, 1.00 equivalents) in DMF (20.00mL). The resulting mixture was stirred at room temperature for 4 hours and extracted three times with EtOAc (50mL). The combined organic layer was washed three times with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 330 mg of 3-methyl-5-(4-nitrophenyl)-1,3-oxazolidin-2-one as a yellow solid. LCMS-APCI(POS.) m / z: 223(M+H) + .

[1541] Example DD

[1542] Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (intermediate 30.1-30.2)

[1543] Step 1: Preparation of methyl-4-oxo-4-(pyridine-3-yl)butanoate (intermediate 30-a)

[1544]

[1545] Et3N (9.40g, 93mmol, 2.00 equivalents) and 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride (1.26g, 4.67mmol, 0.10 equivalents) were added under a nitrogen atmosphere to a solution of 3-pyridinecarboxaldehyde (5.00g, 46.7mmol, 1.00 equivalents) and methyl acrylate (4.80g, 56.0mmol, 1.20 equivalents) in EtOH (50mL). The resulting mixture was stirred overnight at 50°C under a nitrogen atmosphere, cooled to room temperature, concentrated under reduced pressure, and extracted twice with EtOAc (100mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (4:1) to obtain 2.19 g of methyl 4-oxo-4-(pyridine-3-yl)butanoate as a yellow solid. LCMS-APCI(POS.) m / z: 194(M+H) + .

[1546] Step 2: Preparation of 1-(4-nitrobenzyl)-5-(pyridine-3-yl)pyrrolidin-2-one (intermediate 30.1)

[1547]

[1548] NaBH3CN (2.80g, 17.8mmol, 2.00 equivalents) and AcOH (2.67g, 17.8mmol, 2.00 equivalents) were added at 0°C to a solution of methyl 4-oxo-4-(pyridine-3-yl)butanoate (1.72g, 8.9mmol, 1.00 equivalents) and p-nitrobenzylamine (2.00g, 10.688mmol, 1.20 equivalents) in MeOH (20.00mL). The resulting mixture was stirred at 70°C for 2 days, cooled to room temperature, concentrated under reduced pressure, and extracted twice with EtOAc (50mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with EtOAc to obtain 1 g of 1-[(4-nitrophenyl)methyl]-5-(pyridine-3-yl)pyrrolidin-2-one as a pale yellow oil. LCMS-APCI(POS.) m / z: 298(M+H) + .

[1549] Intermediate 30.2 was prepared in a manner similar to intermediate 30.1.

[1550]

[1551] Example EE

[1552] Synthesis of 1-(1-(4-nitrophenyl)ethyl)piperidin-2-one (intermediate 31)

[1553]

[1554] STAB (2.500g, 1.18mmol, 1.98 equivalents) and AcOH (700mg, 1.17mmol, 1.95 equivalents) were added to a stirred mixture of methyl 5-aminopentanoate hydrochloride (1.00g, 0.60mmol, 1.00 equivalents) and PNAP (1.300g, 0.79mmol, 1.32 equivalents) in DCE (10.00mL). The resulting mixture was stirred at room temperature for 2 days, adjusted to pH 8 using saturated NaHCO3 (aq.), and extracted twice with EtOAc (20mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (1:8) to obtain 1 g of 1-[1-(4-nitrophenyl)ethyl]piperidin-2-one (67.52%) as a yellow solid. LCMS-APCI(POS.) m / z: 249 (M+H) + .

[1555] Example FF

[1556] Synthesis of 1-(4-(1,1-deoxydothiomorpholine-3-yl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 32)

[1557] Step 1: Preparation of tert-butyl(2-((2-(4-nitrophenyl)-2-oxoethyl)thio)ethyl)carbamate (intermediate 32-a)

[1558]

[1559] NaI (1.47 g, 9.834 mmol, 0.30 equivalents) and 2-bromo-1-(4-nitrophenyl)ethanolone (8.00 g, 32.781 mmol, 1.00 equivalents) were added at 0°C to a stirred solution of 2-bromo-1-(4-nitrophenyl)ethanolone (8.00 g, 32.781 mmol, 1.00 equivalents) and DIEA (8.47 g, 65.562 mmol, 2.00 equivalents) in ACN (80.00 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was determined by LCMS. Water (200 mL) was added, the mixture was adjusted to pH 7 using HC (aq.), and extracted three times with EtOAc (200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (20:1) to obtain 8.9 g of tert-butyl N-(2-[[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl]ethyl)carbamate (79.76%) as a yellow solid. LCMS-APCI(POS.) m / z: 285(M+H-56) + .

[1560] Step 2: Preparation of tert-butyl(2-((2-(4-nitrophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (intermediate 32-b)

[1561]

[1562] m-CPBA (22.586 g, 130.419 mmol / L, 5 equivalents) was added to a stirred mixture of tert-butyl N-(2-{[2-(4-nitrophenyl)-2-oxoethyl]sulfanyl}ethyl)carbamate (8.9 g, 26.092 mmol / L, 1 equivalent) in DCM (100 mL). The resulting mixture was stirred overnight at room temperature, water (100 mL) was added, and the mixture was extracted three times with EtOAc (200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EA (4:1) to obtain 7 g of tert-butyl N-{2-[2-(4-nitrophenyl)-2-oxoethanesulfonyl]ethyl}carbamate as a light brown solid. LCMS-APCI(POS.) m / z: 317(M+H-56) + .

[1563] Step 3: Preparation of tert-butyl(2-((2-(4-aminophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (intermediate 32-c)

[1564]

[1565] To a stirred mixture of tert-butyl N-{2-[2-(4-nitrophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (7 g, 18.761 mmol / L, 1 equivalent) in EtOH (80 mL), a solution of iron (4.2 g, 75.061 mmol / L, 4 equivalents) and NH4Cl (6.9 g, 131.327 mmol / L, 7 equivalents) in H2O (16 mL) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with CH2Cl2 / MeOH (50:1) to obtain 5.3 g of tert-butyl-N-{2-[2-(4-aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (77.69%) as a light brown solid. LCMS-APCI(POS.) m / z: 287(M+H-56) + .

[1566] Step 4: Preparation of tert-butyl(2-((2-oxo-2-(4-((phenoxycarbonyl)amino)phenyl)ethyl)sulfonyl)ethyl)carbamate (intermediate 32-d)

[1567]

[1568] Phenyl chloroformate (2.05 g, 13.093 mmol, 1.49 equivalents) was added dropwise over a period of 10 minutes at 0°C to a solution of tert-butyl N-{2-[2-(4-aminophenyl)-2-oxoethanesulfonyl]ethyl}carbamate (3 g, 8.761 mmol, 1.00 equivalents) in THF (30 mL). The resulting mixture was stirred at room temperature for 2 hours, then gradually heated to 80°C and stirred overnight at 80°C, cooled to room temperature, concentrated under reduced pressure, ground with hexane:EA=10:1 (30 mL) for purification, and concentrated under reduced pressure to obtain 3.7 g of phenyl N-[4-(2-{2-[(tert-butoxycarbonyl)amino]ethanesulfonyl}acetyl)phenyl]carbamate (91.31%) as a brown solid. LCMS-APCI(POS.) m / z: 407(M+H-56) + .

[1569] Step 5: Preparation of tert-butyl(2-((2-(4-(3-(4-methoxybenzyl)ureido)phenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (intermediate 32-e)

[1570]

[1571] 4-methoxy-benzenemethaneamine (0.4g, 2.916mmol, 1.23 equivalents) and DIEA (0.9g, 6.964mmol, 2.93 equivalents) were added to a solution of phenyl N-[4-(2-{2-[(tert-butoxycarbonyl)amino]ethanesulfonyl}acetyl)phenyl]carbamate (1.1g, 2.378mmol, 1.00 equivalents) in i-PrOH (11mL). The resulting mixture was stirred at 80°C for 4 hours, cooled to room temperature, ground to PE:EA=8:1 (15 mL), purified, and concentrated under reduced pressure to obtain 1.38 g of tert-butyl N-(2-{2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-2-oxoethanesulfonyl}ethyl)carbamate (crude) as a brown solid. LCMS-APCI(POS.) m / z: 450(M+H-56) + .

[1572] Step 6: Preparation of 1-(4-(1,1-deoxydothiomorpholine-3-yl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 32)

[1573]

[1574] HCl (gaseous) in 1,4-dioxane (3 mL, 4 mol / L) was added 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 equivalent) in DCM (12 mL). After stirring at room temperature for 2 hours, the resulting mixture was concentrated under reduced pressure, and NaBH3CN (0.32 g, 5.092 mmol, 2.01 equivalent) and MeOH (12 mL) were added. The resulting mixture was stirred at room temperature for 2 hours, water (30 mL) was added, and the mixture was extracted three times with EtOAc (20 mL). The combined organic layer was washed twice with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 1.1 g (crude) of 1-[4-(1,1-dioxo-1lambda6-thiomorpholine-3-yl)phenyl]-3-[(4-methoxyphenyl)methyl]urea as a brown solid. The crude product (500 mg) was preparatively extracted by HPLC under the following conditions (2#SHIMADZU(HPLC-01)): column, YMC-Actus Triart C 18 230 mg of 1-[4-(1,1-dioxo-1-lambda-6-thiomorpholine-3-yl)phenyl]-3-[(4-methoxyphenyl)methyl]urea was obtained as a white solid by purification under the conditions of ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3H2O) and ACN (from 15% ACN to 45% in 10 min); detector, UV 254 nm, 210 nm. LCMS-APCI(POS.) m / z: 390 (M+H) + .

[1575] Example GG

[1576] Synthesis of 1-(4-(1,1-deoxydothiomorpholine-2-yl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 33)

[1577] Step 1: Preparation of methyl 2-bromo-2-(4-nitrophenyl)acetate (intermediate 33-a)

[1578]

[1579] NBS (6.84 g, 38.427 mmol, 1.5 equivalents) was added to a stirred solution of methyl 2-(4-nitrophenyl)acetate (5 g, 25.618 mmol, 1.00 equivalents) and AIBN (0.21 g, 1.281 mmol, 0.05 equivalents) in CCl4 (50 mL). The resulting mixture was stirred overnight at 80 °C, cooled to room temperature, water (100 mL) was added, and extracted twice with CH2Cl2 (50 mL). The combined organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and C 18 Purification by column chromatography and elution with water (0.05% NH4HCO3) / ACN (1:1) yielded 4.1 g (58.39%) of methyl 2-bromo-2-(4-nitrophenyl)acetate as a yellow oil. LCMS-APCI(POS.) m / z: 274(M+H) + . 1 HNMR(300MHz, DMSO- d 6 ) δ8.34-8.19(m, 2H), 7.89-7.78(m, 2H), 6.17(s, 1H), 3.76(s, 3H).

[1580] Step 2: Preparation of 2-(4-nitrophenyl)thiomorpholine-3-one (intermediate 33-b)

[1581]

[1582] Cysteamine hydrochloride (1.37 g, 12.041 mmol, 1.1 equivalents) and K2CO3 (3.33 g, 24.081 mmol, 2.2 equivalents) were added to a stirred solution of methyl 2-bromo-2-(4-nitrophenyl)acetate (3 g, 10.946 mmol, 1.00 equivalents) in EtOH (30 mL). The resulting mixture was stirred overnight at room temperature, water (50 mL) was added, and the mixture was extracted twice with EA (100 mL). The combined organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EA (1:9) to obtain 1.4 g of 53.68% 2-(4-nitrophenyl)thiomorpholine-3-one as a yellow solid. LCMS-APCI(POS.) m / z: 239(M+H) + .

[1583] Step 3: Preparation of 2-(4-nitrophenyl)thiomorpholine (intermediate 33-c)

[1584]

[1585] BH3-Me2S (2.94 mL, 29.380 mmol, 5 equivalents, 2 mol / L) was added to a stirred solution of 2-(4-nitrophenyl)thiomorpholine-3-one (1.4 g, 5.876 mmol, 1.00 equivalent) in THF (15 mL). The resulting mixture was stirred at 60°C for 1 hour, concentrated under reduced pressure, and HCl (15 mL, 4N) was added to the residue and stirred at 60°C for an additional 30 minutes. The mixture was adjusted to pH 8 using saturated NaHCO3(aq.), concentrated under reduced pressure, and C 18 Purification by column chromatography and elution with water (0.05% NH4HCO3) / ACN (2:1) yielded 590 mg (44.77%) of 2-(4-nitrophenyl)thiomorpholine as a red oil. LCMS-APCI(POS.) m / z: 225(M+H) + .

[1586] Step 4: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (intermediate 33-d)

[1587]

[1588] (Boc)2O (1148.26 mg, 5.262 mmol, 2 equivalents) was added to a stirred solution of 2-(4-nitrophenyl)thiomorpholine (590 mg, 2.631 mmol, 1.00 equivalents) and TEA (798.58 mg, 7.893 mmol, 3 equivalents) in DCM (6 mL). The resulting mixture was stirred overnight at room temperature, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EA (3:1) to obtain 400 mg (46.87%) of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate as a yellow solid. 1 HNMR(300MHz, DMSO- d 6 ) δ8.33-8.17(m, 2H), 7.77-7.66(m, 2H), 7.71-7.54(m, 1H), 6.92(s, 1H), 4.34-4.09(m, 3H), 3.20(ddd, J=13.6, 10.1, 3.2Hz, 1H), 2.88-2.72(m, 1H), 2.77-2.65(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=6.4Hz, 3H), 1.15(s, 1H), 0.99-0.76(m, 2H).

[1589] Step 5: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (intermediate 33-e)

[1590]

[1591] m-CPBA (1063.91 mg, 6.165 mmol, 5 equivalents) was added to a stirred solution of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (400 mg, 1.233 mmol, 1.00 equivalents) in DCM (10 mL). The resulting mixture was stirred overnight at room temperature, saturated Na2SO3 (aq.) (20 mL) was added, and the mixture was extracted twice with EtOAc (20 mL). The combined organic phase was washed twice with saturated NaHCO3 (aq.) (20 mL) and brine (20 mL), dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain 420 mg of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 357(M+H) + .

[1592] Step 6: Preparation of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (intermediate 33-f)

[1593]

[1594] Pd / C (10% Pd, 50% wet with water, 210 mg) was added to a stirred solution of tert-butyl 2-(4-nitrophenyl)-1,1-dioxo-1-lambda-6-thiomorpholine-4-carboxylate (420 mg, 1.178 mmol, 1.00 equivalent) in 5 mL of i-PrOH. The resulting mixture was stirred under H2 at room temperature for 2 hours, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 380 mg of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 327(M+H) + .

[1595] Step 7: Preparation of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide (intermediate 33-g)

[1596]

[1597] Pd / C (10% Pd, 50% wet with water, 210 mg) was added to a stirred solution of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (420 mg, 1.178 mmol, 1.00 equivalent) in i-PrOH (5 mL). The resulting mixture was stirred under H2 at room temperature for 2 hours, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 380 mg of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate-1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 327(M+H) + .

[1598] Step 8: Preparation of 1-(4-(1,1-deoxydothiomorpholine-2-yl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 33)

[1599]

[1600] HCl (gaseous) in 1,4-dioxane (0.5 mL, 4 mol / L) was added to a stirred solution of tert-butyl 2-[4-({[(4-methoxyphenyl)methyl]carbamoyl}amino)phenyl]-1,1-dioxo-1-lambda6-thiomorpholine-4-carboxylate (93 mg, 0.190 mmol, 1.00 equivalents) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, purified by C18 column chromatography, and eluted with water (0.05% NH4HCO3) / ACN (4:1) to obtain 45 mg (60.83%) of 3-[4-(1,1-dioxo-1lambda6-thiomorpholine-2-yl)phenyl]-1-[(4-methoxyphenyl)methyl]urea as a white solid. LCMS-APCI(POS.) m / z: 390(M+H) + .

[1601] Example HH

[1602] Synthesis of N-methyl-N-(4-nitrobenzyl)acetamide (intermediates 34.1 to 34.2)

[1603] Preparation of N-methyl-N-(4-nitrobenzyl)acetamide (intermediate 34)

[1604]

[1605] Acetic anhydride (307 mg, 3.007 mmol, 1.00 equivalent) was added to a stirred mixture of methyl[(4-nitrophenyl)methyl]amine (500 mg, 3.009 mmol, 1.00 equivalent) and TEA (456 mg, 4.506 mmol, 1.50 equivalent) in DCM (4 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted twice with EtOAc (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 630 mg of N-methyl-N-[(4-nitrophenyl)methyl]acetamide as a brown solid. LCMS-APCI(POS.) m / z: 208 (M+H) + .

[1606] Intermediate 30.2 was prepared in a manner similar to intermediate 30.1.

[1607]

[1608] Example II

[1609] Synthesis of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (intermediate 35)

[1610] Step 1: Preparation of tert-butyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (intermediate 35-a)

[1611]

[1612] LiHMDS (53.8 mL in THF, 1 mol / L, 2 equivalents) was added dropwise over a period of 30 minutes under a nitrogen atmosphere at -78°C to a solution of 1-[tert-butoxy(hydroxy)methyl]pyrrolidin-3-one (5 g, 26.704 mmol, 1.00 equivalents) in THF (50 mL). After stirring under a nitrogen atmosphere at -78°C for 1 hour, 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (10.5 g, 29.392 mmol, 1.10 equivalents) was added to the solution under a nitrogen atmosphere at -78°C. The resulting mixture was stirred under a nitrogen atmosphere at -78°C for 2 hours. The product showed no LCMS signal and was determined by TLC. The reaction was quenched with water (50 mL) at 0°C and extracted three times with EtOAc (50 mL). The combined organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 16 g of tert-butyl 3-(trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-1-carboxylate (crude) as a brown oil.

[1613] Step 2: Preparation of tert-butyl-3-(4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (intermediate 35-b)

[1614]

[1615] To a solution of tert-butyl-3-(trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-1-carboxylate (8 g, 12.607 mmol, 1.00 equivalent) and 4-nitrophenylboronic acid (2.5 g, 14.976 mmol, 1.19 equivalent) in dioxane (40 mL), a solution of Pd(dppf)Cl2 (0.9 g, 1.230 mmol, 0.10 equivalent) and K2CO3 (3.5 g, 25.325 mmol, 2.01 equivalent) in H2O (10 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The reaction was determined by LCMS. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EA (6:1) to obtain 2.4 g of tert-butyl-3-(4-nitrophenyl)-2,5-dihydropyrrole-1-carboxylate (65.57%) as a yellow solid. LCMS-APCI(POS.) m / z: 234(M+H-56) + .

[1616] Step 3: Preparation of tert-butyl-3-(4-aminophenyl)pyrrolidine-1-carboxylate (intermediate 35-c)

[1617]

[1618] Pd / C (10% Pd, 50% wet with water, 2.3 g) was added at room temperature to a solution of tert-butyl-3-(4-nitrophenyl)-2,5-dihydropyrrole-1-carboxylate (2.3 g, 7.922 mmol, 1.00 equivalent) in methanol (20 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was determined by LCMS. The resulting mixture was filtered to remove the solid and concentrated under reduced pressure to obtain 1.96 g of brown tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate. LCMS-APCI(POS.) m / z: 206(M+H-56) + .

[1619] Step 4: Preparation of tert-butyl-3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (intermediate 35-d)

[1620]

[1621] Phenyl N-[(4-chlorophenyl)methyl]carbamate (896.6 mg, 3.426 mmol, 1.50 equivalents) and DIEA (590.8 mg, 4.571 mmol, 2.00 equivalents) were added to a solution of tert-butyl-3-(4-aminophenyl)pyrrolidine-1-carboxylate (600 mg, 2.287 mmol, 1.00 equivalents) in i-PrOH (6 mL) at room temperature. The mixture was stirred overnight at 80°C, cooled to room temperature, purified by silica gel column chromatography, and eluted with PE / EA (2:1) to obtain 450 mg of tert-butyl 3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (45.76%) as a yellow semi-solid. LCMS-APCI(POS.) m / z: 347 (M+H-56) + .

[1622] Step 5: Preparation of 1-(4-chlorobenzyl)-3-(4-(pyrrolidin-3-yl)phenyl)urea (intermediate 35-e)

[1623]

[1624] TFA (1 mL) was added at room temperature to a solution of tert-butyl-3-[4-({[(4-chlorophenyl)methyl]carbamoyl}amino)phenyl]pyrrolidin-1-carboxylate (400 mg, 0.930 mmol, 1.00 equivalent) in DCM (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was determined by LCMS. The pH of the resulting mixture was adjusted to 10, and it was extracted three times with CH2Cl2 (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 300 mg of 1-[(4-chlorophenyl)methyl]-3-[4-(pyrrolidin-3-yl)phenyl]urea as a brown semi-solid. LCMS-APCI(POS.) m / z: 330(M+H) + .

[1625] Step 6: Preparation of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidine-3-yl)phenyl)urea (intermediate 35)

[1626]

[1627] MsCl (116.69 mg, 1.019 mmol, 1.2 equivalents) was added at 0°C to a solution of 1-[(4-chlorophenyl)methyl]-3-[4-(pyrrolidin-3-yl)phenyl]urea (280 mg, 0.849 mmol, 1.00 equivalents) and TEA (171.80 mg, 1.698 mmol, 2.00 equivalents) in DCM (4 mL). The resulting mixture was stirred at room temperature for 4 hours and extracted three times with CH2Cl2 (10 mL). The combined organic layer was washed twice with brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by preparative-HPLC under the following conditions (2#SHIMADZU(HPLC-01)): column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (from 30% ACN to 60% for 8 min); detector, UV 254 nm, 210 nm to obtain 230 mg of 1-[(4-chlorophenyl)methyl]-3-[4-(1-methanesulfonylpyrrolidine-3-yl)phenyl]urea (66.42%) as a brown solid. LCMS-APCI(POS.) m / z: 408 (M+H) + .

[1628] Intermediate 35.2 was prepared in a manner similar to intermediate 35.1.

[1629]

[1630] Example JJ

[1631] Synthesis of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (intermediate 36)

[1632] Step 1: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid (intermediate 36-a)

[1633]

[1634] Phenyl N-[(4-chlorophenyl)methyl]carbamate (3.62 g, 13.832 mmol, 1.20 equivalents) was added to a stirred mixture of sulfanylic acid (2 g, 11.548 mmol, 1.00 equivalents) and DIEA (14.91 g, 115.364 mmol, 9.99 equivalents) in isopropyl alcohol (20 mL). The resulting mixture was stirred overnight at 80°C, cooled to room temperature, and C 18 Purification by column chromatography and elution with water (0.05% NH4HCO3) / ACN (20:1) yielded 3.7 g of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid as a brown solid. LC / MS (APCI) m / z: 341[M+H].

[1635] Step 2: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (intermediate 36)

[1636]

[1637] A solution of 4-({[(4-chlorophenyl)methyl]carbamoyl}amino)benzenesulfonic acid (3.5 g, 10.271 mmol, 1.00 equivalent) in thionyl chloride (35 mL) was stirred under a nitrogen atmosphere at 60 °C for 30 minutes. The mixture was cooled to room temp...

Claims

Claim 1 Compound of the following formula (II) or a pharmaceutically acceptable salt thereof. [Formula II] Here, R 1 is a halo or methoxy and;R 6 is hydrogen or a halo; p is 0 or 1, where when p is 1, R 2 is hydrogen or a C1-C6 alkyl or Z 4 and together with intervening atoms, to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C1-C6 alkyl; R 4 is, a) halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 a) aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxos, 5 to 6-membered heteroaryl optionally substituted with one or more independently selected halo or -C1-C6 alkyl substituents, and 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, b) NR f R g C(O)-,c) Z 1 NR a C(O)-,d) Z 2 C(O)NR b -,e) Z 3 (CR c R d ) m NR e -,f) Z 4 S(O)2(CH2) n -,g) Z 5 OC(O)-,h) 5 to 10-membered heteroaryls optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents, i) Z 6 S(O)2N(R s )-,j) Z 7 N(R t )S(O)2-, or k) Z 8 -O-(CH2) q - and; here, R a and R e are each independently hydrogen or C1-C6 alkyl;R b is hydrogen or a C1-C6 alkyl, or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d forms a C3-C6 cycloalkyl group together with the carbon to which they are attached; R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl; and each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 Aryl and; each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl; each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl and R s is hydrogen or -C1-C6 alkyl;R t is hydrogen or -C1-C6 alkyl; m is 0 or 1; n is 0, 1 or 2; q is 0 or 1; and Z 1 and Z 5 are each independently R z Igo;Z 2 and Z 3 Each independently hydrogen or R z and;Z 4 is hydrogen or R z or R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6 is selected from the group consisting of 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, 5 to 6-membered heteroaryl and C1-C6 alkyl; Z 7 C6-C 12 Ariligo;Z 8 is selected from the group consisting of 5 to 6-membered heteroaryls and C3-C6 cycloalkyls; R z is selected from the group consisting of the following, a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyls, and C1-C6 alkoxys; b) C6-C 12 C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls; c) C1-C6 alkoxy; d) halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v are each independently hydrogen or C1-C6 alkyl; e) C6-C 12 Aryl; and f) 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; R 5 is hydrogen or a halo, or R b and together with intervening atoms, it forms a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring, and when p is 0, R 4 is, l) comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, wherein the 3 to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C1-C6 alkyl substituents and optionally further substituted with one or more oxo substituents, m) comprising exactly one cyclic heteroatom.3 to 6-membered heterocycloalkyl or heterocycloalkenyl in which it 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-C6 alkyl substituents, 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, o) 5-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents, p) exactly two cyclic q) a hexacycloalkyl or heterocycloalkenyl comprising heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents, q) a pentagonal aryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal aryl is substituted with exactly one methyl substituent, r) a pentagonal aryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal aryl is substituted with one or more methyl substituents, s) a hexacycloaryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the hexacycloaryl is,. or It is something other than, t) Z 9 -S(O)2-,u) Z 10 -S(O)2-NH-,v) Z 11 -C(O)-NH-,w) Z 12 -CH2-O-,x) Z 13 -O-,y) Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,z) or aa) and, here, Z 9 is cyclopropyl, C6-C 12 Aryl, one or more independently selected R A 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6alkyl), optionally substituted with a substituent, one or more independently selected R B -NH2 substituted with a substituent, and one or more independently selected R C Selected from the group consisting of C1-C6 alkyls optionally substituted with a substituent, except Z 9 Is, It is something other than unsubstituted methyl or unsubstituted ethyl, where R A is -C1-C6 alkyl or -CN and R B is (i) -C1-C6 alkyl-(5 to 10-membered heteroaryl), or (ii) one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl group; R C is a 3 to 8-membered heterocycloalkyl or heterocycloalkenyl; Z 10 is one or more independently selected C6-C 12 It is a C1-C6 alkyl substituted with an aryl substituent; Z 11 C3-C substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents 10 Selected from the group consisting of cycloalkyl and C1-C6alkyl, provided that Z 11 When this is a cycloprofile, R 1 It is something other than methoxy;Z 12 is selected from the group consisting of 5 to 10-membered heteroaryls, 3 to 10-membered heterocycloalkyl or heterocycloalkenyls, C1-C6 alkyls 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); Z 13 is a 5 to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents; Z 14 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; R 5 is hydrogen, provided that (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH and -CH2-thiofuran; (2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, and Other than that; (3) The compound of chemical formula (II) is not the following compound. or Claim 2 In paragraph 1, R 1 A compound characterized by being Cl or F, or a pharmaceutically acceptable salt thereof. Claim 3 In paragraph 1, R 1 A compound characterized by being methoxy or a pharmaceutically acceptable salt thereof. Claim 4 A compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound of formula (II) is a compound of the following formula (IG). [Formula (IG)] Here, R 1 is a halo or methoxy and;R 2 is hydrogen or a C1-C6 alkyl or Z 4 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 3 is hydrogen or C1-C6 alkyl and R 4 is,a) Z 1 NR a C(O)-,b) Z 2 C(O)NR b -,c) Z 3 (CR c R d ) m NR e -,d) Z 4 S(O)2(CH2) n -,e) Z 5 OC(O)-,f) NR f R g C(O)-,g) 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl or C3-C6 cycloalkyl substituents,h) halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 aryl, 3 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxos, 5 to 6-membered heteroaryl optionally substituted with one or more independently selected halo or -C1-C6 alkyl substituents, and 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, i) Z 6 S(O)2N(R s )-,j) Z 7 N(R t )S(O)2-, or k) Z 8 -O-(CH2) q - and; here, R a and R e are each independently hydrogen or C1-C6 alkyl;R b is hydrogen or a C1-C6 alkyl or R 5 and together with intervening atoms to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R c and R d Each is independently hydrogen or a C1-C6 alkyl, or R c and R d forms a C3-C6 cycloalkyl group together with the carbon to which they are attached; R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n , forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl; and each R h is independently a C6-C6 alkyl, -O-C1-C6 alkyl, or optionally substituted with one or more independently selected halo substituents. 12 It is Aryl; each R x is halo, -OH, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -NR o R p Independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl; each R y is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR q R r , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; each R j , R k , R m , R n , R o , R p , R q and R r is independently hydrogen or C1-C6 alkyl and R s is hydrogen or -C1-C6 alkyl;R t is hydrogen or -C1-C6 alkyl; m is 0 or 1; n is 0, 1, or 2; q is 0 or 1; and Z 2 and Z 3 Each independently hydrogen or R z Igo;Z 4 is hydrogen or R z or R 2 and together with intervening atoms to form a 4 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6 is selected from the group consisting of 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, 5 to 6-membered heteroaryl and C1-C6 alkyl; Z 7 C6-C 12 Aril and;Z 8 is selected from the group consisting of 5 to 6-membered heteroaryls and C3-C6 cycloalkyls, and R z is selected from the group consisting of the following: a) -OH, -CN, C3-C6 cycloalkyl, -NHC1-C6 alkyl, C6-C 12 A C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5 to 10-membered heteroaryl, wherein the C6-C 12 The aryl, 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 halos, C1-C6 alkyl and C1-C6 alkoxy; b) C6-C 12 C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkoxy optionally substituted with 5 or 10-membered heteroaryl, wherein the 5 or 10-membered heteroaryl is optionally further substituted with one or more independently selected C1-C6 alkyls; c) C1-C6 alkoxy; d) halo, oxo, -OH, -CN, one or more independently selected R w -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 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 is a halo, -OH, -CN, -C1-C6 alkoxy, -C(O)NR u R v , C6-C 12 Independently selected from the group consisting of aryls and 5 to 6-membered heteroaryls; where R u and R v are each independently hydrogen or C1-C6 alkyl; e) C6-C 12 Aryl; and f) 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; R 5 is hydrogen, halo, or R b and together with intervening atoms, to form a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 6 is hydrogen or halo, Z 1 and Z 5 are each independently R z And, however, (1) R 4 Ga Z 1 NR a When C(O)-, Z 1 It is other than methyl, unsubstituted cyclopropyl, -C(CH3)2CH2OH and -CH2-thiofuran;(2) R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, and Other than that; (3) The compound of chemical formula (IG) is not the following compound. or Claim 5 In paragraph 1, R 2 and R 3 A compound or a pharmaceutically acceptable salt thereof characterized by each being hydrogen. Claim 6 In paragraph 1, R 4 halo, oxo, -OH, -CN, one or more independently selected R y -C1-C6 alkyl optionally substituted with a substituent, -C1-C6 alkoxy, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl optionally substituted with one or more independently selected halo substituents, C6-C optionally substituted with one or more independently selected halo substituents 12 A compound or a pharmaceutically acceptable salt thereof characterized by being a aryl, a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, and a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of a 3 to 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents. Claim 7 In paragraph 1, R 4 A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of the following. Claim 8 In Paragraph 7, R 4 go or A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 9 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (IA) or a pharmaceutically acceptable salt thereof.[Chemical formula (IA)] Claim 10 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (IB) or a pharmaceutically acceptable salt thereof. [Chemical formula (IB)] Claim 11 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (IC) or a pharmaceutically acceptable salt thereof.[Chemical formula (IC)] Claim 12 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (ID) or a pharmaceutically acceptable salt thereof.[Chemical formula (ID)] Claim 13 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (IE) or a pharmaceutically acceptable salt thereof.[Chemical formula (IE)] Claim 14 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following chemical formula (IF) or a pharmaceutically acceptable salt thereof.[Chemical formula (IF)] Claim 15 In Paragraph 14, R f and R g together with the nitrogen to which they are attached, halo, -OH, -CN, oxo, and one or more independently selected R x -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkoxy, -C(O)R optionally substituted with substituents h , -NHC(O)OC1-C6alkyl, -NR j R k , -C(O)NR m R n A compound or a pharmaceutically acceptable salt thereof characterized by forming a 3 to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3 to 6-membered heterocycloalkyl or heterocycloalkenyl and 5 to 6-membered heteroaryl. Claim 16 In Paragraph 14, R f and R g A compound or a pharmaceutically acceptable salt thereof characterized by forming a 5 to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with a -C1-C6 alkyl together with the nitrogen to which they are attached, wherein the -C1-C6 alkyl is optionally substituted with -OH. Claim 17 In Paragraph 14, A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of the following. and Claim 18 In Paragraph 14, go A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 19 A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is a compound of the following formula (II-A) or a pharmaceutically acceptable salt thereof. [Formula (II-A)] Here, R 1 is a halo or methoxy and;R 4 is, l) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents, and m) a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic heteroatom, of 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-C6 alkyl substituents. and ,n) a 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, o) a 5-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents, p) a 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the 6-membered heterocycloalkyl or heterocycloalkenyl is one or more independently selected oxo, -C1-C6 alkyl or -S(O)2-(C1-C6 alkyl) substituents are optionally substituted, q) a pentagonal aryl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the pentagonal aryl is substituted with exactly one methyl substituent, r) a pentagonal aryl comprising exactly two cyclic heteroatoms, both of which are nitrogen atoms, wherein the pentagonal aryl is substituted with one or more methyl substituents, s) a hexagonal aryl comprising one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein the hexagonal aryl is or It is something other than, t) Z 9 -S(O)2-,u) Z 10 -S(O)2-NH-,v) Z 11 -C(O)-NH-,w) Z 12 -CH2-O-,x) Z 13 -O-,y) Z 14 -C(H)(C1-C6alkyl)-NH-C(O)-,z) or aa) and, here, Z 9 is cyclopropyl, C6-C 12 Aryl, one or more independently selected R A 3 to 10-membered heterocycloalkyl or heterocycloalkenyl, -NH(C1-C6alkyl), optionally substituted with a substituent, one or more independently selected R B -NH2 substituted with a substituent and one or more independently selected R C Selected from the group consisting of C1-C6 alkyls optionally substituted with a substituent, except Z 9 Is It is something other than unsubstituted methyl or unsubstituted ethyl, where R A is -C1-C6 alkyl or -CN;R B is (i) -C1-C6 alkyl-(5 to 10-membered heteroaryl), or (ii) one or more independently selected C6-C 12 It is a 5 to 10-membered heteroaryl optionally substituted with an aryl group; R C is a 3 to 8-membered heterocycloalkyl or heterocycloalkenyl; Z 10 is one or more independently selected C6-C 12 It is a C1-C6 alkyl substituted with an aryl substituent; Z 11 C3-C 10 Selected from the group consisting of cycloalkyl, and C1-C6 alkyls substituted with one or more independently selected 3 to 10-membered heterocycloalkyl or heterocycloalkenyl substituents, provided that Z 11 When this is a cycloprofile, R 1 It is something other than methoxy;Z 12 is selected from the group consisting of 5 to 10-membered heteroaryls, 3 to 10-membered heterocycloalkyl or heterocycloalkenyls, C1-C6 alkyls 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); Z 13 is a 5 to 10-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C1-C6 alkyl) substituents; and Z 14 is a 5 to 10-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl substituents; R 6 is hydrogen or a halo, provided that for the compound of the above formula (II-A), R 4 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl, and It is something other than that. Claim 20 In paragraph 1, R 4 A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of the following: a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl substituents and optionally further substituted with one or more oxo substituents; a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly one cyclic heteroatom, of 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-C6 alkyl substituents, 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. Heterocycloalkyl or heterocycloalkenyl, a penterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein the penterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents, and a hexacycloalkyl or heterocycloalkenyl comprising exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein the hexacycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C1-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents. Claim 21 In paragraph 1, R 4 go and A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of Claim 22 In paragraph 1, R 4 a. A compound or a pharmaceutically acceptable salt thereof, characterized in that it comprises exactly two cyclic heteroatoms, both of which are nitrogen atoms, a 3 to 6-membered heterocycloalkyl or heterocycloalkenyl, wherein the 3 to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C1-C6 alkyl substituents and optionally additionally substituted with one or more oxo substituents, or a 6-membered heterocycloalkyl or heterocycloalkenyl comprising exactly two cyclic 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-C6 alkyl, or -S(O)2-(C1-C6 alkyl) substituents. Claim 23 In paragraph 1, R 4 go or A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 24 A compound or a pharmaceutically acceptable salt thereof characterized by being selected from the group consisting of the compounds in Table 1. Claim 25 In paragraph 24, the above compound is A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 26 In paragraph 24, the above compound is A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 27 In paragraph 24, the above compound is A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 28 In paragraph 24, the above compound is A compound or a pharmaceutically acceptable salt thereof characterized by being. Claim 29 Compound of any one of claims 1 to 28 for treating a disease or pathological condition mediated by NAMPT activity in a subject requiring treatment, wherein said disease or pathological condition is cancer, hyperproliferative disease or pathological condition, inflammatory disease or pathological condition, metabolic disorder, heart disease or pathological condition, heart failure, heart failure with preserved ejection fraction, tissue damage caused by chemotherapy, kidney disease, metabolic disease, neurological disease or injury, neurodegenerative disorder or disease, disease caused by impaired stem cell function, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder, obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal neurological injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve damage, A pharmaceutical composition characterized by being selected from the group consisting of polio (poliomyelitis) and spinal cord injury. 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