Compounds useful as ALCAT1 inhibitors

Abstract

ALCAT1 inhibitors having the following general formula are described: These compounds are useful for treating aging and age-related diseases.

Description

Technical Field

[0001] The present invention generally relates to compounds useful as ALCAT1 inhibitors. Such compounds are useful in the treatment of aging and age-related disorders. Background Art

[0002] Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1) is a polyglycerolphospholipid acyltransferase in the endoplasmic reticulum that is primarily known for catalyzing the acylation of monolysocardiolipin and dilysocardiolipin back to cardiolipin.

[0003] Recent studies have implicated the enzyme ALCAT1 in the etiology of oxidative stress and various aging-related diseases, including type 2 diabetes, diabetic complications (nephropathy, retinopathy, and cardiomyopathy), cardiovascular disease, neurological diseases (Parkinson's disease and Alzheimer's disease). ALCAT1 is upregulated by oxidative stress and diet-induced obesity (DIO) and catalyzes the remodeling of cardiolipin (CL) with fatty acyl chains that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, reactive oxygen species (ROS) production, and insulin resistance.

[0004] Dynamic networks are formed when mitochondria undergo fusion events that cause the participating mitochondrial compartments to become continuous. Fusion events allow the components of each network to share solutes, metabolites, and proteins. Therefore, disruption of such networks leads to oxidative stress and mitochondrial fragmentation, which has been implicated in the etiology of aging and age-related diseases.

[0005] In WO 2013 / 123305 (the disclosure of which is incorporated herein by reference in its entirety), the key role of ALCAT1 in regulating mitochondrial biogenesis and mtDNA fidelity was demonstrated. ALCAT1 overexpression severely disrupts mitochondrial fusion, leading to mitochondrial fragmentation and mtDNA depletion. In contrast, targeted inactivation of ALCAT1 in mice significantly increases mitochondrial mass and protects mitochondria from ROS-induced mitochondrial swelling and fragmentation. The role of ALCAT1 in regulating mtDNA fidelity was demonstrated, which was confirmed by previous studies that mitochondrial fusion is necessary to protect mtDNA integrity (Chen H et al., (2010) Cell 141 (2): 280-289).

[0006] WO 2013 / 123305 also provides evidence that ALCAT1 plays a key role in regulating MFN2 expression. MFN2 is required for mitochondrial and endoplasmic morphology and for tethering the ER and mitochondria as a functional bridge. ALCAT1 impairs mitochondrial fusion via MFN2 depletion and links oxidative stress to mitochondrial fragmentation and MFN2 deficiency.

[0007] MFN2 deficiency has also been shown to cause skeletal muscle atrophy, which is consistent with the finding that ALCAT1 deficiency significantly increases skeletal muscle mass in ALCAT1 knockout mice (Li J et al., (2010) Cell Metab 12(2):154-165, Chen H et al., (2010) Cell 141(2):280-289).

[0008] WO 2013 / 123305 identified ALCAT1 as the missing link between mitochondrial fusion defects and reactive oxygen species (ROS) production in metabolic diseases. Cardiolipin (CL) remodeling by ALCAT1 significantly increased the content of docosahexaenoic acid (DHA) in CL, leading to proton leak and oxidative stress. The DHA content in mitochondrial membranes is inversely proportional to lifespan and directly proportional to ROS production and lipid peroxidation index in mammals. Therefore, increased DHA content in CL increases the lipid peroxidation index and is associated with mitochondrial dysfunction in aging and age-related diseases (Han X et al., (2007) Biochemistry 46(21):6417-6428; Sparagna GC & Lesnefoky EJ (2009) J Cardiovasc Pharmacol 53(4):290-301; Lee HJ, (2006) Lzj Jids Health&Dis.5:2; Paradies G et al., (2010) Free Radie Biol Med 4800):1286-1295; Shi Y (2010) J Biomed Res 24(1):6-15).

[0009] Aging and the onset of age-related diseases are associated with oxidative stress and increased mtDNA mutation rates, which have been implicated as major causes of aging and age-related diseases. In addition, MFN2 deficiency is associated with age-related metabolic diseases. By preventing mitochondrial dysfunction, targeted inactivation of ALCAT1 prevents the onset of obesity, fatty liver disease, and cardiomyopathy. Therefore, it is envisioned that the development of chemical inhibitors of ALCAT1 will provide potential therapeutic approaches for aging, age-related diseases, and other conditions caused by mitochondrial dysfunction, such as Barth syndrome.

[0010] WO 2013 / 123305 also shows that ALCAT1 plays a key role in regulating the onset of hypertrophic cardiomyopathy. Overexpression of ALCAT1 leads to hypertrophic growth of H9c2 cells, while elimination of ALCAT1 prevents T4-induced cardiomyopathy and its associated cardiac dysfunction, including ventricular hypertrophy, ventricular fibrosis, and elevated expression of type I and type III collagen. CL remodeling by ALCAT1 leads to depletion of tetralinoleoyl CL (TLCL), which has been identified as the main cause of cardiomyopathy in Barth syndrome.

[0011] Ablation of ALCAT1 expression completely prevented cardiac lipid peroxidation induced by hyperthyroidism.

[0012] Elimination of ALCAT1 also prevented the onset of Barth syndrome by alleviating mitochondrial dysfunction. The development of ALCAT1 inhibitors would provide a potential treatment for Barth syndrome, a fatal familial genetic disease.

[0013] ALCAT1 is upregulated by oxidative stress and with the onset of diabetes and obesity. Targeted inactivation of ALCAT1 prevents the onset of mitochondrial dysfunction and obesity, which are the main causes of type 2 diabetes and cardiovascular disease. The development of ALCAT1 inhibitors will provide potential treatments for cardiac hypertrophy and other heart diseases, which are the leading causes of death in developed countries.

[0014] Therefore, there is a need for compounds that act as ALCAT1 inhibitors, thereby providing treatments for aging and age-related diseases. For example, such compounds can be used to treat diet-induced obesity, type 2 diabetes, diabetic complications (such as nephropathy, cardiomyopathy, retinopathy, and erectile dysfunction), cardiovascular disease, fatty liver disease, neurodegenerative diseases (such as Alzheimer's disease), and cancer. Such compounds can also be used to treat stroke, ischemia, or reperfusion injury. Summary of the invention

[0015] A first aspect of the present invention are compounds according to formula (I) as described herein.

[0016] A second aspect of the present invention is a composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier or diluent.

[0017] A third aspect of the present invention is a compound according to formula (I) as described herein for use in treatment of the human or animal body by therapy.

[0018] A fourth aspect of the invention is a compound according to formula (I) for use in a method of inhibiting or down-regulating ALCAT1.

[0019] A fifth aspect of the present invention is a compound as described herein for use in preventing or treating aging or age-related diseases.

[0020] The sixth aspect of the present invention is the use of a compound according to formula (I) in the preparation of a medicament for preventing or treating aging or age-related diseases.

[0021] A seventh aspect of the present invention is a method of inhibiting ALCAT1, said method comprising administering a therapeutically effective amount of a compound according to formula (I).

[0022] An eighth aspect of the present invention is a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.

[0023] A ninth aspect of the present invention is a method of treatment and / or prevention, which comprises administering to a subject in need of treatment and / or prevention a therapeutically effective amount of an AS compound as described herein, preferably in the form of a pharmaceutical composition.

[0024] The tenth aspect of the present invention is a kit comprising (a) a compound according to formula (I), preferably as a pharmaceutical composition and provided in a suitable container and / or with suitable packaging; and (b) instructions for use, such as written instructions on how to administer the compound.

[0025] Another aspect of the invention is a compound obtainable by a synthesis method as described herein or a process comprising a synthesis method as described herein.

[0026] Another aspect of the invention is a compound obtained by a synthesis method as described herein or a process comprising a synthesis method as described herein.

[0027] Another aspect of the invention are novel intermediates as described herein, which are suitable for use in the synthetic methods described herein.

[0028] Another aspect of the invention is the use of such novel intermediates as described herein in the synthetic methods described herein.

[0029] Another aspect of the invention is a method of synthesizing the compounds described herein.

[0030] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention will also pertain to another aspect of the invention.

[0031] Any sub-headings herein are included for convenience only and should not be construed as limiting the disclosure in any way.

[0032] Compound

[0033] A first aspect of the present invention is a compound according to formula (I):

[0034]

[0035] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0036] in:

[0037] X is selected from O and S;

[0038] G 1 and G 2 are each independently selected from N and CH;

[0039] A is selected from

[0040] H,

[0041] Optionally, one or more groups R A1 Substituted C 1-6 Straight-chain or branched alkyl or alkenyl,

[0042] Optionally, one or more groups R B1 substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,

[0043] Optionally, one or more groups R B2 a substituted 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S,

[0044] -CN,

[0045] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0046] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 、-NR D5 COR C2 ,as well as

[0047] -SR E1 ;

[0048] L is a single bond, or a group L A ,

[0049] Where L A Selected from

[0050] -NR L C(=O)-*, -C(=O)NR L- *,

[0051] -NR L C(=X L )NR L -*,

[0052] -SO2-NR L -*, -NR L -SO2-*,

[0053] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[0054] The asterisk (*) indicates 1 The connection point;

[0055] X L Selected from O and S;

[0056] R L Selected from

[0057] -H,

[0058] -C(=O)(C 1-3 alkyl),

[0059] -P(=O)(OH)2, and

[0060] -S(=O)2NH2;

[0061] When L is a single bond, R 1 is NH2;

[0062] When L is L A When R 1 For R 1L , where R 1L Selected from

[0063] C 1-6 a straight or branched unsubstituted alkyl group;

[0064] Optionally, one to three groups R PH Substituted phenyl,

[0065] Optionally, one or more groups R B3 substituted 5-membered or 6-membered cycloalkyl,

[0066] Optionally, one or more groups R B4Substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and

[0067] Optionally, one or more groups R B5 substituted 8- to 10-membered bicyclic or heterobicyclic containing 1-3 heteroatoms selected from N, O and S;

[0068] Each R PH Independently selected from

[0069] Optionally, one or more groups R A2 Substituted C 1-6 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0070] Optionally, one or more groups R A3 Substituted phenyl,

[0071] Naphthyl,

[0072] -F, -Cl, -Br, -I,

[0073] -COOH, -COOR C1 、-COR C2 , -CONH2, -COONH2, -CONHR D1 、-CON(R D2 )2,

[0074] -NH2, -NHR D4 、-NHR D8 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D7 COOR C1 、-NR D5 COR C2 、-NHSO2(C 1-3 alkyl),

[0075] -SO2NH2, -SO2NHR D1 、-SO2N(R D2 2. -SO2R E2 、-SR E1 ,

[0076] -NO2,

[0077] -CN,

[0078] -OH, and -OR PH4 ;

[0079] Where RPH4 Selected from

[0080] Phenyl,

[0081] Benzyl, and

[0082] Optionally, one or more groups R A5 Substituted C 1-6 Straight or branched chain alkyl;

[0083] Q is selected from (Q1) and (Q2)

[0084]

[0085] The two asterisks (**) indicate the connection points with L;

[0086] Q 1A , Q 2A , Q 3A and Q 4A Two of them are CH;

[0087] Q 1A , Q 2A , Q 3A and Q 4A The other two are independently selected from N, CH and CR Q1 ;

[0088] Q 1B , Q 2B , Q 3B and Q 4B Both of them are CH.

[0089] Q 1B , Q 2B , Q 3B and Q 4B The other two are independently selected from N, CH and CR Q2 ;

[0090] Each R Q1 and each R Q2 Independently selected from

[0091] -F, -Cl, -Br, -I,

[0092] C 1-6 Straight-chain or branched unsubstituted alkyl,

[0093] -OH、-O(C 1-6 alkyl),

[0094] -CN, and

[0095] -N(R D3 )2;

[0096] RC1 and R C2 Each independently selected from

[0097] Optionally, one or more groups R A6 Substituted C 1-6 Straight or branched chain alkyl;

[0098] Optionally one or two groups R E3 substituted 5-membered heteroaryl containing a single heteroatom selected from N, O and S;

[0099] R D1 To R D7 Each independently selected from

[0100] Optionally, one or more groups R A7 Substituted C 1-6 Straight or branched alkyl group,

[0101] -COOH, -COOR C1 、-COR C2 ,

[0102] -C(=NH)NH2,

[0103] Or when two R D2 or two R D3 When groups are attached to a single nitrogen atom, they may, together with the nitrogen atom to which they are attached, form a D9 Substituted 5- or 6-membered heterocyclyl containing 1 to 3 ring heteroatoms selected from N, O and S;

[0104] Where R D9 is optionally substituted by one or more groups R A8 Substituted C 1-6 Straight or branched chain alkyl;

[0105] R D8 is a C containing one or two N atoms optionally substituted by one or more groups selected from 5-6 Heterocyclic group:

[0106] -SH, and

[0107] -C(=O)OR D5A , where R D5A is phenyl or benzyl optionally substituted by a NO2 group;

[0108] R E1 and R E2 Each independently selected from C 1-6 a straight or branched unsubstituted alkyl, alkenyl or alkynyl group;

[0109] RE3 Independently selected from

[0110] -SH; and

[0111] -C(=O)OR E4 ;

[0112] R B1 To R B5 Each independently selected from

[0113] Optionally, one or more groups R A9 Substituted C 1-6 Straight or branched alkyl group,

[0114] -F, -Cl, -Br,

[0115] -OH、-O(C 1-3 alkyl),

[0116] -CN,

[0117] -NO2,

[0118] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0119] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 ;

[0120] R E4 Independently selected

[0121] Optionally one or two groups R A10 substituted phenyl or benzyl;

[0122] R A1 To R A10 Each independently selected from

[0123] -F, -Cl, -Br,

[0124] -OH, -OR T

[0125] -CN, -NO2,

[0126] -C(=O)R T , -COOH, -COOR T 、-CON(R G )2,

[0127] -NH2, -NHR T 、-N(R T )2, -NHC(=O)(R F ) and -N(R D9 )2;

[0128] R F Selected from

[0129] C 1-6 Straight or branched chain unsubstituted alkyl, and

[0130] 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S;

[0131] The group -N(R G )2 is selected from C optionally with one or more selected from linear or branched 1-4 substituted azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidino, piperazino, NC 1-4 Alkyl-piperazinyl, morpholino, azepino or diazepino;

[0132] R T C 1-6 Straight or branched chain unsubstituted alkyl;

[0133] Two R's D9 The groups together with the nitrogen atom to which they are attached form a group selected from

[0134] 5-membered heteroaryl groups containing one or two nitrogen atoms; and

[0135] a 6-membered heterocyclic group containing one or two heteroatoms independently selected from N, O and S,

[0136] Provided that the compound is not selected from any one of compounds (X1) to (X27):

[0137]

[0138]

[0139]

[0140] In some embodiments:

[0141] R L Selected from

[0142] -H, and -C(=O)(C 1-3 alkyl);

[0143] And in -N(R D9 )2 group, two R D9 The groups together with the nitrogen atom to which they are attached form a 5-membered heteroaryl group containing one or two nitrogen atoms.

[0144] Group X

[0145] In some embodiments, X is O.

[0146] In some embodiments, X is S.

[0147] Group G 1

[0148] In some embodiments, G 1 is N.

[0149] In some embodiments, G 1 For CH.

[0150] Group G 2

[0151] In some embodiments, G 2 is N.

[0152] In some embodiments, G 2 For CH.

[0153] Group X, G 1 and G 2

[0154] In some embodiments, X is O, G 1 N and G 2 is N.

[0155] In some embodiments, X is O, G 1 N and G 2 For CH.

[0156] In some embodiments, X is O, G 1 CH and G 2 is N.

[0157] In some embodiments, X is S, G 1 N and G 2 is N.

[0158] In some embodiments, X is S, G 1 CH and G2 is N.

[0159] In some embodiments, X is O, G 1 CH and G 2 For CH.

[0160] In some embodiments, X is O, G 1 and G 2 One of is selected from CH and N, and G 1 and G 2 The other one of them is N.

[0161] In some embodiments, X is S, G 1 and G 2 One of is selected from CH and N, and G 1 and G 2 The other one of them is N.

[0162] Group A

[0163] In some embodiments, A is -H.

[0164] In some embodiments, A is optionally substituted with one or more groups R A1 Substituted C 1-6 Straight-chain or branched alkyl or alkenyl.

[0165] In some embodiments, A is optionally substituted with one or more groups R A1 Substituted C 1-5 Straight or branched chain alkyl or alkenyl.

[0166] In some embodiments, A is optionally substituted with one or more groups R A1 Substituted C 1-5 Straight chain or branched chain alkyl.

[0167] In some embodiments, R A1 Selected from

[0168] -OH, -OR T

[0169] -C(=O)R T , -COOH, -COOR T ,

[0170] -NH2, -NHR T 、-N(R T )2, -NHC(=O)(R F ) and -N(R D9 )2.

[0171] In some embodiments, R A1 Selected from

[0172] -OR T

[0173] -NH2, -NHR T 、-N(R T )2, -NHC(=O)(R F ) and -N(R D9 )2.

[0174] In some embodiments, -A is selected from

[0175] Methyl, ethyl, isopropyl,

[0176] -CH2NMe2, -CH2NHCOMe, -CH2NHCO(R F )、-CH2N(R D3 )2,

[0177] -CH2OMe,

[0178] -CH(NH2)CH3 and -CH(NH2)CH2CH(Me)2.

[0179] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 Substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0180] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 Substituted 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0181] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 Substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S.

[0182] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 The substituted 5-membered heteroaryl group contains 1 heteroatom selected from N, O and S.

[0183] In some embodiments, -A is selected from a 5-membered unsubstituted heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

[0184] In some embodiments, -A is selected from a 5-membered unsubstituted heteroaryl group containing 1 or 2 heteroatoms selected from N, O, and S.

[0185] In some embodiments, R B1 Selected from

[0186] Optionally, one or more groups RA9 Substituted C 1-3 Straight or branched alkyl group,

[0187] -F, -Cl, -Br,

[0188] -CN,

[0189] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0190] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0191] In some embodiments, R B1 Selected from

[0192] Optionally, one or more groups R A9 Substituted C 1-3 Straight or branched alkyl group,

[0193] -F, -Cl, -Br,

[0194] -CN,

[0195] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 and-CON(R D2 )2.

[0196] In some embodiments, R B1 Selected from

[0197] Optionally, one or more groups R A9 Substituted C 1-3 Straight or branched alkyl group,

[0198] -F, -Cl, -Br,

[0199] -CN,

[0200] -COR C2 , -CONH2, -CONHRD1 and-CON(R D2 )2.

[0201] In some embodiments, R B1 Selected from

[0202] C 1-3 Straight chain unsubstituted alkyl,

[0203] -F, -Cl, -Br,

[0204] -CN,

[0205] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 and-CON(R D2 )2.

[0206] In some embodiments, R B1 Selected from

[0207] C 1-3 Straight chain unsubstituted alkyl,

[0208] -F, -Cl, -Br,

[0209] -CN,

[0210] -COOH, -COOR C1 and-COR C2 .

[0211] In some embodiments, R B1 Selected from

[0212] methyl,

[0213] -CH2Cl,

[0214] -F, -Cl, -Br,

[0215] -CN, and

[0216] -C(=O)Me.

[0217] In some embodiments, -A is selected from

[0218]

[0219] Where R AX is a single optional ring substituent selected from:

[0220] Optionally, one or more groups R A9 Substituted C 1-3 Straight or branched alkyl group,

[0221] -F, -Cl, -Br,

[0222] -CN,

[0223] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0224] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0225] In some embodiments, R AX is a single optional ring substituent selected from:

[0226] C 1-3 Straight chain unsubstituted alkyl,

[0227] -F, -Cl, -Br,

[0228] -CN,

[0229] -COOH, -COOR C1 and-COR C2 .

[0230] In some embodiments, R is absent AX , i.e. the ring is unsubstituted.

[0231] In some embodiments, -A is furan-2-yl optionally substituted with one or more groups selected from

[0232] Optionally, one or more groups R A9 Substituted C 1-3 Straight or branched alkyl group,

[0233] -F, -Cl, -Br,

[0234] -CN,

[0235] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(RD2 )2,

[0236] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0237] In some embodiments, -A is furan-2-yl optionally substituted with one or more groups selected from

[0238] C 1-3 Straight chain unsubstituted alkyl,

[0239] -F, -Cl, -Br,

[0240] -CN,

[0241] -COOH, -COOR C1 and-COR C2 .

[0242] In some embodiments, -A is furan-2-yl optionally substituted with a group selected from

[0243] C 1-3 Straight chain unsubstituted alkyl,

[0244] -F, -Cl, -Br,

[0245] -CN,

[0246] -COOH, -COOR C1 and-COR C2 .

[0247] In some embodiments, -A is unsubstituted furan-2-yl.

[0248] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 Substituted 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0249] In some embodiments, -A is selected from optionally substituted with one or more groups R B1 Substituted 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S.

[0250] In some embodiments, -A is selected from a 6-membered unsubstituted heteroaryl group containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from a 6-membered unsubstituted heteroaryl group containing 1 or 2 heteroatoms selected from N.

[0251] In some embodiments, -A is selected from

[0252]

[0253] Where R AY is a single optional ring substituent selected from

[0254] Optionally, one or more groups R A9 Substituted C 1-3 Straight or branched alkyl group,

[0255] -F, -Cl, -Br,

[0256] -CN,

[0257] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0258] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0259] In some embodiments, R is absent AY , i.e. the ring is unsubstituted.

[0260] In some embodiments, -A is selected from optionally substituted with one or more groups R B2 Substituted 4- to 6-membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S.

[0261] In some embodiments, -A is selected from optionally substituted with one or more groups R B2 Substituted 4-membered and 5-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S.

[0262] In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclyl containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclyl containing 1 or 2 heteroatoms selected from N and O. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclyl containing 1 heteroatom selected from N, O, and S.

[0263] In some embodiments, -A is selected from

[0264]

[0265] In some embodiments, -A is -CN.

[0266] In some embodiments, -A is -COOH.

[0267] In some embodiments, -A is -COOR C1 In some embodiments, R C1 Selected from C 1-6 In some embodiments, R C1 Selected from C 1-4 In some embodiments, R C1 Selected from C 1-3 In some embodiments, R C1 It is methyl.

[0268] In some embodiments, -A is -COR C2 In some embodiments, R C2 Selected from C 1-6 In some embodiments, R C2 Selected from C 1-4 In some embodiments, R C2 Selected from C 1-3 In some embodiments, R C2 It is methyl.

[0269] In some embodiments, -A is -CON(R D2 )2. In some embodiments, each R D2 independently selected from optionally one or more groups R A7 Substituted C 1-6 In some embodiments, each R D2 Independently selected from unsubstituted C 1-6 In some embodiments, each RD2 Independently selected from unsubstituted C 1-3 In some embodiments, each R D2 It is methyl.

[0270] In some embodiments, -A is -NHCOR C2 In some embodiments, R C2 Selected from C 1-6 In some embodiments, R C2 Selected from C 1-4 In some embodiments, R C2 Selected from C 1-3 In some embodiments, R C2 It is methyl.

[0271] In some embodiments, -A is -CONH2.

[0272] In some embodiments, -A is -CONHR D1 .

[0273] In some embodiments, -A is -NH2.

[0274] In some embodiments, -A is -NHR D4 .

[0275] In some embodiments, -A is -N(R D3 )2.

[0276] In some embodiments, -A is -NHCOOH.

[0277] In some embodiments, -A is -NHCOOR C1 .

[0278] In some embodiments, -A is -NHCOH.

[0279] In some embodiments, -A is -NR D6 COOH.

[0280] In some embodiments, -A is -NR D7 COOR C1 .

[0281] In some embodiments, -A is -NR D5 COR C2 .

[0282] In some embodiments, -A is -SR E1 In some embodiments, R E1 Selected from C2-6 In some embodiments, R E1 Selected from C 3-6 In some embodiments, R E1 It is allyl.

[0283] Group L

[0284] In some embodiments, L is a single bond. In some embodiments, L is a group L A .

[0285] In some embodiments, L is L A , and L A Selected from

[0286] -NR L C(=O)-*, -C(=O)NR L- *,

[0287] -NR L C(=X L )NR L -*,

[0288] -SO2-NR L -*, -NR L -SO2-*,

[0289] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[0290] The asterisk (*) indicates 1 connection point.

[0291] In some embodiments, L is L A , and L A Selected from -NR L C(=O)-* and -C(=O)NR L -*, where the asterisk (*) indicates 1 connection point.

[0292] In some embodiments, L is L A , and L A For-NR L C(=O)-*, where the asterisk (*) indicates 1 connection point.

[0293] In some embodiments, R L In some embodiments, R L -C(=O)(C 1-3In some embodiments, R L is -C(=O)Me. L is -P(=O)(OH)2. In some embodiments, R L It is -S(=O)2NH2.

[0294] In some embodiments, L A is -NHC(=O)-* or -C(=O)NH-*. In some embodiments, L A is -NHC(=O)-*. In some embodiments, L A For-NR L C(=O)-*, where R L is -P(=O)(OH)2. In some embodiments, L A Yes - NR L C(=O)-*, where R L It is -S(=O)2NH2.

[0295] In some embodiments, L is L A , and L A For-NR L C(=X L )NR L -*. In some embodiments, L is L A , and L A -SO2-NR L -*. In some embodiments, L is L A , and L A For-NR L -SO2-*. In some embodiments, L is L A , and L A -OC(=O)-NR L -*. In some embodiments, L is L A , and L A For-NR L -C(=O)O-*.

[0296] In some embodiments, X L is O. In some embodiments, X L For S.

[0297] Group R 1

[0298] When L is a single bond, R 1 is NH2.

[0299] When L is L A When R 1 For R1L .

[0300] In some embodiments, R 1L Selected from C 1-6 In some embodiments, R 1L It is methyl.

[0301] In some embodiments, R 1L is optionally substituted by 1 to 3 groups R PH In some embodiments, R 1L is optionally substituted by one or two groups R PH In some embodiments, R 1L is optionally replaced by a group R PH In some embodiments, R 1L is optionally represented by two groups R PH In some embodiments, R 1L is optionally substituted by three groups R PH Substituted phenyl.

[0302] In some embodiments, R 1L is unsubstituted phenyl. In some embodiments, R 1L With a single substituent R in the ortho position PH In some embodiments, R 1L With a single substituent R at the meta position PH In some embodiments, R 1L With a single substituent R in the para position PH of phenyl.

[0303] In this context, unless otherwise indicated, the term "in the ortho position" refers to the position on the ring relative to the group L. The terms "in the meta position" and "in the para position" are equally applicable.

[0304] In some embodiments, R 1L A single substituent R is present at the ortho or para position. PH of phenyl.

[0305] In some embodiments, R 1L Two substituents R are present at the two meta positions. PH In some embodiments, R 1L Two substituents R are present at the two ortho positions. PH of phenyl.

[0306] In some embodiments, R 1L With two substituents R PH The two substituents RPH One is in the ortho position and the other is in the para position. 1L With two substituents R PH The two substituents R PH One is in the meta position and the other is in the para position. 1L With two substituents R PH The two substituents R PH The first of the substituents is in the ortho position, and the two substituents R PH In some embodiments, R 1L With two substituents R PH The two substituents R PH The first of the substituents is in the ortho position, and the two substituents R PH The second one is in the meta position, which is the opposite position of the first one.

[0307] In some embodiments, R 1L With three substituents R PH of phenyl.

[0308] In some embodiments, R 1L With three substituents R PH phenyl, wherein the first is in the para position, and the second and third are in the two meta positions. 1L With three substituents R PH wherein the first phenyl group is in the ortho position and the second and third phenyl groups are in the meta positions. 1L With three substituents R PH of phenyl groups, wherein the first one is in the ortho position, the second one is in the para position, and the third one is in the para position with respect to the first one.

[0309] In some embodiments, R 1L for

[0310]

[0311] where Y 1 , Y 2 and Y 3 One of them is CR Y ; Y 1 , Y 2 and Y 3 The second one is independently selected from CR Y and CH; and Y 1 , Y 2 and Y 3 The third one is independently selected from CR Y and CH;

[0312] Each R Y Independently selected from

[0313] Straight or branched unsubstituted C 1-6 alkyl,

[0314] -OR Y1 ;

[0315] -F, -Cl, -Br, -I,

[0316] -CF3, -CH2F, -CF2H,

[0317] -CH2CF3, -CH2CH2F and -CH2CF2H.

[0318] In some embodiments, Y 1 , Y 2 and Y 3 One of them is CR Y ; Y 1 , Y 2 and Y 3 The second one is selected from CR Y and CH; and Y 1 , Y 2 and Y 3 The third party in is CH.

[0319] In some embodiments, Y 1 CR Y And Y 2 and Y 3 Each of which is selected from CH and CR Y .

[0320] In some embodiments, Y 1 CR Y And Y 2 and Y 3 All are CH.

[0321] In some embodiments, Y 1 CR Y , Y 2 and Y 3 One of them is CH and the other is CR Y .

[0322] In some embodiments, Y 1 CR Y , Y 2 CH and Y 3 CR Y .

[0323] In some embodiments, Y 1, Y 2 and Y 3 Each of CR Y .

[0324] In some embodiments, R Y independently selected from linear or branched unsubstituted C 1-6 Alkyl, such as methyl, ethyl or n-propyl.

[0325] In some embodiments, R Y Independently selected from -OR Y1 , such as -OMe, -OEt, -O n Pr, -OCF3, -OCH2F, -OCF2H, -OCH2CF3, -OCH2CH2F or -OCH2CF2H.

[0326] In some embodiments, R Y In some embodiments, R Y Independently selected from -F.

[0327] In some embodiments, R Y Independently selected from

[0328] -CF3, -CH2F, -CF2H,

[0329] -CH2CF3, -CH2CH2F and -CH2CF2H.

[0330] In some embodiments, R Y It is -CF3.

[0331] In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 is -CH2CF2H. In some embodiments, R Y1 It is -CH2CFH2.

[0332] In some embodiments, each R PH Independently selected from

[0333] Optionally, one or more groups R A2 Substituted C 1-6 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0334] Optionally, one or more groups R A3 Substituted phenyl,

[0335] -F, -Cl, -Br, -I,

[0336] -COOH, -COOR C1 、-COR C2 , -CONH2, -COONH2, -CONHR D1 、-CON(R D2 )2,

[0337] -NH2, -NHR D4 、-NHR D8 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D7 COOR C1 、-NR D5 COR C2 、-NHSO2(C 1-3 alkyl),

[0338] -SO2NH2, -SO2NHR D1 、-SO2N(R D2 2. -SO2R E2 、-SR E1 ,

[0339] -NO2,

[0340] -CN,

[0341] -OH, and -OR PH4 .

[0342] In some embodiments, each R PH Independently selected from

[0343] Optionally, one or more groups R A2 Substituted C 1-4 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0344] Unsubstituted phenyl,

[0345] -F, -Cl, -Br, -I,

[0346] -COOH, -COOR C1 、-COR C2 , -CONH2, -COONH2, -CONHR D1 、-CON(RD2 )2,

[0347] -NH2, -NHR D4 、-NHR D8 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D7 COOR C1 、-NR D5 COR C2 、-NHSO2(C 1-3 alkyl),

[0348] -SO2NH2, -SO2NHR D1 、-SO2N(R D2 2. -SO2R E2 、-SR E1 ,

[0349] -NO2,

[0350] -CN,

[0351] -OH, and -OR PH4 .

[0352] In some embodiments, each R PH Independently selected from

[0353] Optionally, one or more groups R A2 Substituted C 1-4 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0354] -F, -Cl, -Br, -I,

[0355] -OH, and -OR PH4 .

[0356] In some embodiments, each R PH Independently selected from

[0357] Optionally, one or more groups R A2 Substituted C 1-6 Straight chain alkyl,

[0358] -F, -Cl, -Br, -I,

[0359] -OH, and -OR PH4 .

[0360] In some embodiments, each R PH Independently selected from

[0361] C optionally substituted by one or more groups selected from -F, -Cl, -Br and -I 1-6 Straight chain alkyl,

[0362] -F, -Cl, -Br, -I,

[0363] -OH, and -OR PH4 , where R PH4 Selected from optionally one or more groups R A5 Substituted C 1-6 Straight chain or branched chain alkyl.

[0364] In some embodiments, R 1L is a first substituent R in the ortho position PH and a second substituent R in the para position to the first substituent PH Phenyl, where R PH The groups are each independently selected from

[0365] Optionally, one or more groups R A2 Substituted C 1-6 Straight chain alkyl,

[0366] -F, -Cl, -Br, -I,

[0367] -OH, and -OR PH4 .

[0368] In some embodiments, each R PH Independently selected from

[0369] -Me, -Et, - t Bu, -CH=CHMe, -CCH, -CCMe, -Ph,

[0370] -OH, -OMe, -OEt, -O n Pr, -O i Pr, -O n Bu, -O-secondary-Bu, -O-iso-Bu, -OPh, -OBn,

[0371] -OCH2CF3, -OCF3, -OCHF2, -OCF2H, -OCH2CHF2, -OCH2CH2F,

[0372] -OCH2C(=O)OH, -OCH2C(=O)OMe,

[0373] -F, -Cl, -Br, -I,

[0374] -CF3, -CHF2, -CN, -CH2CN, -CH(Me)CN, -CH2OH, -CH2OMe, -CH2COOH,

[0375] -COOH, -COOMe, -CONH2, -CONMe2, -CONHMe, -C(=O)Me, -COONH2,

[0376] -SO2Me, -SO2NH2, -SMe,

[0377] -NO2, -NH2, -NMe2, -NHMe, -NHC(=O)Me, -NHSO2Me,

[0378]

[0379] N-pyrrolidinyl, and N-piperidinyl.

[0380] In some embodiments, each R PH Independently selected from

[0381] -Me, -Et, - t Bu, -CH=CHMe, -CCH, -CCMe, -Ph,

[0382] -OH, -OMe, -OEt, -O n Pr, -O n Bu, -O-secondary-Bu, -O-iso-Bu, -OPh, -OBn,

[0383] -OCH2CF3, -OCF3, -OCHF2, -OCF2H, -OCH2CHF2, -OCH2CH2F,

[0384] -OCH2C(=O)OH, -OCH2C(=O)OMe,

[0385] -F, -Cl, -Br, -I,

[0386] -CF3, -CHF2, -CN, -CH2CN, -CH(Me)CN, -CH2OH, -CH2OMe, -CH2COOH,

[0387] -COOH, -COOMe, -CONH2, -CONMe2, -CONHMe, -C(=O)Me, -COONH2,

[0388] -SO2Me, -SO2NH2, -SMe,

[0389] -NO2, -NH2, -NMe2, -NHMe, -NHC(=O)Me, -NHSO2Me,

[0390]

[0391] N-pyrrolidinyl, and N-piperidinyl.

[0392] In some embodiments, R 1L Selected from

[0393]

[0394] Where R PH2 and R PH3 Each independently selected from

[0395] Optionally, one or more groups R A2 Substituted C 1-4 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0396] -F, -Cl, -Br, -I,

[0397] -OH, and -OR PH4 .

[0398] In some embodiments, R PH2 and R PH3 Each independently selected from

[0399] Optionally, one or more groups R A2 Substituted C 1-4 Straight or branched alkyl group,

[0400] -F, -Cl, -Br, -I,

[0401] -OH, and -OR PH4 .

[0402] In some embodiments, R PH2 and R PH3 Each independently selected from

[0403] C 1-4 Straight chain unsubstituted alkyl,

[0404] -F, -Cl, -Br, -I,

[0405] -OH, and -OR PH4 .

[0406] In some embodiments, R PH2 and R PH3 Each independently selected from

[0407] C 1-4Straight chain unsubstituted alkyl,

[0408] -F, -Cl, -Br,

[0409] -OH, and -OR PH4 , where R PH4 independently selected from C optionally substituted by one or more groups selected from -F, -Cl and -Br 1-4 Straight chain alkyl.

[0410] In some embodiments, R PH2 and R PH3 Each independently selected from

[0411] C 1-4 Straight chain unsubstituted alkyl,

[0412] -F, -Cl, -Br,

[0413] -OH, and -OR PH4 , where R PH4 independently selected from C optionally substituted by one or more groups -F 1-4 Straight chain alkyl.

[0414] In some embodiments, R 1L Each R on PH In other embodiments, each R PH The groups are different.

[0415] In some embodiments, R 1L is optionally substituted by one or more groups R B3 Substituted 5-membered or 6-membered cycloalkyl.

[0416] In some embodiments, R 1L It is a 5-membered or 6-membered unsubstituted cycloalkyl group.

[0417] In some embodiments, R 1L is optionally substituted by one or more groups R B3 In some embodiments, R 1L It is a 5-membered unsubstituted cycloalkyl group.

[0418] In some embodiments, R 1L is optionally substituted by one or more groups R B3 In some embodiments, R 1L It is a 6-membered unsubstituted cycloalkyl group.

[0419] In some embodiments, R 1L is selected from unsubstituted cyclopentyl and unsubstituted cyclohexyl.1L It is an unsubstituted cyclohexyl group.

[0420] In some embodiments, R B3 Selected from

[0421] C 1-4 Straight-chain or branched unsubstituted alkyl,

[0422] -F, -Cl, -Br,

[0423] -OH、-O(C 1-3 alkyl),

[0424] -CN,

[0425] -NO2,

[0426] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0427] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0428] In some embodiments, R B3 Selected from

[0429] C 1-4 Straight-chain or branched unsubstituted alkyl,

[0430] -F, -Cl, -Br,

[0431] -OH、-O(C 1-3 alkyl),

[0432] -CN,

[0433] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0434] -NH2, -NHR D4 and -N(R D3)2.

[0435] In some embodiments, R B3 Selected from

[0436] C 1-4 Straight-chain or branched unsubstituted alkyl,

[0437] -F, -Cl, -Br,

[0438] -OH and -O(C 1-3 alkyl).

[0439] In some embodiments, R 1L is optionally substituted by one or more groups R B4 Substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S.

[0440] In some embodiments, R 1L is optionally substituted by one or more groups R B4 Substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0441] In some embodiments, R 1L is optionally substituted by one or more groups R B4 is a substituted 5-membered heteroaryl or heterocyclyl group containing 1 to 3 heteroatoms selected from N, O and S. In some embodiments, R 1L is optionally substituted by one or more groups R B4 Substituted 6-membered heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S.

[0442] In some embodiments, R 1L is a 5-membered or 6-membered unsubstituted heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S.

[0443] In some embodiments, R 1L is optionally substituted by one or more groups R B4 substituted 5-membered or 6-membered heteroaryl or heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S. In some embodiments, R 1L is optionally substituted by one or more groups R B4 substituted 5-membered or 6-membered heteroaryl or heterocyclyl containing 1 heteroatom selected from N, O and S. In some embodiments, R 1L is optionally substituted by one or more groups R B4 Substituted 5-membered or 6-membered heteroaryl or heterocyclic group containing 1 heteroatom selected from N.

[0444] In some embodiments, R 1Lis optionally substituted by one or more groups R B4 In some embodiments, R 1L is optionally one or two independently selected from R B4 A pyridyl group substituted with a group.

[0445] In some embodiments, R 1L is an unsubstituted pyridyl group.

[0446] In some embodiments, R 1L is an unsubstituted piperidinyl.

[0447] In some embodiments, R 1L is optionally substituted by one or more groups R B4 substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S. In some embodiments, R 1L is optionally substituted by one or more groups R B4 substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O. In some embodiments, R 1L is a 5-membered unsubstituted heteroaryl group containing 1 or 2 heteroatoms selected from N and O.

[0448] In some embodiments, R 1L is unsubstituted furanyl. In some embodiments, R 1L is unsubstituted oxazolyl. In some embodiments, R 1L is unsubstituted isoxazolyl.

[0449] In some embodiments, R B4 Selected from

[0450] Optionally, one or more groups R A9 Substituted C 1-4 Straight or branched alkyl group,

[0451] -F, -Cl, -Br,

[0452] -OH、-O(C 1-3 alkyl),

[0453] -CN,

[0454] -NO2,

[0455] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0456] -NH2, -NHR D4、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0457] In some embodiments, R B4 Selected from

[0458] Optionally, one or more groups R A9 Substituted C 1-6 Straight chain alkyl,

[0459] -F, -Cl,

[0460] -OH、-O(C 1-3 alkyl),

[0461] -CN,

[0462] -NO2,

[0463] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0464] In some embodiments, R B4 Selected from

[0465] -F, -Cl,

[0466] -OH、-O(C 1-3 alkyl),

[0467] -CN,

[0468] -NO2,

[0469] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1, and -NR D5 COR C2 .

[0470] In some embodiments, R B4 Selected from

[0471] -F, -Cl,

[0472] -O(C 1-3 alkyl),

[0473] -NO2,

[0474] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0475] In some embodiments, R B4 Selected from

[0476] -F, -Cl,

[0477] -O(C 1-3 alkyl),

[0478] -NO2,

[0479] -NH2, and -NHCOR C2 .

[0480] In some embodiments, R B4 Selected from

[0481] -F, -Cl, -OMe, -NO2, -NH2 and -NHC(=O)Me.

[0482] In some embodiments, R 1L is optionally substituted by one or more groups R B5 Substituted 8- to 10-membered bicyclic or heterobicyclic containing 1-3 heteroatoms selected from N, O and S.

[0483] In this article, the term "bicyclic radical" means a carbocyclic bicyclic ring system in which one, two or none of the rings may be aromatic. The bicyclic ring system may be a fused system or a spirocyclic ring system. Similarly, the term "heterobicyclic radical" means a bicyclic ring system in which one, two or none of the rings may be aromatic, and wherein the bicyclic ring system contains 1-3 heteroatoms selected from N, O and S. The heterobicyclic ring system may be a fused system or a spirocyclic ring system.

[0484] In some embodiments, R 1L is optionally substituted by one or more groups R B5 In some embodiments, R 1L is optionally substituted by one or more groups R B5 Substituted 8- to 10-membered heterobicyclyl containing 1-3 heteroatoms selected from N, O and S.

[0485] In some embodiments, R 1L is optionally substituted by one or more groups R B5 In some embodiments, R 1L is an 8- to 10-membered unsubstituted bicyclic group. 1L is optionally substituted by one or more groups R B5 In some embodiments, R 1L is a 10-membered unsubstituted bicyclic group. 1L is optionally substituted by one or more groups R B5 In some embodiments, R 1L It is an unsubstituted naphthyl.

[0486] In some embodiments, R 1L is optionally substituted by one or more groups R B5 is a 9-membered or 10-membered heterobicyclyl group containing 1 or 2 heteroatoms selected from N, O and S. In some embodiments, R 1L is optionally substituted by one or more groups R B5 substituted 9-membered or 10-membered heterobicyclyl containing 1 or 2 heteroatoms selected from N and O. In some embodiments, R 1L is optionally substituted by one or more groups R B5 Substituted 9- or 10-membered heterobicyclyl containing 1 or 2 selected O heteroatoms.

[0487] In some embodiments, R 1L is an 8- to 10-membered unsubstituted heterobicyclic group containing 1-3 heteroatoms selected from N, O and S. In some embodiments, R 1Lis an 8- to 10-membered unsubstituted heterobicyclic group containing 1 or 2 heteroatoms selected from N, O and S. In some embodiments, R 1L is an 8- to 10-membered unsubstituted heterobicyclic group containing 1 or 2 heteroatoms selected from N and O. In some embodiments, R 1L is an 8- to 10-membered unsubstituted heterobicyclic group containing 1 or 2 heteroatoms selected from O.

[0488] In some embodiments, R 1L Selected from

[0489]

[0490] In some embodiments, the group -N(R G )2 is optionally selected from one or more linear or branched C 1-4 In some embodiments, the group -N(R G )2 is one or more selected from linear or branched C 1-4 In some embodiments, the group -N(R G )2 is one or more selected from linear C 1-4 The piperazinyl group is substituted with an alkyl group.

[0491] Group Q

[0492] In some embodiments, Q is a group (Q1):

[0493]

[0494] The two asterisks (**) indicate the connection points with L;

[0495] Q 1A , Q 2A , Q 3A and Q 4A two of them are CH; and

[0496] Q 1A , Q 2A , Q 3A and Q 4A The other two are independently selected from N, CH and CR Q1 .

[0497] In some embodiments, Q 1A , Q 3A and Q 4A Both are CH, and Q 2A Selected from N, CH and CR Q1 In some embodiments, Q 1A , Q3A and Q 4A Both are CH, and Q 2A Selected from CH and CR Q1 .

[0498] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A All are CH.

[0499] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A One of them is CR Q1 , and Q 1A , Q 2A , Q 3A and Q 4A The other three are CH.

[0500] In some embodiments, Q 1A and Q 3A For CH, Q 2A and Q 4A One of them is CR Q1 , and Q 2A and Q 4A The other one of them is CH.

[0501] In some embodiments, Q 2A , Q 3A and Q 4A Both are CH, and Q 1A CR Q1 In some embodiments, Q 1A , Q 3A and Q 4A Both are CH, and Q 2A CR Q1 In some embodiments, Q 1A , Q 2A and Q 4A Both are CH, and Q 3A CR Q1 .

[0502] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A One of them is CN, and Q 1A , Q 2A , Q 3A and Q 4A The other three are CH.

[0503] In some embodiments, Q 2A , Q 3A and Q 4A Both are CH, and Q 1A In some embodiments, Q 1A , Q 3A and Q 4A Both are CH, and Q 2A In some embodiments, Q 1A , Q 2A and Q 4A Both are CH, and Q 3A In some embodiments, Q 2A , Q 3A and Q 4A Both are CH, and Q 1A In some embodiments, Q 1A , Q 2A and Q 3A Both are CH, and Q 4A For CN.

[0504] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A The two of them are CR independently Q1 , and Q 1A , Q 2A , Q 3A and Q 4A The other two in are CH.

[0505] In some embodiments, Q 2A and Q 4A Each independently is CR Q1 , and Q 1A and Q 3A All are CH.

[0506] In some embodiments, Q 1A and Q 4A Each independently is CR Q1 , and Q 2A and Q 3A All are CH.

[0507] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A Both of them are CN, and Q 1A , Q 2A , Q 3A and Q 4AThe other two in are CH.

[0508] In some embodiments, Q 1A and Q 3A For CH, Q 2A and Q 4A One of them is CN, and Q 2A and Q 4A The other one of them is CH.

[0509] In some embodiments, Q 2A and Q 4A For CH, Q 1A and Q 3A One of them is CN, and Q 1A and Q 3A The other one of them is CH.

[0510] In some embodiments, Q 1A and Q 3A is CH, and Q 2A and Q 4A Each of the Q1 .

[0511] In some embodiments, Q 1A CN, Q 2A , Q 3A and Q 4A One of them is CN, and Q 2A , Q 3A and Q 4A The other two in are CH.

[0512] In some embodiments, Q 1A and Q 2A is CN, and Q 3A and Q 4A All are CH.

[0513] In some embodiments, R Q1 Selected from

[0514] -F, -Cl, -Br, -I,

[0515] C 1-6 Straight chain unsubstituted alkyl,

[0516] -OH、-O(C 1-6 alkyl),

[0517] -CN, and

[0518] -N(R D3 )2.

[0519] In some embodiments, RQ1 Selected from

[0520] -F, -Cl, -Br, -I,

[0521] C 1-3 Straight chain unsubstituted alkyl,

[0522] -OH, -OMe, -OEt,

[0523] -CN, and

[0524] -NMe2.

[0525] In some embodiments, R Q1 is selected from -F, -Cl, -Br and -I. In some embodiments, R Q1 In some embodiments, R Q1 is -F.

[0526] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A One of them is C(Hal), and Q 1A , Q 2A , Q 3A and Q 4A The other three of Q are CH, wherein Hal is selected from F, Cl, Br and I. In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A One of them is CF, and Q 1A , Q 2A , Q 3A and Q 4A The other three are CH.

[0527] In some embodiments, Q 1A , Q 3A and Q 4A Both are CH, and Q 2A For CF.

[0528] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A Wherein both are independently C(Hal), and Q 1A , Q 2A , Q 3A and Q 4A The other two of them are CH, wherein Hal is selected from F, Cl, Br and I. In some embodiments, Q 1A, Q 2A , Q 3A and Q 4A Both of them are CF, and Q 1A , Q 2A , Q 3A and Q 4A The other two in are CH.

[0529] In some embodiments, Q is selected from

[0530]

[0531] In some embodiments, Q is a group (Q2):

[0532]

[0533] The two asterisks (**) indicate the connection points with L;

[0534] Q 1B , Q 2B , Q 3B and Q 4B two of them are CH; and

[0535] Q 1B , Q 2B , Q 3B and Q 4B The other two are independently selected from N, CH and CR Q2 .

[0536] In some embodiments, Q 1B , Q 2B , Q 3B and Q 4B All are CH.

[0537] In some embodiments, Q is selected from (Q1) and (Q2), wherein two asterisks (**) indicate the point of attachment to L; Q 1A , Q 2A , Q 3A and Q 4A The two in are CH; Q 1A , Q 2A , Q 3A and Q 4A The other two are independently selected from N, CH and CR Q1 ; and Q 1B , Q 2B , Q 3B and Q 4B All are CH.

[0538] Compound of Formula IA

[0539] In some embodiments, the compound is according to Formula IA:

[0540]

[0541] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0542] in

[0543] L B Selected from

[0544] -NR L1 C(=O)-*, -C(=O)NR L1 -*,

[0545] -NR L1 C(=X L1 )NR L1 -*,

[0546] -SO2-NR L1 -*, -NR L1 -SO2-*,

[0547] -OC(=O)-NR L1 -*, and -NR L1 -C(=O)O-*;

[0548] Wherein the asterisk (*) indicates the point of attachment to the terminal phenyl group;

[0549] X L1 Selected from O and S;

[0550] R L1 Selected from

[0551] -H,

[0552] -C(=O)(C 1-3 alkyl),

[0553] -P(=O)(OH)2 and

[0554] -S(=O)2NH2;

[0555] Y 1 , Y 2 and Y 3 One of them is CR Y ;

[0556] Y 1 , Y 2 and Y 3 The second one is independently selected from CR Y and CH; and

[0557] Y 1, Y 2 and Y 3 The third one is independently selected from CR Y and CH;

[0558] Q 5A , Q 6A and Q 7A one of is selected from N and CH; and

[0559] Q 5A , Q 6A and Q 7A The other two are independently selected from CH and CR Q3 ;

[0560] Each R Y Independently selected from

[0561] Straight or branched unsubstituted C 1-6 alkyl,

[0562] -OR Y1 ;

[0563] -F, -Cl, -Br, -I,

[0564] -CF3, -CH2F, -CF2H,

[0565] -(CH2) n N(R N1 )2,

[0566] -CH2CF3, -CH2CH2F and -CH2CF2H;

[0567] Among them, in the group -N(R N1 )2, the N atom and the two R N1 The group forms a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O and S;

[0568] n is an integer selected from 1, 2 or 3;

[0569] Where R Y1 Selected from

[0570] Straight or branched unsubstituted C 1-6 alkyl,

[0571] -CF3, -CH2F, -CF2H,

[0572] -(CH2) m N(R N2 )2,

[0573] -CH2CF3, -CH2CH2F and -CH2CF2H;

[0574] Among them, in the group -N(R N2 )2, the N atom and the two R N2 The group forms a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O and S;

[0575] m is an integer selected from 1, 2 and 3;

[0576] R Q3 Selected from

[0577] -F, -Cl, -Br, -I,

[0578] C 1-6 Straight-chain or branched unsubstituted alkyl,

[0579] -OH、-O(C 1-6 alkyl), and

[0580] -CN.

[0581] In some embodiments:

[0582] R L1 Selected from -H and -C(=O)(C 1-3 alkyl);

[0583] Each R Y Independently selected from

[0584] Straight or branched unsubstituted C 1-6 alkyl,

[0585] -OR Y1 ;

[0586] -F, -Cl, -Br, -I,

[0587] -CF3, -CH2F, -CF2H,

[0588] -CH2CF3, -CH2CH2F, and -CH2CF2H; and

[0589] R Y1 Selected from

[0590] Straight or branched unsubstituted C 1-6 alkyl,

[0591] -CF3, -CH2F, -CF2H,

[0592] -CH2CF3, -CH2CH2F and -CH2CF2H.

[0593] Group L B

[0594] In some embodiments, L B Selected from -NR L1 C(=O)-* and -C(=O)NR L1 -*, wherein the asterisk (*) indicates the point of attachment to the terminal phenyl group.

[0595] In some embodiments, L B For-NR L1 C(=O)-*, where the asterisk (*) indicates the point of attachment to the terminal phenyl group.

[0596] In some embodiments, R L1 In some embodiments, R L1 -C(=O)(C 1-3 In some embodiments, R L1 It is -C(=O)Me.

[0597] In some embodiments, L B is -NHC(=O)-*, wherein the asterisk (*) indicates the point of attachment to the terminal phenyl group.

[0598] In some embodiments, L B is -NHC(=O)-* or -C(=O)NH-*. In some embodiments, L B It is -NHC(=O)-*.

[0599] In some embodiments, L B For-NR L C(=O)-*, where R L is -P(=O)(OH)2. In some embodiments, L B For-NR L C(=O)-*, where R L It is -S(=O)2NH2.

[0600] In some embodiments, L B For-NR L1 C(=X L1 )NR L -*. In some embodiments, L B -SO2-NR L1 -*. In some embodiments, L B For-NR L1 -SO2-*. In some embodiments, L B -OC(=O)-NR L1 -*. In some embodiments, L A For-NR L1 -C(=O)O-*.

[0601] In some embodiments, X L1 is O. In some embodiments, X L1 For S.

[0602] Group Y 1 , Y 2 and Y 3

[0603] Y 1 , Y 2 and Y 3 One of them is CR Y ; Y 1 , Y 2 and Y 3 The second one is independently selected from CR Y and CH; and Y 1 , Y 2 and Y 3 The third one is independently selected from CR Y and CH.

[0604] In some embodiments, Y 1 , Y 2 and Y 3 One of them is CR Y ; Y 1 , Y 2 and Y 3 The second one is selected from CR Y and CH; and Y 1 , Y 2 and Y 3 The third party in is CH.

[0605] In some embodiments, Y 1 CR Y And Y 2 and Y 3 Each of which is selected from CH and CR Y .

[0606] In some embodiments, Y 1 CR Y And Y 2 and Y 3 All are CH.

[0607] In some embodiments, Y 1 CR Y , Y 2 and Y 3 One of them is CH and the other is CR Y .

[0608] In some embodiments, Y1 CR Y , Y 2 CH and Y 3 CR Y .

[0609] In some embodiments, Y 1 , Y 2 and Y 3 Each of CR Y .

[0610] In some embodiments, R Y independently selected from linear or branched unsubstituted C 1-6 Alkyl, such as methyl, ethyl or n-propyl.

[0611] In some embodiments, R Y Independently selected from -OR Y1 , such as -OMe, -OEt, -O n Pr, -OCF3, -OCH2F, -OCF2H, -OCH2CF3, -OCH2CH2F or -OCH2CF2H.

[0612] In some embodiments, R Y In some embodiments, R Y Independently selected from -F.

[0613] In some embodiments, R Y Independently selected from

[0614] -CF3, -CH2F, -CF2H,

[0615] -CH2CF3, -CH2CH2F and -CH2CF2H.

[0616] In some embodiments, R Y It is -CF3.

[0617] In some embodiments, R Y -(CH2) n N(R N1 )2. In some embodiments, n is 3. In some embodiments, the group -N(R N1 )2 is a 6-membered heterocyclyl selected from morpholino and piperidinyl. In some embodiments, n is 3 and the group -N(R N1 )2 is a 6-membered heterocyclic group selected from morpholino and piperidinyl.

[0618] In some embodiments, R Y1 In some embodiments, R Y1In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 In some embodiments, R Y1 is -CH2CF2H. In some embodiments, R Y1 It is -CH2CFH2.

[0619] In some embodiments, R Y1 -(CH2) m N(R N2 )2. In some embodiments, m is 2. In some embodiments, the group -N(R N2 )2 is a 6-membered heterocyclyl selected from morpholino and piperidinyl. In some embodiments, m is 2 and the group -N(R N2 )2 is a 6-membered heterocyclic group selected from morpholino and piperidinyl.

[0620] Group Q 5A , Q 6A and Q 7A

[0621] Q 5A , Q 6A and Q 7A one of which is selected from N and CH; and Q 5A , Q 6A and Q 7A The other two are independently selected from CH and CR Q3 .

[0622] In some embodiments, Q 5A , Q 6A and Q 7A In some embodiments, Q 5A and Q 6A One of them is CR Q3 , the other is CH, and Q 7A is CH. In some embodiments, Q 6A and Q 7A One of them is N, the other is CH, and Q 5A For CH.

[0623] In some embodiments, Q 6A CR Q3 , and Q 5A and Q 7A Each of is CH.

[0624] In some embodiments, R Q3 is selected from -F, -Cl, -Br and -I. In some embodiments, R Q3 In some embodiments, Q 6A is CF, and Q 5A and Q 7A Each of is CH.

[0625] In some embodiments, L B is -NHC(=O)-*, wherein the asterisk (*) indicates the point of attachment to the terminal phenyl group; Y 2 CH; Y 1 and Y 3 One of them is CR Y ; Y 1 and Y 3 The second one is selected from CR Y and CH;Q 5A and Q 7A are CH; and Q 6A Selected from N, CH and CR Q3 ;

[0626] Each R Y Independently selected from

[0627] Straight or branched unsubstituted C 1-6 alkyl,

[0628] -OR Y1 ;

[0629] -F, -Cl, -Br, -I,

[0630] -CF3, -CH2F, -CF2H,

[0631] -CH2CF3, -CH2CH2F and -CH2CF2H;

[0632] R Y1 Selected from

[0633] Straight or branched unsubstituted C 1-6 alkyl,

[0634] -CF3, -CH2F, -CF2H,

[0635] -CH2CF3, -CH2CH2F and -CH2CF2H;

[0636] And R Q3 Selected from

[0637] -F, -Cl, -Br, -I,

[0638] C 1-6Straight-chain or branched unsubstituted alkyl,

[0639] -OH、-O(C 1-6 alkyl), and

[0640] -CN.

[0641] Compound of formula (IB)

[0642] In some embodiments, the compound is according to Formula IB:

[0643]

[0644] in

[0645] R Z1 Selected from

[0646] -H,

[0647] -F, -Cl, -Br, and -I;

[0648] And R Z3 Selected from

[0649] -H,

[0650] C optionally substituted with one, two or three substituents each independently selected from -F, -Cl and -Br 1-6 Straight chain alkyl,

[0651] -F, -Cl, -Br, -I, and

[0652] -OR Z5 ;

[0653] Where R Z2 and R Z5 each independently selected from C optionally substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-6 Straight chain alkyl.

[0654] Group R Z1

[0655] In some embodiments, R Z1 In some embodiments, R Z1 In some embodiments, R Z1 is -F.

[0656] Group R Z2

[0657] In some embodiments, R Z2 Selected from C 1-6In some embodiments, R Z2 Selected from C 1-4 In some embodiments, R Z2 Selected from methyl, ethyl or n-propyl.

[0658] In some embodiments, R Z2 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-6 In some embodiments, R Z2 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-4 In some embodiments, R Z2 is selected from methyl or ethyl substituted by one, two or three substituents each independently selected from -F, -Cl and -Br.

[0659] In some embodiments, R Z2 is selected from methyl or ethyl substituted with one, two or three -F substituents.

[0660] In some embodiments, R Z2 Selected from

[0661] -CH2CHF2, -CH2CH2F, -CH2CF3,

[0662] -CHF2, -CH2F and -CF3.

[0663] Group R Z3

[0664] In some embodiments, R Z3 In some embodiments, R Z3 C 1-6 In some embodiments, R Z3 C 1-4 In some embodiments, R Z3 Selected from methyl, ethyl or n-propyl.

[0665] In some embodiments, R Z3 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-6 In some embodiments, R Z3 is selected from C substituted with one, two or three F substituents 1-6 In some embodiments, R Z3 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br1-3 In some embodiments, R Z3 is selected from C substituted with one, two or three F substituents 1-3 In some embodiments, R Z3 Selected from C substituted with three F substituents 1-3 In some embodiments, R Z3 It is -CF3.

[0666] In some embodiments, R Z3 is selected from -F, -Cl, -Br and -I. In some embodiments, R Z3 Selected from -F, -Cl and -Br.

[0667] In some embodiments, R Z3 For-OR Z5 .

[0668] Group R Z5

[0669] In some embodiments, R Z5 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-6 In some embodiments, R Z5 is selected from C substituted by one, two or three substituents each independently selected from -F, -Cl and -Br 1-4 In some embodiments, R Z5 is selected from methyl or ethyl substituted by one, two or three substituents each independently selected from -F, -Cl and -Br.

[0670] In some embodiments, R Z5 is selected from methyl or ethyl substituted with one, two or three -F substituents. Z5 is methyl substituted with one, two or three -F substituents. Z5 It is -CF3.

[0671] In some embodiments,

[0672] R Z1 Selected from -H and -F;

[0673] R Z3 Selected from -H, -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ;and

[0674] R Z2 and R Z5are each independently selected from C optionally substituted with one, two or three -F substituents 1-6 Straight chain alkyl.

[0675] In some embodiments,

[0676] R Z1 for -F;

[0677] R Z3 Selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ;and

[0678] R Z2 and R Z5 are each independently selected from C optionally substituted with one, two or three -F substituents 1-6 Straight chain alkyl.

[0679] In some embodiments,

[0680] R Z1 for -F;

[0681] R Z3 Selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ;and

[0682] R Z2 and R Z5 Each independently selected from C 1-6 Straight chain unsubstituted alkyl.

[0683] In some embodiments,

[0684] R Z1 for -F;

[0685] R Z3 Selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ;and

[0686] R Z2 and R Z5 Each independently selected from C 1-3 Straight chain unsubstituted alkyl.

[0687] The following compounds (X1) to (X27) are believed to be known:

[0688]

[0689]

[0690]

[0691] Therefore, the compound according to the first aspect is not selected from any of compounds (X1) to (X27).

[0692] However, in other aspects described herein, the compound may be selected from compounds (X1) to (X27). Specifically, in some embodiments, the compound for treating a disease as described herein may be selected from compounds (X1) to (X27). Similarly, in some embodiments, the method for treating a disease as described herein may involve the use of a compound selected from (X1) to (X27).

[0693] combination

[0694] It should be understood that certain features of the invention described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable subcombination. 1 , G 2 , A, R A1 -R A10 , R B1 -R B5 , R C1 , R C2 , R D1 -R D9 , R E1 -R E4 , R F , R T ,Q,Q 1A -Q 4A , Q 1B -Q 4B ,L,L A , R 1 All combinations of embodiments of chemical groups represented by , , etc.) are specifically encompassed by the present invention and are disclosed herein as if each and every combination were individually and specifically disclosed to the extent that such combinations encompass compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in embodiments describing such variables are also expressly encompassed by the present invention and are disclosed herein as if each and every such subcombination of chemical groups were individually and specifically disclosed herein. DETAILED DESCRIPTION

[0695] In some embodiments, the compound is selected from the compounds in Table 1:

[0696] Table 1

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724] In some embodiments, the compound is selected from the compounds in Table 2:

[0725] Table 2

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732] In some embodiments, the compound is selected from the compounds in Table 3:

[0733] Table 3

[0734]

[0735]

[0736]

[0737] In some embodiments, the compound is:

[0738]

[0739] Compound 222

[0740] Chirality

[0741] In some embodiments, the compounds may have one or more chiral centers.

[0742] The or each chiral center (if multiples are present) is independently in the R configuration or the S configuration.

[0743] If no configuration is indicated, both configurations are included.

[0744] Substantially purified form

[0745] One aspect of the present invention pertains to compounds as described herein in substantially purified form and / or in a form substantially free of contaminants.

[0746] In one embodiment, the substantially purified form is at least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 97% by weight, such as at least 98% by weight, such as at least 99% by weight.

[0747] Unless otherwise indicated, substantially purified form refers to any stereoisomeric or enantiomeric form of the compound. For example, in one embodiment, substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, substantially purified form refers to one stereoisomer, e.g., an optically pure stereoisomer. In one embodiment, substantially purified form refers to a mixture of enantiomers. In one embodiment, substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, substantially purified form refers to one enantiomer, e.g., an optically pure enantiomer.

[0748] In one embodiment, the contaminants account for no more than 50% by weight, such as no more than 40% by weight, such as no more than 30% by weight, such as no more than 20% by weight, such as no more than 10% by weight, such as no more than 5% by weight, such as no more than 3% by weight, such as no more than 2% by weight, such as no more than 1% by weight.

[0749] Unless otherwise indicated, contaminants refer to other compounds other than stereoisomers or enantiomers. In one embodiment, contaminants refer to other compounds and other stereoisomers. In one embodiment, contaminants refer to other compounds and other enantiomers.

[0750] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., on a molar basis, 60% of the compound is the desired stereoisomer or enantiomer and 40% is the undesired stereoisomer or enantiomer), such as at least 70% optically pure, such as at least 80% optically pure, such as at least 90% optically pure, such as at least 95% optically pure, such as at least 97% optically pure, such as at least 98% optically pure, such as at least 99% optically pure.

[0751] Isomers

[0752] Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, anisotropic, stereoisomer, tautomeric, conformational or anomeric forms, including but not limited to cis and trans; E and Z; c, t and r; endo and extrinsic; R, S and meso; D and L; d and l; (+) and (-); keto, enol and enolate; syn and anti; alpha and beta; upright and equatorial; boat, chair, twist, envelope and half-chair; combinations thereof, hereinafter collectively referred to as "isomers" (or "isomer forms").

[0753] It should be noted that, except for the discussion below regarding tautomeric forms, the term "isomer" as used herein specifically excludes structural (or constitutional) isomers (i.e., isomers that differ in the connectivity between the atoms rather than merely in the spatial location of the atoms). For example, a reference to methoxy, -OCH3, should not be construed as a reference to its structural isomer hydroxymethyl, -CH2OH. Similarly, a reference to o-chlorophenyl should not be construed as a reference to its structural isomer m-chlorophenyl. However, a reference to a class of structures is likely to include structural isomeric forms that fall into that class (e.g., C 1-7 The alkyl group includes n-propyl and isopropyl; the butyl group includes n-butyl, isobutyl, sec-butyl and tert-butyl; the methoxyphenyl group includes o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl).

[0754] The above exclusion does not relate to tautomeric forms, such as the keto form, the enol form and the enolate form, as in, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione / enethiol, N-nitroso / hydroxyazo, and nitro / acid-nitro.

[0755]

[0756] It should be noted that the term "isomer" specifically includes compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; etc.

[0757] Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including mixtures thereof (e.g., racemic mixtures). Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are known in the art or are readily obtained by employing the methods taught herein or known methods in a known manner.

[0758] Salts

[0759] It may be convenient or desirable to prepare, purify and / or handle a corresponding salt of a compound, such as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci. , volume 66, pages 1-19.

[0760] For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then a suitable cation may be used to form a salt. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + ; Alkaline earth metal cations, such as Ca 2+ and Mg 2+ ; and other cations such as Al +3 Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + NR4 + ). Some examples of suitable substituted ammonium ions are those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0761] If the compound is cationic, or has a functional group that could be cationic (e.g., -NH2 could be -NH3 + ), then a suitable anion can be used to form a salt. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0762] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polyorganic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

[0763] Unless otherwise stated, a reference to a particular compound also includes its salt forms.

[0764] Solvates and Hydrates

[0765] It may be convenient or desirable to prepare, purify and / or process the corresponding solvate of a compound. The term "solvate" is used herein in a conventional sense to refer to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, such as a monohydrate, a dihydrate, a trihydrate, etc.

[0766] Unless otherwise stated, a reference to a particular compound also includes its solvate and hydrate forms.

[0767] Chemical synthesis

[0768] Methods for chemically synthesizing the compounds of the invention are described herein. These and / or other well-known methods may be modified and / or adapted in a known manner to facilitate the synthesis of other compounds of the invention.

[0769] Composition

[0770] One aspect of the present invention pertains to a composition (eg, a pharmaceutical composition) comprising a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0771] Another aspect of the present invention relates to a method of preparing a composition (eg, a pharmaceutical composition) comprising mixing a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0772] use

[0773] The compounds described herein are believed to be potent inhibitors of ALCAT1.

[0774] Therefore, it is believed that the compounds described herein are useful in treating aging and age-related diseases.

[0775] Therefore, it is believed that the compounds described herein are useful for treating diseases characterized by one or more of oxidative stress, CL deficiency, docosahexaenoic acid (DHA) enrichment in CL, and mitochondrial dysfunction.

[0776] Therefore, it is believed that the compounds described herein are useful for treating diseases or conditions associated with mitochondrial dysfunction.

[0777] Thus, it is believed that the compounds described herein are useful for treating a disease selected from the group consisting of obesity (such as diet-induced obesity), diabetes (such as type 2 diabetes), diabetic complications (such as neuropathy, cardiomyopathy, retinopathy, and erectile dysfunction), fatty liver disease, cardiovascular disease, neurodegenerative disease, metabolic disease, insulin resistance, and cancer.

[0778] Therefore, it is believed that the compounds described herein are useful for treating a disease selected from the group consisting of stroke, ischemia and reperfusion injury.

[0779] Therefore, it is believed that the compounds described herein are useful in treating Barth syndrome.

[0780] Use in inhibition methods

[0781] One aspect of the invention is a compound as described herein for use in a method of inhibiting the expression, function or activity of ALCAT1 in vivo or in vitro.

[0782] One aspect of the invention is a compound as described herein for use in a method of enhancing the expression, function or activity of MFN2, eg, compared to a baseline control.

[0783] One aspect of the invention is a compound as described herein for use in a method of reducing oxidative stress as measured by reactive oxidative species (ROS), eg, compared to a baseline control.

[0784] One aspect of the present invention is a compound as described herein for use in a method of modulating the structure, function, activity and / or expression of cardiolipin (CL).

[0785] Use in therapeutic approaches

[0786] One aspect of the invention is a compound as described herein for use in treating the human or animal body by therapy. For example, one aspect of the invention is a compound according to one of formula (I), (IA) or (IB) for use in treating the human or animal body by therapy.

[0787] One aspect of the present invention is a compound according to formula (I):

[0788]

[0789] or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in treating the human or animal body by therapy,

[0790] in:

[0791] X is selected from O and S;

[0792] G 1 and G 2 are each independently selected from N and CH;

[0793] A is selected from

[0794] H,

[0795] Optionally, one or more groups R A1 Substituted C 1-6 Straight-chain or branched alkyl or alkenyl,

[0796] Optionally, one or more groups R B1 substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,

[0797] Optionally, one or more groups R B2 a substituted 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S,

[0798] -CN,

[0799] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0800] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 、-NR D5 COR C2 ,as well as

[0801] -SR E1 ;

[0802] L is a single bond, or a group L A ,

[0803] Where LA Selected from

[0804] -NR L C(=O)-*, -C(=O)NR L- *,

[0805] -NR L C(=X L )NR L -*,

[0806] -SO2-NR L -*, -NR L -SO2-*,

[0807] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[0808] The asterisk (*) indicates 1 The connection point;

[0809] X L Selected from O and S;

[0810] R L Selected from

[0811] -H,

[0812] -C(=O)(C 1-3 alkyl),

[0813] -P(=O)(OH)2, and

[0814] -S(=O)2NH2;

[0815] When L is a single bond, R 1 is NH2;

[0816] When L is L A When R 1 For R 1L , where R 1L Selected from

[0817] C 1-6 a straight or branched unsubstituted alkyl group;

[0818] Optionally, one to three groups R PH Substituted phenyl,

[0819] Optionally, one or more groups R B3 substituted 5-membered or 6-membered cycloalkyl,

[0820] Optionally, one or more groups R B4Substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and

[0821] Optionally, one or more groups R B5 substituted 8- to 10-membered bicyclic or heterobicyclic containing 1-3 heteroatoms selected from N, O and S;

[0822] Each R PH Independently selected from

[0823] Optionally, one or more groups R A2 Substituted C 1-6 a straight-chain or branched alkyl, alkenyl or alkynyl group,

[0824] Optionally, one or more groups R A3 Substituted phenyl,

[0825] Naphthyl,

[0826] -F, -Cl, -Br, -I,

[0827] -COOH, -COOR C1 、-COR C2 , -CONH2, -COONH2, -CONHR D1 、-CON(R D2 )2,

[0828] -NH2, -NHR D4 、-NHR D8 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOH、-NHCOR C2 、-NR D7 COOR C1 、-NR D5 COR C2 、-NHSO2(C 1-3 alkyl),

[0829] -SO2NH2, -SO2NHR D1 、-SO2N(R D2 2. -SO2R E2 、-SR E1 ,

[0830] -NO2,

[0831] -CN,

[0832] -OH, and -OR PH4 ;

[0833] Where RPH4 Selected from

[0834] Phenyl,

[0835] Benzyl, and

[0836] Optionally, one or more groups R A5 Substituted C 1-6 Straight or branched chain alkyl;

[0837] Q is selected from (Q1) and (Q2)

[0838]

[0839] The two asterisks (**) indicate the connection points with L;

[0840] Q 1A , Q 2A , Q 3A and Q 4A Two of them are CH;

[0841] Q 1A , Q 2A , Q 3A and Q 4A The other two are independently selected from N, CH and CR Q1 ;

[0842] Q 1B , Q 2B , Q 3B and Q 4B Both of them are CH.

[0843] Q 1B , Q 2B , Q 3B and Q 4B The other two are independently selected from N, CH and CR Q2 ;

[0844] Each R Q1 and each R Q2 Independently selected from

[0845] -F, -Cl, -Br, -I,

[0846] C 1-6 Straight-chain or branched unsubstituted alkyl,

[0847] -OH、-O(C 1-6 alkyl),

[0848] -CN, and

[0849] -N(R D3 )2;

[0850] RC1 and R C2 Each independently selected from

[0851] Optionally, one or more groups R A6 Substituted C 1-6 Straight or branched chain alkyl;

[0852] Optionally one or two groups R E3 substituted 5-membered heteroaryl containing a single heteroatom selected from N, O and S;

[0853] R D1 To R D7 Each independently selected from

[0854] Optionally, one or more groups R A7 Substituted C 1-6 Straight or branched alkyl group,

[0855] -COOH, -COOR C1 、-COR C2 ,

[0856] -C(=NH)NH2,

[0857] Or when two R D2 or two R D3 When groups are attached to a single nitrogen atom, they may, together with the nitrogen atom to which they are attached, form a D9 Substituted 5- or 6-membered heterocyclyl containing 1 to 3 ring heteroatoms selected from N, O and S;

[0858] Where R D9 is optionally substituted by one or more groups R A8 Substituted C 1-6 Straight or branched chain alkyl;

[0859] R D8 is a C containing one or two N atoms optionally substituted by one or more groups selected from 5-6 Heterocyclic group:

[0860] -SH, and

[0861] -C(=O)OR D5A , where R D5A is phenyl or benzyl optionally substituted by a NO2 group;

[0862] R E1 and R E2 Each independently selected from C 1-6 a straight or branched unsubstituted alkyl, alkenyl or alkynyl group;

[0863] RE3 Independently selected from

[0864] -SH; and

[0865] -C(=O)OR E4 ;

[0866] R B1 To R B5 Each independently selected from

[0867] Optionally, one or more groups R A9 Substituted C 1-6 Straight or branched alkyl group,

[0868] -F, -Cl, -Br,

[0869] -OH、-O(C 1-3 alkyl),

[0870] -CN,

[0871] -NO2,

[0872] -COOH, -COOR C1 、-COR C2 , -CONH2, -CONHR D1 、-CON(R D2 )2,

[0873] -NH2, -NHR D4 、-N(R D3 )2, -NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 ;

[0874] R E4 Independently selected

[0875] Optionally one or two groups R A10 substituted phenyl or benzyl;

[0876] R A1 To R A10 Each independently selected from

[0877] -F, -Cl, -Br,

[0878] -OH, -OR T

[0879] -CN, -NO2,

[0880] -C(=O)R T , -COOH, -COOR T 、-CON(R G )2,

[0881] -NH2, -NHR T 、-N(R T )2, -NHC(=O)(R F ) and -N(R D9 )2;

[0882] R F Selected from

[0883] C 1-6 Straight or branched chain unsubstituted alkyl, and

[0884] 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S;

[0885] The group -N(R G )2 is selected from C optionally with one or more selected from linear or branched 1-4 substituted azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidino, piperazino, NC 1-4 alkyl-piperazino, morpholino, azepinyl or diazepinyl;

[0886] R T C 1-6 Straight or branched chain unsubstituted alkyl; and

[0887] Two R's D9 The groups together with the nitrogen atom to which they are attached form a group selected from

[0888] 5-membered heteroaryl groups containing one or two nitrogen atoms; and

[0889] A 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O and S.

[0890] In some embodiments,

[0891] R L Selected from

[0892] -H, and -C(=O)(C 1-3 alkyl);

[0893] And in -N(R D9 )2 group, two R D9 The groups together with the nitrogen atom to which they are attached form a 5-membered heteroaryl group containing one or two nitrogen atoms.

[0894] In some embodiments, the present invention provides a compound as described herein for use in treating senescence or an age-related disease.

[0895] In some embodiments, the present invention provides a compound as described herein for use in treating a disease characterized by one or more of oxidative stress, CL deficiency, docosahexaenoic acid (DHA) enrichment in CL, and mitochondrial dysfunction.

[0896] In some embodiments, the present invention provides a compound as described herein for use in treating or preventing a disease or disorder associated with mitochondrial dysfunction.

[0897] In some embodiments, the present invention provides a compound as described herein for use in treating a disease selected from the group consisting of obesity (such as diet-induced obesity), diabetes (such as type 2 diabetes), diabetic complications (such as neuropathy, cardiomyopathy, retinopathy, and erectile dysfunction), fatty liver disease, cardiovascular disease, neurodegenerative disease, metabolic disease, insulin resistance, and cancer.

[0898] In some embodiments, the present invention provides a compound as described herein for use in treating a disease selected from stroke, ischemia, and reperfusion injury.

[0899] In some embodiments, the present invention provides a compound as described herein for use in preventing or treating Barth syndrome.

[0900] Use in drug production

[0901] One aspect of the invention is the use of a compound as described herein in the preparation of a medicament for treating the human or animal body by therapy. For example, one aspect of the invention is the use of a compound according to one of formula (I), (IA) or (IB) in the preparation of a medicament for treating the human or animal body by therapy.

[0902] One aspect of the present invention is the use of a compound as described herein in the preparation of a medicament for the treatment of aging and age-related diseases.

[0903] One aspect of the invention is the use of a compound as described herein in the preparation of a medicament for treating a disease characterized by one or more of oxidative stress, CL deficiency, docosahexaenoic acid (DHA) enrichment in CL, and mitochondrial dysfunction.

[0904] One aspect of the invention is the use of a compound as described herein in the preparation of a medicament for the treatment of a disease or disorder associated with mitochondrial dysfunction.

[0905] In some embodiments, the present invention provides the use of a compound as described herein in the preparation of a medicament for treating a disease selected from the group consisting of obesity (such as diet-induced obesity), diabetes (such as type 2 diabetes), diabetic complications (such as neuropathy, cardiomyopathy, retinopathy, and erectile dysfunction), fatty liver disease, cardiovascular disease, neurodegenerative disease, metabolic disease, insulin resistance, and cancer.

[0906] In some embodiments, the present invention provides the use of a compound as described herein in the preparation of a medicament for treating a disease selected from stroke, ischemia and reperfusion injury.

[0907] In some embodiments, the present invention provides the use of a compound described herein in the preparation of a medicament for preventing or treating Barth syndrome.

[0908] Treatment

[0909] Another aspect of the invention is a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition. For example, one aspect of the invention is a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to one of formula (I), (IA) or (IB), preferably in the form of a pharmaceutical composition.

[0910] One aspect of the invention is a method of treating or preventing mitochondrial dysfunction in vitro or in vivo, the method comprising administering to a cell or a patient a therapeutically effective amount of a compound as described herein, and preventing or treating mitochondrial dysfunction in vitro or in vivo.

[0911] Diseases and conditions

[0912] As described above, ALCAT1 activity is known to be associated with mitochondrial dysfunction in disease. Therefore, as inhibitors of ALCAT1, the compounds described herein are useful for treating or preventing a variety of age-related diseases and conditions associated with mitochondrial dysfunction.

[0913] In some embodiments, the treatment is treatment of senescence.

[0914] In some embodiments, the treatment is treatment of an age-related disease.

[0915] In some embodiments, the treatment is treatment of a disease characterized by one or more of oxidative stress, CL deficiency, docosahexaenoic acid (DHA) enrichment in CL, and mitochondrial dysfunction.

[0916] In some embodiments, the treatment is treatment of a disease or disorder associated with mitochondrial dysfunction.

[0917] In some embodiments, the treatment is treatment of obesity.

[0918] In some embodiments, the treatment is treatment of diabetes. In some embodiments, the treatment is treatment of type 2 diabetes.

[0919] In some embodiments, the treatment is treatment of diabetic complications. In some embodiments, the treatment is treatment of neuropathy. In some embodiments, the treatment is treatment of cardiomyopathy. In some embodiments, the treatment is treatment of retinopathy. In some embodiments, the treatment is treatment of erectile dysfunction.

[0920] In some embodiments, the treatment is treatment of fatty liver disease.

[0921] In some embodiments, the treatment is treatment of cardiovascular disease.

[0922] In some embodiments, the treatment is treatment of a neurodegenerative disease. In some embodiments, the treatment is treatment of Alzheimer's disease.

[0923] In some embodiments, the treatment is treatment of a metabolic disease.

[0924] In some embodiments, the treatment is treatment of insulin resistance.

[0925] In some embodiments, the treatment is treatment of cancer. In some embodiments, the treatment is treatment of a tumor that overexpresses ALCAT1, or a tumor in which inhibition of ALCAT1 promotes or improves the effect of a cytotoxic tumoricidal agent.

[0926] In some embodiments, the treatment is treatment of stroke, ischemia or reperfusion injury.

[0927] In some embodiments, the treatment is the prevention or treatment of Barth syndrome.

[0928] treat

[0929] The term "treatment" as used herein in the context of treating a disorder generally relates to treatment and therapy for humans or animals (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of a disorder, and includes reducing the rate of progression, reducing the rate of progression, alleviating the symptoms of a disorder, ameliorating a disorder, and curing a disorder. Treatment as a preventive measure (i.e., prevention) is also included. For example, the term "treatment" encompasses patients who have not yet developed a disorder but are at risk of developing a disorder.

[0930] For example, the term "treatment" encompasses use in a patient who may not yet have a disorder or condition but who is at risk of developing the disorder or condition.

[0931] As used herein, the term "therapeutically effective amount" refers to an amount of a compound, or a material, composition or dosage form containing a compound, which is effective to produce some desired therapeutic effect when administered according to the desired treatment regimen and corresponds to a reasonable benefit / risk ratio.

[0932] The term "treatment" includes combination therapy and therapy in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatment and therapy include, but are not limited to, chemotherapy (administration of active drugs, including, for example, drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiotherapy; and gene therapy.

[0933] Reagent test kit

[0934] One aspect of the invention relates to a kit comprising (a) a compound as described herein, or a composition comprising a compound as described herein, e.g., preferably provided in a suitable container and / or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

[0935] The written instructions may also include a list of indications that the compound is suitable for treating.

[0936] Route of administration

[0937] The compound or pharmaceutical composition comprising the compound may be administered to the subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0938] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, (e.g., through the mouth or nose)); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or reservoir, e.g., subcutaneous or intramuscular.

[0939] Subjects / Patients

[0940] The subject / patient can be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., a kangaroo, a wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lagomorph (e.g., a rabbit), an avian (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0941] Furthermore, the subject / patient may be in any of its developmental forms, such as a fetus.

[0942] In a preferred embodiment, the subject / patient is a human.

[0943] preparation

[0944] Although the compound can be administered alone, it is preferably presented as a pharmaceutical preparation (e.g., composition, preparation, medicament) comprising at least one compound as described herein and one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including but not limited to pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners. The preparation may also contain other active agents, such as other therapeutic or prophylactic agents.

[0945] Therefore, the present invention also provides pharmaceutical compositions as described above, and methods for preparing pharmaceutical compositions, the methods comprising mixing at least one compound as described herein with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art (e.g., carriers, diluents, excipients, etc.). If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0946] The term "pharmaceutically acceptable" as used herein relates to compounds, ingredients, materials, compositions, dosage forms, etc., which are suitable for use in contact with the tissues of the subject (e.g., human) of interest, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0947] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks, e.g. Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients , 5th edition, 2005.

[0948] The preparation can be prepared by any method well known in the pharmaceutical field. Such methods include the step of associating the compound with a carrier constituting one or more auxiliary ingredients. Generally, the preparation is prepared by uniformly and intimately associating the compound with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then shaping the product (if necessary).

[0949] The formulation can be prepared to provide fast release or slow release; immediate release, delayed release, timed release, or sustained release; or a combination thereof.

[0950] The formulation may suitably be a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, dragee, mouthwash, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, lozenges, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists or aerosols.

[0951] The formulation may be suitably provided as a patch, plaster, bandage, dressing, etc. impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients (including, for example, penetration enhancers, permeation enhancers and absorption enhancers). The formulation may also be suitably provided in the form of a reservoir or storage container.

[0952] The compound may be dissolved, suspended or mixed with one or more other pharmaceutically acceptable ingredients. The compound may be present in liposomes or other microparticles designed to target the compound, for example, to blood components or one or more organs.

[0953] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

[0954] Preparations suitable for buccal administration include mouthwashes, lozenges, candies, and patches, adhesive plasters, reservoirs and reservoirs. Lozenges are usually contained in compounds in a flavored base, which is usually sucrose and gum arabic or tragacanth. Candies are usually contained in compounds in an inert matrix, such as gelatin and glycerine, or sucrose and gum arabic. Mouthwashes are usually contained in compounds in a suitable liquid carrier.

[0955] Suitable formulations for sublingual administration include tablets, troches, lozenges, capsules and pills.

[0956] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, troches, lozenges, as well as patches, adhesive plasters, reservoirs, and depots.

[0957] Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, reservoirs, and reservoirs.

[0958] Suitable formulations for transdermal administration include gels, pastes, ointments, creams, lotions and oils, as well as patches, adhesive plasters, bandages, dressings, depots and reservoirs.

[0959] Tablets can be prepared by conventional means (e.g., compression or molding), optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a free-flowing form of a compound (such as a powder or granule) optionally with one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silicon dioxide); disintegrants (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methylparaben, propylparaben, sorbic acid); flavoring agents, flavor enhancers, and sweeteners in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the compound in the tablet using, for example, a variable proportion of hydroxypropylmethylcellulose to provide the desired release profile. Tablets may optionally have a coating, for example, to affect release, such as an enteric coating to release in parts of the gastrointestinal tract other than the stomach.

[0960] Ointments are generally prepared from the compound and a paraffin or water-miscible ointment base.

[0961] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least about 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the compound through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0962] Emulsions are usually prepared from a compound and an oil phase, which may optionally contain only an emulsifier (also called an emulsifying substance), or it may contain a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier used as a stabilizer. It is also preferred to include both oil and fat. The emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, and the wax, together with the oil and / or fat, constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0963] Suitable emulsifying substances and emulsion stabilizers include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The selection of suitable oil or fat for preparation is based on realizing the desired cosmetic properties, because the solubility of compound in the oil that most of the pharmaceutical emulsion preparations may be very low. Therefore, the ointment should preferably be a non-greasy, non-staining and washable product, with a suitable consistency to avoid leakage from a test tube or other container. Straight or branched mono- or dibasic alkyl esters can be used, such as diisoadipate, stearic acid isocetyl ester, propylene glycol diester of coconut oil fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or the branched ester mixture referred to as Crodamol CAP, the latter three are preferred esters. Depending on the desired property, these materials can be used alone or in combination. Alternatively, high melting point lipids can be used, such as white soft paraffin and / or liquid paraffin or other mineral oils.

[0964] Where the carrier is a liquid, formulations suitable for intranasal administration include, for example, nasal spray, nasal drops, or aerosol administration by nebulizer, including aqueous or oily solutions of the compound.

[0965] Where the carrier is a solid, formulations suitable for intranasal administration include those presented as, for example, a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, which is administered by inhalation, i.e., rapid inhalation through the nasal passages from a container of the powder held near the nasal cavity.

[0966] Formulations suitable for pulmonary administration (eg, by inhalation or insufflation) include those presented as an aerosol spray from pressurized packs, with the use of a suitable propellant (such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas).

[0967] Suitable formulations for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0968] Formulations suitable for rectal administration may be presented as a suppository with a suitable base containing, for example, a natural or hardened oil, wax, fat, semi-liquid or liquid polyol, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

[0969] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound such carriers as are known in the art to be appropriate.

[0970] Preparations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, antibacterial agents, suspending agents, thickeners, and solutes that make the preparation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohol, polyols, glycerol, vegetable oils, etc. Examples of suitable isotonic carriers for such preparations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 100 μg / mL, for example from about 10 ng / mL to about 10 μg / mL, for example from about 10 ng / mL to about 1 μg / mL. The preparation can be present in a unit dose or multi-dose sealed container (e.g., ampoule and vial), and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0971] dose

[0972] Those skilled in the art will recognize that the appropriate dosage of the compound and the composition comprising the compound may vary from patient to patient. Determining the optimal dosage will generally involve a balance between the therapeutic benefit and any risk or harmful side effects. The dosage level selected will depend on a variety of factors, including but not limited to the activity of the specific compound, the route of administration, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, the severity of the disease, and the patient's species, sex, age, weight, condition, general health, and previous medical history. The amount of the compound and the route of administration will ultimately be determined by a physician, veterinarian, or clinician, although the dosage will generally be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmfulness or harmful side effects.

[0973] Administration can be performed in one dose, continuously or intermittently (e.g., in appropriately spaced divided doses) throughout the course of treatment. Methods for determining the most effective means of administration and dosage are well known to those skilled in the art and will vary depending on the formulation used for treatment, the purpose of treatment, the target cell being treated, and the subject being treated. Single or multiple administrations can be performed with dosage levels and patterns selected by the attending physician, veterinarian, or clinician.

[0974] When the compound is a salt, ester, amide, prodrug, etc., the administration amount is calculated based on the parent compound, so the actual weight to be used is increased proportionally.

[0975] Synthesis method

[0976] Another aspect of the invention is a method of synthesizing the compounds described herein.

[0977] In some embodiments, the method comprises the steps described in the general synthesis described herein.

[0978] Example

[0979] General synthetic route

[0980] Schemes 1 and 2 below show the general syntheses followed to prepare compounds according to the invention:

[0981] Solution 1

[0982]

[0983] Solution 2

[0984]

[0985] The syntheses of some specific compounds according to these reaction schemes are outlined in the examples below.

[0986] Example 1

[0987]

[0988] 3-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[0989] (Compound 192)

[0990] According to the synthetic procedure described in Scheme 1, 3-bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as follows:

[0991] a) N'-(3-nitrobenzoyl)furan-2-carbohydrazide: To a solution of 3-nitrobenzoic acid (10.0 g, 59.8 mmol) in dichloromethane (50 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (7.7 ml, 89.8 mmol) and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of 2-furanoic acid hydrazide (7.6 g, 60.4 mmol) and anhydrous sodium carbonate (6.3 g, 59.8 mmol) in tetrahydrofuran (50 mL) and water (50 mL) at 0°C. The mixture was stirred at 0°C for 1 h and at room temperature for 6 hr. A large amount of precipitation was observed. The product was collected by filtration and washed with water, then finally dried in vacuo to give 14.0 g (85.1% yield) of N'-(3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.

[0992] b) 2-(Furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole: N'-(3-nitrobenzoyl)furan-2-carbohydrazide (14.0 g, 50.9 mmol) was dissolved in phosphorus oxychloride (70 ml), and the mixture was stirred with heating at 80°C for 5 hr. The phosphorus oxychloride was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 12.3 g (93.9% yield) of 2-(furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole as a yellow solid.

[0993] c) 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline: A mixture of 2-(furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole (12.3 g, 47.8 mmol) and Raney nickel (2.0 g) in methanol (100 ml) was stirred at 50° C. for 16 h under a 2.0 MPa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (dichloromethane / methanol=50 / 1) to give 9.4 g (86.5% yield) of 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline as a white solid.

[0994] d) 3-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide: A mixture of 3-bromo-2-methoxybenzoic acid (122.0 mg, 0.53 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (0.5 ml) was stirred at reflux for 1 hr. Excess thionyl chloride was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol) and triethylamine (62.3 mg, 0.62 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (175.5 mg, 90.6% yield) as a white solid.

[0995] 1 H NMR (400MHz, DMSO): δ10.73(s,1H),8.59(s,1H),8.10(s,1H),7.92(d,J=8.0Hz,1H),7.83-7.80(m,2 H),7.63-7.59(m,2H),7.44(d,J=3.6Hz,1H),7.22(t,J=7.6Hz,1H),6.85-6.84(m,1H),3.84(s,3H);

[0996] For [M+H,C 20 H 15 BrN3O4] + LC-HRMS (ESI) calcd. 440.0246, found 440.0246.

[0997] Example 2

[0998]

[0999] 3-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1000] (Compound 193)

[1001] 3-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 3-chloro-2-methoxybenzoic acid (98.5 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (163.0 mg, 93.6% yield) as a yellow solid.

[1002] 1 H NMR (400MHz, DMSO): δ10.72(s,1H),8.59(s,1H),8.10(d,J=1.2Hz,1H),7.92(d,J=8.0Hz,1H),7.82(d,J=7.6Hz,1H),7.67(dd,J=1 .2,8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.57-7.55(m,1H),7.45(d,J=3.6Hz,1H),7.31-7.27(m,1H),6.85-6.84(m,1H),3.86(s,3H);

[1003] For [M+H,C 20 H 15 ClN3O4] + LC-HRMS (ESI) calculated value: 396.0751, found value 396.0756.

[1004] Example 3

[1005]

[1006] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1007] (Compound 120)

[1008] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 5-bromo-2-methoxybenzoic acid (122.0 mg, 0.53 mmol), 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol) and triethylamine (58.7 mg, 0.58 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (184.5 mg, 95.2% yield) as a white solid.

[1009] 1 H NMR (400MHz, DMSO): δ10.50(s,1H),8.56(s,1H),8.10(d,J=0.8Hz,1H),7.91(d,J=8.4Hz,1H),7.80(d,J=7.6Hz,1H),7.74(d,J=2.8Hz ,1H),7.68(dd,J=2.8,8.8Hz,1H),7.60(t,J=8.0Hz,1H),7.48(d,J=3.2Hz,1H),7.17(d,J=9.2Hz,1H),6.85-6.83(m,1H),3.89(s,3H);

[1010] For [M+H,C 20 H 15 BrN3O4] + LC-HRMS (ESI) calcd. 440.0246, found 440.0221.

[1011] Example 4

[1012]

[1013] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1014] (Compound 124)

[1015] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 5-chloro-2-methoxybenzoic acid (98.5 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (162.9 mg, 93.5% yield) as a white solid.

[1016] 1 H NMR (400MHz, DMSO): δ10.50(s,1H),8.57(s,1H),8.10(d,J=0.8Hz,1H),7.91(d,J=8.4Hz,1H),7.80(d,J=7 .6Hz,1H),7.64-7.55(m,3H),7.44(d,J=3.6Hz,1H),7.23(d,J=9.2Hz,1H),6.85-6.83(m,1H),3.90(s,3H);

[1017] For [M+H,C 20 H 15 ClN3O4] + LC-HRMS (ESI) calculated value: 396.0751, found value 396.0749.

[1018] Example 5

[1019]

[1020] N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)

[1021] Benzamide

[1022] (Compound 279)

[1023] N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(trifluoromethoxy)benzoic acid (124.7 mg, 0.53 mmol) and 3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (177.9 mg, 90.8% yield) as a white solid.

[1024] 1 H NMR (400MHz, DMSO): δ10.53(s,1H),8.57(s,1H),8.11-8.10(m,1H),7.93-7.91(m,1H),7.82-7.80(m,1H) ),7.63-7.53(m,3H),7.45(dd,J=0.4,3.6Hz,1H),7.31(d,J=8.8Hz,1H),6.85-6.84(m,1H),3.93(s,3H);

[1025] For [M+H,C 21 H 15 F3N3O5] + LC-HRMS (ESI) calcd. 446.0964, found 446.0960.

[1026] Example 6

[1027]

[1028] N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide

[1029] (Compound 197)

[1030] N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide can be prepared as in Example 1, but from 2-methoxy-5-methylbenzoic acid (87.7 mg, 0.53 mmol) and 3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (155.8 mg, 94.3% yield) as a white solid.

[1031] 1 H NMR (400MHz, DMSO): δ10.39(s,1H),8.60(s,1H),8.10(d,J=0.8Hz,1H),7.92(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.59(t,J= 8.0Hz,1H),7.47-7.44(m,2H),7.33(dd,J=2.0,8.4Hz,1H),7.09(d,J=8.4Hz,1H),6.85-6.84(m,1H),3.88(s,3H),2.30(s,3H);

[1032] For [M+H,C 21 H 18 N3O4] + LC-HRMS (ESI) calcd.: 376.1297, found 376.1310.

[1033] Example 7

[1034]

[1035] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1036] (Compound 123)

[1037] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 1, but from 5-chloro-2-propoxybenzoic acid (113.3 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (171.8 mg, 92.1% yield) as a white solid.

[1038] 1H NMR (400MHz, DMSO): δ10.47(s,1H),8.59(s,1H),8.10(d,J=0.8Hz,1H),7.86(d, J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),7.64(d,J=2.8Hz,1H),7.61(t,J=8.0Hz,1H ),7.54(dd,J=2.8,8.8Hz,1H),7.44(d,J=3.6Hz,1H),7.22(d,J=8.8Hz,1H),6.8 5-6.84(m,1H),4.08(t,J=6.4Hz,2H),1.81-1.74(m,2H),0.96(t,J=7.4Hz,3H);

[1039] For [M+H,C 22 H 19 ClN3O4] + LC-HRMS (ESI) calcd. 424.1064, found 424.1078.

[1040] Example 8

[1041]

[1042] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1043] (Compound 119)

[1044] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 1, but from 5-bromo-2-propoxybenzoic acid (136.8 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (191.4 mg, 92.9% yield) as a white solid.

[1045] 1H NMR (400MHz, DMSO): δ10.47(s,1H),8.58(s,1H),8.10(d,J=1.2Hz,1H),7.86(d ,J=8.4Hz,1H),7.80(d,J=7.6Hz,1H),7.75(d,J=2.4Hz,1H),7.66(dd,J=2.4,8 .8Hz,1H),7.63-7.59(m,1H),7.44(d,J=3.2Hz,1H),7.17(d,J=9.2Hz,1H),6.8 5-6.84(m,1H),4.07(t,J=6.4Hz,2H),1.80-1.73(m,2H),0.96(t,J=7.4Hz,3H);

[1046] For [M+H,C 22 H 19 BrN3O4] + LC-HRMS (ESI) calculated value: 468.0559, found value 468.0568.

[1047] Example 9

[1048]

[1049] 2-Ethoxy-5-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1050] (Compound 125)

[1051] 2-Ethoxy-5-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-ethoxy-5-fluorobenzoic acid (97.2 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (159.4 mg, 92.1% yield) as a beige solid.

[1052] 1H NMR (400MHz, DMSO): δ10.49(s,1H),8.61(s,1H),8.11(d,J=0.8Hz,1H),7.88-7.85(m,1H),7.81(d,J=7.6Hz,1H),7.63-7.59(m,1H),7.50(dd,J=3.2 ,8.8Hz,1H),7.45(d,J=3.2Hz,1H),7.40-7.34(m,1H),7.22(dd,J=4.4,9. 2Hz,1H),6.85-6.84(m,1H),4.17(q,J=6.8Hz,2H),1.39(t,J=7.0Hz,3H);

[1053] For [M+H,C 21 H 17 FN3O4] + LC-HRMS (ESI) calcd. 394.1203, found 394.1200.

[1054] Example 10

[1055]

[1056] 5-Chloro-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1057] (Compound 122)

[1058] 5-Chloro-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 5-chloro-2-ethoxybenzoic acid (105.9 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (170.6 mg, 94.6% yield) as a light yellow solid.

[1059] 1H NMR (400MHz, DMSO): δ10.48(s,1H),8.59(s,1H),8.11(d,J=1.2Hz,1H),7.87(d,J=7.6Hz,1H),7.81(d,J=7.6Hz,1H),7.66(d,J=2.8Hz,1H),7.61( t,J=8.0Hz,1H),7.57-7.54(m,1H),7.44(d,J=3.2Hz,1H),7.22(d,J=8.8 Hz,1H),6.85-6.84(m,1H),4.18(q,J=6.8Hz,2H),1.38(t,J=7.0Hz,3H);

[1060] For [M+H,C 21 H 17 ClN3O4] + LC-HRMS (ESI) calcd. 410.0908, found 410.0910.

[1061] Embodiment 11

[1062]

[1063] 5-Bromo-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1064] (Compound 118)

[1065] 5-Bromo-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 5-bromo-2-ethoxybenzoic acid (129.4 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (187.9 mg, 94.0% yield) as a white solid.

[1066] 1H NMR (400MHz, DMSO): δ10.47(s,1H),8.59(s,1H),8.10(d,J=1.2Hz,1H),7.87(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.77(d,J=2.4Hz,1H),7.67(dd,J =2.8,8.8Hz,1H),7.61(t,J=8.0Hz,1H),7.44(d,J=3.6Hz,1H),7.17(d,J=8 .8Hz,1H),6.85-6.84(m,1H),4.17(q,J=6.8Hz,2H),1.38(t,J=6.8Hz,3H);

[1067] For [M+H,C 21 H 17 BrN3O4] + LC-HRMS (ESI) calcd. 454.0402, found 454.0406.

[1068] Example 12

[1069]

[1070] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-iodobenzamide

[1071] (Compound 200)

[1072] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-iodobenzamide can be prepared as in Example 1, but from 2-ethoxy-5-iodobenzoic acid (154.2 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (197.6 mg, 89.6% yield) as a light yellow solid.

[1073] 1H NMR (400MHz, DMSO): δ10.44(s,1H),8.58(s,1H),8.10(d,J=0.8Hz,1H),7.90(d,J=2.4Hz,1H),7.86(d,J=8.4Hz,1H),7.82-7.79(m,2 H),7.62-7.58(m,1H),7.44(d,J=3.2Hz,1H),7.04(d,J=8.8Hz,1H),6.85-6.84(m,1H),4.17(q,J=6.8Hz,2H),1.38(t,J=6.8Hz,3H);

[1074] For [M+H,C 21 H 17 IN3O4] + LC-HRMS (ESI) calcd. 502.0264, found 502.0264.

[1075] Embodiment 13

[1076]

[1077] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide

[1078] (Compound 218)

[1079] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 1, but from 2-ethoxy-5-methylbenzoic acid (95.1 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (160.4 mg, 93.6% yield) as a white solid.

[1080] 1H NMR (400MHz, DMSO): δ10.40(s,1H),8.63(s,1H),8.11(d,J=1.2Hz,1H),7.86( d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.60(t,J=8.0Hz,1H),7.52(d,J=2.0Hz ,1H),7.45(d,J=2.8Hz,1H),7.32(dd,J=2.0,8.4Hz,1H),7.08(d,J=8.4Hz,1H) ,6.85-6.84(m,1H),4.16(q,J=6.8Hz,2H),2.30(s,3H),1.40(t,J=6.8Hz,3H);

[1081] For [M+H,C 22 H 20 N3O4] + LC-HRMS (ESI) calculated value: 390.1454, found value 390.1458.

[1082] Embodiment 14

[1083]

[1084] 2-Ethoxy-5-ethyl-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1085] (Compound 219)

[1086] 2-Ethoxy-5-ethyl-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-ethoxy-5-ethylbenzoic acid (102.6 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (170.6 mg, 96.1% yield) as a white solid.

[1087] 1H NMR (400MHz, DMSO): δ10.40(s,1H),8.63(s,1H),8.11(d,J=1.2Hz,1H),7.86(d,J=8 .0Hz,1H),7.79(d,J=8.0Hz,1H),7.60(t,J=8.0Hz,1H),7.54(d,J=2.0Hz,1H),7.44( d,J=3.6Hz,1H),7.35-7.33(m,1H),7.10(d,J=8.4Hz,1H),6.85-6.84(m,1H),4.16( q,J=6.8Hz,2H),2.61(q,J=7.6Hz,2H),1.40(t,J=6.8Hz,3H),1.18(t,J=7.6Hz,3H);

[1088] For [M+H,C 23 H 22 N3O4] + LC-HRMS (ESI) calcd. 404.1610, found 404.1607.

[1089] Embodiment 15

[1090]

[1091] 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethoxy)benzamide

[1092] (Compound 211)

[1093] 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethoxy)benzamide can be prepared as in Example 1, but from 2-fluoro-5-(trifluoromethoxy)benzoic acid (118.3 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (179.4 mg, 94.1% yield) as a white solid.

[1094] 1H NMR (400MHz, DMSO): δ10.87(s,1H),8.53(s,1H),8.10(d,J=1.2Hz,1H),7.94(d,J=8.0Hz,1H),7.84(d,J=7. 6Hz,1H),7.78-7.76(m,1H),7.68-7.61(m,2H),7.58-7.54(m,1H),7.45(d,J=3.6Hz,1H),6.85-6.84(m,1H);

[1095] For [M+H,C 20 H 12 F4N3O4] + LC-HRMS (ESI) calcd. 434.0764, found 434.0765.

[1096] Example 16

[1097]

[1098] 5-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)

[1099] Benzamide

[1100] (Compound 228)

[1101] 5-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (125.7 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (178.7 mg, 90.8% yield) as a white solid.

[1102] 1H NMR (400MHz, DMSO): δ10.54(s,1H),8.56(s,1H),8.11(d,J=0.8Hz,1H),7.87-7.84(m,1H),7.81(d,J=8.0Hz,1H),7.61(d, J=8.0Hz,1H),7.49(dd,J=3.2,8.4Hz,1H),7.45-7.41(m,2H),7.36-7.32(m,1H),6.85-6.84(m,1H),4.86(q,J=8.8Hz,2H);

[1103] For [M+H,C 21 H 14 F4N3O4] + LC-HRMS (ESI) calcd. 448.0920, found 448.0917.

[1104] Embodiment 17

[1105]

[1106] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)

[1107] Benzamide

[1108] (Compound 225)

[1109] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-chloro-2-(2,2,2-trifluoroethoxy)benzoic acid (134.4 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (189.6 mg, 92.9% yield) as a white solid.

[1110] 1H NMR (400MHz, DMSO): δ10.55(s,1H),8.54(s,1H),8.11-8.10(m,1H),7.86(d,J=8.4Hz,1H),7.81(d,J=7.6Hz,1 H),7.66-7.59(m,3H),7.44(d,J=3.6Hz,1H),7.34(d,J=8.8Hz,1H),6.85-6.84(m,1H),4.88(q,J=8.8Hz,2H);

[1111] For [M+H,C 21 H 14 ClF3N3O4] + LC-HRMS (ESI) calcd. 464.0625, found 464.0627.

[1112] Embodiment 18

[1113]

[1114] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)

[1115] Benzamide

[1116] (Compound 226)

[1117] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 1, but from 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (157.9 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (207.5 mg, 92.8% yield) as a white solid.

[1118] 1H NMR (400MHz, DMSO): δ10.55(s,1H),8.54(s,1H),8.13(d,J=1.2Hz,1H),7.85(d,J=8.0Hz,1H),7.81(d,J=7.6Hz,1H),7.77- 7.72(m,2H),7.61(t,J=8.0Hz,1H),7.44(d,J=3.2Hz,1H),7.28(d,J=8.4Hz,1H),6.85-6.84(m,1H),4.88(q,J=8.8Hz,2H);

[1119] For [M+H,C 21 H 14 BrF3N3O4] + LC-HRMS (ESI) calcd. 508.0120, found 508.0105.

[1120] Embodiment 19

[1121]

[1122] 3-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1123] (Compound 220)

[1124] 3-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 1, but from 3-fluoro-2-methoxybenzoic acid (89.8 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (158.0 mg, 94.7% yield) as an off-white solid.

[1125] 1 H NMR (400MHz, DMSO): δ10.66(s,1H),8.59(s,1H),8.11(d,J=1.2Hz,1H),7.92(d,J=8.0Hz,1H),7.81(d,J=8.0H z,1H),7.61(t,J=8.0Hz,1H),7.48-7.39(m,3H),7.27-7.22(m,1H),6.85-6.83(m,1H),3.94(d,J=1.2Hz,3H);

[1126] For [M+H,C 20 H 15 FN3O4] + LC-HRMS (ESI) calcd.: 380.1047, found 380.1048.

[1127] Embodiment 20

[1128]

[1129] 3,5-Dibromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1130] (Compound 168)

[1131] 3,5-Dibromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide was prepared as described in Example 1, but from 3,5-dibromo-2-methoxybenzoic acid (163.6 mg, 0.53 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.44 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (205.0 mg, 89.7% yield) as a white solid.

[1132] 1 H NMR (400MHz, DMSO): δ10.80(s,1H),8.55(s,1H),8.10(s,1H),8.06(d,J=2.0Hz,1H),7.90(d,J=8.0Hz ,1H),7.84-7.82(m,2H),7.62(t,J=8.0Hz,1H),7.44(d,J=3.6Hz,1H),6.85-6.83(m,1H),3.84(s,3H);

[1133] For [M+H,C 20 H 14 Br2N3O4] + LC-HRMS (ESI) calculated value: 517.9351, found value 517.9350.

[1134] Embodiment 21

[1135]

[1136] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1137] (Compound 184)

[1138] According to the synthetic procedure described in Scheme 1, 5-chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as follows:

[1139] a) N'-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide: To a solution of 4-fluoro-3-nitrobenzoic acid (10.0 g, 54.0 mmol) in dichloromethane (50 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (6.9 ml, 81.0 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride.

[1140] The acid chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of 2-furanoic acid hydrazide (6.9 g, 54.5 mmol) and anhydrous sodium carbonate (5.7 g, 54.0 mmol) in tetrahydrofuran (50 mL) and water (50 mL) at 0 ° C. The mixture was stirred for 1 h at 0 ° C and for 6 hr at room temperature. A large amount of precipitation was observed. The product was collected by filtration and washed with water, and then finally vacuum dried to obtain 14.4 g (91.0% yield) of N'-(4-fluoro-3-nitrobenzoyl) furan-2-carbohydrazide as a yellow solid.

[1141] b) 2-(4-Fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole: N'-(4-Fluoro-3-nitrobenzoyl)furan-2-carbohydrazide (14.4 g, 49.1 mmol) was dissolved in phosphorus oxychloride (70 ml), and the mixture was stirred with heating at 80°C for 5 hr. The phosphorus oxychloride was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 12.5 g (92.6% yield) of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole as a yellow solid.

[1142] c) 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline: A mixture of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole (12.5 g, 45.4 mmol) and Raney nickel (2.0 g) in methanol (100 ml) was stirred at 50° C. for 16 h under a 2.0 MPa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane / methanol=50 / 1) to give 9.3 g (83.6% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline as a white solid.

[1143] d) 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide: A mixture of 5-chloro-2-methoxybenzoic acid (91.3 mg, 0.49 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (0.5 ml) was stirred at reflux for 1 hr. Excess thionyl chloride was evaporated under reduced pressure to give the acid chloride.

[1144] The acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol) and triethylamine (57.8 mg, 0.57 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (dichloromethane / methanol=100 / 1) to give the title compound (154.9 mg, 91.8% yield) as a white solid.

[1145] 1 H NMR (400MHz, DMSO): δ10.40 (s, 1H), 8.92-8.90 (m, 1H), 8.10 (d, J = 1.2Hz, 1H), 7.91-7.87 (m, 2H), 7.65-7.56(m,2H),7.46(d,J=3.6Hz,1H),7.30(d,J=8.8Hz,1H),6.85-6.83(m,1H),4.01(s,3H);

[1146] For [M+H,C 20 H 14 ClFN3O4] + LC-HRMS (ESI) calcd. 414.0657, found 414.0658.

[1147] Embodiment 22

[1148]

[1149] 5-Chloro-2-ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1150] (Compound 216)

[1151] 5-Chloro-2-ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-ethoxybenzoic acid (98.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (159.6 mg, 91.5% yield) as a white solid.

[1152] 1 H NMR (400MHz, DMSO): δ10.43(s,1H),9.08(d,J=9.6Hz,1H),8.10(s,1H),7.94(d,J=2.8Hz,1H),7.86-7.82(m,1H),7.64-7 .55(m,2H),7.44(d,J=3.6Hz,1H),7.28(d,J=9.2Hz,1H),6.84-6.83(m,1H),4.27(q,J=6.8Hz,2H),1.48(t,J=6.8Hz,3H);

[1153] For [M+H,C 21 H 16 ClFN3O4] + LC-HRMS (ESI) calculated value: 428.0813, found value 428.0812.

[1154] Embodiment 23

[1155]

[1156] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1157] (Compound 128)

[1158] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 21, but from 2-methoxybenzoic acid (74.5 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (140.8 mg, 91.0% yield) as a white solid.

[1159] 1 H NMR (400MHz, DMSO): δ10.44(s,1H),9.01(d,J=6.0Hz,1H),8.11(d,J=1.2Hz,1H),7.99(d,J=6.4Hz,1H),7.90- 7.86(m,1H),7.63-7.57(m,2H),7.46(d,J=3.2Hz,1H),7.16(t,J=7.6Hz,1H),6.85-6.83(m,1H),4.03(s,3H);

[1160] For [M+H,C 20 H 15 FN3O4] + LC-HRMS (ESI) calculated value: 380.1047, found value 380.1052.

[1161] Embodiment 24

[1162]

[1163] 5-Bromo-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1164] (Compound 183)

[1165] 5-Bromo-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide can be prepared as in Example 21, but from 5-bromo-2-methoxybenzoic acid (113.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (179.5 mg, 96.0% yield) as a white solid.

[1166] 1 H NMR (400MHz, DMSO): δ10.40(s,1H),8.92-8.90(m,1H),8.11(d,J=1.2Hz,1H),8.00(d,J=2.4Hz,1H),7.93-7.89(m,1H),7.77(dd ,J=2.4,8.8Hz,1H),7.60(dd,J=8.8,10.4Hz,1H),7.47(d,J=3.6Hz,1H),7.26(d,J=9.2Hz,1H),6.85-6.84(m,1H),4.01(s,3H);

[1167] For [M+H,C 20 H 14 BrFN3O4] + LC-HRMS (ESI) calcd. 458.0152, found 458.0159.

[1168] Embodiment 25

[1169]

[1170] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide

[1171] (Compound 300)

[1172] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide can be prepared as in Example 21, but from 2-methoxy-5-methylbenzoic acid (81.4 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (154.4 mg, 96.2% yield) as a white solid.

[1173] 1H NMR (400MHz, DMSO): δ10.47(s,1H),9.03(d,J=5.6Hz,1H),8.11(d,J=1.2Hz,1H),7.91-7.87(m,1H),7.82(s,1H),7.61(dd,J=8 .8,10.4Hz,1H),7.47(d,J=3.2Hz,1H),7.44-7.41(m,1H),7.19(d,J=8.4Hz,1H),6.86-6.84(m,1H),4.01(s,3H),2.33(s,3H);

[1174] For [M+H,C 21 H 17 FN3O4] + LC-HRMS (ESI) calcd. 394.1203, found 394.1205.

[1175] Embodiment 26

[1176]

[1177] 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1178] (Compound 215)

[1179] 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-methoxy-5-methylbenzoic acid (81.4 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (150.1 mg, 93.5% yield) as a white solid.

[1180] 1H NMR (400MHz, DMSO): δ10.47(s,1H),9.19(d,J=5.6Hz,1H),8.11(d,J=1.2Hz,1H),8.09-8.06(m,1H),7.88-7.84(m,1H),7.63-7.59(m, 2H),7.46(d,J=3.6Hz,1H),7.28(d,J=8.4Hz,1H),7.18-7.14(m,1H),6.85-6.84(m,1H),4.31(q,J=6.8Hz,2H),1.51(t,J=6.8Hz,3H);

[1181] For [M+H,C 21 H 17 FN3O4] + LC-HRMS (ESI) calculated value: 394.1203, found value 394.1228.

[1182] Embodiment 27

[1183]

[1184] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)

[1185] Benzamide

[1186] (Compound 313)

[1187] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 2-(2,2,2-trifluoroethoxy)benzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (160.0 mg, 87.7% yield) as a white solid.

[1188] 1H NMR (400MHz, DMSO): δ10.10(s,1H),8.93(d,J=1.6Hz,1H),8.11(d,J=1.2Hz,1H),7.92-7.85(m,2H),7.63-7.57( m,2H),7.46(d,J=3.2Hz,1H),7.34(d,J=8.4Hz,1H),7.25-7.22(m,1H),6.85-6.84(m,1H),4.98(q,J=8.8Hz,2H);

[1189] For [M+H,C 21 H 14 F4N3O4] + LC-HRMS (ESI) calcd. 448.0920, found 448.0918.

[1190] Embodiment 28

[1191]

[1192] 2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)

[1193] Benzamide

[1194] (Compound 314)

[1195] 2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)benzoic acid (99.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (156.8 mg, 89.5% yield) as a white solid.

[1196] 1H NMR (400MHz, DMSO): δ10.16(s,1H),8.99(d,J=6.0Hz,1H),8.11(d,J=0.8Hz,1H),7.95(d,J=6.4Hz,H),7.91-7.87(m,1H),7.63-7.58(m,2H),7. 46(d,J=3.2Hz,1H),7.33(d,J=8.4Hz,1H),7.22(t,J=7.6Hz,1H),6.85- 6.84(m,1H),6.50(tt,J=3.2,54.6Hz,1H),4.58(dt,J=3.2,14.4Hz,2H);

[1197] For [M+H,C 21 H 15 F3N3O4] + LC-HRMS (ESI) calcd. 430.1015, found 430.1007.

[1198] Embodiment 29

[1199]

[1200] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide

[1201] (Compound 315)

[1202] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 2-(2-fluoroethoxy)benzoic acid (90.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (155.8 mg, 92.8% yield) as a white solid.

[1203] 1H NMR (400MHz, DMSO): δ10.41(s,1H),9.12(d,J=5.6Hz,1H),8.12(s,1H),8.06(d,J=6.8Hz,H),7.91-7.88(m,1H),7.65-7.60(m,2H),7.48(d,J=3.6 Hz,1H),7.32(d,J=8.4Hz,1H),7.23-7.19(m,1H),6.86-6.85(m,1H),4.9 8-4.96(m,1H),4.86-4.84(m,1H),4.59-4.57(m,1H),4.51-4.50(m,1H);

[1204] For [M+H,C 21 H 16 F2N3O4] + LC-HRMS (ESI) calcd. 412.1109, found 412.1095.

[1205] Embodiment 30

[1206]

[1207] 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide

[1208] (Compound 221)

[1209] 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 21, but from 2-ethoxy-5-methylbenzoic acid (88.3 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (151.8 mg, 91.3% yield) as a yellow solid.

[1210] 1H NMR (400MHz, DMSO): δ10.49(d,J=2.0Hz,1H),9.16(dd,J=1.6,3.4Hz,1H),8.10(d,J=0.8Hz,1H),7.85(d,J=1.6Hz,1H),7.82-7.78(m,1H),7.58-7.53 (m,1H),7.43(d,J=3.2Hz,1H),7.37-7.35(m,1H),7.12(d,J=8.4Hz,1H),6. 84-6.83(m,1H),4.24(q,J=6.8Hz,2H),2.92(s,3H),1.48(t,J=6.8Hz,1H);

[1211] For [M+H,C 22 H 19 FN3O4] + LC-HRMS (ESI) calcd. 408.1360, found 408.1356.

[1212] Embodiment 31

[1213]

[1214] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1215] (Compound 222)

[1216] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-ethoxy-5-ethylbenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (159.2 mg, 92.6% yield) as a white solid.

[1217] 1H NMR (400MHz, DMSO): δ10.55(s,1H),9.19(d,J=6.0Hz,1H),8.11(s,1H),7.90(d,J=1.6Hz,1H),7.85-7.82(m,1H),7.62-7.57(m,1H),7.46-7.4 1(m,2H),7.18(d,J=8.4Hz,1H),6.85-6.84(m,1H),4.27(q,J=6.8Hz,2H),2.62(q,J=7.6Hz,2H),1.49(t,J=6.8Hz,3H),1.19(t,J=7.6Hz,3H);

[1218] For [M+H,C 23 H 21 FN3O4] + LC-HRMS (ESI) calcd. 422.1516, found 422.1520.

[1219] Embodiment 32

[1220]

[1221] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1222] (Compound 210)

[1223] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 21, but from 5-fluoro-2-propoxybenzoic acid (97.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (171.0 mg, 98.5% yield) as a light yellow solid.

[1224] 1H NMR (400MHz, DMSO): δ10.47(s,1H),9.11-9.09(m,1H),8.10(d,J=0.8Hz,1H),7.87-7.83(m,1H),7.74(dd,J=3.6,9.2Hz,1H),7.61-7 .56(m,1H),7.46-7.41(m,2H),7.31-7.28(m,1H),6.84-6.83(m,1H),4.18(t,J=6.6Hz,2H),1.91-1.85(m,2H),1.02(t,J=7.2Hz,3H);

[1225] For [M+H,C 22 H 18 F2N3O4] + LC-HRMS (ESI) calcd. 426.1265, found 426.1273.

[1226] Embodiment 33

[1227]

[1228] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1229] (Compound 209)

[1230] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide can be prepared as in Example 21, but from 5-chloro-2-propoxybenzoic acid (105.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (169.3 mg, 93.9% yield) as a light yellow solid.

[1231] 1H NMR (400MHz, DMSO): δ10.41(d,J=1.6Hz,1H),9.07(dd,J=1.6,7.2Hz,1H),8.10(d,J=1.2Hz,1H),7.93(d,J=2.8Hz,1H),7.89-7.85(m,1H),7.64 -7.58(m,2H),7.45(d,J=3.2Hz,1H),7.31(d,J=8.8Hz,1H),6.85-6.84(m,1H),4.19(t,J=6.4Hz,2H),1.91-1.86(m,2H),1.02(t,J=7.2Hz,3H);

[1232] For [M+H,C 22 H 18 ClFN3O4] + LC-HRMS (ESI) calcd. 442.0970, found 442.0961.

[1233] Embodiment 34

[1234]

[1235] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-propoxybenzamide

[1236] (Compound 208)

[1237] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-propoxybenzamide can be prepared as in Example 21, but from 5-methyl-2-propoxybenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (165.2 mg, 96.1% yield) as a yellow solid. 1H NMR (400MHz, DMSO): δ10.48(d,J=1.6Hz,1H),9.16(d,J=6.4Hz,1H),8.11(s,1H),7.86-7.83(m,2H),7.62-7.57(m,1H),7.45(d,J=3.2Hz,1H), 7.39(d,J=8.0Hz,1H),7.17(d,J=8.4Hz,1H),6.85-6.84(m,1H),4.17(t,J=6.4Hz,2H),2.32(s,3H),1.92-1.87(m,2H),1.02(t,J=7.4Hz,3H);

[1238] For [M+H,C 23 H 21 FN3O4] + LC-HRMS (ESI) calcd. 422.1516, found 422.1519.

[1239] Embodiment 35

[1240]

[1241] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1242] (Compound 316)

[1243] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2,2,2-trifluoroethoxy)benzoic acid (124.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (191.0 mg, 97.2% yield) as a white solid.

[1244] 1H NMR (400MHz, DMSO): δ10.24(s,1H),8.85(d,J=6.0Hz,1H),8.11(s,1H),7.94-7.91(m,1H),7.79(d,J=2.4Hz,1H),7.68- 7.65(m,1H),7.62-7.57(m,1H),7.46(d,J=3.2Hz,1H),7.34(d,J=8.8Hz,1H),6.85-6.84(m,1H),4.95(q,J=8.8Hz,2H);

[1245] For [M+H,C 21 H 13 ClF4N3O4] + LC-HRMS (ESI) calculated value: 482.0531, found value 482.0518.

[1246] Embodiment 36

[1247]

[1248] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1249] (Compound 319)

[1250] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide can be prepared as in Example 21, but from 5-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (116.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (178.5 mg, 94.0% yield) as a white solid.

[1251] 1 H NMR (400MHz, DMSO): δ10.22(s,1H),8.88(d,J=6.4Hz,1H),8.11(s,1H),7.94-7.91(m,1H),7.6 3-7.58(m,2H),7.50-7.45(m,2H),7.39-7.36(m,1H),6.85-6.84(m,1H),4.94(q,J=8.8Hz,2H);

[1252] For [M+H,C 21 H 13 F5N3O4] + LC-HRMS (ESI) calculated value: 466.0826, found value 466.0812.

[1253] Embodiment 37

[1254]

[1255] 2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide

[1256] (Compound 323)

[1257] 2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)-5-methylbenzoic acid (105.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (163.2 mg, 90.2% yield) as a white solid.

[1258] 1 H NMR (400MHz, DMSO): δ10.15(s,1H),9.00(d,J=6.0Hz,1H),8.11(d,J=0.8H z,1H),7.91-7.87(m,1H),7.77(s,1H),7.63-7.58(m,1H),7.46(d,J=3.6Hz ,1H),7.42(dd,J=1.6,8.4Hz,1H),7.23(d,J=8.4Hz,1H),6.85-6.84(m,1H ),6.49(tt,J=3.2,14.4Hz,1H),4.54(dt,J=2.8,14.0Hz,2H),2.34(s,3H);

[1259] For [M+H,C 22 H 17 F3N3O4] + LC-HRMS (ESI) calcd. 444.1171, found 444.1170.

[1260] Embodiment 38

[1261]

[1262] 5-Chloro-2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)

[1263] Benzamide

[1264] (Compound 317)

[1265] 5-Chloro-2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2,2-difluoroethoxy)benzoic acid (115.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (169.5 mg, 89.6% yield) as a white solid.

[1266] 1 H NMR (400MHz, DMSO): δ10.22(s,1H),8.93-8.90(m,1H),8.11(d,J=0.8Hz,1H ),7.93-7.90(m,1H),7.86(d,J=2.4Hz,1H),7.66(dd,J=2.8,8.8Hz,1H),7. 61(dd,J=8.8,10.4Hz,1H),7.46(d,J=3.6Hz,1H),7.36(d,J=9.2Hz,1H),6. 85-6.84(m,1H),6.47(tt,J=3.2,14.4Hz,1H),4.56(dt,J=3.2,14.4Hz,2H);

[1267] For [M+H,C 21 H 14 ClF3N3O4] + LC-HRMS (ESI) calcd. 464.0625, found 464.0632.

[1268] Embodiment 39

[1269]

[1270] 2-(2,2-difluoroethoxy)-5-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)

[1271] Benzamide

[1272] (Compound 320)

[1273] 2-(2,2-difluoroethoxy)-5-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(2,2-difluoroethoxy)-5-fluorobenzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (172.5 mg, 94.5% yield) as a white solid.

[1274] 1 H NMR (400MHz, DMSO): δ10.24(s,1H),8.96-8.94(m,1H),8.11(d,J=0.8Hz,1H),7.94-7.90(m,1H),7.69(d,J=3.2,7.2Hz,1H),7.64- 7.59(m,1H),7.51-7.46(m,2H),7.39-7.36(m,1H),6.85-6.84(m,1H),6.47(tt,J=3.2,14.4Hz,1H),4.56(dt,J=3.2,14.4Hz,2H);

[1275] For [M+H,C 21 H 14 F4N3O4] + LC-HRMS (ESI) calcd. 448.0920, found 448.0915.

[1276] Embodiment 40

[1277]

[1278] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)

[1279] Benzamide

[1280] (Compound 318)

[1281] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(2-fluoroethoxy)benzoic acid (107.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (164.6 mg, 90.5% yield) as a white solid.

[1282] 1 H NMR (400MHz, DMSO): δ10.37 (s, 1H), 9.04-9.01 (m, 1H), 8.11 (d, J = 0.8Hz, 1H), 7 .94(d,J=2.8Hz,1H),7.92-7.89(m,1H),7.67(dd,J=2.8,8.8Hz,1H),7.62(dd,J =8.8,10.4Hz,1H),7.46(d,J=3.6Hz,1H),7.35(d,J=9.2Hz,1H),6.85-6.84(m,1 H),4.94-4.92(m,1H),4.82-4.80(m,1H),4.57-4.55(m,1H),4.49-4.76(m,1H);

[1283] For [M+H,C 21 H 15 ClF2N3O4] + LC-HRMS (ESI) calcd. 446.0719, found 446.0716.

[1284] Embodiment 41

[1285]

[1286] 2-(Difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1287] (Compound 302)

[1288] 2-(Difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 2-(difluoromethoxy)benzoic acid (92.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (150.6 mg, 88.9% yield) as a white solid.

[1289] 1 H NMR (400MHz, DMSO): δ10.41(s,1H),8.72(d,J=6.0Hz,1H),8.11(d,J=1.2Hz,1H),7.95-7.91(m,1H),7.76(d,J=6. 8Hz,1H),7.65-7.56(m,2H),7.46-7.39(m,1H),7.33(d,J=8.4Hz,1H),7.26(t,J=73.2Hz,1H),6.84-6.83(m,1H);

[1290] For [M+H,C 20 H 13 F3N3O4] + LC-HRMS (ESI) calcd. 416.0858, found 416.0825.

[1291] Embodiment 42

[1292]

[1293] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-propylbenzamide

[1294] (Compound 281)

[1295] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-propylbenzamide can be prepared as in Example 21, but from 2-methoxy-5-propylbenzoic acid (95.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (146.7 mg, 85.3% yield) as a white solid.

[1296] 1 H NMR (400MHz, DMSO): δ10.46(d,J=1.2Hz,1H),9.03(d,J=5.6Hz,1H),8.11(d,J=1 .2Hz,1H),7.89-7.86(m,1H),7.82(d,J=1.6Hz,1H),7.62-7.57(m,1H),7.46(d,J =3.6Hz,1H),7.43(dd,J=2.0,8.4Hz,1H),7.20(d,J=8.4Hz,1H),6.85-6.84(m,1 H),4.01(s,3H),2.58(t,J=7.6Hz,2H),1.64-1.55(m,2H),0.90(t,J=7.2Hz,3H);

[1297] For [M+H,C 23 H 21 FN3O4] + LC-HRMS (ESI) calcd. 422.1516, found 422.1518.

[1298] Embodiment 43

[1299]

[1300] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide

[1301] (Compound 301)

[1302] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide can be prepared as in Example 21, but from 2-(trifluoromethoxy)benzoic acid (101.0 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (160.5 mg, 90.8% yield) as a white solid.

[1303] 1 H NMR (400MHz, DMSO): δ10.61(s,1H),8.57(d,J=6.0Hz,1H),8.11(d,J=1.2Hz,1H),7.98-7.94(m,1H) ,7.81-7.79(m,1H),7.71-7.67(m,1H),7.62-7.55(m,3H),7.46(d,J=3.2Hz,1H),6.85-6.84(m,1H);

[1304] For [M+H,C 20 H 12 F4N3O4] + LC-HRMS (ESI) calcd. 434.0764, found 434.0748.

[1305] Embodiment 44

[1306]

[1307] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)

[1308] Benzamide

[1309] (Compound 304)

[1310] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide can be prepared as in Example 21, but from 2-(trifluoromethoxy)benzoic acid (117.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (180.7 mg, 94.7% yield) as a white solid.

[1311] 1 H NMR (400MHz, DMSO): δ10.73 (s, 1H), 8.60 (d, J = 5.2Hz, 1H), 8.11 (s, 1H), 7.99-7.95 (m, 1H), 7.92 ( d,J=3.2Hz,1H),7.77-7.75(m,1H),7.62-7.58(m,2H),7.46(d,J=3.2Hz,1H),6.85-6.84(m,1H);

[1312] For [M+H,C 20 H 11 ClF4N3O4] + LC-HRMS (ESI) calculated value: 468.0374, found value 468.0402.

[1313] Embodiment 45

[1314]

[1315] 5-Chloro-2-(difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)

[1316] Benzamide

[1317] (Compound 305)

[1318] 5-Chloro-2-(difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 21, but from 5-chloro-2-(difluoromethoxy)benzoic acid (109.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (170.4 mg, 92.9% yield) as a light yellow solid.

[1319] 1 H NMR (400MHz, DMSO): δ10.55(s,1H),8.73-8.70(m,1H),8.11(d,J=0.8Hz,1H),7.96-7.92(m,1H),7.82(d,J=2.4Hz,1H),7.69(dd ,J=2.8,8.8Hz,1H),7.62-7.57(m,1H),7.46(d,J=3.6Hz,1H),7.37(d,J=8.8Hz,1H),7.26(t,J=73.2Hz,1H),6.85-6.84(m,1H);

[1320] For [M+H,C 20 H 12 ClF3N3O4] + LC-HRMS (ESI) calcd. 450.0468, found 450.0468.

[1321] Embodiment 46

[1322]

[1323] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(fluoromethoxy)

[1324] Benzamide

[1325] (Compound 306)

[1326] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(fluoromethoxy)benzamide can be prepared as in Example 21, but from 5-chloro-2-(fluoromethoxy)benzoic acid (100.2 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (155.6 mg, 88.3% yield) as a yellow solid.

[1327] 1 H NMR (400MHz, DMSO): δ10.41(s,1H),8.75-8.73(m,1H),8.11(d,J=1.2Hz,1H),7.96-7.92(m,1H),7.78(d,J=2.4Hz,1H),7.66(dd, J=2.8,8.8Hz,1H),7.61-7.57(m,1H),7.47(d,J=3.6Hz,1H),7.37(d,J=8.8Hz,1H),6.85-6.84(m,1H),6.04(s,1H),5.90(s,1H);

[1328] For [M+H,C 20 H 13 ClF2N3O4] + LC-HRMS (ESI) calcd. 432.0563, found 432.0555.

[1329] Embodiment 47

[1330]

[1331] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)

[1332] Benzamide

[1333] (Compound 312)

[1334] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide can be prepared as in Example 21, but from 5-fluoro-2-(2-fluoroethoxy)benzoic acid (99.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (168.4 mg, 96.2% yield) as a white solid.

[1335] 1 H NMR (400MHz, DMSO): δ10.43(s,1H),9.06(d,J=5.6Hz,1H),8.11(s,1H),7.91-7.87(m,1H),7.76(dd,J=2.4,9.2Hz,1H),7.64-7.59(m,1H) ),7.52-7.46(m,2H),7.37-7.33(m,1H),6.85-6.84(m,1H),4.94-4.92(m,1H),4.82-4.80(m,1H),4.56-4.54(m,1H),4.49-4.47(m,1H);

[1336] For [M+H,C 21 H 15 F3N3O4] + LC-HRMS (ESI) calcd. 430.1015, found 430.1017.

[1337] Embodiment 48

[1338]

[1339] N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)-5-

[1340] Methylbenzamide

[1341] (Compound 321)

[1342] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)-5-methylbenzamide can be prepared as in Example 21, but from 2-(2-fluoroethoxy)-5-methylbenzoic acid (97.1 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (170.2 mg, 98.1% yield) as a white solid.

[1343] 1 H NMR (400MHz, DMSO): δ10.40(s,1H),9.12(d,J=5.6Hz,1H),8.11(d,J=0.8Hz,1 H),7.88-7.86(m,2H),7.60(dd,J=8.8,10.4Hz,1H),7.46(d,J=3.6Hz,1H),7.4 2(dd,J=2.0,8.4Hz,1H),7.20(d,J=8.4Hz,1H),6.85-6.84(m,1H),4.95-4.93 (m,1H),4.83-4.81(m,1H),4.55-4.53(m,1H),4.47-4.45(m,1H),2.33(s,3H);

[1344] For [M+H,C 22 H 18 F2N3O4] + LC-HRMS (ESI) calcd. 426.1265, found 426.1277.

[1345] Embodiment 49

[1346]

[1347] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide

[1348] (Compound 405)

[1349] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 20, but from 2-methoxy-5-(trifluoromethoxy)benzoic acid (115.7 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (170.3 mg, 90.1% yield) as a white solid.

[1350] 1 H NMR (400MHz, DMSO): δ10.45(s,1H),8.93(d,J=6.8Hz,1H),8.11(s,1H),7.94-7.91(m,1H),7.84(s,1 H),7.67-7.59(m,2H),7.47(d,J=3.6Hz,1H),7.40(d,J=9.2Hz,1H),6.85-6.84(m,1H),4.04(s,3H);

[1351] For [M+H,C 21 H 14 F4N3O5] + LC-HRMS (ESI) calcd. 464.0870, found 464.0865.

[1352] Embodiment 50

[1353]

[1354] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide

[1355] (Compound 416)

[1356] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 21, but from 2-methoxy-5-(trifluoromethyl)benzoic acid (107.9 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (179.1 mg, 98.1% yield) as a white solid.

[1357] 1 H NMR (400MHz, DMSO): δ10.43(s,1H),8.89(d,J=5.6Hz,1H),8.15(s,1H),8.11(s,1H),7. 97-7.91(m,2H),7.63-7.59(m,1H),7.48-7.46(m,2H),6.85-6.84(m,1H),4.07(s,3H);

[1358] For [M+H,C 21 H 14 F4N3O4] + LC-HRMS (ESI) calcd. 448.0920, found 448.0913.

[1359] Embodiment 51

[1360]

[1361] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-(2,2,2-trifluoroethoxy)benzamide

[1362] (Compound 322)

[1363] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 21, but from 5-methyl-2-(2,2,2-trifluoroethoxy)benzoic acid (114.6 mg, 0.49 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (100.0 mg, 0.41 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (173.7 mg, 92.3% yield) as a white solid.

[1364] 1H NMR (400 MHz, DMSO): δ10.07 (s, 1H), 8.93 (d, J=5.6 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.68 (s, 1H), 7.61-7.56 (m, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.42-7.40 (m, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.85-6.84 (m, 1H), 4.94 (q, J=8.8 Hz, 1H), 2.34 (s, 3H); LC-HRMS (ESI) calculated for [M+H, C22H16F4N3O4]+: 462.1077, found 462.1070.

[1365] Embodiment 52

[1366]

[1367] 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide

[1368] (Compound 39)

[1369] According to the synthetic procedure described in Scheme 2, 2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide can be prepared as follows:

[1370] a) 2-(2-fluorobenzamido)isonicotinic acid methyl ester: To a stirred solution of 2-aminoisonicotinic acid methyl ester (1.0 g, 6.6 mmol), 2-fluorobenzoic acid (1.0 g, 7.3 mmol) and N,N-diisopropylethylamine (2.5 g, 19.7 mmol) in dichloromethane (50 ml) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 6.8 g, 13.1 mmol). The solution was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane / ethyl acetate=4 / 1) to give 256.4 mg (14.2% yield) of 2-(2-fluorobenzamido)isonicotinic acid methyl ester as a white solid.

[1371] b) 2-(2-fluorobenzamido)isonicotinic acid: To a solution of 2-(2-fluorobenzamido)isonicotinic acid methyl ester (256.4 mg, 0.93 mmol) in tetrahydrofuran (5 mL) was added 0.5 M lithium hydroxide solution (5 mL). The solution was stirred at room temperature for 12 hr. After concentration, the remaining concentrated solution was acidified to pH 1 by adding 1N hydrochloric acid. A large amount of precipitation was observed. The product was collected by filtration and washed with water, and then finally vacuum dried to obtain 180.5 mg (74.6% yield) of 2-(2-fluorobenzamido)isonicotinic acid as a white solid.

[1372] c) 2-Fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide: To a stirred solution of 2-(2-fluorobenzamido)isonicotinic acid (180.5 mg, 0.69 mmol), 2-furanic acid hydrazide (91.6 mg, 0.73 mmol) and N,N-diisopropylethylamine (267.5 mg, 2.07 mmol) in dichloromethane (10 ml) was added PyBop (468.4 mg, 0.90 mmol). The solution was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash column chromatography (dichloromethane / methanol=100 / 1) to 206.8 mg (81.4% yield) of 2-fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide as a white solid.

[1373] d) 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide: 2-Fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide (206.8 mg, 0.56 mmol) was dissolved in phosphorus oxychloride (2 ml), and the mixture was stirred with heating at 80° C. for 5 hr. The phosphorus oxychloride was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane / methanol=50 / 1) to give the title compound (82.5 mg, 42.1% yield) as a light yellow solid.

[1374] 1H NMR (400MHz, DMSO): δ11.20(s,1H),8.86(s,1H),8.63(d,J=5.2Hz,1H),8.14(s,1H),7.79(d,J=4.8Hz, 1H),7.76-7.73(m,1H),7.64-7.59(m,1H),7.53(d,J=3.6Hz,1H),7.39-7.33(m,2H),6.87-6.86(m,1H);

[1375] For [M+H,C 18 H 12 FN4O3] + LC-HRMS (ESI) calcd. 351.0893, found 351.0898.

[1376] Embodiment 53

[1377]

[1378] 2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide

[1379] (Compound 373)

[1380] According to the synthetic procedure described in Scheme 2, 2-fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide can be prepared as follows:

[1381] a) 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid methyl ester: A mixture of 2-ethoxy-5-ethylbenzoic acid (1.4 g, 7.23 mmol) and N,N-dimethylformamide (0.01 ml) in thionyl chloride (5 ml) was stirred at reflux for 2 hr. Excess thionyl chloride was evaporated under reduced pressure to obtain the acid chloride.

[1382] The acid chloride was dissolved in dichloromethane (20 ml) and added dropwise to a solution of methyl 2-aminoisonicotinate (1.0 g, 6.6 mmol) and pyridine (0.69 ml, 8.54 mmol) in dichloromethane (50 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane / ethyl acetate=4 / 1) to obtain 1.96 g (90.5% yield) of methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate as a pale yellow solid.

[1383] b) 2-(2-Ethoxy-5-ethylbenzamido)isonicotinic acid: By using 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid methyl ester (1.96 g, 5.97 mmol) in the same manner as Example 52, 1.38 g (73.5% yield) of 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid was obtained as a white solid.

[1384] c) 2-Ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide: By using 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid (1.38 g, 4.39 mmol), 2-furanic acid hydrazide (0.58 g, 4.61 mmol), N,N-diisopropylethylamine (1.7 g, 13.17 mmol) and PyBop (2.97 g, 5.71 mmol) to react in the same manner as in Example 52, 1.52 g (82.0% yield) of 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide was obtained as a white solid.

[1385] d) 2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide: By using 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinecarbonyl)pyridin-2-yl)benzamide (1.52 g, 3.60 mmol) and reacting in the same manner as Example 52, 0.76 g (52.2% yield) of the title compound was obtained as a white solid.

[1386] 1 H NMR (400MHz, DMSO): δ10.94(s,1H),8.94(s,1H),8.62(d,J=5.2Hz,1H),8.15(s,1H),7.87(s,1H),7.77(d,J=5.6Hz,1H),7.53(d,J=3.2Hz,1H),7.44 (d,J=7.6Hz,1H),7.20(d,J=8.4Hz,1H),6.88-6.87(m,1H),4.29(q,J=6.8 Hz,2H),2.64(q,J=7.6,Hz,2H),1.50(t,J=6.8,3H),1.20(t,J=7.6Hz,3H);

[1387] For [M+H,C 22 H 21 N4O4] +LC-HRMS (ESI) calcd. 405.1563, found 405.1545.

[1388] Embodiment 54

[1389]

[1390] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide

[1391] (Compound 396)

[1392] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 2-methoxy-5-(trifluoromethyl)benzoic acid (0.32 g, 1.44 mmol). 85.6 mg of the title compound are obtained as a white solid.

[1393] 1 H NMR (400MHz, DMSO): δ10.92(s,1H),8.89(s,1H),8.63(d,J=5.2Hz,1H),8.14(s,1H),8.07(s,1H),7.93(d,J=8 .8Hz,1H),7.80(d,J=5.2Hz,1H),7.53(d,J=3.6Hz,1H),7.44(d,J=8.8Hz,1H),6.87-6.86(m,1H),4.03(s,3H);

[1394] For [M+H,C 20 H 14 F3N4O4] + LC-HRMS (ESI) calcd. 431.0967, found 431.0960.

[1395] Embodiment 55

[1396]

[1397] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethoxy)benzamide

[1398] (Compound 400)

[1399] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethoxy)benzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 2-methoxy-5-(trifluoromethoxy)benzoic acid (0.34 g, 1.44 mmol). 105.3 mg of the title compound are obtained as a white solid.

[1400] 1 H NMR (400MHz, DMSO): δ10.89(s,1H),8.89(s,1H),8.63(d,J=5.2Hz,1H),8.15(s,1H),7.81-7.77(m ,2H),7.63-7.60(m,1H),7.54-7.53(m,1H),7.37(d,J=9.2Hz,1H),6.88-6.87(m,1H),4.01(s,3H);

[1401] For [M+H,C 20 H 14 F3N4O5] + LC-HRMS (ESI) calcd. 447.0916, found 447.0911.

[1402] Embodiment 56

[1403]

[1404] 5-Chloro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxybenzamide

[1405] (Compound 372)

[1406] 5-Chloro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxybenzamide can be prepared as in Example 53, but from methyl 2-aminoisonicotinate (0.20 g, 1.31 mmol) and 5-chloro-2-methoxybenzoic acid (0.27 g, 1.44 mmol). 127.0 mg of the title compound are obtained as a light yellow solid.

[1407] 1H NMR (400MHz, DMSO): δ10.83 (s, 1H), 8.61 (d, J = 0.8Hz, 1H), 8.14 (s, 1H), 7.80-7.77 (m, 2H), 7. 63-7.61(m,1H),7.52(d,J=2.8Hz,1H),7.28(d,J=9.2Hz,1H),6.87-6.86(m,1H),3.97(s,3H);

[1408] For [M+H,C 19 H 14 ClN4O4] + LC-HRMS (ESI) calculated value: 397.0704, found value 397.0689.

[1409] Embodiment 63

[1410]

[1411] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(3-hydroxypropyl)-2-methoxybenzamide

[1412] (Compound 483)

[1413] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(3-hydroxypropyl)-2-methoxybenzamide can be prepared as in Example 1, but from 5-(3-hydroxypropyl)-2-methoxybenzoic acid (105.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol).

[1414] The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (143.0 mg, 65.4% yield) as a yellow solid.

[1415] 1H NMR (400MHz, DMSO) δ10.47 (s, 1H), 9.04 (d, J = 6.0Hz, 1H), 8.12 (s, 1H), 7.92-7.86 (m ,1H),7.84(d,J=1.6Hz,1H),7.66-7.56(m,1H),7.47(d,J=3.5Hz,1H),7.44(dd,J=8. 5,1.9Hz,1H),7.21(d,J=8.5Hz,1H),6.85(dd,J=3.4,1.6Hz,1H),4.49(t,J=5.0Hz,1 H),4.02(s,3H),3.43(dd,J=11.3,6.1Hz,2H),2.70-2.59(m,2H),1.78-1.67(m,2H);

[1416] For [M+H,C 23 H 21 FN3O5] + LC-HRMS (ESI) calcd. 438.1460, found 438.1461.

[1417] Embodiment 64

[1418]

[1419] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-methoxypropyl)benzamide

[1420] (Compound 484)

[1421] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-methoxypropyl)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(3-methoxypropyl)benzoic acid (112.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (167.4 mg, 74.2% yield) as a yellow solid.

[1422] 1H NMR (400MHz, CDCl3) δ10.52(d,J=3.0Hz,1H),9.34(dd,J=7.3,2.1Hz,1H),8.15(d,J=2 .3Hz,1H),7.94(ddd,J=8.5,4.9,2.2Hz,1H),7.67(d,J=1.1Hz,1H),7.37(dd,J=8.4,2 .4Hz,1H),7.31-7.25(m,2H),7.02(d,J=8.5Hz,1H),6.63(dd,J=3.5,1.7Hz,1H),4.23 (t,J=6.2Hz,2H),4.09(s,3H),3.03(s,3H),2.80(t,J=7.5Hz,2H),2.18-2.05(m,2H);

[1423] For [M+H,C 24 H 23 FN3O5] + LC-HRMS (ESI) calculated value: 452.1616, found value 452.1618.

[1424] Embodiment 65

[1425]

[1426] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-(piperidin-1-yl)propyl)benzamide

[1427] (Compound 495)

[1428] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-(piperidin-1-yl)propyl)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(3-(piperidin-1-yl)propyl)benzoic acid (138.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (68.6 mg, 27.2% yield) as a yellow solid.

[1429] 1H NMR(400MHz, CDCl3) δ10.49(d,J=3.0Hz,1H),9.31(dd,J=7.3,1.8Hz,1H),8.07(d,J=2.1Hz, 1H),7.93-7.83(m,1H),7.68(d,J=0.7Hz,1H),7.42(dd,J=8.4,2.1Hz,1H),7.30-7.20(m,2H ),7.00(d,J=8.5Hz,1H),6.63(dd,J=3.4,1.7Hz,1H),4.07(s,3H),3.13-2.94(m,4H),2.92- 2.85(m,2H),2.73(t,J=7.4Hz,2H),2.28-2.17(m,2H),2.10-1.89(m,4H),1.72-1.54(m,2H);

[1430] For [M+H,C 28 H 30 FN4O4] + LC-HRMS (ESI) calculated value: 505.2246, found value 505.2241.

[1431] Embodiment 66

[1432]

[1433] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-morpholinopropyl)benzamide

[1434] (Compound 496)

[1435] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-morpholinopropyl)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(3-morpholinopropyl)benzoic acid (139.6 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (105.8 mg, 41.8% yield) as a yellow solid.

[1436] 1H NMR (400MHz, CDCl3) δ10.54 (s, 1H), 9.36 (d, J = 5.4Hz, 1H), 8.16 (d, J = 2.1Hz, 1H), 7.99-7.90(m,1H),7.68(s,1H),7.36(dd,J=8.4,2.2Hz,1H),7.32-7.26(m,2H),7 .00(d,J=8.5Hz,1H),6.66-6.60(m,1H),4.09(s,3H),3.78-3.71(m,4H),2.69(t, J=7.6Hz,2H),2.53-2.42(m,4H),2.41-2.32(m,2H),1.85(dt,J=15.0,7.6Hz,2H);

[1437] For [M+H,C 27 H 28 FN4O5] + LC-HRMS (ESI) calculated value: 507.2038, found value 507.2033.

[1438] Embodiment 67

[1439]

[1440] 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1441] (Compound 35)

[1442] 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.1 mg, 0.5 mmol) and 4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (113.2 mg, 64.8% yield) as a yellow solid.

[1443] 1 H NMR(400MHz,DMSO)δ10.81(s,1H),8.13-8.04(m,3H),8.01-7.95(m,2H),7.75-7.68(m,1H) ,7.65-7.56(m,1H),7.43(d,J=3.5Hz,1H),7.41-7.32(m,2H),6.83(dd,J=3.4,1.7Hz,1H);

[1444] For [M+H,C 19 H 13 FN3O3] + LC-HRMS (ESI) calcd. 350.0935, found 350.0939.

[1445] Embodiment 69

[1446]

[1447] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)nicotinamide

[1448] (Compound 485)

[1449] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)nicotinamide can be prepared as in Example 1, but from 2-ethoxy-5-ethylnicotinic acid (97.6 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (137.2 mg, 65.0% yield) as a yellow solid.

[1450] 1 H NMR (400MHz, DMSO) δ10.49(s,1H),9.20-9.08(m,1H),8.32-8.19(m,2H),8.14-8.07(m,1H),7.94-7.81(m,1H),7.67-7.57 (m,1H),7.50-7.40(m,1H),6.89-6.80(m,1H),4.63-4.42(m,2H),2.72-2.61(m,2H),1.54-1.38(m,3H),1.30-1.12(m,3H);

[1451] For [M+H,C 22 H 20 FN4O4] + LC-HRMS (ESI) calcd. 423.1463, found 423.1463.

[1452] Embodiment 70

[1453]

[1454] 5-Chloro-N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxynicotinamide

[1455] (Compound 486)

[1456] 5-Chloro-N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxynicotinamide can be prepared as in Example 1, but from 5-chloro-2-methoxynicotinic acid (93.8 mg, 0.5 mmol) and 2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)aniline (123.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (102.3 mg, 49.2% yield) as a yellow solid.

[1457] 1 H NMR (400MHz, CDCl3) δ10.42(s,1H),9.31(dd,J=7.3,2.1Hz,1H),8.59(d,J=2.6Hz,1H),8.31(d,J=2 .6Hz,1H),8.13(s,1H),8.02-7.96(m,1H),7.93(s,1H),7.33(dd,J=10.3,8.7Hz,1H),4.23(s,3H);

[1458] For [M+H,C 18 H 12 ClFN5O4] + LC-HRMS (ESI) calcd. 416.0556, found 416.0557.

[1459] Embodiment 71

[1460]

[1461] N-(3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide

[1462] (Compound 298)

[1463] N-(3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (87.6 mg, 50.2% yield) as a yellow solid.

[1464] 1 H NMR (400MHz, DMSO) δ13.69(s,1H),10.75(s,1H),8.58(s,1H),8.05-8.02(m,1H),7.95(d,J=8.3Hz,1H),7 .83(d,J=7.8Hz,1H),7.72(t,J=7.3Hz,1H),7.65-7.58(m,2H),7.43-7.32(m,2H),6.98(t,J=2.0Hz,1H);

[1465] For [M+H,C 18 H 13 FN5O2] + LC-HRMS (ESI) calcd.: 350.1048, found 350.1042.

[1466] Embodiment 72

[1467]

[1468] 2-Fluoro-N-(3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1469] (Compound 15)

[1470] 2-Fluoro-N-(3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)aniline (121.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (94.5 mg, 51.6% yield) as a yellow solid.

[1471] 1H NMR (400MHz, DMSO) δ10.74(s,1H),8.56(s,1H),8.01-7.94(m,2H),7.92(d,J=3.3Hz,1 H),7.83(d,J=7.7Hz,1H),7.73(t,J=7.2Hz,1H),7.66-7.56(m,2H),7.43-7.30(m,3H);

[1472] For [M+H,C 19 H 13 FN3O2S] + LC-HRMS (ESI) calculated value: 366.0707, found value 366.0701.

[1473] Embodiment 73

[1474]

[1475] 2-Fluoro-N-(3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1476] (Compound 20)

[1477] 2-Fluoro-N-(3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)aniline (113.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (123.1 mg, 70.5% yield) as a yellow solid.

[1478] 1 H NMR (400MHz, DMSO) δ10.73(s,1H),8.63(s,1H),8.56(s,1H),8.00-7.96(m,1H),7.93(d,J=8.1Hz,1H),7 .82(d,J=7.8Hz,1H),7.72(t,J=7.4Hz,1H),7.65-7.57(m,2H),7.42-7.32(m,2H),7.08(d,J=1.0Hz,1H);

[1479] For [M+H,C 19 H 13 FN3O3] + LC-HRMS (ESI) calculated value: 350.0935, found value 350.0938.

[1480] Embodiment 74

[1481]

[1482] 2-Fluoro-N-(3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1483] (Compound 22)

[1484] 2-Fluoro-N-(3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)aniline (115.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (108.5 mg, 61.2% yield) as a yellow solid.

[1485] 1 H NMR (400MHz, DMSO) δ10.72(s,1H),8.49(s,1H),7.94(d,J=8.1Hz,1H),7.79-7.68(m,2H),7.65-7.56( m,2H),7.42-7.29(m,2H),5.33-5.19(m,1H),3.98-3.81(m,2H),2.41-2.26(m,2H),2.13-1.91(m,2H);

[1486] For [M+H,C 19 H 17 FN3O3] + LC-HRMS (ESI) calcd. 354.1248, found 354.1241.

[1487] Embodiment 75

[1488]

[1489] N-(3-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide

[1490] (Compound 289)

[1491] N-(3-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 3-(5-ethyl-1,3,4-oxadiazol-2-yl)aniline (94.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol=100 / 1) to give the title compound (65.3 mg, 42.0% yield) as a yellow solid.

[1492] 1 H NMR (400MHz, DMSO) δ10.70 (s, 1H), 8.49 (s, 1H), 7.90 (d, J = 8.1Hz, 1H), 7.76-7.68 (m, 2 H),7.65-7.54(m,2H),7.44-7.27(m,2H),2.96(q,J=7.5Hz,2H),1.33(t,J=7.5Hz,3H);

[1493] For [M+H,C 17 H 15 FN3O2] + LC-HRMS (ESI) calcd.: 312.1143, found 312.1146.

[1494] Embodiment 76

[1495]

[1496] 2-Fluoro-N-(2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1497] (Compound 290)

[1498] 2-Fluoro-N-(2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)aniline (131.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (125.7 mg, 65.4% yield) as a yellow solid.

[1499] 1H NMR (400MHz, DMSO) δ10.45(s,1H),9.44(s,1H),8.75(d,J=0.5Hz,1H),8.64(d,J=6.0Hz,1H),8.00 (ddd,J=8.5,4.6,2.2Hz,1H),7.82-7.75(m,1H),7.67-7.55(m,2H),7.38(dd,J=15.6,8.0Hz,2H).

[1500] For [M+H,C 18 H 11 F2N4O2S] + LC-HRMS (ESI) calcd.: 385.0565, found: 385.0565.

[1501] Embodiment 77

[1502]

[1503] 2-Fluoro-N-(2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1504] (Compound 79)

[1505] 2-Fluoro-N-(2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide can be prepared as in Example 1, but from 2-fluorobenzoic acid (70.0 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (118.6 mg, 64.6% yield) as a yellow solid.

[1506] 1 H NMR (400MHz, DMSO) δ10.43(s,1H),8.12(s,1H),8.06(t,J=7.6Hz,1H),7.94(t,J=6.5Hz,1H),7.77(t,J=6. 9Hz,1H),7.63(dd,J=13.4,5.8Hz,1H),7.52-7.44(m,2H),7.43-7.29(m,2H),6.85(dd,J=3.5,1.7Hz,1H).

[1507] For [M+H,C 19 H 12 F2N3O3] +LC-HRMS (ESI) calcd.: 368.0841, found 368.0849.

[1508] Scheme 3 below shows the general synthesis followed to prepare some of the compounds according to the present invention:

[1509] Solution 3

[1510]

[1511] According to this method, the following compounds were obtained:

[1512] Embodiment 57

[1513]

[1514] N-(5-chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1515] (Compound 479)

[1516] According to the synthetic procedure described in Scheme 3, N-(5-chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as follows:

[1517] A:

[1518] Methyl 2-fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl)benzoate: To a solution of 4-fluoro-3-(methoxycarbonyl)benzoic acid (1.98 g, 10 mmol) in dichloromethane (20 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise to a suspension of furan-2-carbohydrazide (1.3 g, 10 mmol) and anhydrous sodium carbonate (1.1 g, 10 mmol) in tetrahydrofuran (10 mL) and water (10 mL) at 0°C. The mixture was stirred at 0°C for 1 h and at room temperature for 6 hr. A large amount of precipitation was observed. The product was collected by filtration and washed with water, then finally dried in vacuo to give 2.5 g (81.7% yield) of methyl 2-fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl)benzoate as a white solid.

[1519] B:

[1520] 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazole-2-yl)benzoic acid methyl ester: 2-Fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl)benzoic acid methyl ester (2.5 g, 8.2 mmol) was dissolved in phosphorus oxychloride (40 ml), and the mixture was stirred for 5 hr under heating at 100 ° C. The phosphorus oxychloride was evaporated under reduced pressure, and water was added to the residue. A large amount of precipitation was observed. The product was collected by filtration and washed with water, and then dried in vacuo to obtain 1.8 g (76.4% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazole-2-yl)benzoic acid methyl ester.

[1521] C:

[1522] 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazole-2-yl)benzoic acid: 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazole-2-yl)benzoic acid methyl ester (1.8 g, 6.2 mmol) was dissolved in methanol (20 ml) and water (20 ml), LiOH (0.7 g, 31.2 mmol) was added, and the mixture was stirred at room temperature for 8 hr. Afterwards, the reaction solution was neutralized with 2N hydrochloric acid. The resulting white solid was filtered and washed with water, and then finally vacuum dried to obtain 1.0 g (58.5% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazole-2-yl)benzoic acid.

[1523] D:

[1524] N-(5-Chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide: To a solution of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137 mg, 0.5 mmol) in dichloromethane (10 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 5-chloro-2-fluoroaniline (72.8 mg, 0.5 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (dichloromethane / methanol=100 / 1) to give the title compound (106 mg, 52.8% yield) as a light yellow solid.

[1525] 1H NMR (400MHz, DMSO) δ10.61(s,1H),8.52-8.36(m,1H),8.33-8.22(m,1H),8.12(s,1H),8.08-7. 95(m,1H),7.66(t,J=9.2Hz,1H),7.51(d,J=3.1Hz,1H),7.46-7.25(m,2H),6.91-6.80(m,1H);

[1526] For [M+H,C 19 H 11 ClF2N3O3] + LC-HRMS (ESI) calcd. 402.0452, found 402.0456.

[1527] Embodiment 58

[1528]

[1529] N-(5-chloro-2-methoxyphenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1530] (Compound 480)

[1531] N-(5-chloro-2-methoxyphenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 57, but from 5-chloro-2-methoxyaniline (78.8 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (103.0 mg, 49.8% yield) as a yellow solid.

[1532] 1 H NMR (400MHz, DMSO) δ9.87(d,J=5.7Hz,1H),8.43(d,J=5.1Hz,1H),8.32-8.24(m,1H),8.23-8.18(m,1H),8.14-8.05(m,1H),7. 64(t,J=9.6Hz,1H),7.50(d,J=3.4Hz,1H),7.23(dd,J=8.8,2.5Hz,1H),7.14(d,J=8.8Hz,1H),6.87-6.81(m,1H),3.88(s,3H);

[1533] For [M+H,C20 H 14 ClFN3O4] + LC-HRMS (ESI) calcd. 414.0651, found 414.0658.

[1534] Embodiment 59

[1535]

[1536] N-(2-Fluorophenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1537] (Compound 44)

[1538] N-(2-Fluorophenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 57, but from 2-fluoroaniline (55.6 mg, 0.5 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (128.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (85.7 mg, 49.1% yield) as a yellow solid.

[1539] 1 H NMR (400MHz, DMSO) δ10.45(s,1H),8.65(s,1H),8.30(d,J=7.8Hz,1H),8.24(d,J=7.9Hz,1H),8.11(s,1H),7.80 (t,J=7.8Hz,1H),7.63(t,J=7.6Hz,1H),7.50(d,J=3.5Hz,1H),7.38-7.19(m,3H),6.85(dd,J=3.4,1.6Hz,1H);

[1540] For [M+H,C 19 H 13 FN3O3] + LC-HRMS (ESI) calculated value: 350.0935, found value 350.0938.

[1541] Embodiment 60

[1542]

[1543] N-(5-chloro-2-methoxypyridin-3-yl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1544] (Compound 481)

[1545] N-(5-chloro-2-methoxypyridin-3-yl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 57, but from 5-chloro-2-methoxypyridin-3-amine (79.3 mg, 0.5 mmol) and 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (128.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (110 mg, 53.0% yield) as a yellow solid.

[1546] 1 H NMR (400MHz, DMSO) δ9.99(d,J=9.1Hz,1H),8.52(dd,J=7.0,2.2Hz,1H),8.42(d,J=2.6Hz,1H),8.35-8.30(m,1H),8.12(s, 1H),7.85(d,J=2.7Hz,1H),7.70(dd,J=11.0,8.8Hz,1H),7.51(d,J=3.4Hz,1H),6.86(dd,J=3.5,1.7Hz,1H),3.55(s,3H);

[1547] For [M+H,C 19 H 13 ClFN4O4] + LC-HRMS (ESI) calcd. 415.0604, found 415.0609.

[1548] Embodiment 61

[1549]

[1550] 5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2-methoxypyridin-3-yl)-2-fluorobenzamide

[1551] (Compound 482)

[1552] 5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2-methoxypyridin-3-yl)-2-fluorobenzamide can be prepared as in Example 57, but from 5-chloro-2-methoxypyridin-3-amine (79.3 mg, 0.5 mmol) and 5-(5-(1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzoic acid (136.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (120 mg, 58.0% yield) as a yellow solid.

[1553] 1 H NMR (400MHz, DMSO) δ12.32(s,1H),9.96(d,J=8.5Hz,1H),8.53(d,J=5.9Hz,1H),8.44-8.36(m,1H),8.34-8.2 4(m,1H),7.84(s,1H),7.68(t,J=9.8Hz,1H),7.22-7.07(m,1H),7.00-6.87(m,1H),6.31(s,1H),3.54(s,3H).

[1554] For [M+H,C 19 H 14 ClFN5O3] + LC-HRMS (ESI) calcd. 414.0764, found 414.0767.

[1555] Scheme 4 below shows the general synthesis followed to prepare some of the compounds according to the present invention:

[1556] Solution 4

[1557]

[1558] According to this method, the following compounds were obtained:

[1559] Embodiment 62

[1560]

[1561] 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide

[1562] (Compound 325)

[1563] According to the synthetic procedure described in Scheme 4, 2-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide can be prepared as follows:

[1564] A:

[1565] N'-(4-Fluoro-3-nitrobenzoyl)furan-2-carbohydrazide: To a solution of 4-fluoro-3-nitrobenzoic acid (1.85 g, 10 mmol) in dichloromethane (20 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (1.3 ml, 15 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise to a suspension of 2-furanoic acid hydrazide (1.3 g, 10 mmol) and sodium carbonate (1.1 g, 10 mmol) in tetrahydrofuran (10 mL) and water (10 mL) at 0°C. The mixture was stirred at 0°C for 1 hr and at room temperature for 6 hr. A large amount of precipitation was observed. The product was collected by filtration and washed with water, then finally dried in vacuo to give 2.3 g (78.5% yield) of N'-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.

[1566] B:

[1567] 2-(4-Fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-thiadiazole: N'-(4-Fluoro-3-nitrobenzoyl)furan-2-carbohydrazide (2.3 g, 7.8 mmol), Lawesson's reagent (4.8 g, 11.8 mmol) were dissolved in toluene (40 ml), and the mixture was stirred at 110° C. for 12 hr. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (hexane / ethyl acetate=10 / 1) to give the title compound (1.4 g, 61.2% yield) as a yellow solid.

[1568] C:

[1569] 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazole-2-yl)aniline: A mixture of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-thiadiazole (1.4 g, 4.8 mmol) and Raney nickel (0.3 g) in methanol (30 ml) was stirred at 50 ° C for 16 hr under 2.0 MPa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (dichloromethane / methanol=50 / 1) to give the title compound (1.0 g, 79.6% yield) as a yellow solid.

[1570] D:

[1571] 2-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide: To a solution of 2-fluorobenzoic acid (140 mg, 1 mmol) in dichloromethane (10 ml) were added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (2.6 ml, 30 mmol), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to obtain the acid chloride. The acid chloride was dissolved in dichloromethane (5 ml) and added dropwise to a solution of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)aniline (261.2 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) in dichloromethane (5 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 12 hr. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (dichloromethane / methanol=100 / 1) to give the title compound (215 mg, 56.1% yield) as a light yellow solid.

[1572] 1 H NMR (400MHz, DMSO) δ10.41(s,1H),8.59(d,J=5.8Hz,1H),8.06(s,1H),7.94-7.84(m,1H),7.78(t,J=7 .1Hz,1H),7.63(dd,J=13.4,6.2Hz,1H),7.58-7.49(m,1H),7.45-7.30(m,3H),6.81(d,J=1.6Hz,1H).

[1573] For [M+H,C 19 H 12 F2N3O2S] + LC-HRMS (ESI) calcd. 384.0613, found 384.0610.

[1574] Scheme 5 below shows the general synthesis followed to prepare some of the compounds according to the present invention:

[1575] Solution 5

[1576]

[1577] According to this method, the following compounds were obtained:

[1578] Embodiment 78

[1579]

[1580] (2-Ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid

[1581] (Compound 497)

[1582] According to the synthetic procedure described in Scheme 5, (2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphamidic acid can be prepared as follows:

[1583] A:

[1584] Dibenzyl(2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidate: To a solution of 2-ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide (FTEC-252) (0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% dispersion in mineral oil) (48 mg, 1.2 mmol) and the mixture was stirred at 0°C for 1 hr. Dibenzylphosphoryl chloride (0.36 g, 1.2 mmol) was then added to the mixture at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 12 hr. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (50 mg, 7.3% yield) as a yellow solid.

[1585] B:

[1586] (2-Ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid: A mixture of dibenzyl(2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidate (50 mg, 0.07 mmol), Et3N (0.3 g, 0.3 mmol) and Pd-C (5%) in ethanol (20 ml) was stirred at room temperature for 16 hr under 2.0 MPa hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (dichloromethane / methanol=50 / 1) to give the title compound (20 mg, 54.4% yield) as a solid

[1587] 1H NMR (400MHz, DMSO) δ8.11-8.08(m,1H),8.01-7.94(m,1H),7.83-7.74(m,1H),7.44-7.41(m, 1H),7.23-7.17(m,1H),6.96(s,1H),6.92(d,J=8.5Hz,1H),6.85-6.81(m,1H),6.63-6.53(m 1H), 3.86-3.73(m,2H), 2.46-2.38(m,2H), 1.36(t,J=6.9Hz,3H), 1.05(t,J=7.7Hz,3H).

[1588] LC-HRMS (ESI) calcd for [M+H, C23H22FN3O7]+: 502.1174, found 502.1177.

[1589] Embodiment 79

[1590]

[1591] N-(5-chloro-2-fluorophenyl)-2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1592] (Compound 487)

[1593] N-(5-chloro-2-fluorophenyl)-2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 57, but from 5-chloro-2-fluoroaniline (72.8 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (105 mg, 52.3% yield) as a light yellow solid.

[1594] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=14.2Hz,1H),8.59(d,J=6.8Hz,1H),8.42-8.30(m,2H),7.73-7.70(m, 1H), 7.53 (t, J = 7.8Hz, 1H), 7.31 (d, J = 3.5Hz, 1H), 7.11 (d, J = 8.7Hz, 2H), 6.66 (dd, J = 3.5, 1.7Hz, 1H).

[1595] For [M+H,C 19 H11 ClF2N3O3] + LC-HRMS (ESI) calcd. 402.0452, found 402.0457.

[1596] Embodiment 80

[1597]

[1598] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1599] (Compound 488)

[1600] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 57, but from 2-fluoro-5-(2-morpholinoethoxy)aniline (120.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (100 mg, 40.3% yield) as a light yellow solid.

[1601] 1 H NMR (400MHz, DMSO) δ10.41(s,1H),8.39-8.33(m,1H),8.32-8.23(m,1H),8.14-8.09(m,1H),7.70-7.60(m,1H),7.58-7.48(m ,2H),7.24(t,J=9.2Hz,1H),6.92-6.78(m,2H),4.14-4.05(m,2H),3.67-3.50(m,4H),2.76-2.64(m,2H),2.50-2.43(m,4H).

[1602] For [M+H,C 25 H 23 F2N4O5] + LC-HRMS (ESI) calculated value: 497.1631, found value 497.1638.

[1603] Embodiment 81

[1604]

[1605] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1606] (Compound 489)

[1607] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide can be prepared as in Example 1, but from 2-fluoro-5-(2-morpholinoethoxy)aniline (120.1 mg, 0.5 mmol) and 2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (137.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (155 mg, 62.4% yield) as a light yellow solid.

[1608] 1 H NMR (400MHz, DMSO) δ10.44(s,1H),8.26(t,J=6.7Hz,1H),8.13(d,J=1.1Hz,1H),7. 95(t,J=6.4Hz,1H),7.57(t,J=7.8Hz,1H),7.54-7.50(m,1H),7.49(d,J=3.5Hz,1H ),7.23(t,J=9.7Hz,1H),6.86(dd,J=3.5,1.7Hz,1H),6.82(dt,J=8.9,3.4Hz,1H), 4.08(t,J=5.6Hz,2H),3.70-3.44(m,4H),2.69(t,J=5.4Hz,2H),2.49-2.43(m,4H).

[1609] For [M+H,C 25 H 23 F2N4O5] + LC-HRMS (ESI) calculated value: 497.1631, found value 497.1638.

[1610] Embodiment 82

[1611]

[1612] N-(2-Fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide

[1613] (Compound 490)

[1614] N-(2-Fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(2-morpholinoethoxy)benzoic acid (140.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)aniline (123.1 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (115.3 mg, 45.3% yield) as a yellow solid.

[1615] 1 H NMR (400MHz, DMSO) δ10.54(d,J=2.0Hz,1H),9.06(d,J=5.6Hz,1H),8.84(s,1H),8.20(s,1H),7.92-7.85(m,1H),7.62(dd,J=10.5,8.8Hz,1H ),7.54(d,J=2.4Hz,1H),7.26-7.18(m,2H),4.11(t,J=5.7Hz,2H),4.00(s,3H),3.63-3.53(m,4H),2.70(t,J=5.7Hz,2H),2.50-2.44(m,4H).

[1616] For [M+H,C 25 H 25 FN5O6] + LC-HRMS (ESI) calculated value: 510.1783, found value 510.1786.

[1617] Embodiment 83

[1618]

[1619] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin-1-yl)ethoxy)benzamide

[1620] (Compound 491)

[1621] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin-1-ylethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(2-(piperidin-1-yl)ethoxy)benzoic acid (139.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (130.7 mg, 51.6% yield) as a yellow solid.

[1622] 1 H NMR (400MHz, CDCl3) δ10.60 (s, 1H), 9.33 (d, J = 6.4Hz, 1H), 8.00-7.90 (m, 1H ),7.88-7.79(m,1H),7.72-7.62(m,1H),7.33-7.26(m,2H),7.18-7.08(m,1 H),7.06-6.98(m,1H),6.68-6.59(m,1H),4.66-4.42(m,2H),4.06(s,3H),3 .36-3.24(s,2H),3.23-2.70(s,4H),2.04-1.77(m,4H),1.74-1.46(m,2H).

[1623] For [M+H,C 27 H 28 FN4O5] + LC-HRMS (ESI) calcd.: 507.2038, found 507.2039.

[1624] Embodiment 84

[1625]

[1626] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-methoxyethoxy)benzamide

[1627] (Compound 492)

[1628] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-methoxyethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(2-methoxyethoxy)benzoic acid (113.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (152.3 mg, 67.2% yield) as a yellow solid.

[1629] 1 H NMR (400MHz, DMSO) δ10.55(s,1H),9.05(d,J=5.8Hz,1H),8.14-8.09(m,1H),7.92-7.82(m,1H),7.65-7.58(m,1H),7.54(d,J=2.5Hz,1H) ,7.47(d,J=3.5Hz,1H),7.27-7.16(m,2H),6.85(dd,J=3.5,1.7Hz,1H),4.17-4.07(m,2H),4.00(s,3H),3.70-3.61(m,2H),3.32(s,3H).

[1630] For [M+H,C 23 H 21 FN3O6] + LC-HRMS (ESI) calcd. 454.1409, found 454.1414.

[1631] Embodiment 85

[1632]

[1633] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(2-hydroxyethoxy)-2-methoxybenzamide

[1634] (Compound 493)

[1635] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(2-hydroxyethoxy)-2-methoxybenzamide can be prepared as in Example 1, but from 5-(2-hydroxyethoxy)-2-methoxybenzoic acid (106.1 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (108.5 mg, 49.4% yield) as a yellow solid.

[1636] 1 H NMR (400MHz, CDCl3) δ10.64(s,1H),9.35(d,J=5.5Hz,1H),7.99-7.92(m,1H),7.88(d,J=3.1Hz,1H),7.70-7.66(m,1H),7.3 3-7.27(m,2H),7.17-7.11(m,1H),7.06-7.00(m,1H),6.65-6.61(m,1H),4.22-4.11(m,2H),4.08(s,3H),4.02-3.94(m,2H).

[1637] For [M+H,C 22 H 19 FN3O6] + LC-HRMS (ESI) calcd. 440.1252, found 440.1259.

[1638] Embodiment 86

[1639]

[1640] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide

[1641] (Compound 494)

[1642] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide can be prepared as in Example 1, but from 2-methoxy-5-(2-morpholinoethoxy)benzoic acid (140.7 mg, 0.5 mmol) and 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline (122.6 mg, 0.5 mmol). The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 100 / 1) to give the title compound (145.5 mg, 57.2% yield) as a yellow solid.

[1643] 1 H NMR (400MHz, DMSO) δ10.54 (s, 1H), 9.04 (d, J = 5.4Hz, 1H), 8.11 (d, J = 1.1Hz, 1H), 7.893-7.84(m,1H),7.60(dd,J=10.5,8.7Hz,1H),7.54(d,J=2.4Hz,1H),7.47(d ,J=3.5Hz,1H),7.30-7.18(m,2H),6.85(dd,J=3.5,1.7Hz,1H),4.11(t,J=5.7Hz ,2H),3.99(s,3H),3.69-3.45(m,4H),2.70(t,J=5.7Hz,2H),2.49-2.40(m,4H).

[1644] For [M+H,C 26 H 26 FN4O6] + LC-HRMS (ESI) calculated value: 509.1831, found value 509.1834.

[1645] Biological methods

[1646] Expression of human ALCAT1 in insect cells

[1647] Human ALCAT1 protein was expressed in Spodoptera frugiperda (Sf9) insect cells using the Bac to Bac baculovirus expression system (Invitrogen) according to the manufacturer's instructions. High titer recombinant baculovirus expressing human ALCAT1 protein was generated by several rounds of viral amplification. Sf9 cells were typically infected with recombinant baculovirus for 3 days, harvested in ice-cold phosphate buffered saline (PBS), and homogenized in 20 mm NaCl by French press. The total cell lysate was centrifuged at 10,000 x g for 1 hour at 4 ° C to eliminate the nuclear fraction, followed by ultracentrifugation at 100,000 x g to precipitate the membrane fraction. The membrane fraction was resuspended in enzyme buffer containing 10% glycerol, the protein concentration was quantified, aliquoted, and stored at -80 ° C.

[1648] In vitro acyltransferase assay

[1649] The enzymatic activity of ALCAT1 was determined by measuring the conversion of monolysophospholipid (MLCL) to cardiolipin or lysophosphatidylglycerol (LPG) to phosphatidylglycerol (PG) in an enzyme reaction mixture containing 50 mM Tris / HCl, pH 7.0, 100 μ m lysophospholipid, 25 μ m [ 14 C] acyl-CoA (50 mCi / mmol, American Radiolabeled Chemicals, Inc) and membrane fraction (0.5-2.5 μg) in a total volume of 200 μl. The reaction was incubated at room temperature for 30 min. The lipids were extracted with chloroform, dried, and separated by thin layer chromatography (TLC) using chloroform: hexane: methanol: acetic acid (50: 30: 10: 5, v / v) or chloroform: methanol: water (65: 25: 4, v / v). After separation, the TLC plate was exposed to a PhosphorImager to visualize the radiolabeled product using a Molecular Dynamics Typhoon scanner (Sunnyvale, CA). In some experiments, 100 μM NBD-CoA was used instead of [ 14 C] acyl-CoA. All quantitative data are presented as mean ± SE. The differences between the two groups were statistically analyzed using Student's t-test.

[1650] Cell-based ALCAT1 inhibitor compound assay

[1651] The assay was performed on the H9C2 vector cell line and H9C2 with stable ALCAT1 overexpression. Materials used in the protocol were CoA, LPG, compounds, chloroform, methanol, 0.9% KCl, 6-well plates, 1.5 mL tubes, DMEM, FBS, P / S, and PBS.

[1652] The cells were plated at 8×10 5 Cells were seeded at a density of 10 cells / well in 6-well plates and cultured overnight at 37°C in 5% CO2. Cells were then pretreated with selected compounds (3 μM) for 1 hr and incubated with CoA (5 μM) and LPG (100 μM) with or without selected compounds (3 μM) for another 3 hr.

[1653] The cells were washed once with ice-cold PBS, collected in ice-cold PBS, and centrifuged at 5000 rpm for 5 min at 4° C. 200 μL of chloroform:methanol (2:1) was added to the cell pellet, which was vortexed to suspend the cells and incubated at room temperature for 1 hr.

[1654] 40 μL of 0.9% KCl was added, and the sample was vortexed and then centrifuged at 10000 rpm for 5 min at room temperature. The aqueous phase (upper layer) was discarded, and the organic phase (lower layer) was loaded onto a TLC plate (10 cm×20 cm) at 40 μL / sample.

[1655] The plates were developed in chloroform:methanol:water (65:25:4) for about 30 min and scanned using a Typhoon scanner. The band intensities were analyzed using ImageJ and the inhibitory activity against the test compounds was calculated.

[1656] Determination of ALCAT1 inhibitors

[1657] Compound inhibitors of ALCAT1 enzyme were analyzed by in vitro enzymatic assay as described above. Compound inhibitors were added to the enzyme mixture at a concentration of 1-20 μM before the acyltransferase reaction was started.

[1658] The results for compounds of the invention are shown in the following table, where the % inhibition is given for tests performed with compounds at concentrations of 10 μM and 1 μM. If multiple measurements were performed, this is indicated by a " / " between the multiple values.

[1659]

[1660]

[1661]

[1662] Cell-based ALCAT1 inhibitor assay

[1663] Compound inhibitors of the ALCAT1 enzyme were analyzed by a cell-based in vitro assay as described above. The results are provided in the following table:

[1664]

[1665]

[1666] Some ALCAT1 inhibitors with high activity have also received IC 50 Analysis. IC 50 is the drug concentration that causes 50% inhibition of ALCAT1 enzyme activity. 50 For the analysis, chemical inhibitors of ALCAT1 enzyme were added at various concentrations, namely 100 μM, 33 μM, 10 μM, 3.3 μM, 0.1 μM, 0.003 μM, 0.001 μM. The IC of each compound was analyzed in triplicate. 50 The values ​​were calculated using GraphPad software.

[1667] Using the above assay, the inhibition % and IC were determined for several compounds as well as several reference compounds. 50 The results are summarized as follows.

[1668] The following compounds provide IC 50 Value ≤100nM (≤0.1μM):

[1669] 192, 193, 120, 124, 279, 197, 123, 119, 125, 122, 118, 200, 218, 219, 211, 228, 225, 226, 184, 216, 128, 39, 183, 300, 215, 313, 314, 315, 221, 222, 210, 209, 208, 322, 316, 319, 323, 317, 320, 318, 302, 373, 281, 301, 304, 305, 306, 312, 321, 405, 396, 168, 27, 400, 416, 497.

[1670] The following compounds provide IC 50 Value <35nM (<0.035μM):

[1671] 118, 200, 219, 184, 216, 128, 183, 300, 215, 314, 315, 221, 222, 209, 316, 323, 317, 320, 318, 281, 304, 305, 306, 312, 405 and 416.

[1672] The following compounds provide IC 50 Value <10nM (<0.01μM):222.

[1673] The following table shows the IC values ​​of some compounds of the present invention: 50 result:

[1674]

[1675]

[1676] The disclosures of all references cited herein are hereby specifically incorporated herein by cross-reference as they may be used by one skilled in the art to implement the present invention.

Claims

1. A compound according to formula (IA): or a pharmaceutically acceptable salt thereof, in: L B Selected from -NR L1 C(=O)-* and -C(=O)NR L1 -*, Wherein the asterisk (*) indicates the point of attachment to the terminal phenyl group; R L1 Selected from -H, and -P(=O)(OH)2; Y 1 , Y 2 and Y 3 One of them is CR Y ; Y 1 , Y 2 and Y 3 The second one is independently selected from CR Y and CH; and Y 1 , Y 2 and Y 3 The third one is independently selected from CR Y and CH; Q 5A , Q 6A and Q 7A one of is selected from N and CH; and Q 5A , Q 6A and Q 7A The other two are independently selected from CH and CR Q3 ; Each R Y Independently selected from Straight or branched unsubstituted C 1-6 alkyl, -OR Y1 ; -F, -Cl, -Br, -I, -CF3, -CH2F, -CF2H, -CH2CF3, -CH2CH2F and -CH2CF2H; Where R Y1 Selected from Straight or branched unsubstituted C 1-6 alkyl, -CF3, -CH2F, -CF2H, -CH2CF3, -CH2CH2F and -CH2CF2H; R Q3 Selected from -F, -Cl, -Br, C 1-6 Straight chain unsubstituted alkyl, -O(C 1-6 alkyl), and -CN; Provided that the compound is not selected from any one of compounds (X1) to (X3), (X6), (X9) to (X12), (X15), (X19), (X28) to (X31), (X33) to (X36):

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L B Selected from -NHC(=O)-* and -C(=O)NH-*.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 CR Y And Y 2 and Y 3 Each of which is selected from CH and CR Y .

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Y 2 and Y 3 All are CH.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Y 2 and Y 3 One of them is CH and the other is CR Y .

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Y 2 CH and Y 3 CR Y .

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 5A , Q 6A and Q 7A Each is CH.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 5A and Q 6A One of them is CR Q3 , the other is CH, and Q 7A For CH.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 6A and Q 7A One of them is N, the other is CH, and Q 5A For CH.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R Q3 Selected from -F, -Cl and -Br.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R Q3 is -F.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R L1 is -H.

15. A composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

16. A method for preparing a pharmaceutical composition, the method comprising mixing a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.

17. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a composition according to claim 15 in the preparation of a medicament for treating a disease characterized by one or more of oxidative stress, CL deficiency, docosahexaenoic acid enrichment in CL and mitochondrial dysfunction and associated with the regulation of ALCAT1, wherein CL is cardiolipin and ALCAT1 is acyl-CoA:lysocardiolipin acyltransferase-1.

18. Use according to claim 17, wherein the treatment is the treatment of a disease associated with mitochondrial dysfunction and associated with the regulation of ALCAT1.

19. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a composition according to claim 15 in the preparation of a medicament for treating a disease associated with the regulation of ALCAT1, the disease being selected from obesity, diabetes, diabetic complications, fatty liver disease, cardiovascular disease, neurodegenerative disease, metabolic disease, insulin resistance and cancer, wherein ALCAT1 is acyl-CoA:lysophospholipid acyltransferase-1.

20. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a composition according to claim 15 in the preparation of a medicament for treating aging or age-related diseases associated with the regulation of ALCAT1, wherein ALCAT1 is acyl-CoA:lysocardiolipin acyltransferase-1.

21. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a composition according to claim 15 in the preparation of a medicament for treating a disease associated with the regulation of ALCAT1 selected from stroke, ischemia and reperfusion injury, wherein ALCAT1 is acyl-CoA:lysocardiolipin acyltransferase-1.

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