Compounds useful as ALCAT1 inhibitors

Abstract

An ALCAT1 inhibitor having the general formula: # imgabs0 # is described. These compounds are useful in the treatment of aging and age-related diseases.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880027862X (filing date: March 29, 2018, invention title: Compounds useful as ALCAT1 inhibitors). Technical Field

[0002] The present invention generally relates to compounds useful as ALCAT1 inhibitors. Such compounds can be used to treat aging and age-related disorders. Background Art

[0003] Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1) is a phosphatidylglycerol acyltransferase of the endoplasmic reticulum, which is mainly known for catalyzing the acylation of monolysocardiolipin and dilysocardiolipin back to cardiolipin.

[0004] Recent studies have shown that the enzyme ALCAT1 plays a role in the etiology of oxidative stress and various aging-related diseases, including type 2 diabetes, diabetic complications (nephropathy, retinopathy, and cardiomyopathy), cardiovascular diseases, and 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, production of reactive oxygen species (ROS), and insulin resistance.

[0005] When mitochondria undergo fusion events that result in the compartments involved in the mitochondria becoming continuous, a dynamic network is formed. Fusion events allow the components of each network to share solutes, metabolites, and proteins. Thus, disruption of such networks leads to oxidative stress and mitochondrial fragmentation, which is associated with the etiology of aging and age-related diseases.

[0006] In WO 2013 / 123305 (the entire disclosure of which is incorporated herein by reference), the key role of ALCAT1 in regulating mitochondrial biogenesis and mtDNA fidelity was demonstrated. Overexpression of ALCAT1 severely disrupts mitochondrial fusion, leading to mitochondrial fragmentation and mtDNA depletion. Conversely, 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 showing that mitochondrial fusion is necessary to protect mtDNA integrity (Chen H et al., (2010) Cell 141(2):280-289).

[0007] WO 2013 / 123305 also provides evidence that ALCAT1 plays a key role in regulating MFN2 expression. MFN2 is essential 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.

[0008] 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).

[0009] WO 2013 / 123305 identifies ALCAT1 as the missing link between mitochondrial fusion defects and reactive oxygen species (ROS) production in metabolic diseases. Cardiolipin (CL) remodeling by ALCAT1 significantly increases the content of docosahexaenoic acid (DHA) in CL, leading to proton leak and oxidative stress. The DHA content in the mitochondrial membrane is inversely proportional to lifespan and directly proportional to ROS production and lipid peroxidation index in mammals. Thus, an increase in the 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 E.J (2009) J Cardiovasc Pharmacol 53(4):290 - 301; Lee H - J, (2006) LzjJids Health & Dis.5:2; Paradies G et al., (2010) Free Radie Biol Med 48(0):1286 - 1295; Shi Y (2010) J Biomed Res 24(1):6 - 15).

[0010] The onset of aging and age - related diseases is associated with oxidative stress and increased mtDNA mutation rate, which have been considered as the 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 conceivable that developing chemical inhibitors of ALCAT1 would provide potential therapeutic approaches for aging, age - related diseases, and other conditions caused by mitochondrial dysfunction such as Barth syndrome.

[0011] WO 2013 / 123305 also shows that ALCAT1 plays a key role in regulating the onset of hypertrophic cardiomyopathy. Overexpression of ALCAT1 results in hypertrophic growth of H9c2 cells, while depletion 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 tetra-linoleoyl CL (TLCL), which has been identified as the major cause of cardiomyopathy in Barth syndrome.

[0012] Depletion of ALCAT1 expression completely prevents cardiac lipid peroxidation caused by hyperthyroidism.

[0013] Depletion of ALCAT1 also prevents the onset of Barth syndrome by alleviating mitochondrial dysfunction. Development of an ALCAT1 inhibitor would provide a potential treatment for Barth syndrome, a fatal inherited disorder.

[0014] ALCAT1 is upregulated by oxidative stress and in the onset of diabetes and obesity. Targeted inactivation of ALCAT1 prevents mitochondrial dysfunction and the onset of obesity, which is a major cause of type 2 diabetes and cardiovascular disease. Development of an ALCAT1 inhibitor would provide potential treatments for cardiac hypertrophy and other heart diseases, which are the leading causes of death in developed countries.

[0015] Accordingly, compounds that act as ALCAT1 inhibitors are needed to provide 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

[0016] A first aspect of the invention is a compound according to formula (I) as described herein.

[0017] A second aspect of the invention is a composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier or diluent.

[0018] A third aspect of the invention is a compound according to formula (I) as described herein, for use in the treatment of the human or animal body by therapy.

[0019] A fourth aspect of the invention is a compound according to formula (I) for use in a method of inhibiting or downregulating ALCAT1.

[0020] The fifth aspect of the present invention is the compound described herein, which is used for preventing or treating aging or age-related diseases.

[0021] The sixth aspect of the present invention is the use of the compound according to formula (I) in the preparation of a medicament for preventing or treating aging or age-related diseases.

[0022] The seventh aspect of the present invention is a method for inhibiting ALCAT1, which method comprises administering a therapeutically effective amount of the compound according to formula (I).

[0023] The eighth aspect of the present invention is a treatment method, which method comprises administering a therapeutically effective amount of the compound as described herein to a patient in need of treatment, preferably in the form of a pharmaceutical composition.

[0024] The ninth aspect of the present invention is a method for treatment and / or prevention, which method comprises administering a therapeutically effective amount of the AS compound as described herein to a subject in need of treatment and / or prevention, preferably in the form of a pharmaceutical composition.

[0025] The tenth aspect of the present invention is a kit, which kit comprises (a) a compound according to formula (I), which compound is preferably provided as a pharmaceutical composition and in a suitable container and / or with a suitable package; and (b) instructions for use, such as written instructions on how to administer the compound.

[0026] Another aspect of the present invention is a compound obtainable by the synthetic method as described herein or a method comprising the synthetic method as described herein.

[0027] Another aspect of the present invention is a compound obtained by the synthetic method as described herein or a method comprising the synthetic method as described herein.

[0028] Another aspect of the present invention is a novel intermediate as described herein, which novel intermediate is suitable for the synthetic method as described herein.

[0029] Another aspect of the present invention is the use of such a novel intermediate as described herein in the synthetic method as described herein.

[0030] Another aspect of the present invention is a method for synthesizing the compound as described herein.

[0031] As will be understood by those skilled in the art, the features and preferred embodiments of one aspect of the present invention will also pertain to another aspect of the present invention.

[0032] Any subheadings herein are included for convenience only and should not be construed as limiting the disclosure in any way.

[0033] Compound

[0034] The first aspect of the present invention is a compound according to formula (I):

[0035]

[0036] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0037] wherein:

[0038] X is selected from O and S;

[0039] G 1 and G 2 are each independently selected from N and CH;

[0040] A is selected from

[0041] H,

[0042] optionally substituted by one or more groups R A1 substituted C 1-6 linear or branched alkyl or alkenyl,

[0043] optionally substituted by one or more groups R B1 substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,

[0044] optionally substituted by one or more groups R B2 substituted 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S,

[0045] -CN,

[0046] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0047] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , -NR D5 COR C2 , and

[0048] -SR E1 ;

[0049] L is a single bond, or the group L A ,

[0050] wherein L A is selected from

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

[0052] -NR L C(=X L )NR L -*,

[0053] -SO 2 -NR L -*, -NR L -SO 2 -*,

[0054] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[0055] wherein the asterisk (*) represents the point of attachment to R 1 ;

[0056] X L is selected from O and S;

[0057] R L is selected from

[0058] -H,

[0059] -C(=O)(C 1-3 alkyl),

[0060] -P(=O)(OH) 2 , and

[0061] -S(=O) 2 NH 2 ;

[0062] When L is a single bond, R 1 is NH 2 ;

[0063] When L is L A , R 1 is R 1L wherein R 1L is selected from

[0064] C 1-6 linear or branched unsubstituted alkyl;

[0065] optionally substituted with one to three groups R PHSubstituted phenyl,

[0066] optionally substituted with one or more groups R B3 Substituted 5- or 6-membered cycloalkyl,

[0067] optionally substituted with one or more groups R B4 Substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and

[0068] optionally substituted with one or more groups R B5 Substituted 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O, and S;

[0069] wherein each R PH is independently selected from

[0070] optionally substituted with one or more groups R A2 substituted C 1-6 linear or branched alkyl, alkenyl, or alkynyl,

[0071] optionally substituted with one or more groups R A3 substituted phenyl,

[0072] naphthyl,

[0073] -F, -Cl, -Br, -I,

[0074] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0075] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NR D5 COR C2 , -NHSO 2 (C 1-3 alkyl),

[0076] -SO 2 NH 2 , -SO2 NHR D1 、 -SO 2 N(R D2 ) 2 、 -SO 2 R E2 、 -SR E1 ,

[0077] -NO 2 ,

[0078] -CN,

[0079] -OH, and -OR PH4 ;

[0080] wherein R PH4 is selected from

[0081] phenyl,

[0082] benzyl, and

[0083] optionally substituted by one or more groups R A5 C 1-6 linear or branched alkyl;

[0084] Q is selected from (Q1) and (Q2)

[0085]

[0086] wherein the two asterisks (**) represent the attachment points to L;

[0087] Q 1A 、Q 2A 、Q 3A and Q 4A two of them are CH;

[0088] Q 1A 、Q 2A 、Q 3A and Q 4A the other two are independently selected from N, CH, and CR Q1 ;

[0089] Q 1B 、Q 2B 、Q 3B and Q 4B two of them are CH.

[0090] Q 1B 、Q 2B 、Q 3B and Q 4B the other two are independently selected from N, CH, and CR Q2 ;each R Q1 and each R Q2independently selected from

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

[0092] C 1-6 a straight-chain or branched-chain unsubstituted alkyl group,

[0093] -OH, -O(C 1-6 alkyl),

[0094] -CN, and

[0095] -N(R D3 ) 2 ;

[0096] R C1 and R C2 each independently selected from

[0097] a C A6 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R 1-6 ;

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

[0099] R D1 to R D7 each independently selected from

[0100] a C A7 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R 1-6 ;

[0101] -COOH, -COOR C1 , -COR C2 ,

[0102] -C(=NH)NH 2 ,

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

[0104] wherein R D9 is a C A8 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R 1-6 ;

[0105] R D8is a C containing one or two N atoms optionally substituted by one or more groups selected from the following 5-6 heterocyclic group:

[0106] -SH, and

[0107] -C(=O)OR D5A , where R D5A is a phenyl or benzyl optionally substituted by a NO 2 group;

[0108] R E1 and R E2 are each independently selected from C 1-6 linear or branched unsubstituted alkyl, alkenyl or alkynyl;

[0109] R E3 is independently selected from

[0110] -SH; and

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

[0112] R B1 to R B5 are each independently selected from

[0113] optionally substituted by one or more groups R A9 substituted C 1-6 linear or branched alkyl,

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

[0115] -OH, -O(C 1-3 alkyl),

[0116] -CN,

[0117] -NO 2 ,

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

[0119] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH-NRD7 COOR C1 , and -NR D5 COR C2 ;

[0120] R E4 is independently selected from

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

[0122] R A1 to R A10 are each independently selected from

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

[0124] -OH, -OR T

[0125] -CN, -NO 2 ,

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

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

[0128] R F is selected from

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

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

[0131] The group -N(R G ) 2 is selected from azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-C 1-4 alkyl-piperazinyl, morpholinyl, azepino or diazepino optionally substituted with one or more groups selected from straight-chain or branched C 1-4 alkyl, phenyl or benzyl;

[0132] R Tis C 1-6 a straight-chain or branched-chain unsubstituted alkyl group;

[0133] Two Rs D9 together with the nitrogen atom to which they are attached form a group selected from: a 5-membered heteroaryl group containing one or two nitrogen atoms; and

[0134] a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S,

[0135] provided that the compound is not selected from any of the compounds (X1) to (X27):

[0136]

[0137]

[0138]

[0139] In some embodiments:

[0140] R L is selected from

[0141] -H, and -C(=O)(C 1-3 alkyl);

[0142] and in the -N(R D9 ) 2 group, the two R D9 groups together with the nitrogen atom to which they are attached form a 5-membered heteroaryl group containing one or two nitrogen atoms.

[0143] Group X

[0144] In some embodiments, X is O.

[0145] In some embodiments, X is S.

[0146] Group G 1

[0147] In some embodiments, G 1 is N.

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

[0149] Group G 2

[0150] In some embodiments, G 2 is N.

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

[0152] Groups X, G 1 and G 2

[0153] In some embodiments, X is O, G 1 is N and G 2 is N.

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

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

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

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

[0158] In some embodiments, X is O, G 1 is CH and G 2 is CH.

[0159] In some embodiments, X is O, G 1 and G 2 one of which is selected from CH and N, and G 1 and G 2 the other of which is N.

[0160] In some embodiments, X is S, G 1 and G 2 one of which is selected from CH and N, and G 1 and G 2 the other of which is N.

[0161] Group A

[0162] In some embodiments, A is -H.

[0163] In some embodiments, A is a C A1 linear or branched alkyl or alkenyl optionally substituted with one or more groups R 1-6 groups.

[0164] In some embodiments, A is a C A1 linear or branched alkyl or alkenyl optionally substituted with one or more groups R 1-5 groups.

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

[0166] In some embodiments, R is selected from A1 selected from

[0167] -OH, -OR T

[0168] -C(=O)R T , -COOH, -COOR T ,

[0169] -NH 2 , -NHR T , -N(R T ) 2 , -NHC(=O)(R F ) and -N(R D9 ) 2 .

[0170] In some embodiments, R is selected from A1 selected from

[0171] -OR T

[0172] -NH 2 , -NHR T , -N(R T ) 2 , -NHC(=O)(R F ) and -N(R D9 ) 2 .

[0173] In some embodiments, -A is selected from

[0174] methyl, ethyl, isopropyl,

[0175] -CH 2 NMe 2 , -CH 2 NHCOMe, -CH 2 NHCO(R F ), -CH 2 N(R D3 ) 2 ,

[0176] -CH 2 OMe,

[0177] -CH(NH 2 )CH 3 and -CH(NH 2)CH 2 CH(Me) 2 。

[0178] In some embodiments, -A is selected from 5- or 6-membered heteroaryl optionally substituted with one or more groups R B1 and containing 1 to 3 heteroatoms selected from N, O, and S.

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

[0180] In some embodiments, -A is selected from 5-membered heteroaryl optionally substituted with one or more groups R B1 and containing 1 or 2 heteroatoms selected from N, O, and S.

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

[0182] In some embodiments, -A is selected from 5-membered unsubstituted heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0183] In some embodiments, -A is selected from 5-membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S.

[0184] In some embodiments, R B1 is selected from

[0185] linear or branched C A9 alkyl optionally substituted with one or more groups R 1-3 ,

[0186] -F, -Cl, -Br,

[0187] -CN,

[0188] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0189] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCORC2 ,-NR D6 COOH - NR D7 COOR C1 , and - NR D5 COR C2 .

[0190] In some embodiments, R B1 is selected from

[0191] optionally substituted with one or more groups R A9 C 1-3 linear or branched alkyl

[0192] -F, -Cl, -Br

[0193] -CN

[0194] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 and -CON(R D2 ) 2 .

[0195] In some embodiments, R B1 is selected from

[0196] optionally substituted with one or more groups R A9 C 1-3 linear or branched alkyl

[0197] -F, -Cl, -Br

[0198] -CN

[0199] -COR C2 , -CONH 2 , -CONHR D1 and -CON(R D2 ) 2 .

[0200] In some embodiments, R B1 is selected from

[0201] C 1-3 linear unsubstituted alkyl

[0202] -F, -Cl, -Br

[0203] -CN

[0204] -COOH, -COOR C1 , -COR C2 , -CONH 2, -CONHR D1 and -CON(R D2 ) 2 .

[0205] In some embodiments, R B1 is selected from

[0206] C 1-3 linear unsubstituted alkyl,[

[0207] -F, -Cl, -Br,[

[0208] -CN,[

[0209] -COOH, -COOR C1 and -COR C2 .

[0210] In some embodiments, R B1 is selected from

[0211] methyl,[

[0212] -CH 2 Cl,[

[0213] -F, -Cl, -Br,[

[0214] -CN, and

[0215] -C(=O)Me.[

[0216] In some embodiments, -A is selected from

[0217]

[0218] wherein R AX is a single optional ring substituent selected from:[

[0219] optionally substituted by one or more groups R A9 substituted C 1-3 linear or branched alkyl,[

[0220] -F, -Cl, -Br,[

[0221] -CN,[

[0222] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0223] -NH 2 , -NHR D4, -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 .

[0224] In some embodiments, R AX is a single optional ring substituent selected from the following:

[0225] C 1-3 straight-chain unsubstituted alkyl,

[0226] -F, -Cl, -Br,

[0227] -CN,

[0228] -COOH, -COOR C1 and -COR C2 .

[0229] In some embodiments, there is no R AX , i.e., the ring is unsubstituted.

[0230] In some embodiments, -A is a furan-2-yl optionally substituted by one or more groups selected from the following

[0231] optionally substituted by one or more groups R A9 substituted C 1-3 straight-chain or branched-chain alkyl,

[0232] -F, -Cl, -Br,

[0233] -CN,

[0234] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0235] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NRD7 COOR C1 , and -NR D5 COR C2 .

[0236] In some embodiments, -A is a furan-2-yl optionally substituted with one or more groups selected from

[0237] C 1-3 unsubstituted straight-chain alkyl,

[0238] -F, -Cl, -Br,

[0239] -CN,

[0240] -COOH, -COOR C1 and -COR C2 .

[0241] In some embodiments, -A is a furan-2-yl optionally substituted with a group selected from

[0242] C 1-3 unsubstituted straight-chain alkyl,

[0243] -F, -Cl, -Br,

[0244] -CN,

[0245] -COOH, -COOR C1 and -COR C2 .

[0246] In some embodiments, -A is an unsubstituted furan-2-yl.

[0247] In some embodiments, -A is selected from 6-membered heteroaryl optionally substituted with one or more groups R B1 and containing 1-3 heteroatoms selected from N, O, and S.

[0248] In some embodiments, -A is selected from 6-membered heteroaryl optionally substituted with one or more groups R B1 and containing 1 or 2 heteroatoms selected from N, O, and S.

[0249] In some embodiments, -A is selected from 6-membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from 6-membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N.

[0250] In some embodiments, -A is selected from

[0251]

[0252] wherein RAY is a single optional ring substituent selected from the following

[0253] optionally substituted with one or more groups R A9 substituted C 1-3 linear or branched alkyl

[0254] -F, -Cl, -Br

[0255] -CN

[0256] -COOH, -COOR C1 、-COR C2 、-CONH 2 、-CONHR D1 、-CON(R D2 ) 2 ,

[0257] -NH 2 、-NHR D4 、-N(R D3 ) 2 、-NHCOOH, -NHCOOR C1 、-NHCOR C2 、-NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 .

[0258] In some embodiments, there is no R AY , i.e., the ring is unsubstituted.

[0259] In some embodiments, -A is selected from 4- to 6-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B2 .

[0260] In some embodiments, -A is selected from 4- to 5-membered heterocyclic groups containing 1 or 2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B2 .

[0261] In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclic groups containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclic groups containing 1 or 2 heteroatoms selected from N and O. In some embodiments, -A is selected from 4- to 6-membered unsubstituted heterocyclic groups containing 1 heteroatom selected from N, O, and S.

[0262] In some embodiments, -A is selected from

[0263]

[0264] In some embodiments, -A is -CN.

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

[0266] In some embodiments, -A is -COOR C1 . In some embodiments, R C1 is selected from C 1-6 linear or branched unsubstituted alkyl. In some embodiments, R C1 is selected from C 1-4 linear or branched unsubstituted alkyl. In some embodiments, R C1 is selected from C 1-3 linear unsubstituted alkyl. In some embodiments, R C1 is methyl.

[0267] In some embodiments, -A is -COR C2 . In some embodiments, R C2 is selected from C 1-6 linear or branched unsubstituted alkyl. In some embodiments, R C2 is selected from C 1-4 linear or branched unsubstituted alkyl. In some embodiments, R C2 is selected from C 1-3 linear unsubstituted alkyl. In some embodiments, R C2 is methyl.

[0268] In some embodiments, -A is -CON(R D2 ) 2 . In some embodiments, each R D2 is independently selected from C A7 linear or branched alkyl optionally substituted with one or more groups R 1-6 . In some embodiments, each R D2 is independently selected from unsubstituted C 1-6 linear or branched alkyl. In some embodiments, each R D2 is independently selected from unsubstituted C 1-3 linear or branched alkyl. In some embodiments, each R D2 is methyl.

[0269] In some embodiments, -A is -NHCOR C2 . In some embodiments, R C2 is selected from C 1-6Straight-chain or branched unsubstituted alkyl. In some embodiments, R C2 is selected from C 1-4 Straight-chain or branched unsubstituted alkyl. In some embodiments, R C2 is selected from C 1-3 Straight-chain unsubstituted alkyl. In some embodiments, R C2 is methyl.

[0270] In some embodiments, -A is -CONH 2 .

[0271] In some embodiments, -A is -CONHR D1 .

[0272] In some embodiments, -A is -NH 2 .

[0273] In some embodiments, -A is -NHR D4 .

[0274] In some embodiments, -A is -N(R D3 ) 2 .

[0275] In some embodiments, -A is -NHCOOH.

[0276] In some embodiments, -A is -NHCOOR C1 .

[0277] In some embodiments, -A is -NHCOH.

[0278] In some embodiments, -A is -NR D6 COOH.

[0279] In some embodiments, -A is -NR D7 COOR C1 .

[0280] In some embodiments, -A is -NR D5 COR C2 .

[0281] In some embodiments, -A is -SR E1 . In some embodiments, R E1 is selected from C 2-6 Straight-chain or branched unsubstituted alkenyl. In some embodiments, R E1 is selected from C 3-6 Straight-chain unsubstituted alkenyl. In some embodiments, R E1 is allyl.

[0282] Group L

[0283] In some embodiments, L is a single bond. In some embodiments, L is the group L A .

[0284] In some embodiments, L is L A , and L A is selected from

[0285] -NR L C(=O)-*, -C(=O)NR L- *,

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

[0287] -SO 2 -NR L -*, -NR L -SO 2 -*,

[0288] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[0289] where the asterisk (*) represents the point of attachment to R 1 .

[0290] In some embodiments, L is L A , and L A is selected from -NR L C(=O)-* and -C(=O)NR L -*, where the asterisk (*) represents the point of attachment to R 1 .

[0291] In some embodiments, L is L A , and L A is -NR L C(=O)-*, where the asterisk (*) represents the point of attachment to R 1 .

[0292] In some embodiments, R L is -H. In some embodiments, R L is -C(=O)(C 1-3 alkyl). In some embodiments, R L is -C(=O)Me. In some embodiments, R L is -P(=O)(OH) 2 . In some embodiments, R L is -S(=O)2 NH 2 。

[0293] 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 is -NR L C(=O)-*, where R L is -P(=O)(OH) 2 In some embodiments, L A is -NR L C(=O)-*, where R L is -S(=O) 2 NH 2 。

[0294] In some embodiments, L is L A , and L A is -NR L C(=X L )NR L -*. In some embodiments, L is L A , and L A is -SO 2 -NR L -*. In some embodiments, L is L A , and L A is -NR L -SO 2 -*. In some embodiments, L is L A , and L A is -OC(=O)-NR L -*. In some embodiments, L is L A , and L A is -NR L -C(=O)O-*.

[0295] In some embodiments, X L is O. In some embodiments, X L is S.

[0296] The group R 1

[0297] When L is a single bond, R 1 is NH 2 。

[0298] When L is L A , R 1 is R 1L 。

[0299] In some embodiments, R 1L is selected from C 1-6 a straight-chain or branched unsubstituted alkyl group. In some embodiments, R 1L is methyl.

[0300] In some embodiments, R 1L is a phenyl group optionally substituted with 1-3 groups R PH In some embodiments, R 1L is a phenyl group optionally substituted with one or two groups R PH In some embodiments, R 1L is a phenyl group optionally substituted with one group R PH In some embodiments, R 1L is a phenyl group optionally substituted with two groups R PH In some embodiments, R 1L is a phenyl group optionally substituted with three groups R PH substituted phenyl group.

[0301] In some embodiments, R 1L is an unsubstituted phenyl group. In some embodiments, R 1L is a phenyl group with a single substituent R PH in the ortho position. In some embodiments, R 1L is a phenyl group with a single substituent R PH in the meta position. In some embodiments, R 1L is a phenyl group with a single substituent R PH in the para position.

[0302] As used herein, unless otherwise specified, the term "in the ortho position" refers to the position on the ring relative to the L group. The terms "in the meta position" and "in the para position" apply similarly.

[0303] In some embodiments, R 1L is a phenyl group with a single substituent R PH in the ortho or para position.

[0304] In some embodiments, R 1L is a phenyl group with two substituents R PH in two meta positions. In some embodiments, R 1L is a phenyl group with two substituents R PH in two ortho positions.

[0305] In some embodiments, R 1L is a phenyl group with two substituents R PH where the two substituents R PHOne is in the ortho position and the other is in the para position. In some embodiments, R 1L is a phenyl group with two substituents R PH wherein one of the two substituents R PH is in the meta position and the other is in the para position. In some embodiments, R 1L is a phenyl group with two substituents R PH wherein the first of the two substituents R PH is in the ortho position and the second of the two substituents R PH is in the para position of the first. In some embodiments, R 1L is a phenyl group with two substituents R PH wherein the first of the two substituents R PH is in the ortho position and the second of the two substituents R PH is in the meta position which is the para position of the first.

[0306] In some embodiments, R 1L is a phenyl group with three substituents R PH .

[0307] In some embodiments, R 1L is a phenyl group with three substituents R PH wherein the first is in the para position, and the second and third are in two meta positions. In some embodiments, R 1L is a phenyl group with three substituents R PH wherein the first is in the ortho position, and the second and third are in two meta positions. In some embodiments, R 1L is a phenyl group with three substituents R PH wherein the first is in the ortho position, the second is in the para position, and the third is in the para position of the first.

[0308] In some embodiments, R 1L is

[0309]

[0310] wherein one of Y 1 , Y 2 and Y 3 is CR Y ; the second of Y 1 , Y 2 and Y 3 is independently selected from CR Y and CH; and the third of Y 1 , Y 2 and Y 3 is independently selected from CR Y and CH;

[0311] Each R Y is independently selected from

[0312] a straight-chain or branched unsubstituted C 1-6 alkyl group,

[0313] -OR Y1 ;

[0314] -F, -Cl, -Br, -I,

[0315] -CF 3 、-CH 2 F, -CF 2 H,

[0316] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H.

[0317] In some embodiments, one of Y 1 , Y 2 and Y 3 is CR Y ; a second of Y 1 , Y 2 and Y 3 is selected from CR Y and CH; and a third of Y 1 , Y 2 and Y 3 is CH.

[0318] In some embodiments, Y 1 is CR Y and each of Y 2 and Y 3 is selected from CH and CR Y .

[0319] In some embodiments, Y 1 is CR Y and both Y 2 and Y 3 are CH.

[0320] In some embodiments, Y 1 is CR Y , one of Y 2 and Y 3 is CH and the other is CR Y .

[0321] In some embodiments, Y 1 is CRY and Y 2 is CH and Y 3 is CR Y .

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

[0323] In some embodiments, R Y is independently selected from straight-chain or branched unsubstituted C 1-6 alkyl groups such as methyl, ethyl or n-propyl.

[0324] In some embodiments, R Y is independently selected from -OR Y1 , such as -OMe, -OEt, -O n Pr, -OCF 3 , -OCH 2 F, -OCF 2 H, -OCH 2 CF 3 , -OCH 2 CH 2 F or -OCH 2 CF 2 H.

[0325] In some embodiments, R Y is independently selected from -F, -Cl, -Br and -I. In some embodiments, R Y is independently selected from -F.

[0326] In some embodiments, R Y is independently selected from

[0327] -CF 3 , -CH 2 F, -CF 2 H,

[0328] -CH 2 CF 3 , -CH 2 CH 2 F and -CH 2 CF 2 H.

[0329] In some embodiments, R Y is -CF 3 .

[0330] In some embodiments, R Y1 is methyl. In some embodiments, RY1 is ethyl. In some embodiments, R Y1 is n-propyl. In some embodiments, R Y1 is -CF 3 . In some embodiments, R Y1 is -CF 2 H. In some embodiments, R Y1 is -CFH 2 . In some embodiments, R Y1 is -CH 2 CF 2 H. In some embodiments, R Y1 is -CH 2 CFH 2 .

[0331] In some embodiments, each R PH is independently selected from

[0332] a straight-chain or branched-chain alkyl, alkenyl or alkynyl optionally substituted with one or more groups R A2 , 1-6 a phenyl optionally substituted with one or more groups R

[0333] , A3 -F, -Cl, -Br, -I,

[0334] -COOH, -COOR

[0335] , -COR C1 , -CONH C2 , -COONH 2 , -CONHR 2 , -CON(R D1 ) D2 , 2 ,

[0336] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NR D5 COR C2 , -NHSO 2 (C 1-3 alkyl),

[0337] -SO 2 NH2 、 -SO 2 NHR D1 、 -SO 2 N(R D2 ) 2 、 -SO 2 R E2 、 -SR E1 ,

[0338] -NO 2 ,

[0339] -CN,

[0340] -OH, and -OR PH4 。

[0341] In some embodiments, each R PH is independently selected from

[0342] optionally substituted with one or more groups R A2 C 1-4 a straight-chain or branched alkyl, alkenyl or alkynyl,[[]]

[0343] an unsubstituted phenyl,[[]]

[0344] -F, -Cl, -Br, -I,[[]]

[0345] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0346] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NR D5 COR C2 , -NHSO 2 (C 1-3 alkyl),

[0347] -SO 2 NH 2 , -SO 2 NHR D1 , -SO2 N(R D2 ) 2 、 -SO 2 R E2 、 -SR E1 ,

[0348] -NO 2 ,

[0349] -CN,

[0350] -OH, and -OR PH4 。

[0351] In some embodiments, each R PH is independently selected from

[0352] optionally substituted with one or more groups R A2 C 1-4 straight-chain or branched alkyl, alkenyl or alkynyl,

[0353] -F, -Cl, -Br, -I,

[0354] -OH, and -OR PH4 。

[0355] In some embodiments, each R PH is independently selected from

[0356] optionally substituted with one or more groups R A2 C 1-6 straight-chain alkyl,

[0357] -F, -Cl, -Br, -I,

[0358] -OH, and -OR PH4 。

[0359] In some embodiments, each R PH is independently selected from

[0360] C straight-chain alkyl optionally substituted with one or more groups selected from -F, -Cl, -Br and -I, 1-6 straight-chain alkyl,

[0361] -F, -Cl, -Br, -I,

[0362] -OH, and -OR PH4 wherein R PH4 is selected from straight-chain or branched alkyl optionally substituted with one or more groups R A5 C 1-6 straight-chain or branched alkyl.

[0363] In some embodiments, R 1LIt is a phenyl group with a first substituent R at the ortho position PH and a second substituent R at the para position of the first substituent PH , where the R PH groups are each independently selected from

[0364] a C A2 straight-chain alkyl optionally substituted with one or more groups R 1-6 ,

[0365] -F, -Cl, -Br, -I,

[0366] -OH, and -OR PH4 .

[0367] In some embodiments, each R PH is independently selected from

[0368] -Me, -Et, - t Bu, -CH=CHMe, -CCH, -CCMe, -Ph,

[0369] -OH, -OMe, -OEt, -O n Pr, -O i Pr, -O n Bu, -O-sec-Bu, -O-iso-Bu, -OPh, -OBn,

[0370] -OCH 2 CF 3 , -OCF 3 , -OCHF 2 , -OCF 2 H, -OCH 2 CHF 2 , -OCH 2 CH 2 F,

[0371] -OCH 2 C(=O)OH, -OCH 2 C(=O)OMe,

[0372] -F, -Cl, -Br, -I,

[0373] -CF 3 , -CHF 2 , -CN, -CH 2 CN, -CH(Me)CN, -CH 2 OH, -CH 2 OMe, -CH 2 COOH,

[0374] -COOH, -COOMe, -CONH2 、 -CONMe 2 、 -CONHMe, -C(=O)Me, -COONH 2 ,

[0375] -SO 2 Me, -SO 2 NH 2 、 -SMe,

[0376] -NO 2 、 -NH 2 、 -NMe 2 、 -NHMe, -NHC(=O)Me, -NHSO 2 Me,

[0377]

[0378] N - pyrrolidinyl, and N - piperidinyl.

[0379] In some embodiments, each R PH is independently selected from

[0380] -Me, -Et, - t Bu, -CH=CHMe, -CCH, -CCMe, -Ph,

[0381] -OH, -OMe, -OEt, -O n Pr, -O n Bu, -O - sec - Bu, -O - iso - Bu, -OPh, -OBn,

[0382] -OCH 2 CF 3 、 -OCF 3 、 -OCHF 2 、 -OCF 2 H, -OCH 2 CHF 2 、 -OCH 2 CH 2 F,

[0383] -OCH 2 C(=O)OH, -OCH 2 C(=O)OMe,

[0384] -F, -Cl, -Br, -I,

[0385] -CF 3 、 -CHF 2 、 -CN, -CH 2 CN, -CH(Me)CN, -CH 2 OH, -CH2 OMe, -CH 2 COOH,

[0386] -COOH, -COOMe, -CONH 2 , -CONMe 2 , -CONHMe, -C(=O)Me, -COONH 2 ,

[0387] -SO 2 Me, -SO 2 NH 2 , -SMe,

[0388] -NO 2 , -NH 2 , -NMe 2 , -NHMe, -NHC(=O)Me, -NHSO 2 Me,

[0389]

[0390] N-pyrrolidinyl, and N-piperidinyl.

[0391] In some embodiments, R 1L is selected from

[0392]

[0393] wherein R PH2 and R PH3 are each independently selected from

[0394] optionally substituted with one or more groups R A2 of a C 1-4 straight-chain or branched alkyl, alkenyl or alkynyl,

[0395] -F, -Cl, -Br, -I,

[0396] -OH, and -OR PH4 .

[0397] In some embodiments, R PH2 and R PH3 are each independently selected from

[0398] optionally substituted with one or more groups R A2 of a C 1-4 straight-chain or branched alkyl,

[0399] -F, -Cl, -Br, -I,

[0400] -OH, and -OR PH4 .

[0401] In some embodiments, R PH2 and R PH3 are each independently selected from

[0402] C 1-4 linear unsubstituted alkyl,

[0403] -F, -Cl, -Br, -I,

[0404] -OH, and -OR PH4 .

[0405] In some embodiments, R PH2 and R PH3 are each independently selected from

[0406] C 1-4 linear unsubstituted alkyl,

[0407] -F, -Cl, -Br,

[0408] -OH, and -OR PH4 , where R PH4 is independently selected from C 1-4 linear alkyl optionally substituted with one or more groups selected from -F, -Cl, and -Br.

[0409] In some embodiments, R PH2 and R PH3 are each independently selected from

[0410] C 1-4 linear unsubstituted alkyl,

[0411] -F, -Cl, -Br,

[0412] -OH, and -OR PH4 , where R PH4 is independently selected from C 1-4 linear alkyl optionally substituted with one or more -F groups.

[0413] In some embodiments, each R 1L group on R PH is the same. In other embodiments, each R PH group is different.

[0414] In some embodiments, R 1L is a 5- or 6-membered cycloalkyl optionally substituted with one or more R B3 groups.

[0415] In some embodiments, R 1L is a 5- or 6-membered unsubstituted cycloalkyl.

[0416] In some embodiments, R 1L is a 5-membered cycloalkyl optionally substituted with one or more groups R B3 In some embodiments, R 1L is an unsubstituted 5-membered cycloalkyl.

[0417] In some embodiments, R 1L is a 6-membered cycloalkyl optionally substituted with one or more groups R B3 In some embodiments, R 1L is an unsubstituted 6-membered cycloalkyl.

[0418] In some embodiments, R 1L is selected from unsubstituted cyclopentyl and unsubstituted cyclohexyl. In some embodiments, R 1L is unsubstituted cyclohexyl.

[0419] In some embodiments, R B3 is selected from

[0420] C 1-4 a straight-chain or branched unsubstituted alkyl,

[0421] -F, -Cl, -Br,

[0422] -OH, -O(C 1-3 alkyl),

[0423] -CN,

[0424] -NO 2 ,

[0425] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0426] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 .

[0427] In some embodiments, RB3 Selected from

[0428] C 1-4 a straight-chain or branched unsubstituted alkyl group

[0429] -F, -Cl, -Br

[0430] -OH, -O(C 1-3 alkyl)

[0431] -CN

[0432] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0433] -NH 2 , -NHR D4 and -N(R D3 ) 2 .

[0434] In some embodiments, R B3 is selected from

[0435] C 1-4 a straight-chain or branched unsubstituted alkyl group

[0436] -F, -Cl, -Br

[0437] -OH and -O(C 1-3 alkyl).

[0438] In some embodiments, R 1L is an optionally substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more groups R B4 .

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

[0440] In some embodiments, R 1L is an optionally substituted 5-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more groups R B4 . In some embodiments, R 1L is an optionally substituted 5-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, substituted with one or more groups R B4A 6-membered heteroaryl or heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O, and S.

[0441] In some embodiments, R 1L is a 5- or 6-membered unsubstituted heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S.

[0442] In some embodiments, R 1L is a 5- or 6-membered heteroaryl or heterocyclic group containing 1 or 2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B4 In some embodiments, R 1L is a 5- or 6-membered heteroaryl or heterocyclic group containing 1 heteroatom selected from N, O, and S, optionally substituted with one or more groups R B4 In some embodiments, R 1L is a 5- or 6-membered heteroaryl or heterocyclic group containing 1 heteroatom selected from N, O, and S, optionally substituted with one or more groups R B4 In some embodiments, R

[0443] In some embodiments, R 1L is a pyridyl group optionally substituted with one or more groups R B4 In some embodiments, R 1L is a pyridyl group optionally substituted with one or two groups independently selected from R B4 In some embodiments, R

[0444] is an unsubstituted pyridyl group. 1L In some embodiments, R

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

[0446] In some embodiments, R 1L is a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B4 In some embodiments, R 1L is a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, optionally substituted with one or more groups R B4 In some embodiments, R 1L is a 5-membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N and O.

[0447] In some embodiments, R 1L is an unsubstituted furyl group. In some embodiments, R 1L is an unsubstituted oxazolyl group. In some embodiments, R 1L is an unsubstituted isoxazolyl group.

[0448] In some embodiments, R B4 is selected from

[0449] optionally substituted by one or more groups R A9 a C 1-4 straight-chain or branched-chain alkyl group,

[0450] -F, -Cl, -Br,

[0451] -OH, -O(C 1-3 alkyl),

[0452] -CN,

[0453] -NO 2 ,

[0454] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ), 2 ,

[0455] -NH 2 , -NHR D4 , -N(R D3 ), 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 .

[0456] In some embodiments, R B4 is selected from

[0457] optionally substituted by one or more groups R A9 a C 1-6 straight-chain alkyl group,

[0458] -F, -Cl,

[0459] -OH, -O(C 1-3 alkyl),

[0460] -CN,

[0461] -NO 2 ,

[0462] -NH 2 , -NHR D4, -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 .

[0463] In some embodiments, R B4 is selected from

[0464] -F, -Cl,

[0465] -OH, -O(C 1-3 alkyl),

[0466] -CN,

[0467] -NO 2 ,

[0468] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 .

[0469] In some embodiments, R B4 is selected from

[0470] -F, -Cl,

[0471] -O(C 1-3 alkyl),

[0472] -NO 2 ,

[0473] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 CORC2 。

[0474] In some embodiments, R B4 is selected from

[0475] -F, -Cl,

[0476] -O(C 1-3 alkyl),

[0477] -NO 2 ,

[0478] -NH 2 and -NHCOR C2 。

[0479] In some embodiments, R B4 is selected from

[0480] -F, -Cl, -OMe, -NO 2 ,-NH 2 and -NHC(=O)Me.

[0481] In some embodiments, R 1L is an 8- to 10-membered bicyclic or heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B5 .

[0482] As used herein, the term "bicyclic group" refers to a carbocyclic bicyclic system in which one, two, or none of the rings may be aromatic. The bicyclic system may be a fused system or a spiro system. Similarly, the term "heterobicyclic group" refers to a bicyclic system in which one, two, or none of the rings may be aromatic and which contains 1 to 3 heteroatoms selected from N, O, and S. The heterobicyclic system may be a fused system or a spiro system.

[0483] In some embodiments, R 1L is an 8- to 10-membered bicyclic group optionally substituted with one or more groups R B5 . In some embodiments, R 1L is an 8- to 10-membered heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B5 .

[0484] In some embodiments, R 1L is a 9- or 10-membered bicyclic group optionally substituted with one or more groups R B5 . In some embodiments, R 1L is an unsubstituted 8- to 10-membered bicyclic group. In some embodiments, R 1Lis an optionally 10-membered bicyclic group substituted by one or more groups R B5 In some embodiments, R 1L is an unsubstituted 10-membered bicyclic group. In some embodiments, R 1L is an optionally naphthyl group substituted by one or more groups R B5 In some embodiments, R 1L is an unsubstituted naphthyl group.

[0485] In some embodiments, R 1L is an optionally 9- or 10-membered hetero-bicyclic group containing one or two heteroatoms selected from N, O, and S and substituted by one or more groups R B5 In some embodiments, R 1L is an optionally 9- or 10-membered hetero-bicyclic group containing one or two heteroatoms selected from N and O and substituted by one or more groups R B5 In some embodiments, R 1L is an optionally 9- or 10-membered hetero-bicyclic group containing one or two selected O heteroatoms and substituted by one or more groups R B5

[0486] In some embodiments, R 1L is an unsubstituted 8- to 10-membered hetero-bicyclic group containing 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 1L is an unsubstituted 8- to 10-membered hetero-bicyclic group containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, R 1L is an unsubstituted 8- to 10-membered hetero-bicyclic group containing 1 or 2 heteroatoms selected from N and O. In some embodiments, R 1L is an unsubstituted 8- to 10-membered hetero-bicyclic group containing 1 or 2 heteroatoms selected from O.

[0487] In some embodiments, R 1L is selected from

[0488]

[0489] In some embodiments, the group -N(R G ) 2 is a piperazinyl group optionally substituted by one or more groups selected from straight-chain or branched C 1-4 alkyl, phenyl, or benzyl. In some embodiments, the group -N(R G ) 2 is a piperazinyl group substituted by one or more groups selected from straight-chain or branched C 1-4 alkyl. In some embodiments, the group -N(R G ) 2 ​A piperazinyl group substituted with one or more groups selected from straight-chain C 1-4 alkyl groups.

[0490] Group Q

[0491] In some embodiments, Q is group (Q1):

[0492]

[0493] wherein the two asterisks (**) represent the point of attachment to L;

[0494] Q 1A 、Q 2A 、Q 3A and Q 4A two of them are CH; and

[0495] Q 1A 、Q 2A 、Q 3A and Q 4A the other two are independently selected from N, CH, and CR Q1 .

[0496] In some embodiments, Q 1A 、Q 3A and Q 4A are all CH, and Q 2A is selected from N, CH, and CR Q1 . In some embodiments, Q 1A 、Q 3A and Q 4A are all CH, and Q 2A is selected from CH and CR Q1 .

[0497] In some embodiments, Q 1A 、Q 2A 、Q 3A and Q 4A are all CH.

[0498] In some embodiments, one of Q 1A 、Q 2A 、Q 3A and Q 4A is CR Q1 , and Q 1A 、Q 2A 、Q 3A and Q 4A the other three are all CH.

[0499] In some embodiments, Q 1A and Q 3A are CH, Q 2A and Q4A One of them is CR Q1 , and Q 2A and Q 4A The other one is CH.

[0500] In some embodiments, Q 2A , Q 3A and Q 4A are all CH, and Q 1A is CR Q1 . In some embodiments, Q 1A , Q 3A and Q 4A are all CH, and Q 2A is CR Q1 . In some embodiments, Q 1A , Q 2A and Q 4A are all CH, and Q 3A is CR Q1 .

[0501] In some embodiments, one of Q 1A , Q 2A , Q 3A and Q 4A is CN, and the other three of Q 1A , Q 2A , Q 3A and Q 4A are all CH.

[0502] In some embodiments, Q 2A , Q 3A and Q 4A are all CH, and Q 1A is CN. In some embodiments, Q 1A , Q 3A and Q 4A are all CH, and Q 2A is CN. In some embodiments, Q 1A , Q 2A and Q 4A are all CH, and Q 3A is CN. In some embodiments, Q 2A , Q 3A and Q 4A are all CH, and Q 1A is CN. In some embodiments, Q 1A , Q 2A and Q 3A are all CH, and Q 4A is CN.

[0503] In some embodiments, Q1A , Q 2A , Q 3A and Q 4A of which two each independently are CR Q1 , and Q 1A , Q 2A , Q 3A and Q 4A and the other two of which are both CH.

[0504] In some embodiments, Q 2A and Q 4A each independently are CR Q1 , and Q 1A and Q 3A are both CH.

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

[0506] In some embodiments, two of Q 1A , Q 2A , Q 3A and Q 4A are CN, and Q 1A , Q 2A , Q 3A and Q 4A and the other two of which are both CH.

[0507] In some embodiments, Q 1A and Q 3A are CH, one of Q 2A and Q 4A is CN, and Q 2A and Q 4A and the other is CH.

[0508] In some embodiments, Q 2A and Q 4A are CH, one of Q 1A and Q 3A is CN, and Q 1A and Q 3A and the other is CH.

[0509] In some embodiments, Q 1A and Q 3A are CH, and Q 2A and Q 4A each independently is selected from CR Q1 .

[0510] In some embodiments, Q 1A is CN, and Q 2A , Q 3A and Q 4A among them is CN, and Q 2A , Q 3A and Q 4A the other two among them are both CH.

[0511] In some embodiments, Q 1A and Q 2A are CN, and Q 3A and Q 4A are both CH.

[0512] In some embodiments, R Q1 is selected from

[0513] -F, -Cl, -Br, -I,

[0514] C 1-6 linear unsubstituted alkyl,

[0515] -OH, -O(C 1-6 alkyl),

[0516] -CN, and

[0517] -N(R D3 ) 2 .

[0518] In some embodiments, R Q1 is selected from

[0519] -F, -Cl, -Br, -I,

[0520] C 1-3 linear unsubstituted alkyl,

[0521] -OH, -OMe, -OEt,

[0522] -CN, and

[0523] -NMe 2 .

[0524] In some embodiments, R Q1 is selected from -F, -Cl, -Br and -I. In some embodiments, R Q1 is selected from -F, -Cl and -Br. In some embodiments, R Q1 is -F.

[0525] In some embodiments, Q 1A , Q 2A , Q 3A and Q4A One of them is C(Hal), and Q 1A , Q 2A , Q 3A and Q 4A The other three of and Q are all CH, where 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 of and Q are all CH.

[0526] In some embodiments, Q 1A , Q 3A and Q 4A are all CH, and Q 2A is CF.

[0527] In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A Two of them are each independently C(Hal), and Q 1A , Q 2A , Q 3A and Q 4A The other two of and Q are all CH, where Hal is selected from F, Cl, Br, and I. In some embodiments, Q 1A , Q 2A , Q 3A and Q 4A Two of them are both CF, and Q 1A , Q 2A , Q 3A and Q 4A The other two of and Q are all CH.

[0528] In some embodiments, Q is selected from

[0529]

[0530] In some embodiments, Q is the group (Q2):

[0531]

[0532] where the two asterisks (**) represent the connection points to L;

[0533] Q 1B , Q 2B , Q 3B and Q 4BBoth of them in are CH; and

[0534] Q 1B 、Q 2B 、Q 3B and Q 4B The other two of them are independently selected from N, CH, and CR Q2 .

[0535] In some embodiments, Q 1B 、Q 2B 、Q 3B and Q 4B are all CH.

[0536] In some embodiments, Q is selected from (Q1) and (Q2), where the two asterisks (**) represent the attachment points to L; Q 1A 、Q 2A 、Q 3A and Q 4A Two of them are CH; Q 1A 、Q 2A 、Q 3A and Q 4A The other two of them are independently selected from N, CH, and CR Q1 ; and Q 1B 、Q 2B 、Q 3B and Q 4B are all CH.

[0537] The compound of formula IA

[0538] In some embodiments, the compound is a compound according to formula IA:

[0539]

[0540] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein

[0541] L B is selected from

[0542] -NR L1 C(=O)-*, -C(=O)NR L1 -*,

[0543] -NR L1 C(=X L1 )NR L1 -*,

[0544] -SO 2 -NR L1 -*, -NR L1 -SO 2 -*,

[0545] -OC(=O)-NR L1 -*, and -NR L1 -C(=O)O-*; wherein the asterisk (*) represents the point of attachment to the terminal phenyl group;

[0546] X L1 is selected from O and S;

[0547] R L1 is selected from

[0548] -H,

[0549] -C(=O)(C 1-3 alkyl),

[0550] -P(=O)(OH) 2 and

[0551] -S(=O) 2 NH 2 ;

[0552] Y 1 、Y 2 and Y 3 One of Y Y ;

[0553] Y 1 、Y 2 and Y 3 The second of Y Y and CH; and

[0554] Y 1 ,Y 2 and Y 3 The third of Y Y and CH;

[0555] Q 5A 、Q 6A and Q 7A One of Q

[0556] Q 5A 、Q 6A and Q 7A The other two of Q Q3 ;

[0557] wherein each R Y is independently selected from

[0558] unsubstituted C 1-6 alkyl, straight-chain or branched-chain,

[0559] -OR Y1 ;

[0560] -F, -Cl, -Br, -I,

[0561] -CF 3 、-CH 2 F, -CF 2 H,

[0562] -(CH 2 ) n N(R N1 ) 2 ,

[0563] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H;

[0564] wherein, in the group -N(R N1 ) 2 , the N atom and the two R N1 groups to which it is attached form a 6 - membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S;

[0565] n is an integer selected from 1, 2, or 3;

[0566] wherein R Y1 is selected from

[0567] linear or branched unsubstituted C 1-6 alkyl,

[0568] -CF 3 、-CH 2 F, -CF 2 H,

[0569] -(CH 2 ) m N(R N2 ) 2 ,

[0570] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H;

[0571] wherein, in the group -N(R N2 ) 2 , the N atom and the two R N2 groups to which it is attached form a 6 - membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S;

[0572] m is an integer selected from 1, 2, and 3;

[0573] R Q3 selected from

[0574] -F, -Cl, -Br, -I,

[0575] C 1-6 a straight-chain or branched unsubstituted alkyl group,

[0576] -OH, -O(C 1-6 alkyl), and

[0577] -CN.

[0578] In some embodiments:

[0579] R L1 is selected from -H and -C(=O)(C 1-3 alkyl);

[0580] each R Y is independently selected from

[0581] a straight-chain or branched unsubstituted C 1-6 alkyl group,

[0582] -OR Y1 ;

[0583] -F, -Cl, -Br, -I,

[0584] -CF 3 、-CH 2 F, -CF 2 H,

[0585] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H; and

[0586] R Y1 is selected from

[0587] a straight-chain or branched unsubstituted C 1-6 alkyl group,

[0588] -CF 3 、-CH 2 F, -CF 2 H,

[0589] -CH 2 CF 3 、-CH 2 CH 2 F and -CH2 CF 2 H.

[0590] Group L B

[0591] In some embodiments, L B is selected from -NR L1 C(=O)-*, and -C(=O)NR L1 -*, where the asterisk (*) represents the point of attachment to the terminal phenyl group.

[0592] In some embodiments, L B is -NR L1 C(=O)-*, where the asterisk (*) represents the point of attachment to the terminal phenyl group.

[0593] In some embodiments, R L1 is -H. In some embodiments, R L1 is -C(=O)(C 1-3 alkyl). In some embodiments, R L1 is -C(=O)Me.

[0594] In some embodiments, L B is -NHC(=O)-*, where the asterisk (*) represents the point of attachment to the terminal phenyl group.

[0595] In some embodiments, L B is -NHC(=O)-* or -C(=O)NH-*. In some embodiments, L B is -NHC(=O)-*.

[0596] In some embodiments, L B is -NR L C(=O)-*, where R L is -P(=O)(OH) 2 ). In some embodiments, L B is -NR L C(=O)-*, where R L is -S(=O) 2 NH 2 ).

[0597] In some embodiments, L B is -NR L1 C(=X L1 )NR L -*. In some embodiments, L B is -SO 2 -NR L1 -*. In some embodiments, L B-NR L1 -SO 2 -*. In some embodiments, L B is -OC(=O)-NR L1 -*. In some embodiments, L A is -NR L1 -C(=O)O-*.

[0598] In some embodiments, X L1 is O. In some embodiments, X L1 is S.

[0599] Group Y 1 , Y 2 and Y 3

[0600] 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.

[0601] 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 one is CH.

[0602] In some embodiments, Y 1 is CR Y and each of Y 2 and Y 3 is selected from CH and CR Y .

[0603] In some embodiments, Y 1 is CR Y and both Y 2 and Y 3 are CH.

[0604] In some embodiments, Y 1 is CR Y , Y 2 and Y 3 is one of CH and the other is CR Y .

[0605] In some embodiments, Y 1 is CR Y , Y 2 is CH and Y 3 is CR Y .

[0606] In some embodiments, Y 1 , Y 2 and Y 3 each is CR Y .

[0607] In some embodiments, R Y is independently selected from straight-chain or branched unsubstituted C 1-6 alkyl, such as methyl, ethyl or n-propyl.

[0608] In some embodiments, R Y is independently selected from -OR Y1 , such as -OMe, -OEt, -O n Pr, -OCF 3 , -OCH 2 F, -OCF 2 H, -OCH 2 CF 3 , -OCH 2 CH 2 F or -OCH 2 CF 2 H.

[0609] In some embodiments, R Y is independently selected from -F, -Cl, -Br and -I. In some embodiments, R Y is independently selected from -F.

[0610] In some embodiments, R Y is independently selected from

[0611] -CF 3 , -CH 2 F, -CF 2 H,

[0612] -CH 2 CF 3 , -CH 2 CH 2 F and -CH 2CF 2 H.

[0613] In some embodiments, R Y is -CF 3 .

[0614] In some embodiments, R Y is -(CH 2 ) n N(R N1 ) 2 . In some embodiments, n is 3. In some embodiments, the group -N(R N1 ) 2 is a 6-membered heterocyclic group selected from morpholino and piperidino groups. In some embodiments, n is 3 and the group -N(R N1 ) 2 is a 6-membered heterocyclic group selected from morpholino and piperidino groups.

[0615] In some embodiments, R Y1 is methyl. In some embodiments, R Y1 is ethyl. In some embodiments, R Y1 is n-propyl. In some embodiments, R Y1 is -CF 3 . In some embodiments, R Y1 is -CF 2 H. In some embodiments, R Y1 is -CFH 2 . In some embodiments, R Y1 is -CH 2 CF 2 H. In some embodiments, R Y1 is -CH 2 CFH 2 .

[0616] In some embodiments, R Y1 is -(CH 2 ) m N(R N2 ) 2 . In some embodiments, m is 2. In some embodiments, the group -N(R N2 ) 2 is a 6-membered heterocyclic group selected from morpholino and piperidino groups. In some embodiments, m is 2 and the group -N(R N2 ) 2 is a 6-membered heterocyclic group selected from morpholino and piperidino groups.

[0617] The groups Q 5A , Q 6A and Q 7A

[0618] 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 .

[0619] 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.

[0620] In some embodiments, Q 6A CR Q3 , and Q 5A and Q 7A Each of is CH.

[0621] 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.

[0622] 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 ;

[0623] Each R Y Independently selected from

[0624] An unsubstituted straight-chain or branched C 1-6 alkyl group,

[0625] -OR Y1 ;

[0626] -F, -Cl, -Br, -I,

[0627] -CF 3 , -CH 2 F, -CF 2 H,

[0628] -CH 2 CF 3 , -CH 2 CH 2 F and -CH 2 CF 2 H;

[0629] R Y1 is selected from

[0630] an unsubstituted straight-chain or branched C 1-6 alkyl group,

[0631] -CF 3 , -CH 2 F, -CF 2 H,

[0632] -CH 2 CF 3 , -CH 2 CH 2 F and -CH 2 CF 2 H;

[0633] and R Q3 is selected from

[0634] -F, -Cl, -Br, -I,

[0635] C 1-6 an unsubstituted straight-chain or branched alkyl group,

[0636] -OH, -O(C 1-6 alkyl), and

[0637] -CN.

[0638] The compound of formula (IB)

[0639] In some embodiments, the compound is a compound according to formula IB:

[0640]

[0641] wherein

[0642] R Z1 selected from

[0643] -H,

[0644] -F, -Cl, -Br, and -I;

[0645] and R Z3 selected from

[0646] -H,

[0647] a C straight-chain alkyl optionally substituted with one, two, or three substituents each independently selected from -F, -Cl, and -Br 1-6 straight-chain alkyl,

[0648] -F, -Cl, -Br, -I, and

[0649] -OR Z5 ;

[0650] wherein R Z2 and R Z5 are each independently selected from a C straight-chain alkyl optionally substituted with one, two, or three substituents each independently selected from -F, -Cl, and -Br 1-6 straight-chain alkyl.

[0651] The group R Z1

[0652] In some embodiments, R Z1 is selected from -F, -Cl, and -Br. In some embodiments, R Z1 is selected from -F and -Cl. In some embodiments, R Z1 is -F.

[0653] The group R Z2

[0654] In some embodiments, R Z2 is selected from C 1-6 straight-chain unsubstituted alkyl. In some embodiments, R Z2 is selected from C 1-4 straight-chain unsubstituted alkyl. In some embodiments, R Z2 is selected from methyl, ethyl, or n-propyl.

[0655] In some embodiments, R Z2 is selected from a C straight-chain alkyl substituted with one, two, or three substituents each independently selected from -F, -Cl, and -Br 1-6 straight-chain alkyl. In some embodiments, R Z2 is selected from a C straight-chain alkyl substituted with one, two, or three substituents each independently selected from -F, -Cl, and -Br 1-4Linear alkyl. In some embodiments, R Z2 is selected from methyl or ethyl substituted with one, two or three substituents each independently selected from -F, -Cl and -Br.

[0656] In some embodiments, R Z2 is selected from methyl or ethyl substituted with one, two or three -F substituents.

[0657] In some embodiments, R Z2 is selected from

[0658] -CH 2 CHF 2 、-CH 2 CH 2 F、-CH 2 CF 3 ,

[0659] -CHF 2 、-CH 2 F and -CF 3 。

[0660] The group R Z3

[0661] In some embodiments, R Z3 is -H. In some embodiments, R Z3 is C 1-6 linear unsubstituted alkyl. In some embodiments, R Z3 is C 1-4 linear unsubstituted alkyl. In some embodiments, R Z3 is selected from methyl, ethyl or n-propyl.

[0662] In some embodiments, R Z3 is selected from C 1-6 linear alkyl substituted with one, two or three substituents each independently selected from -F, -Cl and -Br. In some embodiments, R Z3 is selected from C 1-6 linear alkyl substituted with one, two or three F substituents. In some embodiments, R Z3 is selected from C 1-3 linear alkyl substituted with one, two or three substituents each independently selected from -F, -Cl and -Br. In some embodiments, R Z3 is selected from C 1-3 linear alkyl substituted with one, two or three F substituents. In some embodiments, R Z3 is selected from C 1-3 linear alkyl substituted with three F substituents. In some embodiments, R Z3 is -CF3 .

[0663] In some embodiments, R Z3 is selected from -F, -Cl, -Br and -I. In some embodiments, R Z3 Selected from -F, -Cl and -Br.

[0664] In some embodiments, R Z3 For-OR Z5 .

[0665] Group R Z5

[0666] 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.

[0667] 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 For-CF 3 .

[0668] In some embodiments,

[0669] R Z1 Selected from -H and -F;

[0670] R Z3 Selected from -H, -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ;and

[0671] 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.

[0672] In some embodiments,

[0673] R Z1 for -F;

[0674] R Z3 is selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ; and

[0675] R Z2 and R Z5 are each independently selected from C 1-6 linear alkyl optionally substituted with one, two, or three -F substituents.

[0676] In some embodiments,

[0677] R Z1 is -F;

[0678] R Z3 is selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ; and

[0679] R Z2 and R Z5 are each independently selected from C 1-6 linear unsubstituted alkyl.

[0680] In some embodiments,

[0681] R Z1 is -F;

[0682] R Z3 is selected from -Me, -Et, -n Pr, -F, -Cl, -Br, and -OR Z5 ; and

[0683] R Z2 and R Z5 are each independently selected from C 1-3 linear unsubstituted alkyl.

[0684] It is believed that the following compounds (X1) to (X27) are known:

[0685]

[0686]

[0687]

[0688] Thus, the compounds according to the first aspect are not selected from any of the compounds (X1) to (X27).

[0689] However, in other aspects described herein, the compound can be selected from compounds (X1) to (X27). Specifically, in some embodiments, the compounds for treating diseases as described herein can be selected from compounds (X1) to (X27). Similarly, in some embodiments, the methods for treating diseases as described herein may involve using compounds selected from (X1) to (X27).

[0690] Combination

[0691] It should be understood that, for the sake of clarity, certain features of the present invention described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, the various features of the present invention described in the context of a single embodiment for the sake of brevity can also be provided separately or in any suitable sub-combination. All combinations of embodiments belonging to chemical groups represented by variables (e.g., X, G 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 etc.) are specifically included in the present invention and are hereby disclosed as if each and every combination were separately and explicitly disclosed to the extent that such combinations cover compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for their biological activity). Additionally, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also explicitly covered by the present invention and are disclosed herein as if each and every such chemical group sub-combination were separately and explicitly disclosed herein. Detailed Description

[0692] In some embodiments, the compound is selected from the compounds in Table 1:

[0693] Table 1

[0694]

[0695]

[0696]

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

[0722] Table 2

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729] In some embodiments, the compound is selected from the compounds in Table 3:

[0730] Table 3

[0731]

[0732]

[0733]

[0734] In some embodiments, the compound is:

[0735]

[0736] Compound 222

[0737] Chiral

[0738] In some embodiments, the compound may have one or more chiral centers.

[0739] The chiral center or each chiral center (if there are multiple) is independently in the R configuration or the S configuration.

[0740] If no configuration is indicated, both configurations are included.

[0741] Substantially purified form

[0742] One aspect of the present invention relates to a compound in a substantially purified form and / or a form substantially free of contaminants as described herein.

[0743] 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.

[0744] Unless otherwise specified, a substantially purified form refers to a compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, a substantially purified form refers to a stereoisomer, such as an optically pure stereoisomer. In one embodiment, a substantially purified form refers to a mixture of enantiomers. In one embodiment, a substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, a substantially purified form refers to an enantiomer, such as an optically pure enantiomer.

[0745] In one embodiment, the contaminant accounts 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.

[0746] Unless otherwise specified, a contaminant refers to other compounds other than stereoisomers or enantiomers. In one embodiment, a contaminant refers to other compounds and other stereoisomers. In one embodiment, a contaminant refers to other compounds and other enantiomers.

[0747] In one embodiment, a 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.

[0748] Isomer

[0749] Certain compounds can exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, anisotropic, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis forms and trans forms; E forms and Z forms; c forms, t forms and r forms; endo forms and exo forms; R forms, S forms and meso forms; D forms and L forms; d forms and l forms; (+) forms and (-) forms; keto forms, enol forms and enolates forms; syn forms and anti forms; synclinal forms and anticlinal forms; α forms and β forms; axial forms and equatorial forms; boat forms, chair forms, twist forms, envelope forms and half-chair forms; combinations thereof, collectively referred to hereinafter as "isomers" (or "isomeric forms").

[0750] It should be noted that, except for the discussion of tautomeric forms hereinafter, the term "isomers" as used herein specifically excludes structural (or constitutional) isomers (i.e., isomers in which the connections between atoms are different rather than just the spatial positions of the atoms). For example, a reference to methoxyl, -OCH 3 should not be construed as a reference to its structural isomer hydroxymethyl, -CH 2 OH. 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 will likely include structural isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and isopropyl; butyl includes n-butyl, isobutyl, sec-butyl and tert-butyl; methoxyphenyl includes o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl).

[0751] The above exclusion does not apply to tautomeric forms, such as keto forms, enol forms and enolates forms, as in, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidoxime, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro.

[0752]

[0753] It should be noted that the term "isomers" specifically includes compounds having one or more isotope substitutions. For example, H can be in any isotope form, including 1 H, 2 H (D), and 3 H (T); C can be in any isotope form, including 12 C, 13 C, and 14 C; O can be in any isotope form, including 16 O and 18O; etc.

[0754] 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 methods taught herein or known methods in a known manner.

[0755] Salts

[0756] It may be convenient or desirable to prepare, purify, and / or handle the corresponding salts of a compound, e.g., pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J.Pharm.Sci. , Vol. 66, pp. 1-19.

[0757] For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), salts can be formed with suitable cations. 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., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ). Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenethylamine, choline, glucosamine, and tromethamine, as well as amino acids such as lysine and arginine. Examples of common quaternary ammonium ions are N(CH 3 ) 4 + .

[0758] If the compound is cationic, or has a functional group that can be cationic (e.g., -NH 2 can be -NH 3+ ) salts can be formed with suitable anions. 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.

[0759] 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, gluceptonic 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, carboxymethyl cellulose.

[0760] Unless otherwise indicated, reference to a particular compound also includes its salt forms.

[0761] Solvates and hydrates

[0762] The corresponding solvates of the compounds may be convenient or desirable for the preparation, purification, and / or handling of the compounds. The term "solvate" is used herein in its 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, dihydrate, trihydrate, etc.

[0763] Unless otherwise indicated, reference to a particular compound also includes its solvate and hydrate forms.

[0764] Chemical synthesis

[0765] Methods for the chemical synthesis of the compounds of the present invention are described herein. These and / or other well-known methods can be modified and / or adapted in known ways to facilitate the synthesis of other compounds of the present invention.

[0766] Compositions

[0767] One aspect of the present invention relates to a composition (e.g., a pharmaceutical composition) comprising a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0768] Another aspect of the present invention relates to a method for preparing a composition (e.g., a pharmaceutical composition), the method comprising mixing a compound described herein with a pharmaceutically acceptable carrier, diluent, or excipient.

[0769] Use

[0770] It is believed that the compounds described herein are potent inhibitors of ALCAT1.

[0771] Accordingly, it is believed that the compounds described herein can be used for the treatment of aging and age-related diseases.

[0772] Accordingly, it is believed that the compounds described herein can be used for the treatment of diseases characterized by one or more of oxidative stress, CL deficiency, enrichment of docosahexaenoic acid (DHA) in CL, and mitochondrial dysfunction.

[0773] Accordingly, it is believed that the compounds described herein can be used for the treatment of diseases or disorders associated with mitochondrial dysfunction.

[0774] Accordingly, it is believed that the compounds described herein can be used for the treatment of diseases 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.

[0775] Accordingly, it is believed that the compounds described herein can be used for the treatment of diseases selected from stroke, ischemia, and reperfusion injury.

[0776] Accordingly, it is believed that the compounds described herein can be used for the treatment of Barth syndrome.

[0777] Use in an inhibitory method

[0778] 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.

[0779] 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, for example, compared to a baseline control.

[0780] One aspect of the invention is a compound as described herein for use in a method of reducing oxidative stress measured by reactive oxygen species (ROS), for example, compared to a baseline control.

[0781] One aspect of the invention is a compound as described herein for use in a method of modulating the structure, function, activity, and / or expression of cardiolipin (CL).

[0782] Use in a treatment method

[0783] One aspect of the present invention is a compound as described herein, which is used for treating the human or animal body by therapy. For example, one aspect of the present invention is a compound according to one of formula (I), (IA) or (IB), which is used for treating the human or animal body by therapy.

[0784] One aspect of the present invention is a compound according to formula (I):

[0785]

[0786] or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is used for treating the human or animal body by therapy,

[0787] wherein:

[0788] X is selected from O and S;

[0789] G 1 and G 2 are each independently selected from N and CH;

[0790] A is selected from

[0791] H,

[0792] optionally substituted by one or more groups R A1 substituted C 1-6 linear or branched alkyl or alkenyl,

[0793] optionally substituted by one or more groups R B1 substituted 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,

[0794] optionally substituted by one or more groups R B2 substituted 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S,

[0795] -CN,

[0796] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0797] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D6COOH-NR D7 COOR C1 、-NR D5 COR C2 ,as well as

[0798] -SR E1 ;

[0799] L is a single bond, or a group L A ,

[0800] Where L A Selected from

[0801] -NR L C(=O)-*, -C(=O)NR L- *,

[0802] -NR L C(=X L )NR L -*,

[0803] -SO 2 -NR L -*, -NR L -SO 2 -*,

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

[0805] The asterisk (*) indicates 1 The connection point;

[0806] X L Selected from O and S;

[0807] R L Selected from

[0808] -H,

[0809] -C(=O)(C 1-3 alkyl),

[0810] -P(=O)(OH) 2 ,as well as

[0811] -S(=O) 2 NH 2 ;

[0812] When L is a single bond, R 1 For NH 2 ;

[0813] When L is L A When R 1 For R1L , wherein R 1L is selected from

[0814] C 1-6 a straight-chain or branched unsubstituted alkyl group;

[0815] a phenyl group optionally substituted with one to three groups R PH ;

[0816] a 5- or 6-membered cycloalkyl group optionally substituted with one or more groups R B3 ;

[0817] a 5- or 6-membered heteroaryl or heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B4 ; and

[0818] an 8- to 10-membered bicyclic or heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B5 ;

[0819] wherein each R PH is independently selected from

[0820] a C A2 straight-chain or branched alkyl, alkenyl, or alkynyl group optionally substituted with one or more groups R 1-6 ;

[0821] a phenyl group optionally substituted with one or more groups R A3 ;

[0822] a naphthyl group;

[0823] -F, -Cl, -Br, -I;

[0824] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 ) 2 ;

[0825] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NRD5 COR C2 、 -NHSO 2 (C 1-3 alkyl),

[0826] -SO 2 NH 2 、 -SO 2 NHR D1 、 -SO 2 N(R D2 ) 2 、 -SO 2 R E2 、 -SR E1 ,

[0827] -NO 2 ,

[0828] -CN,

[0829] -OH, and -OR PH4 ;

[0830] wherein R PH4 is selected from

[0831] phenyl,

[0832] benzyl, and

[0833] optionally substituted by one or more groups R A5 substituted C 1-6 linear or branched alkyl; Q is selected from (Q1) and (Q2)

[0834]

[0835] wherein the two asterisks (**) represent the point of attachment to L;

[0836] Q 1A 、Q 2A 、Q 3A and Q 4A of which two are CH;

[0837] Q 1A 、Q 2A 、Q 3A and Q 4A of which the other two are independently selected from N, CH, and CR Q1 ; Q 1B 、Q 2B 、Q 3B and Q 4B of which two are CH.

[0838] Q 1B 、Q 2B 、Q 3B and Q4B The other two of them are independently selected from N, CH, and CR Q2 ; each R Q1 and each R Q2 are independently selected from

[0839] -F, -Cl, -Br, -I,

[0840] C 1-6 a straight-chain or branched-chain unsubstituted alkyl group,

[0841] -OH, -O(C 1-6 alkyl),

[0842] -CN, and

[0843] -N(R D3 ) 2 ;

[0844] R C1 and R C2 are each independently selected from

[0845] a C A6 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R 1-6 ;

[0846] a 5-membered heteroaryl group containing a single heteroatom selected from N, O, and S, optionally substituted with one or two groups R E3 ;

[0847] R D1 to R D7 are each independently selected from

[0848] a C A7 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R 1-6 ;

[0849] -COOH, -COOR C1 , -COR C2 ,

[0850] -C(=NH)NH 2 ,

[0851] or when two R D2 or two R D3 groups are attached to a single nitrogen atom, they may together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic group containing 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with one or more groups R D9 ;

[0852] wherein R D9 is a C A8 straight-chain or branched-chain alkyl group optionally substituted with one or more groups R1-6 a linear or branched alkyl group;

[0853] R D8 is a C containing one or two N atoms optionally substituted by one or more groups selected from the following 5-6 heterocyclic group:

[0854] -SH, and

[0855] -C(=O)OR D5A wherein R D5A is a phenyl or benzyl group optionally substituted by a NO 2 group;

[0856] R E1 and R E2 each independently selected from C 1-6 linear or branched unsubstituted alkyl, alkenyl or alkynyl groups;

[0857] R E3 is independently selected from

[0858] -SH; and

[0859] -C(=O)OR E4 ;

[0860] R B1 to R B5 each independently selected from

[0861] a C optionally substituted by one or more groups R A9 linear or branched alkyl group, 1-6

[0862] -F, -Cl, -Br,

[0863] -OH, -O(C 1-3 alkyl),

[0864] -CN,

[0865] -NO 2 C1 ,

[0866] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[0867] -NH 2 , -NHR D4 , -N(R D3 ) 2, -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH-NR D7 COOR C1 , and -NR D5 COR C2 ;

[0868] R E4 is independently selected from

[0869] phenyl or benzyl optionally substituted by one or two groups R A10 ;

[0870] R A1 to R A10 each independently is selected from

[0871] -F, -Cl, -Br,

[0872] -OH, -OR T

[0873] -CN, -NO 2 ,

[0874] -C(=O)R T , -COOH, -COOR T , -CON(R G ) 2 ,

[0875] -NH 2 , -NHR T , -N(R T ) 2 , -NHC(=O)(R F ) and -N(R D9 ) 2 ;

[0876] R F is selected from

[0877] C 1-6 a straight-chain or branched unsubstituted alkyl, and

[0878] a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S;

[0879] The group -N(R G ) 2 is selected from azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-C 1-4 optionally substituted by one or more groups selected from straight-chain or branched C 1-4an alkyl-piperazinyl, morpholinyl, azanyl or diazanyl group;

[0880] R T is C 1-6 a straight-chain or branched unsubstituted alkyl group; and

[0881] Two R D9 groups together with the nitrogen atom to which they are attached form a group selected from: a 5-membered heteroaryl group containing one or two nitrogen atoms; and

[0882] a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O and S.

[0883] In some embodiments,

[0884] R L is selected from

[0885] -H, and -C(=O)(C 1-3 alkyl);

[0886] and in the -N(R D9 ) 2 group, the two R D9 groups together with the nitrogen atom to which they are attached form a 5-membered heteroaryl group containing one or two nitrogen atoms.

[0887] In some embodiments, the present invention provides a compound as described herein for treating aging or age-related diseases.

[0888] In some embodiments, the present invention provides a compound as described herein for treating a disease characterized by one or more of oxidative stress, CL deficiency, enrichment of docosahexaenoic acid (DHA) in CL, and mitochondrial dysfunction.

[0889] In some embodiments, the present invention provides a compound as described herein for treating or preventing a disease or disorder associated with mitochondrial dysfunction.

[0890] In some embodiments, the present invention provides a compound as described herein for treating a disease selected from: 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.

[0891] In some embodiments, the present invention provides a compound as described herein for treating a disease selected from stroke, ischemia and reperfusion injury.

[0892] In some embodiments, the present invention provides a compound as described herein for preventing or treating Barth syndrome.

[0893] Use in the production of pharmaceuticals

[0894] One aspect of the present invention is the use of a compound as described herein in the preparation of a medicament for treating a human or animal body by therapy. For example, one aspect of the present invention is the use of a compound according to one of formula (I), (IA) or (IB) in the preparation of a medicament for treating a human or animal body by therapy.

[0895] One aspect of the present invention is the use of a compound as described herein in the preparation of a medicament for treating aging and age-related diseases.

[0896] One aspect of the present 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, enrichment of docosahexaenoic acid (DHA) in CL, and mitochondrial dysfunction.

[0897] One aspect of the present invention is the use of a compound as described herein in the preparation of a medicament for treating a disease or disorder associated with mitochondrial dysfunction.

[0898] 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.

[0899] 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.

[0900] In some embodiments, the present invention provides the use of a compound as described herein in the preparation of a medicament for preventing or treating Barth syndrome.

[0901] Method of treatment

[0902] Another aspect of the present invention is a method of treatment, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition. For example, one aspect of the present invention is a method of treatment, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to one of formula (I), (IA) or (IB), preferably in the form of a pharmaceutical composition.

[0903] One aspect of the invention is a method for 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.

[0904] Diseases and disorders

[0905] As described above, ALCAT1 activity is known to be associated with mitochondrial dysfunction in diseases. Thus, as an inhibitor of ALCAT1, the compounds described herein can be used to treat or prevent a variety of age-related diseases and disorders associated with mitochondrial dysfunction.

[0906] In some embodiments, the treatment is for treating aging.

[0907] In some embodiments, the treatment is for treating an age-related disease.

[0908] In some embodiments, the treatment is for treating a disease characterized by one or more of oxidative stress, CL deficiency, enrichment of docosahexaenoic acid (DHA) in CL, and mitochondrial dysfunction.

[0909] In some embodiments, the treatment is for treating a disease or disorder associated with mitochondrial dysfunction.

[0910] In some embodiments, the treatment is for treating obesity.

[0911] In some embodiments, the treatment is for treating diabetes. In some embodiments, the treatment is for treating type 2 diabetes.

[0912] In some embodiments, the treatment is for treating diabetes complications. In some embodiments, the treatment is for treating neuropathy. In some embodiments, the treatment is for treating cardiomyopathy. In some embodiments, the treatment is for treating retinopathy. In some embodiments, the treatment is for treating erectile dysfunction.

[0913] In some embodiments, the treatment is for treating fatty liver disease.

[0914] In some embodiments, the treatment is for treating cardiovascular disease.

[0915] In some embodiments, the treatment is for treating neurodegenerative diseases. In some embodiments, the treatment is for treating Alzheimer's disease.

[0916] In some embodiments, the treatment is for treating metabolic diseases.

[0917] In some embodiments, the treatment is for insulin tolerance.

[0918] In some embodiments, the treatment is for cancer. In some embodiments, the treatment is for tumors that overexpress ALCAT1 or for tumors in which inhibition of ALCAT1 potentiates or improves the action of cytotoxic anti-tumor agents.

[0919] In some embodiments, the treatment is for stroke, ischemia or reperfusion injury.

[0920] In some embodiments, the treatment is for the prevention or treatment of Barth syndrome.

[0921] Treatment

[0922] As used herein, the term "treatment" in the context of treating a disorder generally refers to the treatment and therapy of a human or animal (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of the disorder, and includes reducing the rate of progression, decreasing the rate of progression, alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder. Treatment also includes treatment as a prophylactic measure (i.e., prevention). For example, the term "treatment" encompasses patients who have not yet developed a disorder but are at risk of developing a disorder.

[0923] For example, the term "treatment" encompasses patients who may not yet have a disorder or disease but are at risk of developing a disorder or disease.

[0924] As used herein, the term "therapeutically effective amount" refers to the amount of a compound, or a material, composition or dosage form comprising the compound, which when administered according to a desired treatment regimen is capable of effectively producing some desired therapeutic effect and which corresponds to a reasonable benefit / risk ratio.

[0925] The term "treatment" includes combination treatments and therapies in which, for example, two or more treatments or therapies are combined sequentially or simultaneously. Examples of treatments and therapies include, but are not limited to, chemotherapy (administration of an active agent, including for example a drug, an antibody (e.g., as in immunotherapy), a prodrug (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiotherapy; and gene therapy.

[0926] Kit

[0927] 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, preferably provided in a suitable container and / or with a suitable package; and (b) instructions for use, such as written instructions on how to administer the compound or composition.

[0928] The written description may also include a list of indications for which the compound is suitable for treatment.

[0929] Route of administration

[0930] The compound or a pharmaceutical composition comprising the compound can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0931] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patch, plaster, etc.); transmucosal (including, e.g., by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by using, e.g., inhalation or insufflation via an aerosol, (e.g., by mouth or nose)); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; by, e.g., subcutaneous or intramuscular implantation of a depot or reservoir.

[0932] Subject / patient

[0933] The subject / patient can be a chordate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0934] In addition, the subject / patient can be any of its developmental forms, such as a fetus.

[0935] In a preferred embodiment, the subject / patient is a human.

[0936] Formulation

[0937] Although the compounds can be administered alone, they are preferably presented in the form of a pharmaceutical preparation (e.g., composition, formulation, 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, said other pharmaceutically acceptable ingredients 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 sweetening agents. The preparation may also contain other active agents, such as other therapeutic or prophylactic agents.

[0938] Accordingly, the present invention also provides a pharmaceutical composition as described above, and a method for preparing a pharmaceutical composition, said method comprising mixing at least one compound as described herein with one or more other pharmaceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) well known to those skilled in the art. If the formulated ingredients are discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0939] As used herein, the term "pharmaceutically acceptable" pertains to compounds, ingredients, materials, compositions, dosage forms, etc. that are, within the scope of reasonable medical judgment, suitable for contact with the tissues of the subject of interest (e.g., a human) without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the preparation.

[0940] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks, such as Remington's Pharmaceutical Sciences Remington: The Science and Practice of Pharmacy, 18th Edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients Goodman & Gilman's The Pharmacological Basis of Therapeutics, 5th Edition, 2005.

[0941] The preparation can be made by any method well known in the pharmaceutical art. Such methods include the step of associating the compound with a carrier that constitutes one or more accessory ingredients. Generally, the preparation is made by uniformly and intimately associating the compound with a carrier (e.g., a liquid carrier, a subdivided solid carrier, etc.) and then shaping the product (if necessary).

[0942] The preparation can be formulated to provide rapid release or slow release; immediate release, delayed release, timed release, or sustained release; or combinations thereof.

[0943] The preparation may suitably be a liquid, a solution (e.g., aqueous, non-aqueous), a suspension (e.g., aqueous, non-aqueous), an emulsion (e.g., oil-in-water, water-in-oil), an elixir, a syrup, a sugar bait, a mouthwash, a drop, a tablet (including, for example, a coated tablet), a granule, a powder, a lozenge, a troche, a capsule (including, for example, hard and soft gelatin capsules), a cachet, a pill, an ampoule, a bolus, a suppository, a pessary, a tincture, a gel, a paste, an ointment, a cream, a lotion, an oil, a foam, a spray, a mist or an aerosol.

[0944] The preparation may suitably be provided as a patch, a plaster, a bandage, a dressing, etc. impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients (including, for example, a penetration enhancer, a permeation enhancer and an absorption enhancer). The preparation may also suitably be provided in the form of a depot or a reservoir.

[0945] The compound may be dissolved in, suspended in or mixed with one or more other pharmaceutically acceptable ingredients. The compound may be present in liposomes or other microparticles which are designed to target the compound, for example, to blood components or one or more organs.

[0946] Preparations 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, sugar baits, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

[0947] Preparations suitable for buccal administration include mouthwashes, lozenges, troches, as well as patches, plasters, depots and reservoirs. Lozenges usually contain the compound in a flavored base which is usually sucrose and gum arabic or tragacanth. Troches usually contain the compound in an inert matrix such as gelatin and glycerin, or sucrose and gum arabic. Mouthwashes usually contain the compound in a suitable liquid carrier.

[0948] Preparations suitable for sublingual administration include tablets, lozenges, troches, capsules and pills.

[0949] Preparations 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, lozenges, troches, as well as patches, plasters, depots and reservoirs.

[0950] Formulations suitable for transmucosal administration other than oral 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, plasters, reservoirs, and depots.

[0951] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, plasters, bandages, dressings, reservoirs, and depots.

[0952] 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 in a suitable machine a free-flowing form of the compound, such as a powder or granule, optionally mixed with one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl paraben, propyl paraben, sorbic acid); flavoring agents, flavor enhancers, and sweetening agents. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can be optionally coated or scored and can be formulated to provide slow or controlled release of the compound in the tablet, for example, using variable proportions of hydroxypropylmethylcellulose, to provide the desired release characteristics. Tablets can 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.

[0953] Ointments are generally prepared from the compound and an alkane or a water-miscible ointment base.

[0954] Creams are generally prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can 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 can desirably include compounds that enhance the 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.

[0955] Emulsions are usually prepared from compounds and an oil phase, which may optionally contain only an emulsifier (also known as an emulsifying substance), or it may contain at least one emulsifier in combination with a fat or an oil or a mixture of 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 an oil and a 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 oil disperse phase of the cream formulation.

[0956] Suitable emulsifying substances and emulsifying stabilizers include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The choice of a suitable oil or fat for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils that might be used for pharmaceutical emulsion formulations may be very low. Thus, the cream should preferably be a non-greasy, non-staining, and washable product with an appropriate consistency to avoid leakage from test tubes or other containers. Straight-chain or branched mono- or di-alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut oil fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a mixture of branched esters known as Crodamol CAP may be used, with the latter three being preferred esters. Depending on the desired properties, these substances may be used alone or in combination. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0957] In cases where the vehicle is liquid, formulations suitable for intranasal administration include, for example, nasal sprays, nasal drops, or aerosol administration using a nebulizer, including aqueous or oily solutions of the compound.

[0958] In cases where the vehicle is solid, formulations suitable for intranasal administration include those present, for example, as a coarse powder with a particle size in the range of about 20 to about 500 microns, which are administered by sniffing, i.e., by rapid inhalation through the nasal passages from a container of the powder held near the nose.

[0959] Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those provided as an aerosol spray from a pressurized package using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.

[0960] Formulations suitable for ocular administration include eye drops in which the compound is dissolved or suspended in a suitable vehicle, especially an aqueous solvent of the compound.

[0961] Preparations suitable for rectal administration may be presented as suppositories with a suitable base, which base comprises, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as solutions or suspensions for treatment by enema.

[0962] Preparations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations, which formulations, in addition to the compound, also comprise such carriers as are known in the art to be suitable.

[0963] 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, bacteriostatic agents, suspending agents, thickening agents, and solutes that render the preparation isotonic with the blood (or other relevant body fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, 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. Generally, 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 may be present in unit dose or multi-dose sealed containers (e.g., ampoules and vials), and may be stored under lyophilized (freeze-dried) conditions that require only the immediate addition of a sterile liquid carrier (e.g., water for injection) prior to use. Temporary injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0964] Dosage

[0965] Those skilled in the art will recognize that the appropriate dosage of the compound, as well as of the compositions containing the compound, may vary from patient to patient. Determining the optimal dosage will generally involve a balance between the therapeutic benefit and any risks or adverse side effects. The dosage level selected will depend on a variety of factors, including but not limited to the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount and route of administration of the compound will ultimately be determined by a physician, veterinarian, or clinician, although generally the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmfulness or adverse side effects.

[0966] It can be administered in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods for determining the most effective means and dosages of administration are well known to those skilled in the art and will vary depending on the formulation used for treatment, the purpose of the treatment, the target cells being treated, and the subject being treated. Single or multiple administrations can be carried out at dosage levels and in a manner selected by the attending physician, veterinarian, or clinician.

[0967] When the compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, and thus the actual weight to be used is proportionally increased.

[0968] Synthesis methods

[0969] Another aspect of the present invention is a method for synthesizing the compounds described herein.

[0970] In some embodiments, the method includes the steps described in the general synthesis described herein.

[0971] Examples

[0972] General synthetic route

[0973] The following Schemes 1 and 2 show the general synthesis followed for preparing the compounds according to the present invention:

[0974] Scheme 1

[0975]

[0976] Scheme 2

[0977]

[0978] The synthesis of some specific compounds according to these reaction schemes is listed in the examples below.

[0979] Example 1

[0980]

[0981] 3-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[0982] (Compound 192)

[0983] According to the synthesis 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:

[0984] a) N'-(3-Nitrobenzoyl)furan-2-carbohydrazide: To a solution of 3-nitrobenzoic acid (10.0 g, 59.8 mmol) in dichloromethane (50 ml) was 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 h. The solvent was evaporated under reduced pressure to obtain the acyl chloride. The acyl chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise at 0 °C to a suspension of 2-furohydrazide (7.6 g, 60.4 mmol) and anhydrous sodium carbonate (6.3 g, 59.8 mmol) in tetrahydrofuran (50 mL) and water (50 mL). The mixture was stirred at 0 °C for 1 h and at room temperature for 6 h. A large amount of precipitate was observed. The product was collected by filtration, washed with water, and finally dried in vacuo to obtain 14.0 g (85.1% yield) of N'-(3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.

[0985] 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 phosphoryl chloride (70 ml), and the mixture was heated and stirred at 80 °C for 5 h. Phosphoryl chloride 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12.3 g (93.9% yield) of 2-(furan-2-yl)-5-(3-nitrophenyl)-1,3,4-oxadiazole as a yellow solid.

[0986] 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 hydrogen atmosphere of 2.0 Mpa. 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 obtain 9.4 g (86.5% yield) of 3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)aniline as a white solid.

[0987] 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 refluxed with stirring for 1 hr. The excess thionyl chloride was evaporated under reduced pressure to give the acyl chloride. The acyl chloride was dissolved in dichloromethane (5 ml) and added dropwise at 0 °C 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). 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 (175.5 mg, 90.6% yield) as a white solid.

[0988] 1 H NMR (400 MHz, DMSO): δ 10.73 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.63 - 7.59 (m, 2H), 7.44 (d, J = 3.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.85 - 6.84 (m, 1H), 3.84 (s, 3H);

[0989] For [M+H, C 20 H 15 BrN 3 O 4 + The calculated value of LC-HRMS (ESI): 440.0246, found 440.0246.

[0990] Example 2

[0991]

[0992] 3-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[0993] (Compound 193)

[0994] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (163.0 mg, 93.6% yield), as a yellow solid.

[0995] 1 H NMR (400 MHz, DMSO): δ 10.72 (s, 1H), 8.59 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.67 (dd, J = 1.2, 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.45 (d, J = 3.6 Hz, 1H), 7.31 - 7.27 (m, 1H), 6.85 - 6.84 (m, 1H), 3.86 (s, 3H);

[0996] For [M+H,C 20 H 15 ClN 3 O 4 + The calculated value of LC-HRMS (ESI) for [M+H,C

[0997] Example 3

[0998]

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

[1000] (Compound 120)

[1001] ​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 was prepared 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (184.5 mg, 95.2% yield) as a white solid.

[1002] 1 H NMR (400 MHz, DMSO): δ 10.50 (s, 1H), 8.56 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.68 (dd, J = 2.8, 8.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 6.85 - 6.83 (m, 1H), 3.89 (s, 3H);

[1003] Calculated for [M+H,C 20 H 15 BrN 3 O 4 + is 440.0246, found 440.0221 by LC-HRMS (ESI).

[1004] Example 4

[1005]

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

[1007] (Compound 124)

[1008] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (162.9 mg, 93.5% yield) as a white solid.

[1009] 1 H NMR (400 MHz, DMSO): δ 10.50 (s, 1H), 8.57 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.64 - 7.55 (m, 3H), 7.44 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 6.85 - 6.83 (m, 1H), 3.90 (s, 3H);

[1010] For [M + H,C 20 H 15 ClN 3 O 4 + The calculated value of LC-HRMS (ESI) for is 396.0751, found 396.0749.

[1011] Example 5

[1012]

[1013] N-(3-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide

[1014] (Compound 279)

[1015] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (177.9 mg, 90.8% yield) as a white solid.

[1016] 1 H NMR (400 MHz, DMSO): δ 10.53 (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, 3.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 3.93 (s, 3H);

[1017] For [M+H,C 21 H 15 F 3 N 3 O 5 + The calculated value of LC-HRMS (ESI) for [M+H,C

[1018] Example 6

[1019]

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

[1021] (Compound 197)

[1022] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (155.8 mg, 94.3% yield) as a white solid.

[1023] 1 H NMR (400 MHz, DMSO): δ 10.39 (s, 1H), 8.60 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.33 (dd, J = 2.0, 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 3.88 (s, 3H), 2.30 (s, 3H);

[1024] For [M + H, C 21 H 18 N 3 O 4 + The calculated value of LC-HRMS (ESI) is 376.1297, and the measured value is 376.1310.

[1025] Example 7

[1026]

[1027] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1028] (Compound 123)

[1029] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (171.8 mg, 92.1% yield) as a white solid.

[1030] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.54 (dd, J = 2.8, 8.8 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 1.81 - 1.74 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H);

[1031] For [M + H, C 22 H 19 ClN 3 O 4 + The calculated value of LC-HRMS (ESI) is 424.1064, and the measured value is 424.1078.

[1032] Example 8

[1033]

[1034] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1035] (Compound 119)

[1036] ​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 is prepared 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (191.4 mg, 92.9% yield) as a white solid.

[1037] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.58 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.4, 8.8 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.07 (t, J = 6.4 Hz, 2H), 1.80 - 1.73 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H);

[1038] For [M + H, C 22 H 19 BrN 3 O 4 + The calculated value of LC-HRMS (ESI) is 468.0559, and the measured value is 468.0568.

[1039] Example 9

[1040]

[1041] 2-Ethoxy-5-fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1042] (Compound 125)

[1043] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (159.4 mg, 92.1% yield) as a beige solid.

[1044] 1 H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 8.61 (s, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.88 - 7.85 (m, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.50 (dd, J = 3.2, 8.8 Hz, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.22 (dd, J = 4.4, 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.17 (q, J = 6.8 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H);

[1045] For [M+H,C 21 H 17 FN 3 O 4 + The calculated value of LC-HRMS (ESI) for is 394.1203, found 394.1200.

[1046] Example 10

[1047]

[1048] 5-Chloro-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1049] (Compound 122)

[1050] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (170.6 mg, 94.6% yield) as a light yellow solid.

[1051] 1 H NMR (400 MHz, DMSO): δ 10.48 (s, 1H), 8.59 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.18 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H);

[1052] For [M+H, C 21 H 17 ClN 3 O 4 + the calculated value of LC-HRMS (ESI): 410.0908, found 410.0910.

[1053] Example 11

[1054]

[1055] 5-Bromo-2-ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1056] (Compound 118)

[1057] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (187.9 mg, 94.0% yield) as a white solid.

[1058] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 2.8, 8.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.17 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H);

[1059] For [M+H,C 21 H 17 BrN 3 O 4 + The calculated value of LC-HRMS (ESI) for [M+H,C

[1060] Example 12

[1061]

[1062] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-iodobenzamide

[1063] (Compound 200)

[1064] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (197.6 mg, 89.6% yield) as a pale yellow solid.

[1065] 1 H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 8.58 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.82 - 7.79 (m, 2H), 7.62 - 7.58 (m, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.17 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H);

[1066] Calculated for [M+H,C 21 H 17 IN 3 O 4 + : 502.0264, found 502.0264.

[1067] Example 13

[1068]

[1069] 2-Ethoxy-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide

[1070] (Compound 218)

[1071] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (160.4 mg, 93.6% yield) as a white solid.

[1072] 1 H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.63 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.32 (dd, J = 2.0, 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.16 (q, J = 6.8 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J = 6.8 Hz, 3H);

[1073] Calculated for [M+H, C 22 H 20 N 3 O 4 + LC-HRMS (ESI): 390.1454, found 390.1458.

[1074] Example 14

[1075]

[1076] 2-Ethoxy-5-ethyl-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1077] (Compound 219)

[1078] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (170.6 mg, 96.1% yield) as a white solid.

[1079] 1 1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.63 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.35 - 7.33 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.16 (q, J = 6.8 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 6.8 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H);

[1080] Calculated for [M+H,C 23 H 22 N 3 O 4 + LC-HRMS (ESI): 404.1610, found 404.1607.

[1081] Example 15

[1082]

[1083] 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(trifluoromethoxy)benzamide

[1084] (Compound 211)

[1085] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (179.4 mg, 94.1% yield) as a white solid.

[1086] 1 H NMR (400 MHz, DMSO): δ 10.87 (s, 1H), 8.53 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.68 - 7.61 (m, 2H), 7.58 - 7.54 (m, 1H), 7.45 (d, J = 3.6 Hz, 1H), 6.85 - 6.84 (m, 1H);

[1087] For [M + H, C 20 H 12 F 4 N 3 O 4 + The calculated value of LC - HRMS (ESI) for [M + H, C

[1088] Example 16

[1089]

[1090] 5 - Fluoro - N-(3-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)-2-(2,2,2 - trifluoroethoxy)benzamide

[1091] (Compound 228)

[1092] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (178.7 mg, 90.8% yield) as a white solid.

[1093] 1 H NMR (400 MHz, DMSO): δ 10.54 (s, 1H), 8.56 (s, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.87 - 7.84 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 3.2, 8.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.36 - 7.32 (m, 1H), 6.85 - 6.84 (m, 1H), 4.86 (q, J = 8.8 Hz, 2H);

[1094] For [M + H, C 21 H 14 F 4 N 3 O 4 + The calculated value of LC - HRMS (ESI): 448.0920, the measured value 448.0917.

[1095] Example 17

[1096]

[1097] 5-Chloro-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1098] (Compound 225)

[1099] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (189.6 mg, 92.9% yield) as a white solid.

[1100] 1 H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.54 (s, 1H), 8.11 - 8.10 (m, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.44 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.88 (q, J = 8.8 Hz, 2H);

[1101] For [M+H,C 21 H 14 ClF 3 N 3 O 4 + The LC-HRMS (ESI) calculated value for [M+H,C

[1102] Example 18

[1103]

[1104] 5-Bromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1105] (Compound 226)

[1106] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (207.5 mg, 92.8% yield) as a white solid.

[1107] 1 H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.54 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.88 (q, J = 8.8 Hz, 2H);

[1108] For [M+H,C 21 H 14 BrF 3 N 3 O 4 + The calculated value of LC-HRMS (ESI) for [M+H,C

[1109] Example 19

[1110]

[1111] 3-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1112] (Compound 220)

[1113] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (158.0 mg, yield 94.7%) as an off-white solid.

[1114] 1 1H NMR (400 MHz, DMSO): δ 10.66 (s, 1H), 8.59 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.48 - 7.39 (m, 3H), 7.27 - 7.22 (m, 1H), 6.85 - 6.83 (m, 1H), 3.94 (d, J = 1.2 Hz, 3H);

[1115] For [M+H,C 20 H 15 FN 3 O 4 + The calculated value of LC-HRMS (ESI) for is 380.1047, found 380.1048.

[1116] Example 20

[1117]

[1118] 3,5-Dibromo-N-(3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1119] (Compound 168)

[1120] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (205.0 mg, 89.7% yield) as a white solid.

[1121] 1 H NMR (400 MHz, DMSO): δ 10.80 (s, 1H), 8.55 (s, 1H), 8.10 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 - 7.82 (m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 6.85 - 6.83 (m, 1H), 3.84 (s, 3H);

[1122] For [M+H, C 20 H 14 Br 2 N 3 O 4 + the LC-HRMS (ESI) calculated value: 517.9351, found 517.9350.

[1123] Example 21

[1124]

[1125] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1126] (Compound 184)

[1127] 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:

[1128] ​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) was 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 h. The solvent was evaporated under reduced pressure to obtain the acyl chloride.

[1129] The acyl chloride was dissolved in tetrahydrofuran (50 ml) and added dropwise at 0 °C to a suspension of 2-furoic 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). The mixture was stirred at 0 °C for 1 h and at room temperature for 6 h. A large amount of precipitate was observed. The product was collected by filtration, washed with water, and finally dried in vacuo to obtain 14.4 g (91.0% yield) of N'-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide as a yellow solid.

[1130] 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 phosphoryl chloride (70 ml), and the mixture was heated and stirred at 80 °C for 5 h. Phosphoryl chloride 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12.5 g (92.6% yield) of 2-(4-fluoro-3-nitrophenyl)-5-(furan-2-yl)-1,3,4-oxadiazole as a yellow solid.

[1131] 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 hydrogen atmosphere of 2.0 Mpa. 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 obtain 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.

[1132] 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 refluxed with stirring for 1 hr. The excess thionyl chloride was evaporated under reduced pressure to obtain the acyl chloride.

[1133] The acyl chloride was dissolved in dichloromethane (5 ml) and added dropwise at 0 °C 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). 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 afford the title compound (154.9 mg, 91.8% yield) as a white solid.

[1134] 1 1H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.92 - 8.90 (m, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.91 - 7.87 (m, 2H), 7.65 - 7.56 (m, 2H), 7.46 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.85 - 6.83 (m, 1H), 4.01 (s, 3H);

[1135] Calculated for [M+H, C 20 H 14 ClFN 3 O 4 : 414.0657, found 414.0658. +

[1136] Example 22

[1137]

[1138] 5-Chloro-2-ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1139] (Compound 216)

[1140] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (159.6 mg, 91.5% yield) as a white solid.

[1141] 1 H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 9.08 (d, J = 9.6 Hz, 1H), 8.10 (s, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.86 - 7.82 (m, 1H), 7.64 - 7.55 (m, 2H), 7.44 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.84 - 6.83 (m, 1H), 4.27 (q, J = 6.8 Hz, 2H), 1.48 (t, J = 6.8 Hz, 3H);

[1142] For [M+H,C 21 H 16 ClFN 3 O 4 + The calculated value of LC-HRMS (ESI) for

[1143] Example 23

[1144]

[1145] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1146] (Compound 128)

[1147] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (140.8 mg, 91.0% yield) as a white solid.

[1148] 1 H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 9.01 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 6.4 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.63 - 7.57 (m, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.85 - 6.83 (m, 1H), 4.03 (s, 3H);

[1149] For [M+H,C 20 H 15 FN 3 O 4 + The calculated value of LC-HRMS (ESI) for

[1150] Example 24

[1151]

[1152] 5-Bromo-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxybenzamide

[1153] (Compound 183)

[1154] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (179.5 mg, 96.0% yield) as a white solid.

[1155] 1 H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 8.92 - 8.90 (m, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.77 (dd, J = 2.4, 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 10.4 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.01 (s, 3H);

[1156] For [M+H, C 20 H 14 BrFN 3 O 4 + the LC-HRMS (ESI) calculated value for: 458.0152, found 458.0159.

[1157] Example 25

[1158]

[1159] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-methylbenzamide

[1160] (Compound 300)

[1161] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (154.4 mg, 96.2% yield) as a white solid.

[1162] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.03 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.82 (s, 1H), 7.61 (dd, J = 8.8, 10.4 Hz, 1H), 7.47 (d, J = 3.2 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.86 - 6.84 (m, 1H), 4.01 (s, 3H), 2.33 (s, 3H);

[1163] For [M + H, C 21 H 17 FN 3 O 4 + The calculated value of LC-HRMS (ESI) is 394.1203, and the measured value is 394.1205.

[1164] Example 26

[1165]

[1166] 2-Ethoxy-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1167] (Compound 215)

[1168] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (150.1 mg, 93.5% yield) as a white solid.

[1169] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.19 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.88 - 7.84 (m, 1H), 7.63 - 7.59 (m, 2H), 7.46 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.18 - 7.14 (m, 1H), 6.85 - 6.84 (m, 1H), 4.31 (q, J = 6.8 Hz, 2H), 1.51 (t, J = 6.8 Hz, 3H);

[1170] Calculated for [M+H,C 21 H 17 FN 3 O 4 + of LC-HRMS (ESI): 394.1203, found 394.1228.

[1171] Example 27

[1172]

[1173] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1174] (Compound 313)

[1175] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (160.0 mg, 87.7% yield) as a white solid.

[1176] 1 H NMR (400 MHz, DMSO): δ 10.10 (s, 1H), 8.93 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.92 - 7.85 (m, 2H), 7.63 - 7.57 (m, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.25 - 7.22 (m, 1H), 6.85 - 6.84 (m, 1H), 4.98 (q, J = 8.8 Hz, 2H);

[1177] For [M + H, C 21 H 14 F 4 N 3 O 4 + The LC - HRMS (ESI) calculated value for is 448.0920, found 448.0918.

[1178] Example 28

[1179]

[1180] 2-(2,2 - Difluoroethoxy)-N-(2 - fluoro - 5-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)benzamide

[1181] (Compound 314)

[1182] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (156.8 mg, 89.5% yield) as a white solid.

[1183] 1 H NMR (400 MHz, DMSO): δ 10.16 (s, 1H), 8.99 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.95 (d, J = 6.4 Hz, H), 7.91 - 7.87 (m, 1H), 7.63 - 7.58 (m, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.85 - 6.84 (m, 1H), 6.50 (tt, J = 3.2, 54.6 Hz, 1H), 4.58 (dt, J = 3.2, 14.4 Hz, 2H);

[1184] For [M+H,C 21 H 15 F 3 N 3 O 4 + The LC-HRMS (ESI) calculated value for [M+H,C

[1185] Example 29

[1186]

[1187] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide

[1188] (Compound 315)

[1189] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (155.8 mg, yield 92.8%) as a white solid.

[1190] 1 H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 9.12 (d, J = 5.6 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J = 6.8 Hz, 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 = 8.4 Hz, 1H), 7.23 - 7.19 (m, 1H), 6.86 - 6.85 (m, 1H), 4.98 - 4.96 (m, 1H), 4.86 - 4.84 (m, 1H), 4.59 - 4.57 (m, 1H), 4.51 - 4.50 (m, 1H);

[1191] For [M + H,C 21 H 16 F 2 N 3 O 4 + the LC - HRMS (ESI) calculated value: 412.1109, found 412.1095.

[1192] Example 30

[1193]

[1194] 2 - Ethoxy - N-(2 - fluoro - 5-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)-5 - methylbenzamide

[1195] (Compound 221)

[1196] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (151.8 mg, 91.3% yield) as a yellow solid.

[1197] 1 H NMR (400 MHz, DMSO): δ 10.49 (d, J = 2.0 Hz, 1H), 9.16 (dd, J = 1.6, 3.4 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.58 - 7.53 (m, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.37 - 7.35 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.84 - 6.83 (m, 1H), 4.24 (q, J = 6.8 Hz, 2H), 2.92 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H);

[1198] Calculated for [M+H,C 22 H 19 FN 3 O 4 + is 408.1360, found 408.1356.

[1199] Example 31

[1200]

[1201] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1202] (Compound 222)

[1203] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (159.2 mg, 92.6% yield) as a white solid.

[1204] 1 H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 9.19 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.62 - 7.57 (m, 1H), 7.46 - 7.41 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.27 (q, J = 6.8 Hz, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H);

[1205] Calculated for [M+H,C 23 H 21 FN 3 O 4 + of LC-HRMS (ESI): 422.1516, found 422.1520.

[1206] Example 32

[1207]

[1208] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1209] (Compound 210)

[1210] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (171.0 mg, yield 98.5%), as a pale yellow solid.

[1211] 1 H NMR (400 MHz, DMSO): δ 10.47 (s, 1H), 9.11 - 9.09 (m, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.74 (dd, J = 3.6, 9.2 Hz, 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 = 6.6 Hz, 2H), 1.91 - 1.85 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H);

[1212] For [M+H, C 22 H 18 F 2 N 3 O 4 + The LC-HRMS (ESI) calculated value for [M+H, C

[1213] Example 33

[1214]

[1215] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-propoxybenzamide

[1216] (Compound 209)

[1217] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (169.3 mg, 93.9% yield) as a pale yellow solid.

[1218] 1 H NMR (400 MHz, DMSO): δ 10.41 (d, J = 1.6 Hz, 1H), 9.07 (dd, J = 1.6, 7.2 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.64 - 7.58 (m, 2H), 7.45 (d, J = 3.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.19 (t, J = 6.4 Hz, 2H), 1.91 - 1.86 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H);

[1219] Calculated for [M + H, C 22 H 18 ClFN 3 O 4 + : 442.0970, found 442.0961.

[1220] Example 34

[1221]

[1222] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-propoxybenzamide

[1223] (Compound 208)

[1224] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (165.2 mg, 96.1% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO): δ 10.48 (d, J = 1.6 Hz, 1H), 9.16 (d, J = 6.4 Hz, 1H), 8.11 (s, 1H), 7.86 - 7.83 (m, 2H), 7.62 - 7.57 (m, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.17 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.92 - 1.87 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H);

[1225] Calculated for [M+H,C 23 H 21 FN 3 O 4 + LC-HRMS (ESI): 422.1516, found 422.1519.

[1226] Example 35

[1227]

[1228] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1229] (Compound 316)

[1230] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (191.0 mg, 97.2% yield) as a white solid.

[1231] 1 H NMR (400 MHz, DMSO): δ 10.24 (s, 1H), 8.85 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.94 - 7.91 (m, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.62 - 7.57 (m, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.95 (q, J = 8.8 Hz, 2H);

[1232] For [M + H, C 21 H 13 ClF 4 N 3 O 4 + The LC - HRMS (ESI) calculated value for [M + H, C

[1233] Example 36

[1234]

[1235] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2,2,2-trifluoroethoxy)benzamide

[1236] (Compound 319)

[1237] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (178.5 mg, 94.0% yield) as a white solid.

[1238] 1 1H NMR (400 MHz, DMSO): δ 10.22 (s, 1H), 8.88 (d, J = 6.4 Hz, 1H), 8.11 (s, 1H), 7.94 - 7.91 (m, 1H), 7.63 - 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 = 8.8 Hz, 2H);

[1239] Calculated for [M+H,C 21 H 13 F 5 N 3 O 4 + LC-HRMS (ESI): calcd for 466.0826, found 466.0812.

[1240] Example 37

[1241]

[1242] 2-(2,2-Difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methylbenzamide

[1243] (Compound 323)

[1244] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (163.2 mg, 90.2% yield) as a white solid.

[1245] 1 H NMR (400 MHz, DMSO): δ 10.15 (s, 1H), 9.00 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.77 (s, 1H), 7.63 - 7.58 (m, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.42 (dd, J = 1.6, 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 6.49 (tt, J = 3.2, 14.4 Hz, 1H), 4.54 (dt, J = 2.8, 14.0 Hz, 2H), 2.34 (s, 3H);

[1246] For [M + H, C 22 H 17 F 3 N 3 O 4 + The calculated value of LC-HRMS (ESI) is 444.1171, and the measured value is 444.1170.

[1247] Example 38

[1248]

[1249] 5-Chloro-2-(2,2-difluoroethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1250] (Compound 317)

[1251] ​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 is prepared 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (169.5 mg, 89.6% yield) as a white solid.

[1252] 1 H NMR (400 MHz, DMSO): δ 10.22 (s, 1H), 8.93 - 8.90 (m, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.93 - 7.90 (m, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.8, 8.8 Hz, 1H), 7.61 (dd, J = 8.8, 10.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 6.47 (tt, J = 3.2, 14.4 Hz, 1H), 4.56 (dt, J = 3.2, 14.4 Hz, 2H);

[1253] For [M+H,C 21 H 14 ClF 3 N 3 O 4 + The LC-HRMS (ESI) calculated for: 464.0625, found 464.0632.

[1254] Example 39

[1255]

[1256] 2-(2,2-Difluoroethoxy)-5-fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1257] (Compound 320)

[1258] ​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 is prepared 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (172.5 mg, 94.5% yield) as a white solid.

[1259] 1 H NMR (400 MHz, DMSO): δ 10.24 (s, 1H), 8.96 - 8.94 (m, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.94 - 7.90 (m, 1H), 7.69 (d, J = 3.2, 7.2 Hz, 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, 14.4 Hz, 1H), 4.56 (dt, J = 3.2, 14.4 Hz, 2H);

[1260] For [M+H, C 21 H 14 F 4 N 3 O 4 + The calculated value of LC-HRMS (ESI): 448.0920, the measured value 448.0915.

[1261] Example 40

[1262]

[1263] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide

[1264] (Compound 318)

[1265] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (164.6 mg, 90.5% yield) as a white solid.

[1266] 1 H NMR (400 MHz, DMSO): δ 10.37 (s, 1H), 9.04 - 9.01 (m, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.67 (dd, J = 2.8, 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 10.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.94 - 4.92 (m, 1H), 4.82 - 4.80 (m, 1H), 4.57 - 4.55 (m, 1H), 4.49 - 4.76 (m, 1H);

[1267] For [M+H,C 21 H 15 ClF 2 N 3 O 4 + The LC-HRMS (ESI) calculated for: 446.0719, found 446.0716.

[1268] Example 41

[1269]

[1270] 2-(Difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1271] (Compound 302)

[1272] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (150.6 mg, yield 88.9%) as a white solid.

[1273] 1 H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 8.72 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.46 - 7.39 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 73.2 Hz, 1H), 6.84 - 6.83 (m, 1H);

[1274] For [M + H, C 20 H 13 F 3 N 3 O 4 + The LC - HRMS (ESI) calculated value for [M + H, C

[1275] Example 42

[1276]

[1277] N-(2 - fluoro - 5-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)-2 - methoxy - 5 - propylbenzamide

[1278] (Compound 281)

[1279] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (146.7 mg, 85.3% yield) as a white solid.

[1280] 1 H NMR (400 MHz, DMSO): δ 10.46 (d, J = 1.2 Hz, 1H), 9.03 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.89 - 7.86 (m, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.43 (dd, J = 2.0, 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.01 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H), 1.64 - 1.55 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H);

[1281] For [M + H, C 23 H 21 FN 3 O 4 + The calculated value of LC - HRMS (ESI) is 422.1516, and the measured value is 422.1518.

[1282] Example 43

[1283]

[1284] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide

[1285] (Compound 301)

[1286] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (160.5 mg, 90.8% yield) as a white solid.

[1287] 1 H NMR (400 MHz, DMSO): δ 10.61 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 1.2 Hz, 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 = 3.2 Hz, 1H), 6.85 - 6.84 (m, 1H);

[1288] For [M+H,C 20 H 12 F 4 N 3 O 4 + The LC-HRMS (ESI) calculated for [M+H]+: 434.0764, found 434.0748.

[1289] Example 44

[1290]

[1291] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(trifluoromethoxy)benzamide

[1292] (Compound 304)

[1293] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (180.7 mg, 94.7% yield) as a white solid.

[1294] 1 H NMR (400 MHz, DMSO): δ 10.73 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.99 - 7.95 (m, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.77 - 7.75 (m, 1H), 7.62 - 7.58 (m, 2H), 7.46 (d, J = 3.2 Hz, 1H), 6.85 - 6.84 (m, 1H);

[1295] For [M+H,C 20 H 11 ClF 4 N 3 O 4 + The LC-HRMS (ESI) calculated value for [M+H,C

[1296] Example 45

[1297]

[1298] 5-Chloro-2-(difluoromethoxy)-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1299] (Compound 305)

[1300] ​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 is prepared 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (170.4 mg, 92.9% yield) as a pale yellow solid.

[1301] 1 H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.73 - 8.70 (m, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 2.8, 8.8 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.26 (t, J = 73.2 Hz, 1H), 6.85 - 6.84 (m, 1H);

[1302] For [M+H,C 20 H 12 ClF 3 N 3 O 4 + The LC-HRMS (ESI) calculated value for is 450.0468, found 450.0468.

[1303] Example 46

[1304]

[1305] 5-Chloro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(fluoromethoxy)benzamide

[1306] (Compound 306)

[1307] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (155.6 mg, 88.3% yield) as a yellow solid.

[1308] 1 H NMR (400 MHz, DMSO): δ 10.41 (s, 1H), 8.75 - 8.73 (m, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.8, 8.8 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.85 - 6.84 (m, 1H), 6.04 (s, 1H), 5.90 (s, 1H);

[1309] For [M + H, C 20 H 13 ClF 2 N 3 O 4 + The LC - HRMS (ESI) calculated value for: 432.0563, found 432.0555.

[1310] Example 47

[1311]

[1312] 5-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)benzamide

[1313] (Compound 312)

[1314] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (168.4 mg, 96.2% yield) as a white solid.

[1315] 1 H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 9.06 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.91 - 7.87 (m, 1H), 7.76 (dd, J = 2.4, 9.2 Hz, 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);

[1316] For [M + H, C 21 H 15 F 3 N 3 O 4 + the LC - HRMS (ESI) calcd for: 430.1015, found 430.1017.

[1317] Example 48

[1318]

[1319] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-(2-fluoroethoxy)-5-

[1320] methylbenzamide

[1321] (Compound 321)

[1322] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (170.2 mg, 98.1% yield) as a white solid.

[1323] 1 H NMR (400 MHz, DMSO): δ 10.40 (s, 1H), 9.12 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.88 - 7.86 (m, 2H), 7.60 (dd, J = 8.8, 10.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.42 (dd, J = 2.0, 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 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);

[1324] For [M+H, C 22 H 18 F 2 N 3 O 4 + The calculated value of LC-HRMS (ESI) for

[1325] Example 49

[1326]

[1327] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethoxy)benzamide

[1328] (Compound 405)

[1329] ​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 20, but from 2-methoxy-5-(trifluoromethyl)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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (170.3 mg, 90.1% yield) as a white solid.

[1330] 1 H NMR (400 MHz, DMSO): δ 10.45 (s, 1H), 8.93 (d, J = 6.8 Hz, 1H), 8.11 (s, 1H), 7.94 - 7.91 (m, 1H), 7.84 (s, 1H), 7.67 - 7.59 (m, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 6.85 - 6.84 (m, 1H), 4.04 (s, 3H);

[1331] For [M+H, C 21 H 14 F 4 N 3 O 5 + The LC-HRMS (ESI) calculated value for [M+H]+ is 464.0870, found 464.0865.

[1332] Example 50

[1333]

[1334] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(trifluoromethyl)benzamide

[1335] (Compound 416)

[1336] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (179.1 mg, 98.1% yield) as a white solid.

[1337] 1 H NMR (400 MHz, DMSO): δ 10.43 (s, 1H), 8.89 (d, J = 5.6 Hz, 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);

[1338] For [M + H, C 21 H 14 F 4 N 3 O 4 + The LC - HRMS (ESI) calculated value for [M + H] is 448.0920, found 448.0913.

[1339] Example 51

[1340]

[1341] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-methyl-2-(2,2,2-trifluoroethoxy)benzamide

[1342] (Compound 322)

[1343] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (173.7 mg, 92.3% yield) as a white solid.

[1344] 1H NMR (400 MHz, DMSO): δ 10.07 (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); Calculated for [M+H, C22H16F4N3O4]+: 462.1077, found 462.1070.

[1345] Example 52

[1346]

[1347] 2-Fluoro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide

[1348] (Compound 39)

[1349] 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:

[1350] a) Methyl 2-(2-fluorobenzamido)isonicotinate: To a stirred solution of methyl 2-aminoisonicotinate (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 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (n-hexane / ethyl acetate = 4 / 1) to give 256.4 mg (14.2% yield) of methyl 2-(2-fluorobenzamido)isonicotinate as a white solid.

[1351] b) 2-(2-fluorobenzamido)isonicotinic acid: To a solution of methyl 2-(2-fluorobenzamido)isonicotinate (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 h. After concentration, the remaining concentrated solution was acidified to pH 1 by addition of 1 N hydrochloric acid. A large amount of precipitate was observed. The product was collected by filtration, washed with water and finally dried in vacuo to give 180.5 mg (74.6% yield) of 2-(2-fluorobenzamido)isonicotinic acid as a white solid.

[1352] c) 2-Fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide: To a stirred solution of 2-(2-fluorobenzamido)isonicotinic acid (180.5 mg, 0.69 mmol), 2-furoic 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 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give 206.8 mg (81.4% yield) of 2-fluoro-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide as a white solid.

[1353] 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 phosphoryl chloride (2 ml), and the mixture was heated and stirred at 80 °C for 5 h. Phosphoryl chloride 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, 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 pale yellow solid.

[1354] 1 H NMR (400 MHz, DMSO): δ 11.20 (s, 1H), 8.86 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.64 - 7.59 (m, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.39 - 7.33 (m, 2H), 6.87 - 6.86 (m, 1H);

[1355] For [M+H,C 18 H 12 FN 4 O 3 + The calculated value of LC-HRMS (ESI) for: 351.0893, found 351.0898.

[1356] Example 53

[1357]

[1358] 2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide

[1359] (Compound 373)

[1360] 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:

[1361] ​a) Methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate: 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 refluxed with stirring for 2 h. The excess thionyl chloride was evaporated under reduced pressure to obtain the acyl chloride.

[1362] The acyl chloride was dissolved in dichloromethane (20 ml) and added dropwise at 0 °C 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). 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.

[1363] b) 2-(2-Ethoxy-5-ethylbenzamido)isonicotinic acid: Using methyl 2-(2-ethoxy-5-ethylbenzamido)isonicotinate (1.96 g, 5.97 mmol), the reaction was carried out in the same manner as in Example 52 to obtain 1.38 g (73.5% yield) of 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid as a white solid.

[1364] c) 2-Ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide: Using 2-(2-ethoxy-5-ethylbenzamido)isonicotinic acid (1.38 g, 4.39 mmol), 2-furoic 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), the reaction was carried out in the same manner as in Example 52 to obtain 1.52 g (82.0% yield) of 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide as a white solid.

[1365] d) 2-Ethoxy-5-ethyl-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide: Using 2-ethoxy-5-ethyl-N-(4-(2-(furan-2-carbonyl)hydrazinocarbonyl)pyridin-2-yl)benzamide (1.52 g, 3.60 mmol), the reaction was carried out in the same manner as in Example 52 to obtain 0.76 g (52.2% yield) of the title compound as a white solid.

[1366] 11H NMR (400 MHz, DMSO): δ 10.94 (s, 1H), 8.94 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 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 = 7.6 Hz, 3H);

[1367] For [M+H, C 22 H 21 N 4 O 4 + The calculated value of LC-HRMS (ESI) for is 405.1563, and the measured value is 405.1545.

[1368] Example 54

[1369]

[1370] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide

[1371] (Compound 396)

[1372] 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 was obtained as a white solid.

[1373] 1 1H NMR (400 MHz, DMSO): δ 10.92 (s, 1H), 8.89 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.87 - 6.86 (m, 1H), 4.03 (s, 3H);​

[1374] For [M+H,C 20 H 14 F 3 N 4 O 4 + The LC-HRMS(ESI) calculated value: 431.0967, measured value 431.0960.

[1375] Example 55

[1376]

[1377] N-(4-(5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxy-5-(trifluoromethoxy)benzamide

[1378] (Compound 400)

[1379] 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 was obtained as a white solid.

[1380] 1 H NMR(400 MHz, DMSO): δ 10.89 (s, 1H), 8.89 (s, 1H), 8.63 (d, J = 5.2 Hz, 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 = 9.2 Hz, 1H), 6.88 - 6.87 (m, 1H), 4.01 (s, 3H);

[1381] For [M+H,C 20 H 14 F 3 N 4 O 5 + The LC-HRMS(ESI) calculated value: 447.0916, measured value 447.0911.

[1382] Example 56

[1383]

[1384] ​​5-Chloro-N-(4-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-2-methoxybenzamide

[1385] (Compound 372)

[1386] 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 was obtained as a pale yellow solid.

[1387] 1 H NMR (400 MHz, DMSO): δ 10.83 (s, 1H), 8.61 (d, J = 0.8 Hz, 1H), 8.14 (s, 1H), 7.80 - 7.77 (m, 2H), 7.63 - 7.61 (m, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.87 - 6.86 (m, 1H), 3.97 (s, 3H);

[1388] For [M+H,C 19 H 14 ClN 4 O 4 + The calculated value of LC-HRMS (ESI) for [M+H,C

[1389] Example 63

[1390]

[1391] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(3-hydroxypropyl)-2-methoxybenzamide

[1392] (Compound 483)

[1393] 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). ​

[1394] 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.

[1395] 1 1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.04 (d, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.92 - 7.86 (m, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.44 (dd, J = 8.5, 1.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.85 (dd, J = 3.4, 1.6 Hz, 1H), 4.49 (t, J = 5.0 Hz, 1H), 4.02 (s, 3H), 3.43 (dd, J = 11.3, 6.1 Hz, 2H), 2.70 - 2.59 (m, 2H), 1.78 - 1.67 (m, 2H);

[1396] For [M+H, C 23 H 21 FN 3 O 5 + Calculated for LC - HRMS (ESI): 438.1460, found 438.1461.

[1397] Example 64

[1398]

[1399] N-(2 - Fluoro - 5-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)-2 - methoxy - 5-(3 - methoxypropyl)benzamide

[1400] (Compound 484)

[1401] 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.​

[1402] 1 H NMR (400 MHz, CDCl 3 ) δ 10.52 (d, J = 3.0 Hz, 1H), 9.34 (dd, J = 7.3, 2.1 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.94 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.67 (d, J = 1.1 Hz, 1H), 7.37 (dd, J = 8.4, 2.4 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.02 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 3.5, 1.7 Hz, 1H), 4.23 (t, J = 6.2 Hz, 2H), 4.09 (s, 3H), 3.03 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.18 - 2.05 (m, 2H);

[1403] For [M + H, C 24 H 23 FN 3 O 5 + The calculated value of LC - HRMS (ESI) for: 452.1616, found 452.1618.

[1404] Example 65

[1405]

[1406] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(3-(piperidin

[1407] -1-yl)propyl)benzamide

[1408] (Compound 495)

[1409] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (68.6 mg, 27.2% yield), as a yellow solid.

[1410] ​1 H NMR (400 MHz, CDCl 3 ) δ 10.49 (d, J = 3.0 Hz, 1H), 9.31 (dd, J = 7.3, 1.8 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.93 - 7.83 (m, 1H), 7.68 (d, J = 0.7 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.00 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 3.4, 1.7 Hz, 1H), 4.07 (s, 3H), 3.13 - 2.94 (m, 4H), 2.92 - 2.85 (m, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.28 - 2.17 (m, 2H), 2.10 - 1.89 (m, 4H), 1.72 - 1.54 (m, 2H);

[1411] For [M + H, C 28 H 30 FN 4 O 4 + The calculated value of LC - HRMS (ESI) for

[1412] Example 66

[1413]

[1414] N-(2 - fluoro - 5-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)-2 - methoxy - 5-(3 - morpholinopropyl)benzamide

[1415] (Compound 496)

[1416] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (105.8 mg, 41.8% yield), as a yellow solid.

[1417] 1 H NMR (400 MHz, CDCl 3 ​)δ 10.54 (s, 1H), 9.36 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.99 - 7.90 (m, 1H), 7.68 (s, 1H), 7.36 (dd, J = 8.4, 2.2 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.00 (d, J = 8.5 Hz, 1H), 6.66 - 6.60 (m, 1H), 4.09 (s, 3H), 3.78 - 3.71 (m, 4H), 2.69 (t, J = 7.6 Hz, 2H), 2.53 - 2.42 (m, 4H), 2.41 - 2.32 (m, 2H), 1.85 (dt, J = 15.0, 7.6 Hz, 2H);

[1418] For [M + H, C 27 H 28 FN 4 O 5 ) + The calculated value of LC - HRMS(ESI) for [M + H, C

[1419] Example 67

[1420]

[1421] 2 - Fluoro - N-(4-(5-(furan - 2 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)benzamide

[1422] (Compound 35)

[1423] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (113.2 mg, 64.8% yield), as a yellow solid.

[1424] 1 1H NMR (400 MHz, DMSO) δ 10.81 (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 = 3.5 Hz, 1H), 7.41 - 7.32 (m, 2H), 6.83 (dd, J = 3.4, 1.7 Hz, 1H);

[1425] For [M+H,C 19 H 13 FN 3 O 3 + The LC-HRMS(ESI) calculated value: 350.0935, measured value 350.0939.

[1426] Example 69

[1427]

[1428] 2-Ethoxy-5-ethyl-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)nicotinamide

[1429] (Compound 485)

[1430] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (137.2 mg, 65.0% yield), as a yellow solid.

[1431] 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);

[1432] For [M+H,C 22 H 20 FN 4 O 4 + The LC-HRMS(ESI) calculated value: 423.1463, measured value 423.1463.

[1433] Example 70 ​​

[1434]

[1435] 5-Chloro-N-(2-fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxynicotinamide

[1436] (Compound 486)

[1437] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (102.3 mg, 49.2% yield) as a yellow solid.

[1438] 1 H NMR (400 MHz, CDCl 3 ) δ 10.42 (s, 1H), 9.31 (dd, J = 7.3, 2.1 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.13 (s, 1H), 8.02 - 7.96 (m, 1H), 7.93 (s, 1H), 7.33 (dd, J = 10.3, 8.7 Hz, 1H), 4.23 (s, 3H);

[1439] Calculated for [M+H, C 18 H 12 ClFN 5 O 4 + : 416.0556, found 416.0557.

[1440] Example 71

[1441]

[1442] N-(3-(5-(1H-Pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide

[1443] (Compound 298)

[1444] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (87.6 mg, 50.2% yield) as a yellow solid.

[1445] 1 H NMR (400 MHz, DMSO) δ 13.69 (s, 1H), 10.75 (s, 1H), 8.58 (s, 1H), 8.05 - 8.02 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.43 - 7.32 (m, 2H), 6.98 (t, J = 2.0 Hz, 1H);

[1446] For [M+H,C 18 H 13 FN 5 O 2 + The calculated value of LC-HRMS (ESI) for

[1447] Example 72

[1448]

[1449] 2-Fluoro-N-(3-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1450] (Compound 15)

[1451] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (94.5 mg, 51.6% yield) as a yellow solid.

[1452] 1 ​1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.56 (s, 1H), 8.01 - 7.94 (m, 2H), 7.92 (d, J = 3.3 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.43 - 7.30 (m, 3H);

[1453] For [M + H, C 19 H 13 FN 3 O 2 S] + the LC - HRMS (ESI) calculated value for: 366.0707, found 366.0701.

[1454] Example 73

[1455]

[1456] 2 - Fluoro - N-(3-(5-(furan - 3 - yl)-1,3,4 - oxadiazol - 2 - yl)phenyl)benzamide

[1457] (Compound 20)

[1458] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (123.1 mg, 70.5% yield), as a yellow solid.

[1459] 1 1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.00 - 7.96 (m, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.42 - 7.32 (m, 2H), 7.08 (d, J = 1.0 Hz, 1H);

[1460] For [M + H, C 19 H 13 FN 3 O 3 ​+ LC-HRMS(ESI) calculated value: 350.0935, found 350.0938.

[1461] Example 74

[1462]

[1463] 2-Fluoro-N-(3-(5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1464] (Compound 22)

[1465] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (108.5 mg, 61.2% yield) as a yellow solid.

[1466] 1 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 8.49 (s, 1H), 7.94 (d, J = 8.1 Hz, 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);

[1467] For [M+H, C 19 H 17 F 3 N 3 + LC-HRMS(ESI) calculated value: 354.1248, found 354.1241.

[1468] Example 75

[1469]

[1470] N-(3-(5-Ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-fluorobenzamide

[1471] (Compound 289) ​

[1472] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (65.3 mg, 42.0% yield) as a yellow solid.

[1473] 1 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.49 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.65 - 7.54 (m, 2H), 7.44 - 7.27 (m, 2H), 2.96 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H);

[1474] Calculated for [M + H, C 17 H 15 FN 3 O 2 + : 312.1143, found 312.1146.

[1475] Example 76

[1476]

[1477] 2-Fluoro-N-(2-fluoro-5-(5-(thiazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1478] (Compound 290)

[1479] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (125.7 mg, 65.4% yield) as a yellow solid.

[1480] 1 ​1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.44 (s, 1H), 8.75 (d, J = 0.5 Hz, 1H), 8.64 (d, J = 6.0 Hz, 1H), 8.00 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.67 - 7.55 (m, 2H), 7.38 (dd, J = 15.6, 8.0 Hz, 2H).

[1481] For [M+H, C 18 H 11 F 2 N 4 O 2 S] + Calculated for [M+H, C

[1482] Example 77

[1483]

[1484] 2-Fluoro-N-(2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide

[1485] (Compound 79)

[1486] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (118.6 mg, 64.6% yield) as a yellow solid.

[1487] 1 1H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 8.12 (s, 1H), 8.06 (t, J = 7.6 Hz, 1H), 7.94 (t, J = 6.5 Hz, 1H), 7.77 (t, J = 6.9 Hz, 1H), 7.63 (dd, J = 13.4, 5.8 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.43 - 7.29 (m, 2H), 6.85 (dd, J = 3.5, 1.7 Hz, 1H).

[1488] For [M+H, C 19 H12 F 2 N 3 O 3 + Calculated value of LC-HRMS(ESI) for

[1489] The following Scheme 3 shows the general synthesis followed for preparing some of the compounds of the present invention:

[1490] Scheme 3

[1491]

[1492] The following compounds were prepared according to this method:

[1493] Example 57

[1494]

[1495] N-(5-Chloro-2-fluorophenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1496] (Compound 479)

[1497] 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:

[1498] A:

[1499] 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) was 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 h. The solvent was evaporated under reduced pressure to give the acyl chloride. The acyl chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise at 0 °C 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). The mixture was stirred at 0 °C for 1 h and at room temperature for 6 h. A large amount of precipitate was observed. The product was collected by filtration, washed with water, and 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.

[1500] B: ​

[1501] Methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate: Methyl 2-fluoro-5-(2-(furan-2-carbonyl)hydrazine-1-carbonyl)benzoate (2.5 g, 8.2 mmol) was dissolved in phosphoryl chloride (40 ml), and the mixture was heated and stirred at 100 °C for 5 h. Phosphoryl chloride was evaporated under reduced pressure, and water was added to the residue. A large amount of precipitate was observed. The product was collected by filtration, washed with water, and then dried in vacuo to obtain 1.8 g (76.4% yield) of methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate.

[1502] C:

[1503] 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid: Methyl 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoate (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 h. Thereafter, the reaction solution was neutralized with 2N hydrochloric acid. The resulting white solid was filtered, washed with water, and finally dried in vacuo to obtain 1.0 g (58.5% yield) of 2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzoic acid.

[1504] D:

[1505] 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 h. The solvent was evaporated under reduced pressure to obtain the acyl chloride. The acyl chloride was dissolved in dichloromethane (5 ml) and added dropwise at 0 °C to a solution of 5-chloro-2-fluoroaniline (72.8 mg, 0.5 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (5 ml). 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 obtain the title compound (106 mg, 52.8% yield) as a light yellow solid.

[1506] 11H NMR (400 MHz, DMSO) δ 10.61 (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 = 9.2 Hz, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.46 - 7.25 (m, 2H), 6.91 - 6.80 (m, 1H);

[1507] For [M+H, C 19 H 11 ClF 2 N 3 O 3 + The calculated value of LC-HRMS (ESI) for: 402.0452, found 402.0456.

[1508] Example 58

[1509]

[1510] N-(5-Chloro-2-methoxyphenyl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1511] (Compound 480)

[1512] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (103.0 mg, 49.8% yield), as a yellow solid.

[1513] 1 1H NMR (400 MHz, DMSO) δ 9.87 (d, J = 5.7 Hz, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.32 - 8.24 (m, 1H), 8.23 - 8.18 (m, 1H), 8.14 - 8.05 (m, 1H), 7.64 (t, J = 9.6 Hz, 1H), 7.50 (d, J = 3.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.5 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.87 - 6.81 (m, 1H), 3.88 (s, 3H);​

[1514] For [M+H,C 20 H 14 ClFN 3 O 4 + The calculated value of LC-HRMS(ESI) for it is 414.0651, and the measured value is 414.0658.

[1515] Example 59

[1516]

[1517] N-(2-Fluorophenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1518] (Compound 44)

[1519] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (85.7 mg, 49.1% yield) as a yellow solid.

[1520] 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);

[1521] For [M+H,C 19 H 13 FN 3 O 3 + The calculated value of LC-HRMS(ESI) for it is 350.0935, and the measured value is 350.0938.

[1522] Example 60

[1523] ​​

[1524] N-(5-Chloro-2-methoxypyridin-3-yl)-2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1525] (Compound 481)

[1526] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (110 mg, 53.0% yield) as a yellow solid.

[1527] 1 H NMR (400 MHz, DMSO) δ 9.99 (d, J = 9.1 Hz, 1H), 8.52 (dd, J = 7.0, 2.2 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.35 - 8.30 (m, 1H), 8.12 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 11.0, 8.8 Hz, 1H), 7.51 (d, J = 3.4 Hz, 1H), 6.86 (dd, J = 3.5, 1.7 Hz, 1H), 3.55 (s, 3H);

[1528] Calculated for [M + H, C 19 H 13 ClFN 4 O 4 + : 415.0604, found 415.0609.

[1529] Example 61

[1530]

[1531] 5-(5-(1H-Pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2-methoxypyridin-3-

[1532] yl)-2-fluorobenzamide

[1533] (Compound 482)

[1534] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (120 mg, 58.0% yield) as a yellow solid.

[1535] 1 H NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 9.96 (d, J = 8.5 Hz, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.44 - 8.36 (m, 1H), 8.34 - 8.24 (m, 1H), 7.84 (s, 1H), 7.68 (t, J = 9.8 Hz, 1H), 7.22 - 7.07 (m, 1H), 7.00 - 6.87 (m, 1H), 6.31 (s, 1H), 3.54 (s, 3H).

[1536] For [M+H,C 19 H 14 ClFN 5 O 3 + the LC-HRMS (ESI) calculated for [M+H,C

[1537] The following Scheme 4 shows the general synthesis followed for the preparation of some of the compounds according to the invention:

[1538] Scheme 4

[1539]

[1540] The following compounds were prepared according to this method:

[1541] Example 62

[1542]

[1543] 2-Fluoro-N-(3-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide

[1544] (Compound 325)

[1545] ​According to the synthesis 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:

[1546] A:

[1547] 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) was 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 h. The solvent was evaporated under reduced pressure to obtain the acyl chloride. The acyl chloride was dissolved in tetrahydrofuran (20 ml) and added dropwise to a suspension of 2-furohydrazide (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 h and at room temperature for 6 h. A large amount of precipitate was observed. The product was collected by filtration, washed with water, and finally dried in vacuo to obtain 2.3 g (78.5% yield) of N'-(4-fluoro-3-nitrobenzoyl)furan-2-carbohydrazide as a white solid.

[1548] B:

[1549] 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) and 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 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (hexane / ethyl acetate = 10 / 1) to obtain the title compound (1.4 g, 61.2% yield) as a yellow solid.

[1550] C:

[1551] 2-Fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-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 h under a hydrogen atmosphere of 2.0 Mpa. 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 obtain the title compound (1.0 g, 79.6% yield) as a yellow solid.

[1552] D:

[1553] 2-Fluoro-N-(2-fluoro-5-(5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)benzamide: To dichloromethane (10 ml) of 2-fluorobenzoic acid (140 mg, 1 mmol) was 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 acyl chloride. The acyl chloride was dissolved in dichloromethane (5 ml) and added dropwise at 0 °C 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). 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to obtain the title compound (215 mg, 56.1% yield) as a pale yellow solid.

[1554] 1 H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.59 (d, J = 5.8 Hz, 1H), 8.06 (s, 1H), 7.94 - 7.84 (m, 1H), 7.78 (t, J = 7.1 Hz, 1H), 7.63 (dd, J = 13.4, 6.2 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.45 - 7.30 (m, 3H), 6.81 (d, J = 1.6 Hz, 1H).

[1555] For [M+H, C 19 H 12 F 2 N 3 O 2 S] + The calculated value of LC-HRMS (ESI): 384.0613, the measured value 384.0610.

[1556] The following Scheme 5 shows the general synthesis followed for preparing some of the compounds according to the present invention:

[1557] Scheme 5

[1558]

[1559] The following compounds were prepared according to this method:

[1560] Example 78

[1561]

[1562] (2-Ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid

[1563] (Compound 497)

[1564] According to the synthesis procedure described in Scheme 5, (2-Ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)phosphoramidic acid can be prepared as follows:

[1565] A:

[1566] Dibenzyl (2-ethoxy-5-ethylbenzoyl)(2-fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)aminophosphate: 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 h. Then, at 0 °C, dibenzylphosphoryl chloride (0.36 g, 1.2 mmol) was added to the mixture. The reaction mixture was slowly warmed to room temperature and stirred at this temperature 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 (50 mg, 7.3% yield) as a yellow solid.

[1567] B:

[1568] (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)aminophosphate (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 under a hydrogen atmosphere of 2.0 Mpa for 16 h. 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 the title compound (20 mg, 54.4% yield) as a solid

[1569] 1H NMR (400 MHz, DMSO) δ 8.11 - 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 = 8.5 Hz, 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 = 6.9 Hz, 3H), 1.05 (t, J = 7.7 Hz, 3H).

[1570] Calculated for [M + H, C23H22FN3O7]+: 502.1174, found 502.1177.

[1571] Example 79

[1572]

[1573] N-(5-Chloro-2-fluorophenyl)-2-fluoro-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1574] (Compound 487)

[1575] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (105 mg, 52.3% yield) as a pale yellow solid.

[1576] 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 14.2 Hz, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.42 - 8.30 (m, 2H), 7.73 - 7.70 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 3.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.66 (dd, J = 3.5, 1.7 Hz, 1H).

[1577] Calculated for [M + H, C19 H 11 ClF 2 N 3 O 3 + LC-HRMS(ESI) calculated value for

[1578] Example 80

[1579]

[1580] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-5-(5-(furan-2-yl)-1,3,4-oxadiazol

[1581] -2-yl)benzamide

[1582] (Compound 488)

[1583] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (100 mg, 40.3% yield) as a pale yellow solid.

[1584] 1 H NMR (400 MHz, DMSO) δ 10.41 (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 = 9.2 Hz, 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).

[1585] For [M+H, C 25 H 23 F 2 N 4 O 5 + ​​LC-HRMS(ESI) calculated value: 497.1631, found 497.1638.

[1586] Example 81

[1587]

[1588] 2-Fluoro-N-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)benzamide

[1589] -2-yl)benzamide

[1590] (Compound 489)

[1591] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (155 mg, 62.4% yield) as a pale yellow solid.

[1592] 1 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.26 (t, J = 6.7 Hz, 1H), 8.13 (d, J = 1.1 Hz, 1H), 7.95 (t, J = 6.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.49 (d, J = 3.5 Hz, 1H), 7.23 (t, J = 9.7 Hz, 1H), 6.86 (dd, J = 3.5, 1.7 Hz, 1H), 6.82 (dt, J = 8.9, 3.4 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.70 - 3.44 (m, 4H), 2.69 (t, J = 5.4 Hz, 2H), 2.49 - 2.43 (m, 4H).

[1593] For [M + H, C 25 H 23 F 2 N 4 O 5 + LC-HRMS(ESI) calculated value: 497.1631, found 497.1638. ​

[1594] Example 82

[1595]

[1596] N-(2-Fluoro-5-(5-(oxazol-5-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide

[1597] (Compound 490)

[1598] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to afford the title compound (115.3 mg, 45.3% yield) as a yellow solid.

[1599] 1 H NMR (400 MHz, DMSO) δ 10.54 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 5.6 Hz, 1H), 8.84 (s, 1H), 8.20 (s, 1H), 7.92 - 7.85 (m, 1H), 7.62 (dd, J = 10.5, 8.8 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.26 - 7.18 (m, 2H), 4.11 (t, J = 5.7 Hz, 2H), 4.00 (s, 3H), 3.63 - 3.53 (m, 4H), 2.70 (t, J = 5.7 Hz, 2H), 2.50 - 2.44 (m, 4H).

[1600] Calculated for [M+H,C 25 H 25 FN 5 O 6 + : 510.1783, found 510.1786 by LC - HRMS (ESI).

[1601] Example 83

[1602]

[1603] ​N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin

[1604] -1-yl)ethoxy)benzamide

[1605] (Compound 491)

[1606] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-(piperidin-1-yl)ethoxy)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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (130.7 mg, 51.6% yield) as a yellow solid.

[1607] 1 H NMR (400 MHz, CDCl 3 ) δ 10.60 (s, 1H), 9.33 (d, J = 6.4 Hz, 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, 1H), 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).

[1608] Calculated for [M+H, C 27 H 28 FN 4 O 5 + : 507.2038, found 507.2039.

[1609] Example 84

[1610]

[1611] ​N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-methoxyethoxy)benzamide

[1612] (Compound 492)

[1613] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (152.3 mg, 67.2% yield) as a yellow solid.

[1614] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.05 (d, J = 5.8 Hz, 1H), 8.14 - 8.09 (m, 1H), 7.92 - 7.82 (m, 1H), 7.65 - 7.58 (m, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.27 - 7.16 (m, 2H), 6.85 (dd, J = 3.5, 1.7 Hz, 1H), 4.17 - 4.07 (m, 2H), 4.00 (s, 3H), 3.70 - 3.61 (m, 2H), 3.32 (s, 3H).

[1615] Calculated for [M+H,C 23 H 21 FN 3 O 6 + : 454.1409, found 454.1414 by LC-HRMS (ESI).

[1616] Example 85

[1617]

[1618] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-5-(2-hydroxyethoxy)-2-

[1619] methoxybenzamide

[1620] (Compound 493) ​

[1621] 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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (108.5 mg, 49.4% yield) as a yellow solid.

[1622] 1 H NMR (400 MHz, CDCl 3 ) δ 10.64 (s, 1H), 9.35 (d, J = 5.5 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.33 - 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).

[1623] For [M+H, C 22 H 19 FN 3 O 6 + the calculated value of LC-HRMS (ESI) is 440.1252, and the measured value is 440.1259.

[1624] Example 86

[1625]

[1626] N-(2-Fluoro-5-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-5-(2-morpholinoethoxy)benzamide

[1627] (Compound 494)

[1628] ​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 flash column chromatography on silica gel (dichloromethane / methanol = 100 / 1) to give the title compound (145.5 mg, 57.2% yield) as a yellow solid.

[1629] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.04 (d, J = 5.4 Hz, 1H), 8.11 (d, J = 1.1 Hz, 1H), 7.893 - 7.84 (m, 1H), 7.60 (dd, J = 10.5, 8.7 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.30 - 7.18 (m, 2H), 6.85 (dd, J = 3.5, 1.7 Hz, 1H), 4.11 (t, J = 5.7 Hz, 2H), 3.99 (s, 3H), 3.69 - 3.45 (m, 4H), 2.70 (t, J = 5.7 Hz, 2H), 2.49 - 2.40 (m, 4H).

[1630] For [M + H, C 26 H 26 FN 4 O 6 + The calculated value of LC-HRMS (ESI) for is 509.1831, found 509.1834.

[1631] Biological methods

[1632] Expression of human ALCAT1 in insect cells

[1633] ​The human ALCAT1 protein was expressed in Spodoptera frugiperda (Sf9) insect cells by using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's instructions. A high-titer recombinant baculovirus expressing the human ALCAT1 protein was generated by several rounds of virus amplification. Sf9 cells were typically infected with the recombinant baculovirus for 3 days, harvested in ice-cold phosphate-buffered saline (PBS), and homogenized in 20 mM NaCl by a French press. The total cell lysate was centrifuged at 10,000 x g for 1 h at 4 °C to remove the nuclear fraction, and then ultracentrifuged at 100,000 x g to pellet the membrane fraction. The membrane fraction was resuspended in an enzyme buffer containing 10% glycerol, quantified for protein concentration, aliquoted, and stored at -80 °C.

[1634] In vitro acyltransferase assay

[1635] The enzymatic activity of ALCAT1 was determined by measuring the conversion of monolysocardiolipin (MLCL) to cardiolipin or lysophosphatidylglycerol (LPG) to phosphatidylglycerol (PG) in the enzyme reaction mixture containing 50 mM Tris / HCl, pH 7.0, 100 μM lysophospholipid, 25 μM 14 C] acyl-CoA (50 mCi / mmol, American Radiolabeled Chemicals, Inc) and the membrane fraction (0.5 - 2.5 μg) with 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 products using a Molecular Dynamics Typhoon scanner (Sunnyvale, CA). In some experiments, 100 μM of NBD-CoA was used in the enzymatic reaction to replace 14 C] acyl-coenzyme A. All quantitative data were expressed as mean ± S.E. The statistical analysis of the differences between two groups was performed using the Student's t-test.

[1636] Cell-based ALCAT1 inhibitor compound assay

[1637] Assays were performed on H9C2 vector cell lines and H9C2 with stable ALCAT1 overexpression. The 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.

[1638] Cells were seeded in 6-well plates at a density of 8×10 5 cells / well and cultured overnight at 37 °C in 5% CO 2 . Then the cells were pretreated with the selected compound (3 μM) for 1 hr and incubated for an additional 3 hr with coenzyme A (5 μM) and LPG (100 μM) with or without the selected compound (3 μM).

[1639] 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, vortexed to suspend the cells, and incubated at room temperature for 1 hr.

[1640] 40 μL of 0.9% KCl was added, and the samples were 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 TLC plates (10 cm × 20 cm) at 40 μL / sample.

[1641] The plates were developed in chloroform:methanol:water (65:25:4) for approximately 30 min and scanned using a Typhoon scanner. Band intensities were analyzed using ImageJ, and the inhibitory activity against the test compound was calculated.

[1642] Assay for ALCAT1 inhibitors

[1643] Compound inhibitors of the ALCAT1 enzyme were analyzed by the in vitro enzymatic assay described above. The compound inhibitor was added to the enzyme mixture at a concentration of 1 - 20 μM before the start of the acyltransferase reaction.

[1644] The results of the compounds of the present invention are shown in the table below, where the inhibition % of tests using the compounds at concentrations of 10 μM and 1 μM are provided. If multiple measurements were made, they are indicated by " / " between the multiple values.

[1645]

[1646]

[1647]

[1648] Cell-based ALCAT1 inhibitor assay

[1649] Analyze compound inhibitors of the ALCAT1 enzyme by the cell-based in vitro assay described above. The results are provided in the following table:

[1650]

[1651]

[1652] Some highly active ALCAT1 inhibitors were also subjected to IC 50 analysis. IC 50 is the drug concentration that causes 50% inhibition of the ALCAT1 enzyme activity. For the IC 50 analysis, chemical inhibitors of the ALCAT1 enzyme were added at various concentrations, which were 100 μM, 33 μM, 10 μM, 3.3 μM, 0.1 μM, 0.003 μM, and 0.001 μM, respectively. The IC 50 values of each compound were analyzed in triplicate and calculated by GraphPad software.

[1653] Using the above assay, the inhibition percentages and IC 50 values of several compounds and several reference compounds were determined. The results are summarized below.

[1654] The following compounds provided IC 50 values ≤ 100 nM (≤ 0.1 μM):

[1655] 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.

[1656] The following compounds provided IC 50 values < 35 nM (< 0.035 μM):

[1657] 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.

[1658] The following compounds provide an IC 50 value < 10 nM (< 0.01 μM): 222.

[1659] The following table shows the IC 50 results of some compounds of the present invention:

[1660]

[1661]

[1662] The disclosures of all references cited herein are hereby incorporated by cross-reference in their entirety as they may be used by those skilled in the art to implement the present invention.

[1663] In summary, the present invention includes but is not limited to the following items:

[1664] 1. A compound according to formula (I):

[1665]

[1666] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[1667] wherein:

[1668] X is selected from O and S;

[1669] G 1 and G 2 are each independently selected from N and CH;

[1670] A is selected from

[1671] H,

[1672] optionally substituted with one or more groups R A1 substituted C 1-6 linear or branched alkyl or alkenyl,

[1673] 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,

[1674] optionally substituted with one or more groups R B2 substituted 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S,

[1675] -CN,

[1676] -COOH, -COOR C1 -COR C2 -CONH 2 -CONHRD1 ,-CON(R D2 ) 2 ,

[1677] -NH 2 ,-NHR D4 ,-N(R D3 ) 2 ,-NHCOOH,-NHCOOR C1 ,-NHCOH,-NHCOR C2 ,-NR D6 COOH-NR D7 COOR C1 ,-NR D5 COR C2 , and

[1678] -SR E1 ;

[1679] L is a single bond, or the group L A ,

[1680] wherein L A is selected from

[1681] -NR L C(=O)-*, -C(=O)NR L- *,

[1682] -NR L C(=X L )NR L -*,

[1683] -SO 2 -NR L -*, -NR L -SO 2 -*,

[1684] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[1685] wherein the asterisk (*) represents the point of attachment to R 1 ;

[1686] X L is selected from O and S;

[1687] R L is selected from

[1688] -H,

[1689] -C(=O)(C 1-3 alkyl),

[1690] -P(=O)(OH) 2 , and

[1691] -S(=O) 2 NH 2 ;

[1692] When L is a single bond, R 1 is NH 2 ;

[1693] When L is L A , R 1 is R 1L , where R 1L is selected from

[1694] C 1-6 a straight-chain or branched unsubstituted alkyl group;

[1695] a phenyl group optionally substituted with one to three groups R PH ;

[1696] a 5- or 6-membered cycloalkyl group optionally substituted with one or more groups R B3 ;

[1697] a 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B4 , and

[1698] an 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B5 ;

[1699] where each R PH is independently selected from

[1700] a C A2 straight-chain or branched alkyl, alkenyl, or alkynyl group optionally substituted with one or more groups R 1-6 ;

[1701] a phenyl group optionally substituted with one or more groups R A3 ;

[1702] naphthyl;

[1703] -F, -Cl, -Br, -I,

[1704] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 )2 ,

[1705] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NR D5 COR C2 , -NHSO 2 (C 1-3 alkyl),

[1706] -SO 2 NH 2 , -SO 2 NHR D1 , -SO 2 N(R D2 ) 2 , -SO 2 R E2 , -SR E1 ,

[1707] -NO 2 ,

[1708] , -CN,

[1709] , -OH, and -OR PH4 ;

[1710] wherein R PH4 is selected from

[1711] phenyl,

[1712] benzyl, and

[1713] optionally substituted by one or more groups R A5 substituted C 1-6 linear or branched alkyl;

[1714] Q is selected from (Q1) and (Q2)

[1715]

[1716] wherein the two asterisks (**) represent the attachment points to L;

[1717] Q 1A , Q 2A , Q 3A and Q 4A in which two of them are CH;

[1718] Q 1A , Q 2A , Q 3A and Q 4A The other two are independently selected from N, CH and CR Q1 ;

[1719] Q 1B , Q 2B , Q 3B and Q 4B Both of them are CH.

[1720] Q 1B , Q 2B , Q 3B and Q 4B The other two are independently selected from N, CH and CR Q2 ;

[1721] Each R Q1 and each R Q2 Independently selected from

[1722] -F, -Cl, -Br, -I,

[1723] C 1-6 Straight-chain or branched unsubstituted alkyl,

[1724] -OH、-O(C 1-6 alkyl),

[1725] -CN, and

[1726] -N(R D3 ) 2 ;

[1727] R C1 and R C2 Each independently selected from

[1728] Optionally, one or more groups R A6 Substituted C 1-6 Straight or branched chain alkyl;

[1729] Optionally one or two groups R E3 substituted 5-membered heteroaryl containing a single heteroatom selected from N, O and S;

[1730] R D1 To R D7 Each independently selected from

[1731] Optionally, one or more groups R A7 Substituted C 1-6 Straight or branched alkyl group,

[1732] -COOH, -COORC1 、 -COR C2 ,

[1733] -C(=NH)NH 2 ,

[1734] or when two R D2 or two R D3 groups are attached to a single nitrogen atom, they may together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group containing 1-3 ring heteroatoms selected from N, O and S, optionally substituted by one or more groups R D9 ;

[1735] wherein R D9 is a C A8 straight-chain or branched-chain alkyl optionally substituted by one or more groups R 1-6 ;

[1736] R D8 is a C 5-6 heterocyclic group containing one or two N atoms, optionally substituted by one or more groups selected from the following:

[1737] -SH, and

[1738] -C(=O)OR D5A , wherein R D5A is a phenyl or benzyl optionally substituted by a NO 2 group;

[1739] R E1 and R E2 are each independently selected from C 1-6 straight-chain or branched-chain unsubstituted alkyl, alkenyl or alkynyl;

[1740] R E3 is independently selected from

[1741] -SH; and

[1742] -C(=O)OR E4 ;

[1743] R B1 to R B5 are each independently selected from

[1744] C A9 straight-chain or branched-chain alkyl optionally substituted by one or more groups R 1-6 ,

[1745] -F, -Cl, -Br,

[1746] -OH, -O(C 1-3 alkyl),

[1747] -CN,

[1748] -NO 2 ,

[1749] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[1750] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 ;

[1751] R E4 is independently selected from

[1752] phenyl or benzyl optionally substituted with one or two groups R A10 ;

[1753] R A1 to R A10 are each independently selected from

[1754] -F, -Cl, -Br,

[1755] -OH, -OR T

[1756] -CN, -NO 2 ,

[1757] -C(=O)R T , -COOH, -COOR T , -CON(R G ) 2 ,

[1758] -NH 2 , -NHR T , -N(R T ) 2 , -NHC(=O)(R F ) and -N(R D9 ) 2 ;

[1759] R F selected from

[1760] C 1-6 a straight-chain or branched unsubstituted alkyl group, and

[1761] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

[1762] the group -N(R G ) 2 is selected from azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-C 1-4 alkyl-piperazinyl, morpholinyl, aziridinyl, or diaziridinyl optionally substituted by one or more groups selected from straight-chain or branched C 1-4 alkyl groups, phenyl groups, or benzyl groups;

[1763] R T is a C 1-6 straight-chain or branched unsubstituted alkyl group;

[1764] two R D9 groups together with the nitrogen atom to which they are attached form a group selected from a 5-membered heteroaryl group containing one or two nitrogen atoms; and

[1765] a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S,

[1766] provided that the compound is not selected from any of the compounds (X1) to (X27):

[1767]

[1768]

[1769]

[1770] 2. The compound according to item 1, wherein X is O.

[1771] 3. The compound according to item 1 or 2, wherein G 1 and G 2 are both N.

[1772] 4. The compound according to any one of items 1 to 3, wherein A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted by one or more groups R B1 .

[1773] 5. The compound according to item 4, wherein A is optionally substituted by one or more groups R B1A substituted 5-membered heteroaryl containing a heteroatom selected from N, O, and S.

[1774] 6. The compound according to any one of items 1 to 5, wherein R B1 is selected from

[1775] optionally substituted by one or more groups R A9 substituted C 1-3 linear or branched alkyl,

[1776] -F, -Cl, -Br,

[1777] -CN,

[1778] -COR C2 、-CONH 2 、-CONHR D1 and -CON(R D2 ) 2 .

[1779] 7. The compound according to any one of items 1 to 6, wherein A is unsubstituted furan-2-yl.

[1780] 8. The compound according to any one of items 1 to 7, wherein L is L A and R 1L is selected from

[1781] optionally substituted by one to three groups R PH substituted phenyl,

[1782] optionally substituted by one or more groups R B3 substituted 5- or 6-membered cycloalkyl,

[1783] optionally substituted by one or more groups R B4 substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and

[1784] optionally substituted by one or more groups R B5 substituted 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O, and S.

[1785] 9. The compound according to any one of items 1 to 8, wherein L is -NHC(=O)-* or -C(=O)NH-*.

[1786] 10. The compound according to item 9, wherein L is -NHC(=O)-*.

[1787] 11. The compound according to any one of items 1 to 10, wherein R 1L is selected from

[1788] Phenyl substituted by one to three groups R PH Substituted phenyl,

[1789] Optionally substituted 5- or 6-membered cycloalkyl by one or more groups R B3 Substituted 5- or 6-membered cycloalkyl,

[1790] Optionally substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O and S by one or more groups R B4 Substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O and S, and

[1791] Optionally substituted 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O and S by one or more groups R B5 Substituted 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O and S.

[1792] 12. The compound according to any one of items 1 to 11, wherein L is L A And R 1L Is phenyl substituted by one or more groups R PH Substituted phenyl.

[1793] 13. The compound according to item 12, wherein R PH Is selected from

[1794] Optionally substituted C A2 Straight-chain or branched-chain alkyl by one or more groups R 1-4 Substituted straight-chain or branched-chain alkyl,

[1795] Optionally substituted C A2 Alkenyl or alkynyl by one or more groups R 2-3 Substituted alkenyl or alkynyl,

[1796] Optionally substituted phenyl by one or more groups R A3 Substituted phenyl,

[1797] -F, -Cl, -Br, -I,

[1798] -COOH, -COOMe, -COMe, -CONH 2 Substituted, -CONHMe, -CONMe 2 Substituted,

[1799] -NH 2 Substituted, -NHMe, -NHAc-NHR D8 Substituted, -NMe 2 Substituted, -NHSO 2 Substituted Me,

[1800] -SO 2 NH 2 Substituted, -SO 2 Substituted Me, -SMe,

[1801] -NO2 ,

[1802] -CN,

[1803] -OH and -OR PH4 .

[1804] 14. A compound according to item 12 or 13, wherein R 1L is

[1805]

[1806] wherein one of Y 1 , Y 2 and Y 3 is CR Y ; a second one of Y 1 , Y 2 and Y 3 is independently selected from CR Y and CH; and a third one of Y 1 , Y 2 and Y 3 is independently selected from CR Y and CH;

[1807] wherein each R Y is independently selected from

[1808] linear or branched unsubstituted C 1-6 alkyl,

[1809] -OR Y1 ;

[1810] -F, -Cl, -Br, -I,

[1811] -CF 3 , -CH 2 F, -CF 2 H,

[1812] -CH 2 CF 3 , -CH 2 CH 2 F and -CH 2 CF 2 H.

[1813] 15. A compound according to item 14, wherein Y 2 is CH, and each of Y 1 and Y 3 is independently CR Y .

[1814] 16. A compound according to any one of items 1 to 15, wherein Q is (Q1).

[1815] 17. The compound according to item 16, wherein Q 1A , Q 3A and Q 4A are each CH and Q 2A is selected from N, CH, and CR Q1 .

[1816] 18. The compound according to item 17, wherein Q 2A is selected from CH and CR Q1 .

[1817] 19. The compound according to any one of the preceding items, wherein R Q1 is F.

[1818] 20. The compound according to any one of items 1 to 19, wherein:

[1819] X is O;

[1820] G 1 and G 2 are both N;

[1821] A is a 5-membered heteroaryl including one oxygen atom and one or two nitrogen atoms, optionally substituted by one or more groups R B1 ;

[1822] Q is (Q1), and R Q1 is selected from F, Cl, and Br;

[1823] L is -NHC(=O)-* or -C(=O)NH-*;

[1824] R 1 is R 1L , and R 1L is a phenyl substituted at the ortho position by a group selected from

[1825] optionally substituted by one or more groups R A2 C 1-6 straight-chain or branched-chain alkyl, alkenyl, or alkynyl,

[1826] -F, -Cl, -Br, -I,

[1827] -OH, and -OR PH4 ,

[1828] and is optionally further substituted at another ring position by a group selected from

[1829] optionally substituted by one or more groups R A2 C 1-6 straight-chain or branched-chain alkyl, alkenyl, or alkynyl,

[1830] -F, -Cl, -Br, -I,

[1831] -OH, and -OR PH4 .

[1832] 21. The compound according to any one of items 1 to 20, wherein the compound is selected from the compounds according to formula (IA):

[1833]

[1834] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[1835] wherein

[1836] L B is selected from

[1837] -NR L1 C(=O)-*, -C(=O)NR L1 -*,

[1838] -NR L1 C(=X L1 )NR L1 -*,

[1839] -SO 2 -NR L1 -*, -NR L1 -SO 2 -*,

[1840] -OC(=O)-NR L1 -*, and -NR L1 -C(=O)O-*;

[1841] wherein the asterisk (*) represents the point of attachment to the terminal phenyl;

[1842] X L1 is selected from O and S;

[1843] R L1 is selected from

[1844] -H,

[1845] -C(=O)(C 1-3 alkyl),

[1846] -P(=O)(OH) 2 , and

[1847] -S(=O) 2 NH 2 ;

[1848] Y 1 、Y2 and Y 3 one of them is CR Y ;

[1849] Y 1 、Y 2 and Y 3 the second one of them is independently selected from CR Y and CH; and

[1850] Y 1 ,Y 2 and Y 3 the third one of them is independently selected from CR Y and CH;

[1851] Q 5A 、Q 6A and Q 7A one of them is selected from N and CH; and

[1852] Q 5A 、Q 6A and Q 7A the other two of them are each independently selected from CH and CR Q3 ;

[1853] where each R Y is independently selected from

[1854] linear or branched unsubstituted C 1-6 alkyl,

[1855] -OR Y1 ;

[1856] -F, -Cl, -Br, -I,

[1857] -CF 3 、-CH 2 F, -CF 2 H,

[1858] -(CH 2 ) n N(R N1 ) 2 ,

[1859] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H;

[1860] wherein, in the group -N(R N1 ) 2 the N atom and the two Rs attached thereto N1The group forms a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S;

[1861] n is an integer selected from 1, 2, or 3;

[1862] wherein R Y1 is selected from

[1863] unsubstituted C 1-6 alkyl,

[1864] -CF 3 、-CH 2 F, -CF 2 H,

[1865] -(CH 2 ) m N(R N2 ) 2 ,

[1866] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H;

[1867] wherein, in the group -N(R N2 ) 2 , the N atom and the two R N2 groups to which it is attached form a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S;

[1868] m is an integer selected from 1, 2, and 3;

[1869] R Q3 is selected from

[1870] -F, -Cl, -Br, -I,

[1871] C 1-6 unsubstituted linear or branched alkyl,

[1872] -OH, -O(C 1-6 alkyl), and

[1873] -CN.

[1874] 22. The compound according to item 21, wherein L B is selected from -NHC(=O)-* and -C(=O)NH-*.

[1875] 23. The compound according to item 21 or 22, wherein Y 1 is CR Yand Y 2 and Y 3 each of which is selected from CH and CR Y .

[1876] 24. The compound according to item 23, wherein Y 2 and Y 3 are both CH.

[1877] 25. The compound according to item 23, wherein Y 2 and Y 3 one of which is CH and the other is CR Y .

[1878] 26. The compound according to item 25, wherein Y 2 is CH and Y 3 is CR Y .

[1879] 27. The compound according to any one of items 21 to 26, wherein Q 5A , Q 6A and Q 7A are each CH.

[1880] 28. The compound according to any one of items 21 to 26, wherein Q 5A and Q 6A one of which is CR Q3 , the other is CH, and Q 7A is CH.

[1881] 29. The compound according to any one of items 21 to 26, wherein Q 6A and Q 7A one of which is N and the other is CH, and Q 5A is CH.

[1882] 30. The compound according to any one of items 21 to 28, wherein R Q3 is selected from -F, -Cl, -Br and -I.

[1883] 31. The compound according to item 30, wherein R Q3 is -F.

[1884] 32. The compound according to any one of items 1 to 31, the compound is selected from

[1885]

[1886]

[1887]

[1888]

[1889]

[1890] 33. The compound according to item 32, wherein the compound is selected from

[1891]

[1892]

[1893]

[1894] 34. The compound according to any one of items 1 to 20, wherein

[1895] R L is selected from

[1896] -H, and -C(=O)(C 1-3 alkyl);

[1897] and in the -N(R D9 ) 2 group, the two R D9 groups together with the nitrogen atom to which they are attached form a 5-membered heteroaryl containing one or two nitrogen atoms.

[1898] 35. The compound according to any one of items 21 to 31, wherein

[1899] R L1 is selected from -H and -C(=O)(C 1-3 alkyl);

[1900] Each R Y is independently selected from

[1901] linear or branched unsubstituted C 1-6 alkyl,

[1902] -OR Y1 ;

[1903] -F, -Cl, -Br, -I,

[1904] -CF 3 、-CH 2 F, -CF 2 H,

[1905] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H; and

[1906] R Y1 selected from

[1907] unsubstituted straight-chain or branched C 1-6 alkyl,

[1908] -CF 3 、-CH 2 F, -CF 2 H,

[1909] -CH 2 CF 3 、-CH 2 CH 2 F and -CH 2 CF 2 H.

[1910] 36. A composition comprising a compound according to any one of items 1 to 35 and a pharmaceutically acceptable carrier, diluent or excipient.

[1911] 37. A method for preparing a pharmaceutical composition, the method comprising mixing a compound according to any one of items 1 to 35 with a pharmaceutically acceptable carrier, diluent or excipient.

[1912] 38. A compound according to any one of items 1 to 35 or a composition according to item 36, the compound or composition for treating a human or animal body by therapy.

[1913] 39. A compound according to formula (I):

[1914]

[1915] or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is used for treating a human or animal body by therapy,

[1916] wherein:

[1917] X is selected from O and S;

[1918] G 1 and G 2 are each independently selected from N and CH;

[1919] A is selected from

[1920] H,

[1921] optionally substituted with one or more groups R A1 substituted C 1-6 straight-chain or branched alkyl or alkenyl,

[1922] optionally substituted with one or more groups R B1A 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S,

[1923] optionally substituted by one or more groups R B2 A 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S,

[1924] -CN,

[1925] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[1926] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , -NR D5 COR C2 , and

[1927] -SR E1 ;

[1928] L is a single bond, or the group L A ,

[1929] wherein L A is selected from

[1930] -NR L C(=O)-*, -C(=O)NR L- *,

[1931] -NR L C(=X L )NR L -*,

[1932] -SO 2 -NR L -*, -NR L -SO 2 -*,

[1933] -OC(=O)-NR L -*, and -NR L -C(=O)O-*;

[1934] wherein the asterisk (*) represents the connection point with R 1 ;

[1935] X L is selected from O and S;

[1936] R L is selected from

[1937] -H,

[1938] -C(=O)(C 1-3 alkyl),

[1939] -P(=O)(OH) 2 , and

[1940] -S(=O) 2 NH 2 ;

[1941] When L is a single bond, R 1 is NH 2 ;

[1942] When L is L A , R 1 is R 1L , where R 1L is selected from

[1943] C 1-6 linear or branched unsubstituted alkyl;

[1944] optionally substituted by one to three groups R PH substituted phenyl,

[1945] optionally substituted by one or more groups R B3 substituted 5- or 6-membered cycloalkyl,

[1946] optionally substituted by one or more groups R B4 substituted 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O and S, and

[1947] optionally substituted by one or more groups R B5 substituted 8- to 10-membered bicyclic or heterobicyclic group containing 1-3 heteroatoms selected from N, O and S;

[1948] where each R PH is independently selected from

[1949] optionally substituted by one or more groups R A2 substituted C 1-6 linear or branched alkyl, alkenyl or alkynyl,

[1950] optionally substituted by one or more groups RA3 Substituted phenyl

[1951] Naphthyl

[1952] -F, -Cl, -Br, -I

[1953] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[1954] -NH 2 , -NHR D4 , -NHR D8 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOH, -NHCOR C2 , -NR D7 COOR C1 , -NR D5 COR C2 , -NHSO 2 (C 1-3 alkyl)

[1955] -SO 2 NH 2 , -SO 2 NHR D1 , -SO 2 N(R D2 ) 2 , -SO 2 R E2 , -SR E1 ,

[1956] -NO 2 ,

[1957] , -CN

[1958] , -OH, and -OR PH4 ;

[1959] wherein R PH4 is selected from

[1960] phenyl

[1961] benzyl, and

[1962] optionally substituted with one or more groups R A5 substituted C 1-6Straight-chain or branched-chain alkyl;

[1963] Q is selected from (Q1) and (Q2)

[1964]

[1965] wherein the two asterisks (**) represent the connection points to L;

[1966] Q 1A , Q 2A , Q 3A and Q 4A are CH;

[1967] Q 1A , Q 2A , Q 3A and Q 4A are independently selected from N, CH, and CR Q1 ;

[1968] Q 1B , Q 2B , Q 3B and Q 4B are CH.

[1969] Q 1B , Q 2B , Q 3B and Q 4B are independently selected from N, CH, and CR Q2 ;

[1970] Each R Q1 and each R Q2 are independently selected from

[1971] -F, -Cl, -Br, -I,

[1972] C 1-6 Straight-chain or branched-chain unsubstituted alkyl,

[1973] -OH, -O(C 1-6 alkyl),

[1974] -CN, and

[1975] -N(R D3 ) 2 ;

[1976] R C1 and R C2 are each independently selected from

[1977] Optionally substituted by one or more groups R A6 substituted C 1-6 Straight-chain or branched-chain alkyl;

[1978] Optionally substituted by one or two groups R E3 A 5-membered heteroaryl containing a single heteroatom selected from N, O, and S;

[1979] R D1 to R D7 Each independently selected from

[1980] Optionally substituted by one or more groups R A7 C 1-6 A straight-chain or branched alkyl,

[1981] -COOH, -COOR C1 , -COR C2 ,

[1982] -C(=NH)NH 2 ,

[1983] Or when two R D2 or two R D3 groups are attached to a single nitrogen atom, they may together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group containing 1-3 ring heteroatoms selected from N, O, and S, optionally substituted by one or more groups R D9 ;

[1984] Wherein R D9 is a C A8 straight-chain or branched alkyl optionally substituted by one or more groups R 1-6 ;

[1985] R D8 is a C 5-6 heterocyclic group containing one or two N atoms, optionally substituted by one or more groups selected from the following:

[1986] -SH, and

[1987] -C(=O)OR D5A , wherein R D5A is a phenyl or benzyl optionally substituted by NO 2 groups;

[1988] R E1 and R E2 each independently selected from C 1-6 straight-chain or branched unsubstituted alkyl, alkenyl or alkynyl;

[1989] R E3 independently selected from

[1990] -SH; and

[1991] -C(=O)OR E4 ;

[1992] R B1 to R B5 each independently selected from

[1993] optionally substituted with one or more groups R A9 of a C 1-6 straight-chain or branched alkyl group,

[1994] -F, -Cl, -Br,

[1995] -OH, -O(C 1-3 alkyl),

[1996] -CN,

[1997] -NO 2 ,

[1998] -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 ,

[1999] -NH 2 , -NHR D4 , -N(R D3 ) 2 , -NHCOOH, -NHCOOR C1 , -NHCOR C2 , -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 ;

[2000] R E4 is independently selected from

[2001] a phenyl or benzyl group optionally substituted with one or two groups R A10 ;

[2002] R A1 to R A10 each independently selected from

[2003] -F, -Cl, -Br,

[2004] -OH, -OR T

[2005] -CN, -NO 2 ,

[2006] -C(=O)R T, -COOH, -COOR T , -CON(R G ) 2 ,

[2007] -NH 2 , -NHR T , -N(R T ) 2 , -NHC(=O)(R F ) and -N(R D9 ) 2 ;

[2008] R F is selected from

[2009] C 1-6 a straight-chain or branched unsubstituted alkyl group, and

[2010] a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

[2011] The group -N(R G ) 2 is selected from azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-C 1-4 alkyl-piperazinyl, morpholinyl, aziridinyl, or diaziridinyl optionally substituted by one or more groups selected from straight-chain or branched C 1-4 alkyl, phenyl, or benzyl;

[2012] R T is a C 1-6 straight-chain or branched unsubstituted alkyl group; and

[2013] The two R D9 groups together with the nitrogen atom to which they are attached form a group selected from

[2014] a 5-membered heteroaryl group containing one or two nitrogen atoms; and

[2015] a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O, and S.

[2016] 40. The compound used according to item 39, wherein

[2017] R L is selected from

[2018] -H, and -C(=O)(C 1-3 alkyl);

[2019] And in the -N(R D9 ) 2 group, the two R D9The groups, together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl containing one or two nitrogen atoms.

[2020] 41. The compound or composition used according to item 38, 39 or 40, wherein the treatment is the prevention or treatment of aging or age-related diseases.

[2021] 42. The compound or composition used according to item 38, 39 or 40, wherein the treatment is the treatment of a disease characterized by one or more of oxidative stress, CL deficiency, enrichment of docosahexaenoic acid (DHA) in CL, and mitochondrial dysfunction.

[2022] 43. The compound or composition used according to item 38, 39 or 40, wherein the treatment is the treatment of a disease related to mitochondrial dysfunction.

[2023] 44. The compound or composition used according to item 38, 39 or 40, wherein the treatment is the treatment of a disease selected from the following: 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 tolerance, and cancer.

[2024] 45. The compound or composition used according to item 38, 39 or 40, wherein the treatment is the treatment of a disease selected from stroke, ischemia, and reperfusion injury.

[2025] 46. Use of the compound according to any one of items 1 to 35 in the preparation of a medicament for the treatment of aging or age-related diseases.

[2026] 47. A treatment method, which includes administering a therapeutically effective amount of the compound according to any one of items 1 to 35 or the composition according to item 36 to a patient in need of treatment.

[2027] 48. A method for treating aging or age-related diseases, which includes administering a therapeutically effective amount of the compound according to any one of items 1 to 35 or the composition according to item 36 to a patient in need of treatment.

[2028] 49. A method for treating a disease selected from stroke, ischemia, and reperfusion injury, which includes administering a therapeutically effective amount of the compound according to any one of items 1 to 35 or the composition according to item 36 to a patient in need of treatment.

Claims

1. A compound according to formula (I): or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: X is selected from O and S; G 1 and G 2 each independently selected from N and CH; A is selected from H， Optionally substituted by one or more groups R A1 substituted C 1-6 a straight-chain or branched alkyl or alkenyl group Optionally substituted by one or more groups R B1 A 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, substituted Optionally substituted by one or more groups R B2 A 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, -CN, -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 , -NH 2 、 -NHR D4 、 -N(R D3 ) 2 、 -NHCOOH, -NHCOOR C1 、 -NHCOH, -NHCOR C2 、 -NR D6 COOH - NR D7 COOR C1 、 -NR D5 COR C2 , and -SR E1 ; L is a single bond or the group L A , where L A selected from -NR L C(=O)-*, -C(=O)NR L- *, -NR L C(=X L )NR L -*, -SO 2 -NR L -*, -NR L -SO 2 -*, -OC(=O)-NR L -*, and -NR L -C(=O)O-*; where the asterisk (*) indicates the connection point with R 1 ; X L Selected from O and S; R L Selected from -H， -C(=O)(C 1-3 alkyl), -P(=O)(OH) 2 , and -S(=O) 2 NH 2 ; When L is a single bond, R 1 is NH 2 ; When L is L A , R 1 is R 1L , where R 1L is selected from C 1-6 An unsubstituted alkyl group which is straight-chain or branched-chain; Optionally substituted by one to three groups R PH substituted phenyl group, Optionally substituted by one or more groups R B3 A 5- or 6-membered cycloalkyl group Optionally substituted by one or more groups R B4 a 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O and S, and Optionally substituted by one or more groups R B5 An 8- to 10-membered bicyclic or heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, and S, which is substituted where each R PH is independently selected from Optionally substituted by one or more groups R A2 substituted C 1-6 a straight-chain or branched alkyl, alkenyl or alkynyl group Optionally substituted by one or more groups R A3 substituted phenyl, naphthyl, -F, -Cl, -Br, -I, -COOH, -COOR C1 , -COR C2 , -CONH 2 , -COONH 2 , -CONHR D1 , -CON(R D2 ) 2 , -NH 2 、 -NHR D4 、 -NHR D8 、 -N(R D3 ) 2 、 -NHCOOH, -NHCOOR C1 、 -NHCOH, -NHCOR C2 、 -NR D7 COOR C1 、 -NR D5 COR C2 、 -NHSO 2 (C 1-3 alkyl), -SO 2 NH 2 、 -SO 2 NHR D1 、 -SO 2 N(R D2 ) 2 、 -SO 2 R E2 、 -SR E1 , -NO 2 , -CN, -OH, and -OR PH4 ; wherein R PH4 is selected from phenyl, benzyl, and Optionally substituted by one or more groups R A5 substituted C 1-6 straight-chain or branched alkyl; Q is selected from (Q1) and (Q2) wherein the two asterisks (**) represent the point of attachment to L; Q 1A , Q 2A , Q 3A and Q 4A Two of them are CH; Q 1A and Q 2A and Q 3A and Q 4A and the other two of Q Q1 Q1 are independently selected from N, CH, and CR 1B ; two of Q 2B 2B and Q 3B 3B and Q 4B 4B are CH Q 1B and Q 2B and Q 3B and Q 4B and the other two of Q are independently selected from N, CH, and CR Q2 ; each R Q1 and each R Q2 is independently selected from -F, -Cl, -Br, -I, C 1-6 a straight-chain or branched unsubstituted alkyl group -OH, -O(C 1-6 alkyl), -CN, and -N(R D3 ) 2 ; R C1 and R C2 each independently selected from Optionally substituted by one or more groups R A6 substituted C 1-6 straight-chain or branched alkyl; Optionally substituted by one or two groups R E3 A 5-membered heteroaryl containing a single heteroatom selected from N, O, and S, which is substituted R D1 to R D7 each independently selected from Optionally substituted by one or more groups R A7 a C 1-6 linear or branched alkyl group, -COOH, -COOR C1 , -COR C2 , -C(=NH)NH 2 , or when two Rs D2 or two Rs D3 groups are attached to a single nitrogen atom, they may together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group optionally substituted by one or more groups R D9 and containing 1-3 ring heteroatoms selected from N, O and S; wherein R D9 is an optionally C A8 straight-chain or branched-chain alkyl group which is substituted by one or more groups R 1-6 groups; R D8 is a C containing one or two N atoms optionally substituted by one or more groups selected from the following 5-6 heterocyclic group: -SH, and -C(=O)OR D5A , wherein R D5A is phenyl or benzyl optionally substituted with a NO 2 group; R E1 and R E2 each independently selected from C 1-6 a straight-chain or branched unsubstituted alkyl, alkenyl or alkynyl; R E3 independently selected from -SH; and -C(=O)OR E4 ; R B1 to R B5 each independently selected from Optionally substituted by one or more groups R A9 A C 1-6 Straight-chain or branched-chain alkyl group -F, -Cl, -Br, -OH, -O(C 1-3 alkyl), -CN, -NO 2 , -COOH, -COOR C1 , -COR C2 , -CONH 2 , -CONHR D1 , -CON(R D2 ) 2 , -NH 2 、 -NHR D4 、 -N(R D3 ) 2 、 -NHCOOH, -NHCOOR C1 、 -NHCOR C2 、 -NR D6 COOH - NR D7 COOR C1 , and -NR D5 COR C2 ; R E4 independently selected from Optionally substituted by one or two groups R A10 Substituted phenyl or benzyl; R A1 to R A10 each independently selected from -F, -Cl, -Br, -OH, -OR T -CN, -NO 2 , -C(=O)R T 、 -COOH, -COOR T 、 -CON(R G ) 2 , -NH 2 、-NHR T 、-N(R T ) 2 、-NHC(=O)(R F ) and -N(R D9 ) 2 ; R F selected from C 1-6 Straight-chain or branched unsubstituted alkyl, and a 5- to 6-membered heteroaryl containing 1 - 3 heteroatoms selected from N, O and S; The group -N(R G ) 2 is selected from azetidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-C 1-4 alkyl-piperazinyl, morpholinyl, aza or diaza groups optionally substituted by one or more groups selected from straight-chain or branched C 1-4 alkyl, phenyl or benzyl; R T is C 1-6 a straight-chain or branched-chain unsubstituted alkyl group; Two Rs D9 The two R groups, together with the nitrogen atom to which they are attached, form a group selected from: a 5-membered heteroaryl group containing one or two nitrogen atoms; and a 6-membered heterocyclic group containing one or two heteroatoms each independently selected from N, O and S, provided that the compound is not selected from any one of compounds (X1) to (X27):

2. The compound according to claim 1, wherein X is O.

3. The compound according to claim 1 or 2, wherein G 1 and G 2 are both N.

4. The compound according to any one of claims 1 to 3, wherein A is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more groups R B1 and substituted with one or more groups R 5. The compound according to claim 4, wherein A is a 5-membered heteroaryl containing a heteroatom selected from N, O, and S and optionally substituted by one or more groups R B1 substituted.

6. The compound according to any one of claims 1 to 5, wherein R B1 is selected from C A9 straight-chain or branched-chain alkyl optionally substituted with one or more groups R 1-3 and is optionally substituted with one or more groups R -F, -Cl, -Br, -CN, -COR C2 、-CONH 2 ,-CONHR D1 and-CON(R D2 ) 2 .

7. The compound according to any one of claims 1 to 6, wherein A is unsubstituted furan-2-yl.

8. A compound according to any one of claims 1 to 7, wherein L is L A and R 1L is selected from Optionally substituted by one to three groups R PH substituted phenyl, Optionally substituted by one or more groups R B3 A 5- or 6-membered cycloalkyl group Optionally substituted by one or more groups R B4 A 5- or 6-membered heteroaryl or heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and Optionally substituted by one or more groups R B5 An 8- to 10-membered bicyclic or heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, and S, which is substituted.

9. The compound according to any one of claims 1 to 8, wherein L is -NHC(=O)-* or -C(=O)NH-*.

10. The compound according to claim 9, wherein L is -NHC(=O)-*.

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