CN108727250A - Piperidines AMPK agonists and its medical usage - Google Patents

Abstract

The invention discloses a kind of piperidines with AMPK agonist activities and preparation method thereof and medical usages, are structural formula such as formula (I) compound represented, its pharmaceutically acceptable salt or ester or prodrug or N- oxides or solvate.Structure such as formula (I) compound represented of the present invention may activate AMPK signal paths by activating adiponectin receptors, thus can be used for preparing the drug for preventing or treating the disease that AMPK is mediated.

Description

Piperidine AMPK agonist and its medical application

technical field

The invention relates to the field of biomedicine, in particular to a piperidine compound with AMPK agonist activity, and also relates to a preparation method of the compound and its medical use as an AMPK agonist.

This patent application claims the priority of the Chinese patent application (application number 201710269119.2, application date: April 18, 2017, name of invention: piperidine compounds with AMPK activation, its preparation method and medical use).

Background technique

AMPK (adenylate-activated protein kinase) is a key kinase that regulates energy metabolism and inflammatory responses in the body. Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood lipids (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammation, and anti-apoptosis. Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor, etc. (Physiol. Rev. 2009, 89, 1025). However, few AMPK agonists in the pipeline have entered clinical studies due to safety or efficacy reasons. For example, although the broad-spectrum AMPK-β subunit agonist MK-8722 can lower blood sugar, it was found in rats and monkeys that the side effects of irreversible cardiac hypertrophy occurred in the animal heart (Science 2017, 357, 507). The selective AMPK-β1 subunit agonist PF-249 only lowers blood lipids, but does not have hypoglycemic activity (CellMetab. 2017, 25, 1147).

On the other hand, adiponectin is an important cytokine secreted by adipocytes, which activates the AMPK signaling pathway by activating adiponectin receptor 1 (AdipoR1) (Nat. Med. 2002, 8, 1288). Studies have found that small-molecule adiponectin receptor agonists can well simulate the biological effects of adiponectin in vivo, improve insulin resistance, lower blood sugar, and prolong the lifespan of mice fed a high-fat diet (Nature2013, 503, 493). However, so far no small molecule adiponectin receptor agonists have entered the clinical research stage.

In summary, there is an urgent need to develop new AMPK agonists with high activity and less toxic side effects in clinical practice.

Contents of the invention

The object of the present invention is to provide a piperidine compound with AMPK agonistic activity.

Another object of the present invention is to provide the medical use of the piperidine compound as an AMPK agonist. The compounds have significant agonistic activity on AMPK at the biochemical and cellular levels in vitro, and may activate the AMPK signaling pathway by activating adiponectin receptors, and thus can be used to prepare drugs for preventing or treating various diseases mediated by AMPK.

For realizing the purpose, technical scheme of the present invention is as follows:

The compound represented by the following formula (I) described in the present invention, its pharmaceutically acceptable salt or ester or solvate:

Wherein, R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S(O) ₂ R, C(O)R, C( O)OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO )R, NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO)N(R) ₂ , NR(CO)NHR, NR(CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR , NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C(NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or, every two of R ¹ , R ² and R ³ together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted or, each two of R ⁶ , R ⁷ and R ⁸ together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted Substituted cycloalkane ring, substituted or unsubstituted heterocycloalkane ring or substituted or unsubstituted heterocycloalkene ring; wherein, the substituents are selected from: F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, OR, COOH, COOR, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ;

R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl, or alkynyl; wherein the phenyl is unfused or ^R9 is fused, ^R9 is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is ^unfused or fused with R10, ^R10 is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is ^unfused or fused with R, R ¹¹ is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said alkyl, alkenyl or alkynyl is unsubstituted or replaced by one or two or three independently Substituted by a substituent selected from the group consisting of: R ¹² , OH, (O), C(O)OH, CN, NH ₂ , F, Cl, Br, I, CF ₃ , CF ₂ CF ₃ , NC(R ¹³ ) (R ¹⁴ ), R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O) NH ₂ , C(O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ or NHC( O)CH( _CH3 )NHC(O)-CH( _CH3 ) ^NHR15 ;

R ¹² is a spiroalkyl group of 2 to 5 carbons, each of which is unsubstituted or replaced by OH, (O), CN, NH ₂ , F, Cl, Br, I, CF ₃ , CF ₂ CF ₃ , NH (CH ₃ ) or N(CH ₃ ) ₂ substitution;

R ¹³ and R ¹⁴ are independently selected alkyl groups, or together with the N to which they are attached are aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine- 1-radicals, each having a _CH moiety that is unsubstituted or replaced by O, C(O), CNOH, CNOCH ₃ , S, S(O), S(O) ₂ or NH;

^R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl or alkynyl; wherein the phenyl is unfused or R ¹⁶ is fused, R ¹⁶ is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is unfused or fused with R ¹⁷ , R ¹⁷ is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unfused or fused with R ¹⁸ , R ¹⁸ is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said alkyl, alkenyl or alkynyl is unsubstituted or replaced by one or two or three independently Substituents selected from the following substituents: R ¹⁹ , OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S(O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC(O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O) OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, Cl, Br, I, _CF3 or _{CF2CF3 ;}

R ¹⁹ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl or alkynyl; wherein the phenyl is unfused or with R ²⁰ is fused, R ²⁰ is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is unfused or fused with R ²¹ , R ²¹ is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is ^unfused or fused with R, R ²² is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

n=0～10;

R ⁴ and R ⁵ are each H, F, or an alkyl group of 1 to 6 carbons; or, R ⁴ and R ⁵ together with the atoms they are connected to form a substituted or unsubstituted cycloalkane ring, substituted or unsubstituted Heterocycloalkane rings or substituted or unsubstituted heterocycloalkene rings;

X is S(O) ₂ , C(O) or CH ₂ ;

P, Q, W, Y and Z are each CH, N or C substituted by one of R6, ^R7 and ^R8 , and at least ^three of P, Q, W, Y and Z are not N;

R' is H, F, OH, CN, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ or an alkyl group with 1 to 6 carbons, and R' can be in the α of the 4-amino group in the piperidine ring and when R' is other than H, the compound may be a diastereomer or a mixture of enantiomers or a diastereomer and/or enantiomer provided in an enriched form.

In certain embodiments, the diastereomeric enriched form of the compound of the present invention is reflected in a diastereomeric excess (de) of 70-100%, preferably 90-100%, more preferably It is 95～100%, most preferably 98～100%; The enriched form of its enantiomer of the compound of the present invention is reflected in enantiomeric excess (enantiomeric excess, ee) is 70～100%, preferably 90～ 100%, more preferably 95-100%, most preferably 98-100%.

In certain embodiments, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof:

R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S(O) ₂ R, C(O)R, C(O) OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO)R , NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO)N(R) ₂ , NR(CO)NHR, NR( CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR, NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C(NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or, each of R ¹ , R ² and R ³ is combined with The atoms to which they are attached together form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring ^; or, each of R6, ^R7 and ^R8 forms a substituted or Or unsubstituted benzene ring or substituted or unsubstituted heteroaryl ring; wherein, the substituent is selected from: F, Cl, Br, CN, OR, COOH, COOR, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ;

R is phenyl, heteroaryl or alkyl; wherein said alkyl is unsubstituted or substituted by one, two or three substituents independently selected from: OH, F, CF ₃ , CF ₂ CF ₃ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O)NH ₂ , C (O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ or NHC(O)CH( _CH3 )NHC(O)CH( _CH3 ) ^NHR15 ;

R ¹⁵ is an alkyl group, and the alkyl group is unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S( O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC( O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O)OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O) )NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, CF ₃ or CF ₂ CF ₃ ; wherein R ¹⁹ is an alkyl group;

n=0～6;

R ⁴ and R ⁵ are each H, F or methyl;

X is S(O) ₂ , C(O) or CH ₂ ;

P, Q, W, Y and Z are each CH, N or C substituted by one of ^R6 , ^R7 and ^R8 , and at least four of P, Q, W, Y and Z are not N;

R' is H, F or an alkyl group with 1 to 6 carbons, and R' can be substituted on the alpha carbon or beta carbon of the 4-amino group in the piperidine ring; and when R' is not H, the compound It may be provided as a mixture of diastereomers or enantiomers or as an enriched form of diastereomers and/or enantiomers.

In certain embodiments, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof:

R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S(O) ₂ R, C(O)R, C(O) OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO)R , NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO)N(R) ₂ , NR(CO)NHR, NR( CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR, NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C(NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or, each of R ¹ , R ² and R ³ is combined with The atoms to which they are attached together form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaryl ring ^; or, each of R6, ^R7 and ^R8 forms a substituted or Or unsubstituted benzene ring or substituted or unsubstituted heteroaryl ring; wherein, the substituent is selected from: F, Cl, Br, CN, OR, COOH, COOR, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ;

R is phenyl, heteroaryl or alkyl; wherein said alkyl is unsubstituted or substituted by one, two or three substituents independently selected from: OH, F, CF ₃ , CF ₂ CF ₃ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O)NH ₂ , C (O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ ;

R ¹⁵ is an alkyl group, and the alkyl group is unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S( O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC( O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O)OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O) )NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, CF ₃ or CF ₂ CF ₃ ; wherein R ¹⁹ is an alkyl group;

n=0～5;

R ⁴ and R ⁵ are each H or methyl;

X is S(O) ₂ , C(O) or CH ₂ ;

P, Q, W, Y and Z are each CH, N or C substituted by one of ^R6 , ^R7 and ^R8 , and at least four of P, Q, W, Y and Z are not N;

R' is H, F or methyl, and R' may be substituted on the α-carbon or β-carbon of the 4-amino group in the piperidine ring; Mixtures of enantiomers or enantiomers or diastereoisomers and/or enantiomer enriched forms. In certain embodiments, the compounds have a diastereomeric purity of greater than 98%. For example, the compound may be a diastereomerically pure cis compound or a diastereomerically pure trans compound. In certain embodiments, the compounds have an enantiomeric purity of greater than 98%.

In certain embodiments, the compound of the present invention is a compound shown in Table 1 or a pharmaceutically acceptable salt or ester or solvate thereof:

Table 1. Structure and naming of compounds

The compounds of the present invention are also available as pharmaceutically acceptable salts. The salt may be a salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphate, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, niacin, nitric acid, orotic acid, oxalic acid, bitters Acid, L-pyroglutamic acid, saccharic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-Benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, Camphoric Acid, Camphorsulfonic Acid, Dichloroacetic Acid, Ethanesulfonic Acid. On the other hand, the salt can also be a salt formed between the compound of the present invention and metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.) or ammonium ions . For example, compound 239 can be prepared as a sodium salt (compound 596).

The compounds of the present invention may also be formulated into pharmaceutical compositions in the form of esters, prodrugs, N-oxides or solvates thereof. For example, if the compounds of the present invention are carboxylic acids (such as compounds 119, 411, 415 and 467, etc.), they can form ester prodrugs (such as N-(2-hydroxyethyl) acetamide, etc.) with appropriate alcohols ( Such as compounds 272, 424, 416 and 468, etc.).

The compound of formula (I) or its pharmaceutically acceptable salt or ester or solvate of the present invention is a novel AMPK agonist, which may activate the AMPK signaling pathway by activating the adiponectin receptor, and thus can be used for the preparation of prophylactic or Medicines for the following diseases.

The compound of the present invention can be used to prevent or treat various diseases related to abnormal metabolism or cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, Myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, complications of diabetes (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing, etc.), non-alcoholic Fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, hyperuricemia, gout, osteoporosis, stroke or cerebral infarction, etc.

The compounds of the present invention can be used to prevent or treat secondary diseases caused by various inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve injury diseases or pathogen infection, for example, pneumonia, tuberculosis, inflammatory bowel disease ( such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis arthritis, osteoarthritis, synovitis, tendonitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloids, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis , pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, idiopathic pulmonary fibrosis, cystic fibrosis, Parkinson's disease, Alzheimer's disease, alpha - Synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia, neuralgia, Down syndrome, Hallerwarden-Spp disease, Huntington's disease, or Wilson disease Wait.

The compounds of the present invention are useful in the treatment or modulation of mitochondrial dysfunction and disorders including: myasthenia, myoclonus, exercise intolerance, Kearns-Sell syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial Myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like episodes. Likewise, the compounds of the invention are also useful in the treatment of muscular dystrophic states, eg, Duchenne muscular dystrophy, concha muscular dystrophy or Friedrich's ataxia.

The compound of the present invention has antitumor effect. The tumors include, but are not limited to: bone cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, cholera Chirkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningeal sarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, neurofibroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, Colon cancer, rectal cancer, kidney cancer, prostate cancer, lymphoma, testicular cancer, mesenchymal cell carcinoma, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma, etc.

The pharmaceutical composition for preventing or treating the above-mentioned diseases of the present invention contains a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and a pharmaceutically acceptable auxiliary material. Optionally mixable excipients can vary depending on dosage forms, administration forms, and the like. Examples of excipients include excipients, binders, disintegrants, lubricants, correctives, fragrances, colorants or sweeteners, etc. The pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches and other conventional pharmaceutical preparations.

If necessary, the compound of the present invention can be used in combination with one or more other types of drugs for the prevention or treatment of the above diseases, including but not limited to the following combinations.

Other types of prophylactic or therapeutic drugs that can be selected to be used in combination with the compounds of the present invention can be one or more antidiabetic drugs, including metformin, sulfonylurea hypoglycemic drugs (such as glibenclamide and glimepiride, etc. ), glucosidase inhibitors (such as acarbose and miglitol, etc.), PPARγ agonists (such as pioglitazone and rosiglitazone), PPARα/γ dual agonists, dipeptidyl peptidase IV (DPP- IV) Inhibitors (such as sitagliptin, saxagliptin, alogliptin and linagliptin, etc.), glinide hypoglycemic agents (such as repaglinide and nateglinide, etc.), SGLT2 Inhibitors (such as canagliflozin, dapagliflozin, empagliflozin, empagliflozin, rupagliflozin and topagliflozin, etc.), glucokinase agonists (such as HMS5552, etc.), insulin, pancreatic hyperplasia Glucagon-like peptide-1 (GLP-1) drugs (such as exenatide, liraglutide, lixisenatide, dulaglutide, beinaglutide and albiglutide, etc.), PTP1B inhibitors , a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, an AMPK agonist, a GPR40 agonist, or a GPR120 agonist.

Other types of prophylactic or therapeutic drugs that can optionally be used in combination with the compounds of the present invention can be one or more weight loss drugs, including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-1 ) drugs (such as exenatide, liraglutide, lixisenatide, dulaglutide, benaglutide and albiglutide, etc.), etc.

Other types of prophylactic or therapeutic drugs that can be selected to be used in combination with the compounds of the present invention can be one or more anti-nonalcoholic fatty liver disease drugs, including: AMPK agonists (such as metformin), farnesoid X receptor ( FXR) agonists (such as obeticholic acid, GS-9674, EDP-305 and LJN452, etc.), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, etc.), apoptosis signal-regulated kinase-1 ( ASK1) inhibitors (such as Selonsertib, etc.), PPAR agonists (such as Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc.), caspase (caspase) inhibitors (such as Emricasan, etc.), stearoyl-CoA desaturation Enzyme 1 (SCD1) inhibitors (such as Aramchol, etc.), long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (such as Semaglutide, etc.), inhibition of apical sodium-dependent bile salt transporter (ASBT) Drugs (such as Volixibat, etc.), vascular adhesion protein 1 (VAP-1) inhibitors (such as BI 1467335, etc.), CCR5R blockers (such as Cenicriviroc, etc.) and thyroid hormone receptor beta (THR-β) agonists (such as MGL-3196, etc.) etc.

Other types of prophylactic or therapeutic drugs that can be selected to be used in combination with the compounds of the present invention can be one or more blood lipid-lowering drugs, including niacin, statins (such as lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosvastatin and pitavastatin), cholesterol absorption inhibitors (such as ezetimibe, etc.), fibrates (such as clofibrate, benzalkonium Fibrate, fenofibrate, etc.), PCSK9 inhibitors (such as Evolocumab and Alirocumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.), etc.

The preparation of the compound of the present invention can be carried out with reference to the following synthetic routes or improved methods.

Synthetic route 1.

Synthetic route 2.

Synthetic route 3.

Synthetic route 4.

Synthetic route 5.

Synthetic route 6.

Synthetic route 7.

Synthetic route 8.

In the above synthetic route, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R' are consistent with those in the compound of formula (I); m is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9.

The compound prepared by the present invention with the structure shown in formula (I) has significant AMPK agonistic activity, and the agonistic activity of the compound of the present invention on AMPK is adiponectin receptor 1 (AdipoR1) dependent, and is a specific adiponectin receptor 1 (AdipoR1)-dependent The compound of formula (I) in the present invention can be used to prepare medicines for AMPK-related diseases in organisms, for example, it can be used to prevent and treat diabetes and its complications, hyperlipidemia and non-alcoholic fatty liver disease, Cardiomyopathy and heart failure etc.

Description of drawings

Figure 1 is a graph showing the effect of compounds on AMPK phosphorylation in C2C12 cells;

Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation in AdipoR1 wild-type or AdipoR1 knockout HEK293T cells;

Fig. 3 is the impact diagram of calcium chelator EGTA on compound AMPK agonistic activity;

Fig. 4 is the time-FBG relationship diagram of compounds 111 and 119 hypoglycemic;

Figure 5 is a graph showing the levels of TC, LDL, HDL in serum and TG in liver tissue after oral administration of compound 119 to mice;

Figure 6 is the liver HE staining diagram of mice after oral administration of Compound 119;

Figure 7 is the liver oil red staining diagram of mice after oral administration of Compound 119;

Figure 8 is a graph showing the levels of ALT and AST in the serum of mice after oral administration of Compound 119;

Fig. 9 is a graph showing the effect of compound 119 on the SD rat model of heart failure.

Detailed ways

The invention discloses a compound and its preparation method, an intermediate of the compound and its preparation method, and the application of the compound as an AMPK agonist. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

Example 1

N-(1-Benzylpiperidin-4-yl)-2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamide (Compound 1)

Take phenol (5g, 53.1mmol) and p-chlorobenzoyl chloride (9.76g, 55.8mmol) and dissolve in dichloromethane (DCM) (50mL), add triethylamine (7.4mL), stir overnight at room temperature, and use Saturated sodium carbonate (10mL) quenched, the aqueous phase was extracted with DCM (10mLx3), washed with saturated brine (10mlx3), dried over anhydrous sodium sulfate, and spin-dried to obtain white solid compound I-3 (11.88g, yield 95 %). Take compound I-3 (7g, 30mmol) and AlCl ₃ (12g, 90mmol) in a reaction flask, heat and stir at 140°C for 2 hours, quench the reaction with water (100mL), extract the aqueous phase with DCM (50mLx3), and saturate Wash with brine (10ml x3), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate=30:1) to obtain compound I-4 ( Yellow solid, 4.7 g, yield 67%).

Dissolve compound I-4 (1g, 4.3mmol) and potassium carbonate (1.78g, 12.89mmol) in N,N-dimethylformamide (DMF) (30mL), stir at room temperature for half an hour, and then add dropwise Ethyl 2-bromo-2-methylpropanoate (1.89 mL). React at 70°C for 5 h, cool to room temperature, add water (50 mL), extract the aqueous phase with ethyl acetate (30 mL x 3), wash the organic phase with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, and evaporate under reduced pressure solvent, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10:1) to obtain compound I-5 (white solid, 1.3 g, yield 90%).

A mixed solution of compound I-5 (1.3 g) dissolved in THF (20 mL) and CH ₃ OH (2 mL) was added, 5 wt % NaOH aqueous solution (10 mL) was added, and heated to reflux. After the reaction was complete, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), the pH was adjusted to acidic with 1N HCl, and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound I-6 (white solid, 1.13 g, yield 94%).

Dissolve compound 1-6 (200mg, 0.6275mmol) in anhydrous DMF (1mL), add 1,1-carbonyldiimidazole (CDI) (117mg, 0.7216mmol), heat at 70°C for 1h, then add N-Boc - 4-aminopiperidine (126 mg, 0.6275 mmol), continue to react for 2 hours. Cool to room temperature, add water (10 mL), extract the aqueous phase with ethyl acetate (10 mL x 3), wash the organic phase with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and pass the residue through column layer Purification by analysis (eluent: petroleum ether/ethyl acetate = 2:1) gave compound 1-7 (white solid, 260 mg, yield 83%).

Dissolve compound I-7 (211mg, 0.42mmol) in DCM (10mL), add trifluoroacetic acid (2mL) under ice-bath conditions, react overnight, spin dry, add DCM (10mL), adjust pH with saturated sodium bicarbonate To alkaline, the aqueous phase was extracted with DCM (10mLx3), the organic phase was washed with saturated brine (10mLx3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound I-8 (white solid, 174mg, yield 98%).

Compound I-8 (90 mg, 0.225 mmol) was dissolved in DMF (1 mL), potassium carbonate (47 mg) and benzyl bromide (0.03 mL) were added, and stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to obtain compound 1 (white solid, 87mg, yield 80%): ¹ H NMR (300MHz , CDCl ₃ ) δ7.73(t, J=8.7Hz, 4H), 7.46(d, J=8.4Hz, 2H), 7.28(m, 5H), 6.95(d, J=8.7Hz, 2H), 6.28 (d, J=8.1Hz, 1H), 3.95-3.73(m, 1H), 3.47(s, 2H), 2.77(d, J=11.8Hz, 2H), 2.12(t, J=10.8Hz, 2H) , 1.88(d, J=11.5Hz, 2H), 1.59(s, 6H), 1.40(dd, J=11.5, 9.3Hz, 2H).ESI-MS: m/z 492.2[M+H] ⁺ .

Example 2

2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-methylpropionamide (Compound 5)

Compound I-8 (Example 1, 220 mg, 0.55 mmol) and p-chlorobenzoyl chloride (106 mg, 0.60 mmol) were dissolved in DCM (5 mL), and triethylamine (56 mg, 0.55 mmol) was added at room temperature, and reaction 2 After 1 hour, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 2:1) to obtain compound 5 (white solid, 150 mg): ¹ H NMR (300 MHz, d ₆ -DMSO) δ7.93 (d, J=8.2Hz, 1H), 7.67-7.57 (m, 4H), 7.56-7.48 (m, 2H), 7.43-7.34 (m, 2H), 7.28-7.19 (m , 2H), 6.87(d, J=8.8Hz, 2H), 4.24(dt, J=18.2, 9.5Hz, 1H), 3.95-3.72(m, 1H), 3.59-3.27(m, 1H), 3.07- 2.92 (m, 1H), 2.85-2.72 (m, 1H), 1.71-1.47 (m, 2H), 1.43 (s, 6H), 1.36-1.23 (m, 2H). ESI-MS: m/z 562.1[ M+Na] ⁺ .

Example 3

2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropionamide (Compound 6)

Compound 6 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.74(d, J=9.0Hz, 2H), 7.71(d, J=9.2Hz, 2H), 7.58(d, J=7.7Hz, 2H), 7.45(d, J=8.3Hz, 2H), 7.40(d, J=7.8Hz, 2H), 6.95(d, J=8.2Hz, 2H), 6.32(d, J= 7.7Hz, 1H), 3.95-3.69(m, 1H), 3.50(s, 2H), 2.72(d, J=10.6Hz, 2H), 2.15(t, J=10.8Hz, 2H), 1.88(d, J=10.3Hz, 2H), 1.59(s, 6H), 1.37-1.47(m, 2H). ESI-MS: m/z 539.3[M+Na] ⁺ .

Example 4

2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propionamide ( Compound 7)

Compound 7 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.76(s, 2H), 7.71(d, J=8.8Hz, 2H), 7.54(d, J=7.9Hz, 2H), 7.45(d, J=8.4Hz, 2H), 7.44-7.37(m, 2H), 6.95(d, J=8.5Hz, 2H), 6.32(d, J=7.8Hz, 1H), 3.82( s, 1H), 3.51(s, 2H), 2.74(d, J=11.3Hz, 2H), 2.14(t, J=11.0Hz, 2H), 1.88(d, J=10.8Hz, 2H), 1.59( s, 6H), 1.37-1.47 (m, 2H). ESI-MS: m/z 582.3 [M+Na] ⁺ .

Example 5

2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropionamide (Compound 8)

Compound 8 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.73(d, J=8.1Hz, 2H), 7.70(d, J=7.9Hz, 2H), 7.44(d, J=7.4Hz, 2H), 7.17(d, J=7.3Hz, 2H), 6.94(d, J=7.5Hz, 2H), 6.82(d, J=7.3Hz, 2H), 6.30(d, J= 6.3Hz, 1H), 3.80(s, 1H), 3.78(s, 3H), 3.40(s, 2H), 2.91-2.61(m, 2H), 2.09(t, J=10.2Hz, 2H), 1.87( d, J=10.2Hz, 2H), 1.59(s, 6H), 1.37-1.47(m, 2H). ESI-MS: m/z 544.3[M+Na] ⁺ .

Example 6

N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamide (compound 9)

Compound 9 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.91 (d, J=7.9Hz, 1H), 7.70 (dd, J=8.6, 3.6Hz, 4H), 7.60(d, J=8.4Hz, 2H), 7.51-7.29(m, 2H), 7.18(td, J=8.4, 2.3Hz, 1H), 6.96(d, J=8.7Hz, 2H), 3.64(s , 1H), 3.47(s, 2H), 2.72(d, J=11.1Hz, 2H), 2.06(t, J=11.0Hz, 2H), 1.60(d, J=12.1Hz, 2H), 1.52(s , 6H), 1.40-1.50 (m, 2H).ESI-MS: m/z 567.1[M+Na] ⁺ .

Example 7

2-(4-Chlorophenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropionamide (Compound 3)

Compound 3 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.89 (d, J=8.0Hz, 1H), 7.77 (d, J=7.7Hz, 2H), 7.47 ( d, J=7.7Hz, 2H), 7.31(d, J=8.4Hz, 2H), 6.87(d, J=8.1Hz, 2H), 3.75-3.55(m, 1H), 3.53(s, 2H), 2.71(d, J=11.4Hz, 2H), 2.00(t, J=11.0Hz, 2H), 1.59(t, J=10.5Hz, 2H), 1.49(dd, J=12.1, 1.8Hz, 2H), 1.41(s, 6H).ESI-MS: m/z 413.3[M+H] ⁺ .

Example 8

N-(1-Benzylpiperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide (Compound 10)

Compound 10 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.85 (d, J=6.8Hz, 1H), 7.30 (s, 2H), 7.30-7.10 (dd, J =11.2, 4.5Hz, 5H), 6.84(d, J=8.3Hz, 2H), 3.59(dd, J=17.6, 7.1Hz, 1H), 3.41(s, 2H), 2.71(d, J=11.8Hz , 2H), 2.08-1.81 (m, 2H), 1.57 (d, J=10.8Hz, 2H), 1.55-1.43 (m, 2H), 1.38 (s, 6H). ESI-MS: m/z 409.2[ M+Na] ⁺ .

Example 9

2-(4-Chlorophenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propionamide (compound 11)

Compound 11 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.90 (d, J=7.9Hz, 1H), 7.67 (d, J=7.8Hz, 2H), 7.50 ( d, J = 7.8Hz, 2H), 7.31 (d, J = 7.6Hz, 2H), 6.87 (dd, J = 8.1, 0.5Hz, 2H), 3.61 (dd, J = 17.1, 12.0Hz, 1H), 3.54(d, J=13.4Hz, 2H), 2.72(d, J=10.7Hz, 2H), 2.00(t, J=11.1Hz, 2H), 1.59(t, J=10.5Hz, 2H), 1.55- 1.44(m, 2H), 1.41(s, 6H).ESI-MS: m/z 475.3[M+Na] ⁺ .

Example 10

2-(4-Chlorophenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propionamide (Compound 12)

Compound 12 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.86 (d, J=7.9Hz, 1H), 7.31 (d, J=8.6Hz, 2H), 7.17( d, J=7.9Hz, 2H), 6.86(dd, J=7.6, 1.2Hz, 4H), 3.72(s, 3H), 3.59(dd, J=7.3, 4.3Hz, 1H), 3.35(s, 2H ), 2.72(d, J=11.0Hz, 2H), 1.92(d, J=8.3Hz, 2H), 1.59(d, J=10.1Hz, 2H), 1.53-1.44(m, 2H), 1.41(s , 6H).ESI-MS: m/z 440.2[M+Na] ⁺ .

Example 11

N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide (compound 13)

Compound 13 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.87 (d, J=7.9Hz, 1H), 7.65-7.43 (m, 1H), 7.38 (dd, J = 8.7, 1.9Hz, 1H), 7.31 (d, J = 8.7Hz, 2H), 7.20 (dd, J = 11.5, 5.2Hz, 1H), 6.87 (d, J = 8.7Hz, 2H), 3.73-3.55 (m, 1H), 3.48(s, 2H), 2.74(d, J=10.7Hz, 2H), 2.06(t, J=10.6Hz, 2H), 1.61(d, J=9.4Hz, 2H), 1.52 (d, J=11.1Hz, 2H), 1.43(s, 6H).ESI-MS: m/z 463.0[M+Na] ⁺ .

Example 12

N-(1-benzoylpiperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide (Compound 23)

Compound 23 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.42 (dd, J=7.0, 3.0Hz, 5H), 7.31-7.24 (m, 2H), 6.86 (d, J =8.9Hz, 2H), 6.63(d, J=8.0Hz, 1H), 4.81-4.50(m, 1H), 4.16-3.97(m, 1H), 3.97-3.56(m, 1H), 3.34-2.86( m, 2H), 2.07-1.87(m, 2H), 1.50(s, 7H), 1.41-1.28(m, 2H). ESI-MS: m/z 423.2[M+Na] ⁺ .

Example 13

N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide (Compound 24)

Compound 24 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.30(q, J=8.5Hz, 4H), 7.22-7.17(m, 2H), 6.79(d, J=8.8 Hz, 2H), 6.53(d, J=7.9Hz, 1H), 4.53(dd, J=56.8, 30.4Hz, 1H), 4.12-3.96(m, 1H), 3.91-3.48(m, 1H), 3.16 -2.81(m, 2H), 2.04-1.84(m, 2H), 1.43(s, 6H), 1.50-1.35(m, 2H). ESI-MS: m/z 458.1[M+Na] ⁺ .

Example 14

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-methylphenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 25)

2-(4-Chlorophenoxy)-2-methyl-N-(piperidin-4-yl)propanamide (100 mg, 0.337 mmol) and p-toluenesulfonyl chloride (64 mg, 0.34 mmol) were dissolved in DCM ( 10 mL), added triethylamine (300 μL), stirred overnight at room temperature, evaporated the solvent under reduced pressure, and purified the residue by column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain compound 25 (white solid, 100mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.65(d, J=8.1Hz, 2H), 7.35(d, J=8.0Hz, 2H), 7.25(d, J=8.8Hz , 2H), 6.83(d, J=8.8Hz, 2H), 6.54(d, J=8.1Hz, 1H), 3.80-3.65(m, 3H), 2.46(s, 3H), 2.42(s, 2H) , 1.98(d, J=10.5Hz, 2H), 1.55(dd, J=12.5, 3.8Hz, 2H), 1.47(s, 6H).ESI-MS: m/z 474.1[M+Na] ⁺ .

Example 15

2-(4-Chlorophenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropionamide (Compound 26)

Compound 26 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ8.63 (d, J=5.5Hz, 2H), 7.35-7.15 (m, 3H), 6.79 (d, J=8.7 Hz, 2H), 6.55(d, J=7.3Hz, 1H), 4.59(d, J=11.6Hz, 1H), 3.99(dd, J=16.3, 11.7Hz, 1H), 3.56(d, J=12.5 Hz, 1H), 3.12(dd, J=19.9, 9.2Hz, 1H), 2.98-2.83(m, 1H), 1.93(dd, J=19.0, 7.6Hz, 2H), 1.43(s, 6H), 1.26 (dd, J=14.6, 8.6Hz, 2H).ESI-MS: m/z 425.2[M+Na] ⁺ .

Example 16

2-(4-Chlorophenoxy)-2-methyl-N-(1-nicotinoylpiperidin-4-yl)propionamide (Compound 27)

Compound 27 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ8.59 (s, 2H), 7.67 (d, J=7.6Hz, 1H), 7.35-7.22 (m, 1H), 7.25-7.12(m, 2H), 6.78(d, J=8.3Hz, 2H), 6.56(d, J=7.4Hz, 1H), 4.73-4.40(m, 1H), 4.11-3.92(m, 1H) , 3.80-3.45(m, 1H), 3.27-2.81(m, 2H), 2.07-1.79(m, 2H), 1.43(s, 6H), 1.35-1.15(m, 2H).ESI-MS: m/ z 424.2[M+Na] ⁺ .

Example 17

N-(1-benzylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropionamide (compound 28)

Compound 28 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.35-7.25 (m, 5H), 7.04 (d, J=7.5Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 6.67(d, J=8.2Hz, 1H), 6.63(s, 1H), 3.91-3.79(m, 1H), 3.48(s, 2H), 2.79(d, J=11.1Hz, 2H ), 2.23(s, 3H), 2.18(s, 3H), 2.12(d, J=11.3Hz, 2H), 1.92(d, J=9.9Hz, 2H), 1.58-1.37(m, 8H).ESI -MS: m/z 381.3[M+H] ⁺ .

Example 18

N-(1-benzoylpiperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropionamide (compound 29)

Compound 29 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.53-7.28 (m, 5H), 7.06 (d, J=7.6Hz, 1H), 6.76 (dd, J=12.6 , 8.0Hz, 2H), 6.61(s, 1H), 4.71-4.47(m, 1H), 4.16-4.04(m, 1H), 3.82-3.57(m, 1H), 3.20-3.00(m, 2H), 2.25(s, 3H), 2.19(s, 3H), 2.10-1.92(m, 2H), 1.51(s, 6H), 1.46-1.30(m, 2H). ESI-MS: m/z 417.5 [M+ Na] ⁺ .

Example 19

N-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropionamide (Compound 30)

Compound 30 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.51-7.28 (m, 4H), 7.06 (d, J=7.6Hz, 1H), 6.76 (dd, J=14.2 , 8.0Hz, 2H), 6.61(s, 1H), 4.78-4.46(m, 1H), 4.21-4.02(m, 1H), 3.86-3.55(m, 1H), 3.26-2.95(m, 2H), 2.25(s, 3H), 2.19(s, 3H), 2.09-1.91(m, 2H), 1.51(s, 6H), 1.45-1.29(m, 2H). ESI-MS: m/z 451.2 [M+ Na] ⁺ .

Example 20

2-(2,5-Dimethylphenoxy)-N-(1-isonicotinylpiperidin-4-yl)-2-methylpropionamide (Compound 31)

Compound 31 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ8.69 (d, J=5.9Hz, 2H), 7.25 (s, 1H), 7.13-7.00 (m, 2H), 6.78(d, J=7.5Hz, 2H), 6.60(s, 1H), 4.63(d, J=14.7Hz, 1H), 4.14-4.10(m, 1H), 3.63-3.50(m, 1H), 3.21 -3.16(m, 1H), 3.04-2.92(m, 1H), 2.25(s, 3H), 2.19(s, 3H), 2.09-1.98(m, 2H), 1.51(s, 6H), 1.42-1.30 (m, 2H).ESI-MS: m/z418.2[M+Na] ⁺ .

Example 21

(2,5-Dimethylphenoxy)-2-methyl-N-(1-nicotinoylpiperidin-4-yl)propionamide (compound 32)

Compound 32 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ8.78-8.53 (m, 2H), 7.74 (dt, J=7.8, 1.9Hz, 1H), 7.36 (dd, J =7.5, 5.2Hz, 1H), 7.06(d, J=7.6Hz, 1H), 6.76(t, J=8.2Hz, 2H), 6.60(s, 1H), 4.79-4.48(m, 1H), 4.14 (tt, J=6.5, 3.8Hz, 1H), 3.89-3.58(m, 1H), 3.42-3.00(m, 2H), 2.25(s, 3H), 2.19(s, 3H), 2.02(s, 2H ), 1.51(s, 6H), 1.31(d, J=10.4Hz, 2H).ESI-MS: m/z 418.2[M+Na] ⁺ .

Example 22

(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-methylpropionamide (compound 33)

Compound 33 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.26(t, J=4.1Hz, 2H), 7.14-6.84(m, 3H), 6.76(d, J=7.5 Hz, 1H), 6.68(d, J=8.3Hz, 1H), 6.64(s, 1H), 3.94-3.78(m, 1H), 3.44(s, 2H), 2.76(d, J=11.6Hz, 2H ), 2.24(s, 3H), 2.18(s, 3H), 2.18-2.08(m, 2H), 2.00-1.88(m, 2H), 1.51(s, 6H), 1.50-1.32(m, 2H). ESI-MS: m/z 421.3[M+Na] ⁺ .

Example 23

(2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propionamide (compound 34 )

Compound 34 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60(d, J=8.2Hz, 2H), 7.42(d, J=8.2Hz, 2H), 7.05(d, J=7.6Hz, 1H), 6.77(d, J=7.8Hz, 1H), 6.69(d, J=8.5Hz, 1H), 6.64(s, 1H), 3.95-3.84(m, 1H), 3.52( s, 2H), 2.75(d, J=11.8Hz, 2H), 2.25(s, 3H), 2.19(s, 4H), 2.19(s, 2H), 1.94(dd, J=12.5, 2.6Hz, 2H ), 1.51(s, 6H), 1.50-1.39(m, 2H).ESI-MS: m/z 447.2[MH] ^- .

Example 24

N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropionamide (Compound 35)

Compound 35 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60(d, J=8.2Hz, 2H), 7.42(d, J=8.2Hz, 2H), 7.05(d, J=7.6Hz, 1H), 6.77(d, J=7.8Hz, 1H), 6.69(d, J=8.5Hz, 1H), 6.64(s, 1H), 3.95-3.84(m, 1H), 3.52( s, 2H), 2.75(d, J=11.8Hz, 2H), 2.25(s, 3H), 2.19(s, 4H), 2.19(s, 2H), 1.94(dd, J=12.5, 2.6Hz, 2H ), 1.51(s, 6H), 1.50-1.39(m, 2H). ESI-MS: m/z 443.2[M+K] ⁺ .

Example 25

(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropionamide (Compound 36)

Compound 36 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.20(d, J=8.5Hz, 2H), 7.04(d, J=7.7Hz, 1H), 6.84(d, J=8.6Hz, 2H), 6.76(d, J=7.6Hz, 1H), 6.67(d, J=8.3Hz, 1H), 6.63(s, 1H), 3.97-3.83(m, 1H), 3.80( s, 3H), 3.42(s, 2H), 2.78(d, J=10.6Hz, 2H), 2.24(s, 3H), 2.18(s, 3H), 2.11(d, J=10.8Hz, 2H), 2.00-1.82(m, 2H), 1.50(s, 6H), 1.49-1.37(m, 2H). ESI-MS: m/z 433.5[M+Na] ⁺ .

Example 26

5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)pentanamide ( Compound 19)

Dissolve gemfibrozil (II-1) (250mg, 1mmol) in anhydrous DMF (2mL), add CDI (186mg, 1.149mmol), stir at 70°C for 1h, then add N-Boc-4-aminopiper Pyridine (200mg, 1mmol), reacted for 2h. Cooled to room temperature, added water (10mL), extracted with ethyl acetate (20mL x3), washed the organic phase with saturated NaHCO ₃ (10mL x3), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue was subjected to column chromatography ( Eluent: petroleum ether/ethyl acetate=2:1) to obtain compound II-2 (white solid, 340 mg, yield 79%).

Compound II-2 (340 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added under ice-cooling, and stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the pH was adjusted to alkaline with saturated sodium bicarbonate, extracted with ethyl acetate (30mL x3), washed with saturated NaCl (10mL x3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound II- 3 (colorless liquid, 260 mg, yield 99%).

Using compound II-3 as a raw material, compound 19 was obtained by referring to the method of Example 1 (yield 78%): ¹ H NMR (300MHz, d ₆ -DMSO) δ7.67 (d, J=8.1Hz, 2H), 7.51(d, J=7.9Hz, 2H), 7.13(d, J=7.8Hz, 1H), 6.96(d, J=7.6Hz, 1H), 6.68(s, 1H), 6.60(d, J=7.3 Hz, 1H), 3.88(s, 2H), 3.59(s, 1H), 3.53(s, 2H), 2.75(d, J=10.8Hz, 2H), 2.22(s, 3H), 2.08(s, 3H ), 2.00(t, J=11.4Hz, 2H), 1.60(s, 2H), 1.59(s, 4H), 1.56-1.41(m, 2H), 1.09(s, 6H).ESI-MS: m/ z 513.3[M+Na] ⁺ .

Example 27

N-(1-benzylpiperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (compound 38)

Compound 38 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.38-7.27 (m, 5H), 6.90 (dd, J=18.4, 7.7Hz, 3H), 5.49 (s, 1H), 3.93(t, J=5.6Hz, 2H), 3.89-3.75(m, 1H), 3.49(s, 2H), 2.79(d, J=12.0Hz, 2H), 2.14(t, J=10.8Hz, 2H), 2.00-1.81(m, 4H), 1.76-1.69(m, 2H), 1.51-1.36(m, 2H), 1.19(s, 6H).ESI-MS: m/z 417.3 [M+Na] ⁺ .

Example 28

N-(1-benzylpiperidin-4-yl)-5-(4-chlorophenoxy)-2,2-dimethylpentanamide (compound 39)

Compound 39 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.37-7.29(m, 4H), 7.21(d, J=8.6Hz, 2H), 6.80(d , J=8.6Hz, 2H), 5.48(d, J=7.8Hz, 1H), 3.89(t, J=5.1Hz, 2H), 3.85-3.73(m, 1H), 3.49(s, 2H), 2.79 (d, J=11.6Hz, 2H), 2.13(t, J=11.2Hz, 2H), 1.89(d, J=11.0Hz, 2H), 1.80-1.64(m, 4H), 1.52-1.38(m, 2H), 1.19(s, 6H).ESI-MS: m/z 429.1[M+H] ⁺ .

Example 29

N-(1-benzylpiperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound 40)

Compound 40 was obtained by referring to Synthesis Route 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.32 (d, J=3.8Hz, 3H), 7.27 (d, J=4.5Hz, 3H), 6.95-6.83(m, 2H), 5.51(d, J=7.3Hz, 1H), 3.99(t, J=5.6Hz, 2H), 3.88-3.74(m, 1H), 3.50(s, 2H), 2.80 (d, J=11.6Hz, 2H), 2.14(t, J=10.7Hz, 2H), 1.91(d, J=9.8Hz, 2H), 1.82-1.66(m, 4H), 1.51-1.35(m, 2H), 1.21(s, 6H). ESI-MS: m/z 463.0[M+H] ⁺ .

Example 30

N-(1-benzylpiperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide (compound 41)

Compound 41 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.37-7.29 (m, 4H), 6.83 (s, 4H), 5.52 (d, J=7.2Hz , 1H), 3.90(t, J=8.8Hz, 2H), 3.86-3.79(m, 1H), 3.78(s, 3H), 3.51(s, 2H), 2.80(d, J=11.7Hz, 2H) , 2.14(t, J=11.4Hz, 2H), 1.90(d, J=11.4Hz, 2H), 1.75-1.66(m, 4H), 1.51-1.38(m, 2H), 1.20(s, 6H). ESI-MS: m/z 447.2[M+Na] ⁺ .

Example 31

N-(1-benzylpiperidin-4-yl)-2,2-dimethyl-5-(p-tolyloxy)pentanamide (compound 42)

Compound 42 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.38-7.29(m, 5H), 7.08(d, J=8.5Hz, 2H), 6.79(d , J=8.5Hz, 2H), 5.51(d, J=7.3Hz, 1H), 3.91(t, J=5.7Hz, 2H), 3.89-3.79(m, 1H), 3.51(s, 2H), 2.80 (d, J=11.9Hz, 2H), 2.29(s, 3H), 2.15(t, J=10.5Hz, 2H), 1.91(d, J=12.6Hz, 2H), 1.69(d, J=3.8Hz , 4H), 1.50-1.40(m, 2H), 1.20(s, 6H).ESI-MS: m/z 410.2[M+H] ⁺ .

Example 32

N-(1-Benzylpiperidin-4-yl)-5-(5-isopropyl-2-methylphenoxy)-2,2-dimethylpentanamide (Compound 43)

Compound 43 was obtained by referring to Synthetic Route 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.37-7.26(m, 5H), 7.04(d, J=7.5Hz, 1H), 6.72(d , J=7.5Hz, 1H), 6.65(s, 1H), 5.47(d, J=6.6Hz, 1H), 3.93(t, J=5.4Hz, 2H), 3.88-3.76(m, 1H), 3.49 (s, 2H), 2.96-2.82(m, 1H), 2.82-2.69(m, 2H), 2.27-2.17(m, 3H), 2.17-2.04(m, 2H), 1.94-1.84(m, 2H) , 1.82-1.68(m, 4H), 1.52-1.38(m, 2H), 1.27-1.17(m, 12H).ESI-MS: m/z 451.2[M+H] ⁺ .

Example 33

N-(1-benzylpiperidin-4-yl)-5-(3,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 44)

Compound 44 was obtained by referring to Synthetic Route 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.36-7.29 (m, 4H), 7.28-7.24 (m, 1H), 6.60 (s, 1H) , 6.52(s, 2H), 5.51(d, J=7.5Hz, 1H), 3.91(t, J=5.7Hz, 2H), 3.86-3.74(m, 1H), 3.51(s, 2H), 2.80( d, J=11.9Hz, 2H), 2.29(s, 6H), 2.15(t, J=10.6Hz, 2H), 1.91(d, J=10.7Hz, 2H), 1.78-1.68(m, 4H), 1.53-1.40(m, 2H), 1.23(d, J=16.7Hz, 6H).ESI-MS: m/z 423.1[M+H] ⁺ .

Example 34

N-(1-benzylpiperidin-4-yl)-2,2-dimethyl-5-(o-tolyloxy)pentanamide (compound 45)

Compound 45 was obtained by referring to Synthetic Route 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.40-7.23 (m, 5H), 7.19-7.05 (m, 2H), 6.94-6.68 (m, 2H), 5.47(d, J=5.7Hz, 1H), 3.92(d, J=5.0Hz, 2H), 3.87-3.70(m, 1H), 3.49(s, 2H), 2.79(d, J=10.7 Hz, 2H), 2.33-2.07(m, 5H), 1.90(d, J=11.7Hz, 2H), 1.70(s, 4H), 1.54-1.34(m, 2H), 1.20(s, 6H).ESI -MS: m/z 409.2[M+H] ⁺ .

Example 35

N-(1-benzylpiperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide (compound 46)

Compound 46 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.30(d, J=3.6Hz, 5H), 6.13(s, 2H), 5.50(d, J =7.5Hz, 1H), 3.89(t, J=5.5Hz, 2H), 3.83(s, 6H), 3.78(s, 1H), 3.77(s, 3H), 3.48(s, 2H), 2.79(d , J=11.9Hz, 2H), 2.12(t, J=10.8Hz, 2H), 1.90(d, J=11.6Hz, 2H), 1.66(d, J=9.1Hz, 4H), 1.54-1.40(m , 2H), 1.19(s, 6H).ESI-MS: m/z 485.1[M+H] ⁺ .

Example 36

N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (compound 47)

Compound 47 was obtained by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.62 (d, J=8.1Hz, 2H), 7.45 (d, J=8.2Hz, 2H), 7.31(s, 2H), 6.93(dd, J=20.1, 7.7Hz, 3H), 5.53(d, J=7.4Hz, 1H), 3.95(t, J=5.5Hz, 2H), 3.89-3.78(m , 1H), 3.55(s, 2H), 2.77(d, J=11.6Hz, 2H), 2.18(t, J=11.0Hz, 2H), 1.92(d, J=12.1Hz, 2H), 1.78-1.66 (m, 4H), 1.49-1.37 (m, 2H), 1.21 (s, 6H). ESI-MS: m/z 442.2 [M+Na] ⁺ .

Example 37

N-(1-(3-cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (compound 48)

Compound 48 was obtained by referring to Synthetic Route 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.68-7.63 (m, 1H), 7.58-7.50 (m, 2H), 7.42 (d, J= 7.6Hz, 1H), 7.33-7.27(m, 2H), 6.98-6.84(m, 3H), 5.51(d, J=7.1Hz, 1H), 3.94(t, J=5.6Hz, 2H), 3.86- 3.78(m, 1H), 3.51(s, 2H), 2.76(d, J=12.1Hz, 2H), 2.18(d, J=12.8Hz, 2H), 1.91(d, J=14.0Hz, 2H), 1.82-1.68(m, 4H), 1.55-1.35(m, 2H), 1.20(s, 6H). ESI-MS: m/z 442.2[M+Na] ⁺ .

Example 38

N-(1-(2-cyanobenzyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (compound 49)

Compound 49 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.65(d, J=7.8Hz, 1H), 7.58-7.48(m, 2H), 7.36(d , J=7.0Hz, 1H), 7.25(d, J=5.8Hz, 2H), 6.90(dd, J=16.8, 8.0Hz, 3H), 5.51(d, J=8.0Hz, 1H), 3.93(t , J=5.5Hz, 2H), 3.89-3.77(m, 1H), 3.68(s, 2H), 2.79(d, J=11.5Hz, 2H), 2.26(t, J=11.4Hz, 2H), 1.90 (d, J=13.1Hz, 2H), 1.79-1.65(m, 4H), 1.54-1.43(m, 2H), 1.19(s, 6H).ESI-MS: m/z 442.1[M+Na] ⁺ .

Example 39

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 50)

Compound 50 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.68(s, 1H), 7.55(d, J=7.2Hz, 2H), 7.48-7.37(m , 1H), 7.29(d, J=7.4Hz, 2H), 6.89(s, 2H), 5.53(d, J=7.2Hz, 1H), 4.00(t, J=5.2Hz, 2H), 3.83(tdd , J=15.4, 8.0, 3.1Hz, 1H), 3.52(s, 2H), 2.77(d, J=10.5Hz, 2H), 2.17(t, J=11.1Hz, 2H), 1.90(t, J= 12.2Hz, 2H), 1.88-1.68(m, 4H), 1.57-1.37(m, 2H), 1.22(s, 6H). ESI-MS: m/z 512.1[M+Na] ⁺ .

Example 40

N-(1-(3-cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 51)

Compound 51 was obtained by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60 (d, J=8.2Hz, 2H), 7.43 (d, J=8.0Hz, 2H), 7.25(s, 1H), 6.87(d, J=3.2Hz, 2H), 5.51(d, J=7.9Hz, 1H), 3.84(d, J=6.5Hz, 2H), 3.83(s, 1H), 3.52(s, 2H), 2.75(d, J=11.4Hz, 2H), 2.16(t, J=11.6Hz, 2H), 1.98-1.89(m, 2H), 1.83-1.73(m, 4H), 1.52 -1.39(m, 2H), 1.22(s, 6H).ESI-MS: m/z 512.1[M+Na] ⁺ .

Example 41

N-(1-(2-cyanobenzyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (Compound 52)

Compound 52 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.64(d, J=7.5Hz, 1H), 7.59-7.43(m, 2H), 7.35(t , J=7.8Hz, 1H), 7.26(s, 1H), 6.97-6.77(m, 2H), 5.51(d, J=6.6Hz, 1H), 3.96(dd, J=15.0, 8.8Hz, 2H) , 3.82(dt, J=15.1, 7.6Hz, 1H), 3.71(d, J=18.4Hz, 2H), 2.80(d, J=10.9Hz, 2H), 2.27(t, J=11.4Hz, 2H) , 1.90(d, J=12.0Hz, 2H), 1.83-1.69(m, 4H), 1.53-1.42(m, 2H), 1.20(s, 6H).ESI-MS: M/Z m/z 487.3[ MH] ^- .

Example 42

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-propionylbenzoyl)piperidin-4-yl)pentanamide (Compound 53)

Compound 53 was obtained by referring to Synthesis Scheme 5 and Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.32 (d, J=7.8Hz, 2H), 7.23 (d, J=7.7Hz, 2H), 7.01(d, J=7.4Hz, 1H), 6.66(d, J=7.3Hz, 1H), 6.61(s, 1H), 5.69(d, J=7.5Hz, 1H), 4.14-3.99(m, 1H ), 3.95-3.83(m, 2H), 3.20-2.89(m, 2H), 2.68(q, J=7.5Hz, 2H), 2.31(s, 3H), 2.18(s, 3H), 2.04-1.86( m, 2H), 1.71(s, 4H), 1.28(s, 2H), 1.21(s, 6H). ESI-MS: m/z 493.1[M+H] ⁺ .

Example 43

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-tolylpiperidin-4-yl)pentanamide (Compound 54)

Compound II-3 (Example 26) (260 mg, 0.78 mmol) and triethylamine (305 μL) were dissolved in dichloromethane (15 mL), and a dichloromethane solution of p-toluenesulfonyl chloride (180 mg, 0.95 mmol) was added dropwise under ice-cooling. Methane solution (2 mL), naturally warmed to room temperature, stirred overnight. The reaction solution was concentrated under reduced pressure, added with saturated aqueous sodium carbonate (20 mL), and extracted with dichloromethane (3 x 30 mL). The organic phase was washed successively with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane/methanol=150:1) to obtain compound 54 (white solid, 320 mg, yield 85%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.64 (d, J=8.1Hz, 2H), 7.34(d, J=7.9Hz, 2H), 7.01(d, J=7.4Hz, 1H), 6.68(d, J=7.6Hz, 1H), 6.60(s , 1H), 5.57(d, J=7.4Hz, 1H), 3.91(t, J=5.0Hz, 2H), 3.84-3.75(m, 2H), 3.75-3.67(m, 1H), 2.46(s, 3H), 2.39(d, J=11.6Hz, 2H), 2.31(s, 3H), 2.18(s, 3H), 1.95(d, J=12.3Hz, 2H), 1.67(m, 4H), 1.55( td, J=12.1, 3.7Hz, 2H), 1.19(s, 6H).ESI-MS: m/z 509.2[M+Na] ⁺ .

Example 44

N-(1-benzoylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 55)

Compound 55 was prepared according to the method of Examples 2 and 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.38-7.26 (m, 5H), 7.01 (d, J=7.4Hz, 1H), 6.67 (d, J =7.6Hz, 1H), 6.62(s, 1H), 3.94(s, 2H), 3.67(d, J=4.4Hz, 3H), 3.47(s, 2H), 2.42(d, J=4.7Hz, 4H ), 2.31(s, 3H), 2.16(s, 3H), 1.79(s, 4H), 1.29(s, 6H). ESI-MS: m/z 437.1[M+H] ⁺ .

Example 45

N-(1-(2-chlorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 56)

Compound 56 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.44 (d, J=7.0Hz, 1H), 7.30 (dd, J=7.5, 1.6Hz, 1H), 7.20- 7.11(m, 2H), 6.94(d, J=7.5Hz, 1H), 6.59(d, J=7.5Hz, 1H), 6.54(s, 1H), 5.48(d, J=7.7Hz, 1H), 3.85(t, J=5.5Hz, 2H), 3.81-3.73(m, 1H), 3.61(s, 2H), 2.83(d, J=11.3Hz, 2H), 2.30-2.24(m, 2H), 2.24 (s, 3H), 2.11(s, 3H), 1.91-1.81(m, 4H), 1.79-1.70(m, 2H), 1.46(d, J=10.9Hz, 2H), 1.14(s, 6H). ESI-MS: m/z 458.2[M+H] ⁺ .

Example 46

N-(1-(2-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 57)

Compound 57 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.44 (d, J=7.0Hz, 1H), 7.30 (dd, J=7.5, 1.6Hz, 1H), 7.20- 7.11(m, 2H), 6.94(d, J=7.5Hz, 1H), 6.59(d, J=7.5Hz, 1H), 6.54(s, 1H), 5.48(d, J=7.7Hz, 1H), 3.85(t, J=5.5Hz, 2H), 3.81-3.73(m, 1H), 3.61(s, 2H), 2.83(d, J=11.3Hz, 2H), 2.30-2.24(m, 2H), 2.24 (s, 3H), 2.11(s, 3H), 1.91-1.81(m, 4H), 1.79-1.70(m, 2H), 1.46(d, J=10.9Hz, 2H), 1.14(s, 6H). ESI-MS: m/z 448.1[M+H] ⁺ .

Example 47

N-(1-(3-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 58)

Compound 58 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.44 (d, J=7.0Hz, 1H), 7.30 (dd, J=7.5, 1.6Hz, 1H), 7.20- 7.11(m, 2H), 6.94(d, J=7.5Hz, 1H), 6.59(d, J=7.5Hz, 1H), 6.54(s, 1H), 5.48(d, J=7.7Hz, 1H), 3.85(t, J=5.5Hz, 2H), 3.81-3.73(m, 1H), 3.61(s, 2H), 2.83(d, J=11.3Hz, 2H), 2.30-2.24(m, 2H), 2.24 (s, 3H), 2.11(s, 3H), 1.91-1.81(m, 4H), 1.79-1.70(m, 2H), 1.46(d, J=10.9Hz, 2H), 1.14(s, 6H). ESI-MS: m/z 448.1[M+H] ⁺ .

Example 48

N-(1-Benzylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (compound 59)

Compound 59 was prepared by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.37-7.28 (m, 5H), 7.03 (d, J=7.5Hz, 1H), 6.69 (d , J=7.5Hz, 1H), 6.64(s, 1H), 5.37(d, J=7.6Hz, 1H), 4.01(t, J=5.9Hz, 2H), 3.93-3.75(m, 1H), 3.50 (s, 2H), 2.79(d, J=11.8Hz, 2H), 2.40(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.20(s, 3H), 2.14(t, J= 10.1Hz, 4H), 1.94-1.85(m, 2H), 1.51-1.37(m, 2H). ESI-MS: m/z 381.2[M+H] ⁺ .

Example 49

N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 60)

Compound 60 was prepared by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.62 (d, J=8.1Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.03(d, J=7.5Hz, 1H), 6.69(d, J=7.4Hz, 1H), 6.64(s, 1H), 5.36(d, J=7.8Hz, 1H), 4.01(t, J=5.9 Hz, 2H), 3.89-3.77(m, 1H), 3.52(s, 2H), 2.74(d, J=11.7Hz, 2H), 2.40(t, J=7.3Hz, 2H), 2.32(s, 3H ), 2.20(s, 3H), 2.16(m, 2H), 2.15-2.07(m, 2H), 1.97-1.86(m, 2H), 1.49-1.37(m, 2H). ESI-MS: m/z 406.4[M+H] ⁺ .

Example 50

N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 61)

Compound 61 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.65 (d, J=7.5Hz, 1H), 7.59-7.48 (m, 2H), 7.40-7.32 (m, 1H), 7.02(d, J=7.5Hz, 1H), 6.73-6.60(m, 2H), 5.40(d, J=7.5Hz, 1H), 4.01(t, J=5.9Hz, 2H) , 3.91-3.78(m, 1H), 3.68(s, 2H), 2.78(d, J=11.9Hz, 2H), 2.40(t, J=7.3Hz, 2H), 2.31(s, 3H), 2.25( dd, J=11.5, 2.1Hz, 2H), 2.20(s, 3H), 2.14(dd, J=13.3, 7.0Hz, 2H), 1.96-1.85(m, 2H), 1.53-1.38(m, 2H) .ESI-MS: m/z 428.1[M+Na] ⁺ .

Example 51

N-(1-(3-cyanobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 62)

Compound 62 was prepared by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.66(s, 1H), 7.60-7.50(m, 2H), 7.43(t, J=7.7Hz , 1H), 7.03(d, J=7.4Hz, 1H), 6.70(d, J=7.5Hz, 1H), 6.65(s, 1H), 5.49(d, J=7.9Hz, 1H), 4.01(t , J=5.9Hz, 2H), 3.90-3.76(m, 1H), 3.50(s, 2H), 2.75(d, J=11.6Hz, 2H), 2.42(t, J=7.3Hz, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.15 (m, 4H), 1.91 (d, J=10.6Hz, 2H), 1.51-1.37 (m, 2H). ESI-MS: m/z 428.2[ M+Na] ⁺ .

Example 52

N-(1-(4-chlorobenzyl)piperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (Compound 63)

Compound 63 was prepared according to the method of Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.34-7.22 (m, 5H), 7.03 (d, J=7.5Hz, 1H), 6.70 (d , J=7.5Hz, 1H), 6.65(s, 1H), 5.38(d, J=7.8Hz, 1H), 4.01(t, J=5.9Hz, 2H), 3.89-3.76(m, 1H), 3.45 (s, 2H), 2.76(d, J=11.8Hz, 2H), 2.40(t, J=7.3Hz, 2H), 2.33(s, 3H), 2.20(s, 3H), 2.18-2.14(m, 2H), 2.12(m, 2H), 1.95-1.85(m, 2H), 1.49-1.37(m, 2H). ESI-MS: m/z 415.2[M+H] ⁺ .

Example 53

4-(2,5-Dimethylphenoxy)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)butanamide (Compound 64)

Compound 64 was obtained by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.58 (d, J=8.1Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 7.02(d, J=7.4Hz, 1H), 6.75-6.61(m, 2H), 5.35(d, J=7.7Hz, 1H), 3.98(s, 2H), 3.92-3.76(m, 1H), 3.55 (s, 2H), 2.79(d, J=11.7Hz, 2H), 2.32(s, 3H), 2.26(t, J=7.0Hz, 2H), 2.19(s, 3H), 2.16(m, 2H) , 1.93(m, 4H), 1.53-1.39(m, 2H).ESI-MS: m/z 449.2[M+H] ⁺ .

Example 54

4-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzyl)piperidin-4-yl)butanamide (Compound 65)

Compound 65 was prepared by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.28(s, 2H), 7.01(t, J=8.8Hz, 3H), 6.69(d, J =7.5Hz, 1H), 6.64(s, 1H), 5.35(d, J=7.4Hz, 1H), 4.01(t, J=5.8Hz, 2H), 3.89-3.77(m, 1H), 3.44(s , 2H), 2.76(d, J=11.4Hz, 2H), 2.40(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.20(s, 3H), 2.18-2.08(m, 4H) , 1.90(d, J=12.4Hz, 2H), 1.49-1.37(m, 2H).ESI-MS: m/z 397.7[MH] ^- .

Example 55

4-(2,5-Dimethylphenoxy)-N-(1-(2-methylbenzyl)piperidin-4-yl)butanamide (Compound 66)

Compound 66 was prepared by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.26(dd, J=9.4, 4.3Hz, 2H), 7.17(m, 2H), 7.02(d , J=7.5Hz, 1H), 6.69(d, J=7.5Hz, 1H), 6.64(s, 1H), 5.35(d, J=7.7Hz, 1H), 4.01(t, J=5.7Hz, 2H ), 3.93-3.76(m, 1H), 3.44(s, 2H), 2.77(d, J=8.7Hz, 2H), 2.41(d, J=7.3Hz, 2H), 2.36(s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 2.14 (m, 4H), 1.89 (d, J=10.8Hz, 2H), 1.48-1.33 (m, 2H). ESI-MS: m/z 417.2[ M+Na] ⁺ .

Example 56

N-(1-benzoylpiperidin-4-yl)-4-(2,5-dimethylphenoxy)butanamide (compound 67)

Compound 67 was prepared according to the method of Synthetic Route 5 and Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.41(m, 5H), 7.03(d, J=7.5Hz, 1H), 6.69(d, J =7.4Hz, 1H), 6.64(s, 1H), 5.50(d, J=7.4Hz, 1H), 4.78-4.50(m, 1H), 4.04(ddd, J=20.4, 9.2, 4.4Hz, 3H) , 3.91-3.58(m, 1H), 3.19-2.87(m, 2H), 2.41(t, J=7.2Hz, 2H), 2.32(s, 3H), 2.20(s, 3H), 2.17-2.10(m , 2H), 2.03-1.89(m, 2H), 1.48-1.30(m, 2H).ESI-MS: m/z 417.2[M+Na] ⁺ .

Example 57

4-(2,5-Dimethylphenoxy)-N-(1-nicotinoylpiperidin-4-yl)butanamide (Compound 68)

Compound 68 was prepared according to the method of Synthesis Scheme 5 and Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ8.73-8.62 (m, 2H), 7.76 (d, J=7.8Hz, 1H), 7.40 (dd , J=7.6, 5.0Hz, 1H), 7.03(d, J=7.4Hz, 1H), 6.70(d, J=7.6Hz, 1H), 6.64(s, 1H), 5.68(d, J=6.7Hz , 1H), 4.76-4.55(m, 1H), 4.16-4.04(m, 1H), 4.03-3.94(m, 2H), 3.79-3.60(m, 1H), 3.29-3.09(m, 1H), 3.08 -2.87(m, 1H), 2.42(t, J=7.2Hz, 2H), 2.32(s, 3H), 2.19(s, 3H), 2.16-2.09(m, 2H), 2.09-1.91(m, 2H ), 1.55-1.33(m, 2H).ESI-MS: m/z 419.1[M+H] ⁺ .

Example 58

N-(1-Benzylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 69)

Compound 69 was prepared according to the method of Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.33 (m5H), 7.02 (d, J=7.4Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.64(s, 1H), 5.34(d, J=7.5Hz, 1H), 3.98(s, 2H), 3.90-3.75(m, 1H), 3.51(s, 2H), 2.82(d , J=11.6Hz, 2H), 2.32(s, 3H), 2.26(m, 2H), 2.19(s, 3H), 2.13(d, J=11.3Hz, 2H), 1.94-1.81(m, 6H) , 1.54-1.37(m, 2H).ESI-MS: m/z 395.3[M+H] ⁺ .

Example 59

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (compound 70)

Compound 70 was obtained by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.62 (d, J=8.1Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 7.02(d, J=7.4Hz, 1H), 6.68(d, J=7.7Hz, 1H), 6.64(s, 1H), 5.33(d, J=7.4Hz, 1H), 3.98(s, 2H), 3.92-3.74(m, 1H), 3.54(s, 2H), 2.77(d, J=11.8Hz, 2H), 2.32(s, 3H), 2.26(t, J=6.6Hz, 2H), 2.19(s , 3H), 2.14(d, J=12.0Hz, 2H), 1.98-1.83(m, 6H), 1.47(td, J=11.7, 3.1Hz, 2H).ESI-MS: m/z 442.2 [M+ Na] ⁺ .

Example 60

5-(2,5-Dimethylphenoxy)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)pentanamide (Compound 71)

Compound 71 was obtained by referring to Synthesis Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.58 (d, J=8.1Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 7.02(d, J=7.4Hz, 1H), 6.75-6.61(m, 2H), 5.35(d, J=7.7Hz, 1H), 3.98(s, 2H), 3.92-3.76(m, 1H), 3.55 (s, 2H), 2.79(d, J=11.7Hz, 2H), 2.32(s, 3H), 2.26(t, J=7.0Hz, 2H), 2.19(s, 3H), 2.16(s, 2H) , 1.99-1.83(m, 6H), 1.53-1.39(m, 2H).ESI-MS: m/z 485.3[M+Na] ⁺ .

Example 61

N-(1-(2-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (compound 72)

Compound 72 was prepared by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.66(d, J=7.7Hz, 1H), 7.60-7.49(m, 2H), 7.36(t , J=7.3Hz, 1H), 7.01(d, J=7.4Hz, 1H), 6.72-6.61(m, 2H), 5.37(d, J=7.6Hz, 1H), 3.98(d, J=5.1Hz , 2H), 3.91-3.76(m, 1H), 3.69(s, 2H), 2.81(d, J=11.7Hz, 2H), 2.32(s, 3H), 2.27(m, 2H), 2.25(m, 2H), 2.19(s, 3H), 1.94-1.81(m, 6H), 1.54-1.40(m, 2H). ESI-MS: m/z 442.1[M+Na] ⁺ .

Example 62

N-(1-(3-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (compound 73)

Compound 73 was obtained by referring to Synthetic Scheme 5 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.67(s, 1H), 7.55(d, J=8.4Hz, 2H), 7.44(d, J =7.6Hz, 1H), 7.02(d, J=7.4Hz, 1H), 6.71-6.60(m, 2H), 5.36(d, J=7.8Hz, 1H), 3.98(t, J=5.4Hz, 2H ), 3.92-3.77(m, 1H), 3.52(s, 2H), 2.78(d, J=11.8Hz, 2H), 2.32(s, 3H), 2.27(t, J=7.0Hz, 2H), 2.19 (s, 3H), 2.19-2.12(m, 2H), 1.90(m, 6H), 1.52-1.42(m, 2H). ESI-MS: m/z 442.2[M+Na] ⁺ .

Example 63

N-(1-benzylpiperidin-4-yl)-5-(2,5-diisopropylphenoxy)-2,2-dimethylpentanamide (compound 37)

Compound 37 was obtained by referring to Synthetic Route 5 and Example 1: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.44-7.27 (m, 5H), 7.14-7.06 (m, 3H), 5.57 (d, J= 8.8Hz, 1H), 3.89-3.79(m, 1H), 3.72(dt, J=10.7, 3.6Hz, 2H), 3.48(s, 2H), 3.29(dd, J=17.3, 10.5Hz, 2H), 2.79(d, J=11.3Hz, 2H), 2.14(t, J=11.1Hz, 2H), 1.91(d, J=9.1Hz, 2H), 1.73(s, 4H), 1.51-1.40(m, 2H ), 1.27-1.18(m, 18H).ESI-MS: m/z 479.2[M+H] ⁺ .

Example 64

N-(1-Benzylpiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 2)

Compound 2 was prepared according to the method of Examples 1 and 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.38-7.24 (s, 5H), 6.99 (d, J=7.3Hz, 1H), 6.65 (d, J =7.4Hz, 1H), 6.60(s, 1H), 5.55(d, J=7.4Hz, 1H), 3.90(s, 2H), 3.80(s, 1H), 3.54(s, 2H), 2.85(d , J=11.2Hz, 2H), 2.26(d, J=15.7Hz, 3H), 2.21-2.11(m, 5H), 1.89(d, J=11.6Hz, 2H), 1.68(s, 4H), 1.58 -1.38(m, 2H), 1.19(s, 6H).ESI-MS: m/z 423.3[M+H] ⁺ .

Example 65

N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 18)

Compound 18 was prepared according to the method of Examples 1 and 43: ¹ H NMR (300MHz, d ₆ -DMSO) δ7.78 (d, J=4.6Hz, 2H), 7.49 (d, J=4.1Hz, 2H), 7.16-7.00(m, 2H), 6.64(d, J=20.2Hz, 2H), 3.88(s, 2H), 3.55(s, 1H), 3.53(s, 2H), 2.73(d, J=6.2Hz , 2H), 2.23(s, 3H), 2.08(s, 3H), 2.10-1.90(m, 2H), 1.58(s, 4H), 1.60-1.40(m, 2H), 1.36-1.16(m, 2H ), 1.09(s, 6H).ESI-MS: m/z 470.3[M+Na] ⁺ .

Example 66

5-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 20)

Compound 20 was obtained by referring to the method of Examples 1 and 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.20(d, J=8.2Hz, 2H), 6.99(d, J=7.3Hz, 1H), 6.84( d, J=8.3Hz, 2H), 6.64(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.48(d, J=7.6Hz, 1H), 3.89(d, J=5.4Hz, 2H), 3.79(s, 3H), 3.78-3.74(m, 1H), 3.42(s, 2H), 2.77(d, J=11.4Hz, 2H), 2.29(s, 3H), 2.16(s, 3H ), 2.10-1.98 (d, J=11.1Hz, 2H), 1.87 (s, 4H), 1.65 (s, 2H), 1.51-1.31 (m, 2H), 1.18 (s, 6H).ESI-MS: m/z 475.3[M+Na] ⁺ .

Example 67

N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound twenty one)

Compound 21 was prepared according to the method of Examples 1 and 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.54-7.38 (m, 1H), 7.12 (dd, J=8.5, 2.5Hz, 1H), 7.06-6.94 (m, 2H), 6.67(d, J=7.4Hz, 1H), 6.62(s, 1H), 5.50(d, J=7.7Hz, 1H), 3.94(t, J=5.5Hz, 2H), 3.89 -3.74(m, 1H), 3.57(s, 2H), 2.81(d, J=11.9Hz, 2H), 2.31(d, J=6.3Hz, 3H), 2.25(s, 2H), 2.19(s, 3H), 1.92(d, J=11.0Hz, 2H), 1.72(s, 4H), 1.55-1.36(m, 3H), 1.22(s, 6H). ESI-MS: m/z 475.3 [M+H ] ⁺ .

Example 68

N-(1-(4-chlorobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 22)

Compound 22 was prepared according to the method of Examples 2 and 43: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.52 (d, J=8.3Hz, 2H), 7.37 (d, J=8.3Hz, 2H), 7.23(d, J=7.6Hz, 1H), 6.96(d, J=7.4Hz, 1H), 6.67(s, 1H), 6.59(d, J=7.5Hz, 1H), 3.94-3.77(m, 3H ), 3.61-3.38(m, 1H), 3.18-2.99(m, 1H), 2.93-2.70(m, 2H), 2.22(s, 3H), 2.07(s, 3H), 1.78-1.61(m, 2H ), 1.58(s, 4H), 1.45-1.30(m, 2H), 1.08(s, 6H). ESI-MS: m/z 494.1[M+Na] ⁺ .

Example 69

2-(4-(4-chlorobenzyl)phenoxy)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-methylpropionamide (compound 14)

Compound 14 was prepared according to the method of Synthesis Scheme 1 and Example 1: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.78(d, J=7.6Hz, 3H), 7.49(d, J=7.7Hz, 2H ), 7.31(d, J=8.2Hz, 2H), 7.2l(d, J=8.2Hz, 2H), 7.10(d, J=8.3Hz, 2H), 6.79(d, J=8.3Hz, 2H) , 3.85(s, 2H), 3.70-3.50(m, 3H), 2.72(d, J=8.8Hz, 2H), 2.21-1.96(m, 2H), 1.69-1.56(m, 2H), 1.56-1.40 (m, 2H), 1.40 (s, 6H). ESI-MS: m/z 503.1[M+H] ⁺ .

Example 70

N-(1-benzylpiperidin-4-yl)-2-(4-(4-chlorobenzyl)phenoxy)-2-methylpropanamide (Compound 4)

Compound 4 was obtained by referring to Synthetic Route 1 and Example 1: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.78 (d, J=7.7Hz, lH), 7.37-7.26 (m, 5H), 7.26 -7.18(m, 4H), 7.09(d, J=8.0Hz, 2H), 6.80(d, J=8.1Hz, 2H), 3.85(s, 2H), 3.61(ddd, J=8.2, 7.0, 2.9 Hz, lH), 3.41(s, 2H), 2.71(d, J=10.4Hz, 2H), 1.95(t, J=10.8Hz, 2H), 1.59(d, J=8.9Hz, 2H), 1.47( d, J=11.4Hz, 2H), 1.38(s, 6H).ESI-MS: m/z 475.3[MH] ^- .

Example 71

N-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropionamide (compound 17)

Compound 17 was prepared according to the method of Synthesis Scheme 1 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.48-7.33 (m, 1H), 7.24 (d, J=8.8Hz, 2H), 7.07 (dd , J=14.0, 8.2Hz, 4H), 6.94(td, J=8.4, 2.4Hz, 1H), 6.82(d, J=8.4Hz, 2H), 6.60(d, J=7.7Hz, 1H), 3.89 (s, 2H), 3.86-3.77(m, 1H), 3.54(s, 2H), 2.78(d, J=11.6Hz, 2H), 2.24(t, J=10.7Hz, 2H), 1.91(d, J=10.9Hz, 2H), 1.47(s, 6H), 1.46-1.33(m, 2H). ESI-MS: m/z 529.2[M+H] ⁺ .

Example 72

2-(4-(4-chlorobenzyl)phenoxy)-2-methyl-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)propanamide (compound 15)

Compound 15 was prepared according to the method of Synthesis Scheme 1 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.58 (d, J=8.0Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 7.26(d, J=8.3Hz, 2H), 7.09(dd, J=13.1, 8.4Hz, 4H), 6.85(d, J=8.4Hz, 2H), 6.63(d, J=8.0Hz, 1H), 3.91(s, 2H), 3.88-3.77(m, 1H), 3.54(s, 2H), 2.78(d, J=11.7Hz, 2H), 2.17(t, J=11.3Hz, 2H), 1.93(d , J=10.8Hz, 2H), 1.49(s, 6H), 1.48-1.39(m, 2H).ESI-MS: m/z 546.1[M+H] ⁺ .

Example 73

2-(4-(4-Chlorobenzyl)phenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-2-methylpropionamide (compound 16)

Compound 16 was prepared according to the method of Synthesis Scheme 1 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.22(dd, J=13.8, 8.5Hz, 4H), 7.06(dd, J=16.1, 8.3Hz , 4H), 6.83(t, J=8.0Hz, 4H), 6.58(d, J=8.0Hz, 1H), 3.89(s, 2H), 3.83(s, 1H), 3.79(s, 3H), 3.42 (s, 2H), 2.77 (d, J = 11.6Hz, 2H), 2.11 (t, J = 10.7Hz, 2H), 1.89 (d, J = 12.3Hz, 2H), 1.47 (s, 6H), 1.50 -1.30(m, 2H).ESI-MS: m/z 507.3[M+H] ⁺ .

Example 74

2-(4-Benzoylphenoxy)-N-(1-benzylpiperidin-4-yl)-2-methylpropionamide (compound 74)

Compound 74 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.81-7.50 (m, 5H), 7.46 (d, J=8.4Hz, 2H), 7.28-7.10 (m, 5H ), 7.01(d, J=8.7Hz, 2H), 6.10(d, J=8.1Hz, 1H), 3.95-3.73(m, 1H), 3.47(s, 2H), 2.65(d, J=11.8Hz , 2H), 2.20(t, J=10.8Hz, 2H), 1.88(d, J=11.5Hz, 2H), 1.45(s, 6H), 1.45-1.20(m, 2H). ESI-MS: m/z 479.1[M+Na] ⁺ .

Example 75

2-(4-Benzoylphenoxy)-N-(1-benzoylpiperidin-4-yl)acetamide (Compound 96)

Compound 96 was obtained by referring to the method of Example 2: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85 (d, J=8.7Hz, 2H), 7.76 (d, J=7.0Hz, 2H), 7.63-7.53( m, 1H), 7.53-7.44(m, 2H), 7.43-7.33(m, 5H), 7.00(d, J=8.7Hz, 2H), 6.45(d, J=7.5Hz, 1H), 4.80-4.49 (m, 3H), 4.24-4.07(m, 1H), 3.99-3.67(m, 1H), 3.24-2.85(m, 2H), 2.16-1.86(m, 2H), 1.53-1.19(m, 2H) .ESI-MS: m/z 443.3[M+H] ⁺ .

Example 76

2-(4-benzoylphenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)acetamide (Compound 97)

Compound 97 was prepared by referring to Synthetic Scheme 2 and Example 43: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.15(d, J=8.5Hz, 3H), 7.93(d, J=8.5Hz, 2H ), 7.75(d, J=8.8Hz, 2H), 7.72-7.62(m, 3H), 7.60-7.52(m, 2H), 7.07(d, J=8.8Hz, 2H), 4.57(s, 2H) , 3.76-3.64(m, 1H), 3.63-3.50(m, 2H), 2.61-2.52(m, 2H), 1.84-1.72(m, 2H), 1.59-1.42(m, 2H).ESI-MS: m/z 526.1[M+Na] ⁺ .

Example 77

N-((3S,4S)-1-((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)- 2,2-Dimethylpentanamide (Compound 98)

Take compound II-1 (200mg, 0.8mmoL) and place it in a reaction flask, add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (456mg, 1.2mmoL), under the protection of nitrogen, was added anhydrous DMF (5mL), stirred and dissolved at room temperature, then added N,N-diisopropylethylamine (DIPEA) (0.66mL), Stir at room temperature for 0.5h. Optically pure (3S, 4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (175mg, 0.8mmoL) was dissolved in anhydrous DMF (2mL), and added dropwise to the reaction flask with a syringe, Stirring was continued at room temperature for 4h. Add water (20mL) to dilute the reaction solution, and extract with ethyl acetate (10mLx3). The organic phase was washed with water (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain compound III-1 (light yellow liquid, 250 mg, yield 69%).

Compound III-1 (250mg, 0.56mmoL) was dissolved in dichloromethane (5mL), trifluoroacetic acid (3mL) was added under ice-cooling, and stirred overnight at room temperature. Spin to dry, adjust the pH to alkaline with saturated sodium bicarbonate, extract with ethyl acetate (10mL x3), wash with saturated NaCl (20mL), dry with anhydrous sodium sulfate, and spin dry to obtain compound III-2 (pale yellow liquid, 160mg, Yield 82%).

Compound III-2 (160mg, 0.45mmoL) was dissolved in DCM (5mL), triethylamine (0.095mL) and p-cyanobenzenesulfonyl chloride (92mg, 0.46mmoL) were added, and stirred at room temperature for 4h. After spin-drying, the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 98 (white solid, 200 mg, yield 85%): ¹ H NMR (300 MHz, CDCl ₃ )δ8.01-7.85 (m, 4H), 7.04 (d, J = 7.4Hz, 1H), 6.71 (d, J = 7.4Hz, 1H), 6.64 (s, 1H), 5.68 (d, J = 7.1 Hz, 1H), 4.61-4.33(m, 1H), 4.16-4.04(m, 1H), 3.95(t, J=4.2Hz, 3H), 3.81-3.70(m, 1H), 2.66-2.54(m, 2H), 2.34(s, 3H), 2.20(s, 3H), 2.19-2.11(m, 1H), 1.80-1.70(m, 4H), 1.61-1.52(m, 1H), 1.24(s, 6H) .ESI-MS: m/z 538.3[M+Na] ⁺ .ee=99.8% (chiral HPLC analysis conditions: ChiralpakIC4.6mm×250mm, column temperature: 25°C; mobile phase: 70% n-hexane/30% iso propanol; flow rate: 1mL/min; detection wavelength: UV254nm; retention time: 16.0min). In the following examples, unless otherwise specified, the detection of the ee value adopts the above-mentioned similar conditions.

Example 78

4-(2,5-Dimethylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (compound 101)

Compound 101 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.22(d, J=8.5Hz, 2H), 7.03(d, J=7.4Hz, 1H), 6.69(d, J=7.5Hz, 1H), 6.64(s, 1H), 5.39(d, J=7.7Hz, 1H), 4.01(t, J=5.9Hz, 2H), 3.82(s, 4H), 3.43(s, 2H), 2.77(d, J=11.6Hz, 2H), 2.39(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.20(s, 3H), 2.11(dd, J=14.5, 8.3 Hz, 4H), 1.90(d, J=13.1Hz, 3H), 1.49-1.35(m, 2H).ESI-MS: m/z 411.0[M+H] ⁺ .

Example 79

4-(2,5-Dimethylphenoxy)-N-(1-(3-methoxybenzyl)piperidin-4-yl)butanamide (compound 102)

Compound 102 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.24(dd, J=8.0Hz, 1H), 7.03(d, J=7.4Hz, 1H), 6.90(d, J=4.5Hz, 2H), 6.82(dd, J=8.2Hz, 1H), 6.69(d, J=7.5Hz, 1H), 6.64(s, 1H), 5.39(d, J=7.6Hz, 1H) , 4.01(t, J=5.9Hz, 2H), 3.88-3.76(m, 4H), 3.47(s, 2H), 2.85-2.71(m, 2H), 2.40(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.20(s, 3H), 2.18-2.07(m, 4H), 1.93-1.83(m, 2H), 1.51-1.38(m, 2H). ESI-MS: m/z 411.1[ M+H] ⁺ .

Example 80

4-(2,5-Dimethylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)butanamide (compound 103)

Compound 103 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.79-7.69 (m, 2H), 7.65-7.50 (m, 3H), 6.99 (d, J=7.5Hz, 1H ), 6.66(d, J=7.6Hz, 1H), 6.60(s, 1H), 5.46(d, J=8.0Hz, 1H), 3.96(t, J=5.9Hz, 2H), 3.80-3.64(m , 3H), 2.45-2.31(m, 4H), 2.29(s, 3H), 2.15(s, 3H), 2.12-2.03(m, 2H), 2.00-1.89(m, 2H), 1.48(ddd, J =22.7, 11.4, 3.2Hz, 2H).ESI-MS: m/z 453.2[M+Na] ⁺ .

Example 81

N-(1-Benzylpiperidin-4-yl)-4-(5-isopropyl-2-methylphenoxy)butanamide (compound 104)

Compound 104 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.39-7.27 (m, 5H), 7.10 (d, J=7.6Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.72(s, 1H), 5.45(d, J=7.7Hz, 1H), 4.05(t, J=5.8Hz, 2H), 3.93-3.78(m, 1H), 3.51(s, 2H ), 2.93-2.85(m, 1H), 2.85-2.76(m, 2H), 2.43(t, J=7.2Hz, 2H), 2.23(s, 3H), 2.20-2.09(m, 4H), 1.97- 1.86(m, 2H), 1.53-1.36(m, 2H), 1.27(d, J=6.9Hz, 6H).ESI-MS: m/z 409.0[M+H] ⁺ .

Example 82

N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(5-isopropyl-2-methylphenoxy)butanamide (compound 105)

Compound 105 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.63(d, J=8.2Hz, 2H), 7.46(d, J=8.0Hz, 2H), 7.09(d, J=7.5Hz, 1H), 6.78(d, J=7.6Hz, 1H), 6.71(s, 1H), 5.43(d, J=7.7Hz, 1H), 4.05(t, J=5.8Hz, 2H) , 3.95-3.78(m, 1H), 3.54(s, 2H), 2.94-2.82(m, 1H), 2.8-2.7(m, 2H), 2.43(t, J=7.2Hz, 2H), 2.23(s , 3H), 2.25-2.15(m, 4H), 1.97-1.87(m, 2H), 1.50-1.37(m, 2H), 1.26(d, J=6.9Hz, 6H).ESI-MS: m/z 434.2[M+H] ⁺ .

Example 83

4-(5-isopropyl-2-methylphenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (compound 106)

Compound 106 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.24(d, J=8.6Hz, 2H), 7.09(d, J=7.6Hz, 1H), 6.89(d, J=8.7Hz, 2H), 6.78(dd, J=7.5Hz, 1.5Hz, 1H), 6.71(d, 1H), 5.40(d, J=7.8Hz, 1H), 4.05(t, J=5.9Hz , 2H), 3.89-3.80(m, 4H), 3.44(s, 2H), 2.95-2.85(m, 1H), 2.83-2.73(m, 2H), 2.42(t, J=7.3Hz, 2H), 2.23(s, 3H), 2.21-2.06(m, 4H), 1.97-1.83(m, 3H), 1.49-1.37(m, 2H), 1.27(d, J=6.9Hz, 6H).ESI-MS: m/z 439.2[M+H] ⁺ .

Example 84

N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(2,5-dichlorophenoxy)butanamide (compound 107)

Compound 107 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60(d, J=8.2Hz, 2H), 7.42(d, J=8.2Hz, 2H), 7.29(d, J=5.1Hz, 1H), 6.91(s, 1H), 6.88(d, J=2.2Hz, 1H), 5.48(d, J=7.5Hz, 1H), 4.06(t, J=5.8Hz, 2H) , 3.89-3.70(m, 1H), 3.50(s, 2H), 2.78-2.67(m, 2H), 2.42(t, J=7.1Hz, 2H), 2.22-2.09(m, 4H), 1.92-1.81 (m, 2H), 1.43-1.31 (m, 2H). ESI-MS: m/z 446.3 [M+H] ⁺ .

Example 85

4-(2,5-dichlorophenoxy)-N-(1-(4-methoxybenzyl)piperidin-4-yl)butanamide (compound 99)

Compound 99 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.28(d, J=6.5Hz, 2H), 7.20(d, J=8.6Hz, 2H), 6.90(s, 1H), 6.88-6.82(m, 2H), 5.46(d, J=7.9Hz, 1H), 4.05(t, J=5.8Hz, 2H), 3.85-3.73(m, 4H), 3.40(s, 2H ), 2.80-2.70(m, 2H), 2.41(t, J=7.0Hz, 2H), 2.23-2.14(m, 2H), 1.90-1.73(m, 4H), 1.43-1.33(m, 2H).ESI -MS: m/z 451.2[M+H] ⁺ .

Example 86

4-((4-(5-(2,5-dimethylphenoxy)pentyl)piperidin-1-yl)methyl)benzamide (Compound 100)

Compound 100 was obtained by referring to the method of Example 1: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.88(s, 1H), 7.80(d, J=7.5Hz, 2H), 7.68(d, J=7.3 Hz, 1H), 7.32(d, J=7.3Hz, 2H), 7.25(s, 1H), 6.95(d, J=7.5Hz, 1H), 6.69(s, 1H), 6.59(d, J=7.4 Hz, 1H), 3.90(t, J=6.0Hz, 2H), 3.56-3.42(m, 3H), 2.75-2.64(m, 2H), 2.22(s, 3H), 2.13-1.91(m, 7H) , 1.71-1.56(m, 6H), 1.39-1.29(m, 2H).ESI-MS: m/z 438.2[M+H] ⁺ .

Example 87

5-(2,5-dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 108)

Compound 108 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.77(m, 2H), 7.21(dd, J=8.6Hz, 8.6Hz, 2H), 7.00(d, J= 7.5Hz, 1H), 6.66(d, J=7.5Hz, 1H), 6.59(s, 1H), 5.44(d, J=8.1Hz, 1H), 3.90(t, J=5.1Hz, 2H), 3.80 -3.67(m, 3H), 2.40(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.01-1.91(m, 2H), 1.73-1.65(m, 4H), 1.52-1.41 (m, 2H), 1.17(s, 6H).ESI-MS: m/z 529.2[M+K] ⁺ .

Example 88

5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(1-((4-nitrophenyl)sulfonyl)piperidin-4-yl)pentanamide ( Compound 109)

Compound 109 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.41(d, J=8.8Hz, 2H), 7.97(d, J=8.7Hz, 2H), 7.03(d, J=7.4Hz, 1H), 6.69(d, J=7.4Hz, 1H), 6.62(s, 1H), 5.51(d, J=7.2Hz, 1H), 3.97-3.72(m, 5H), 2.58- 2.44(m, 2H), 2.32(s, 3H), 2.19(s, 3H), 2.01(d, J=12.2Hz, 2H), 1.77-1.66(m, 4H), 1.56-1.44(m, 2H) , 1.21(s, 6H).ESI-MS: m/z540.2[M+Na] ⁺ .

Example 89

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(phenylsulfonyl)piperidin-4-yl)pentanamide (compound 110)

Compound 110 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.78 (d, J=8.1Hz, 2H), 7.67-7.53 (m, 3H), 7.03 (d, J=7.3 Hz, 1H), 6.69(d, J=7.2Hz, 1H), 6.62(s, 1H), 5.51(d, J=7.6Hz, 1H), 3.92(t, J=5.3Hz, 2H), 3.83- 3.68(m, 3H), 2.48-2.35(m, 2H), 2.32(s, 3H), 2.19(s, 3H), 2.03-1.91(m, 2H), 1.76-1.64(m, 4H), 1.55- 1.44(m, 2H), 1.20(s, 6H). ESI-MS: m/z 473.2[M+H] ⁺ .

Example 90

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide ( Compound 111)

Compound 111 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.81 (m, 4H), 7.02 (d, J=7.4Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.61(s, 1H), 5.49(d, J=7.5Hz, 1H), 3.92(t, J=5.1Hz, 2H), 3.85-3.71(m, 3H), 2.57-2.43(m , 2H), 2.31(s, 3H), 2.18(s, 3H), 2.04-1.94(m, 2H), 1.76-1.65(m, 4H), 1.55-1.43(m, 2H), 1.20(s, 6H ).ESI-MS: m/z 520.2[M+Na] ⁺ .

Example 91

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl ) valeramide (compound 112)

Compound 112 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.88(d, J=8.0Hz, 2H), 7.80(d, J=8.3Hz, 2H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.2Hz, 1H), 6.58(s, 1H), 5.45(d, J=7.4Hz, 1H), 3.90(t, J=6.0Hz, 2H) , 3.85-3.67(m, 3H), 2.51-2.38(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.02-1.91(m, 2H), 1.73-1.61(m, 4H) , 1.51-1.39(m, 2H), 1.17(s, 6H).ESI-MS: m/z 563.2[M+Na] ⁺ .

Example 92

5-(2,5-Dimethylphenoxy)-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 113)

Compound 113 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.64(d, J=8.8Hz, 2H), 6.96(d, J=8.6Hz, 3H), 6.62(d, J=7.5Hz, 1H), 6.55(s, 1H), 5.49(d, J=7.8Hz, 1H), 3.88-3.82(m, 5H), 3.75-3.60(m, 3H), 2.38-2.27(m , 2H), 2.25(s, 3H), 2.12(s, 3H), 1.95-1.84(m, 2H), 1.71-1.61(m, 4H), 1.53-1.39(m, 2H), 1.13(s, 6H ).ESI-MS: m/z 525.2[M+Na] ⁺ .

Example 93

N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 114)

Compound 114 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.11-8.05 (m, 1H), 7.94-7.87 (m, 1H), 7.82-7.68 (m, 2H), 7.02 (d, J=7.4Hz, 1H), 6.68(d, J=7.4Hz, 1H), 6.62(s, 1H), 5.54(d, J=7.5Hz, 1H), 3.93(t, J=5.4Hz , 2H), 3.95-3.87(m, 2H), 3.88-3.80(m, 1H), 2.87-2.78(m, 2H), 2.32(s, 3H), 2.19(s, 3H), 2.05-1.98(m , 2H), 1.78-1.63(m, 4H), 1.56-1.50(m, 2H), 1.21(s, 6H). ESI-MS: m/z 545.2[M+K] ⁺ .

Example 94

N-(1-((2-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide ( Compound 115)

Compound 115 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.05 (dd, J=7.8, 1.2Hz, 1H), 7.87 (dd, J=7.5, 1.2Hz, 1H), 7.79-7.65(m, 2H), 6.99(d, J=7.4Hz, 1H), 6.65(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.51(d, J=7.5Hz, 1H ), 3.94-3.76(m, 5H), 2.85-2.70(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.03-1.92(m, 2H), 1.73-1.64(m, 4H ), 1.56-1.43(m, 2H), 1.18(s, 6H).ESI-MS: m/z 520.1[M+Na] ⁺ .

Example 95

N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide ( Compound 116)

Compound 116 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.09(s, 1H), 8.01(d, J=7.9Hz, 1H), 7.92(d, J=7.8Hz, 1H), 7.73(dd, J=7.8, 7.8Hz, 1H), 7.04(d, J=7.4Hz, 1H), 6.71(d, J=7.4Hz, 1H), 6.63(s, 1H), 5.51( d, J=7.6Hz, 1H), 3.95(t, J=5.1Hz, 2H), 3.82-3.70(m, 3H), 2.53-2.45(m, 2H), 2.34(s, 3H), 2.20(s , 3H), 2.06-1.98(m, 2H), 1.80-1.65(m, 4H), 1.53(ddd, J=15.8, 12.4, 4.0Hz, 2H), 1.22(s, 6H).ESI-MS: m /z 520.1[M+Na] ⁺ .

Example 96

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzamide (compound 117)

Compound 117 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.96(d, J=8.3Hz, 2H), 7.83(d, J=8.2Hz, 2H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.97(br s, 2H), 5.46(d, J=7.5Hz, 1H), 3.89(t , J=5.0Hz, 2H), 3.84-3.74(m, 2H), 3.74-3.64(m, 1H), 2.50-2.38(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.01-1.89(m, 2H), 1.73-1.64(m, 4H), 1.54-1.41(m, 2H), 1.17(s, 6H). ESI-MS: m/z 538.3[M+Na] ⁺ .

Example 97

Methyl 4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoate (compound 118 )

Compound 118 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19(d, J=8.3Hz, 2H), 7.82(d, J=8.3Hz, 2H), 7.00(d, 1H), 6.66(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.44(d, J=7.5Hz, 1H), 3.97(s, 3H), 3.89(t, J=5.2Hz, 2H), 3.84-3.76(m, 2H), 3.74-3.63(m, 1H), 2.49-2.37(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.02-1.91(m, 2H), 1.74-1.62(m, 4H), 1.51-1.38(m, 2H), 1.17(s, 6H). ESI-MS: m/z 553.3[M+Na] ⁺ .

Example 98

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 119)

Compound 118 (400mg, 0.75mmoL) was dissolved in methanol and tetrahydrofuran (5:1, 24mL), 1N NaOH (2mL) was added, and stirred overnight at room temperature. Evaporate the solvent under reduced pressure, add 1N HCl to make it acidic, a white solid precipitates out, filter, wash with water, collect the white solid, add 20mL of petroleum ether and stir for 2h, filter with suction, and dry in vacuo to obtain compound 119 (white solid, 380mg, yield 98%): ¹ H NMR (300MHz, CDCl ₃ ) δ13.47(br s, 1H), 8.17(d, J=8.3Hz, 2H), 7.86(d, J=8.2Hz, 2H), 7.22(d , J=7.6Hz, 1H), 6.98(d, J=7.4Hz, 1H), 6.69(s, 1H), 6.63(d, J=7.5Hz, 1H), 3.87(t, J=6.0Hz, 2H ), 3.67-3.51(m, 3H), 2.47-2.34(m, 2H), 2.24(s, 3H), 2.09(s, 3H), 1.76-1.67(m, 2H), 1.61-1.41(m, 6H ), 1.07(s, 6H).ESI-MS: m/z 539.2[M+Na] ⁺ .

Example 99

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 120)

Compound 120 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ9.01 (d, J=1.5Hz, 1H), 8.85 (dd, J=5.1, 1.5Hz, 1H), 8.06( d, J=8.0Hz, 1H), 7.51(dd, J=7.8, 5.1Hz, 1H), 7.02(d, J=7.5Hz, 1H), 6.68(d, J=7.4Hz, 1H), 6.61( s, 1H), 5.48(d, J=7.4Hz, 1H), 3.91(t, J=5.2Hz, 2H), 3.90-3.65(m, 3H), 2.49(m, 2H), 2.31(s, 3H ), 2.18(s, 3H), 2.00(m, 2H), 1.76-1.66(m, 4H), 1.58-1.44(m, 2H), 1.20(s, 6H). ESI-MS: m/z 474.2[ M+H] ⁺ .

Example 100

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4- base) pentamide (compound 121)

Compound 121 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.84(d, J=8.7Hz, 2H), 7.40(d, J=8.3Hz, 2H), 7.04(d, J=7.4Hz, 1H), 6.70(d, J=7.5Hz, 1H), 6.63(s, 1H), 5.57(d, J=7.5Hz, 1H), 3.94(t, J=4.9Hz, 2H) , 3.88-3.72(m, 3H), 2.53-2.40(m, 2H), 2.33(s, 3H), 2.20(s, 3H), 2.06-1.96(m, 2H), 1.77-1.68(m, 4H) , 1.63-1.47(m, 2H), 1.21(s, 6H).ESI-MS: m/z 579.3[M+Na] ⁺ .

Example 101

N-(2-(dimethylamino)ethyl)-4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidine -1-yl)sulfonyl)benzamide (compound 122)

Dissolve compound 119 (100mg, 0.19mmoL), HATU (111mg, 0.29mmoL) and DIPEA (0.16mL) in anhydrous DMF (5mL), stir at room temperature for 30min, add N,N-dimethyldiethylamine (0.032mL ), stirred at room temperature for 4h. Add water (20 mL) to quench the reaction, extract with ethyl acetate (10 mL x 3), wash the organic phase with saturated sodium chloride (20 mL) and water (20 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane/methanol/triethylamine=50:1:1), and the obtained oil was added to saturated hydrochloric acid-ethanol solution and stirred for 30 min. The solvent was distilled off under reduced pressure, and the residue was crystallized from methanol-ether to obtain the hydrochloride salt of compound 122 (white solid, 70 mg, yield 63%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.98 (d, J= 8.3Hz, 2H), 7.81(d, J=8.3Hz, 2H), 7.21(br s, 1H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.5Hz, 1H), 6.59(s, 1H), 5.52(d, J=7.8Hz, 1H), 3.89(t, J=5.3Hz, 2H), 3.83-3.75(m, 2H), 3.74-3.65(m, 1H), 3.58 (dd, J=11.0, 5.2Hz, 2H), 2.63(t, J=5.7Hz, 2H), 2.49-2.38(m, 2H), 2.38-2.32(m, 6H), 2.29(s, 3H), 2.16(s, 3H), 1.99-1.90(m, 2H), 1.76-1.61(m, 4H), 1.55-1.41(m, 2H), 1.18(s, 6H). ESI-MS: m/z 587.3[ M+H] ⁺ .

Example 102

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(4-methylpiperazine-1-carbonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 123)

The hydrochloride salt of compound 123 was prepared according to the method of Example 101: ¹ H NMR (300MHz, CDCl ₃ ) δ13.75(s, 1H), 7.84(d, J=7.8Hz, 2H), 7.60(d, J =7.8Hz, 2H), 7.00(d, J=7.3Hz, 1H), 6.66(d, J=7.3Hz, 1H), 6.59(s, 1H), 5.49(d, J=7.6Hz, 1H), 3.89(t, J=4.8Hz, 2H), 3.85-3.77(m, 2H), 3.76-3.66(m, 1H), 3.48(s, 3H), 2.84(s, 4H), 2.52-2.39(m, 2H), 2.29(s, 3H), 2.22-2.10(m, 7H), 2.01-1.92(m, 2H), 1.75-1.63(m, 4H), 1.55-1.44(m, 2H), 1.18(s, 6H).ESI-MS: m/z621.2[M+Na] ⁺ .

Example 103

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(naphthalene-2-ylsulfonyl)piperidin-4-yl)pentanamide (compound 124)

Compound 124 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.33(s, 1H), 7.97(d, J=8.3Hz, 2H), 7.92(d, J=7.7Hz, 1H), 7.73(d, J=8.7Hz, 1H), 7.70-7.59(m, 2H), 6.99(d, J=7.4Hz, 1H), 6.65(d, J=7.4Hz, 1H), 6.57( s, 1H), 5.46(d, J=7.4Hz, 1H), 3.92-3.79(m, 4H), 3.78-3.62(m, 1H), 2.55-2.41(m, 2H), 2.28(s, 3H) , 2.15(s, 3H), 2.00-1.89(m, 2H), 1.72-1.60(m, 4H), 1.55-1.41(m, 2H), 1.16(s, 6H). ESI-MS: m/z 545.3 [M+Na] ⁺ .

Example 104

N-(1-(4-cyanobenzoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 125)

Take 4-cyanobenzoic acid (80mg, 0.54mmol) and dichloromethane (5mL) to dissolve, add dropwise oxalyl chloride (54μL, 0.63mmol) under ice-cooling, add two drops of DMF, and naturally warm to room temperature. After stirring for 5 h, it was cooled in an ice bath again, triethylamine (125 μL) was added, and compound II-3 (Example 26, 150 mg, 0.45 mmol) was added after stirring for 5 minutes, and the mixture was naturally warmed to room temperature. After the reaction was complete, the reaction solution was concentrated, added with saturated aqueous sodium carbonate solution (10 mL), and extracted with dichloromethane (3×10 mL). The organic phase was washed successively with saturated sodium bicarbonate (10 mL), water (5 mL) and saturated sodium chloride solution (5 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=50:1) to obtain compound 125 (white solid, 154 mg, yield 74%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.71(d, J=7.5Hz, 2H), 7.48(d, J=7.5Hz, 2H), 7.00(d, J=6.9Hz, 1H), 6.66(d, J=7.0Hz, 1H), 6.60(s, 1H), 5.52(d, J=6.1Hz, 1H), 4.76-4.52(m, 1H), 4.13-3.97(m, 1H), 3.98-3.85(m, 2H), 3.71 -3.42(m, 1H), 3.24-2.80(m, 2H), 2.29(s, 3H), 2.17(s, 3H), 2.09-1.86(m, 2H), 1.81-1.64(m, 4H), 1.50 -1.28(m, 2H), 1.20(s, 6H).ESI-MS: m/z 484.2[M+Na] ⁺ .

Example 105

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)pentanamide (compound 126)

Compound 126 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.83(d, J=8.0Hz, 2H), 7.57(d, J=7.9Hz, 2H), 7.23( d, J=7.7Hz, 1H), 6.96(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.4Hz, 1H), 4.53-4.33(m, 1H), 3.96-3.77(m, 3H), 3.52-3.38(m, 1H), 3.20-3.02(m, 1H), 2.99-2.81(m, 1H), 2.22(s, 3H), 2.08(s, 3H), 1.86-1.24(m, 8H), 1.09(s, 6H).ESI-MS: m/z 527.2[M+Na] ⁺ .

Example 106

5-(2,5-dimethylphenoxy)-N-(1-(4-methoxybenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 127 )

Compound 127 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.32 (d, J=8.4Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 7.00( d, J=8.4Hz, 2H), 6.96(d, J=7.2Hz, 1H), 6.68(s, 1H), 6.60(d, J=7.4Hz, 1H), 4.47-3.59(m, 8H), 3.14-2.85(m, 2H), 2.22(s, 3H), 2.08(s, 3H), 1.76-1.62(m, 2H), 1.58(s, 4H), 1.47-1.31(m, 2H), 1.09( s, 6H).ESI-MS: m/z 489.3[M+Na] ⁺ .

Example 107

5-(2,5-Dimethylphenoxy)-N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 128)

Compound 128 was prepared according to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.48-7.36(m, 2H), 7.34-7.24(m, 2H), 7.21(d, J=8.0Hz , 1H), 6.96(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.3Hz, 1H), 4.51-4.25(m, 1H), 3.96-3.78(m, 3H), 3.67-3.44(m, 1H), 3.18-2.74(m, 2H), 2.22(s, 3H), 2.08(s, 3H), 1.78-1.52(m, 6H), 1.50-1.26(m, 2H), 1.09(s, 6H).ESI-MS: m/z 477.3[M+Na] ⁺ .

Example 108

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzoyl)piperidin-4-yl)pentanamide (compound 129)

Compound 129 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, CDCl ₃ ) δ8.27(d, J=8.7Hz, 2H), 7.54(d, J=8.7Hz, 2H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.7Hz, 1H), 6.60(s, 1H), 5.52(d, J=7.3Hz, 1H), 4.82-4.54(m, 1H), 4.17- 3.98(m, 1H), 3.92(t, 2H), 3.70-3.43(m, 1H), 3.26-2.81(m, 2H), 2.29(s, 3H), 2.17(s, 3H), 2.09-1.89( m, 2H), 1.79-1.63(m, 4H), 1.49-1.25(m, 2H), 1.21(s, 6H). ESI-MS: m/z 504.3[M+Na] ⁺ .

Example 109

Methyl 4-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidine-1-carbonyl)benzoate (compound 130)

Compound 130 was prepared according to the method of Example 104: ¹ H NMR (300MHz, CDCl ₃ ) δ8.08(d, J=8.0Hz, 2H), 7.44(d, J=7.9Hz, 2H), 7.00(d, J=7.4Hz, 1H), 6.78-6.53(m, 2H), 5.53(d, J=7.4Hz, 1H), 4.80-4.55(m, 1H), 4.12-3.99(m, 1H), 3.99-3.86 (m, 5H), 3.74-3.46(m, 1H), 3.24-2.82(m, 2H), 2.29(s, 3H), 2.17(s, 3H), 2.10-1.83(m, 2H), 1.81-1.65 (m, 4H), 1.56-1.29 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 517.2[M+Na] ⁺ .

Example 110

N-(1-(2-naphthoyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide (compound 131)

Compound 131 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.04-7.89 (m, 4H), 7.65-7.54 (m, 2H), 7.47 (d, J=8.3Hz , 1H), 7.24(d, J=7.7Hz, 1H), 6.94(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.57(d, J=7.4Hz, 1H), 4.63-4.29 (m, 1H), 3.98-3.76(m, 3H), 3.73-3.49(m, 1H), 3.21-2.77(m, 2H), 2.21(s, 3H), 2.08(s, 3H), 1.86-1.29 (m, 8H), 1.10 (s, 6H). ESI-MS: m/z 509.3[M+Na] ⁺ .

Example 111

4-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidine-1-carbonyl)benzoic acid (compound 132)

Referring to the method of Example 98, compound 130 was hydrolyzed to obtain compound 132: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.12 (brs, 1H), 8.01 (d, J=8.1Hz, 2H), 7.45 (d, J=8.2Hz, 2H), 7.22(d, J=7.8Hz, 1H), 6.96(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.5Hz , 1H), 4.55-4.34(m, 1H), 3.98-3.76(m, 3H), 3.55-3.40(m, 1H), 3.18-2.77(m, 2H), 2.22(s, 3H), 2.08(s , 3H), 1.84-1.32(m, 8H), 1.09(s, 6H).ESI-MS: m/z 503.2[M+Na] ⁺ .

Example 112

4-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidine-1-carbonyl)benzamide (compound 133)

Compound 133 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.07 (brs, 1H), 7.93 (d, J=8.1Hz, 2H), 7.49 (brs, 1H), 7.41(d, J=8.0Hz, 2H), 7.26(d, J=7.9Hz, 1H), 6.96(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.3 Hz, 1H), 4.50-4.35(m, 1H), 3.96-3.77(m, 3H), 3.54-3.40(m, 1H), 3.17-3.03(m, 1H), 2.93-2.78(m, 1H), 2.22(s, 3H), 2.08(s, 3H), 1.82-1.30(m, 8H), 1.09(s, 6H). ESI-MS: m/z 502.3[M+Na] ⁺ .

Example 113

4-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidine-1-carbonyl)-N,N-dimethylbenzamide (compound 134)

Compound 134 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, CDCl ₃ ) δ7.51-7.36 (m, 4H), 7.00 (d, J=7.4Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 6.60(s, 1H), 5.52(d, J=7.6Hz, 1H), 4.83-4.44(m, 1H), 4.11-3.96(m, 1H), 3.92(t, J=4.9Hz , 2H), 3.83-3.56(m, 1H), 3.25-2.79(m, 8H), 2.29(s, 3H), 2.17(s, 3H), 2.06-1.85(m, 2H), 1.79-1.64(m , 4H), 1.53-1.27(m, 2H), 1.20(s, 6H).ESI-MS: m/z 530.3[M+Na] ⁺ .

Example 114

N-(1-(benzo[d][1,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)- 2,2-Dimethylpentanamide (Compound 135)

Compound 135 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.20 (d, J=7.9Hz, 1H), 7.05-6.82 (m, 4H), 6.68 (s, 1H ), 6.60(d, J=7.5Hz, 1H), 6.08(s, 2H), 4.46-3.58(m, 5H), 3.08-2.80(m, 2H), 2.22(s, 3H), 2.08(s, 3H), 1.76-1.51(m, 6H), 1.49-1.27(m, 2H), 1.09(s, 6H). ESI-MS: m/z 503.3[M+Na] ⁺ .

Example 115

N-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-carbonyl)piperidin-4-yl)-5-(2,5-dimethyl phenoxy)-2,2-dimethylpentanamide (compound 136)

Compound 136 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.48(d, J=8.2Hz, 1H), 7.43(s, 1H), 7.21(d, J=8.1 Hz, 2H), 6.96(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.3Hz, 1H), 4.55-4.19(m, 1H), 3.99-3.77(m , 3H), 3.74-3.46(m, 1H), 3.18-2.77(m, 2H), 2.22(s, 3H), 2.08(s, 3H), 1.80-1.51(m, 6H), 1.49-1.27(m , 2H), 1.09(s, 6H).ESI-MS: m/z 539.3[M+Na] ⁺ .

Example 116

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(quinoline-6-carbonyl)piperidin-4-yl)pentanamide (compound 137)

Compound 137 was prepared according to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.97(d, J=2.8Hz, 1H), 8.44(d, J=8.0Hz, 1H), 8.09( d, J=8.6Hz, 1H), 8.00(s, 1H), 7.71(d, J=8.4Hz, 1H), 7.61(dd, J=8.2, 4.2Hz, 1H), 7.24(d, J=7.7 Hz, 1H), 6.94(d, J=7.4Hz, 1H), 6.67(s, 1H), 6.57(d, J=7.3Hz, 1H), 4.58-4.30(m, 1H), 3.97-3.79(m , 3H), 3.72-3.49(m, 1H), 3.23-2.83(m, 2H), 2.21(s, 3H), 2.07(s, 3H), 1.87-1.31(m, 8H), 1.10(s, 6H ).ESI-MS: m/z 510.3[M+Na] ⁺ .

Example 117

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(pyrazine-2-carbonyl)piperidin-4-yl)pentanamide (compound 138)

Compound 138 was obtained by referring to the method of Example 104: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.84-8.78 (m, 1H), 8.75 (d, J=2.5Hz, 1H), 8.70-8.62 (m , 1H), 7.30(d, J=8.0Hz, 1H), 6.96(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.59(d, J=7.4Hz, 1H), 4.52-4.33 (m, 1H), 3.98-3.79(m, 3H), 3.69-3.56(m, 1H), 3.19-3.05(m, 1H), 2.98-2.83(m, 1H), 2.22(s, 3H), 2.07 (s, 3H), 1.83-1.72(m, 1H), 1.68-1.39(m, 7H), 1.08(s, 6H). ESI-MS: m/z 461.2[M+Na] ⁺ .

Example 118

2-(4-Benzoylphenoxy)-N-(1-(phenylsulfonyl)piperidin-4-yl)acetamide (Compound 139)

Compound 139 was prepared according to the method of Synthesis Scheme 1 and Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.84 (d, J=8.6Hz, 2H), 7.80-7.71 (m, 4H), 7.68-7.40 (m, 6H), 6.97(d, J=8.6Hz, 2H), 6.43(d, J=8.2Hz, 1H), 4.52(s, 2H), 3.92-3.73(m, 3H), 2.52-2.37( m, 2H), 2.09-1.95(m, 2H), 1.72-1.59(m, 2H). ESI-MS: m/z 479.2[M+H] ⁺ .

Example 119

N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-5-(2-methoxyphenoxy)-2,2-dimethylpentanamide (compound 140)

Compound IV-1 (1.1mL, 10mmoL) was dissolved in DMF (20mL), compound IV-2 (2.23g, 10mmoL) and potassium carbonate (2.07g, 15mmoL) were added in sequence, and heated to reflux under N ₂ protection. After reacting for about 8 h, cool to room temperature, add 1N NaOH solution (60 mL), and extract with ethyl acetate (60 mL x 3). The organic phase was washed successively with saturated sodium carbonate (60mLx2), water (20mLx2) and saturated brine (60mLx2), dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=75:1) to obtain compound IV-3 (yellow oil, 1.741 g, yield 66%).

Compound IV-3 (532mg, 2mmoL) was dissolved in methanol (10mL) and THF (10mL), 2N aqueous sodium hydroxide solution (2mL) was added, heated to reflux for 6h, and cooled to room temperature. The reaction solution was concentrated under reduced pressure, diluted with an appropriate amount of water, the pH of the aqueous phase was adjusted to about 2-3 with hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound IV-4 (white solid, 460 mg, yield 91%).

Compound IV-5 (2 g, 10 mmoL) was dissolved in dichloromethane (60 mL), compound IV-6 (2.62 g, 13 mmoL) and triethylamine (2.78 mL, 20 mmoL) were added, and reacted at room temperature for 10 h. Dichloromethane (60 mL) was added to dilute the reaction solution, the organic phase was washed with water (60 mL x3) and saturated brine (60 mL x2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was washed with ethyl acetate, and suction filtered to obtain compound IV-7 (3.297 g, yield 90%).

Compound IV-7 (3.297g, 9mmoL) was suspended in dichloromethane (30mL), and trifluoroacetic acid (6.7mL, 90mmol) was added dropwise under ice cooling. After reacting at room temperature for 6 h, the solvent and trifluoroacetic acid were evaporated under reduced pressure. Add water (100 mL) to dilute, adjust the pH to alkaline with 1N NaOH aqueous solution, a large amount of white solid precipitates, filter with suction to obtain compound IV-8 (white solid, 2.175 g, yield 91%).

Compound IV-4 (163 mg, 0.64 mmol) was dissolved in anhydrous dichloromethane (5 mL), and oxalyl chloride (108 μL, 1.28 mmol) and 2 drops of DMF were added dropwise under ice-cooling, and reacted at room temperature for 5 h. Dichloromethane and unreacted oxalyl chloride were evaporated under reduced pressure to obtain acid chloride. Compound IV-8 (188mg, 0.71mmoL) was dissolved in anhydrous dichloromethane (3mL), the acid chloride prepared above and triethylamine (178μL, 1.28mmoL) were added in sequence, and stirred overnight at room temperature. DCM (20 mL) was added to dilute the reaction solution, washed with water (10 mL x3) and saturated brine (10 mL x2), dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to obtain compound 140 (white solid, 138 mg, yield 43%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7. 90-7.78(m, 4H), 6.97-6.82(m, 4H), 5.68(d, J=7.3Hz, 1H), 3.96(t, J=5.9Hz, 2H), 3.87(s, 3H), 3.82 -3.65(m, 3H), 2.51-2.39(m, 2H), 2.01-1.90(m, 2H), 1.80-1.64(m, 4H), 1.58-1.42(m, 2H), 1.16(s, 6H) .ESI-MS: m/z 522.2[M+Na] ⁺ .

Example 120

N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-5-(4-methoxyphenoxy)-2,2-dimethylpentanamide (compound 141)

Compound 141 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.78 (m, 4H), 6.87-6.74 (m, 4H), 5.54 (d, J=7.4Hz, 1H ), 3.90-3.66(m, 5H), 3.77(s, 3H), 2.52-2.40(m, 2H), 2.04-1.91(m, 2H), 1.70-1.62(m, 4H), 1.58-1.41(m , 2H), 1.17(s, 6H).ESI-MS: m/z522.2[M+Na] ⁺ .

Example 121

N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-2,2-dimethyl-5-phenoxypentanamide (142)

Compound 142 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.79 (m, 4H), 7.33-7.23 (m, 2H), 7.00-6.91 (m, 1H), 6.86 (d, J=8.0Hz, 2H), 5.52(d, J=7.5Hz, 1H), 3.91(t, J=5.3Hz, 2H), 3.84-3.66(m, 3H), 2.52-2.40(m, 2H), 2.03-1.93(m, 2H), 1.77-1.62(m, 4H), 1.57-1.35(m, 2H), 1.17(s, 6H). ESI-MS: m/z 492.2 [M+Na] ⁺ .

Example 122

N-(1-(4-cyanobenzenesulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)pentanamide (Compound 143)

Compound 143 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.13(d, J=7.8Hz, 2H), 7.92(d, J=7.9Hz, 2H), 7.75( d, J=7.0Hz, 1H), 6.97(d, J=7.3Hz, 1H), 6.70(s, 1H), 6.62(d, J=7.0Hz, 1H), 3.91(t, J=5.7Hz, 2H), 3.67-3.46(m, 3H), 2.65-2.52(m, 2H), 2.24(s, 3H), 2.13-2.02(m, 5H), 1.82-1.56(m, 6H), 1.44-1.28( m, 2H).ESI-MS: m/z 470.2[M+H] ⁺ .

Example 123

2-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide (compound 147)

Compound 147 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.87(s, 1H), 7.59(dd, J=7.5Hz, 1.3Hz, 1H), 7.45-7.29( m, 4H), 7.15(d, J=7.9Hz, 1H), 6.96(d, J=7.5Hz, 1H), 6.67(s, 1H), 6.59(d, J=7.4Hz, 1H), 3.87( t, 2H), 3.65-3.55(m, 1H), 3.54(s, 2H), 2.80-2.70(m, 2H), 2.22(s, 3H), 2.11-1.99(m, 5H), 1.68-1.52( m, 6H), 1.49-1.35 (m, 2H), 1.07 (s, 6H). ESI-MS: m/z 466.2 [M+H] ⁺ .

Example 124

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzamide (compound 148)

Compound 148 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.91(s, 1H), 7.82(d, J=8.1Hz, 2H), 7.35(d, J=8.1 Hz, 2H), 7.29(s, 1H), 7.14(d, J=7.9Hz, 1H), 6.97(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.60(d, J=7.4 Hz, 1H), 3.88(s, 2H), 3.56(d, J=7.5Hz, 1H), 3.48(s, 2H), 2.75(d, J=11.3Hz, 2H), 2.23(s, 3H), 2.08(s, 3H), 1.97(dd, J=14.0, 7.5Hz, 2H), 1.60(d, J=14.9Hz, 6H), 1.49(d, J=9.1Hz, 2H), 1.08(s, 6H ).ESI-MS: m/z 466.2[M+H] ⁺ .

Example 125

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)benzoate (compound 149 )

Compound 149 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, CDCl ₃ ) δ7.98(d, J=8.1Hz, 2H), 7.38(d, J=8.1Hz, 2H), 6.99(d, J=7.4Hz, 1H), 6.65(d, J=7.5Hz, 1H), 6.60(s, 1H), 5.49(d, J=7.6Hz, 1H), 3.96-3.87(m, 5H), 3.86- 3.74(m, 1H), 3.53(s, 2H), 2.83-2.70(m, 2H), 2.29(s, 3H), 2.17(s, 3H), 2.16-2.09(m, 2H), 1.97-1.83( m, 2H), 1.73-1.64(m, 4H), 1.50-1.39(m, 2H), 1.19(s, 6H). ESI-MS: m/z 481.2[M+H] ⁺ .

Example 126

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)methyl)benzoic acid (compound 150)

Referring to the method of Example 98, compound 149 was hydrolyzed to obtain compound 150: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.18 (br s, 1H), 7.99 (d, J=8.1Hz, 2H), 7.78(d, J=7.9Hz, 2H), 7.59(d, J=7.0Hz, 1H), 6.97(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.60(d, J=7.3 Hz, 1H), 4.30(s, 2H), 3.87(t, J=6.0Hz, 2H), 3.83-3.71(m, 1H), 3.32-3.22(m, 2H), 3.04-2.90(m, 2H) , 2.23(s, 3H), 2.08(s, 3H), 1.96-1.76(m, 4H), 1.65-1.51(m, 4H), 1.08(s, 6H).ESI-MS: m/z 467.2[M +H] ⁺ .

Example 127

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)methyl)-N-methylbenzyl Amide (compound 151)

Compound 151 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.33(q, J=4.4Hz, 1H), 7.76(d, J=8.1Hz, 2H), 7.33( d, J=8.1Hz, 2H), 7.09(d, J=7.9Hz, 1H), 6.94(d, J=7.4Hz, 1H), 6.66(s, 1H), 6.58(d, J=7.4Hz, 1H), 3.86(t, J=6.0Hz, 2H), 3.59-3.50(m, 1H), 3.46(s, 2H), 2.75(d, J=4.5Hz, 3H), 2.74-2.68(m, 2H ), 2.20(s, 3H), 2.06(s, 3H), 2.01-1.88(m, 2H), 1.63-1.53(m, 6H), 1.51-1.40(m, 2H), 1.06(s, 6H). ESI-MS: m/z 480.3[M+H] ⁺ .

Example 128

5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4-yl)pentanamide ( Compound 152)

Compound 152 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, CDCl ₃ ) δ7.89(d, J=8.1Hz, 2H), 7.53(d, J=8.0Hz, 2H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.5Hz, 1H), 6.60(s, 1H), 5.49(d, J=7.6Hz, 1H), 3.92(t, J=5.3Hz, 2H) , 3.87-3.74(m, 1H), 3.57(s, 2H), 3.05(s, 3H), 2.83-2.71(m, 2H), 2.30(s, 3H), 2.23-2.11(m, 5H), 1.95 -1.86(m, 2H), 1.76-1.68(m, 4H), 1.52-1.40(m, 2H), 1.20(s, 6H). ESI-MS: m/z 501.3[M+H] ⁺ .

Example 129

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-nitrobenzyl)piperidin-4-yl)pentanamide (compound 153)

Compound 153 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, CDCl ₃ ) δ8.20(d, J=8.5Hz, 2H), 7.54(d, J=8.4Hz, 2H), 7.03(d, J=7.4Hz, 1H), 6.69(d, J=7.5Hz, 1H), 6.64(s, 1H), 5.58(d, J=7.6Hz, 1H), 3.95(t, J=5.4Hz, 2H) , 3.91-3.80(m, 1H), 3.63(s, 2H), 2.88-2.76(m, 2H), 2.33(s, 3H), 2.28-2.18(m, 5H), 2.01-1.90(m, 2H) , 1.80-1.68(m, 4H), 1.60-1.44(m, 2H), 1.24(s, 6H). ESI-MS: m/z 468.2[M+H] ⁺ .

Example 130

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)pentanamide (compound 154)

Compound 154 was obtained by referring to the method of Example 26: ¹ H NMR (300MHz, CDCl ₃ ) δ7.32(d, J=8.5Hz, 2H), 7.14(d, J=8.1Hz, 2H), 6.99(d, J=7.4Hz, 1H), 6.65(d, J=7.5Hz, 1H), 6.60(s, 1H), 5.48(d, J=7.6Hz, 1H), 3.91(t, J=5.5Hz, 2H) , 3.85-3.72(m, 1H), 3.46(s, 2H), 2.81-2.70(m, 2H), 2.29(s, 3H), 2.17(s, 3H), 2.15-2.07(m, 2H), 1.95 -1.84(m, 2H), 1.76-1.63(m, 4H), 1.49-1.35(m, 3H), 1.19(s, 6H). ESI-MS: m/z 507.2[M+H] ⁺ .

Example 131

2-(4-benzoylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (Compound 196)

Compound 196 was prepared according to the method of Synthesis Route 1 and Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.94-8.87(m, 2H), 8.21-8.04(m, 2H), 7.74(d, J=8.8Hz, 2H), 7.72-7.62(m, 4H), 7.60-7.52(m, 2H), 7.07(d, J=8.8Hz, 2H), 4.57(s, 2H), 3.77-3.65(m , 1H), 3.64-3.54 (m, 2H), 2.68-2.53 (m, 2H), 1.90-1.74 (m, 2H), 1.63-1.44 (m, 2H). ESI-MS: m/z 480.2 [M +H] ⁺ .

Example 132

N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfonyl)phenoxy)acetamide (Compound 216)

Compound 216 was prepared according to the method of Synthesis Route 1 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.99-7.87(m, 4H), 7.60-7.46(m, 3H), 7.41(d, J= 9.8Hz, 2H), 7.36(d, J=6.0Hz, 2H), 7.01(d, J=8.8Hz, 2H), 6.48(d, J=7.9Hz, 1H), 4.48(s, 2H), 3.99 (s, 1H), 3.77(s, 2H), 3.07(s, 2H), 2.40(s, 2H), 1.96(s, 4H). ESI-MS: m/z 465.0[M+H] ⁺ .

Example 133

N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylsulfinyl)phenoxy)acetamide (Compound 217)

Compound 217 was prepared according to the method of Synthesis Scheme 1 and Example 1: ¹ H NMR (300MHz, CDCl ₃ ) δ7.54(d, J=3.6Hz, 2H), 7.39(dd, J=16.6, 7.7Hz, 7H ), 7.22(d, J=10.4Hz, 1H), 7.05(d, J=8.5Hz, 2H), 6.92(d, J=8.7Hz, 2H), 6.75(d, J=7.8Hz, 1H), 4.46(s, 2H), 4.03(s, 1H), 4.00(s, 2H), 3.31(d, J=10.2Hz, 2H), 2.64(t, J=11.0Hz, 2H), 2.21(d, J =10.8Hz, 2H), 2.05 (d, J=12.8Hz, 2H).ESI-MS: m/z 449.3[M+H] ⁺ .

Example 134

N-(1-Benzylpiperidin-4-yl)-2-(4-(phenylthio)phenoxy)acetamide (Compound 218)

Compound 218 was obtained by referring to Synthetic Route 1 and Example 1: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.45-7.36 (m, 2H), 7.35-7.27 (m, 5H), 7.19 (ddd, J= 9.4, 7.8, 4.8Hz, 5H), 6.94-6.83(m, 2H), 6.38(d, J=7.9Hz, 1H), 4.46(s, 2H), 3.99-3.84(m, 1H), 3.49(s , 2H), 2.79(d, J=11.9Hz, 2H), 2.14(t, J=11.4Hz, 2H), 1.91(d, J=10.1Hz, 2H), 1.51(td, J=14.6, 3.6Hz , 2H).ESI-MS: m/z 433.2[M+H] ⁺ .

Example 135

N-(1-benzylpiperidin-4-yl)-2-((5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)acetamide (compound 219)

7-Methoxy-1-tetralone (176mg, 1.0mmol) and aluminum chloride (330mg, 2.5mmol) were dissolved in toluene (5mL), and heated to reflux overnight. Cool to room temperature, add 1N hydrochloric acid, extract with ethyl acetate (20mL x 3), wash the organic phase with saturated brine (10mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the crude product through a silica gel column Purification by chromatography (eluent: petroleum ether/ethyl acetate=5:1) gave 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (white solid, 147 mg). Using 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one as raw material, compound 219 was obtained by referring to the method of Synthesis Route 1 and Example 1: ¹ HNMR (300MHz, CDCl ₃ )δ8.03(d , J=8.7Hz, 1H), 7.35-7.27(m, 5H), 6.84(dd, J=8.7, 2.5Hz, 1H), 6.72(d, J=2.3Hz, 1H), 6.34(d, J= 7.9Hz, 1H), 4.51(s, 2H), 3.98-3.81(m, 1H), 3.49(s, 2H), 2.93(t, J=6.0Hz, 2H), 2.80(d, J=11.9Hz, 2H), 2.70-2.56(m, 2H), 2.20-2.07(m, 4H), 1.92(d, J=9.7Hz, 2H), 1.59-1.43(m, 2H). ESI-MS: m/z 393.2 [M+H] ⁺ .

Example 136

5-(4-chlorophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 221)

Compound 221 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.83 (m, 4H), 7.22 (d, J=8.9Hz, 2H), 6.78 (d, J=8.9 Hz, 2H), 5.57(d, J=7.9Hz, 1H), 3.92-3.79(m, 4H), 3.77-3.66(m, 1H), 2.48-2.35(m, 2H), 2.04-1.93(m, 2H), 1.75-1.62(m, 4H), 1.59-1.44(m, 2H), 1.18(s, 6H). ESI-MS: m/z 526.2[M+Na] ⁺ .

Example 137

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentane Amide (compound 222)

Compound 222 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.90-7.81 (m, 4H), 6.12 (s, 2H), 5.52 (d, J=7.7Hz, 1H), 3.92-3.66(m, 14H), 2.52-2.40(m, 2H), 2.05-1.95(m, 2H), 1.72-1.61(m, 4H), 1.56-1.44(m, 2H), 1.18(s, 6H ).ESI-MS: m/z 582.3[M+Na] ⁺ .

Example 138

N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trimethoxyphenoxy)pentanamide (compound 223)

Compound 223 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.69(d, J=8.5Hz, 2H), 7.52(d, J=8.5Hz, 2H), 6.12(s, 2H), 5.51(d, J=7.3Hz, 1H), 3.92-3.63(m, 14H), 2.48-2.35(m, 2H), 2.03-1.93(m, 2H), 1.74-1.62(m, 4H) , 1.54-1.43(m, 2H), 1.18(s, 6H).ESI-MS: m/z 591.3[M+Na] ⁺ .

Example 139

trans-N-(1-((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2 -Dimethylpentanamide (compound 78)

Referring to the method of Example 77, replace (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester with (±)-trans-4-amino-3-fluoropiperidine-1 - tert-butyl formate to obtain compound 78: ¹ H NMR (300MHz, CDCl ₃ ) δ7.93-7.76 (m, 4H), 7.00 (d, J=7.1Hz, 1H), 6.66 (d, J=7.0 Hz, 1H), 6.59(s, 1H), 5.73(d, J=6.7Hz, 1H), 4.58-4.30(m, 1H), 4.11-4.00(m, 1H), 3.98-3.86(m, 3H) , 3.77-3.64(m, 1H), 2.62-2.42(m, 2H), 2.29(s, 3H), 2.21-2.07(m, 4H), 1.75-1.64(m, 4H), 1.61-1.52(m, 1H), 1.20(s, 6H).ESI-MS: m/z 538.3[M+Na] ⁺ .

Example 140

trans-5-(2,5-dimethylphenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethyl valeramide (compound 224)

Compound 224 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ9.01 (d, J=1.7Hz, 1H), 8.88 (dd, J=4.7Hz, 1.3Hz, 1H), 8.07 (d, J=8.0Hz, 1H), 7.53 (dd, J=8.0, 4.9Hz, 1H), 7.01 (d, J=7.5Hz, 1H), 6.67 (d, J=7.6Hz, 1H), 6.60 (s, 1H), 5.65 (d, J=7.1Hz, 1H), 4.52-4.33 (m, 1H), 4.15-4.05 (m, 1H), 3.97-3.86 (m, 3H), 3.79-3.70 (m , 1H), 2.58-2.46(m, 2H), 2.30(s, 3H), 2.16(s, 3H), 1.76-1.65(m, 4H), 1.62-1.48(m, 2H), 1.21(s, 6H ).ESI-MS: m/z514.2[M+Na] ⁺ .

Example 141

trans-4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (compound 225)

Compound 225 was prepared according to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.54(s, 1H), 8.14(d, J=8.2Hz, 2H), 7.88(d, J=8.2 Hz, 2H), 7.45(d, J=7.7Hz, 1H), 6.95(d, J=7.3Hz, 1H), 6.66(s, 1H), 6.59(d, J=7.5Hz, 1H), 4.64- 4.42(m, 1H), 3.92-3.73(m, 4H), 3.55-3.42(m, 1H), 2.68-2.55(m, 2H), 2.21(s, 3H), 2.04(s, 3H), 1.77- 1.67(m, 1H), 1.61-1.45(m, 5H), 1.05(s, 5H). ESI-MS: m/z 557.3[M+Na] ⁺ .

Example 142

5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2 -Dimethylpentanamide (compound 226)

Compound 226 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ9.00(s, 1H), 8.86(d, J=4.1Hz, 1H), 8.05(d, J=7.9Hz, 1H), 7.51(dd, J=7.7, 5.0Hz, 1H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.68(d, J=7.3Hz, 1H), 4.58-4.30(m, 1H), 4.13-4.03(m, 1H), 3.98-3.86(m, 3H), 3.78-3.68(m, 1H) , 2.60-2.48(m, 2H), 2.30(s, 3H), 2.20-2.09(m, 4H), 1.76-1.66(m, 4H), 1.64-1.50(m, 1H), 1.20(s, 6H) .ESI-MS: m/z 514.3[M+Na] ⁺ .

Example 143

4-(((3S,4S)-4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) Sulfonyl)benzoic acid (compound 227)

Compound 227 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.13(d, J=8.0Hz, 2H), 7.83(d, J=8.0Hz, 2H), 7.44(d, J=7.9Hz, 1H), 6.97(d, J=7.3Hz, 1H), 6.68(s, 1H), 6.61(d, J=7.2Hz, 1H), 4.70-4.43( m, 1H), 3.96-3.77(m, 4H), 3.55-3.43(m, 1H), 2.69-2.56(m, 2H), 2.24(s, 3H), 2.07(s, 3H), 1.81-1.70( m, 1H), 1.63-1.49(m, 5H), 1.08(s, 6H). ESI-MS: m/z 557.2[M+Na] ⁺ .

Example 144

2-(4-(4-Chlorobenzoyl)phenoxy)-N-(1--((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 228)

Compound 228 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.82 (m, 4H), 7.79-7.69 (m, 4H), 7.47 (d, J=7.9Hz, 2H ), 6.93(d, J=8.1Hz, 2H), 6.34(d, J=7.9Hz, 1H), 3.83-3.70(m, 3H), 2.59-2.44(m, 2H), 2.03-1.93(m, 2H), 1.57(s, 6H), 1.55-1.42(m, 2H). ESI-MS: m/z 566.2[M+H] ⁺ .

Example 145

N-(1-((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2, 2-Dimethylpentanamide (Compound 229)

Compound 111 (200 mg), sodium azide (53 mg), and ammonium chloride (44 mg) were dissolved in DMF (5 mL), heated and stirred in an oil bath at 125° C. for 24 h. Cool to room temperature, add water (20 mL), extract with ethyl acetate (10 mL x 3), wash the organic phase with brine (20 mL), water (20 mL) and brine (20 mL) successively, dry over anhydrous sodium sulfate, and concentrate the solvent under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane/methanol/glacial acetic acid=400:20:1) to obtain compound 229 (white solid, 160 mg, yield 74%): ¹ H NMR (300 MHz, DMSO -d ₆ )δ8.29(d, J=8.3Hz, 2H), 7.95(d, J=8.3Hz, 2H), 7.21(d, J=7.6Hz, 1H), 6.97(d, J=7.4Hz , 1H), 6.67(s, 1H), 6.61(d, J=7.5Hz, 1H), 3.86(t, J=5.4Hz, 2H), 3.71-3.61(m, 2H), 3.60-3.49(m, 1H), 2.48-2.37(m, 2H), 2.23(s, 3H), 2.07(s, 3H), 1.78-1.67(m, 2H), 1.61-1.53(m, 4H), 1.53-1.44(m, 2H), 1.06(s, 6H).ESI-MS: m/z 539.2[MH] ^- .

Example 146

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound 230)

Compound 230 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.94-7.79 (m, 4H), 7.29 (d, 1H), 6.93-6.84 (m, 2H), 5.51 (d , J=7.3Hz, 1H), 3.97(t, J=5.4Hz, 2H), 3.87-3.76(m, 2H), 3.76-3.67(m, 1H), 2.53-2.39(m, 2H), 2.08- 1.91(m, 2H), 1.83-1.61(m, 4H), 1.54-1.42(m, 2H), 1.18(s, 6H). ESI-MS: m/z 560.1[M+Na] ⁺ .

Example 147

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl ) valeramide (compound 231)

Compound 231 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18(d, J=8.3Hz, 2H), 7.99(d, J=8.3Hz, 2H), 7.22( d, J=7.7Hz, 1H), 6.97(d, J=7.4Hz, 1H), 6.68(s, 1H), 6.62(d, J=7.3Hz, 1H), 3.93-3.80(m, 2H), 3.73-3.60(m, 2H), 3.59-3.49(m, 1H), 3.31(s, 3H), 2.47-2.38(m, 2H), 2.24(s, 3H), 2.08(s, 3H), 1.77- 1.65(m, 2H), 1.62-1.53(m, 4H), 1.53-1.41(m, 2H), 1.06(s, 6H). ESI-MS: m/z 573.2[M+Na] ⁺ .

Example 148

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl 5-(4-(methylsulfonyl)phenoxy)pentanamide ( Compound 232)

Compound 232 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.12 (d, J=8.2Hz, 2H), 7.91 (d, J=8.2Hz, 2H), 7.82( d, J=8.7Hz, 2H), 7.23(d, J=7.9Hz, 1H), 7.11(d, J=8.7Hz, 2H), 4.07-3.96(m, 2H), 3.70-3.58(m, 2H ), 3.58-3.50(m, 1H), 3.15(s, 3H), 2.48-2.37(m, 2H), 1.75-1.64(m, 2H), 1.62-1.52(m, 4H), 1.52-1.40(m , 2H), 1.06(s, 6H).ESI-MS: m/z 570.4[M+Na] ⁺ .

Example 149

2-((4-oxo-3-phenyl-4H-chromen-7-yl)oxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (compound 233)

Compound 233 was obtained by referring to Synthesis Scheme 1 and Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.92(d, J=1.9Hz, 1H), 8.89(d, J=4.9Hz, 1H ), 8.47(s, 1H), 8.16(d, J=8.0Hz, 2H), 8.06(d, J=8.5Hz, 1H), 7.69(dd, J=7.9, 4.8Hz, 1H), 7.58(d , J=6.7Hz, 2H), 7.41(dq, J=14.1, 7.0Hz, 3H), 7.17-7.09(m, 2H), 4.64(s, 2H), 3.70(s, 1H), 3.65-3.55( m, 2H), 2.57(dd, J=20.3, 8.9Hz, 2H), 1.82(d, J=10.4Hz, 2H), 1.54(dd, J=20.1, 11.0Hz, 2H).ESI-MS: m /z 520.1[M+H] ⁺ .

Example 150

2-((4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)acetamide (compound 234)

Compound 234 was obtained by referring to Synthesis Scheme 1 and Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.91(d, J=2.1Hz, 1H), 8.89(d, J=4.9Hz, 1H ), 8.16 (d, J=8.0Hz, 2H), 8.08 (d, J=5.5Hz, 2H), 7.97 (d, J=8.8Hz, 1H), 7.69 (dd, J=7.9, 4.9Hz, 1H ), 7.60(d, J=6.0Hz, 3H), 7.28(d, J=2.0Hz, 1H), 7.12(d, J=8.8Hz, 1H), 6.97(s, 1H), 4.65(s, 2H ), 3.70(s, 1H), 3.60(d, J=15.2Hz, 2H), 2.58(t, J=11.6Hz, 2H), 1.82(d, J=10.5Hz, 2H), 1.63-1.46(m , 2H).ESI-MS: m/z 520.2[M+H] ⁺ .

Example 151

N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-5-(2,6-difluorophenoxy)-2,2-dimethylpentanamide (compound 235 )

Compound 235 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.68 (d, J=8.3Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 7.02-6.82( m, 3H), 5.58(d, J=7.1Hz, 1H), 4.14-4.02(m, 2H), 3.80-3.65(m, 3H), 2.50-2.35(m, 2H), 2.02-1.90(m, 2H), 1.73-1.61(m, 4H), 1.53-1.41(m, 2H), 1.16(s, 6H). ESI-MS: m/z 537.2[M+Na] ⁺ .

Example 152

2,2-Dimethyl-5-phenoxy-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide (compound 236)

Compound 236 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.99(s, 1H), 8.83(d, J=4.4Hz, 1H), 8.04(d, J=7.9Hz, 1H), 7.53-7.44(m, 1H), 7.32-7.22(m, 2H), 6.98-6.90(m, 1H), 6.86(d, J=7.9Hz, 2H), 5.50(d, J=7.4Hz , 1H), 3.91(t, J=5.1Hz, 2H), 3.87-3.65(m, 3H), 2.54-2.39(m, 2H), 2.03-1.91(m, 2H), 1.75-1.62(m, 4H ), 1.56-1.39 (m, 2H), 1.17 (s, 6H). ESI-MS: m/z 468.2[M+Na] ⁺ .

Example 153

5-(2,6-difluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)pentanamide (compound 237)

Compound 237 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.99(s, 1H), 8.83(d, J=4.0Hz, 1H), 8.04(d, J=7.7Hz, 1H), 7.54-7.45(m, 1H), 7.02-6.84(m, 3H), 5.61(d, J=7.0Hz, 1H), 4.14-4.03(m, 2H), 3.88-3.68(m, 3H) , 2.54-2.42(m, 2H), 2.07-1.93(m, 2H), 1.74-1.64(m, 4H), 1.58-1.42(m, 2H), 1.17(s, 6H).ESI-MS: m/ z 504.2[M+Na] ⁺ .

Example 154

2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 238 )

Compound 238 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.95-8.85 (m, 2H), 8.15 (d, J=7.7Hz, 1H), 7.83 (d, J =8.6Hz, 2H), 7.69(dd, J=7.7, 4.9Hz, 1H), 7.26(d, J=7.8Hz, 1H), 7.12(d, J=8.5Hz, 2H), 4.06-3.96(m , 2H), 3.70-3.59(m, 2H), 3.59-3.50(m, 1H), 3.15(s, 3H), 2.47-2.35(m, 2H), 1.77-1.64(m, 2H), 1.63-1.53 (m, 4H), 1.53-1.41 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 524.1 [M+H] ⁺ .

Example 155

4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 239)

Compound 239 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47 (brs, 1H), 8.15 (dd, J=8.4, 2.2Hz, 2H), 7.90-7.77 (m , 4H), 7.22(d, J=7.7Hz, 1H), 7.11(dd, J=8.9, 2.2Hz, 2H), 4.09-3.92(m, 2H), 3.68-3.57(m, 2H), 3.56- 3.47(m, 1H), 3.14(s, 3H), 2.46-2.33(m, 2H), 1.75-1.63(m, 2H), 1.62-1.52(m, 4H), 1.52-1.40(m, 2H), 1.06(s, 6H).ESI-MS: m/z 567.2[M+H] ⁺ .

Example 156

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methyl-2-(4-(methylsulfonyl)phenoxy)propanamide (compound 240 )

Compound 240 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.12(d, J=8.2Hz, 2H), 8.03(d, J=6.8Hz, 1H), 7.88( d, J=8.4Hz, 2H), 7.81(d, J=8.8Hz, 2H), 6.97(d, J=8.8Hz, 2H), 3.73-3.60(m, 1H), 3.60-3.46(m, 2H ), 3.17(s, 3H), 2.49-2.40(m, 2H), 1.73-1.60(m, 2H), 1.56-1.37(m, 8H). ESI-MS: m/z 528.2[M+Na] ⁺ .

Example 157

N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl-2-(4-(methylsulfonyl)phenoxy)propionamide (Compound 241)

Compound 241 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.96-8.79 (m, 2H), 8.12 (d, J=8.0Hz, 1H), 8.06 (d, J =8.0Hz, 1H), 7.81(d, J=8.6Hz, 2H), 7.68(dd, J=7.8, 4.9Hz, 1H), 6.97(d, J=8.6Hz, 2H), 3.73-3.61(m , 1H), 3.60-3.47(m, 2H), 3.17(s, 3H), 2.48-2.40(m, 2H), 1.67(d, J=10.5Hz, 2H), 1.57-1.36(m, 8H). ESI-MS: m/z 482.2[M+H] ⁺ .

Example 158

4-((4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 242)

Compound 242 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48(brs, 1H), 8.15(d, J=8.2Hz, 2H), 8.03(d, J=7.7 Hz, 1H), 7.88-7.74(m, 4H), 6.97(d, J=8.7Hz, 2H), 3.66-3.46(m, 3H), 3.16(s, 3H), 2.48-2.35(m, 2H) , 1.72-1.59(m, 2H), 1.58-1.33(m, 8H).ESI-MS: m/z 525.4[M+H] ⁺ .

Example 159

2-(4-chlorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide ( Compound 243)

Using 2-(4-chlorophenoxy)-2-methylpropionic acid as the raw material, compound 243 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8. 93(s, 1H), 8.90(d, J=4.1Hz, 1H), 8.24(d, J=8.5Hz, 1H), 8.18(d, J=8.1Hz, 1H), 7.69(dd, J=7.8 , 4.9Hz, 1H), 7.30(d, J=8.7Hz, 2H), 6.86(d, J=8.7Hz, 2H), 4.71-4.44(m, 1H), 4.02-3.88(m, 1H), 3.86 -3.74(m, 1H), 3.56-3.45(m, 1H), 2.79-2.61(m, 2H), 1.82-1.71(m, 1H), 1.63-1.50(m, 1H), 1.40(s, 3H) , 1.39(s, 3H).ESI-MS: m/z 478.1[M+Na] ⁺ .

Example 160

trans-2-(4-chlorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropanamide (Compound 244)

Compound 244 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ9.00(s, 1H), 8.86(d, J=4.7Hz, 1H), 8.06(d, J=8.0 Hz, 1H), 7.51(dd, J=7.6, 5.1Hz, 1H), 7.24(d, J=8.9Hz, 2H), 6.84(d, J=8.8Hz, 2H), 6.70(d, J=7.7 Hz, 1H), 4.61-4.33(m, 1H), 4.12-3.88(m, 2H), 3.80-3.69(m, 1H), 2.67-2.53(m, 2H), 2.22-2.08(m, 1H), 1.72-1.62(m, 1H), 1.48(s, 3H), 1.46(s, 3H). ESI-MS: m/z 478.1[M+Na] ⁺ .

Example 161

N-((3S,4S)-1-((3-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)- 2,2-Dimethylpentanamide (Compound 245)

Compound 245 was obtained by referring to the method of Example 77: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.09(s, 1H), 8.02(d, J=7.9Hz, 1H), 7.93(d, J=7.7Hz , 1H), 7.74(dd, J=7.8Hz, 7.8Hz, 1H), 7.03(d, J=7.3Hz, 1H), 6.69(d, J=7.3Hz, 1H), 6.62(s, 1H), 5.67(d, J=7.3Hz, 1H), 4.61-4.33(m, 1H), 4.15-4.04(m, 1H), 4.02-3.88(m, 3H), 3.80-3.69(m, 1H), 2.66- 2.50(m, 2H), 2.32(s, 3H), 2.24-2.13(m, 4H), 1.83-1.68(m, 4H), 1.59-1.50(m, 1H), 1.23(s, 6H).ESI- MS: m/z 538.3[M+Na] ⁺ .

Example 162

2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propionamide (compound 246)

Compound 246 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.98(d, J=1.8Hz, 1H), 8.84(dd, J=4.8, 1.4Hz, 1H), 8.04( d, J=8.1Hz, 1H), 7.80-7.68(m, 4H), 7.54-7.43(m, 3H), 6.93(d, J=8.7Hz, 2H), 6.35(d, J=7.9Hz, 1H ), 3.89-3.72(m, 3H), 2.58-2.44(m, 2H), 2.07-1.93(m, 2H), 1.60(s, 6H), 1.55-1.47(m, 2H).ESI-MS: m /z 564.2[M+Na] ⁺ .

Example 163

trans-N-(1-((4-(1H-tetrazol-5-yl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethyl Phenoxy)-2,2-dimethylpentanamide (compound 247)

Compound 247 was obtained by referring to the method of Examples 139 and 145: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.28 (d, J=7.8Hz, 2H), 7.99 (d, J=7.8Hz, 2H), 7.41(d, J=7.9Hz, 1H), 6.95(d, J=7.2Hz, 1H), 6.66(s, 1H), 6.60(d, J=7.3Hz, 1H), 4.71-4.42(m, 1H ), 3.95-3.77(m, 4H), 3.59-3.47(m, 1H), 2.74-2.57(m, 2H), 2.22(s, 3H), 2.05(s, 3H), 1.83-1.67(m, 1H ), 1.62-1.45(m, 5H), 1.06(s, 6H).ESI-MS: m/z 557.2[MH] ^- .

Example 164

2-(4-Chlorophenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 248)

Compound 248 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.90-7.82 (m, 4H), 7.24 (d, J=8.7Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.54(d, J=8.6Hz, 1H), 3.82-3.70(m, 3H), 2.57-2.44(m, 2H), 2.05-1.94(m, 2H), 1.58-1.54(m, 1H), 1.54-1.50(m, 1H), 1.46(s, 6H). ESI-MS: m/z 484.1[M+Na] ⁺ .

Example 165

2-(4-Chlorophenoxy)-N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 249)

Compound 249 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.69(d, J=8.5Hz, 2H), 7.52(d, J=8.5Hz, 2H), 7.23(d, J=8.8Hz, 2H), 6.81(d, J=8.8Hz, 2H), 6.54(d, J=7.9Hz, 1H), 3.83-3.66(m, 3H), 2.54-2.37(m, 2H), 2.04-1.92(m, 2H), 1.61-1.49(m, 2H), 1.45(s, 6H). ESI-MS: m/z 493.0[M+Na] ⁺ .

Example 166

2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propionamide (compound 250)

Compound 250 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ9.01 (d, J=1.6Hz, 1H), 8.86 (dd, J=4.7, 1.2Hz, 1H), 8.06( d, J=8.0Hz, 1H), 7.52(dd, J=7.9, 4.9Hz, 1H), 7.25(d, J=8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 6.56( d, J=7.7Hz, 1H), 3.88-3.71(m, 3H), 2.62-2.47(m, 2H), 2.08-1.95(m, 2H), 1.61-1.50(m, 2H), 1.48(s, 6H).ESI-MS: m/z 460.2[M+Na] ⁺ .

Example 167

4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 251)

Compound 251 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.45 (br s, 1H), 8.14 (d, J=8.2Hz, 2H), 7.97 (d, J= 7.7Hz, 1H), 7.81(d, J=8.2Hz, 2H), 7.30(d, J=8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 3.70-3.58(m, 1H) , 3.58-3.47(m, 2H), 2.46-2.37(m, 2H), 1.73-1.63(m, 2H), 1.61-1.45(m, 2H), 1.39(s, 6H).ESI-MS: m/ z 479.2[MH] ^- .

Example 168

N-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropanamide (Compound 252)

Compound 252 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.70(d, J=8.3Hz, 2H), 7.53(d, J=8.4Hz, 2H), 7.06(d, J=7.4Hz, 1H), 6.79(d, J=7.6Hz, 1H), 6.69(d, J=8.8Hz, 1H), 6.58(s, 1H), 3.89-3.76(m, 1H), 3.70( d, J=12.1Hz, 2H), 2.52(t, J=10.7Hz, 2H), 2.26(s, 3H), 2.16(s, 3H), 2.02(d, J=11.5Hz, 3H), 1.64- 1.54(m, 2H), 1.50(s, 6H).ESI-MS: m/z 487.2[M+Na] ⁺ .

Example 169

N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-(2,5-dimethylphenoxy)-2-methylpropionamide (compound 253)

Compound 253 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.86(dd, 4H), 7.05(d, J=7.2Hz, 1H), 6.78(d, J=7.5Hz, 1H), 6.68(d, J=8.5Hz, 1H), 6.56(s, 1H), 3.90-3.78(m, 1H), 3.74(d, J=11.8Hz, 2H), 2.55(t, J=11.8 Hz, 2H), 2.24(s, 3H), 2.16(s, 3H), 2.02(d, J=15.0Hz, 2H), 1.54(d, J=4.1Hz, 2H), 1.48(s, 6H). ESI-MS: m/z 478.2[M+Na] ⁺ .

Example 170

2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 254)

Compound 254 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.90(d, J=8.1Hz, 2H), 7.83(d, J=8.4Hz, 2H), 7.06(d, J=7.6Hz, 1H), 6.79(d, J=7.6Hz, 1H), 6.69(d, J=7.9Hz, 1H), 6.58(s, 1H), 3.90-3.79(m, 1H), 3.74( d, J=12.9Hz, 2H), 2.56(t, J=10.9Hz, 2H), 2.26(s, 3H), 2.16(s, 3H), 2.04(d, J=10.9Hz, 2H), 1.59( dd, J=12.4, 3.4Hz, 2H), 1.50(s, 6H).ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 171

2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (compound 255)

Compound 255 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.01(s, 1H), 8.86(d, J=4.5Hz, 1H), 8.06(dd, J=8.0 , 1.5Hz, 1H), 7.51(dd, J=7.9, 4.9Hz, 1H), 7.06(d, J=7.6Hz, 1H), 6.79(d, J=7.6Hz, 1H), 6.70(d, J =7.9Hz, 1H), 6.59(s, 1H), 3.93-3.83(m, 1H), 3.78(d, J=12.0Hz, 2H), 2.58(t, J=11.6Hz, 2H), 2.26(s , 3H), 2.17(s, 3H), 2.04(d, J=9.8Hz, 2H), 1.66-1.55(m, 2H), 1.50(s, 6H).ESI-MS: m/z 454.2 [M+ Na] ⁺ .

Example 172

4-((4-(2-(2,5-dimethylphenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 256)

Compound 256 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.41(s, 1H), 8.15(d, J=8.2Hz, 2H), 7.89(d, J=8.0 Hz, 1H), 7.82(d, J=8.2Hz, 2H), 7.01(d, J=7.6Hz, 1H), 6.70(d, J=7.4Hz, 1H), 6.51(s, 1H), 3.68( ddd, J=14.3, 6.7, 3.7Hz, 1H), 3.52(d, J=12.2Hz, 2H), 2.44(s, 2H), 2.17(s, 3H), 2.10(s, 3H), 1.73(d , J=14.6Hz, 2H), 1.58(dd, J=21.9, 11.7Hz, 2H), 1.36(s, 6H).ESI-MS: m/z 497.2[M+Na] ⁺ .

Example 173

2-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl Propionamide (compound 257)

Compound 257 was prepared according to the method of Examples 14 and 77: ¹ H NMR (300MHz, CDCl ₃ ) δ9.03(s, 1H), 8.88(d, J=4.6Hz, 1H), 8.08(d, J=7.9 Hz, 1H), 7.58-7.48(m, 1H), 7.06(d, J=7.6Hz, 1H), 6.81(t, J=9.1Hz, 2H), 6.64(s, 1H), 4.50(dtd, J = 48.8, 9.1, 5.1Hz, 1H), 4.06 (dd, J = 11.1, 6.0Hz, 2H), 3.74 (d, J = 12.3Hz, 1H), 2.65 (t, J = 10.6Hz, 2H), 2.26 (s, 3H), 2.19 (s, 4H), 1.74-1.57 (m, 3H), 1.52 (d, J=13.0Hz, 6H). ESI-MS: m/z 472.2[M+Na] ⁺ .

Example 174

trans-2-(2,5-Dimethylphenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 258)

Compound 258 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ9.03(s, 1H), 8.89(d, J=4.4Hz, 1H), 8.08(d, J=8.1 Hz, 1H), 7.54(dd, J=7.8, 4.9Hz, 1H), 7.07(d, J=7.6Hz, 1H), 6.81(t, J=7.5Hz, 2H), 6.64(s, 1H), 4.64-4.36(m, 2H), 4.13-3.95(m, 2H), 3.75(d, J=12.0Hz, 1H), 2.65(t, J=10.6Hz, 2H), 2.26(s, 3H), 2.19 (s, 4H), 1.75-1.60 (m, 2H), 1.52 (d, J=13.1Hz, 6H). ESI-MS: m/z 472.2[M+Na] ⁺ .

Example 175

2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 259)

Compound 259 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.12(d, J=8.4Hz, 2H), 7.95(d, J=8.4Hz, 2H), 7.05(d, J=7.5Hz, 1H), 6.77(d, J=7.4Hz, 1H), 6.67(d, J=7.8Hz, 1H), 6.57(s, 1H), 3.84(ddd, J=9.2, 4.3, 2.2 Hz, 1H), 3.75(d, J=11.7Hz, 2H), 3.11(s, 3H), 2.59(t, J=10.9Hz, 2H), 2.24(s, 3H), 2.15(s, 3H), 2.03(d, J=9.4Hz, 2H), 1.61(dd, J=10.8, 4.2Hz, 2H), 1.48(s, 6H).ESI-MS: m/z 531.2[M+Na] ⁺ .

Example 176

5-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2 , 2-Dimethylpentanamide (compound 260)

Compound 260 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.79 (dd, J=7.2, 5.2Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 7.00(d, J=7.3Hz, 1H), 6.66(d, J=7.3Hz, 1H), 6.59(s, 1H), 5.61(d, J=6.9Hz, 1H), 4.56-4.27( m, 1H), 4.11-4.00(m, 1H), 3.98-3.82(m, 3H), 3.75-3.64(m, 1H), 2.52-2.38(m, 2H), 2.30(s, 3H), 2.22- 2.07(m, 4H), 1.76-1.63(m, 4H), 1.53-1.46(m, 1H), 1.20(s, 6H). ESI-MS: m/z 531.3[M+Na] ⁺ .

Example 177

trans-5-(2,5-dimethylphenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2- Dimethylvaleramide (Compound 261)

Compound 261 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85-7.74 (m, 2H), 7.23 (d, J=8.4Hz, 2H), 7.00 (d, J=7.4 Hz, 1H), 6.66(d, J=7.2Hz, 1H), 6.59(s, 1H), 5.62(d, J=7.3Hz, 1H), 4.57-4.30(m, 1H), 4.10-4.01(m , 1H), 3.96-3.84(m, 3H), 3.70(d, J=11.9Hz, 1H), 2.45(t, J=10.9Hz, 2H), 2.30(s, 3H), 2.22-2.09(m, 4H), 1.78-1.64(m, 4H), 1.52(s, 1H), 1.16(s, 6H). ESI-MS: m/z 531.3[M+Na] ⁺ .

Example 178

4-(((3S,4S)-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Acyl)benzoic acid (compound 262)

Compound 262 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47 (s, 1H), 8.16 (d, J=8.3Hz, 2H), 7.90 ( d, J=8.4Hz, 2H), 7.43(d, J=8.5Hz, 2H), 7.19(d, J=2.0Hz, 1H), 7.03-6.98(m, 1H), 4.43-4.68(m, 1H ), 4.07-3.97(m, 2H), 3.93-3.77(m, 2H), 3.58-3.45(m, 1H), 2.72-2.55(m, 2H), 1.81-1.69(m, 1H), 1.63-1.49 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 575.1 [M+H] ⁺ .

Example 179

trans-4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 265)

Compound 265 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.55-13.22 (m, 1H), 8.16 (d, J=8.3Hz, 2H), 7.89 (d , J=8.3Hz, 2H), 7.47-7.24(m, 2H), 7.06-6.92(m, 1H), 6.78-6.63(m, 1H), 4..43-4.67(m, 1H), 3.95- 3.75(m, 4H), 3.56-3.45(m, 1H), 2.75-2.57(m, 2H), 1.46-1.80(m, 6H), 1.06(s, 6H). ESI-MS: m/z 543.2[ M+H] ⁺ .

Example 180

trans-N-(1-((3,4-difluorophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2 , 2-Dimethylpentanamide (compound 268)

Compound 268 was prepared according to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.93(t, J=8.1Hz, 1H), 7.82-7.63(m, 2H), 7.42(d, J =8.3Hz, 1H), 6.97(d, J=7.5Hz, 1H), 6.73-6.56(m, 2H), 4.67-4.43(m, 1H), 3.92-3.77(m, 4H), 3.50(d, J=12.0Hz, 1H), 2.72-2.58(m, 2H), 2.24(s, 3H), 2.07(s, 3H), 1.49-1.79(m, 6H), 1.08(s, 6H).ESI-MS : m/z 549.2[M+Na] ⁺ .

Example 181

5-(3-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 270)

Compound 270 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.88 (dd, J=5.7, 3.5Hz, 2H), 8.21-8.07 (m, 1H), 7.67 (dd , J=8.1, 4.8Hz, 1H), 7.35-7.12(m, 2H), 6.80-6.65(m, 3H), 3.89(d, J=4.5Hz, 2H), 3.61(t, J=10.0Hz, 3H), 2.46-2.35(m, 2H), 1.76-1.60(m, 2H), 1.61-1.37(m, 6H), 1.04(s, 6H). ESI-MS: m/z 486.2[M+Na] ⁺ .

Example 182

5-(2-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 271)

Compound 271 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.89(d, J=6.1Hz, 2H), 8.15(d, J=8.1Hz, 1H), 7.69( dd, J=8.1, 4.8Hz, 1H), 7.38-6.99(m, 4H), 6.91(d, J=7.9Hz, 1H), 3.97(m, 2H), 3.63(d, J=12.2Hz, 2H ), 3.50-3.39(m, 1H), 2.42(d, J=12.4Hz, 2H), 1.78-1.63(m, 2H), 1.62-1.34(m, 6H), 1.06(s, 6H).ESI- MS: m/z 486.2[M+Na] ⁺ .

Example 183

4-((4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoic acid-(acetylamino) - ethyl ester (compound 272)

Compound 119 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (22 μL) and DMF (2 drops) were added dropwise under ice-cooling. After reacting for about 5 hours, the solvent and unreacted oxalyl chloride were distilled off under reduced pressure to obtain acid chloride. N-(2-Hydroxyethyl)acetamide (19 μL, 0.19 mmol) was dissolved in dichloromethane (2 mL), and the above-prepared acid chloride and triethylamine (40 μL, 0.29 mmol) were added under ice cooling, and reacted for 12 hours. Dichloromethane (5mL) was added to dilute the reaction solution, the organic phase was washed with water (5mL x3) and saturated brine (5mL x2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent : dichloromethane/methanol=100:1) to obtain compound 272 (white solid, 48mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.20 (d, J=8.2Hz, 2H), 8.16- 8.06(m, 1H), 7.88(d, J=8.2Hz, 2H), 7.23(d, J=7.5Hz, 1H), 6.97(d, J=7.4Hz, 1H), 6.71-6.57(m, 2H ), 4.30(t, J=5.2Hz, 2H), 3.86(s, 2H), 3.69-3.5(m, 3H), 3.43(d, J=5.3Hz, 2H), 2.33-2.44(m, 2H) , 2.23(s, 3H), 2.07(s, 3H), 1.83(s, 3H), 1.75-1.49(m, 8H), 1.06(s, 6H). ESI-MS: m/z 624.3 [M+Na ] ⁺ .

Example 184

5-(3,4-difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 273)

Compound 273 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.02-8.75 (m, 2H), 8.24-8.04 (m, 1H), 7.69 (dd, J=8.1, 4.8Hz, 1H), 7.41-7.25(m, 1H), 7.22(d, J=7.8Hz, 1H), 7.10-6.87(m, 1H), 6.83-6.58(m, 1H), 3.89(m, 2H ), 3.72-3.49(m, 3H), 2.48-2.24(m, 2H), 1.84-1.62(m, 2H), 1.62-1.35(m, 6H), 1.05(s, 6H).ESI-MS: m /z 504.2[M+Na] ⁺ .

Example 185

trans-5-(2,6-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 274)

Compound 274 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.02-8.81 (m, 2H), 8.20 (d, J=8.0Hz, 1H), 7.74-7.63 (m, 1H), 7.42(d, J=8.0Hz, 1H), 7.12(d, J=9.3Hz, 3H), 4.42-4.68(m, 1H), 4.00(s, 2H), 3.83(s, 2H), 3.52 (d, J=11.9Hz, 1H), 2.80-2.63 (m, 2H), 1.45-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M +Na] ⁺ .

Example 186

5-(2,6-difluorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2- Dimethylvaleramide (Compound 276)

Compound 276 was prepared according to the method of Examples 119 and 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.00-8.85 (m, 2H), 8.20 (d, J=7.9Hz, 1H ), 7.72-7.66(m, 1H), 7.42(d, J=7.9Hz, 1H), 7.20-7.04(m, 3H), 4.69-4.43(m, 1H), 4.01(s, 2H), 3.84( s, 2H), 3.58-3.47 (m, 1H), 2.82-2.63 (m, 2H), 1.49-1.76 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 522.2 [M+ Na] ⁺ .

Example 187

5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 277)

Compound 277 was prepared by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18 (d, J=8.4Hz, 2H), 8.00 (d, J=8.2Hz, 2H), 7.31- 7.19(m, 2H), 7.17-7.10(m, 1H), 7.04-6.94(m, 1H), 3.96(t, J=4.0, 3.3Hz, 2H), 3.71-3.57(m, 2H), 3.49- 3.36(m, 1H), 3.32(s, 3H), 2.49-2.32(m, 2H), 1.81-1.64(m, 2H), 1.63-1.33(m, 6H), 1.05(s, 6H).ESI- MS: m/z 581.3[M+Na] ⁺ .

Example 188

2-(4-benzoylphenoxy)-N-(1-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 75)

Compound 75 was prepared according to the method of Examples 1 and 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.10 (d, J=8.4Hz, 2H), 8.02 (d, J=7.7Hz, 1H), 7.88(d, J=8.4Hz, 2H), 7.75-7.62(m, 5H), 7.61-7.51(m, 2H), 6.93(d, J=8.7Hz, 2H), 3.71-3.61(m, 1H) , 3.60-3.48(m, 2H), 2.49-2.42(m, 2H), 1.74-1.59(m, 2H), 1.49(s, 6H), 1.48-1.39(m, 2H).ESI-MS: m/ z 532.2[M+H] ⁺ .

Example 189

2-(4-benzoylphenoxy)-N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)acetamide (compound 76)

Compound 76 was prepared according to the method of Examples 1 and 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.23-8.17 (m, 2H), 8.10 (d, J=7.6Hz, 1H), 8.06 (d , J=7.9Hz, 1H), 7.90-7.81(m, 1H), 7.74(d, J=8.7Hz, 2H), 7.71-7.62(m, 3H), 7.59-7.51(m, 2H), 7.07( d, J=8.6Hz, 2H), 4.60-4.53(s, 2H), 3.77-3.64(m, 1H), 3.65-3.53(m, 2H), 2.65-2.54(m, 2H), 1.87-1.70( m, 2H), 1.59-1.45 (m, 2H). ESI-MS: m/z 504.2 [M+H] ⁺ .

Example 190

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl ) valeramide (compound 77)

Compound 77 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, DMSO.d ₆ ) δ8.28(d, J=7.6Hz, 1H), 8.15(s, 1H), 8.08(d, J=8.0 Hz, 1H), 7.98-7.89(m, 1H), 7.22(d, J=7.5Hz, 1H), 6.97(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.62(d, J =7.4Hz, 1H), 3.92-3.80(m, 2H), 3.72-3.49(m, 3H), 3.34(s, 3H), 2.47-2.35(m, 2H), 2.23(s, 3H), 2.08( s, 3H), 1.77-1.66 (m, 2H), 1.62-1.53 (m, 4H), 1.53-1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 573.2 [M+ Na] ⁺ .

Example 191

4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 278)

Compound 278 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.16(d, J=8.0Hz, 2H), 7.85(d, J=8.0 Hz, 2H), 7.33-7.06(m, 3H), 7.05-6.93(m, 1H), 4.05-3.77(m, 2H), 3.72-3.44(m, 3H), 2.46-2.31(m, 2H), 1.82-1.39(m, 8H), 1.05(s, 6H).ESI-MS: m/z 523.2[MH] ^- .

Example 192

trans-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 280 )

Compound 280 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.15(d, J=8.1Hz, 2H), 7.88(d, J =8.2Hz, 2H), 7.48-7.32(m, 2H), 7.18(d, J=2.4Hz, 1H), 7.03-6.95(m, 1H), 4.71-4.41(m, 1H), 4.00(t, J=5.3Hz, 2H), 3.93-3.74(m, 2H), 3.58-3.44(m, 1H), 2.72-2.54(m, 2H), 1.82-1.67(m, 1H), 1.66-1.47(m, 5H), 1.06(s, 6H).ESI-MS: m/z 575.1[M+H] ⁺ .

Example 193

5-(2-methoxyphenoxy)-N-((3S,4S)-1-((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-Dimethylpentanamide (Compound 284)

Compound 284 was prepared according to the method of Examples 119 and 77: ¹ H NMR (300MHz, CDCl ₃ ) δ7.90-7.79 (m, 4H), 6.99-6.83 (m, 4H), 5.95 (d, J=7.5Hz , 1H), 4.61-4.34(m, 1H), 4.08-3.93(m, 4H), 3.87(s, 3H), 3.73-3.63(m, 1H), 2.61-2.49(m, 2H), 2.17-2.05 (m, 1H), 1.82-1.67(m, 4H), 1.57-1.48(m, 1H), 1.19(s, 6H). ESI-MS: m/z 540.1[M+Na] ⁺ .

Example 194

5-(2-methoxyphenoxy)-N-((3S,4S)-1-((3-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2, 2-Dimethylpentanamide (Compound 285)

Compound 285 was prepared according to the method of Examples 119 and 77: ¹ H NMR (300MHz, CDCl ₃ ) δ8.06(s, 1H), 7.98(d, J=7.9Hz, 1H), 7.89(d, J=7.7 Hz, 1H), 7.72-7.66(m, 1H), 6.97-6.85(m, 4H), 5.95(d, J=7.5Hz, 1H), 4.62-4.34(m, 1H), 4.10-4.02(m, 1H), 4.03-3.96(m, 3H), 3.87(s, 3H), 3.74-3.65(m, 1H), 2.60-2.49(m, 2H), 2.17-2.03(m, 1H), 1.81-1.67( m, 4H), 1.58-1.48 (m, 1H), 1.19 (s, 6H). ESI-MS: m/z 540.1[M+Na] ⁺ .

Example 195

5-(2,5-dichlorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 287)

Compound 287 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.95-8.83 (m, 2H), 8.15 (d, J=7.9Hz, 1H), 7.69 (dd, J =8.1, 4.8Hz, 1H), 7.44(d, J=8.4Hz, 1H), 7.27-7.15(m, 2H), 7.01(dd, J=8.5, 2.3Hz, 1H), 4.12-3.96(m, 2H), 3.70-3.60(m, 2H), 3.60-3.50(m, 1H), 2.48-2.37(m, 2H), 1.78-1.66(m, 2H), 1.64-1.54(m, 4H), 1.53- 1.42(m, 2H), 1.06(s, 6H). ESI-MS: m/z 536.2[M+Na] ⁺ .

Example 196

trans-5-(2,4-difluorophenoxy)-N-(3fluoro-1-(pyridine-3-sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (Compound 289)

Compound 289 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.00(s, 1H), 8.86(d, J=4.1Hz, 1H), 8.06(d, J =7.9Hz, 1H), 7.51(dd, J=7.7, 4.9Hz, 1H), 6.98-6.68(m, 3H), 5.80(d, J=7.4Hz, 1H), 4.68-4.34(m, 1H) , 4.17-3.85(m, 4H), 3.74(d, J=11.9Hz, 1H), 2.56(dd, J=13.8, 11.6Hz, 2H), 2.13(d, J=13.4Hz, 1H), 1.88- 1.53(m, 6H), 1.19(s, 6H).ESI-MS: m/z 500.2[M+H] ⁺ .

Example 197

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(1-((2,4,5-trifluorophenyl)sulfonyl)piperidin-4-yl ) valeramide (compound 290)

Compound 290 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.80-7.69 (m, 1H), 7.18-7.07 (m, 1H), 7.04 (d, J=7.4Hz, 1H ), 6.70(d, J=7.3Hz, 1H), 6.63(s, 1H), 5.52(d, J=7.5Hz, 1H), 4.02-3.77(m, 5H), 2.84-2.69(m, 2H) , 2.33(s, 3H), 2.20(s, 3H), 2.09-1.95(m, 2H), 1.80-1.66(m, 4H), 1.54-1.45(m, 2H), 1.23(s, 6H).ESI -MS: m/z 549.3[M+Na] ⁺ .

Example 198

N-(1-((5-chloro-2,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2- Dimethylvaleramide (Compound 291)

Compound 291 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.99-7.87 (m, 1H), 7.13-7.03 (m, 1H), 7.00 (d, J=7.4Hz, 1H ), 6.66(d, J=7.3Hz, 1H), 6.59(s, 1H), 5.49(d, J=7.2Hz, 1H), 3.97-3.77(m, 5H), 2.81-2.64(m, 2H) , 2.30(s, 3H), 2.16(s, 3H), 2.07-1.93(m, 2H), 1.80-1.64(m, 4H), 1.51-1.42(m, 2H), 1.19(s, 6H).ESI -MS: m/z 565.2[M+Na] ⁺ .

Example 199

N-(1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethyl Valeramide (compound 292)

Compound 292 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.83 (dd, J=6.4, 1.5Hz, 1H), 7.70-7.59 (m, 1H), 7.34-7.27 (m , 1H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.48(d, J=7.4Hz, 1H), 3.89(t , J=5.1Hz, 2H), 3.84-3.70(m, 3H), 2.51-2.36(m, 2H), 2.29(s, 3H), 2.16(s, 3H), 2.03-1.91(m, 2H), 1.76-1.62(m, 4H), 1.54-1.41(m, 2H), 1.18(s, 6H). ESI-MS: m/z 547.2[M+Na] ⁺ .

Example 200

N-(1-((2-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethyl Valeramide (compound 293)

Compound 293 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ8.17-8.05 (m, 1H), 7.32-7.26 (m, 1H), 7.18-7.07 (m, 1H), 7.03 (d, J=7.4Hz, 1H), 6.69(d, J=7.4Hz, 1H), 6.63(s, 1H), 5.53(d, J=7.5Hz, 1H), 4.03-3.75(m, 5H) , 2.99-2.79(m, 2H), 2.33(s, 3H), 2.20(s, 3H), 2.03-1.93(m, 2H), 1.81-1.65(m, 4H), 1.54-1.40(m, 2H) , 1.23(s, 6H).ESI-MS: m/z547.2[M+Na] ⁺ .

Example 201

N-(1-((3,5-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentane Amide (compound 294)

Compound 294 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.32 (d, J=4.1Hz, 2H), 7.07 (dd, J=21.0, 7.9Hz, 2H), 6.70( d, J=7.3Hz, 1H), 6.63(s, 1H), 5.51(d, J=7.2Hz, 1H), 3.98-3.90(m, 2H), 3.82(d, J=12.1Hz, 2H), 3.78-3.72(m, 1H), 2.52(t, J=11.6Hz, 2H), 2.33(s, 3H), 2.20(s, 3H), 2.02(d, J=11.6Hz, 2H), 1.71(s , 4H), 1.59-1.46(m, 2H), 1.22(s, 6H).ESI-MS: m/z 531.3[M+Na] ⁺ .

Example 202

N-(1-((2,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentane Amide (compound 295)

Compound 295 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.88 (dd, J=14.7, 8.1Hz, 1H), 6.99 (dd, J=16.1, 8.1Hz, 3H), 6.68(d, J=7.4Hz, 1H), 6.61(s, 1H), 5.49(d, J=7.1Hz, 1H), 3.92(d, J=5.3Hz, 2H), 3.86(d, J=12.7 Hz, 3H), 2.70(t, J=12.1Hz, 2H), 2.32(s, 3H), 2.18(s, 3H), 2.00(d, J=12.7Hz, 2H), 1.70(s, 4H), 1.48(ddd, J=15.7, 12.6, 3.7Hz, 2H), 1.21(s, 6H).ESI-MS: m/z 531.3[M+Na] ⁺ .

Example 203

N-(1-((5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethyl Valeramide (compound 296)

Compound 296 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl3) δ7.32(d, J=4.1Hz, 2H), 7.07(dd, J=21.0, 7.9Hz, 2H), 6.70(d , J=7.3Hz, 1H), 6.63(s, 1H), 5.51(d, J=7.2Hz, 1H), 3.98-3.90(m, 2H), 3.82(d, J=12.1Hz, 2H), 3.78 -3.72(m, 1H), 2.52(t, J=11.6Hz, 2H), 2.33(s, 3H), 2.20(s, 3H), 2.02(d, J=11.6Hz, 2H), 1.71(s, 4H), 1.59-1.46(m, 2H), 1.22(s, 6H).ESI-MS: m/z 547.3[M+Na] ⁺ .

Example 204

N-(1-((2,6-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentane Amide (Compound 297)

Compound 297 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.82-7.72 (m, 1H), 7.38-7.25 (m, 3H), 6.97 (d, J=7.6Hz , 1H), 6.72-6.66(m, 1H), 6.61(d, J=7.3Hz, 1H), 3.89-3.83(m, 2H), 3.74-3.62(m, 3H), 2.76-2.66(m, 2H ), 2.24(s, 3H), 2.08(s, 3H), 1.77-1.69(m, 2H), 1.59-1.54(m, 4H), 1.52-1.44(m, 2H), 1.07(s, 6H). ESI-MS: m/z 531.3[M+Na] ⁺ .

Example 205

5-(2,5-Dimethylphenoxy)-N-(1--((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)-2 , 2-Dimethylpentanamide (compound 298)

Compound 298 was prepared according to the method of Example 43: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.20-8.10 (m, 1H), 8.03-7.93 (m, 1H), 7.88-7.77 (m, 1H) , 7.25(d, J=7.8Hz, 1H), 6.97(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.62(d, J=7.6Hz, 1H), 3.85(t, J= 10.6Hz, 2H), 3.68-3.55(m, 3H), 2.48-2.39(m, 2H), 2.23(s, 3H), 2.08(s, 3H), 1.76-1.64(m, 2H), 1.61-1.53 (m, 4H), 1.52-1.42 (m, 2H), 1.06 (s, 6H). ESI-MS: m/z 581.3[M+Na] ⁺ .

Example 206

5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (compound 299 )

Compound 299 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ9.06(d, J=2.8Hz, 1H), 8.49(d, J=7.2Hz, 1H), 8.25(d, J=8.2Hz, 1H), 8.04(d, J=8.1Hz, 1H), 7.63(t, J=7.7Hz, 1H), 7.54(dd, J=8.2, 4.1Hz, 1H), 7.01(d, J=7.4Hz, 1H), 6.67(d, J=7.4Hz, 1H), 6.61(s, 1H), 5.55(d, J=7.6Hz, 1H), 4.11(d, J=12.9Hz, 2H) , 3.90(t, J=5.3Hz, 2H), 3.87-3.73(m, 1H), 2.92(t, J=12.1Hz, 2H), 2.31(s, 3H), 2.17(s, 3H), 1.96( d, J=11.0Hz, 2H), 1.69(s, 4H), 1.52(ddd, J=15.3, 12.1, 3.7Hz, 2H), 1.19(s, 6H). ESI-MS: m/z 546.3 [M +Na] ⁺ .

Example 207

Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide ( Compound 300)

Compound 300 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.00-8.86(m, 2H), 8.32(d, J=8.3Hz, 1H), 8.20(d , J=8.1Hz, 1H), 7.74-7.62(m, 1H), 7.38-7.22(m, 1H), 7.14-6.92(m, 2H), 4.79-4.50(m, 1H), 4.04-3.80(m , 2H), 3.61-3.50(m, 1H), 2.81-2.62(m, 2H), 1.89-1.73(m, 1H), 1.73-1.55(m, 1H), 1.37(s, 3H), 1.35(s , 3H).ESI-MS: m/z 480.1[M+Na] ⁺ .

Example 208

Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2-Methylpropionamide (Compound 301)

Compound 301 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.38-8.28 (m, 1H), 8.19 (d, J=8.2Hz, 2H), 8.05 (d , J=8.2Hz, 2H), 7.36-7.23(m, 1H), 7.12-6.93(m, 2H), 4.76-4.54(m, 1H), 3.95-3.78(m, 2H), 3.60-3.47(m , 1H), 3.32(s, 3H), 2.76-2.60(m, 2H), 1.88-1.76(m, 1H), 1.72-1.58(m, 1H), 1.37(s, 3H), 1.35(s, 3H ).ESI-MS: m/z 557.1[M+Na] ⁺ .

Example 209

2-(2,3-Difluoro-4-methylphenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4- base) propionamide (compound 302)

Compound 302 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.20(d, J=2.8Hz, 2H), 8.07(d, J=8.0Hz, 1H), 8.01( d, J=5.1Hz, 2H), 7.03-6.93(m, 1H), 6.74-6.64(m, 1H), 3.63(d, J=11.9Hz, 1H), 3.65-3.63(m, 2H), 3.31 (s, 3H), 2.60-2.52(m, 2H), 2.21(s, 3H), 1.79-1.68(m, 2H), 1.61-1.52(m, 2H), 1.38(s, 6H).ESI-MS : m/z 553.3[M+Na] ⁺ .

Example 210

4-(2,3-difluoro-4-methylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)butanamide ( Compound 303)

Compound 303 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.22-8.15 (m, 2H), 8.05-7.96 (m, 2H), 7.82 (d, J=7.5Hz , 1H), 7.03-6.93(m, 1H), 6.91-6.83(m, 1H), 4.01(t, J=6.3Hz, 2H), 3.71-3.61(m, 1H), 3.59-3.48(m, 2H ), 3.32(s, 3H), 2.59(t, J=12.2Hz, 2H), 2.51-2.49(m, 2H), 2.19(s, 3H), 1.95-1.86(m, 2H), 1.83-1.74( m, 2H), 1.48-1.31 (m, 2H). ESI-MS: m/z 553.3 [M+Na] ⁺ .

Example 211

5-(2,3-difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-yl)pentanamide (compound 304)

Compound 304 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.21-8.14 (m, 2H), 8.00 (d, J=9Hz, 1H), 7.97 (d, J= 9Hz, 1H), 7.20(d, J=7.7Hz, 1H), 7.02-6.92(m, 1H), 6.89-6.81(m, 1H), 3.97(t, J=6Hz, 2H), 3.64(d, 1H), 3.29-3.24(m, 2H), 2.49(s, 3H), 2.47-2.36(m, 2H), 2.18(s, 3H), 1.74-1.64(m, 2H), 1.59-1.50(m, 4H), 1.50-1.36(m, 2H), 1.04(s, 6H).ESI-MS: m/z 595.3[M+Na] ⁺ .

Example 212

5-(2,3-Difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 305)

Compound 305 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.11-8.72 (m, 2H), 8.04 (d, J=7.9Hz, 1H), 7.50 (d, J=6.5 Hz, 1H), 6.87-6.70(m, 1H), 6.69-6.51(m, 1H), 5.58(d, J=6.8Hz, 1H), 3.96(t, J=12Hz, 1H), 3.92-3.82( m, 1H), 3.84-3.70(m, 2H), 2.23(s, 3H), 2.13-2.03(m, 2H), 2.03-1.92(m, 2H), 1.81-1.58(m, 4H), 1.57- 1.46(m, 2H), 1.16(s, 6H). ESI-MS: m/z 518.2[M+Na] ⁺ .

Example 213

4-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)butanamide (compound 306)

Compound 306 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.16 (d, J=8.1Hz, 2H), 7.99 (d, J=8.2Hz, 2H), 7.79( d, J=7.4Hz, 1H), 6.96(d, J=7.4Hz, 1H), 6.67(s, 1H), 6.60(d, J=7.5Hz, 1H), 3.89(t, J=6.2Hz, 2H), 3.53(d, J=12.7Hz, 3H), 3.29(s, 1H), 2.57(t, J=11.4Hz, 2H), 2.21(d, J=7.3Hz, 5H), 2.06(s, 3H), 1.89(q, J=6.8Hz, 2H), 1.77(d, J=11.4Hz, 2H), 1.49-1.10(m, 4H).ESI-MS: m/z 531.2[M+Na] ⁺ .

Example 214

4-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)butanamide (Compound 307)

Compound 307 was prepared according to the method of Example 119: ¹ H NMR (300MHz, Chloroform-d) δ7.76 (dd, J=8.5, 5.0Hz, 2H), 7.23 (dd, J=14.5, 6.5Hz, 3H) , 7.00(d, J=7.4Hz, 1H), 6.67(d, J=7.6Hz, 1H), 6.60(s, 1H), 5.43(d, J=8.0Hz, 1H), 3.96(t, J= 5.9Hz, 2H), 3.74(d, J=11.7Hz, 3H), 2.49-2.32(m, 4H), 2.29(s, 3H), 2.15(s, 4H), 2.11(d, J=9.2Hz, 3H), 1.96(d, J=12.1Hz, 2H), 1.59(s, 1H), 1.48(qd, J=12.0, 4.1Hz, 2H).ESI-MS: m/z 471.3[M+Na] ⁺ .

Example 215

4-(2,5-Dimethylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)butanamide (compound 308)

Compound 308 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, Chloroform-d) δ9.00 (d, J=2.3Hz, 1H), 8.86 (dd, J=4.9, 1.6Hz, 1H), 8.05 (dt, J=8.0, 2.0Hz, 1H), 7.51(dd, J=8.0, 4.8Hz, 1H), 7.02(d, J=7.4Hz, 1H), 6.69(d, J=7.5Hz, 1H) , 6.62(s, 1H), 5.45(d, J=8.0Hz, 1H), 3.98(t, J=5.8Hz, 2H), 3.80(dt, J=8.9, 4.3Hz, 3H), 2.58-2.43( m, 2H), 2.39(t, J=7.3Hz, 2H), 2.31(s, 3H), 2.17(s, 3H), 2.13(d, J=7.0Hz, 2H), 2.00(d, J=12.9 Hz, 2H), 1.50 (qd, J=12.0, 3.9Hz, 2H).ESI-MS: m/z 454.2[M+Na] ⁺ .

Example 216

trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) -2,2-Dimethylpentanamide (compound 309)

Compound 309 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19 (d, J=8.2Hz, 2H), 8.05 (d, J=8.3Hz, 2H), 7.52-7.37(m, 2H), 7.24-7.07(m, 2H), 4.75-4.36(m, 1H), 4.12-3.74(m, 4H), 3.62-3.46(m, 1H), 3.33(s, 3H ), 2.81-2.57(m, 2H), 1.83-1.67(m, 1H), 1.67-1.43(m, 5H), 1.07(s, 6H). ESI-MS: m/z 615.2[M+Na] ⁺ .

Example 217

trans-5-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-(pyridine-3-sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 310)

Compound 310 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.01-8.93 (m, 1H), 8.93-8.84 (m, 1H), 8.31-8.11 (m, 1H), 7.78-7.65(m, 1H), 7.52-7.34(m, 2H), 7.27-7.08(m, 2H), 4.70-4.40(m, 1H), 4.06-3.76(m, 4H), 3.65- 3.45(m, 1H), 2.82-2.60(m, 2H), 1.86-1.65(m, 1H), 1.65-1.43(m, 5H), 1.07(s, 6H). ESI-MS: m/z 538.2[ M+Na] ⁺ .

Example 218

5-(2,5-dichlorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 312)

Compound 312 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.32-8.21 (m, 1H), 8.20-8.12 (m, 1H), 8.12-8.03 (m, 1H) , 7.94(t, J=7.8Hz, 1H), 7.49-7.39(m, 1H), 7.29-7.16(m, 2H), 7.06-6.96(m, 1H), 4.09-3.95(m, 2H), 3.73 -3.48(m, 3H), 3.35(s, 3H), 2.42(t, J=11.7Hz, 2H), 1.78-1.65(m, 2H), 1.60-1.43(m, 6H), 1.06(s, 6H ).ESI-MS: m/z 613.3[M+Na] ⁺ .

Example 219

5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine -4-yl)pentanamide (compound 313)

Compound 313 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.33(s, 1H), 8.19(d, J=7.9Hz, 1H), 8.04(d, J=7.8Hz, 1H), 7.80(app t, J=7.8Hz, 1H), 7.69(d, J=7.9Hz, 1H), 7.28(d, J=6.9Hz, 1H), 7.16(s, 1H), 5.50(d , J=7.6Hz, 1H), 4.06(t, J=5.2Hz, 2H), 3.88-3.78(m, 2H), 3.78-3.68(m, 1H), 3.12(s, 3H), 2.54-2.38( m, 2H), 2.05-1.90 (m, 2H), 1.80-1.64 (m, 4H), 1.56-1.43 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 681.2 [M+ Na] ⁺ .

Example 220

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 314)

Compound 314 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.93-8.87 (m, 2H), 8.17-8.13 (m, 1H), 7.69 (dd, J=7.9, 4.9Hz, 1H), 7.22(d, J=7.7Hz, 1H), 7.09(t, J=8.8Hz, 2H), 6.94-6.87(m, 2H), 3.90-3.83(m, 2H), 3.69- 3.52(m, 3H), 2.49-2.38(m, 2H), 1.77-1.66(m, 2H), 1.54(s, 6H). ESI-MS: m/z 486.2[M+Na] ⁺ .

Example 221

3-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-ylpropionamide (Compound 315)

Compound 315 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.86-7.57 (m, 1H), 7.21 (t, J=8.3Hz, 1H), 7.00 (d, J=7.4 Hz, 1H), 6.68(d, J=7.3Hz, 1H), 6.62(s, 1H), 6.29(s, 1H), 4.17(t, J=5.6Hz, 1H), 3.74(d, J=11.1 Hz, 1H), 2.61(t, J=5.5Hz, 1H), 2.38(t, J=11.5Hz, 1H), 2.29(s, 1H), 2.12(s, 1H), 1.98(d, J=12.1 Hz, 1H), 1.55 (dd, J=21.0, 11.1Hz, 1H).ESI-MS: m/z 457.2[M+Na] ⁺ .

Example 222

3-(2,5-Dimethylphenoxy)-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propionamide (compound 317)

Compound 317 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.97 (s, 1H), 8.87-8.80 (m, 1H), 8.03 (d, J=8.0Hz, 1H), 7.49(dd, J=7.7, 4.9Hz, 1H), 7.01(d, J=7.5Hz, 1H), 6.70(d, J=7.4Hz, 1H), 6.63(s, 1H), 6.09(d, J =7.7Hz, 1H), 4.19(t, J=5.7Hz, 2H), 3.79(d, J=11.7Hz, 3H), 2.63(t, J=5.7Hz, 2H), 2.46(t, J=11.7 Hz, 2H), 2.30(s, 3H), 2.13(s, 3H), 2.02(d, J=15.2Hz, 3H), 1.62-1.37(m, 4H). ESI-MS: m/z 440.2 [M +Na] ⁺ .

Example 223

3-(2,5-Dimethylphenoxy)-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 319)

Compound 319 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19(d, J=8.2Hz, 1H), 8.01(d, J=8.2Hz, 1H), 7.97( d, J=7.5Hz, 1H), 6.97(d, J=7.4Hz, 1H), 6.72(s, 1H), 6.63(d, J=7.4Hz, 1H), 5.76(s, 1H), 4.12( t, J=5.8Hz, 1H), 3.68-3.58(m, 1H), 3.54(d, J=11.9Hz, 1H), 3.32(s, 3H), 2.63(t, J=10.6Hz, 1H), 2.48(d, J=5.9Hz, 2H), 2.24(s, 2H), 2.02(s, 2H), 1.81(d, J=10.5Hz, 1H), 1.43(dd, J=20.1, 9.8Hz, 1H ), 1.27 (d, J=6.8Hz, 2H).ESI-MS: m/z 517.1[M+Na] ⁺ .

Example 224

5-(2,4-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 320 )

Compound 320 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.81 (dd, J=8.7, 5.2Hz, 2H), 7.48 (dd, J=8.7Hz, 2H), 7.32-7.08(m, 3H), 6.98(d, J=8.8Hz, 1H), 3.95(m, 2H), 3.66-3.46(m, 3H), 2.43-2.26(m, 2H), 1.81-1.64( m, 2H), 1.60-1.39(m, 6H), 1.05(s, 6H). ESI-MS: m/z 521.1[M+Na] ⁺ .

Example 225

5-(4-bromo-2,6-difluorophenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide ( Compound 321)

Compound 321 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.16-8.75 (m, 2H), 8.15 (d, J=8.1Hz, 1H), 7.69 (dd, J =8.0, 4.8Hz, 1H), 7.50(d, J=7.7Hz, 2H), 7.21(d, J=7.8Hz, 1H), 4.03(t, J=5.1Hz, 2H), 3.72-3.51(m , 3H), 2.48-2.35 (m, 2H), 1.76-1.63 (m, 2H), 1.59-1.40 (m, 6H), 1.04 (s, 6H). ESI-MS: m/z 582.0 [M+Na ] ⁺ .

Example 226

trans-N-(1-((2,4-difluorophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-5-(2,5-dimethylphenoxy)-2 , 2-Dimethylpentanamide (compound 322)

Compound 322 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.89 (dd, J=15.0, 8.2Hz, 1H), 7.61 (t, J=9.9Hz, 1H), 7.44(d, J=7.5Hz, 1H), 7.33(t, J=8.2Hz, 1H), 6.97(d, J=7.4Hz, 1H), 6.73-6.54(m, 2H), 4.42-4.68(m , 1H), 4.02-3.77(m, 4H), 3.52(d, J=13.1Hz, 1H), 2.98-2.75(m, 2H), 2.24(s, 3H), 2.07(s, 3H), 1.82- 1.48(m, 1H), 1.09(s, 6H). ESI-MS: m/z 549.2[M+Na] ⁺ .

Example 227

trans-5-(2,6-difluorophenoxy)-N-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2-dimethylpentane Amide (compound 323)

Compound 323 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.95(s, 1H), 8.89(d, J=4.8Hz, 1H), 8.20(d, J =8.0Hz, 1H), 7.68(dd, J=8.0, 5.0Hz, 1H), 7.41(d, J=8.2Hz, 1H), 7.18-7.06(m, 3H), 4.74-4.36(m, 0H) , 4.01(t, J=5.8Hz, 2H), 3.94-3.76(m, 2H), 3.62-3.40(m, 1H), 2.86-2.59(m, 2H), 1.87-1.63(m, 1H), 1.63 -1.44(m, 5H), 1.06(s, 6H).ESI-MS: m/z 522.3[M+Na] ⁺ .

Example 228

trans-5-(2,6-difluorophenoxy)-N-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl valeramide (compound 324)

Compound 324 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.86 (dd, J=8.6, 5.1Hz, 2H), 7.55-7.37 (m, 3H), 7.18 -7.07(m, 3H), 4.92-4.25(m, 1H), 4.02(t, J=5.6Hz, 2H), 3.92-3.72(m, 2H), 3.54-3.42(m, 1H), 2.69-2.55 (m, 2H), 1.84-1.68(m, 1H), 1.65-1.45(m, 5H), 1.06(s, 6H). ESI-MS: m/z 539.3[M+Na] ⁺ .

Example 229

Trans-5-(2,6-difluorophenoxy)-N-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2 , 2-Dimethylpentanamide (compound 325)

Compound 325 was obtained by referring to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19 (d, J=8.2Hz, 2H), 8.05 (d, J=8.5Hz, 2H), 7.46(d, J=8.2Hz, 1H), 7.17-7.05(m, 3H), 4.69-4.42(m, 1H), 4.02(t, 2H), 3.96-3.77(m, 2H), 3.61-3.46( m, 1H), 3.33(s, 3H), 2.79-2.58(m, 2H), 1.85-1.69(m, 1H), 1.63-1.45(m, 5H), 1.06(s, 6H).ESI-MS: m/z 599.2[M+Na] ⁺ .

Example 230

N-((3S,4S)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(2-methoxyphenoxy)-2,2 -Dimethylpentanamide (compound 328)

Compound 328 was prepared according to the method of Examples 119 and 77: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.81-7.74 (m, 2H), 7.24-7.17 (m, 2H), 6.98-6.83 (m, 4H), 5.92(d, J=7.5Hz, 1H), 4.60-4.33(m, 1H), 4.07-3.94(m, 4H), 3.87(s, 3H), 3.72-3.61(m, 1H ), 2.51-2.36(m, 2H), 2.15-2.03(m, 1H), 1.85-1.65(m, 4H), 1.59-1.48(m, 1H), 1.19(s, 6H).ESI-MS: m /z 533.1[M+Na] ⁺ .

Example 231

5-(4-chlorophenyl)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide (compound 329 )

Compound 329 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18 (d, J=8.2Hz, 2H), 7.99 (d, J=8.3Hz, 2H), 7.30( d, J=8.7Hz, 2H), 7.23(d, J=7.8Hz, 1H), 6.91(d, J=8.7Hz, 2H), 3.95-3.82(m, 2H), 3.72-3.49(m, 3H ), 3.33(s, 3H), 2.43(t, J=11.1Hz, 2H), 1.70(d, J=11.0Hz, 2H), 1.61-1.40(m, 6H), 1.05(s, 3H).ESI -MS: m/z 579.1[M+Na] ⁺ .

Example 232

5-(4-chlorophenyl)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 330)

Compound 330 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.80 (dd, J=8.4, 5.3Hz, 2H), 7.48 (t, J=8.7Hz, 2H), 7.30(d, J=8.8Hz, 2H), 7.21(d, J=7.6Hz, 1H), 6.91(d, J=8.8Hz, 2H), 3.95-3.83(m, 2H), 3.65-3.48(m , 3H), 2.35(t, J=11.3Hz, 2H), 1.69(d, J=10.6Hz, 2H), 1.60-1.40(m, 6H), 1.05(s, 6H).ESI-MS: m/ z 519.1[M+Na] ⁺ .

Example 233

5-(4-chlorophenyl)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (compound 331)

Compound 331 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.89 (m, 2H), 8.15 (d, J=8.1Hz, 1H), 7.69 (dd, J=7.6 , 4.9Hz, 1H), 7.30(d, J=8.9Hz, 2H), 7.21(d, J=7.5Hz, 1H), 6.91(d, J=8.9Hz, 2H), 3.94-3.83(m, 2H ), 3.70-3.54(m, 3H), 2.44(t, J=11.6Hz, 2H), 1.70(d, J=10.4Hz, 2H), 1.59-1.42(m, 6H), 1.05(s, 6H) .ESI-MS: m/z 502.1[M+Na] ⁺ .

Example 234

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanamide ( Compound 332)

Compound 332 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.88-7.75 (m, 4H), 7.56-7.40 (m, 2H), 7.25 (d, J=7.8Hz , 1H), 7.12(d, J=8.8Hz, 2H), 4.10-3.92(m, 2H), 3.65-3.47(m, 3H), 3.15(s, 3H), 2.40-2.26(m, 2H), 1.77-1.62(m, 2H), 1.62-1.40(m, 6H), 1.06(s, 6H). ESI-MS: m/z 541.4[M+H] ⁺ .

Example 235

5-(2,4-difluorophenoxy)-N-((3S,4S)-3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2,2- Dimethylvaleramide (Compound 334)

Compound 334 was prepared according to the method of Examples 119 and 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.95 (s, 1H), 8.90 (d, J=4.0Hz, 1H), 8.21(d, J=8.0Hz, 1H), 7.69(dd, J=7.8, 4.9Hz, 1H), 7.44(d, J=8.0Hz, 1H), 7.31-6.91(m, 3H), 4.71-4.39 (m, 1H), 4.04-3.77(m, 4H), 3.63-3.46(m, 1H), 2.83-2.60(m, 2H), 1.85-1.45(m, 6H), 1.07(s, 6H).ESI -MS: m/z 522.2[M+Na] ⁺ .

Example 236

N-(1-((3,4-difluorophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentane Amide (compound 341)

Compound 341 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.67-7.50 (m, 2H), 7.41-7.30 (m, 1H), 7.02 (d, J=7.4Hz, 1H ), 6.68(d, J=7.3Hz, 1H), 6.61(s, 1H), 5.50(d, J=7.3Hz, 1H), 3.92(t, J=4.9Hz, 2H), 3.85-3.72(m , 3H), 2.53-2.40(m, 2H), 2.32(s, 3H), 2.18(s, 3H), 2.05-1.94(m, 2H), 1.75-1.66(m, 4H), 1.57-1.46(m , 2H), 1.20(s, 6H).ESI-MS: m/z 509.3[M+H] ⁺ .

Example 237

2-(3,4-difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide ( Compound 342)

Compound 342 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.32(s, 1H), 8.19(d, J=7.8Hz, 1H), 8.04(d, J=7.8Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7.06(dd, J=18.8, 9.2Hz, 1H), 6.74(ddd, J=11.2, 6.7, 2.8Hz, 1H), 6.61(dt, J =4.3, 3.9Hz, 1H), 6.52(d, J=7.7Hz, 1H), 3.80(m, 3H), 3.11(s, 3H), 2.55(t, J=11.8Hz, 2H), 2.02(d , J=12.6Hz, 2H), 1.63-1.52(m, 2H), 1.45(s, 6H).ESI-MS: m/z 539.1[M+Na] ⁺ .

Example 238

Trans-2-(3,4-difluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide ( Compound 343)

Compound 343 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ9.01(s, 1H), 8.87(d, J=4.1Hz, 1H), 8.07(d, J=8.0 Hz, 1H), 7.53(dd, J=7.7, 5.0Hz, 1H), 7.07(dd, J=18.7, 9.2Hz, 1H), 6.84-6.73(m, 1H), 6.72-6.59(m, 2H) , 4.63-4.35(m, 1H), 4.17-4.05(m, 1H), 4.03-3.89(m, 1H), 3.78(dd, J=12.3, 1.2Hz, 1H), 2.65-2.51(m, 2H) , 2.25-2.10(m, 1H), 1.74-1.61(m, 1H), 1.48(s, 3H), 1.46(s, 3H). ESI-MS: m/z 558.1[M+H] ^+.

Example 239

Trans-2-(3,4-difluorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2-Methylpropionamide (Compound 344)

Compound 344 was obtained by referring to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.29 (d, J=8.4Hz, 1H), 8.17 (d, J=8.2Hz, 2H), 8.03(d, J=8.3Hz, 2H), 7.32(dd, J=19.6, 9.6Hz, 1H), 6.94(ddd, J=12.0, 6.8, 2.7Hz, 1H), 6.71(d, J=8.9Hz , 1H), 4.74-4.42(m, 1H), 4.01-3.83(m, 2H), 3.54(d, J=11.6Hz, 1H), 3.29(s, 3H), 2.66(dd, J=24.9, 11.5 Hz, 2H), 1.82-1.69(m, 1H), 1.67-1.48(m, 1H), 1.40(s, 3H), 1.37(s, 3H). ESI-MS: m/z 533.2[MH] ^- .

Example 240

trans-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl)phenoxy)propane Amide (Compound 346)

Compound 346 was obtained by referring to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ9.03 (s, 1H), 8.89 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.53(dd, J=7.8, 4.8Hz, 1H), 7.48-7.34(m, 2H), 7.18(s, 1H), 7.10(d, J=7.7Hz, 1H), 6.65(d, J=7.9Hz , 1H), 4.49(ddd, J=13.4, 9.3, 4.7Hz, 1H), 4.22-3.90(m, 3H), 3.77(d, J=11.3Hz, 1H), 2.62(t, J=12.9Hz, 2H), 2.17(d, J=13.2Hz, 1H), 1.73(ddd, J=16.0, 12.2, 4.8Hz, 2H), 1.54(d, J=4.7Hz, 6H).ESI-MS: m/z 513 .2[M+Na] ⁺ .

Example 241

trans-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methyl-2-(3-(trifluoromethane base) phenoxy) propionamide (compound 347)

Compound 347 was obtained by referring to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.30 (d, J=8.4Hz, 1H), 8.16 (d, J=8.3Hz, 2H), 8.01(d, J=8.3Hz, 2H), 7.48(t, J=7.8Hz, 1H), 7.34(d, J=7.5Hz, 1H), 7.12(d, J=7.8Hz, 2H), 4.67- 4.43(m, 1H), 3.98-3.87(m, 1H), 3.87-3.74(m, 1H), 3.56-3.44(m, 1H), 2.74-2.56(m, 2H), 1.75(dd, J=14.7 , 10.7Hz, 1H), 1.58(dd, J=17.1, 8.7Hz, 1H), 1.44(s, 3H), 1.41(s, 3H).ESI-MS: m/z 589.3[M+Na] ⁺ .

Example 242

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 348)

Compound 348 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.16(d, J=8.0Hz, 2H), 7.98(d, J=8.4Hz, 2H), 7.25(d, J=8.8Hz, 2H), 6.84(d, J=8.8Hz, 2H), 6.54(d, J=8.3Hz, 1H), 3.81(d, J=11.3Hz, 3H), 3.14(s, 3H) , 2.58(t, J=11.0Hz, 2H), 2.07-1.99(m, 2H), 1.65-1.57(m, 2H), 1.48(s, 6H).ESI-MS: m/z 537.2 [M+Na ] ⁺ .

Example 243

trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) -2-Methylpropionamide (compound 349)

Compound 349 was obtained by referring to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.35 (d, J=8.2Hz, 1H), 8.18 (d, J=8.4Hz, 2H), 8.03(d, J=8.3Hz, 2H), 7.47(d, J=12.8Hz, 1H), 7.16(d, J=7.5Hz, 1H), 6.95(t, J=8.8Hz, 1H), 4.60( d, J=52.1Hz, 1H), 3.95(d, J=20.0Hz, 1H), 3.87-3.77(m, 1H), 3.51(dd, J=10.9, 4.0Hz, 1H), 3.33(s, 3H ), 2.65(t, J=13.2Hz, 2H), 1.85-1.70(m, 1H), 1.66-1.56(m, 1H), 1.38(s, 3H), 1.37(s, 3H).ESI-MS: m/z 573.2[M+Na] ⁺ .

Example 244

trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl Propionamide (compound 350)

Compound 350 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82 (dd, J=8.6, 5.0Hz, 2H), 7.32-7.25 (m, 2H), 7.16 (dd , J=10.2, 2.2Hz, 1H), 7.03(dt, J=16.9, 9.2Hz, 3H), 4.54(dtd, J=48.7, 9.2, 5.0Hz, 1H), 4.09-3.86(m, 2H), 3.69(d, J=11.9Hz, 1H), 2.61(dt, J=15.5, 8.0Hz, 2H), 2.19(d, J=13.4Hz, 1H), 1.79-1.66(m, 1H), 1.49(s , 3H), 1.47(s, 3H).ESI-MS: m/z 513.1[M+Na] ⁺ .

Example 245

trans-2-(4-chloro-2-fluorophenoxy)-N-(3-fluoro-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 351)

Compound 351 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.93(s, 1H), 8.89(d, J=4.7Hz, 1H), 8.33(d, J =8.4Hz, 1H), 8.18(d, J=8.1Hz, 1H), 7.68(dd, J=7.9, 4.8Hz, 1H), 7.46(dd, J=10.7, 2.3Hz, 1H), 7.16(d , J=8.6Hz, 1H), 6.96(t, J=8.9Hz, 1H), 4.59(dtd, J=13.8, 8.9, 4.2Hz, 1H), 4.02-3.77(m, 2H), 3.51(d, J=12.1Hz, 1H), 2.69(dd, J=23.5, 12.3Hz, 2H), 1.81-1.54(m, 2H), 1.39(s, 3H), 1.37(s, 3H).ESI-MS: m /z 496.2[M+Na] ⁺ .

Example 246

2-(2,5-Dimethylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 352)

Compound 352 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.79(dd, J=8.6, 5.1Hz, 2H), 7.24(t, J=8.5Hz, 2H), 7.07( d, J=7.6Hz, 1H), 6.80(d, J=7.6Hz, 1H), 6.68(d, J=7.7Hz, 1H), 6.60(s, 1H), 3.89-3.77(m, 1H), 3.72(d, J=12.0Hz, 2H), 2.53(t, J=10.7Hz, 2H), 2.27(s, 3H), 2.18(s, 3H), 2.03(d, J=11.9Hz, 2H), 1.58(m, 2H), 1.51(s, 6H).ESI-MS: m/z 471.2[M+Na] ⁺ .

Example 247

Trans-2-(2,5-dimethylphenoxy)-N-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2-Methylpropionamide (Compound 353)

Compound 353 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ8.17(d, J=8.4Hz, 2H), 8.17(d, J=8.4Hz, 2H), 8.00( d, J=8.4Hz, 2H), 8.00(d, J=8.4Hz, 2H), 7.07(d, J=7.7Hz, 1H), 7.07(d, J=7.7Hz, 1H), 6.82(t, J=10.1Hz, 2H), 6.82(t, J=10.1Hz, 2H), 6.64(s, 1H), 6.64(s, 1H), 4.66-4.35(m, 1H), 4.04(s, 2H), 3.73(d, J=12.5Hz, 1H), 3.14(s, 3H), 2.67(t, J=10.8Hz, 2H), 2.26(s, 3H), 2.19(s, 3H), 1.72-1.64(m , 1H), 1.52 (d, J=12.9Hz, 6H).ESI-MS: m/z 525.4[MH] ⁺ .

Example 248

2-(2,5-Dimethylphenoxy)-N-((3S,4S)-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4 -yl)-2-methylpropanamide (compound 354)

Compound 354 was prepared according to the method of Examples 14 and 77: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ8.16(d, J=8.2Hz, 2H), 7.99(d, J=8.2Hz, 2H), 7.07(d, J=7.6Hz, 1H), 6.82(dd, J=15.9, 8.0Hz, 2H), 6.64(s, 1H), 4.66-4.37(m, 1H), 4.04(s, 2H ), 3.73(d, J=12.2Hz, 1H), 3.13(s, 3H), 2.67(t, J=10.7Hz, 2H), 2.26(s, 3H), 2.19(s, 3H), 1.76-1.64 (m, 1H), 1.52 (d, J=12.9Hz, 6H).ESI-MS: M/Z 549.2[M+Na] ⁺ .

Example 249

5-(4-chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 355)

Compound 355 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d6) δ7.94-7.69 (m, 2H), 7.61-7.33 (m, 3H), 7.33-7.02 (m, 3H), 4.10-3.88(m, 2H), 3.67-3.41(m, 3H), 2.41-2.22(m, 2H), 1.78-1.62(m, 2H), 1.62-1.37(m, 6H), 1.05(s, 6H ).ESI-MS: m/z 537.3[M+Na] ⁺ .

Example 250

5-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl valeramide (compound 356)

Compound 356 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.77 (dd, J=8.5, 5.1Hz, 2H), 7.23 (dd, J=14.5, 5.9Hz, 2H), 7.12-6.72(m, 3H), 5.56(d, J=7.5Hz, 1H), 3.90(t, J=5.3Hz, 2H), 3.85-3.59(m, 3H), 2.39(t, J=11.6Hz , 2H), 1.97(d, J=11.4Hz, 2H), 1.80-1.43(m, 6H), 1.18(s, 6H).ESI-MS: m/z 571.2[M+Na] ⁺ .

Example 251

N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (Compound 357)

Compound 357 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.32(s, 1H), 8.19(d, J=7.8Hz, 1H), 8.03(d, J=7.6Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7.37(t, J=8.0Hz, 1H), 7.19(d, J=7.6Hz, 1H), 7.10-6.99(m, 2H), 5.52( d, J=7.8Hz, 1H), 4.01(t, J=5.9Hz, 2H), 3.78(d, J=11.7Hz, 3H), 3.12(s, 3H), 2.50(t, J=11.3Hz, 2H), 2.36(t, J=7.2Hz, 2H), 2.21-2.05(m, 2H), 2.02(dd, J=20.6, 8.6Hz, 2H), 1.65-1.34(m, 2H).ESI-MS : m/z 571.1[M+Na] ⁺ .

Example 252

5-(2,3-difluoro-4-methylphenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 360)

Compound 360 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.86-7.69 (m, 2H), 7.33-7.16 (m, 2H), 6.86-6.74 (m, 1H), 6.66 -6.53(m, 1H), 5.75(d, J=8.1Hz, 1H), 3.98(t, J=5.3Hz, 2H), 3.89-3.78(m, 1H), 3.78-3.61(m, 2H), 2.43-2.34(m, 2H), 2.24(s, 3H), 2.04-1.89(m, 2H), 1.76-1.62(m, 4H), 1.62-1.50(m, 2H), 1.18(s, 6H). ESI-MS: m/z 535.2[M+Na] ⁺ .

Example 253

5-(2,3-Difluoro-4-methylphenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 361)

Compound 361 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.62-7.50 (m, 2H), 7.51-7.41 (m, 1H), 7.38-7.29 (m, 1H), 6.88 -6.72(m, 1H), 6.69-6.51(m, 1H), 5.56(d, J=7.6Hz, 2H), 3.96(t, J=5.5Hz, 2H), 3.86-3.76(m, 1H), 3.77-3.63(m, 2H), 2.56-2.36(m, 2H), 2.23(s, 3H), 2.07-1.87(m, 2H), 1.79-1.60(m, 4H), 1.55-1.44(m, 2H ), 1.17(s, 6H).ESI-MS: m/z 535.2[M+Na] ⁺ .

Example 254

5-(2,3-difluoro-4-methylphenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piper Pyridin-4-yl)pentanamide (Compound 362)

Compound 362 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.88-7.75 (m, 2H), 7.43-7.32 (m, 2H), 6.89-6.70 (m, 1H), 6.66 -6.52(m, 1H), 5.59(d, J=7.8Hz, 1H), 3.96(t, J=5.3Hz, 2H), 3.85-3.76(m, 1H), 3.77-3.62(m, 2H), 2.56-2.37(m, 2H), 2.23(s, 3H), 2.06-1.88(m, 2H), 1.81-1.58(m, 4H), 1.59-1.46(m, 2H), 1.25-1.04(m, 6H ).ESI-MS: m/z 601.2[M+Na] ⁺ .

Example 255

Trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2,2-Dimethylpentanamide (Compound 367)

Compound 367 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ8.18(d, J=8.3Hz, 2H), 8.05(d, J=8.3Hz, 2H), 7.44( d, J=8.4Hz, 2H), 7.19(d, J=1.9Hz, 1H), 7.01(dd, J=8.5, 1.9Hz, 1H), 4.74-4.43(m, 1H), 4.08-3.96(m , 2H), 3.96-3.80(m, 2H), 3.59-3.49(m, 1H), 3.32(s, 3H), 2.82-2.59(m, 2H), 1.87-1.67(m, 1H), 1.69-1.44 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 631.2[M+Na] ⁺ .

Example 256

Trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2,2-Dimethylpentanamide (Compound 368)

Compound 368 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, CD ₃ CN) δ8.27-8.16 (m, 2H), 8.08 (d, J=8.0Hz, 1H), 7.92-7.81( m, 1H), 7.34(d, J=8.5Hz, 1H), 7.04(d, J=2.3Hz, 1H), 6.94(dd, J=8.5, 2.4Hz, 1H), 6.27(d, J=8.3 Hz, 1H), 4.70-4.37(m, 1H), 4.00(t, J=5.8Hz, 2H), 3.97-3.82(m, 2H), 3.65-3.51(m, 1H), 3.13(s, 3H) , 2.78-2.59(m, 2H), 1.91-1.81(m, 1H), 1.75-1.53(m, 5H), 1.12(s, 6H). ESI-MS: m/z 631.2[M+Na] ⁺ .

Example 257

trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methylvaleramide (compound 369)

Compound 369 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.92-7.81 (m, 2H), 7.56-7.38 (m, 4H), 7.19 (d, J= 2.0Hz, 1H), 7.01(dd, J=8.5, 2.3Hz, 1H), 4.73-4.43(m, 1H), 4.10-3.95(m, 2H), 3.94-3.73(m, 2H), 3.55-3.41 (m, 1H), 2.66-2.53 (m, 2H), 1.86-1.68 (m, 1H), 1.67-1.44 (m, 5H), 1.08 (s, 6H). ESI-MS: m/z 571.2 [M +Na] ⁺ .

Example 258

2-(4-(4-chlorobenzoyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 370)

Compound 370 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.01 (d, J=7.8Hz, 1H), 7.85-7.66 (m, 6H), 7.62 (d, J =8.2Hz, 2H), 7.53-7.39(m, 2H), 6.93(d, J=8.6Hz, 2H), 3.71-3.56(m, 1H), 3.56-3.44(m, 2H), 2.45-2.32( m, 2H), 1.75-1.60 (m, 2H), 1.59-1.35 (m, 8H). ESI-MS: m/z 581.2[M+Na] ⁺ .

Example 259

5-(2,6-difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 373)

Compound 373 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.33-8.25 (m, 1H), 8.19-8.14 (m, 1H), 8.12-8.06 (m, 1H) , 7.99-7.90(m, 1H), 7.21(d, J=7.7Hz, 1H), 7.16-7.08(m, 3H), 4.02(t, J=5.3Hz, 2H), 3.73-3.50(m, 3H ), 3.35(s, 3H), 2.48-2.36(m, 2H), 1.77-1.60(m, 2H), 1.60-1.41(m, 6H), 1.04(s, 6H). ESI-MS: m/z 581.1[M+Na] ⁺ .

Example 260

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propionamide (Compound 375)

Compound 375 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.87-7.68 (m, 2H), 7.46-7.33 (m, 1H), 7.26-7.15 (m, 3H), 7.11 -6.94(m, 2H), 5.67(d, J=7.0Hz, 1H), 4.27(t, J=5.9Hz, 2H), 3.90-3.65(m, 3H), 2.62(t, J=5.9Hz, 2H), 2.51-2.31(m, 2H), 2.11-1.86(m, 2H), 1.60-1.54(m, 2H). ESI-MS: m/z 497.3[M+Na] ⁺ .

Example 261

N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propanamide (Compound 376)

Compound 376 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CD ₃ OD-d ₄ ) δ8.21 (d, J=8.3Hz, 2H), 8.05 (d, J=8.4Hz, 2H), 7.53-7.39(m, 1H), 7.29-7.10(m, 3H), 4.29(t, J=5.8Hz, 2H), 3.84-3.68(m, 3H), 3.21(s, 3H), 2.70-2.56( m, 4H), 1.98-1.85 (m, 2H), 1.65-1.50 (m, 2H). ESI-MS: m/z 557.3[M+Na] ⁺ .

Example 262

2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,4,6-trifluorophenoxy)pentanamide (compound 377 )

Compound 377 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.03-8.80 (m, 2H), 8.26-8.09 (m, 1H), 7.69 (dd, J=8.1, 4.8Hz, 1H), 7.35-7.06(m, 3H), 3.97(d, J=5.5Hz, 2H), 3.61(t, J=14.8Hz, 3H), 2.49-2.33(m, 2H), 1.70( d, J=11.0Hz, 2H), 1.59-1.39(m, 6H), 1.04(s, 6H).ESI-MS: m/z 522.1[M+Na] ⁺ .

Example 263

5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 379)

Compound 379 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82-7.73 (m, 2H), 7.69 (d, J=8.0Hz, 1H), 7.30-7.19 (m, 3H ), 7.15(s, 1H), 5.53(d, J=7.7Hz, 1H), 4.06(t, J=5.3Hz, 2H), 3.82-3.68(m, 3H), 2.45-2.30(m, 2H) , 2.02-1.88(m, 2H), 1.81-1.64(m, 4H), 1.55-1.43(m, 2H), 1.18(s, 6H). ESI-MS: m/z 621.3[M+Na] ⁺ .

Example 264

5-(4-fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)- Piperidin-4-yl)pentanamide (Compound 380)

Compound 380 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.13(d, J=7.8Hz, 2H), 7.96(d, J=7.9Hz, 2H), 7.18-6.94( m, 3H), 5.46(d, J=6.0Hz, 1H), 3.97-3.64(m, 6H), 3.11(s, 3H), 2.50(t, J=11.6Hz, 2H), 2.08-1.92(m , 2H), 1.54-1.40(m, 3H), 1.31-1.21(m, 2H), 1.18(s, 6H). ESI-MS: m/z 631.3[M+Na] ⁺ .

Example 265

5-(4-fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentane Amide (compound 381)

Compound 381 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.99(s, 1H), 8.84(d, J=4.0Hz, 1H), 8.04(d, J=7.7Hz, 1H), 7.57-7.41(m, 1H), 7.06(dd, J=23.3, 13.4Hz, 3H), 5.65(d, J=7.3Hz, 1H), 3.99-3.64(m, 5H), 2.46(t , J=11.4Hz, 2H), 1.99(d, J=11.5Hz, 2H), 1.79-1.45(m, 6H), 1.26-1.07(m, 6H).ESI-MS: m/z 554.2 [M+ Na] ⁺ .

Example 266

5-(4-fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 382)

Compound 382 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.80 (d, J=8.7Hz, 2H), 7.38 (d, J=8.3Hz, 2H), 7.14-6.93( m, 3H), 5.80(d, J=7.7Hz, 1H), 3.97-3.67(m, 5H), 2.41(t, J=11.4Hz, 2H), 1.97(d, J=12.2Hz, 2H), 1.50-1.80(m, 6H), 1.17(s, 6H).ESI-MS: m/z 637.1[M+Na] ⁺ .

Example 267

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (Compound 383)

Compound 383 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.76 (dd, J=8.4, 5.1Hz, 2H), 7.37 (t, J=7.9Hz, 1H), 7.33- 7.15(m, 3H), 7.12-6.97(m, 2H), 5.57(d, J=7.5Hz, 1H), 4.01(t, J=5.8Hz, 2H), 3.86-3.65(m, 3H), 2.49 -2.26(m, 4H), 2.18-2.05(m, 2H), 2.04-1.86(m, 2H), 1.61-1.42(m, 2H). ESI-MS: m/z 511.2[M+Na] ⁺ .

Example 268

Trans-2-(2,4-difluorophenoxy)-N-(3-fluoro-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2-Methylpropionamide (Compound 391)

Compound 391 was obtained by referring to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.39-8.25(m, 2H), 8.19(s, 1H), 8.14(d, J=7.7Hz , 1H), 8.01-7.89(m, 1H), 7.37-7.24(m, 1H), 7.10-6.92(m, 2H), 4.77-4.52(m, 1H), 4.02-3.84(m, 2H), 3.62 -3.52(m, 1H), 3.35(s, 3H), 2.74-2.59(m, 2H), 1.88-1.76(m, 1H), 1.73-1.60(m, 1H), 1.37(s, 3H), 1.35 (s, 3H).ESI-MS: m/z557.2[M+Na] ⁺ .

Example 269

2-(2,4-difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide ( Compound 392)

Compound 392 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.28 (d, J=7.6Hz, 1H), 8.15 (s, 1H), 8.13-8.00 (m, 2H ), 8.00-7.89(m, 1H), 7.35-7.23(m, 1H), 7.09-6.93(m, 2H), 3.72-3.57(m, 3H), 3.30(s, 3H), 2.48-2.37(m , 2H), 1.81-1.68(m, 2H), 1.69-1.51(m, 2H), 1.35(s, 6H). ESI-MS: m/z 539.1[M+Na] ⁺ .

Example 270

N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (compound 394)

Compound 394 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.27-8.11 (m, 2H), 8.08-7.94 (m, 2H), 7.89-7.77 (m, 1H) , 7.51(t, J=7.8Hz, 1H), 7.33-7.14(m, 3H), 4.03(t, J=6.1Hz, 2H), 3.70-3.46(m, 3H), 3.32(s, 3H), 2.60(t, J=11.0Hz, 2H), 2.21(t, J=7.2Hz, 2H), 2.00-1.85(m, 2H), 1.85-1.72(m, 2H), 1.50-1.29(m, 2H) .ESI-MS: m/z 571.3[M+Na] ⁺ .

Example 271

N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-4-(3-(trifluoromethyl)phenoxy)butanamide (Compound 395)

Compound 395 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.96-8.85 (m, 2H), 8.20-8.11 (m, 1H), 7.87-7.77 (m, 1H) , 7.74-7.64(m, 1H), 7.51(t, J=8.0Hz, 1H), 7.32-7.15(m, 3H), 4.02(t, J=6.3Hz, 2H), 3.68-3.46(m, 3H ), 2.59(t, J=10.4Hz, 2H), 2.21(t, J=7.3Hz, 2H), 2.01-1.85(m, 2H), 1.85-1.73(m, 2H), 1.48-1.29(m, 2H).ESI-MS: m/z 494.3[M+Na] ⁺ .

Example 272

5-(2,3-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 396 )

Compound 396 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.87-7.74 (m, 2H), 7.54-7.42 (m, 2H), 7.23 (d, J=7.2Hz , 1H), 7.17-7.04(m, 1H), 7.04-6.90(m, 2H), 4.11-3.94(m, 2H), 3.69-3.45(m, 3H), 2.35(t, J=11.3Hz, 2H ), 1.78-1.64(m, 2H), 1.64-1.40(m, 6H), 1.06(s, 6H). ESI-MS: m/z 521.3[M+Na] ⁺ .

Example 273

2,2-Dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-5-(3,4,5-trifluorophenoxy base) pentamide (compound 397)

Compound 397 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18(d, J=8.2Hz, 2H), 8.00(d, J=8.3Hz, 2H), 7.23( d, J=7.7Hz, 1H), 6.98-6.84(m, 2H), 4.02-3.85(m, 2H), 3.73-3.49(m, 3H), 3.32(s, 3H), 2.49-2.37(m, 2H), 1.81-1.63(m, 2H), 1.63-1.38(m, 6H), 1.05(s, 6H). ESI-MS: m/z 599.4[M+Na] ⁺ .

Example 274

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(3,4,5-trifluorophenoxy)pentanamide ( Compound 398)

Compound 398 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.87-7.76 (m, 2H), 7.49 (t, J=8.7Hz, 2H), 7.22 (d, J =7.6Hz, 1H), 6.98-6.85(m, 2H), 3.97-3.86(m, 2H), 3.66-3.48(m, 3H), 2.36(t, J=11.3Hz, 2H), 1.77-1.64( m, 2H), 1.61-1.41 (m, 6H), 1.06 (s, 6H). ESI-MS: m/z 539.3[M+Na] ⁺ .

Example 275

2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2,3,4-trifluorophenoxy)pentanamide (compound 399 )

Compound 399 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.05-8.93 (m, 1H), 8.91-8.78 (m, 1H), 8.11-7.99 (m, 1H), 7.57 -7.45(m, 1H), 6.91-6.72(m, 2H), 5.74(d, J=7.1Hz, 1H), 4.20-4.05(m, 2H), 3.92-3.67(m, 3H), 2.47(t , J=11.4Hz, 2H), 2.03-1.95(m, 2H), 1.78-1.64(m, 4H), 1.64-1.47(m, 2H), 1.17(s, 6H).ESI-MS: m/z 522.3[M+Na] ⁺ .

Example 276

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2,3,4-trifluorophenoxy)pentanamide ( Compound 400)

Compound 400 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82-7.72 (m, 2H), 7.22 (t, J=8.4Hz, 2H), 6.90-6.73 (m, 2H ), 5.78(d, J=7.7Hz, 1H), 4.22-4.03(m, 2H), 3.85-3.68(m, 3H), 2.39(t, J=11.7Hz, 2H), 2.05-1.90(m, 2H), 1.74-1.61(m, 4H), 1.62-1.49(m, 2H), 1.16(s, 6H). ESI-MS: m/z 539.3[M+Na] ⁺ .

Example 277

2,2-Dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-5-(2-(trifluoromethyl)phenoxy)pentanamide (compound 401 )

Compound 401 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.04-8.93 (m, 1H), 8.88-8.78 (m, 1H), 8.10-7.98 (m, 1H), 7.61 -7.53(m, 1H), 7.52-7.39(m, 2H), 7.05-6.88(m, 2H), 5.65(d, J=7.5Hz, 1H), 4.10-3.91(m, 2H), 3.90-3.63 (m, 3H), 2.46(t, J=11.8Hz, 2H), 2.02-1.91(m, 2H), 1.80-1.62(m, 4H), 1.62-1.43(m, 2H), 1.17(s, 6H ).ESI-MS: m/z 536.3[M+Na] ⁺ .

Example 278

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(2-(trifluoromethyl)phenoxy)pentanamide ( Compound 402)

Compound 402 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85-7.68(m, 2H), 7.64-7.51(m, 1H), 7.45(t, J=7.8Hz, 1H ), 7.21(t, J=8.5Hz, 2H), 7.07-6.87(m, 2H), 5.67(d, J=7.7Hz, 1H), 4.07-3.95(m, 2H), 3.84-3.65(m, 3H), 2.39(t, J=11.1Hz, 2H), 2.01-1.87(m, 2H), 1.79-1.61(m, 4H), 1.61-1.45(m, 2H), 1.17(s, 6H).ESI -MS: m/z 553.3[M+Na] ⁺ .

Example 279

5-(4-fluoro-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentane Amide (Compound 403)

Compound 403 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.04-8.93 (m, 1H), 8.90-8.78 (m, 1H), 8.11-8.00 (m, 1H), 7.55 -7.46(m, 1H), 7.32-7.24(m, 1H), 7.21-7.10(m, 1H), 6.94-6.84(m, 1H), 5.64(d, J=7.5Hz, 1H), 4.04-3.91 (m, 2H), 3.90-3.69(m, 3H), 2.47(t, J=11.7Hz, 2H), 2.05-1.93(m, 2H), 1.80-1.62(m, 4H), 1.60-1.48(m , 2H), 1.17(s, 6H).ESI-MS: m/z 554.3[M+Na] ⁺ .

Example 280

5-(4-fluoro-2-(trifluoromethyl)phenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl valeramide (compound 404)

Compound 404 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85-7.70 (m, 2H), 7.34-7.10 (m, 4H), 6.96-6.84 (m, 1H), 5.68 (d, J=7.7Hz, 1H), 4.05-3.89(m, 2H), 3.87-3.64(m, 3H), 2.40(t, J=11.4Hz, 2H), 2.03-1.88(m, 2H), 1.76-1.61(m, 4H), 1.61-1.46(m, 2H), 1.22-1.08(s, 6H). ESI-MS: m/z 571.3[M+Na] ⁺ .

Example 281

5-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methylvaleramide (Compound 408)

Referring to the method of Example 77, with 5-(4-chlorophenoxy)-2,2-dimethylpentanoic acid and optically pure (3R,4R)-4-amino-3-fluoropiperidine-1- Tert-butyl formate was used as raw material to obtain compound 408: ee>99% (chiral HPLC analysis conditions: Chiralpak IC4.6mm×250mm, column temperature: 25°C; mobile phase: 60% n-hexane/40% isopropanol; Flow rate: 1mL/min; detection wavelength: UV254nm; retention time: 18.1min); ¹ H NMR (300MHz, CDCl ₃ ) δ7.76-7.67(m, 2H), 7.19-7.09(m, 4H), 6.71(d , J=8.9Hz, 2H), 5.59(d, J=7.2Hz, 1H), 4.53-4.24(m, 1H), 4.06-3.95(m, 1H), 3.92-3.74(m, 3H), 3.70- 3.59(m, 1H), 2.44-2.30(m, 2H), 2.12-1.99(m, 1H), 1.65-1.57(m, 3H), 1.54-1.41(m, 2H), 1.12(s, 6H). ESI-MS: m/z 537.2[M+Na] ⁺ .

Example 282

4-(((3R,4R)-4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 409)

Compound 409 was obtained by referring to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.43 (s, 1H), 8.16 (d, J=8.1Hz, 2H), 7.90 ( d, J=8.1Hz, 2H), 7.43(d, J=8.1Hz, 1H), 7.30(d, J=8.6Hz, 2H), 6.91(d, J=8.7Hz, 2H), 4.69-4.41( m, 1H), 3.98-3.70(m, 4H), 3.57-3.41(m, 1H), 2.75-2.55(m, 2H), 1.83-1.66(m, 1H), 1.63-1.41(m, 5H), 1.07(s, 6H).ESI-MS: m/z 563.2[M+Na] ⁺ .

Example 283

N-(1-(pyridine-3-sulfonyl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenoxy)propionamide (Compound 410)

Compound 410 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, CDCl ₃ ) δ9.01 (s, 1H), 8.93-8.79 (m, 1H), 8.23-7.95 (m, 1H), 7.64-7.46 (m, 1H), 7.46-7.34(m, 1H), 7.27-7.20(m, 1H), 7.16-6.98(m, 2H), 5.72(d, J=7.1Hz, 1H), 4.29(t, J =5.8Hz, 2H), 3.95-3.77(m, 3H), 2.64(t, J=5.8Hz, 2H), 2.59-2.42(m, 2H), 2.21-1.94(m, 2H), 1.75-1.61( m, 2H).ESI-MS: m/z 480.2[M+Na] ⁺ .

Example 284

trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamide)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 411 )

Compound 411 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.16(d, J=8.3Hz, 2H), 7.90(d, J =8.3Hz, 2H), 7.44(d, J=8.2Hz, 1H), 7.30(d, J=8.9Hz, 2H), 6.91(d, J=8.9Hz, 2H), 4.73-4.40(m, 1H ), 3.97-3.75(m, 4H), 3.59-3.43(m, 1H), 2.79-2.55(m, 2H), 1.84-1.65(m, 1H), 1.61-1.42(m, 5H), 1.06(s , 6H).ESI-MS: m/z563.2[M+Na] ⁺ .

Example 285

trans-5-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentane Amide (Compound 412)

Compound 412 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.86-7.72 (m, 2H), 7.30-7.25 (m, 1H), 7.24-7.15 (m, 3H) , 6.83-6.73(m, 2H), 5.80-5.55(m, 1H), 4.63-4.23(m, 1H), 4.18-3.99(m, 1H), 3.99-3.79(m, 3H), 3.79-3.63( m, 1H), 2.56-2.36(m, 2H), 2.23-2.06(m, 1H), 1.76-1.61(m, 5H), 1.19(s, 6H). ESI-MS: m/z 537.2 [M+ Na] ⁺ .

Example 286

trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 415)

Compound 415 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.46(s, 1H), 8.29(d, J=8.4Hz, 1H), 8.16(d, J = 8.2Hz, 2H), 7.89 (d, J = 8.2Hz, 2H), 7.32 (dd, J = 19.6, 9.6Hz, 1H), 6.94 (ddd, J = 12.1, 6.8, 2.6Hz, 1H), 6.77 -6.65(m, 1H), 4.75-4.40(m, 1H), 4.06-3.71(m, 2H), 3.51(d, J=11.3Hz, 1H), 3.32(s, 1H), 2.70-2.55(m , 2H), 1.82-1.70(m, 1H), 1.70-1.50(m, 1H), 1.39(d, J=10.1Hz, 6H).ESI-MS: m/z 499.1[MH] ^- .

Example 287

trans-4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2- Acetamido ethyl ester (compound 416)

Using compound 415 (Example 286) as a raw material, compound 416 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.23 (d, J=8.2Hz, 2H), 7.87 (d, J =8.2Hz, 2H), 7.07(dd, J=18.7, 9.3Hz, 1H), 6.84-6.58(m, 3H), 5.83(s, 1H), 4.71-4.32(m, 3H), 4.16-4.04( m, 1H), 4.00-3.86(m, 1H), 3.83-3.61(dt, 3H), 2.64-2.46(m, 2H), 2.24-2.09(m, 1H), 2.03(s, 3H), 1.75- 1.62(m, 1H), 1.48(d, J=6.8Hz, 6H).ESI-MS: m/z 608.2[M+Na] ⁺ .

Example 288

5-(2,5-bis(trifluoromethyl)phenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl Valeramide (compound 417)

Compound 417 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl3) δ7.71 (d, J=8.0Hz, 1H), 7.55 (m, 2H), 7.49 (d, J=7.8Hz, 1H ), 7.34(m, 2H), 7.18(s, 1H), 5.49(d, J=7.6Hz, 1H), 4.08(t, J=5.4Hz, 2H), 3.87-3.66(m, 3H), 2.46 (t, J=11.4Hz, 2H), 1.98(d, J=11.3Hz, 2H), 1.85-1.63(m, 4H), 1.57-1.44(m, 2H), 1.20(s, 6H).ESI- MS: m/z 621.3 [M+Na] ⁺ .

Example 289

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalene-2-yloxy)pentanamide (compound 418)

Compound 418 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.86-7.73 (m, 5H), 7.54-7.40 (m, 3H), 7.39-7.29 (m, 1H) , 7.29-7.20(m, 2H), 7.18-7.09(m, 1H), 4.10-3.97(m, 3H), 3.62-3.45(m, 4H), 2.37-2.24(m, 2H), 1.67-1.59( m, 4H), 1.55-1.42 (m, 2H), 1.08 (s, 6H). ESI-MS: m/z 535.2 [M+Na] ⁺ .

Example 290

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(naphthalene-1-yloxy)pentanamide (compound 419)

Compound 419 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.16 (d, J=7.9Hz, 1H), 7.90-7.75 (m, 3H), 7.57-7.34 (m , 6H), 7.28(d, J=7.6Hz, 1H), 6.91(d, J=7.1Hz, 1H), 4.16-4.01(m, 2H), 3.67-3.48(m, 3H), 2.42-2.27( m, 2H), 1.80-1.62(m, 6H), 1.59-1.45(m, 2H), 1.10(s, 6H). ESI-MS: m/z 535.2[M+Na] ⁺ .

Example 291

trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid 2- Acetamido ethyl ester (compound 424)

Using compound 411 (Example 284) as a raw material, compound 424 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.22 (d, J=7.6Hz, 2H), 7.85 (d, J =7.7Hz, 2H), 7.21(d, J=8.3Hz, 2H), 6.78(d, J=8.4Hz, 2H), 5.92-5.57(m, 2H), 4.68-4.30(m, 3H), 4.20 -3.81(m, 4H), 3.81-3.57(m, 3H), 2.60-2.38(m, 2H), 2.27-1.94(m, 4H), 1.68-1.52(m, 5H), 1.23(s, 6H) .ESI-MS: m/z648.2[M+Na] ⁺ .

Example 292

cis-5-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentane Amide (Compound 425)

Referring to the method of Example 139, with 5-(4-chlorophenoxy)-2,2-dimethylpentanoic acid and (±)-cis-4-amino-3-fluoropiperidine-1-carboxylic acid tert Butyl ester was used as starting material to obtain compound 425: ¹ H NMR (300MHz, CDCl ₃ ) δ7.89-7.75 (m, 2H), 7.25-7.09 (m, 4H), 6.78 (d, J=8.8Hz, 2H) , 5.87(d, J=7.6Hz, 1H), 4.87-4.50(m, 1H), 4.25-4.07(m, 1H), 4.07-3.74(m, 4H), 2.80-2.48(m, 2H), 1.94 -1.74(m, 2H), 1.66-1.52(m, 3H), 1.19(s, 6H). ESI-MS: m/z 537.1[M+Na] ⁺ .

Example 293

5-(4-Chloro-2-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl ) valeramide (compound 426)

Compound 426 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.23-8.03 (m, 2H), 8.04-7.88 (m, 2H), 7.10 (dd, J=10.8, 2.5Hz , 0H), 7.07-6.98(m, 1H), 6.91-6.75(m, 1H), 5.56(d, J=7.7Hz, 1H), 3.95(t, J=5.6Hz, 1H), 3.89-3.82( m, 1H), 3.81-3.68(m, 2H), 3.11(s, 3H), 2.59-2.41(m, 2H), 2.04-1.89(m, 2H), 1.76-1.62(m, 4H), 1.58- 1.45(m, 2H), 1.17(s, 6H).ESI-MS: m/z 597.1[M+Na] ⁺ .

Example 294

cis-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 427)

Compound 427 was obtained by referring to the method of Example 292: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.51(s, 1H), 8.15(d, J=8.2Hz, 2H), 7.86(d, J=8.2 Hz, 2H), 7.38(d, J=7.4Hz, 1H), 7.30(d, J=8.8Hz, 2H), 6.91(d, J=8.8Hz, 2H), 4.80-4.55(m, 1H), 3.99-3.63(m, 5H), 2.89-2.53(m, 2H), 1.96-1.71(m, 1H), 1.64-1.43(m, 5H), 1.08(d, J=3.4Hz, 6H).ESI- MS: m/z 563.2[M+Na] ⁺ .

Example 295

4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 428)

Compound 428 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48(s, 1H), 8.14(d, J=8.1Hz, 2H), 8.02(d, J=7.9 Hz, 1H), 7.81(d, J=8.1Hz, 2H), 7.76-7.66(m, 4H), 7.62(d, J=8.2Hz, 2H), 6.92(d, J=8.4Hz, 2H), 3.71-3.59(m, 1H), 3.59-3.46(m, 2H), 2.56-2.45(m, 4H), 1.68(d, J=10.9Hz, 2H), 1.49(s, 6H).ESI-MS: m/z 607.3[M+Na] ⁺ .

Example 296

trans-4-((4-(5-(2,5-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 429)

Compound 429 was prepared according to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49 (s, 1H), 8.24-8.10 (m, 2H), 8.01-7.79 (m, 2H), 7.45 (d, J=8.2Hz, 1H), 7.23(ddd, J=11.5, 9.0, 5.5Hz, 1H), 7.06(ddd, J=10.3, 6.9, 3.0Hz, 1H), 6.82-6.64(m, 1H ), 4.74-4.39(m, 1H), 3.97(t, 2H), 3.94-3.74(m, 2H), 3.51(d, J=12.1Hz, 1H), 2.73-2.54(m, 2H), 1.86- 1.44(m, 6H), 1.07(s, 6H).ESI-MS: m/z 565.2[M+Na] ⁺ .

Example 297

Methyl 4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoate (Compound 430 )

Compound 430 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.14(d, J=8.1Hz, 2H), 8.02(d, J=7.9Hz, 1H), 7.82( d, J=8.2Hz, 2H), 7.76-7.46(m, 6H), 6.90(d, J=8.4Hz, 2H), 3.88(s, 3H), 3.68-3.43(m, 3H), 2.40(d , J=11.5Hz, 2H), 1.66(d, J=12.9Hz, 2H), 1.55-1.38(m, 8H).ESI-MS: m/z 621.1[M+Na] ⁺ .

Example 298

trans-2-(4-chlorophenoxy)-N-(3-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 431)

Compound 431 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.63-7.53 (m, 2H), 7.62-7.36 (m, 1H), 7.51-7.22 (m, 1H) , 7.27(d, J=5.3Hz, 2H), 6.85(d, J=8.4Hz, 2H), 6.73(d, J=8.3Hz, 1H), 4.71-4.24(m, 1H), 4.20-3.61( m, 4H), 2.70-2.40 (m, 2H), 1.74-1.62 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H). ESI-MS: m/z 495.2 [M+Na] ⁺ .

Example 299

2-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropane Amide (Compound 432)

Referring to the methods of Examples 14 and 281, using optically pure (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester as raw material, compound 432 was prepared: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.63-7.53(m, 2H), 7.62-7.36(m, 1H), 7.51-7.22(m, 1H), 7.27(d, J=5.3Hz, 2H), 6.85( d, J=8.4Hz, 2H), 6.73(d, J=8.3Hz, 1H), 4.71-4.24(m, 1H), 4.20-3.61(m, 4H), 2.70-2.40(m, 2H), 1.74 -1.62(m, 1H), 1.50(s, 3H), 1.48(s, 3H). ESI-MS: m/z 495.2[M+Na] ⁺ .

Example 300

trans-3-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 433)

Compound 433 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CD ₃ OD) δ8.38(s, 1H), 8.33(d, J=7.9Hz, 1H), 8.02(d, J= 7.8Hz, 1H), 7.77(t, J=7.8Hz, 1H), 7.24(d, J=8.4Hz, 2H), 6.89(d, J=8.4Hz, 2H), 4.79-4.33(m, 1H) , 4.12-3.84(m, 2H), 3.79-3.58(m, 1H), 2.75-2.39(m, 2H), 2.04-1.84(m, 1H), 1.82-1.59(m, 1H), 1.49(s, 3H), 1.46(s, 3H).ESI-MS: m/z 497.2[MH] ^- .

Example 301

3-(((3R,4R)-4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 434)

Compound 434 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, Methanol-d ₄ ) δ8.38(s, 1H), 8.33(d, J=7.9Hz, 1H), 8.02( d, J=7.8Hz, 1H), 7.77(t, J=7.8Hz, 1H), 7.24(d, J=8.4Hz, 2H), 6.89(d, J=8.4Hz, 2H), 4.79-4.33( m, 1H), 4.12-3.84(m, 2H), 3.79-3.58(m, 1H), 2.75-2.39(m, 2H), 2.04-1.84(m, 1H), 1.82-1.59(m, 1H), 1.49(s, 3H), 1.46(s, 3H).ESI-MS: m/z 497.2[MH] ^- .

Example 302

trans-2-(4-chlorophenoxy)-N-(4-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 435)

Compound 435 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.80 (dd, J=8.6, 5.0Hz, 2H), 7.40-7.12 (m, 4H), 6.85 (d , J=8.8Hz, 2H), 6.73(d, J=8.3Hz, 1H), 4.71-4.24(m, 1H), 4.19-3.86(m, 2H), 3.85-3.58(m, 1H), 2.67- 2.36(m, 2H), 2.29-1.99(m, 1H), 1.81-1.50(m, 1H), 1.50(s, 3H), 1.48(s, 3H). ESI-MS: m/z 495.2 [M+ Na] ⁺ .

Example 303

2-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropane Amide (compound 436)

Compound 436 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.80 (dd, J=8.6, 5.0Hz, 2H), 7.40-7.12 (m, 4H), 6.85(d, J=8.8Hz, 2H), 6.73(d, J=8.3Hz, 1H), 4.71-4.24(m, 1H), 4.19-3.86(m, 2H), 3.85-3.58(m, 1H) , 2.67-2.36(m, 2H), 2.29-1.99(m, 1H), 1.81-1.50(m, 1H), 1.50(s, 3H), 1.48(s, 3H). ESI-MS: m/z 495.2 [M+Na] ⁺ .

Example 304

2-(4-Chloro-2-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 437)

Compound 437 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.80 (s, 2H), 7.28-7.21 (m, 2H), 7.16 (d, J=10.1Hz, 1H ), 7.06(s, 1H), 6.97(t, J=8.3Hz, 1H), 6.88(dd, J=4.3, 2.6Hz, 1H), 3.73(d, J=10.8Hz, 3H), 2.55(t , J=11.1Hz, 2H), 2.04(d, J=10.9Hz, 2H), 1.62(s, 3H), 1.29(t, J=19.4Hz, 6H).ESI-MS: m/z 495.1 [M +Na] ⁺ .

Example 305

2-(4-Chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 438)

Compound 438 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.57 (t, J=4.8Hz, 2H), 7.50 (dd, J=8.1, 1.0Hz, 1H), 7.34(ddd, J=9.4, 7.0, 2.6Hz, 1H), 7.16(dd, J=10.2, 2.4Hz, 1H), 7.11-7.04(m, 1H), 6.97(t, J=8.6Hz, 1H) , 6.88(d, J=7.6Hz, 1H), 3.88-3.70(m, 3H), 2.58(t, J=11.7Hz, 2H), 2.05(d, J=10.0Hz, 2H), 1.68-1.57( m, 3H), 1.46(s, 6H). ESI-MS: m/z 495.2[M+Na] ⁺ .

Example 306

2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-(phenylsulfonyl)piperidin-4-yl)propanamide (compound 439)

Compound 439 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl3) δ7.78 (d, J=7.7Hz, 2H), 7.65-7.60 (m, 1H), 7.56 (dd, J=9.8, 4.8Hz, 2H), 7.06(d, J=7.5Hz, 1H), 6.79(d, J=7.4Hz, 1H), 6.70-6.63(m, 1H), 6.60(s, 1H), 3.77(t, J=11.8Hz, 3H), 2.52(t, J=10.8Hz, 3H), 2.27(s, 3H), 2.17(s, 3H), 2.01(d, J=12.7Hz, 3H), 1.59-1.53( m, 2H), 1.50 (s, 6H). ESI-MS: m/z 453.2[M+Na] ⁺ .

Example 307

2-(2,5-Dimethylphenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 440)

Compound 440 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.29(d, J=7.6Hz, 1H), 8.15(s, 1H), 8.08(d, J=7.5 Hz, 1H), 7.95(t, J=8.0Hz, 2H), 7.03(d, J=7.4Hz, 1H), 6.71(d, J=7.5Hz, 1H), 6.52(s, 1H), 4.04( dd, J=14.3, 7.2Hz, 1H), 3.68-3.57(m, 2H), 3.35(s, 3H), 2.46(dd, J=11.6, 3.0Hz, 2H), 2.18(s, 3H), 2.12 (s, 3H), 1.74 (d, J = 12.9Hz, 2H), 1.59 (dt, J = 9.2, 7.4Hz, 2H), 1.37 (s, 6H). ESI-MS: m/z 531.2 [M+ Na] ⁺ .

Example 308

2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 441)

Compound 441 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.17 (d, J=8.4Hz, 2H), 8.07 (m, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.45(m, 1H), 7.17(m, 1H), 6.94(m, 1H), 3.59(m, 3H), 3.31(s, 3H), 2.44(s, 2H), 1.72(m , 2H), 1.54(m, 2H), 1.37(s, 6H).ESI-MS: m/z555.1[M+Na] ⁺ .

Example 309

2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 442)

Compound 442 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.27(d, J=7.7Hz, 1H), 8.13(m, 1H), 8.06(d, J=7.9 Hz, 2H), 7.98-7.88(m, 1H), 7.45(dd, J=10.8, 2.5Hz, 1H), 7.21-7.10(m, 1H), 6.99-6.88(m, 1H), 3.68-3.55( m, 3H), 3.33(s, 3H), 2.44-2.35(m, 2H), 1.78-1.65(m, 2H), 1.62-1.47(m, 2H), 1.36(s, 6H).ESI-MS: m/z 555.1[M+Na] ⁺ .

Example 310

4-(((3R,4R)-4-(5-(2,5-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Acyl)benzoic acid (compound 443)

Compound 443 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.54 (s, 1H), 8.17 (d, J=8.3Hz, 2H), 7.90 ( d, J=8.3Hz, 2H), 7.46(d, J=8.1Hz, 1H), 7.31-7.15(m, 1H), 7.12-7.00(m, 1H), 6.81-6.66(m, 1H), 4.71 -4.42(m, 1H), 4.01-3.95(m, 2H), 3.93-3.77(m, 2H), 3.51(d, J=11.8Hz, 1H), 2.72-2.55(m, 2H), 1.84-1.69 (m, 1H), 1.65-1.46(m, 5H), 1.07(s, 6H). ESI-MS: m/z 565.2[M+Na] ⁺ .

Example 311

4-(((3S,4S)-4-(5-(2,5-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Acyl)benzoic acid (compound 444)

Compound 444 was obtained by referring to the method of Example 77: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.17 (d, J=8.2Hz, 2H), 7.90 ( d, J=8.3Hz, 2H), 7.46(d, J=8.2Hz, 1H), 7.31-7.17(m, 1H), 7.13-6.99(m, 1H), 6.78-6.67(m, 1H), 4.68 -4.43(m, 1H), 4.03-3.94(m, 2H), 3.93-3.76(m, 2H), 3.51(d, J=11.8Hz, 1H), 2.73-2.54(m, 2H), 1.83-1.71 (m, 1H), 1.66-1.47(m, 5H), 1.07(s, 6H). ESI-MS: m/z 565.2[M+Na] ⁺ .

Example 312

2-(4-(4-chlorobenzoyl)phenoxy)-N-((3R,4R)-3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl )-2-Methylpropionamide (compound 445)

Compound 445 was prepared according to the method of Examples 14 and 281: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.85-7.67 (m, 6H), 7.54-7.43 (m, 2H), 7.27-7.19 (m, 2H), 7.02-6.90(m, 2H), 6.53(d, J=7.9Hz, 1H), 4.58-4.27(m, 1H), 4.12-3.89(m, 2H), 3.81-3.64(m , 1H), 2.58-2.39(m, 2H), 2.18-2.01(m, 1H), 1.70-1.57(m, 7H). ESI-MS: m/z 599.2[M+Na] ⁺ .

Example 313

5-(2,5-dichlorophenoxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 446)

Compound 446 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.25-8.12 (m, 2H), 8.06-7.95 (m, 2H), 7.49-7.41 (m, 1H) , 7.30-7.16(m, 2H), 7.06-6.98(m, 1H), 4.15-3.94(m, 2H), 3.72-3.50(m, 3H), 3.33(s, 3H), 2.49-2.37(m, 2H), 1.80-1.64(m, 2H), 1.64-1.41(m, 6H), 1.06(s, 6H). ESI-MS: m/z 613.1[M+Na] ⁺ .

Example 314

trans-2-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 447)

Compound 447 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.86-7.71 (m, 2H), 7.24 (dd, J=8.1, 6..0Hz, 4H), 6.83(d, J=8.1Hz, 2H), 6.70(d, J=7.3Hz, 1H), 4.62-4.29(m, 1H), 4.10-3.83(m, 2H), 3.79-3.62(m, 1H) , 2.59-2.38 (m, 2H), 2.20-2.02 (m, 1H), 1.80-1.63 (m, 1H), 1.47 (d, J=6.0Hz, 6H).ESI-MS: m/z 495.2 [M +Na] ⁺ .

Example 315

trans-4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 448)

Compound 448 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48(s, 1H), 8.25(d, J=8.0Hz, 1H), 8.16(d, J =7.6Hz, 2H), 7.88(d, J=7.6Hz, 2H), 7.29(d, J=8.1Hz, 2H), 6.86(d, J=8.1Hz, 2H), 4.76-4.37(m, 1H ), 4.05-3.69(m, 2H), 3.55-3.41(m, 1H), 2.80-2.56(m, 2H), 1.86-1.69(m, 1H), 1.67-1.50(m, 1H), 1.49-1.11 (m, 6H).ESI-MS: m/z 497.1[MH] ^- .

Example 316

trans-2-(4-(4-chlorobenzoyl)phenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2 -Methyl propionamide (compound 449)

Compound 449 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.42-8.18 (m, 1H), 8.05-7.34 (m, 10H), 7.17-6.78 (m, 2H), 4.81-4.25(m, 1H), 4.10-3.63(m, 2H), 3.52-3.37(m, 1H), 2.83-2.57(m, 2H), 2.01-1.67(m, 2H), 1.51( s, 6H).ESI-MS: m/z 599.2[M+Na] ⁺ .

Example 317

4-(((3R,4R)-4-(5-(2,6-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Acyl)benzoic acid (compound 450)

Compound 450 was prepared according to the method of Examples 119 and 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.16 (d, J=8.1Hz, 2H), 7.90(d, J=8.1Hz, 2H), 7.43(d, J=8.2Hz, 1H), 7.18-7.07(m, 3H), 4.74-4.39(m, 1H), 4.02(t, J=5.8Hz , 2H), 3.93-3.74(m, 2H), 3.57-3.41(m, 1H), 2.73-2.55(m, 2H), 1.81-1.67(m, 1H), 1.62-1.44(m, 5H), 1.06 (s, 6H).ESI-MS: m/z565.2[M+Na] ⁺ .

Example 318

4-(((3R,4R)-4-(5-(4-chloro-2-fluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl) Sulfonyl)benzoic acid (compound 451)

Compound 451 was prepared according to the method of Examples 119 and 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.46 (s, 1H), 8.16 (d, J=8.0Hz, 2H), 7.90(d, J=8.0Hz, 2H), 7.49-7.36(m, 2H), 7.23-7.09(m, 2H), 4.69-4.40(m, 1H), 3.97(t, 2H), 3.91-3.76( m, 2H), 3.57-3.43(m, 1H), 2.75-2.55(m, 2H), 1.82-1.67(m, 1H), 1.66-1.44(m, 5H), 1.06(s, 6H).ESI- MS: m/z 557.2 [MH] ^-

Example 319

2-(4-Chloro-2-fluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propane Amide (Compound 452)

Compound 452 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85 (d, J=8.0Hz, 2H), 7.40 (d, J=7.9Hz, 2H), 7.16 (dd, J=10.2, 1.2Hz, 1H), 7.08(d, J=8.0Hz, 1H), 6.97(t, J=8.5Hz, 1H), 6.88(d, J=9.0Hz, 1H), 3.85-3.69( m, 3H), 2.66-2.48(m, 2H), 2.05(dd, J=11.6, 1.4Hz, 2H), 1.71-1.61(m, 2H), 1.46(s, 6H).ESI-MS: m/ z 561.2[M+Na] ⁺ .

Example 320

2-(3,4-Difluorophenoxy)-2-methyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 453)

Compound 453 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.83 (d, J=8.6Hz, 2H), 7.39 (d, J=8.2Hz, 2H), 7.08 (dd, J=18.7, 9.3Hz, 1H), 6.82-6.71(m, 1H), 6.68-6.60(m, 1H), 6.56(d, J=7.4Hz, 1H), 3.79(d, J=11.5Hz, 2H ), 3.76-3.70(m, 1H), 2.50(t, J=11.4Hz, 2H), 2.02(d, J=11.7Hz, 2H), 1.63-1.54(m, J=11.8, 2.8Hz, 2H) , 1.47(s, 6H).ESI-MS: m/z 545.2[M+Na] ⁺ .

Example 321

N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound 454)

Compound 454 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl3) δ8.05 (s, 1H), 7.98 (d, J=7.8Hz, 1H), 7.89 (d, J=7.7Hz, 1H ), 7.73-7.66(m, 1H), 7.28(d, J=9.1Hz, 1H), 6.92-6.85(m, 2H), 5.53(d, J=7.1Hz, 1H), 3.97(t, J= 5.5Hz, 2H), 3.86-3.69(m, 3H), 2.54-2.40(m, 2H), 2.04-1.93(m, 2H), 1.80-1.69(m, 4H), 1.59-1.50(m, 2H) , 1.19(s, 6H).ESI-MS: m/z560.2[M+Na] ⁺ .

Example 322

2-(2,3-difluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide ( Compound 455)

Compound 455 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18 (d, J=8.3Hz, 2H), 8.06-7.94 (m, 3H), 7.33 (dd, J =19.7, 9.6Hz, 1H), 6.99-6.87(m, 1H), 6.74-6.63(m, 1H), 3.72-3.53(m, 3H), 3.31(s, 3H), 2.47-2.32(m, 2H ), 1.78-1.65(m, 2H), 1.64-1.48(m, 2H), 1.39(s, 6H). ESI-MS: m/z 539.2[M+Na] ⁺ .

Example 323

2-(2,3-difluorophenoxy)-2-methyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide ( Compound 456)

Compound 456 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.28(d, J=7.8Hz, 1H), 8.15(s, 1H), 8.11-7.99(m, 2H ), 7.98-7.89(m, 1H), 7.33(dd, J=19.6, 9.7Hz, 1H), 6.99-6.86(m, 1H), 6.75-6.62(m, 1H), 3.72-3.57(m, 3H ), 3.34(s, 3H), 2.46-2.34(m, 2H), 1.80-1.63(m, 2H), 1.63-1.46(m, 2H), 1.39(s, 6H). ESI-MS: m/z 539.2[M+Na] ⁺ .

Example 324

2-(4-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 457)

Compound 457 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.90-7.64 (m, 2H), 7.32-7.25 (m, 1H), 7.23-7.15 (m, 1H), 7.04 -6.75(m, 4H), 6.63(d, J=7.5Hz, 1H), 3.88-3.62(m, 3H), 2.59-2.37(m, 2H), 2.12-1.86(m, 2H), 1.59-1.47 (m, 3H), 1.43(s, 6H).ESI-MS: m/z 461.2[M+Na] ⁺ .

Example 325

4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 458)

Compound 458 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48 (s, 1H), 8.20-8.09 (m, 2H), 8.02 (d, J=7.9Hz, 1H ), 7.87-7.76(m, 2H), 7.76-7.66(m, 4H), 7.62(d, J=8.2Hz, 2H), 6.92(d, J=8.4Hz, 2H), 3.62(d, 1H) , 3.53(d, J=11.9Hz, 2H), 2.41(d, J=11.9Hz, 2H), 1.67(d, J=10.9Hz, 2H), 1.58-1.40(m, 8H).ESI-MS: m/z 607.3[M+Na] ⁺ .

Example 326

2-(4-chlorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propanamide (compound 459)

Compound 459 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.95-7.75 (d, J=7.9Hz, 2H), 7.57 (d, J=7.9Hz, 2H), 7.23 (d, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 6.53(d, J=7.6Hz, 1H), 4.02-3.55(m, 9H), 3.52-3.17(m, 2H), 2.62-2.40(m, 2H), 2.12-1.89(m, 2H), 1.57-1.50(m, 2H), 1.44(s, 6H). ESI-MS: m/z 572.3[M+Na] ⁺ .

Example 327

N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,4-difluorophenoxy)-2,2-dimethylpentanamide (compound 460)

Compound 460 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.10-8.02 (m, 1H), 7.98 (d, J=7.9Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.75-7.64(m, 1H), 6.94-6.81(m, 2H), 6.81-6.71(m, 1H), 5.67(d, J=8.0Hz, 1H), 3.94(t, J= 5.4Hz, 2H), 3.88-3.81(m, 1H), 3.82-3.67(m, 2H), 2.55-2.38(m, 2H), 2.07-1.91(m, 2H), 1.78-1.60(m, 4H) , 1.59-1.47(m, 2H), 1.17(s, 6H).ESI-MS: m/z 528.2[M+Na] ⁺ .

Example 328

5-(2,4-difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 461 )

Compound 461 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60-7.51 (m, 2H), 7.50-7.40 (m, 1H), 7.38-7.28 (m, 1H), 6.95 -6.81(m, 2H), 6.81-6.70(m, 1H), 5.57(d, J=7.8Hz, 1H), 3.94(t, J=5.4Hz, 2H), 3.84-3.65(m, 3H), 2.58-2.33(m, 2H), 2.07-1.86(m, 2H), 1.74-1.60(m, 4H), 1.52(dd, J=12.1, 3.9Hz, 2H), 1.17(s, 6H).ESI- MS: m/z 521.2[M+Na] ⁺ .

Example 329

5-(4-chloro-2-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 462)

Compound 462 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, Chloroform-d) δ7.59-7.51 (m, 2H), 7.51-7.43 (m, 1H), 7.37-7.28 (m, 1H), 7.10(dd, J=10.8, 2.5Hz, 1H), 7.07-6.98(m, 1H), 6.91-6.78(m, 1H), 5.56(d, J=7.8Hz, 1H), 3.95(t, J= 5.7Hz, 2H), 3.84-3.62(m, 3H), 2.53-2.32(m, 2H), 2.03-1.91(m, 2H), 1.81-1.60(m, 4H), 1.56-1.47(m, 2H) , 1.17(s, 6H).ESI-MS: m/z 537.2[M+Na] ⁺ .

Example 330

3-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 463)

Compound 463 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.24 (d, J=7.8Hz, 1H), 8.21-8.16 (m, 1H ), 7.98(d, J=7.8Hz, 1H), 7.85-7.72(m, 1H), 7.32-7.17(m, 2H), 7.16-7.08(m, 1H), 7.05-6.91(m, 1H), 3.95(t, J=5.4Hz, 2H), 3.68-3.60(m, 1H), 3.61-3.45(m, 2H), 2.46-2.29(m, 2H), 1.76-1.64(m, 2H), 1.59- 1.49(m, 4H), 1.50-1.39(m, 2H), 1.05(s, 6H). ESI-MS: m/z 547.2[M+Na] ⁺ .

Example 331

trans-4-((4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (compound 464)

Compound 464 was prepared according to the method of Examples 14 and 139: ¹ H NMR (300MHz, CDCl ₃ ) δ13.52(s, 1H), 8.28(d, J=8.4Hz, 1H), 8.15(d, J=8.2 Hz, 2H), 7.86(d, J=8.2Hz, 2H), 7.71(dd, J=8.3, 4.7Hz, 4H), 7.62(d, J=8.4Hz, 2H), 6.94(d, J=8.6 Hz, 2H), 4.71-4.39(m, 1H), 4.02-3.65(m, 2H), 3.50-3.37(m, 1H), 2.74-2.57(m, 2H), 1.85-1.66(m, 1H), 1.61-1.53(m, 1H), 1.50(s, 6H).ESI-MS: m/z 601.2[MH] ^- .

Example 332

5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 465)

Compound 465 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.33(s, 1H), 8.19(d, J=7.1Hz, 1H), 8.04(d, J=7.5Hz, 1H), 7.79(dd, J=7.5Hz, 7.1Hz, 1H), 6.95-6.71(m, 3H), 5.59(d, J=6.9Hz, 1H), 4.02-3.90(m, 2H), 3.88- 3.64(m, 3H), 3.12(s, 3H), 2.57-2.41(m, 2H), 2.07-1.92(m, 2H), 1.79-1.60(m, 6H), 1.17(s, 6H).ESI- MS: m/z 581.2[M+Na] ⁺ .

Example 333

trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Methyl formate (compound 466)

Compound 466 was obtained by referring to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18 (d, J=8.3Hz, 2H), 7.93 (d, J=8.3Hz, 2H), 7.43(d, J=8.1Hz, 1H), 7.34-6.90(m, 3H), 4.71-4.41(m, 1H), 4.06-3.93(m, 2H), 3.91(s, 3H), 3.88-3.77( m, 2H), 3.58-3.45(m, 1H), 2.75-2.55(m, 2H), 1.82-1.69(m, 1H), 1.61-1.51(m, 5H), 1.07(s, 6H).ESI- MS: m/z 579.2[M+Na] ⁺ .

Example 334

trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 467)

Compound 467 was prepared according to the method of Examples 119 and 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.16(d, J=8.2Hz, 2H), 7.90(d, J =8.2Hz, 2H), 7.43(d, J=8.1Hz, 1H), 7.32-6.91(m, 3H), 4.73-4.40(m, 1H), 4.01-3.90(m, 2H), 3.89-3.75( m, 2H), 3.57-3.44(m, 1H), 2.77-2.55(m, 2H), 1.83-1.69(m, 1H), 1.63-1.47(m, 5H), 1.07(s, 6H).ESI- MS: m/z 541.2[MH] ^- .

Example 335

trans-4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene (2-Acetamido) ethyl formate (compound 468)

Using compound 467 (Example 334) as a raw material, compound 468 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.21 (d, J=8.3Hz, 2H), 8.15-8.06 (m, 1H), 7.93(d, J=8.3Hz, 2H), 7.44(d, J=7.6Hz, 1H), 7.32-6.90(m, 3H), 4.70-4.39(m, 1H), 4.31( t, J=5.4Hz, 2H), 4.06-3.90(m, 2H), 3.90-3.75(m, 2H), 3.61-3.49(m, 1H), 3.48-3.38(m, 2H), 2.72-2.57( m, 2H), 1.83(s, 3H), 1.77-1.70(m, 1H), 1.64-1.48(m, 5H), 1.07(s, 6H). ESI-MS: m/z 650.1 [M+Na] ⁺ .

Example 336

4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 469)

Compound 469 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.16(d, J=8.0Hz, 2H), 7.85(d, J=8.0Hz, 2H), 7.22( d, J=7.8Hz, 1H), 7.09(t, J=8.7Hz, 2H), 6.90(p, J=4.2Hz, 2H), 3.91-3.82(m, 2H), 3.67-3.56(m, 3H ), 2.48-2.33(m, 2H), 1.76-1.64(m, 2H), 1.59-1.43(m, 6H), 1.05(s, 6H). ESI-MS: m/z 505.2[MH] ^- .

Example 337

5-(4-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 470)

Compound 470 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.54 (d, J=3.9Hz, 2H), 7.46 (d, J=7.6Hz, 1H), 7.39-7.27( m, 1H), 6.95(t, J=8.6Hz, 2H), 6.86-6.71(m, 2H), 5.53(d, J=7.8Hz, 1H), 3.96-3.58(m, 5H), 2.44(t , J=11.9Hz, 2H), 2.07-1.85(m, 2H), 1.75-1.46(m, 6H), 1.17(s, 6H).ESI-MS: m/z 503.2[M+Na] ⁺ .

Example 338

5-(4-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 471)

Compound 471 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.77 (dd, J=8.7, 5.0Hz, 2H), 7.33-7.13 (m, 2H), 7.03-6.87 (m , 2H), 6.79(dd, J=9.1, 4.2Hz, 2H), 5.53(d, J=7.8Hz, 1H), 3.97-3.62(m, 5H), 2.49-2.25(m, 2H), 2.05- 1.85(m, 2H), 1.77-1.42(m, 6H), 1.17(s, 6H). ESI-MS: m/z 503.2[M+Na] ⁺ .

Example 339

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)pentanamide ( Compound 472)

Compound 472 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.33(s, 1H), 8.19(d, J=7.8Hz, 1H), 8.04(d, J=7.8Hz, 1H), 7.79(t, J=7.8Hz, 1H), 6.95(t, J=8.4Hz, 2H), 6.79(dd, J=9.0, 4.4Hz, 2H), 5.54(d, J=7.6Hz, 1H), 4.01-3.64(m, 5H), 3.12(s, 3H), 2.49(t, J=11.9Hz, 2H), 2.12-1.88(m, 2H), 1.80-1.42(m, 6H), 1.17 (s, 6H).ESI-MS: m/z 563.2[M+Na] ⁺ .

Example 340

2-Acetamidoethyl 4-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoate (compound 473)

Using compound 278 (Example 191) as a raw material, compound 473 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.1Hz, 2H), 7.83 (d, J =8.1Hz, 2H), 6.94-6.72(m, 3H), 5.85(br s, 1H), 5.57(d, J=7.7Hz, 1H), 4.47(t, J=5.2Hz, 2H), 3.94( t, J=5.0Hz, 2H), 3.87-3.75(m, 2H), 3.75-3.61(m, 3H), 2.51-2.36(m, 2H), 2.01(s, 3H), 1.99-1.91(m, 2H), 1.77-1.64(m, 4H), 1.57-1.43(m, 2H), 1.17(s, 6H). ESI-MS: m/z 632.2[M+Na] ⁺ .

Example 341

4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 474)

Compound 474 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48 (s, 1H), 8.20-8.11 (m, 2H), 7.98 (d, J=7.9Hz, 1H ), 7.88-7.79(m, 2H), 7.18-7.02(m, 2H), 6.93-6.81(m, 2H), 3.69-3.51(m, 3H), 2.49-2.37(m, 2H), 1.79-1.66 (m, 2H), 1.62-1.47 (m, 2H), 1.35 (s, 6H). ESI-MS: m/z 487.1 [M+Na] ⁺ .

Example 342

4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamide)piperidin-1-yl)sulfonyl)benzoic acid (compound 475)

Compound 475 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47(s, 1H), 8.16(d, J=8.3Hz, 2H), 7.85(d, J=8.2 Hz, 2H), 7.30(d, J=8.8Hz, 2H), 7.21(d, J=7.8Hz, 1H), 6.91(d, J=8.9Hz, 2H), 3.96-3.83(m, 2H), 3.70-3.50(m, 3H), 2.47-2.34(m, 2H), 1.77-1.61(m, 2H), 1.60-1.39(m, 6H), 1.08(s, 6H).ESI-MS: m/z 545.2[M+Na] ⁺ .

Example 343

4-(((3R,4R)-4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl)benzoic acid (compound 476)

Compound 476 was prepared according to the method of Examples 14 and 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.28 (d, J=8.3Hz, 1H), 8.19-8.09(m, 2H), 7.92-7.79(m, 2H), 7.77-7.66(m, 4H), 7.66-7.58(m, 2H), 6.99-6.89(m, 2H), 4.68-4.40(m , 1H), 4.01-3.68(m, 2H), 3.55-3.35(m, 2H), 2.76-2.56(m, 2H), 1.87-1.66(m, 1H), 1.50(s, 6H).ESI-MS : m/z 601.1[MH] ^- .

Example 344

4-(((3R,4R)-4-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl) Sulfonyl) methyl benzoate (compound 477)

Compound 477 was obtained by referring to the method of Examples 14 and 281: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ8.21 (d, J=8.4Hz, 2H), 7.83 (d, J=8.5Hz, 2H), 7.79-7.67(m, 4H), 7.47(d, J=8.5Hz, 2H), 6.95(d, J=8.7Hz, 2H), 6.53(d, J=8.4Hz, 1H), 4.57- 4.27(m, 1H), 4.13-3.88(m, 5H), 3.80-3.67(m, 1H), 2.57-2.42(m, 2H), 2.20-2.03(m, 1H), 1.69-1.57(m, 7H ).ESI-MS: m/z 639.2[M+Na] ⁺ .

Example 345

2-Acetamidoethyl 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamide)piperidin-1-yl)sulfonyl)benzoate (compound 478)

Using compound 475 (Example 342) as a raw material, compound 478 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19 (d, J=8.3Hz, 2H), 8.08(s , 1H), 7.87(d, J=8.3Hz, 2H), 7.29(d, J=8.8Hz, 2H), 7.21(d, J=7.0Hz, 1H), 6.90(d, J=8.9Hz, 2H ), 4.29(t, J=5.1Hz, 2H), 3.93-3.81(m, 2H), 3.70-3.49(m, 3H), 3.45-3.35(m, 2H), 2.44-2.29(m, 2H), 1.81(s, 3H), 1.74-1.61(m, 2H), 1.59-1.38(m, 6H), 1.03(s, 6H). ESI-MS: m/z 630.2[M+Na] ⁺ .

Example 346

4-((4-(2-(4-chlorophenoxy)-2-methylpropanamide)piperidin-1-yl)sulfonyl)benzoic acid-2-(acetylamino)-ethyl ester (compound 479 )

Using compound 251 (Example 167) as a raw material, compound 479 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19 (d, J=8.1Hz, 2H), 8.09(s , 1H), 7.99(d, J=7.7Hz, 1H), 7.86(d, J=8.1Hz, 2H), 7.30(d, J=8.6Hz, 2H), 6.83(d, J=8.7Hz, 2H ), 4.31(t, J=5.2Hz, 2H), 3.68-3.50(m, 3H), 3.44(q, J=5.4Hz, 2H), 2.47-2.35(m, 2H), 1.83(s, 3H) , 1.74-1.62(m, 2H), 1.61-1.45(m, 2H), 1.39(s, 6H).ESI-MS: m/z 588.2[M+Na] ⁺ .

Example 347

4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoic acid (Compound 480)

Compound 480 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.44(s, 1H), 8.16(d, J=8.0Hz, 2H), 7.84(d, J=8.1 Hz, 2H), 7.42-7.25(d, 1H), 7.25-7.17(m, 1H), 7.09-6.93(m, 1H), 6.81-6.62(m, 1H), 3.88(m, 2H), 3.72- 3.50(m, 2H), 3.38-3.24(m, 1H), 2.40(m, 2H), 1.82-1.61(m, 2H), 1.64-1.39(m, 6H), 1.05(s, 6H).ESI- MS: m/z 547.2[M+Na] ⁺ .

Example 348

3-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 481)

Compound 481 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.80 (s, 1H), 8.24 (d, J=7.8Hz, 1H), 8.19 (s, 1H), 7.97(d, J=7.8Hz, 1H), 7.86-7.70(m, 1H), 7.50-7.24(m, 1H), 7.20(d, J=7.7Hz, 1H), 7.10-6.91(m, 1H) , 6.82-6.63(m, 1H), 3.88(m, 2H), 3.72-3.45(m, 2H), 3.41-3.16(m, 1H), 2.46-2.32(m, 2H), 1.79-1.64(m, 2H), 1.63-1.41(m, 6H), 1.05(s, 6H). ESI-MS: m/z 547.2[M+Na] ⁺ .

Example 349

5-(3,4-difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 482 )

Compound 482 was prepared according to the method of Example 119: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.77-7.65 (m, 1H), 7.63-7.51 (m, 3H), 7.39-7.26 (m, 1H) , 7.23(d, J=7.7Hz, 1H), 7.12-6.93(m, 1H), 6.84-6.62(m, 1H), 3.89(t, 2H), 3.71-3.46(m, 3H), 2.48-2.23 (m, 2H), 1.81-1.61(m, 2H), 1.61-1.37(m, 6H), 1.05(s, 6H). ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 350

5-(3,4-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 483 )

Compound 483 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.86-7.72 (m, 2H), 7.57-7.41 (m, 2H), 7.40-7.25 (m, 1H) , 7.22(d, J=7.8Hz, 1H), 7.08-6.91(m, 1H), 6.72(d, J=9.1Hz, 1H), 3.88(m, 2H), 3.70-3.44(m, 3H), 2.46-2.23(m, 2H), 1.80-1.61(m, 2H), 1.62-1.35(m, 6H), 1.05(s, 6H). ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 351

2-(3,4-Difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 484)

Compound 484 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.64-7.51 (m, 2H), 7.51-7.41 (m, 1H), 7.40-7.28 (m, 1H), 7.15 -6.98(m, 1H), 6.82-6.69(m, 1H), 6.68-6.58(m, 1H), 6.57-6.47(m, 1H), 3.90-3.67(m, 3H), 2.63-2.41(m, 2H), 2.13-1.91(m, 2H), 1.64-1.56(m, 2H), 1.45(s, 6H). ESI-MS: m/z 479.1[M+Na] ⁺ .

Example 352

2-(3,4-Difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 485)

Compound 485 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82-7.68 (m, 2H), 7.25-7.14 (m, 2H), 7.10-6.95 (m, 1H), 6.79 -6.66(m, 1H), 6.65-6.49(m, 2H), 3.87-3.62(m, 3H), 2.52-2.34(m, 2H), 2.06-1.90(m, 2H), 1.65-1.48(m, 2H), 1.44(s, 6H).ESI-MS: m/z 479.1[M+Na] ⁺ .

Example 353

Trans-5-(3,4-difluorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methylvaleramide (compound 486)

Compound 486 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.79 (dd, J=8.4, 5.0Hz, 2H), 7.25 (dd, J=10.4, 6.1Hz, 2H), 7.03(dd, J=18.8, 9.3Hz, 1H), 6.79-6.60(m, 1H), 6.55(d, J=9.0Hz, 1H), 5.68(d, J=7.4Hz, 1H), 4.67-4.30 (m, 1H), 4.19-4.02(m, 1H), 3.99-3.79(m, 3H), 3.79-3.65(m, 1H), 2.60-2.33(m, 2H), 2.26-2.05(m, 1H) , 1.66(s, 5H), 1.20(s, 6H).ESI-MS: m/z 539.2[M+Na] ⁺ .

Example 354

5-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)- 2,2-Dimethylpentanamide (Compound 487)

Compound 487 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19(d, J=8.4Hz, 2H), 8.05(d, J=8.4Hz, 2H), 7.44(d, J=8.3Hz, 1H), 7.30(d, J=8.9Hz, 2H), 6.91(d, J=8.9Hz, 2H), 4.72-4.41(m, 1H), 3.97- 3.77(m, 4H), 3.59-3.46(m, 1H), 3.31(s, 3H), 2.76-2.60(m, 2H), 1.82-1.69(m, 1H), 1.63-1.45(m, 5H), 1.07(s, 6H).ESI-MS: m/z 597.1[M+Na] ⁺ .

Example 355

5-(4-chlorophenoxy)-N-((3R,4R)-3-fluoro-1-((4-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl) -2,2-Dimethylpentanamide (Compound 488)

Compound 488 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.83 (d, J=8.7Hz, 2H), 7.39 (d, J=8.4Hz, 2H) , 7.21(d, J=8.9Hz, 2H), 6.78(d, J=8.9Hz, 2H), 5.66(d, J=7.4Hz, 1H), 4.60-4.32(m, 1H), 4.15-4.03( m, 1H), 3.98-3.91(m, 1H), 3.88(t, J=5.1Hz, 2H), 3.79-3.67(m, 1H), 2.56-2.42(m, 2H), 2.23-2.09(m, 1H), 1.70-1.65(m, 3H), 1.61-1.54(m, 2H), 1.20(s, 6H). ESI-MS: m/z 603.2[M+Na] ⁺ .

Example 356

5-(4-chlorophenoxy)-N-((3R,4R)-1-((4-cyanophenyl)sulfonyl)-3-fluoropiperidin-4-yl)-2,2- Dimethylvaleramide (Compound 489)

Compound 489 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, CDCl ₃ ) δ7.91-7.83 (m, 4H), 7.21 (d, J=8.8Hz, 2H), 6.78 ( d, J=8.8Hz, 2H), 5.65(d, J=7.2Hz, 1H), 4.60-4.32(m, 1H), 4.15-4.02(m, 1H), 3.99-3.92(m, 1H), 3.88 (d, J=5.0Hz, 2H), 3.79-3.66(m, 1H), 2.62-2.48(m, 2H), 2.22-2.08(m, 1H), 1.69-1.65(m, 3H), 1.60-1.52 (m, 2H), 1.20 (s, 6H). ESI-MS: m/z 544.2[M+Na] ⁺ .

Example 357

3-(((3R,4R)-4-(5-(4-chlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 490)

Compound 490 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.40(s, 1H), 8.37(s, 1H), 8.30(d, J=7.9 Hz, 1H), 8.01(d, J=7.8Hz, 1H), 7.77(t, J=7.8Hz, 1H), 7.41(d, J=8.1Hz, 1H), 7.30(d, J=8.6Hz, 2H), 6.91(d, J=8.7Hz, 2H), 4.69-4.41(m, 1H), 3.88(s, 4H), 3.51(d, J=12.0Hz, 1H), 2.75-2.55(m, 2H ), 1.83-1.66(m, 1H), 1.55(s, 5H), 1.07(s, 6H). ESI-MS: m/z 563.2[M+Na] ⁺ .

Example 358

4-((4-(5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid ( Compound 491)

Compound 491 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d6) δ13.47(s, 1H), 8.16(d, J=8.3Hz, 2H), 7.85(d, J=8.2Hz , 3H), 7.52(s, 1H), 7.44(d, J=8.0Hz, 1H), 7.20(d, J=7.6Hz, 1H), 4.14(dd, J=10.7, 3.4Hz, 2H), 3.62 (dd, J=7.1, 4.6Hz, 2H), 3.57-3.49(m, 1H), 2.39(t, J=11.3Hz, 2H), 1.70(d, J=14.5Hz, 2H), 1.60-1.54( m, 4H), 1.52-1.39 (m, 2H), 1.05 (s, 6H). ESI-MS: m/z 647.4[M+Na] ⁺ .

Example 359

5-(2,5-dimethylphenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 492)

Compound 492 was obtained by referring to the method of Example 43: ¹ H NMR (300MHz, CDCl ₃ ) δ7.53 (d, J=5.6Hz, 2H), 7.46 (d, J=7.4Hz, 1H), 7.36-7.28( m, 1H), 7.00(d, J=7.4Hz, 1H), 6.66(d, J=7.4Hz, 1H), 6.59(s, 1H), 5.50(d, J=7.5Hz, 1H), 3.89( t, J=5.1Hz, 2H), 3.82-3.75(m, 2H), 3.74-3.63(m, 1H), 2.43(t, J=11.4Hz, 2H), 2.29(s, 3H), 2.16(s , 3H), 1.96(d, J=11.0Hz, 2H), 1.73-1.65(m, 4H), 1.49(ddd, J=23.5, 11.9, 3.6Hz, 2H), 1.18(s, 6H).ESI- MS: m/z 513.2[M+Na] ⁺ .

Example 360

N-(1-((3-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(2,5-dichlorophenoxy)-2,2-dimethylpentanamide (compound 493)

Compound 493 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.05(s, 1H), 7.98(d, J=7.8Hz, 1H), 7.89(d, J=7.7Hz, 1H), 7.70(t, J=7.9Hz, 1H), 7.30(s, 1H), 6.91(d, J=2.1Hz, 1H), 6.87(s, 1H), 5.53(d, J=7.1Hz, 1H), 3.97(t, J=5.5Hz, 2H), 3.86-3.78(m, 2H), 3.77-3.67(m, 1H), 2.46(t, J=11.1Hz, 2H), 1.99(d, J =12.0Hz, 2H), 1.78-1.66(m, 4H), 1.60-1.48(m, 2H), 1.19(s, 6H).ESI-MS: m/z 560.2[M+Na] ⁺ .

Example 361

5-(2,5-bis(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)piper Pyridine-4-yl)pentanamide (compound 494)

Compound 494 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.83(d, J=8.7Hz, 2H), 7.71(d, J=8.1Hz, 1H), 7.39(d, J=8.4Hz, 2H), 7.31(s, 1H), 7.18(s, 1H), 5.56(d, J=7.7Hz, 1H), 4.08(t, J=5.4Hz, 2H), 3.81(d, J=12.1Hz, 2H), 3.75-3.68(m, 1H), 2.45(t, J=11.1Hz, 2H), 1.98(d, J=10.9Hz, 2H), 1.84-1.67(m, 4H), 1.54(qd, J=12.3, 3.8Hz, 2H), 1.20(s, 6H).ESI-MS: m/z 687.1[M+Na] ⁺ .

Example 362

5-(2,3-difluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 495 )

Compound 495 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.62-7.40 (m, 3H), 7.39-7.27 (m, 1H), 7.03-6.89 (m, 1H), 6.82 -6.64(m, 2H), 5.53(d, J=6.8Hz, 1H), 4.08-3.92(m, 2H), 3.85-3.63(m, 3H), 2.45(t, J=11.0Hz, 2H), 2.07-1.88(m, 2H), 1.81-1.60(m, 4H), 1.55-1.43(m, 2H), 1.17(s, 6H). ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 363

trans-5-(3,4-difluorophenoxy)-N-((3R,4R)-3-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl) -2,2-Dimethylpentanamide (Compound 496)

Compound 496 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.56(s, 2H), 7.48(d, J=7.5Hz, 1H), 7.35(s, 1H), 7.03( q, J=9.4Hz, 1H), 6.66(dd, J=11.8, 6.6Hz, 1H), 6.55(d, J=8.9Hz, 1H), 5.69(d, J=7.3Hz, 1H), 4.47( ddd, J=49.3, 14.4, 9.4Hz, 1H), 4.18-4.02(m, 1H), 4.02-3.79(m, 3H), 3.79-3.66(m, 1H), 2.50(dd, J=14.1, 7.5 Hz, 2H), 2.24-2.10(m, 1H), 1.77-1.59(m, 5H), 1.20(s, 6H). ESI-MS: m/z 539.2[M+Na] ⁺ .

Example 364

trans-4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamido)-2-methylpiperidin-1-yl)sulfonyl)benzoic acid ( Compound 497)

Dissolve compound V-1 (256mg, 1mmol) in anhydrous DMF (2mL), add CDI (186mg, 1.149mmol), stir at 70°C for 1h, then add (±)-trans-4-amino-2- Methylpiperidine-1-carboxylic acid tert-butyl ester (214mg, 1mmol), reacted for 2h. Cooled to room temperature, added water (10mL), extracted with ethyl acetate (20mL x3), the organic phase was washed with saturated NaHCO ₃ (10mLx3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (washing Removal agent: petroleum ether/ethyl acetate = 2:1) and purified to obtain compound V-2 (white solid, 366 mg, yield 81%).

Compound V-2 (366mg) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1mL) was added under ice-cooling, and stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the pH was adjusted to alkaline with saturated sodium bicarbonate, extracted with ethyl acetate (30mL x3), washed with saturated NaCl (10mL x3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound V- 3 (colorless liquid, 279 mg, yield 98%).

Compound V-3 (158mg, 0.45mmoL) was dissolved in DCM (5mL), triethylamine (0.095mL) and methyl chlorosulfonylbenzoate (115mg, 0.46mmoL) were added, and stirred at room temperature for 4h. After spinning to dryness, the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound V-4 (186 mg, yield 75%).

Compound V-4 (186mg, 0.34mmoL) was dissolved in methanol and tetrahydrofuran (5:1, 20mL), 1N NaOH (2mL) was added, and stirred overnight at room temperature. Evaporate the solvent under reduced pressure, add 1N HCl to make it acidic, a white solid precipitates out, filter, wash with water, collect the white solid, add 20mL of petroleum ether and stir for 2h, filter with suction, and dry in vacuo to obtain compound 497 (white solid, 176mg, yield 97%): ¹ H NMR (300MHz, DMSO-d ₆ ) δ 13.47(s, 1H), 8.16(d, J=8.3Hz, 2H), 7.85(d, J=8.2Hz, 2H), 7.30( d, J=8.8Hz, 2H), 7.21(d, J=7.8Hz, 1H), 6.91(d, J=8.9Hz, 2H), 3.88(t, 2H), 3.70-3.50(m, 3H), 2.40(m, 1H), 1.69(m, 2H), 1.60-1.39(m, 6H), 1.16(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI-MS: m/z 560.2 [M+Na] ⁺ .

Example 365

trans-5-(4-chlorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl Valeramide (compound 498)

Compound 498 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.80 (dd, J=8.4, 5.3Hz, 2H), 7.48 (t, J=8.7Hz, 2H), 7.30(d, J=8.8Hz, 2H), 7.21(d, J=7.6Hz, 1H), 6.91(d, J=8.8Hz, 2H), 3.95-3.83(m, 2H), 3.65-3.48(m , 3H), 2.35(m, 1H), 1.69(m, 2H), 1.60-1.40(m, 6H), 1.15(s, 6H), 1.08(d, J=6.8Hz, 3H).ESI-MS: m/z 560.2[M+Na] ⁺ .

Example 366

trans-5-(4-chlorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl Valeramide (compound 499)

Compound 499 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.79(m, 1H), 7.58-7.60(m, 2H), 7.47(m, 1H), 7.21(d , J=7.6Hz, 2H), 6.91(d, J=8.8Hz, 2H), 3.93-3.81(m, 2H), 3.64-3.47(m, 3H), 2.34(m, 1H), 1.68(m, 2H), 1.60-1.40(m, 6H), 1.15(s, 6H), 1.08(d, J=6.8Hz, 3H).ESI-MS: m/z 560.2[M+Na] ⁺ .

Example 367

trans-5-(4-chlorophenoxy)-2,2-dimethyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)pentanamide (Compound 500)

Compound 500 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.88 (m, 2H), 8.16 (d, J=8.1Hz, 1H), 7.68 (dd, J=7.6 , 4.9Hz, 1H), 7.21(d, J=7.6Hz, 2H), 6.91(d, J=8.8Hz, 2H), 3.93-3.81(m, 2H), 3.64-3.47(m, 3H), 2.34 (m, 1H), 1.68(m, 2H), 1.60-1.40(m, 6H), 1.15(s, 6H), 1.08(d, J=6.8Hz, 3H). ESI-MS: m/z 517.1[ M+Na] ⁺ .

Example 368

trans-4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanamido)-2-methylpiperidin-1-yl)sulfonyl)benzoic acid ( Compound 501)

Compound 501 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47(s, 1H), 8.16(d, J=8.0Hz, 2H), 7.85(d, J=8.0 Hz, 2H), 7.22(d, J=7.8Hz, 1H), 7.09(t, J=8.7Hz, 2H), 6.90(p, J=4.2Hz, 2H), 3.88(t, 2H), 3.70- 3.50(m, 3H), 2.40(m, 1H), 1.69(m, 2H), 1.60-1.39(m, 6H), 1.16(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI -MS: m/z 543.2[M+Na] ⁺ .

Example 369

trans-5-(4-fluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl Valeramide (compound 502)

Compound 502 was prepared according to the method of Example 364: ¹ H NMR (300MHz, CDCl ₃ ) δ7.77 (dd, J=8.7, 5.0Hz, 2H), 7.33-7.13 (m, 2H), 7.03-6.87 (m , 2H), 6.79(dd, J=9.1, 4.2Hz, 2H), 5.53(d, J=7.8Hz, 1H), 3.87(t, 2H), 3.71-3.51(m, 3H), 2.40(m, 1H), 1.68(m, 2H), 1.60-1.39(m, 6H), 1.16(s, 6H), 1.06(d, J=6.8Hz, 3H). ESI-MS: m/z 517.2 [M+Na ] ⁺ .

Example 370

trans-5-(2,4-difluorophenoxy)-N-(1-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2- Dimethylvaleramide (compound 503)

Compound 503 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.81 (dd, J=8.7, 5.2Hz, 2H), 7.48 (t, J=8.7Hz, 2H), 7.32-7.08(m, 3H), 6.98(t, J=8.8Hz, 1H), 3.95(m, 2H), 3.59(m, 3H), 2.35(m, 1H), 1.70(m, 2H), 1.60 -1.39(m, 6H), 1.05(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI-MS: m/z 535.1[M+Na] ⁺ .

Example 371

trans-5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl ) valeramide (compound 504)

Compound 504 was prepared according to the method of Example 364: ¹ H NMR (300MHz, CDCl ₃ ) δ9.04 (m, 1H), 8.90 (m, 1H), 8.11-8.00 (m, 1H), 7.55-7.46 (m , 1H), 7.32-7.24(m, 1H), 7.21-7.10(m, 1H), 6.94-6.84(m, 1H), 5.64(d, J=7.5Hz, 1H), 3.92(m, 2H), 3.90-3.69(m, 3H), 2.47(m, 2H), 2.05-1.93(m, 1H), 1.80-1.62(m, 4H), 1.60-1.48(m, 2H), 1.17(s, 6H), 1.06 (d, J=6.8Hz, 3H).ESI-MS: m/z 518.3[M+Na] ⁺ .

Example 372

5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(1-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)pentane Amide (Compound 505)

Compound 505 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.05 (m, 1H), 8.88 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18(m, 1H), 6.88(m, 1H), 5.63(d, J=7.5Hz, 1H), 4.03-3.90(m, 2H), 3.90-3.69(m, 3H), 2.45(m, 2H) , 2.36(s, 3H), 2.04-1.92(m, 2H), 1.80-1.61(m, 4H), 1.61-1.50(m, 2H), 1.16(s, 6H). ESI-MS: m/z 518.2 [M+Na] ⁺ .

Example 373

5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(1-((2-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)pentane Amide (Compound 506)

Compound 506 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.88 (m, 1H), 8.45 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.18(m, 1H), 6.88(m, 1H), 5.62(d, J=7.5Hz, 1H), 4.02-3.91(m, 2H), 3.89-3.70(m, 3H), 2.50(s, 3H) , 2.44(m, 2H), 2.03-1.90(m, 2H), 1.80-1.62(m, 4H), 1.60-1.52(m, 2H), 1.17(s, 6H).ESI-MS: m/z 518.2 [M+Na] ⁺ .

Example 374

trans-2-(3,4-difluorophenoxy)-2-methyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propionamide (Compound 507)

Compound 507 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.03(m, 1H), 8.90(m, 1H), 8.10(m, 1H), 7.54-7.47(m , 1H), 7.30(d, J=7.5Hz, 1H), 7.09(m, 1H), 6.82-6.70(m, 1H), 6.69-6.57(m, 1H), 3.60-3.38(m, 3H), 2.80(m, 1H), 1.64-1.56(m, 4H), 1.45(s, 6H), 1.06(d, J=6.8Hz, 3H). ESI-MS: m/z 476.1[M+Na] ⁺ .

Example 375

trans-N-(1-((4-fluorophenyl)sulfonyl)-2-methylpiperidin-4-yl)-2,2-dimethyl-5-(4-(methylsulfonyl) Phenoxy)pentanamide (compound 508)

Compound 508 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.88-7.75 (m, 4H), 7.56-7.40 (m, 2H), 7.25 (d, J=7.8Hz , 1H), 7.12(d, J=8.8Hz, 2H), 4.10-3.92(m, 2H), 3.65-3.47(m, 3H), 3.15(s, 3H), 2.40(m, 1H), 1.77- 1.62(m, 2H), 1.62-1.40(m, 6H), 1.10(s, 6H).1.06(d, J=6.8Hz, 3H).ESI-MS: m/z 577.4[M+Na] ⁺ .

Example 376

trans-5-(4-chlorophenoxy)-2,2-dimethyl-N-(2-methyl-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine- 4-yl) propionamide (compound 509)

Compound 509 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18(d, J=8.2Hz, 2H), 7.99(d, J=8.3Hz, 2H), 7.30( d, J=8.7Hz, 2H), 7.23(d, J=7.8Hz, 1H), 6.91(d, J=8.7Hz, 2H), 3.95-3.82(m, 2H), 3.72-3.49(m, 3H ), 3.33(s, 3H), 2.42(m, 1H), 1.70(m, 2H), 1.61-1.40(m, 6H), 1.10(s, 3H), 1.06(d, J=6.8Hz, 3H) .ESI-MS: m/z 572.2[M+H] ⁺ .

Example 377

Trans-2-(4-chlorophenoxy)-2-methyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl)propanamide (compound 510 )

Compound 510 was prepared by referring to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.01 (d, J=1.6Hz, 1H), 8.86 (d, J=3.5Hz, 1H), 8.06( d, J=8.0Hz, 1H), 7.52(dd, J=7.9, 4.9Hz, 1H), 7.25(d, J=8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 6.56( d, J=7.7Hz, 1H), 3.80(m, 3H), 2.54(t, J=11.2Hz, 2H), 2.02(m, 1H), 1.61-1.50(m, 2H), 1.48(s, 6H ), 1.06 (d, J=6.8Hz, 3H).ESI-MS: m/z 474.2[M+Na] ⁺ .

Example 378

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)propionamide (compound 511)

Compound 511 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.90(s, 1H), 8.51(m, 1H), 7.48(m, 1H), 7.25(d, J =8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 6.56(d, J=7.7Hz, 1H), 3.80(m, 3H), 2.55(t, J=11.2Hz, 2H), 2.36(s, 3H), 2.02(d, J=12.1Hz, 2H), 1.61-1.50(m, 2H), 1.48(s, 6H). ESI-MS: m/z 452.2[M+H] ⁺ .

Example 379

2-(4-Chlorophenoxy)-2-methyl-N-(1-((2-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)propionamide (compound 512)

Compound 512 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.82 (m, 1H), 8.45 (m, 1H), 7.68 (m, 1H), 7.25 (d, J =8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 6.54(d, J=7.6Hz, 1H), 3.80(m, 3H), 2.54(t, J=11.2Hz, 2H), 2.42(s, 3H), 2.01(d, J=12.1Hz, 2H), 1.60-1.51(m, 2H), 1.45(s, 6H). ESI-MS: m/z 452.2[M+H] ⁺ .

Example 380

2-(4-fluorophenoxy)-2-methyl-N-(1-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)propionamide (compound 513)

Compound 513 was prepared according to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.88(s, 1H), 8.45(m, 1H), 7.46(m, 1H), 7.15(d, J =8.8Hz, 2H), 6.63(d, J=8.8Hz, 2H), 6.45(d, J=7.6Hz, 1H), 3.67(m, 3H), 2.51(t, J=11.2Hz, 2H), 2.35(s, 3H), 2.01(d, J=12.1Hz, 2H), 1.60-1.50(m, 2H), 1.42(s, 6H). ESI-MS: m/z 436.2[M+H] ⁺ .

Example 381

2-(4-fluorophenoxy)-2-methyl-N-(1-((2-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)propionamide (Compound 514)

Compound 514 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.80 (m, 1H), 8.41 (m, 1H), 7.62 (m, 1H), 7.16 (d, J =8.8Hz, 2H), 6.62(d, J=8.8Hz, 2H), 6.43(d, J=7.6Hz, 1H), 3.66(m, 3H), 2.50(t, J=11.2Hz, 2H), 2.41(s, 3H), 2.02(d, J=12.1Hz, 2H), 1.60-1.50(m, 2H), 1.42(s, 6H). ESI-MS: m/z 436.2[M+H] ⁺ .

Example 382

5-(3,4-difluorophenoxy)-2,2-dimethyl-N-(1-((4-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)pentane Amide (compound 515)

Compound 515 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.90(s, 1H), 8.46(m, 1H), 7.46(m, 1H), 7.29(m, 2H ), 7.01(m, 1H), 6.72(d, J=7.6Hz, 1H), 3.89(m, 2H), 3.64(m, 3H), 2.50(m, 2H), 2.36(s, 3H), 1.84 -1.62(m, 2H), 1.53(s, 6H), 1.05(s, 6H). ESI-MS: m/z 396.2[M+H] ⁺ .

Example 383

5-(3,4-difluorophenoxy)-2,2-dimethyl-N-(1-((2-methylpyridin-3-yl)sulfonyl)piperidin-4-yl)pentane Amide (Compound 516)

Compound 516 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.80 (m, 1H), 8.41 (m, 1H), 7.62 (m, 1H), 7.28 (m, 2H ), 7.01(m, 1H), 6.73(d, J=7.6Hz, 1H), 3.88(m, 2H), 3.64(m, 3H), 2.48(m, 2H), 2.41(s, 3H), 1.84 -1.62(m, 2H), 1.53(s, 6H), 1.05(s, 6H). ESI-MS: m/z 396.2[M+H] ⁺ .

Example 384

trans-5-(3,4-difluorophenoxy)-2,2-dimethyl-N-(2-methyl-1-(pyridin-3-ylsulfonyl)piperidin-4-yl ) valeramide (compound 517)

Compound 517 was prepared according to the method of Example 364: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.01-8.74 (m, 2H), 8.16 (m, 1H), 7.69 (m, 1H), 7.29 (m , 2H), 7.0l(m, 1H), 6.72(m, 1H), 3.89(s, 2H), 3.64(m, 3H), 2.48(m, 1H), 1.84-1.62(m, 2H), 1.53 (m, 6H), 1.10 (s, 6H), 1.06 (d, J=6.8Hz, 3H). ESI-MS: m/z 518.2[M+Na] ⁺ .

Example 385

Trans-2-(3,4-difluorophenoxy)-2-methyl-N-(2-methyl-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine- 4-yl) propionamide (compound 518)

Compound 518 was prepared according to the method of Example 364: ¹ H NMR (300MHz, CDCl ₃ ) δ8.32(s, 1H), 8.19(d, J=7.8Hz, 1H), 8.04(d, J=7.8Hz, 1H), 7.79(t, J=7.8Hz, 1H), 7.06(dd, J=18.8, 9.2Hz, 1H), 6.74(ddd, J=11.2, 6.7, 2.8Hz, 1H), 6.61(dt, J =4.3, 3.9Hz, 1H), 6.52(d, J=7.7Hz, 1H), 3.80(m, 3H), 3.11(s, 3H), 2.55(t, J=11.8Hz, 2H), 2.01(m , 1H), 1.63-1.52(m, 2H), 1.45(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI-MS: m/z 553.1[M+Na] ⁺ .

Example 386

Trans-2-(2,4-difluorophenoxy)-2-methyl-N-(2-methyl-1-((3-(methylsulfonyl)phenyl)sulfonyl)piperidine- 4-yl) propionamide (compound 519)

Compound 519 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.29 (d, J=7.6Hz, 1H), 8.16 (s, 1H), 8.07 (m, 2H), 7.95(m, 1H), 7.30(d, J=8.7Hz, 1H), 7.03(m, 2H), 3.65(m, 3H), 3.31(s, 3H), 2.44(m, 1H), 1.76(m , 2H), 1.60(m, 2H), 1.36(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI-MS: m/z 539.1[M+Na] ⁺ .

Example 387

trans-5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(2-methyl-1-((3-(methylsulfonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 520)

Compound 520 was obtained by referring to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.29 (d, J=7.6Hz, 1H), 8.16 (s, 1H), 8.07 (m, 2H), 7.95(m, 1H), 7.30(d, J=8.7Hz, 1H), 7.03(m, 2H), 3.96(m, 2H), 3.62(m, 2H), 3.44(m, 1H), 3.31(s , 3H), 2.43(m, 1H), 1.71(d, J=11.6Hz, 2H), 1.63-1.33(m, 6H), 1.10(s, 6H), 1.06(d, J=6.8Hz, 3H) .ESI-MS: m/z 581.3[M+Na] ⁺ .

Example 388

trans-3-((4-(5-(2,4-difluorophenoxy)-2,2-dimethylpentanylamino)-2-methylpiperidin-1-yl)sulfonyl) Benzoic acid (compound 521)

Compound 521 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.28 (m, 1H), 8.19 (m, 1H), 8.02-7.93 (m , 1H), 7.79(t, J=7.8Hz, 1H), 7.31(m, 1H), 7.12(dd, J=9.4, 5.5Hz, 1H), 6.98(t, J=8.9Hz, 1H), 3.94 (m, 2H), 3.67-3.48(m, 3H), 2.39(m, 1H), 1.70(d, J=12.6Hz, 2H), 1.61-1.40(m, 6H), 1.10(s, 6H), 1.06 (d, J=6.8Hz, 3H).ESI-MS: m/z 561.2[M+Na] ⁺ .

Example 389

trans-3-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanylamino)-2-methylpiperidin-1-yl)sulfonyl) Benzoic acid (compound 522)

Compound 522 was prepared according to the method of Example 364: ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.80 (s, 1H), 8.33 (m, 2H), 7.84 (d, J=8.1Hz, 2H), 7.68(m, 2H), 7.40(m, 1H), 6.88(m, 1H), 3.88(m, 2H), 3.62(d, J=12.0Hz, 2H), 3.37(d, J=37.2Hz, 1H ), 2.40(m, 1H), 1.70(d, J=10.5Hz, 2H), 1.62-1.41(m, 6H), 1.10(s, 6H), 1.06(d, J=6.8Hz, 3H).ESI -MS: m/z 561.2[M+Na] ⁺ .

Example 390

trans-4-((3-fluoro-4-(5-(4-fluorophenoxy)-2,2-dimethylpentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 523)

Compound 523 was prepared according to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.16(d, J=8.1Hz, 2H), 7.90(d, J=8.1 Hz, 2H), 7.43(d, J=8.2Hz, 1H), 7.09(t, J=8.8Hz, 2H), 6.95-6.85(m, 2H), 4.71-4.43(m, 1H), 3.98-3.74 (m, 4H), 3.55-3.45(m, 1H), 2.76-2.56(m, 2H), 1.84-1.69(m, 1H), 1.65-1.44(m, 5H), 1.07(s, 6H).ESI -MS: m/z 547.2[M+Na] ⁺ .

Example 391

trans-4-((3-fluoro-4-(5-(4-fluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoic acid 2- Acetamido ethyl ester (compound 524)

Using compound 523 (Example 390) as a raw material, compound 524 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.20(d, J=8.2Hz, 2H), 8.08(t , J=4.9Hz, 1H), 7.93(d, J=8.2Hz, 2H), 7.42(d, J=8.2Hz, 1H), 7.13-7.03(m, 2H), 6.94-6.85(m, 2H) , 4.70-4.43(m, 1H), 4.31(t, J=5.5Hz, 2H), 3.94-3.78(m, 4H), 3.58-3.48(m, 1H), 3.48-3.38(m, 2H), 2.74 -2.56(m, 2H), 1.83(s, 3H), 1.79-1.69(m, 1H), 1.63-1.47(m, 5H), 1.07(s, 6H). ESI-MS: m/z 632.2 [M +Na] ⁺ .

Example 392

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)pentane Amide (compound 525)

Using compound 475 (Example 342) as a raw material, compound 525 was obtained by referring to the method of Example 101: ¹ H NMR (300MHz, CDCl ₃ -d) δ7.81 (d, J=8.0Hz, 2H), 7.56 (d , J=8.0Hz, 2H), 7.24-7.19(m, 2H), 6.85-6.72(m, 2H), 5.50(d, J=7.7Hz, 1H), 3.88(t, J=5.4Hz, 2H) , 3.84-3.55(m, 9H), 3.51-3.29(m, 2H), 2.55-2.38(m, 2H), 2.02-1.89(m, 2H), 1.73-1.62(m, 4H), 1.49(dd, J=12.0, 3.9Hz, 2H), 1.17(s, 6H).ESI-MS: m/z 614.3[M+Na] ⁺ .

Example 393

5-(4-chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl valeramide (compound 526)

Compound 526 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.22-8.09 (m, 1H), 8.03 (d, J=8.2Hz, 2H), 7.95 (d, J =8.3Hz, 2H), 7.35-7.25(m, 2H), 7.21(d, J=7.7Hz, 1H), 6.96-6.84(m, 2H), 3.87(t, J=8.3Hz, 2H), 3.69 -3.46(m, 3H), 2.42(t, J=12.6Hz, 2H), 2.16(dq, J=7.0, 3.5Hz, 1H), 1.69(m, 2H), 1.60-1.38(m, 6H), 1.04(s, 6H), 0.48(dd, J=7.1, 4.6Hz, 2H), 0.37(dd, J=3.9Hz, 2H).ESI-MS: m/z 620.2[M+Na] ⁺ .

Example 394

2-(4-Chlorophenoxy)-N-(1-((4-(N-cyclopropylsulfonamide)-phenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 527)

Compound 527 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.16 (d, J=2.8Hz, 1H), 8.06-7.94 (m, 4H), 7.92 (s, 1H ), 7.29(d, J=8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 3.69-3.50(m, 3H), 2.43(d, J=11.9Hz, 2H), 2.21-2.10 (m, 1H), 1.69(d, J=12.5Hz, 2H), 1.54(t, J=11.3Hz, 2H), 1.38(s, 6H), 0.48(dd, J=7.2, 4.8Hz, 2H) , 0.37 (dd, J=3.6Hz, 2H).ESI-MS: m/z 578.2[M+Na] ⁺ .

Example 395

(((3R,4R)-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl) Benzoic acid (compound 528)

Compound 528 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47 (s, 1H), 8.16 (d, J=8.1Hz, 2H), 7.90 ( d, J=8.2Hz, 2H), 7.43(d, J=8.4Hz, 2H), 7.19(s, 1H), 7.04-6.96(m, 1H), 4.71-4.44(m, 1H), 4.07-3.97 (m, 2H), 3.92-3.77(m, 2H), 3.58-3.45(m, 1H), 2.57-2.34(m, 2H), 1.81-1.70(m, 1H), 1.57(s, 5H), 1.08 (s, 6H).ESI-MS: m/z 597.3[M+Na] ⁺ .

Example 396

trans-3-((4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzene Formic acid (compound 529)

Compound 529 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.29-8.16 (m, 2H), 8.03 (d, J=7.9Hz, 1H), 7.84-7.75 (m , 1H), 7.43(d, J=8.4Hz, 2H), 7.23-7.16(m, 1H), 7.06-6.97(m, 1H), 4.70-4.46(m, 1H), 4.08-3.98(m, 2H ), 3.92-3.76(m, 2H), 3.56-3.41(m, 1H), 2.75-2.55(m, 2H), 1.82-1.71(m, 1H), 1.66-1.49(m, 5H), 1.07(s , 6H).ESI-MS: m/z597.1[M+Na] ⁺ .

Example 397

3-(((3R,4R)-4-(5-(2,5-dichlorophenoxy)-2,2-dimethylpentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl Acyl)benzoic acid (compound 530)

Compound 530 was prepared according to the method of Example 281: ee>99%; ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52 (s, 1H), 8.31-8.18 (m, 2H), 8.02 (d, J =7.6Hz, 1H), 7.85-7.75(m, 1H), 7.43(d, J=8.3Hz, 2H), 7.24-7.16(m, 1H), 7.01(d, J=8.4Hz, 1H), 4.72 -4.45(m, 1H), 4.10-3.97(m, 2H), 3.93-3.75(m, 2H), 3.56-3.45(m, 1H), 2.75-2.56(m, 2H), 1.83-1.71(m, 1H), 1.66-1.46(m, 5H), 1.07(s, 6H). ESI-MS: m/z 597.2[M+Na] ⁺ .

Example 398

2-(4-fluorophenoxy)-2-methyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 531)

Compound 531 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.22-8.14 (m, 2H), 8.04-7.94 (m, 3H), 7.15-7.04 (m, 2H) , 6.93-6.83(m, 2H), 3.71-3.55(m, 3H), 3.31(s, 3H), 2.49-2.43(m, 2H), 1.79-1.65(m, 2H), 1.65-1.47(m, 2H), 1.36(s, 6H).ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 399

2-(4-fluorophenoxy)-N-(1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (Compound 532)

Compound 532 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.59-7.50 (m, 2H), 7.50-7.43 (m, 1H), 7.38-7.27 (m, 1H), 7.02 -6.91(m, 2H), 6.90-6.81(m, 2H), 6.63(d, J=8.1Hz, 1H), 3.85-3.71(m, 3H), 2.60-2.46(m, 2H), 2.07-1.95 (m, 2H), 1.64-1.48 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 461.2[M+Na] ⁺ .

Example 400

trans-5-(2,5-dichlorophenoxy)-N-(3-fluoro-1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-di Methylvaleramide (compound 533)

Compound 533 was prepared according to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.59-7.53 (m, 2H), 7.51-7.45 (m, 1H), 7.39-7.31 (m, 1H), 7.30 -7.26(m, 1H), 6.91-6.85(m, 2H), 5.69(d, J=7.5Hz, 1H), 4.60-4.32(m, 1H), 4.14-4.03(m, 1H), 4.01-3.92 (m, 3H), 3.77-3.67(m, 1H), 2.56-2.43(m, 2H), 2.19-2.07(m, 1H), 1.79-1.69(m, 4H), 1.29-1.23(m, 1H) , 1.21(s, 6H).ESI-MS: m/z 571.2[M+Na] ⁺ .

Example 401

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (compound 534)

Compound 534 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.08-9.01 (m, 1H), 8.52-8.43 (m, 1H), 8.27-8.20 (m, 1H), 8.07 -7.99(m, 1H), 7.68-7.57(m, 1H), 7.57-7.48(m, 1H), 7.01-6.89(m, 2H), 6.84-6.74(m, 2H), 5.55(d, J= 7.6Hz, 1H), 4.18-4.02(m, 2H), 3.94-3.74(m, 3H), 2.98-2.83(m, 2H), 2.03-1.88(m, 2H), 1.74-1.59(m, 4H) , 1.56-1.43(m, 2H), 1.17(s, 6H).ESI-MS: m/z 536.3[M+Na] ⁺ .

Example 402

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-(quinolin-8-ylsulfonyl)piperidin-4-yl)pentanamide (compound 535)

Compound 535 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ9.08-9.02 (m, 1H), 8.50-8.44 (m, 1H), 8.27-8.21 (m, 1H), 8.06 -8.00(m, 1H), 7.67-7.57(m, 1H), 7.56-7.49(m, 1H), 7.24-7.15(m, 2H), 6.82-6.72(m, 2H), 5.53(d, J= 7.4Hz, 1H), 4.16-4.04(m, 2H), 3.94-3.77(m, 3H), 2.98-2.84(m, 2H), 2.01-1.88(m, 2H), 1.75-1.61(m, 4H) , 1.55-1.45(m, 2H), 1.17(s, 6H).ESI-MS: m/z 552.2[M+Na] ⁺ .

Example 403

4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)(2-acetylamino)ethyl benzoate (Compound 536)

Compound 536 was prepared according to the method of Examples 14 and 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.25-8.15 (m, 2H), 7.90-7.79 (m, 2H), 7.01-6.91 (m, 2H) , 6.90-6.80(m, 2H), 6.63(d, J=7.3Hz, 1H), 5.88-5.74(m, 1H), 4.53-4.43(m, 2H), 3.83-3.72(m, 3H), 3.72 -3.63(m, 2H), 2.58-2.44(m, 2H), 2.01(s, 3H), 2.00-1.95(m, 2H), 1.58-1.50(m, 2H), 1.43(s, 6H).ESI -MS: m/z 572.3[M+Na] ⁺ .

Example 404

3-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 537)

Compound 537 was prepared according to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.32 (s, 1H), 8.28-8.22 (m, 1H), 8.21-8.16 (m, 1H), 8.01 -7.91(m, 2H), 7.83-7.74(m, 1H), 7.13-7.03(m, 2H), 6.92-6.82(m, 2H), 3.69-3.52(m, 3H), 2.47-2.37(m, 2H), 1.80-1.66(m, 2H), 1.65-1.48(m, 2H), 1.35(s, 6H). ESI-MS: m/z 463.1[MH] ^- .

Example 405

4-(((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 538)

Compound 538 was prepared according to the method of Examples 14 and 281: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48 (s, 1H), 8.29-8.21 (m, 1H), 8.19-8.12 (m, 2H) , 7.93-7.85(m, 2H), 7.13-7.03(m, 2H), 6.94-6.84(m, 2H), 4.75-4.48(m, 1H), 4.01-3.74(m, 2H), 3.55-3.42( m, 1H), 2.76-2.57(m, 2H), 1.86-1.71(m, 1H), 1.70-1.51(m, 1H), 1.40-1.32(m, 6H). ESI-MS: m/z 481.1[ MH] ^- .

Example 406

N-((3R,4R)-3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2-(4-fluorophenoxy)- 2-Methylpropionamide (Compound 539)

Compound 539 was prepared according to the method of Examples 14 and 281: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.30-8.23(m, 1H), 8.22-8.15(m, 2H), 8.08-8.01(m, 2H), 7.14-7.05(m, 2H), 6.96-6.85(m, 2H), 4.76-4.50(m, 1H), 4.03-3.78(m, 2H), 3.58-3.44(m, 1H), 3.32( s, 3H), 2.79-2.60 (m, 2H), 1.84-1.72 (m, 1H), 1.71-1.51 (m, 1H), 1.41-1.30 (m, 6H). ESI-MS: m/z 539.2[ M+Na] ⁺ .

Example 407

3-(((3R,4R)-3-fluoro-4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 540)

Compound 540 was prepared according to the method of Examples 14 and 281: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.56 (s, 1H), 8.31-8.16 (m, 3H), 8.04-7.98 (m, 1H) , 7.83-7.75(m, 1H), 7.15-7.02(m, 2H), 6.95-6.83(m, 2H), 4.76-4.48(m, 1H), 4.02-3.72(m, 2H), 3.58-3.42( m, 1H), 2.73-2.55(m, 2H), 1.86-1.71(m, 1H), 1.71-1.51(m, 1H), 1.43-1.30(m, 6H). ESI-MS: m/z 481.1[ MH] ^- .

Example 408

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)pentane Amide (compound 541)

Compound 541 was obtained by referring to the method of Example 101: ¹ H NMR (300MHz, CDCl ₃ -d) δ7.81 (d, J=8.2Hz, 2H), 7.56 (d, J=8.3Hz, 2H), 7.01- 6.90(m, 2H), 6.84-6.74(m, 2H), 5.51(d, J=7.7Hz, 1H), 3.87(t, J=5.2Hz, 2H), 3.84-3.50(m, 9H), 3.50 -3.23(m, 2H), 2.46(td, J=12.2, 1.7Hz 2H), 2.03-1.90(m, 2H), 1.75-1.60(m, 4H), 1.54-1.41(m, 2H), 1.17( s, 6H).ESI-MS: m/z 598.3[M+Na] ⁺ .

Example 409

4-((4-(2-Methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)ethyl Esters (compound 542)

Compound 542 was obtained by referring to the method of Examples 14 and 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19 (d, J=8.2Hz, 2H), 8.08 (t, J=5.2Hz, 1H), 8.02(d, J=7.9Hz, 1H), 7.85(d, J=8.3Hz, 2H), 7.81(d, J=8.7Hz, 2H), 6.97(d, J=8.7Hz, 2H), 4.31( t, J=5.5Hz, 2H), 3.69-3.60(m, 1H), 3.60-3.51(m, 2H), 3.48-3.39(m, 2H), 3.16(s, 3H), 2.52-2.48(m, 2H), 2.47-2.36(m, 2H), 1.83(s, 3H), 1.72-1.61(m, 2H), 1.48(s, 6H). ESI-MS: m/z 632.2[M+Na] ⁺ .

Example 410

trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 543)

Compound 543 was prepared according to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.25(d, J=8.5Hz, 1H), 8.15(s, 2H), 7.87(d, 2H), 7.80(d, 2H), 6.99(d, 2H), 4.68-4.39(m, 1H), 4.00-3.83(m, 1H), 3.83-3.70(m, 1H), 3.51- 3.41(m, 1H), 3.17(s, 3H), 2.73-2.55(m, 2H), 1.81-1.72(m, 1H), 1.60-1.52(m, 1H), 1.49(d, J=2.3Hz, 6H).ESI-MS: m/z 541.1[MH] ^- .

Example 411

trans-4-((3-fluoro-4-(2-methyl-2-(4-(methylsulfonyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-Acetamido) ethyl ester (compound 544)

Compound 544 was obtained by referring to the methods of Examples 14, 139 and 183: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.25(d, J=8.5Hz, 1H), 8.20(d, J=8.1Hz, 2H ), 8.08(t, 1H), 7.90(d, J=8.3Hz, 2H), 7.81(d, J=8.4Hz, 2H), 6.99(d, J=8.6Hz, 2H), 4.67-4.39(m , 1H), 4.31(t, J=5.5Hz, 2H), 4.02-3.86(m, 1H), 3.85-3.71(m, 1H), 3.53-3.38(m, 3H), 3.17(s, 3H), 2.72-2.56(m, 2H), 1.83(s, 3H), 1.80-1.68(m, 1H), 1.60-1.52(m, 1H), 1.48(d, J=2.4Hz, 6H).ESI-MS: m/z 650.2[M+Na] ⁺ .

Example 412

trans-N-(3-fluoro-1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)-2-methyl-2-(4-(methyl (sulfonyl)phenoxy)propionamide (compound 545)

Using compound 543 (Example 410) as a raw material, compound 545 was obtained by referring to the method of Example 101: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.26 (d, J=8.4Hz, 1H), 7.86-7.77 (m, 4H), 7.65(d, 2H), 6.99(d, 2H), 4.68-4.42(m, 1H), 4.02-3.86(m, 1H), 3.83-3.72(m, 1H), 3.71-3.30 (m, 9H), 3.16(s, 3H), 2.73-2.54(m, 2H), 1.85-1.69(m, 1H), 1.64-1.53(m, 1H), 1.49(d, J=2.6Hz, 6H ).ESI-MS: m/z 634.2[M+Na] ⁺ .

Example 413

2-Methyl-2-(4-(methylsulfonyl)phenoxy)-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl ) propionamide (compound 546)

Compound 546 was obtained by referring to the method of Example 101: ¹ H NMR (300MHz, CDCl ₃ -d) δ7.84 (d, J=8.6Hz, 2H), 7.80 (d, J=8.1Hz, 2H), 7.57( d, J=7.9Hz, 2H), 6.98(d, J=8.4Hz, 2H), 6.27(d, J=8.0Hz, 1H), 3.90-3.55(m, 9H), 3.51-3.30(m, 2H ), 3.05(s, 3H), 2.60-2.43(m, 2H), 2.01-1.87(m, 2H), 1.56(s, 6H), 1.52-1.44(m, 2H). ESI-MS: m/z 616.2[M+Na] ⁺ .

Example 414

4-(((3R,4R)-4-(2-(4-chlorophenoxy)-2-methylpropionamido)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 547)

Compound 547 was prepared according to the method of Examples 14 and 281: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.50(s, 1H), 8.25(d, J=8.5Hz, 1H), 8.16(d, J =8.0Hz, 2H), 7.87(d, J=8.1Hz, 2H), 7.29(d, J=8.6Hz, 2H), 6.85(d, J=8.5Hz, 2H), 4.73-4.42(m, 1H ), 4.06-3.84(m, 1H), 3.83-3.68(m, 1H), 3.56-3.39(m, 1H), 2.79-2.57(m, 2H), 1.88-1.68(m, 1H), 1.66-1.47 (m, 1H), 1.39 (d, J=4.6Hz, 6H).ESI-MS: m/z 497.1[MH] ^- .

Example 415

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)pentanamide (compound 548)

Compound 548 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.05 (d, J=8.3Hz, 2H), 7.94 (d, J=8.3Hz, 2H), 7.63( brs, 2H), 7.30(d, J=8.9Hz, 2H), 7.24(d, J=7.8Hz, 1H), 6.91(d, J=8.9Hz, 2H), 3.98-3.80(m, 2H), 3.70-3.59(m, 2H), 3.59-3.48(m, 1H), 2.47-2.34(m, 2H), 1.79-1.64(m, 2H), 1.62-1.39(m, 6H), 1.05(s, 6H ).ESI-MS: m/z580.2[M+Na] ⁺ .

Example 416

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide (compound 549)

Compound 549 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.89 (d, J=5.4Hz, 2H), 7.69-7.53 (m, 2H), 7.23 (d, J=8.9 Hz, 2H), 6.80(d, J=8.9Hz, 2H), 5.56(d, J=7.8Hz, 1H), 4.02-3.67(m, 5H), 2.51(td, J=12.2, 2.6Hz, 2H ), 1.99 (dd, J=13.3, 3.7Hz, 2H), 1.62-1.24 (m, 6H), 1.19 (s, 6H). ESI-MS: m/z 502.2[M+Na] ⁺ .

Example 417

2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propionamide (Compound 550)

Compound 550 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.89(d, J=5.6Hz, 2H), 7.61(d, J=5.7Hz, 2H), 7.25(d, J=8.8Hz, 2H), 6.83(d, J=8.8Hz, 2H), 6.56(d, J=7.8Hz, 1H), 3.90-3.70(m, 3H), 2.58(td, J=12.2, 2.6 Hz, 2H), 2.02(d, J=12.7Hz, 2H), 1.63-1.52(m, 2H), 1.47(s, 6H).ESI-MS: m/z 460.1[M+Na] ⁺ .

Example 418

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)pentanamide (compound 551)

Compound 551 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.88 (d, J=5.2Hz, 2H), 7.67-7.51 (m, 2H), 7.09-6.87 (m, 2H ), 6.79(dd, J=9.2, 4.2Hz, 2H), 5.64(d, J=7.8Hz, 1H), 4.02-3.62(m, 5H), 2.49(td, J=12.1, 2.6Hz, 2H) , 2.09-1.87(m, 2H), 1.64-1.22(m, 6H), 1.17(s, 6H).ESI-MS: m/z 486.2[M+Na] ⁺ .

Example 419

2-(4-fluorophenoxy)-2-methyl-N-(1-(pyridine-4-sulfonyl)piperidin-4-yl)propionamide (Compound 552)

Compound 552 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.87 (d, J=5.9Hz, 2H), 7.60 (d, J=6.0Hz, 2H), 7.05-6.93( m, 2H), 6.91-6.77(m, 2H), 6.69(d, J=8.1Hz, 1H), 3.96-3.64(m, 3H), 2.56(td, J=12.0, 2.6Hz, 2H), 2.02 (dd, J=13.2, 3.7Hz, 2H), 1.69-1.51 (m, 2H), 1.43 (s, 6H). ESI-MS: m/z 444.2[M+Na] ⁺ .

Example 420

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide (compound 553)

Compound 553 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.81-8.61 (m, 1H), 8.03-7.79 (m, 2H), 7.50 (dd, J=4.6Hz, 1H ), 7.20(d, J=8.9Hz, 2H), 6.78(d, J=8.9Hz, 2H), 5.74(d, J=7.9Hz, 1H), 4.15-3.69(m, 5H), 2.99-2.67 (m, 2H), 1.96 (dd, J=12.9, 3.7Hz, 2H), 1.77-1.45 (m, 6H), 1.18 (s, 6H). ESI-MS: m/z 502.2 [M+Na] ⁺ .

Example 421

2-(4-Chlorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propionamide (Compound 554)

Compound 554 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.78-8.66 (m, 1H), 7.95 (dd, J=3.9, 1.6Hz, 2H), 7.61-7.43 (m , 1H), 7.25(d, J=8.8Hz, 2H), 6.92-6.77(m, 2H), 6.60(d, J=8.1Hz, 1H), 4.02-3.80(m, 3H), 2.95(td, J=12.2, 2.6Hz, 2H), 2.13-1.86(m, 2H), 1.63-1.53(m, 2H), 1.50(s, 6H). ESI-MS: m/z 460.1[M+Na] ⁺ .

Example 422

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)pentanamide (compound 555)

Compound 555 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.82-8.62 (m, 1H), 8.05-7.83 (m, 2H), 7.51 (dd, J=4.5Hz, 1H ), 7.06-6.88(m, 2H), 6.88-6.69(m, 2H), 5.80(d, J=7.9Hz, 1H), 4.10-3.70(m, 5H), 2.85(td, J=12.3, 2.5 Hz, 2H), 1.97(dd, J=12.9, 3.7Hz, 2H), 1.65-1.25(m, 6H), 1.19(s, 6H).ESI-MS: m/z 486.2[M+Na] ⁺ .

Example 423

2-(4-fluorophenoxy)-2-methyl-N-(1-(pyridine-2-sulfonyl)piperidin-4-yl)propionamide (compound 556)

Compound 556 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.72 (d, J=4.7Hz, 1H), 8.03-7.86 (m, 2H), 7.62-7.46 (m, 1H ), 7.07-6.94(m, 2H), 6.89(dd, J=9.0, 4.5Hz, 2H), 6.71(d, J=8.1Hz, 1H), 4.16-3.70(m, 3H), 3.13-2.73( m, 2H), 2.19-1.89(m, 2H), 1.69-1.52(m, 2H), 1.47(s, 6H). ESI-MS: m/z 444.1[M+Na] ⁺ .

Example 424

5-((7-bromonaphthalene-2-yl)oxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidine-4 -yl) pentamide (compound 557)

Compound 557 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.16(d, J=8.2Hz, 2H), 8.02(d, J=2.0Hz, 1H), 7.96( d, J=8.2Hz, 2H), 7.79(dd, J=13.8, 8.8Hz, 2H), 7.43(dd, J=8.7, 2.0Hz, 1H), 7.33-7.20(m, 2H), 7.15(dd , J=8.9, 2.5Hz, 1H), 4.13-3.91(m, 2H), 3.67-3.45(m, 3H), 3.29(s, 3H), 2.45-2.31(m, 2H), 1.77-1.37(m , 8H), 1.05(s, 6H).ESI-MS: m/z 673.1[M+Na] ⁺ .

Example 425

2,2-Dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentyl Amide (compound 558)

Compound 558 was prepared according to the method of Example 119: ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.76 (d, J=4.1Hz, 1H), 8.33-8.13 (m, 3H), 8.01 (d, J =8.0Hz, 2H), 7.94(d, J=9.1Hz, 1H), 7.48(dd, J=8.3, 4.2Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.35(s, 1H ), 7.26(d, J=7.7Hz, 1H), 4.09(d, J=5.4Hz, 2H), 3.73-3.51(m, 3H), 3.34(s, 3H), 2.46(t, J=12.1Hz , 2H), 1.79-1.45(m, 8H), 1.11(s, 6H).ESI-MS: m/z 596.3[M+Na] ⁺ .

Example 426

5-((5,7-dibromoquinolin-8-yl)oxy)-2,2-dimethyl-N-(1-((4-(methylsulfonyl)phenyl)sulfonyl) Piperidin-4-yl)pentanamide (compound 559)

Compound 559 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.99 (dd, J=4.2, 1.6Hz, 1H), 8.48 (dd, J=8.6, 1.6Hz, 1H ), 8.36-8.07(m, 3H), 7.98(d, J=8.2Hz, 2H), 7.74(dd, J=8.6, 4.1Hz, 1H), 7.22(d, J=7.8Hz, 1H), 4.41 -4.21(m, 2H), 3.70-3.43(m, 3H), 3.30(s, 3H), 2.44-2.33(m, 2H), 1.80-1.54(m, 6H), 1.54-1.31(m, 2H) , 1.05(s, 6H).ESI-MS: m/z 754.0[M+Na] ⁺ .

Example 427

5-((7-bromonaphthalen-2-yl)oxy)-2,2-dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)pentanamide (compound 560)

Compound 560 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.50(s, 1H), 8.15(d, J=8.2Hz, 2H), 8.02(d, J=2.0 Hz, 1H), 7.94-7.72(m, 4H), 7.43(dd, J=8.7, 2.0Hz, 1H), 7.31-7.20(m, 2H), 7.15(dd, J=9.0, 2.4Hz, 1H) , 4.10-3.91(m, 2H), 3.65-3.45(m, 3H), 2.32(t, J=11.6Hz, 2H), 1.80-1.30(m, 8H), 1.05(s, 6H).ESI-MS : m/z 615.1[MH] ^- .

Example 428

2,2-Dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidin-4-yl)-5-(quinolin-6-yloxy)pentanamide (compound 561)

Compound 561 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49 (s, 1H), 8.72 (dd, J=4.1, 1.7Hz, 1H), 8.18 (dd, J =19.2, 8.2Hz, 3H), 7.97-7.77(m, 3H), 7.45(dd, J=8.4, 4.2Hz, 1H), 7.39-7.19(m, 3H), 4.09-3.97(m, 2H), 3.67-3.44(m, 3H), 2.33(t, J=11.7Hz, 2H), 1.72-1.37(m, 8H), 1.06(s, 6H). ESI-MS: m/z 540.3[M+H] ⁺ .

Example 429

2-(4-fluorophenoxy)-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-2-methylpropionamide (compound 562)

Compound 562 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ7.69 (d, J=8.8Hz, 2H), 7.07-6.89 (m, 4H), 6.89-6.78 (m, 2H ), 6.62(d, J=7.9Hz, 1H), 3.88(s, 3H), 3.81-3.63(m, 3H), 2.54-2.32(m, 2H), 2.07-1.87(m, 2H), 1.68- 1.56(m, 2H), 1.43(s, 6H).ESI-MS: m/z 473.2[M+Na] ⁺ .

Example 430

2-(4-fluorophenoxy)-2-methyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 563)

Compound 563 was prepared according to the method of Examples 14 and 101: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82 (d, J=7.8Hz, 2H), 7.57 (d, J=7.8Hz, 2H), 7.03- 6.91(m, 2H), 6.91-6.80(m, 2H), 6.64(d, J=7.9Hz, 1H), 4.00-3.54(m, 9H), 3.51-3.23(m, 2H), 2.59-2.40( m, 2H), 2.09-1.90(m, 2H), 1.58-1.49(m, 2H), 1.43(s, 6H). ESI-MS: m/z 556.2[M+Na] ⁺ .

Example 431

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)sulfonyl Acyl)piperidin-4-yl)propionamide (compound 564)

Compound 564 was prepared according to the method of Examples 14 and 101: ¹ H NMR (300MHz, CDCl ₃ ) δ7.80(d, J=7.7Hz, 2H), 7.61(d, J=7.7Hz, 2H), 7.22( d, J=8.6Hz, 2H), 6.81(d, J=8.6Hz, 2H), 6.54(d, J=8.0Hz, 1H), 4.08-3.94(m, 1H), 3.89-3.65(m, 4H ), 3.65-3.38(m, 2H), 2.93-2.63(m, 4H), 2.59-2.39(m, 4H), 2.37-2.07(m, 3H), 2.06-1.90(m, 3H), 1.65-1.47 (m, 2H), 1.44 (s, 6H). ESI-MS: m/z 577.3[M+H] ⁺ .

Example 432

trans-5-(2,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-fluoropiperidine-4- base)-2,2-dimethylpentanamide (compound 565)

Compound 565 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.61-7.50 (m, 2H), 7.11-6.95 (m, 1H), 6.88 (d, J=8.2Hz, 1H ), 6.73-6.61(m, 1H), 6.59-6.48(m, 1H), 5.86(d, J=7.5Hz, 1H), 4.71(t, J=8.8Hz, 2H), 4.63-4.32(m, 1H), 4.12-4.02(m, 1H), 4.00-3.89(m, 1H), 3.85(t, J=5.3Hz, 2H), 3.76-3.64(m, 1H), 3.29(t, J=8.7Hz , 2H), 2.45-2.25 (m, 2H), 2.18-2.05 (m, 1H), 1.79-1.61 (m, 5H), 1.19 (s, 6H). ESI-MS: m/z 563.3 [M+Na ] ⁺ .

Example 433

trans-5-(3,4-difluorophenoxy)-N-(1-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-fluoropiperidine-4- base)-2,2-dimethylpentanamide (compound 566)

Compound 566 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, CDCl ₃ ) δ7.64-7.49 (m, 2H), 6.94-6.79 (m, 3H), 6.79-6.71 (m, 1H), 5.78 (d, J=7.5Hz, 1H), 4.70(t, J=8.8Hz, 2H), 4.62-4.30(m, 1H), 4.10-4.00(m, 1H), 4.00-3.83(m, 3H), 3.76-3.61(m, 1H), 3.29(t, J=8.8Hz, 2H), 2.49-2.31(m, 2H), 2.18-2.05(m, 1H), 1.80-1.60(m, 5H), 1.19( s, 6H).ESI-MS: m/z563.3[M+Na] ⁺ .

Example 434

2-(4-chlorophenoxy)-2-methyl-N-(1-((4-(4-methylpiperidine-1-carbonyl)phenyl)sulfonyl)piperidin-4-yl) Propionamide (compound 567)

Compound 567 was prepared according to the method of Examples 14 and 101: ¹ H NMR (300MHz, CDCl ₃ ) δ7.80(d, J=8.2Hz, 2H), 7.56(d, J=8.2Hz, 2H), 7.23( d, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 6.52(d, J=7.9Hz, 1H), 3.93-3.64(m, 5H), 3.55-3.26(m, 2H ), 2.64-2.44(m, 4H), 2.43-2.25(m, 5H), 2.06-1.92(m, 2H), 1.61-1.49(m, 2H), 1.46(s, 6H).ESI-MS: m /z 563.3[M+H] ⁺ .

Example 435

5-(3,4-difluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidine-4- base) pentamide (compound 568)

Compound 568 was prepared according to the method of Examples 119 and 101: ¹ H NMR (300MHz, CDCl ₃ ) δ7.82 (d, J=8.2Hz, 2H), 7.57 (d, J=8.2Hz, 2H), 7.11- 6.95(m, 1H), 6.75-6.61(m, 1H), 6.61-6.48(m, 1H), 5.52(d, J=7.7Hz, 1H), 4.00-3.54(m, 11H), 3.53-3.23( m, 2H), 2.46(t, J=11.1Hz, 2H), 2.10-1.87(m, 2H), 1.78-1.63(m, 4H), 1.55-1.40(m, 2H), 1.17(s, 6H) .ESI-MS: m/z616.3[M+Na] ⁺ .

Example 436

5-(2,4-difluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholine-4-carbonyl)phenyl)sulfonyl)piperidine-4- base) pentamide (compound 569)

Compound 569 was prepared according to the method of Examples 119 and 101: ¹ H NMR (300MHz, CDCl ₃ ) δ7.81 (d, J=8.1Hz, 2H), 7.56 (d, J=8.1Hz, 2H), 6.98- 6.67(m, 3H), 5.55(d, J=7.6Hz, 1H), 3.93(t, J=5.4Hz, 2H), 3.88-3.54(m, 9H), 3.51-3.23(m, 2H), 2.46 (t, J=11.5Hz, 2H), 2.06-1.88(m, 2H), 1.77-1.61(m, 4H), 1.55-1.42(m, 2H), 1.17(s, 6H).ESI-MS: m /z 616.3[M+Na] ⁺ .

Example 437

N-(1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-(4-chlorophenoxy)-2-methylpropanamide (compound 570)

Compound 570 was prepared according to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.13-7.99 (m, 1H), 7.30-7.23 (m, 2H), 7.23-7.19 (m, 1H), 7.17 -7.02(m, 1H), 6.90-6.76(m, 2H), 6.55(d, J=7.6Hz, 1H), 4.03-3.87(m, 1H), 3.87-3.70(m, 2H), 3.04-2.82 (m, 2H), 2.11-1.87(m, 2H), 1.56-1.51(m, 2H), 1.47(s, 6H). ESI-MS: m/z 511.1[M+Na] ⁺ .

Example 438

N-(1-((2,6-difluorophenylsulfonyl)piperidin-4-yl)-5-(4-fluorophenoxy)-2,2-dimethylpentanamide (compound 571)

Compound 571 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.60-7.43 (m, 1H), 7.14-6.89 (m, 4H), 6.85-6.73 (m, 2H), 5.55 (d, J=7.9Hz, 1H), 4.02-3.72(m, 5H), 2.84-2.65(m, 2H), 2.08-1.90(m, 2H), 1.74-1.62(m, 4H), 1.56-1.44 (m, 2H), 1.18(s, 6H).ESI-MS: m/z 521.2[M+Na] ⁺ .

Example 439

2-(4-chlorophenoxy)-2-methyl-N-(1-((4-(N-methylsulfamoyl)phenyl)sulfonyl)piperidin-4-yl)propionamide ( Compound 572)

Compound 572 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.03(d, J=8.4Hz, 2H), 7.90(d, J=8.4Hz, 2H), 7.22(d, J=8.8Hz, 2H), 6.81(d, J=8.8Hz, 2H), 6.52(d, J=7.3Hz, 1H), 4.50-4.39(m, 1H), 3.86-3.69(m, 3H), 2.73(d, J=5.3Hz, 3H), 2.62-2.46(m, 2H), 2.06-1.94(m, 2H), 1.58-1.54(m, 2H), 1.46(s, 6H).ESI-MS: m/z 552.1[M+Na] ⁺ .

Example 440

4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (Compound 573)

Compound 573 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.41(s, 1H), 8.15(d, J=8.3Hz, 2H), 7.99(d, J=7.9 Hz, 1H), 7.83(d, J=8.3Hz, 2H), 7.38-7.25(m, 1H), 6.97-6.87(m, 1H), 6.72-6.63(m, 1H), 3.65-3.54(m, 3H), 2.48-2.38(m, 2H), 1.75-1.65(m, 2H), 1.61-1.47(m, 2H), 1.39(s, 6H). ESI-MS: m/z 481.1[MH] ^- .

Example 441

4-((4-(2-(3,4-difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid-2-acetamidoethyl ester (compound 574)

Compound 574 was prepared according to the method of Examples 14 and 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.1Hz, 2H), 7.83 (d, J=8.1Hz, 2H), 7.12- 6.99(m, 1H), 6.78-6.67(m, 1H), 6.67-6.57(m, 1H), 6.57-6.44(m, 1H), 5.85(s, 1H), 4.47(t, J=4.7Hz, 2H), 3.84-3.63(m, 5H), 2.57-2.43(m, 2H), 2.01(s, 3H), 2.00-1.93(m, 2H), 1.61-1.53(m, 2H), 1.45(s, 6H).ESI-MS: m/z 590.2[M+Na] ⁺ .

Example 442

4-((4-(2-(2,4-difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 575)

Compound 575 was prepared according to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.42(s, 1H), 8.14(d, J=8.3Hz, 2H), 8.00(d, J=7.9 Hz, 1H), 7.83(d, J=8.3Hz, 2H), 7.30-7.21(m, 1H), 7.06-6.92(m, 2H), 3.68-3.51(m, 3H), 2.46-2.35(m, 2H), 1.79-1.67(m, 2H), 1.65-1.48(m, 2H), 1.33(s, 6H). ESI-MS: m/z 481.2[MH] ^- .

Example 443

4-((4-(2-(2,4-difluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzoic acid-2-acetamidoethyl ester (compound 576)

Compound 576 was obtained by referring to the method of Examples 14 and 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.23 (d, J=8.0Hz, 2H), 7.87 (d, J=8.0Hz, 2H), 7.08- 6.77(m, 4H), 5.89(br s, 1H), 4.50(t, J=4.7Hz, 2H), 3.87-3.63(m, 5H), 2.68-2.52(m, 2H), 2.15-2.05(m , 2H), 2.04(s, 3H), 1.72-1.57(m, 2H), 1.45(s, 6H). ESI-MS: m/z 590.2[M+Na] ⁺ .

Example 444

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)pentanamide (compound 577)

Compound 577 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ7.96-7.87 (m, 4H), 7.22 (d, J=9.0Hz, 2H), 6.78 (d, J=8.9 Hz, 2H), 5.51-5.43(m, 1H), 3.88(t, J=5.6Hz, 2H), 3.85-3.77(m, 3H), 3.78-3.72(m, 4H), 3.11-2.99(m, 4H), 2.58-2.45(m, 2H), 2.06-1.92(m, 2H), 1.72-1.61(m, 4H), 1.53-1.44(m, 2H), 1.17(s, 6H).ESI-MS: m/z 650.2[M+Na] ⁺ .

Example 445

5-(4-fluorophenoxy)-2,2-dimethyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)pentanamide (compound 578)

Compound 578 was prepared according to the method of Example 119: ¹ H NMR (300MHz, CDCl ₃ ) δ8.06-7.84 (m, 4H), 7.02-6.90 (m, 2H), 6.87-6.74 (m, 2H), 5.53 -5.47(m, 1H), 3.98-3.59(m, 9H), 3.12-2.96(m, 4H), 2.56-2.45(m, 2H), 2.04-1.95(m, 2H), 1.74-1.59(m, 4H), 1.54-1.46(m, 2H), 1.18(s, 6H). ESI-MS: m/z 634.2[M+Na] ⁺ .

Example 446

2-(4-fluorophenoxy)-2-methyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 579)

Compound 579 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.02-7.86 (m, 4H), 7.02-6.92 (m, 2H), 6.90-6.81 (m, 2H), 6.69 -6.62(m, 1H), 3.86-3.79(m, 2H), 3.80-3.74(m, 4H), 3.11-2.97(m, 4H), 2.64-2.46(m, 3H), 2.05-1.98(m, 2H), 1.56-1.48(m, 2H), 1.43(s, 6H). ESI-MS: m/z 570.2[M+H] ⁺ .

Example 447

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-(morpholino)phenyl)sulfonyl)piperidin-4-yl)propionamide (compound 580)

Compound 580 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, CDCl ₃ ) δ8.02-7.86 (m, 4H), 7.30 (d, J=8.4Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69(m, 1H), 3.86-3.79(m, 2H), 3.80-3.74(m, 4H), 3.11-2.97(m, 4H), 2.64-2.46(m, 3H), 2.05- 1.98(m, 2H), 1.56-1.48(m, 2H), 1.43(s, 6H). ESI-MS: m/z 587.2[M+H] ⁺ .

Example 448

cis-2-(4-chlorophenoxy)-N-(3-fluoro-1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methylpropanamide (compound 581)

Compound 581 was prepared according to the method of Examples 14 and 292: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85-7.77 (m, 2H), 7.25-7.17 (m, 3H), 6.91 (d, J=8.2Hz , 1H), 6.86-6.78(m, 2H), 4.82-4.56(m, 1H), 4.24-4.09(m, 1H), 4.08-3.78(m, 2H), 2.87-2.65(m, 1H), 2.66 -2.53(m, 2H), 1.93-1.70(m, 1H), 1.46(s, 6H). ESI-MS: m/z 573.2[M+H] ⁺ .

Example 449

cis-4-((-4-(2-(4-chlorophenoxy)-2-methylpropionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (Compound 582)

Compound 582 was obtained by referring to the method of Examples 14 and 292: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.15 (d, J=8.2Hz, 2H), 7.99 (d, J=7.6Hz, 1H), 7.86(d, J=8.2Hz, 2H), 7.30(d, J=8.7Hz, 2H), 6.88(d, J=8.7Hz, 2H), 4.88-4.58(m, 1H), 4.03-3.77(m , 2H), 3.77-3.65(m, 1H), 2.92-2.69(m, 1H), 2.67-2.53(m, 1H), 1.99-1.74(m, 1H), 1.65-1.48(m, 1H), 1.42 (s, 3H), 1.40 (s, 3H). ESI-MS: m/z 499.2 [M+H] ⁺ .

Example 450

5-((5,7-dibromoquinolin-8-yl)oxy)-2,2-dimethyl-N-(1-((4-carboxyphenyl)sulfonyl)piperidine-4- base) pentamide (compound 583)

Compound 583 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.56 (s, 1H), 8.99 (dd, J=4.1, 1.7Hz, 1H), 8.48 (dd, J =8.6, 1.6Hz, 1H), 8.32-8.06(m, 3H), 7.99-7.67(m, 3H), 7.23(d, J=7.8Hz, 1H), 4.34-4.17(m, 2H), 3.66- 3.44(m, 3H), 2.35(t, J=11.8Hz, 2H), 1.77-1.31(m, 8H), 1.04(s, 6H).ESI-MS: m/z 696.0[MH] ^- .

Example 451

trans-((-4-(3-(2,5-dimethylphenoxy)propionylamino)-3-fluoropiperidin-1-yl)sulfonyl)benzoic acid (compound 584)

Compound 584 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.52(s, 1H), 8.18(d, J=8.1Hz, 2H), 8.10(d, J=7.7 Hz, 1H), 7.91(d, J=8.1Hz, 2H), 6.96(d, J=7.4Hz, 1H), 6.72(s, 1H), 6.62(d, J=7.3Hz, 1H), 4.66- 4.30(m, 1H), 4.23-4.01(m, 2H), 3.92(m, 1H), 3.68-3.47(m, 1H), 3.43-3.22(m, 1H), 3.10-2.98(m, 1H), 2.98-2.80(m, 1H), 2.52(m, 2H), 2.24(s, 3H), 2.00(s, 3H), 1.89(m, 1H), 1.60-1.38(m, 1H).ESI-MS: m/z 477.3[MH] ^- .

Example 452

2-Acetamidoethyl 4-((4-(2-(4-fluorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzenesulfonate (Compound 585)

Compound 585 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.25-8.16 (m, 1H), 8.07-7.97 (m, 3H), 7.94 (d, J=8.3Hz , 2H), 7.15-7.04(m, 2H), 6.92-6.84(m, 2H), 3.94(t, J=5.5Hz, 2H), 3.57(d, 1H), 3.14-3.06(m, 4H), 3.03(d, J=7.3Hz, 2H), 1.93(s, 3H), 1.79-1.66(m, 2H), 1.63-1.47(m, 2H), 1.36(s, 6H).ESI-MS: m/ z 608.2[M+Na] ⁺ .

Example 453

2-Acetamidoethyl 4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzenesulfonate (compound 586)

Compound 586 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.12(t, J=5.7Hz, 1H), 7.99(d, J=8.1Hz, 2H), 7.91( d, J=8.2Hz, 2H), 7.18(d, J=7.8Hz, 1H), 7.12-6.98(m, 2H), 6.93-6.79(m, 2H), 3.90(t, J=5.5Hz, 2H ), 3.86-3.77(m, 2H), 3.67-3.47(m, 3H), 3.13-2.97(m, 2H), 2.39(d, J=12.1Hz, 2H), 1.89(s, 3H), 1.68( d, J=12.2Hz, 2H), 1.56-1.46(m, 4H), 1.46-1.38(m, 2H), 1.02(s, 6H).ESI-MS: m/z 626.2[MH] ^- .

Example 454

2-Acetamidoethyl 4-((4-(2-(4-chlorophenoxy)-2-methylpropionylamino)piperidin-1-yl)sulfonyl)benzenesulfonate (compound 587)

Compound 587 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.26-8.14 (m, 1H), 8.11-7.97 (m, 3H), 7.93 (d, J=8.2Hz , 2H), 7.31(d, J=8.4Hz, 2H), 6.84(d, J=8.4Hz, 2H), 3.94(t, J=5.5Hz, 2H), 3.56(d, J=12.0Hz, 1H ), 3.17-3.05(m, 4H), 3.06-2.97(m, 2H), 1.93(s, 3H), 1.77-1.64(m, 2H), 1.61-1.46(m, 2H), 1.39(s, 6H ).ESI-MS: m/z 624.2[M+Na] ⁺ .

Example 455

2-Acetamidoethyl 4-((4-(5-(4-chlorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzenesulfonate (compound 588)

Compound 588 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.26-8.16 (m, 1H), 8.04 (d, J=8.2Hz, 2H), 7.95 (d, J =8.2Hz, 2H), 7.31(d, J=2.5Hz, 1H), 7.29(d, J=2.2Hz, 1H), 7.25(d, J=7.8Hz, 1H), 6.94(d, J=4.0 Hz, 1H), 6.90(d, J=1.8Hz, 1H), 3.94(t, J=5.5Hz, 2H), 3.92-3.82(m, 2H), 3.68-3.51(m, 3H), 3.13-3.00 (m, 4H), 1.93(s, 3H), 1.78-1.64(m, 2H), 1.60-1.50(m, 4H), 1.50-1.42(m, 2H), 1.05(s, 6H).ESI-MS : m/z 642.2[MH] ^- .

Example 456

4-((4-(2-methyl-2-(3-(trifluoromethyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 489)

Compound 589 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.48(s, 1H), 8.14(d, J=8.2Hz, 2H), 8.06(d, J=7.7 Hz, 1H), 7.82(d, J=8.2Hz, 2H), 7.49(dd, 1H), 7.34(d, J=7.6Hz, 1H), 7.17-7.05(m, 2H), 3.72-3.57(m , 1H), 3.57-3.48(m, 2H), 2.47-2.35(m, 2H), 1.72-1.61(m, 2H), 1.59-1.49(m, 2H), 1.44(s, 6H).ESI-MS : m/z 513.1[MH] ^- .

Example 457

4-((4-(2-Methyl-2-(3-(trifluoromethyl)phenoxy)propionylamino)piperidin-1-yl)sulfonyl)benzoic acid (2-acetylamino)ethyl Esters (Compound 590)

Compound 590 was obtained by referring to the method of Examples 14 and 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.0Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.47- 7.30(m, 2H), 7.12(s, 1H), 7.05(d, J=7.6Hz, 1H), 6.46(d, J=7.4Hz, 1H), 5.90-5.76(m, 1H), 4.47(t , J=4.8Hz, 2H), 3.91-3.59(m, 5H), 2.59-2.37(m, 2H), 2.12-1.87(m, 2H), 2.10(s, 3H), 1.65-1.55(m, 2H ), 1.50(s, 6H).ESI-MS: m/z622.2[M+Na] ⁺ .

Example 458

2-(4-Chlorophenoxy)-2-methyl-N-(1-((4-sulfamoylphenyl)sulfonyl)piperidin-4-yl)propionamide (Compound 591)

Compound 591 was obtained by referring to the method of Example 14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.05 (d, J=8.3Hz, 2H), 7.99 (d, J=8.0Hz, 1H), 7.91( d, J=8.3Hz, 2H), 7.62(s, 2H), 7.31(d, J=8.8Hz, 2H), 6.84(d, J=8.8Hz, 2H), 3.77-3.44(m, 3H), 2.48-2.36(m, 2H), 1.77-1.62(m, 2H), 1.62-1.45(m, 2H), 1.39(s, 6H). ESI-MS: m/z 538.1[M+Na] ⁺ .

Example 459

5-((1-bromonaphthalen-2-yl)oxy)-N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2,2-dimethylpentanamide (compound 592)

Compound 592 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.18 (d, J=8.4Hz, 2H), 8.08 (d, J=8.5Hz, 1H), 7.99- 7.88(m, 4H), 7.67-7.58(m, 1H), 7.51-7.41(m, 2H), 7.21(d, J=7.9Hz, 1H), 4.19-4.11(m, 2H), 3.66-3.54( m, 3H), 3.31(s, 3H), 2.45-2.37(m, 2H), 1.71-1.60(m, 6H), 1.52-1.42(m, 2H), 1.07(s, 6H).ESI-MS: m/z 652.2[M+H] ⁺ .

Example 460

N-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-5-(isoquinolin-5-yloxy)-2,2-dimethylpentanamide (compound 593 )

Compound 593 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.25 (s, 1H), 8.49 (d, J=5.8Hz, 1H), 7.97-7.92 (m, 1H ), 7.83-7.74(m, 2H), 7.66-7.61(m, 1H), 7.60-7.52(m, 1H), 7.52-7.41(m, 2H), 7.29-7.21(m, 1H), 7.20-7.12 (m, 1H), 4.16-4.05(m, 2H), 3.65-3.47(m, 3H), 3.27-3.22(m, 2H), 2.39-2.23(m, 2H), 1.79-1.61(m, 4H) , 1.55-1.43(m, 2H), 1.23(s, 3H), 1.09(s, 3H).ESI-MS: m/z 536.2[M+Na] ⁺ .

Example 461

4-((4-(5-(isoquinolin-5-yloxy)-2,2-dimethylpentanylamino)piperidin-1-yl)sulfonyl)benzoic acid (compound 594)

Compound 594 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.26(s, 1H), 8.50(d, J=5.8Hz, 1H), 8.10(d, J=8.0 Hz, 2H), 7.95(d, J=5.9Hz, 1H), 7.74-7.52(m, 4H), 7.34-7.24(m, 2H), 7.18(d, J=7.9Hz, 1H), 4.16-4.07 (m, 2H), 3.66-3.51(m, 3H), 2.33-2.24(m, 2H), 1.80-1.66(m, 6H), 1.57-1.46(m, 2H), 1.24(s, 3H), 1.10 (s, 3H).ESI-MS: m/z 540.2[M+H] ⁺ .

Example 462

4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoic acid 2-acetylamino Ethyl ester (compound 595)

Compound 595 was prepared according to the method of Examples 119 and 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.20 (d, J=8.3Hz, 2H), 7.84 (d, J=3.5Hz, 2H), 7.82( d, J=3.0Hz, 2H), 6.97(d, J=8.7Hz, 2H), 5.90(brs, 1H), 5.55(d, J=7.8Hz, 1H), 4.46(t, J=5.2Hz, 2H), 3.99(t, J=5.6Hz, 2H), 3.88-3.77(m, 2H), 3.76-3.62(m, 3H), 3.03(s, 3H), 2.48-2.34(m, 2H), 2.01 (s, 3H), 1.99-1.90 (m, 2H), 1.79-1.64 (m, 4H), 1.56-1.45 (m, 2H), 1.18 (s, 6H). ESI-MS: m/z 674.3 [M +Na] ⁺ .

Example 463

Sodium 4-((4-(2,2-dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)piperidin-1-yl)sulfonyl)benzoate (compound 596)

Compound 239 (Example 155) was made into sodium salt to obtain compound 596: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.03(d, J=8.1Hz, 2H), 7.82(d, J=8.7Hz , 2H), 7.61(d, J=8.1Hz, 2H), 7.24(d, J=7.5Hz, 1H), 7.11(d, J=8.7Hz, 2H), 4.07-3.94(m, 2H), 3.64 -3.43(m, 3H), 3.15(s, 3H), 2.39-2.23(m, 2H), 1.74-1.63(m, 2H), 1.59-1.54(m, 3H), 1.54-1.45(m, 2H) , 1.05(s, 6H).ESI-MS: m/z611.2[M+Na] ⁺ .

Example 464

2-Acetamidoethyl 4-((4-(5-(3,4-difluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoate (Compound 597)

Compound 597 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.1Hz, 2H), 7.83 (d, J=8.1Hz, 2H), 7.13-6.95( m, 1H), 6.74-6.60(m, 1H), 6.57-6.50(m, 1H), 5.92-5.77(m, 1H), 5.51(d, J=7.8Hz, 1H), 4.62-4.35(m, 2H), 3.98-3.73(m, 4H), 3.73-3.57(m, 3H), 2.64-2.27(m, 2H), 2.17-1.90(m, 4H), 1.73-1.38(m, 7H), 1.17( s, 6H).ESI-MS: m/z 632.3[M+Na] ⁺ .

Example 465

2-Acetamidoethyl 4-((4-(5-(4-fluorophenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoate (Compound 598 )

Compound 598 was obtained by referring to the method of Example 183: ¹ H NMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.3Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.03-6.89( m, 2H), 6.86-6.72(m, 2H), 5.95-5.77(m, 1H), 5.53(d, J=7.8Hz, 1H), 4.46(t, J=5.3Hz, 2H), 3.95-3.60 (m, 7H), 2.50-2.34 (m, 2H), 2.11-1.91 (m, 5H), 1.59-1.27 (m, 6H), 1.17 (s, 6H). ESI-MS: m/z 592.2 [M +H] ⁺ .

Example 466

5-(4-chlorophenoxy)-2,2-dimethyl-N-(1-((4-(N-methylsulfamoyl)phenyl)sulfonyl)piperidin-4-yl) Valeramide (compound 599)

Compound 599 was obtained by referring to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.01 (d, J=8.4Hz, 2H), 7.96 (d, J=8.4Hz, 2H), 7.73( s, 1H), 7.30(d, J=8.8Hz, 2H), 7.22(d, J=7.6Hz, 1H), 6.91(d, J=8.8Hz, 2H), 3.93-3.84(m, 2H), 3.66-3.51(m, 3H), 2.47(s, 3H), 2.45-2.37(m, 2H), 1.70(d, J=10.7Hz, 2H), 1.56-1.51(m, 4H), 1.51-1.41( m, 2H), 1.05(s, 6H). ESI-MS: m/z 594.1[M+Na] ⁺ .

Example 467

trans-4-((4-(2,2-Dimethyl-5-(4-(methylsulfonyl)phenoxy)pentanoylamino)-3-fluoropiperidin-1-yl)sulfonyl ) Benzoic acid (compound 600)

Compound 600 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.49(s, 1H), 8.15(d, J=8.4Hz, 2H), 7.89(d, J=8.4 Hz, 2H), 7.81(d, J=8.8Hz, 2H), 7.45(d, J=8.0Hz, 1H), 7.10(d, J=8.9Hz, 2H), 4.69-4.42(m, 1H), 4.00(t, J=5.2Hz, 2H), 3.93-3.75(m, 2H), 3.58-3.45(m, 1H), 3.14(s, 3H), 2.71-2.54(m, 2H), 1.81-1.68( m, 1H), 1.65-1.54(m, 4H), 1.54-1.46(m, 1H), 1.07(s, 6H). ESI-MS: m/z 607.2[M+Na] ⁺ .

Example 468

Trans-N-(3-fluoro-1-((4-(methylsulfonyl)phenyl)sulfonyl)piperidin-4-yl)-2,2-dimethyl-5-(4-( Methylsulfonyl)phenoxy)pentanamide (compound 601)

Compound 601 was obtained by referring to the method of Example 139: ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.19(d, J=8.3Hz, 2H), 8.05(d, J=8.3Hz, 2H), 7.82( d, J=8.6Hz, 2H), 7.45(d, J=8.1Hz, 1H), 7.11(d, J=8.7Hz, 2H), 4.71-4.44(m, 1H), 4.01(t, J=5.2 Hz, 2H), 3.93-3.82(m, 2H), 3.60-3.48(m, 1H), 3.32(s, 3H), 3.15(s, 3H), 2.77-2.60(m, 2H), 1.82-1.70( m, 1H), 1.65-1.56(m, 4H), 1.56-1.47(m, 1H), 1.08(s, 6H). ESI-MS: m/z 641.2[M+Na] ⁺ .

Example 469

4-((4-(2,2-Dimethyl-5-(3-(trifluoromethyl)phenoxy)pentanamido)piperidin-1-yl)sulfonyl)benzoic acid (compound 602)

Compound 602 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.47(s, 1H), 8.15(d, J=8.3Hz, 2H), 7.84(d, J=8.2 Hz, 2H), 7.25(m, 1H), 7.21(d, J=7.8Hz, 1H), 7.18(m, 1H), 7.13(m, 1H), 6.90(m, 1H), 3.96-3.83(m , 2H), 3.70-3.50(m, 3H), 2.47-2.34(m, 2H), 1.77-1.61(m, 2H), 1.60-1.39(m, 6H), 1.08(s, 6H).ESI-MS : m/z 555.2[MH] ^- .

Example 470

4-((4-(5-(4-fluoro-3-(trifluoromethyl)phenoxy)-2,2-dimethylpentanamido)piperidin-1-yl)sulfonyl)benzoic acid (Compound 603)

Compound 603 was prepared according to the method of Example 119: ¹ H NMR (300MHz, DMSO-d ₆ ) δ13.41(s, 1H), 8.14(d, J=8.3Hz, 2H), 7.85(d, J=8.2 Hz, 2H), 7.30(d, J=7.8Hz, 1H), 7.25-6.98(m, 3H), 3.95-3.82(m, 2H), 3.69-3.51(m, 3H), 2.46-2.35(m, 2H), 1.76-1.62(m, 2H), 1.60-1.39(m, 6H), 1.08(s, 6H). ESI-MS: m/z 573.2[MH] ^- .

Example 471

Test of compound's ability to promote phosphorylation and activation of AMPK (Thr172) in C2C12 cells

The C2C12 cells were plated in a 12-well plate, and the medium containing 10% bovine serum was used to promote cell growth to a density of 70-80%, and the medium containing 2.0% horse serum was replaced every day to induce cell differentiation. After complete differentiation, starve for 6-8 hours. The test compound (10 μM) was added to the 12-well plate, the 0.1% DMSO group was set as the negative control, and the AICAR (100 μM) group was set as the positive control. After 2 hours of administration, the medium was discarded, washed twice with pre-cooled PBS, 100 μl of lysate was added to each well, and the lysate was collected. Western Blot technology was used to detect the phosphorylation of AMPK, and then grayscale scanning was performed. The ratio of pAMPK/AMPK in the negative control group was defined as 1, and the ratio of pAMPK/AMPK in the test compound was the relative ratio of the negative control group. The ratio of pAMPK/AMPK reflects the ability of the compound to promote the phosphorylation and activation of AMPK. The experimental results are shown in Table 2 and Figure 1.

Table 2. Compounds promote the activity of AMPK phosphorylation in C2C12 cells

Figure 1 is a graph showing the effect of compounds on AMPK phosphorylation in C2C12 cells: (a)/(c) are the expressions of pAMPK and AMPK after stimulating C2C12 cells with different concentrations of compound 111 for 2 hours; (b)/(d) are different concentrations of compound 119 The expression of pAMPK and AMPK after stimulating C2C12 cells for 2 hours. Experimental results show that the compounds of the present invention have significant AMPK agonistic activity (Table 2). For example, compounds 111 and 119 respectively dose-dependently promoted the phosphorylation of AMPK in C2C12 cells (Fig. 1). The above results indicate that the compounds of the present invention are clear AMPK agonists.

Example 472

Effects of Compounds on AMPK Phosphorylation in AdipoR1 Knockout Cells

In order to confirm whether the compound of the present invention activates AMPK through adiponectin receptor 1 (AdipoR1), an AdipoR1 knockout HEK293T cell line was constructed, and the effect of the test compound on AMPK phosphorylation was detected.

Wild-type HEK293T and AdipoR1-knockout HEK293T cells were plated in 6-well plates, cultured with medium containing 10% bovine serum, and starved for 6 hours with 1% serum after confluence. Test compounds (1, 5, 10, 30, 50 μM) were added into 6-well plates, and the 0.1% DMSO group was set as negative control. After 2 hours, the medium was discarded, washed twice with pre-cooled PBS, 150 μl of lysate was added to each well, the lysate was collected, and the expression of downstream AMPK and pAMPK was detected by Western Blot technology. The experimental results are shown in Figure 2.

Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation in AdipoR1 wild-type or AdipoR1-knockout HEK293T cells: pAMPK and AMPK expression in wild-type or AdipoR1-knockout HEK293T cells treated with different concentrations of compound 119 for 2 hours. The experimental results showed that compound 119 had significant AMPK phosphorylation agonistic activity on wild-type HEK293T cells, while compound 119 did not show phosphorylation agonistic activity on AMPK in AdipoR1 knockout cells even at high concentrations. The above results indicate that the agonistic activity of the compounds of the present invention on AMPK is AdipoR1-dependent, that is, the compounds of the present invention are specific adiponectin receptor agonists.

Example 473

Antagonistic effect of calcium chelator EGTA on the agonistic activity of compound AMPK

The activation of intracellular AMPK by adiponectin mainly depends on promoting the influx of extracellular calcium ions and activating the upstream kinase CaMKK of AMPK. EGTA can complex extracellular calcium ions, thereby antagonizing the activation of AMPK mediated by adiponectin or small molecule adiponectin receptor agonists.

Before administering compound 119 to stimulate C2C12 cells, EGTA (5 mM) was incubated with C2C12 cells for 20 min, and then administered for two hours, and the expression of downstream AMPK and pAMPK was detected by Western Blot technique. The experimental results are shown in Figure 3.

Figure 3 is a graph showing the effect of the calcium chelator EGTA on the agonistic activity of the compound AMPK: in the presence or absence of EGTA (5 mM), the expression of pAMPK and AMPK after 10 μM and 30 μM compound 119 stimulated C2C12 cells for 2 hours. The experimental results showed that compound 119 could significantly activate AMPK without pretreatment of cells with EGTA. In the case of pretreatment of cells with EGTA, EGTA completely antagonized the AMPK agonistic effect of compound 119, even if the concentration of compound 119 was increased, EGTA also prevented the agonistic effect of compound 119 on AMPK in C2C12 cells. The above results indicate that the agonistic effect of the compounds of the present invention on AMPK is dependent on extracellular calcium ions, which is consistent with the behavior of adiponectin or small molecule adiponectin receptor agonists.

Example 474

In vivo hypoglycemic activity evaluation of compounds

Experimental animals: C57B1/6J mice, male, 8 weeks old, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Reagents and instruments: blood glucose meter (Roche, Excellence Model), gavage needle, scissors.

Drugs and preparations: Compounds 111, 119 and positive drug rosiglitazone (purchased from Sigma) were used to prepare a suspension with 0.5% CMC-Na.

Experimental method: 8-week-old male C5781/6J mice were fed adaptively for one week, and randomly divided into negative control group (control: 0.5% CMCNa), positive control group (rosiglitazone, 10mg/Kg), test compound group 1 (compound 111, 10 mg/Kg), test compound group 2 (compound 119, 10 mg/Kg), 6 rats in each group, fasting without food and water for 6 hours before the experiment. Before giving the mouse hyperglycemia stimulation 60min (recorded as -60min), cut the tail and take blood to measure the blood glucose level, and administer immediately; 2g/Kg glucose aqueous solution was injected intraperitoneally; after that, blood glucose levels of mice were measured at 20, 40, 60 and 90 min in sequence. Blood glucose test results were collected, and the curves of blood glucose levels over time in each group were drawn. Table 3 and Figure 4 show the blood glucose changes of compounds 111, 119 and rosiglitazone at various time points in animals.

Table 3. Effects of compounds on glucose tolerance in normal mice (*p<0.05, **p<0.01 vs control)

The experimental results showed that after intraperitoneal injection of 2g/Kg glucose in normal mice, the blood glucose increased significantly at 20, 40 and 60 minutes. Administration of compound 119 can significantly reduce blood glucose levels in mice at 20, 40 and 60 min, while compound 111 and rosiglitazone can significantly reduce blood glucose levels at 20 and 60 min. The above results show that the compound of the present invention has significant hypoglycemic activity, and thus can be used to prevent and treat diabetes and its complications.

Example 475

Evaluation of Compounds' Anti-hyperlipidemia and Anti-nonalcoholic Fatty Liver Activity

Animals: 32 male C57BL/J6 mice, SPF grade, 8 weeks old, weighing 20 g, purchased from Beijing Weitong Lihua. All animals were maintained on a 12-h alternating circadian rhythm with free access to food and drink.

Obeticholic acid (OCA): purchased from Jiangsu Vicare Pharmaceutical Technology Co., Ltd.

High-fat diet for mice: purchased from Research Diets (D12492, 60kcal%).

Mouse standard diet: purchased from Research Diets (D12450B, 10kcal%).

Animal grouping and modeling: mice were randomly divided into 4 groups according to body weight: normal diet control group (CHOW), high-fat diet model group (HFD), positive drug obeticholic acid (5mg/Kg) group (HFD+OCA) and Compound 119 (10 mg/kg) group (HFD+119). The control group was fed with normal control diet, and the other groups were fed with high-fat diet for 20 weeks.

Experimental method: After 20 weeks of modeling, the control group and the high-fat feed model group were given 0.5% CMC-Na by intragastric administration every day, the OCA group was given the CMC-Na suspension of OCA by intragastric administration every day, and the 119 groups were given intragastric administration every day. A CMC-Na suspension of compound 119 was administered. Administration for 4 weeks, during this period the normal feed control group was given normal feed, and the other three groups were given high-fat feed. The mice in each group were weighed every day, and their body weight, hair, feces and activities were carefully observed and recorded.

Materials collection and testing: After 4 weeks of administration, fasting without food and water for 12 hours in advance, taking blood from eyeballs in the morning of the next day, killing and taking liver. The right lobule tissue of the liver was fixed with 4% paraformaldehyde for tissue sectioning. The whole blood was allowed to stand at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and the serum was collected. Take 100 mg of liver tissue, homogenize it with 0.9 mL pre-cooled normal saline, centrifuge the homogenate at 4°C and 3000 rpm for 15 minutes, and take the supernatant. The samples were sent to the automatic biochemical analyzer in the Department of Pathology, Jiangsu Hospital of Integrated Traditional Chinese and Western Medicine to measure the levels of TG, TC, LDL, HDL, AST and ALT in serum, and the level of TG in the supernatant of liver tissue homogenate. Send the pretreated tissues to Google Biotechnology Co., Ltd. to make HE-stained sections and oil red-stained sections. The experimental results are shown in Figure 5-8.

Figure 5 shows the hypolipidemic and anti-fatty liver effects of compound 119: the levels of TC, LDL, HDL in mouse serum and TG in liver tissue. Figure 6 shows the anti-fatty liver effect of Compound 119: HE staining. Figure 7 shows the anti-fatty liver effect of compound 119: oil red staining. Figure 8 shows the anti-fatty liver inflammation effect of compound 119: ALT and AST levels in mouse serum.

The experimental results showed that: compared with the normal diet control group, it was found that the high-fat diet significantly increased the levels of total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in serum, and triglycerides in liver tissue Esters (TG) also increased significantly. Compared with the high-fat diet model group, both the obeticholic acid group (HFD+OCA) and compound 119 group (HFD+119) could significantly down-regulate serum TC, LDL, HDL and TG levels in liver tissue (Figure 5). The livers of mice in the high-fat model group were khaki with inconspicuous edges. Observation under the HE staining microscope (Figure 6), there were obvious lipid vacuoles in the liver cells, the nuclei were located at the edge of the cells, the liver cells were swollen, balloon-like lesions, and the edges between cells were unclear. Oil red staining showed obvious fat accumulation in the liver of the model group. The results of oil red staining (Figure 7) showed that the lipid accumulation in the 119-administered group was significantly less than that in the model group, the hepatocyte tissue morphology was more complete, and the intercellular margins were clear. In addition, compared with the normal control group, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of the high-fat diet model group were significantly increased, and after administration of compound 119, the levels of serum ALT and AST in the model group were significantly down (Figure 8). The above results show that the compound of the present invention can be used for the prevention and treatment of hyperlipidemia and non-alcoholic fatty liver disease.

Example 476

Improvement effect of compound on SD rat heart failure model

Experimental animals: SD rats, male, 8 weeks old, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Reagents and instruments: Brain natriuretic peptide (BNP) detection kit was purchased from Wuhan Uersen Trading Co., Ltd. Animal cell/tissue mitochondria rough extraction kit and mitochondrial damage/oxidation fluorescence detection kit were purchased from Shanghai Jiemei Gene Pharmaceutical Technology Co., Ltd.

Drugs and preparations: 250 mg of isoproterenol (purchased from Sigma) was dissolved in 100 mL of 0.09% normal saline to make a final concentration of 2.5 mg/kg, and prepared fresh each time it was used. Compound 119 (oral dose: 10 mg/kg) was dissolved in 0.5% sodium carboxymethylcellulose to make a final concentration of 1 mg/mL.

Establishment of heart failure model: 40 8-week-old male SD rats were fed adaptively for one week, randomly divided into 4 groups, blank group (n=10), and injected intraperitoneally with an equal volume of normal saline every day; the model group was injected intraperitoneally with 2.5mg/ Kg of isoproterenol, after four weeks, the rats appear yellow hair, weight loss, and early symptoms of heart failure accompanied by asthma.

Experimental method: 1) blank group (Control, n=10): daily intraperitoneal injection of an equal volume of normal saline, and intragastric administration of an equal volume of 0.5% sodium carboxymethylcellulose; 2) model group (Model, n=15): each Daily intraperitoneal injection of 2.5mg/kg isoproterenol, intragastric administration of equal volume of 0.5% sodium carboxymethylcellulose, continued for 4 weeks; 3) administration group (compound 119, n=15): daily intraperitoneal injection of 2.5mg/kg After kg isoproterenol, compound 119 (10 mg/kg) was administered orally immediately for 4 weeks.

Evaluation of animal heart failure by color echocardiography: At the end of 4 weeks, the rats were anesthetized, and the heart function was detected by echocardiography in the left long axis section of the parasternal side of the rats. The detection indicators mainly include: ejection fraction (EF), fractional shortening (FS), end-diastolic interventricular septal thickness (IVSd), end-systolic interventricular septal thickness (IVSd), end-diastolic left ventricular posterior wall thickness (LVPWd), end-diastolic left ventricular Indoor diameter (LVEDd), systolic left ventricular posterior wall thickness (LVPWs), end-systolic left ventricular diameter (LVEDs), diastolic left ventricular mass (LV Mass; d), systolic left ventricular mass (LV mass; s), Diastolic left ventricular volume (LVVol; d), systolic left ventricular volume (LV Vol; s).

Rat heart treatment: at the end of 4 weeks, the rats were weighed (Body Weight, BW), blood was taken from the orbit, and the neck was broken to kill. ), left ventricle weight (LVW). Left heart tissue was taken from each group, divided into three parts, fixed in tissue fixative, and used for paraffin embedding for tissue sectioning; the remaining two parts were quick-frozen in liquid nitrogen and stored in a -80°C refrigerator for Western Blot and PCR detection etc. Calculation of heart-to-body ratio in rats: cardiac index=heart weight/body weight, left ventricle index=left ventricle weight/body weight.

The experimental results are shown in Figure 9 and Table 4.

Table 4. Cardiac parameters of SD rats

Fig. 9 is a graph showing the effect of compound 119 on the heart failure model of SD rats: (a) ratio of whole heart weight to body weight; (b) ratio of left ventricle weight to body weight. The experimental results show that: after intraperitoneal injection of 2.5mg/Kg isoproterenol (ISO) in rats, the number of death in the model group was 7, and the survival rate was 53%; the number of death in the compound 119 administration group was 2, and the survival rate was 87%, indicating that compound 119 can delay the death of animals caused by ISO modeling. Compared with the normal group, after ISO modeling, the ratio of whole heart to body weight and left ventricle weight to body weight of SD rats in the model group increased significantly, and severe myocardial hypertrophy occurred. Compared with the model group, the ratio of whole heart and body weight, as well as the weight of left ventricle and body weight of the rats administered with compound 119 were significantly reduced.

The above results show that the compound of the present invention can significantly improve the ejection fraction of animal models of heart failure and improve myocardial hypertrophy. It can improve cardiac lipid accumulation, improve cardiac energy metabolism, anti-inflammation and anti-apoptosis by activating AMPK, thereby exerting cardioprotective effect, so it can be used to prevent and treat cardiomyopathy and heart failure.

Example 477

tablet

Compound 119 (50 g) prepared in Example 98, hydroxypropylmethylcellulose E (150 g), starch (200 g), an appropriate amount of povidone K30 and magnesium stearate (1 g) were mixed, granulated, and compressed into tablets .

Claims (9)

1. The compound shown in formula (I), its pharmaceutically acceptable salt or ester or solvate: R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S(O) ₂ R, C(O)R, C(O) OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO)R , NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO)N(R) ₂ , NR(CO)NHR, NR( CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR, NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C(NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or, each of R ¹ , R ² and R ³ is combined with The atoms to which they are attached together form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heteroaryl ring Cycloalkene ring; or, each two of R ⁶ , R ⁷ and R ⁸ together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, substituted or unsubstituted heterocycloalkane ring or substituted or unsubstituted heterocycloalkene ring; R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl, or alkynyl; wherein the phenyl is unfused or ^R9 is fused, ^R9 is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is ^unfused or fused with R10, ^R10 is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is ^unfused or fused with R, R ¹¹ is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said alkyl, alkenyl or alkynyl is unsubstituted or replaced by one or two or three independently Substituted by a substituent selected from the group consisting of: R ¹² , OH, (O), C(O)OH, CN, NH ₂ , F, Cl, Br, I, CF ₃ , CF ₂ CF ₃ , NC(R ¹³ ) (R ¹⁴ ), R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O) NH ₂ , C(O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ or NHC( O)CH( _CH3 )NHC(O)-CH( _CH3 ) ^NHR15 ; R ¹² is a spiroalkyl group of 2 to 5 carbons, each of which is unsubstituted or replaced by OH, (O), CN, NH ₂ , F, Cl, Br, I, CF ₃ , CF ₂ CF ₃ , NH (CH ₃ ) or N(CH ₃ ) ₂ substitution; R ¹³ and R ¹⁴ are independently selected alkyl groups, or together with the N they are attached to are aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine -1-groups, each having a _CH moiety that is unsubstituted or replaced by O, C(O), CNOH, CNOCH ₃ , S, S(O), S(O) ₂ or NH; ^R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl or alkynyl; wherein the phenyl is unfused or R ¹⁶ is fused, R ¹⁶ is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is unfused or fused with R ¹⁷ , R ¹⁷ is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unfused or fused with R ¹⁸ , R ¹⁸ is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said alkyl, alkenyl or alkynyl is unsubstituted or replaced by one or two or three independently Substituents selected from the following substituents: R ¹⁹ , OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S(O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC(O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O) OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, Cl, Br, I, _CF3 or _{CF2CF3 ;} R ¹⁹ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkenyl or alkynyl; wherein the phenyl is unfused or with R ²⁰ is fused, R ²⁰ is benzene, heteroaryl, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; the heteroaryl is unfused or fused with R ²¹ , R ²¹ is benzene, heterocycloalkane Aromatic hydrocarbon, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of said cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is ^unfused or fused with R, R ²² is benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; n=0～10; R ⁴ and R ⁵ are each H, F, or an alkyl group of 1 to 6 carbons; or, R ⁴ and R ⁵ together with the atoms they are connected to form a substituted or unsubstituted cycloalkane ring, substituted or unsubstituted Heterocycloalkane rings or substituted or unsubstituted heterocycloalkene rings; X is S(O) ₂ , C(O) or CH ₂ ; P, Q, W, Y and Z are each CH, N or C substituted by one of R6, ^R7 and ^R8 , and at least ^three of P, Q, W, Y and Z are not N; R' is H, F, OH, CN, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ or an alkyl group with 1 to 6 carbons, and R' can be in the α of the 4-amino group in the piperidine ring Substitution on carbon or β carbon. 2. The compound of claim 1, wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S( O) ₂ R, C(O)R, C(O)OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO)R, NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO) )N(R) ₂ , NR(CO)NHR, NR(CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR, NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C (NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or , each two of R ¹ , R ² and R ³ together with the atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring; or, R ⁶ , R ⁷ and R ⁸ Each two of which together with the atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring; R is phenyl, heteroaryl or alkyl; wherein said alkyl is unsubstituted or substituted by one, two or three substituents independently selected from: OH, F, CF ₃ , CF ₂ CF ₃ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O)NH ₂ , C (O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ , NHC(O)CH(CH ₃ )NHC(O)CH(CH ₃ )NH ₂ or NHC(O)CH( _CH3 )NHC(O)CH( _CH3 ) ^NHR15 ; R ¹⁵ is an alkyl group, and the alkyl group is unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S( O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC( O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O)OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O) )NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, CF ₃ or CF ₂ CF ₃ ; wherein R ¹⁹ is an alkyl group; n=0～6; R ⁴ and R ⁵ are each H, F or methyl; X is S(O) ₂ , C(O) or CH ₂ ; P, Q, W, Y and Z are each CH, N or C substituted by one of ^R6 , ^R7 and ^R8 , and at least four of P, Q, W, Y and Z are not N; R' is H, F or an alkyl group with 1 to 6 carbons, and R' can be substituted on the α-position carbon or the β-position carbon of the 4-amino group in the piperidine ring. 3. The compound of claim 1, wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each H, R, OR, SR, S(O)R, S( O) ₂ R, C(O)R, C(O)OH, C(O)OR, OC(O)R, NHR, N(R) ₂ , C(O)NH ₂ , C(O)NHR, C(O)N(R) ₂ , NH(CO)R, NR(CO)R, NH(CO)OR, NR(CO)OR, NH(CO)NH ₂ , NH(CO)NHR, NH(CO) )N(R) ₂ , NR(CO)NHR, NR(CO)N(R) ₂ , SO ₂ NH ₂ , SO ₂ NHR, SO ₂ N(R) ₂ , NHSO ₂ R, NRSO ₂ R, NHSO ₂ NHR, NHSO ₂ N(R) ₂ , NRSO ₂ NHR, NRSO ₂ N(R) ₂ , C(O)NHNOH, C(O)NHNOR, C(O)NHSO ₂ R, C(NH)NH ₂ , C (NH)NHR, C(NH)N(R) ₂ , F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ ; or , each two of R ¹ , R ² and R ³ together with the atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring; or, R ⁶ , R ⁷ and R ⁸ Each two of which together with the atoms to which they are attached form a substituted or unsubstituted benzene ring or a substituted or unsubstituted heteroaromatic ring; R is phenyl, heteroaryl or alkyl; wherein said alkyl is unsubstituted or substituted by one, two or three substituents independently selected from: OH, F, CF ₃ , CF ₂ CF ₃ , OR ¹⁵ , SR ¹⁵ , S(O)R ¹⁵ , S(O) ₂ R ¹⁵ , NHR ¹⁵ , N(R ¹⁵ ) ₂ , C(O)R ¹⁵ , C(O)NH ₂ , C (O)NHR ¹⁵ , C(O)N(R ¹⁵ ) ₂ , NHC(O)R ¹⁵ , NR ¹⁵ C(O)R ¹⁵ , NHSO ₂ R ¹⁵ , NHC(O)OR ¹⁵ , SO ₂ NHR ¹⁵ , SO ₂ N(R ¹⁵ ) ₂ , NHC(O)NH ₂ , NHC(O)NHR ¹⁵ ; R ¹⁵ is an alkyl group, and the alkyl group is unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of OR ¹⁹ , SR ¹⁹ , S(O)R ¹⁹ , S( O) ₂ R ¹⁹ , NHR ¹⁹ , N(R ¹⁹ ) ₂ , C(O)R ¹⁹ , C(O)NH ₂ , C(O)NHR ¹⁹ , C(O)N(R ¹⁹ ) ₂ , NHC( O)R ¹⁹ , NR ¹⁹ C(O)R ¹⁹ , NHSO ₂ R ¹⁹ , NHC(O)OR ¹⁹ , SO ₂ NHR ¹⁹ , SO ₂ N(R ¹⁹ ) ₂ , NHC(O)NH ₂ , NHC(O) )NHR ¹⁹ , OH, (O), C(O)OH, CN, NH ₂ , F, CF ₃ or CF ₂ CF ₃ ; wherein R ¹⁹ is an alkyl group; n=0～5; R ⁴ and R ⁵ are each H or methyl; X is S(O) ₂ , C(O) or CH ₂ ; P, Q, W, Y and Z are each CH, N or C substituted by one of ^R6 , ^R7 and ^R8 , and at least four of P, Q, W, Y and Z are not N; R' is H, F or methyl, and R' may be substituted on the alpha carbon or beta carbon of the 4-amino group in the piperidine ring. 4. The compound of claim 1, wherein when R' is not H, the compound is available as a diastereomer or a mixture of enantiomers or diastereomers and/or Alternatively, it is provided in enantiomerically enriched form. 5. The compound of claim 1, wherein the compound or its pharmaceutically acceptable salt or ester or solvate is selected from: 6. A pharmaceutical composition, which comprises the compound according to any one of claims 1-5 as an active ingredient, and pharmaceutically acceptable auxiliary materials. 7. the pharmaceutical composition as claimed in claim 6, is characterized in that, described pharmaceutical composition is capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalation, ointment, Suppository or patch. 8. The compound according to any one of claims 1 to 5 is used in the preparation of prevention or treatment of metabolic abnormality-related diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve damage diseases, and pathogenic infections. Use in medicines for secondary diseases or tumors. 9. The use of the compound according to any one of claims 1 to 5 in the preparation of drugs for preventing or treating AMPK-mediated diseases.