Piperidine Derivatives for GPR119 agonist

Technical Field

The present invention relates to novel compounds that are useful in the treatment of metabolic disorders, including diabetes mellitus (types I and II) and related disorders, pharmaceutical compositions comprising the compounds, and therapeutic uses for the compounds.

Background Art

Diabetes mellitus is a severe disorder that affects more and more human in the world. The forecast of International Diabetes Federation alludes that the total worldwide number of human with diabetes mellitus will be 380,000,000 (three hundred eighty million) until 2025. The attack rate of diabetes mellitus is increasing along with a growing tendency of obesity in many countries. The severe effect of diabetes mellitus includes the increased risk of stroke, heart disease, kidney failure, blindness and amputation. Cardiovascular disorders are more than 70% leading cause of all death in human with Type II diabetes (T2DM) [B. Pourcet et al. Expert Opin. Emerging Drugs 2006, 11, 379-401].

Diabetes mellitus is characterized in the insulin secretion and/or the disturbance of insulin signal reaction in peripheral tissues. There are two types' diabetes mellitus, that is, insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus. Most of the patients with diabetes mellitus are suffering from non-insulin-dependent diabetes mellitus, which is known as Type II diabetes or NIDDM. Because of the severe consequence of diabetes mellitus, the control of diabetes mellitus is necessary desperately.

The treatment of NIDDM generally begins weight loss, healthy diet and exercise program. Although these factors are important especially to dissolve the increased risk of cardiovascular disorders related to diabetes mellitus, they are not effective generally for the control of diabetes mellitus itself. There are many drugs useful for the treatment of diabetes mellitus, including insulin, metformin, sulfonylureas, acarbose, thiazolidinedione, GLP-1 analogue and DPP IV inhibitor. However, some of such treatment agents have a problem including more than one disadvantage of hypoglycemic episodes, weight gain, gastrointestinal problems and loss in responsiveness to therapy over time. Although many medicines for the treatment of diabetes mellitus through the various mechanisms are approved, lots of medicines still are under clinical appraisal, and there still is need to develop novel compound for the treatment of diabetes mellitus. Recently, the research result showing the observation that beta-cell function of diabetes patient declines over time regardless of success or failure of treatment with diet, sulfonylureas, metformin or insulin has been published [R. R. Holman Metabolism 2006, 55, S2-S5].

GPRl 19 is a protein consisted of 335 amino acids expressed in beta-cell of pancreatic islet [Z.-L. Chu et al., Endocrinol. 2007, J 48, 2601-2609] and gastro-intestinal tract [Z.-L. Chu et. al. Endocrinol. 2008, 149, 2038-2047]. Said protein belongs to the receptor family coupled to G-protein, and some candidates including oleoylethanolamide (OEA), N-oleoyldopamine and olvanil are suggested as intrinsic ligand [H. A. Overton et al. Brit. J. Pharmacol. 2007, 1-6].

It is supported from many research using cell line and animal that GPRl 19 may perform a certain function in glucose-dependent secretion of insulin, and targeting to GPRl 19 receptor may be effective to the treatment of diabetes mellitus. Activation of GPRl 19 receptor by lisophosphatidilcholine forces up the glucose-dependent secretion in the pancreas beta-cell line of mice, and the insulin secretion can be blocked by GPRl 19-specific siRNA [T. Soga et al. Biochem. Biophys. Res. Commun. 2005, 326]

Therefore, GPRl 19 receptor activator is needed for the treatment of disorders, such as diabetes mellitus.

Disclosure Technical Problem The object of this invention is to provide a novel piperidine derivative, stereoisomers thereof, pharmaceutically acceptable salts thereof, and a preparing method thereof.

The other object of this invention is to provide a novel piperidine derivative being able to control GPRl 19 activity with low adverse effect, stereoisomers thereof, pharmaceutically acceptable salts thereof, and a preparing method thereof.

Technical Solution

To achieve the above objects, the present invention provides a novel piperidine derivative of the following formula 1, stereoisomers thereof, and pharmaceutically acceptable

wherein

WisOorN-R _h ;

R _a , R _b and R _h are each independently H or Ci _-3 alkyl;

R _c is -F or -C _1-3 hyperfluoride alkyl;

R _d and R _e are each independently selected from the group consisting of H, halogen, -Ci, ₅ alkyl and -C _3-7 cycloalkyl, wherein -Ci _-5 alkyl and -C _3-7 cycloalkyl are each independently unsubstituted or substituted with halogen, -CN, -OC _1-5 alkyl or -Ci _-5 alkyl;

or Rd and R _e are combined to form a -C _3-7 cycloalkyl, wherein the -C _3-7 cycloalkyl is unsubstituted or su itu d wih h lo en - C- alk l or - - alk l

wherein

Rf _! and Rf ₂ are each independently H, halogen, -Ci _-5 alkyl, -Ci _-5 alkyl (OH), -OCi _-5 alkyl or CN; , wherein Rki and Rk ₂ are each independently H, halogen, -Ci _-5 alkyl, -C] _-5 alkyl (OH), -OC _1-5 alkyl or -CN;

Q is H, -S(0)R _h -S(0) ₂ R!, -C(0)R!, -C(0)ORi, -C(0)NHR,, -C(0)NR ₂ R ₃ , -S(0) NHR, ,

wherein

Ri is H, -CF ₃ , -C _1-5 alkyl, 3 to 7-membered heterocyclic ring, C _3-7 cycloalkyl, or Ar,

R ₂ and R ₃ are each independently C _1-5 alkyl, C _3-7 cycloalkyl, 3 to 7-membered heterocyclic ring or Ar (in Rj, R ₂ and R ₃ , -C _1-5 alkyl, 3 to 7-membered heterocyclic ring, C _3-7 cycloalkyl and Ar may be each independently substituted with Rxj and Rx ₂ .),

or R ₂ and R ₃ together with the N atoms to which they are bonded may form a 5- or 6- membered heterocyclic aromatic or non-aromatic ring compound further having 0 to 3 members selected independently from the group consisting of N, O, S and C (O), wherein the heterocyclic aromatic or non-aromatic ring compound may be substituted with Rxj and Rx ₂ , wherein Ar is C6 monocyclic aromatic compound; or 5- or 6-membered heteroaryl group comprising 1 to 3 members selected from the group consisting of N, O and S,

wherein Rxi and Rx ₂ are each independently H, -OH, halogen, -CN, -CF ₃ , 3- to 7- membered heterocyclic ring, -C1.5 alkyl, -C3.7 cycloalkyl, -Ci _-5 alkyl( -Ci _-5 alkyl(OR ₄ ), -C\. , -C(0)R4, -C(0)OR-i, -S(0) ₂ R4, -OR4, [wherein R4 and R5 are each independently H, -C _1-5 alkyl or -

C _3-7 cycloalkyl.].

In addition, preferably,

W is O;

R _a and Rb are each independently H;

Rd and R _e are each independently -C _\ s alkyl,

or Rd and Re are combined to form a -C _3-7 cycloalkyl, wherein the -C3.7 cycloalkyl is

unsubstituted or substituted with halogen, -OC1.5 alkyl or -Ci _-5 alkyl; is selected from the group consisting of:

and Rf ₂ are each independently H, halogen, -Ci _-S alkyl, -C1.5 alkyl(OH), -OC _1-5 alkyl or -CN;

is selected from the group consisting of: , wherein Rk[ and Rk ₂ are each independently

H, halogen, -C _1-5 alkyl, -C _1-5 alkyl(OH), -OC _1-5 alkyl or -CN;

Q is -S(0) ₂ R _l5 -C(0)NR ₂ R ₃ or -S(0) ₂ NR ₂ R ₃ ,

wherein R _l5 R ₂ and R ₃ are each independently C _1-5 alkyl substituted with Rxi and Rx ₂ , or R ₂ and R ₃ together with the N atoms to which they are bonded may form a 5- or 6- membered heterocyclic aromatic or non-aromatic ring compound further having 0 to 3 members selected independently from the group consisting of N, O, S and C(O),

wherein the heterocyclic aromatic or non-aromatic ring compound may be substituted with R i and Rx ₂ ,

wherein Rxj and Rx ₂ are each independently H, -OH, halogen, -CN, -CF ₃ , 3- to 7- membered heterocyclic ring, -C _1-5 alkyl, -C _3-7 cycloalkyl, -C _1-5 alkyl(OH), -C\s alkyl(OR4), - C _1-5 alkyl(halogen), -C(0)NR ₄ R ₅ , -C(0)R ₄ , -C(0)OR4, -S(0) ₂ R4 or -OR4 [wherein R4 and R _s are each independently H, -C _1-5 alkyl or -C _3-7 cycloalkyl.].

In addition, more preferably,

W is O;

R _a and R _b are each independently H;

c is -F or -CF ₃ ;

R _d and R _e are each independently -Ci _-5 alkyl, or R _d and R _e are combined to form -C ₃ . ₇ cycloalkyl, wherein the -C _3- cycloalkyl is unsubstituted or substituted with halogen, -OC _1-5 alkyl or -C _1-5 alkyl; s selected from the group consisting of:

wherein Rf] and Rf ₂ are each independently H, halogen, -C _1-5 alkyl, -C _1-5 alkyl(OH), -OC _1-5 alkyl or -CN; selected from the group consisting of:

, wherein Rk _t and Rk ₂ are each independently

H, halogen, -C _1-5 alkyl, -C _1-5 alkyl(OH), -OCi _-5 alkyl or ^CN;

Q is -C(0)NR ₂ R ₃ ,

wherein R ₂ and R ₃ together with the N atoms to which they are bonded may form a 5- or 6-membered heterocyclic aromatic or non-aromatic ring compound further having 0 to 3 members selected independently from the group consisting of N, O, S and C(O), wherein the heterocyclic aromatic or non-aromatic ring compound may be substituted with Rxi and Rx ₂ ,

wherein Rxj and Rx ₂ are each independently H, -OH, halogen, -CN, -CF ₃ , 3- to 7- membered heterocyclic ring, -Ci _-5 alkyl, -C _3-7 cycloalkyl, -C _1-5 alkyl(OH), -C _1-5 alkyl(OR4), - C _1-5 alkyl(halogen), -C(0)NR ₄ R ₅ , -C(0)R4, -C(0)OR ₄ , -S(0) ₂ R4 or -OR4 [wherein R4 and R ₅ are each independently H, -C1-5 alkyl or -C _3-7 cycloalkyl.].

Also, alternatively,

W is O;

R _a and R _b are each independently H;

c is -F or -CF ₃ ;

R _d and R _e are each independently selected from the group consisting of -CH ₃ and -

is selected from the group consisting of:

, wherein Rfi and Rf ₂ are each independently

is selected from the group consisting of:

, wherein Rkt and Rk ₂ are each independently H,

-F or -CN;

selected from the group consisting of:

wherein Rxj and Rx ₂ are each independently H, OH, -F, -CN, -CF ₃ , -CH ₂ OH or -C(0)NH ₂ .

The compound of formula 1 may be used generally as a form of pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts thereof include

pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salt, organic amine addition salt, amino acid addition salt and sulfonate salt. Acid addition salts include inorganic acid addition salts, such as hydrogen chloride salt, sulfonic acid salt and phosphoric acid salt; and organic acid addition salts, such as alkyl sulfonate, aryl sulfonate, acetate, malate, fumarate, tartrate, citrate and lactate. Examples of metal salts include alkali metal salt, such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt, calcium salt, aluminium salt and zinc salt. Examples of ammonium salt include ammonium salt and

tetramethylammonium salt. Examples of organic amine addition salts include salts with morpholine and piperidine. Examples of amino acid addition salts include salts with glycine, phenylalanine, glutamic acid and lysine. Examples of sulfonate salt include mesylate, tosylate and benzenesulfonic acid salts.

The term of "stereoisomer" means the isomer molecules that have the same molecular formula and bonds, but differ by their three-dimensional orientation.

Specific examples of preferred compounds of formula 1 according to the present invention include:

Compound 431: 1 -(2-fluoro-2-methylpropyl)-4-((4'-(methylsulfonyl)biphenyl-4 - yloxy)methyl)piperidine Compound 470: 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl)-2,3- dihydrobenzo [b] thiophene 1 , 1 -dioxide

Compound 498: methyl 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphe nyl- 4-carboxylate

Compound 499: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)- 1 -(2,2,2- trifluoroethyl)piperidine

Compound 500: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclopropyl)methyl)piperidine

Compound 515 : 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxamide

Compound 516: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N,N- dimethylbiphenyl-4-carboxamide

Compound 517: (4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(morpholino)methanone

Compound 524: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)-l-(3,3,3- trifluoropropyl)piperidine

Compound 526: N-cyclopropyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 527: N-cyclobutyl-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 528: N-cyclopentyl-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 529: N-cyclohexyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 530: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(pyrrolidin- 1 -yl)methanone

Compound 531 : (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(piperidin- 1 -yl)methanone

Compound 533: 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(4 - hydroxybutyl)biphenyl-4-carboxamide

Compound 534: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- methylbiphenyl-4-carboxamide

Compound 540: 5-(4-((l-(2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)phenyl )-2,3- dihydrobenzo[b]thiophene 1,1 -dioxide Compound 542 : 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidine

Compound 546 : 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclopentyl)methyl)piperidine

Compound 547: l-(2,2-difluoropropyl)-4-((4'-(methylsulfonyl)biphenyl-4- yloxy)methyl)piperidine

Compound 548: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid

Compound 549: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(2- hydroxyethyl)biphenyl-4-carboxamide

Compound 550: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(3- hydroxypropyl)biphenyl-4-carboxamide

Compound 551 : 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(2 - hydroxyethyl)-N-methylbiphenyl-4-carboxamide

Compound 552: N,N-dimethyl-4'-((l -((1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 553 : (R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4- yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 554: (S)-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 555: (R)-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 556: (S)-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 557: (R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4- yl)(2-(methoxymethyl)pyrrolidin- 1 -yl)methanone

Compound 558: (S)-(4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)b iphenyl-4- yl)(2-(methoxymethyl)pyrrolidin- 1 -yl)methanone

Compound 559: N-butyl-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(2- hydroxyethyl)biphenyl-4-carboxamide

Compound 560: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(furan-2 - ylmethyl)biphenyl-4-carboxamide

Compound 561 : 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- propylbiphenyl-4-carboxamide Compound 562: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- propylbiphenyl-4-carboxamide

Compound 563 : N-benzyl-N-ethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenyl-4-carboxamide

Compound 564: (S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4- yl)(2-(trifluoromethyl)pyrrolidin- 1 -yl)methanone

Compound 565: (S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 566: (4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -fluoropyrrolidin- 1 -yl)methanone

Compound 567: (4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(4-(hydroxymethyl)piperidin- 1 -yl)methanone

Compound 568: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(4-hydroxypiperidin- 1 -yl)methanone

Compound 569: (4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 570: (R)-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -fluoropyrrolidin- 1 -yl)methanone

Compound 571 : (S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4- yl)(3 -fluoropyrrolidin- 1 -yl)methanone

Compound 574 : 4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridin-3 -yl)benzoic acid

Compound 575: 1 -(4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)ethanone

Compound 576 : N,N-dimethyl-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)pyridin-3 -yl)benzamide

Compound 578: (S)-(3-hydroxypyrrolidin-l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)meth

Compound 579: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4-(6-((l-((l- (trifluoromemyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyr idin-3-yl)phenyl)mema^^

Compound 580: N,N-dimethyl-4-(6-((l-((l- (trifluoromethyl)cyclopropyl)memyl)piperidin-4-yl)methoxy)py ridin-3-yl)benzamide

Compound 581 : (S)-l-(4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piper idin-4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide Compound 582 : morpholino(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)pyridin-3-yl)phenyl)methanone

Compound 583: piperidin-l-yl(4-(6-((l-((l- (trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)p yridin-3-yl)phenyl)methanone Compound 584: pyrrolidin-l-yl(4-(6-((l-((l-

(trifluoromethyl)cyclopropyl)methyl)p^

Compound 585: (S)-(3-hydroxypyrrolidin-l^yl)(4-(6-((l-((l- (trifluoromethyl)cyclopropyl)memyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)methano

Compound 586 : (S)- 1 -(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 587: (4-(hydroxymethyl)piperidin-l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)p yridin-3-yl)phenyl)methanone

Compound 588: (4-(hydroxymethyl)piperidin-l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)methanone Compound 589: 5-(4-(methylsulfonyl)phenyl)-2-(( 1 -(( 1 -

(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methox y)pyridine

Compound 593: 1 -(4-(5-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)ethanone

Compound 594: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]py razin-7(8H)-yl)methanone

Compound 595: (3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyraz in-7(8H)- yl)(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridin-3 - yl)phenyl)methanone

Compound 596: 2-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5-(4- (methylsulfonyl)phenyl)pyridine

Compound 597: 5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-2-(4- (methylsulfonyl)phenyl)pyridine

Compound 598: N-ethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)-N- methylbiphenyl-4-carboxamide

Compound 599 : 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-isopropy l-N- methylbiphenyl-4-carboxamide

Compound 600: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(3 -hydroxyazetidin- 1 -yl)methanone Compound 601 : (3,3-difluoroazetidin-l-yl)(4'-((l-(2-fluoro-2-methylpropyl) piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 602: N-tert-butyl-4'-((l-(2-fluoro-2-methylpropyI)piperidin-4- yl)methoxy)biphenyl-4-carboxarnide

Compound 603 : 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- isopropylbiphenyl-4-carboxamide

Compound 604: N,N-diethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 605: 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(l -hydroxy-2- methylpropan-2-yl)biphenyl-4-carboxamide

Compound 606: (S)-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- N-(l - hydroxypropan-2-yl)biphenyl-4-carboxamide

Compound 607: (R)-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- N-(l- hydroxybutan-2-yl)biphenyl-4-carboxamide

Compound 608 : (R)-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-( 1 - hydroxy-3-methylbutan-2-yl)biphenyl-4-carboxamide

Compound 609: (S)-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- N-(l- hydroxy-3-methylbutan-2-yl)biphenyl-4-carboxamide

Compound 610: N-(l,3-dihydroxypropan-2-yl)-4'-((l-(2-fluoro-2-methylpropyl )piperidin- 4-yl)methoxy)biphenyl-4-carboxamide

Compound 611: N-(2,3-dihydroxypropyl)-4'-((l-(2-fluoro-2-methylpropyl)pipe ridin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 612: (R)-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 613: (S)-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 614: 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N,N- dimethylbiphenyl-4-sulfonamide

Compound 615: l-(2-fluoro-2-methylpropyl)-4-((4 ^, -(pyrrolidin-l-ylsulfonyl)biphenyl-4- yloxy)methyl)piperidine

Compound 616: 1 -(2-fluoro-2-methylpropyl)-4-((4'-(piperidin- 1 -ylsulfonyl)biphenyl-4- yloxy)methyl)piperidine

Compound 617: 2-(4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)-5- (methylsulfonyl)pyridine Compound 618: 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl)-2- (methylsulfonyl)pyridine

Compound 619: (R)-methyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylate

Compound 620: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylic acid

Compound 621 : 2-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N - methylbiphenyl-4-ylcarboxamido)acetic acid

Compound 622: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(thiazolidin-3-yl)methanone

Compound 623: (4-(cyclopropanecarbonyl)piperazin-l-yl)(4'-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-yl)methanone

Compound 624: (4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(4-(methylsulfonyl)piperazin- 1 -yl)methanone

Compound 625: (S)-methyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylate

Compound 626: tert-butyl 4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazine- 1 -carboxylate

Compound 627: (4-benzylpiperazin- 1 -yl)(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 628: l-(4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazin- 1 -yl)ethanone

Compound 629 : (3 ,3-difluoropyrrolidin- 1 -yl)(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 630: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(piperazin- 1 -yl)methanone

Compound 631 : N,N-dimethyl-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)p iperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 632: (S)-(3-hydroxypyrrolidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-yl)methanone

Compound 633: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-yl)methanone

Compound 634: (3-hydroxypiperidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-yl)methanone Compound 635: (S)-l-(4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-caxboxamide

Compound 636: N-(2-hydroxyethyl)-4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-carboxamide

Compound 637: N-(2-hydroxyethyl)-N-methyl-4'-(( 1 -(( 1 -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )biphenyl-4-carboxamide

Compound 638: 3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N,N- dimethylbiphenyl-4-carboxamide

Compound 639: N,N-diethyl-3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 640: (S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 641 : (R)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl)m ethanone

Compound 642: (3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 643 : 3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(l - hydroxy-2-methylpropan-2-yl)biphenyl-4-carboxamide

Compound 644: (S)-l -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 645: methyl 2-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-ylcarboxamido)acetate

Compound 646: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(oxetan- 3- yl)biphenyl-4-carboxamide

Compound 647 : methyl 3 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-ylcarboxamido)propanoate

Compound 648: (R)-methyl 2-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-ylcarboxamido)-3-hydroxypropanoate

Compound 649: (S)-methyl 2-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-ylcarboxamido)-3-hydroxypropanoate

Compound 650: ethyl 4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-ylcarboxamido)piperidin- 1 -carboxylate

Compound 651 : 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- pentylbiphenyl-4-carboxamide Compound 652: (R)-(4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin-3- yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 653: (S)-l-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyridin-

3- yl)benzoyl)pyrrolidine-2-carboxamide

Compound 654: (S)-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridin-3- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 655 : (R)-(4'-((l -(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4-yl)(2- (hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 656: (S)-l-(4'-((l-(2-fluoropentyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 657: (R)-(2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 658: (S)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 659: (S)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 666: (S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)biphenyl-

4- ylsulfonyl)pyrrolidin-3 -ol

Compound 667: (R)-(l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)biphenyl- 4-ylsulfonyl)pyrrolidin-2-yl)methanol

Compound 668 : (S)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-ylsulfonyl)pyrrolidine-2-carboxamide

Compound 669: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)biphenyl- 4-ylsulfonyl)piperidin-3-ol

Compound 670: (S)-l-(4*-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)biphenyl-

4-ylsulfonyl)piperidin-3 -ol

Compound 671 : (R)-l-(4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piper idin-4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 672: (R)-(3 -hydroxypiperidin- 1 -yl)(4-(6-(( 1-((1- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridin-3 -yl)phenyl)methanone

Compound 673: (S)-(3 -hydroxypiperidin- l-yl)(4-(6-(( 1-((1- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)methanone

Compound 674: 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- sulfonamide Compound 675 : 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N- methylbiphenyl-4-sulfonamide

Compound 676: 5-(4-(methylsulfonyl)phenyl)-2-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridine

Compound 677: ethyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidih-4- yl)methoxy)biphenylcarbonyl)piperidine-3 -carboxylate

Compound 678: ethyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxylate

Compound 679: ethyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxylate

Compound 680: (4-ethylpiperazin- 1 -yl)(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 681: (4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(4-isopropylpiperazin- 1 -yl)methanone

Compound 682: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 683: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-N,N-dimethylpyrrolidine-2-carbo xamide

Compound 684: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-N-methylpyrrolidine-2-carboxami de

Compound 685: (4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(4-methylpiperazin- 1 -yl)methanone

Compound 686: (3,5-dimethylpiperazin-l-yl)(4'-((l-(2-fluoro-2-methylpropyl )piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 687: (2,6-dimethylmorpholino)(4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenyl-4-yl)methanone

Compound 688: 4'-((l -(2-fluoropropyl)piperidin-4-yl)methoxy)-N,N-dimethylbipheny l-4- carboxamide

Compound 689: (4'-((l -(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4-yl)(3- hydroxypiperidin-l-yl)methanone

Compound 690: (4'-((l-(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-yl) (3- hydroxypiperidin- 1 -yl)methanone

Compound 691 : (S)-l-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyridin- 2-yl)benzoyl)pyrrolidine-2-carboxamide Compound 692: (R)-(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin-2- yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 693 : (S)-(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin-2- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 694: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin- l-yl)methanone

Compound 695 : (S)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 696: (S)-l -(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 697: (R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin- l-yl)methanone

Compound 698: (R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 699: (S)-(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 700: (R)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 701 : (S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 702: (R)-(3-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 703 : (S)-(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 704: (2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((R)-2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 705: (2S)-l-(2,2'-difluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 706: (S)-l-(2'-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 707: (R)-(2'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl)m ethanone

Compound 708: (R)-(2'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone Compound 709: (R)-(2'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 710: (S)-l -(2',3 -difluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 711 : (R)-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl)m ethanone

Compound 712: (R)-(2',3 -difluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 713: (R)-(2',3-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- l-yl)methanone

Compound 714: 1 -(2-fluoro-2-methylpropyl)-4-((2-fluoro-4'-(methylsulfonyl)b iphenyl-4- yloxy)methyl)piperidine

Compound 715: (S)-(3-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 716: (R)-(3 -fluoro-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)pyridin-3 -yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 717: (S)-l -(3-fluoro-4-(6-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 718: (R)-(3 -fluoro-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)pyridin-3-yl)phenyl)(3-hydroxypiperidin-l-yl)me thanone

Compound 719: (S)-(3 -fluoro-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 720: (S)-(2-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 721 : (R)-(2-fluoro-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)pyridin-3 -yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 722: (S)-l-(2-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)met hyl)piperidin- 4-yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 723 : (R)-(2-fluoro-4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)pyridin-3-yl)phenyl)(3-hydroxypiperidin-l-yl)me thanone

Compound 724: (S)-(2-fluoro-4-(6-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 725: (S)-(3'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone Compound 726: (R)-(3'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 727: (R)-(3'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 728: (S)-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl)m ethanone

Compound 729: (R)-(3'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 730: (S)-l-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperid in-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 731 : (S)-(3,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 732: (S)-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 733: (R)-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl -4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 734: (R)-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 735: (S)-(2 ₎ 3 ^, -difluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 736: (R)-(2,3'-difluoro-4 ^, -((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 737: (S)-(2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 738: (S)-(2'-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 739: (S)-(2'-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 740: (S)-(2'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 741 : (2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((S)-3-hydroxypiperidin-l-yl)methan one

Compound 742: (2,2'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((R)-3 -hydroxypyrrolidin- 1 -yl)methanone Compound 743 : (2,2'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((S)-3-hydroxypyrrolidin-l-yl)metha none

Compound 744: (2,2'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((S)-2-(hydroxymethyl)pyrrolidin-l- yl)methanone

Compound 745: (2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((R)-3-hydroxypiperidin- 1 -yl)methanone

Compound 746: (S)-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 747: (S)-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 748: (S)-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl -4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 749: (R)-(2-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-yl)methanone

Compound 750: (S)-l-(2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 751 : (R)-(2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl)m ethanone

Compound 752: (S)-(2,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 753: (S)-l-(2 _> 3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 754: (R)-(2,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 755: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 756: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 757: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 758: (R)-(6-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyridin-3-yl)(3-hydroxypiperidin-l-yl)meth anone

Compound 759: (R)-(5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyridin-2-yl)(3 -hydroxypiperidin- 1 -yl)methanone Compound 760: (S)-l-(4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 761 : (R)-(4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 763: (R)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridin-2- yl)phenyl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 764: (S)-(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin-2- yl)phenyl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 765: (S)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridin-2- yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 766: (R)-(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin-2- yl)phenyl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 767: (S)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 768: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 769: (S)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin- l-yl)methanone

Compound 770: (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 771 : (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 772: (S)-(3 -hydroxypyrrolidin- l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methoxy)p yridin-3-yl)phenyl)methanone Compound 773: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4-(6-((l-((l-

(trifluoromemyl)cyclopentyl)methyl)piperidin-4-yl)methoxy )pyridin-3-yl)phenyl)methanone

Compound 774 : (S)- 1 -(4-(6-((l -(( 1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoyl)pyrrolidin-2-carboxamide

Compound 775: (R)-(3 -hydroxypiperidin- l-yl)(4-(6-(( 1-((1- ( fluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methoxy)pyrid in-3 -yl)phenyl)methanone

Compound 776: (S)-(3 -hydroxypyrrolidin- l-yl)(4-(6-(( 1-((1- (trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)methanone

Compound 777: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)phenyl)methanone Compound 778: (S)-l-(4-(6-((l-((l-(trifluoromethyl)cyclohexyl)methyl)piper idin-4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidin-2-carboxamide

Compound 779: (R)-(3-hydroxypiperidin-l-yl)(4-(6-((l-((l- (trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)memoxy)pyr idin-3-yl)phenyl)methanone Compound 782: (S)-l-(5-(3-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)phenyl)picolinoyl)pyrrolidine-2-carboxamide

Compound 783: (R)-(5-(3-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyridin-2-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 784: (R)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)phenyl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 785: (R)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)phenyl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 786: (S)-(2-fluoro-4-(6-((l-(2-fluoro-2-metl ylpropyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 787 : (S)-(2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3 -yl)phenyl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 789: l-((l-fluorocyclohexyl)methyl)-4-((4'-(methylsulfonyl)biphen yl-4- yloxy)methyl)piperidine

Compound 790: 4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazin-2-one

Compound 791 : l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carbonitrile

Compound 792: l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 793: (3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone

Compound 794: (R)-(3-hydroxypiperidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-yl)methanone

Compound 795: (S)-(3 -hydroxypiperidin- l-yl)(4'-((l-((l -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )biphenyl-4-yl)methanone

Compound 796: (R)-(3 -hydroxypyrrolidin- l-yl)(4'-((l-((l - (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-yl)methanone Compound 797: (S)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4'-((l-((l- (trifluoromemyl)cyclobutyl)memyl)piperidin-4-yl)methoxy)biph enyl-4-yl)methanone

Compound 798: 1 -(4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 799: l-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 800: 1 -(3,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 801 : l-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 802: l-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 803 : 1 -(2,2'-difluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 804: l-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) pyridin-2- yl)benzoyl)piperidine-4-carboxamide

Compound 805 : 1 -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)piperidine-4-carboxamide

Compound 806: (R)-l-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 807: (S)-l-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 809 : (R)-(4'-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 810: (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 - ' fluorobiphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 811: (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 - fluorobiphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 812: (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 - fluorobiphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 813: 1 -(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)piperidine-4-carboxamide

Compound 814: 1 -(4'-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 - fluorobiphenylcarbonyl)piperidine-4-carboxamide Compound 815: (S)-(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)memoxy)pyridin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin-l -yl)methanone

Compound 816: (R)- 1 -(3 ,3'-difluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 817: (S)-l-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperid in-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 818: 1 -(2,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxamide

Compound 819: (R)-l-(2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperid in-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 820: (S)-l-(2,3'-difluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 821 : (R)-l-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyridin- 2-yl)benzoyl)piperidine-2-carboxamide

Compound 822: (R)- 1 -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 823 : (R)- 1 -(2',3-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 824: (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 825: (2R)-l-(2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperi din-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 828: (S)-l-(4-(6-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidi n-4- yl)methoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 829: (R)-(3-hydroxypiperidin-l-yl)(4-(6-((l-(3,3,3-trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methoxy)pyridin-3-yl)phenyl)me thanone

Compound 830: N-(3,4-dihydroxyphenethyl)-4'-((l-(2-fluoro-2-methylpropyl)p iperidin-4- yl)methoxy)biphenyl-4-carboxamide

Compound 831 : (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 832: (S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 833 : (S)- 1 -(2'-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide Compound 834: (R)-(2'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 835: (S)-(2'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 836: (S)-(2'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl )piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-yl)methanone

Compound 837: (S)-l-(3'-fluoro-4'-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 838: (R)-(3 '-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 839: (S)-(3'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 840: (R)-(3'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 842: (S)-(3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 843 : (S)- 1 -(3 -fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 844: (R)-(3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 845 : (S)-(3-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 846: (R)-(3-fluoro-4'-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 847: (S)-l-(2,3 ifluoro-4'-((l-((l-

(trifluoromethyl)cyclobutyl)memyl)piperidin-4-yl)methoxy) biphenylcarbonyl)pyrrolidine-2- carboxamide

Compound 848: (R)-(2,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)me thyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 849 : (R)-(2,3 '-difluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l -yl)methanone

Compound 850: (S)-(2,3'-difluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone Compound 851 : (S)-(2,3'-difluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 852: (R)-(4'-(((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methyl)(methyl)amino)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 853: (R)-(4'-(ethyl((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methyl)amino)biphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 854: (R)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-2-carboxamide

Compound 855: (S)-l -(2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-2-carboxamide

Compound 856: l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-4-carboxamide

Compound 857: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)piperidine-2-carboxamide

Compound 858: (S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l- yl)methanone

Compound 859: (R)-(4'-((l-(2-fluoro-2-met ylpropyl)piperidin-4- yl)memylamino)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-y l)methanone

Compound 860: (2S)-l-(2,6'-difluoro-4'-((l-(2-£luoro-2-methylpropyl)piper idin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 861 : (S)-l-(3,6 ^, -difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 862: (R)-l-(3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-2-carboxamide

Compound 863: (S)-l-(3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-2-carboxamide

Compound 864: l-(3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-4-carboxamide

Compound 866: (S)-l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) -3- fluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 867: (R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 868: (S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide Compound 869: (S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-yl)(3 -hydro xypyrrolidin- 1 -yl)methanone

Compound 870: (S)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 871 : (R)- 1 -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)piperidine-3-carboxamide

Compound 872: (R)- 1 -(3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 873 : (R)- 1 -(2'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 874: (S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-3 -carboxamide

Compound 875: (S)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 876: (S)-l-(2'-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 877 : (R)- 1 -(2'-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 878 : (S)- 1 -(2'-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 879: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 880: (R)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 881 : (R)-l-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 882: (R)-l-(2 ^, -fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin- 4-yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 883 : (S)-(3'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-yl)methanone

Compound 884: (S)-l-(3*-fluoro-4 ^, -((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin- 4- yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide

Compound 885: (R)-l-(3'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)meth yl)piperidin- 4-yl)methoxy)biphenylcarbonyl)piperidine-3-carboxamide Compound 886 : (R)- 1 -(3 '-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 887 : (S)- 1 -(3 '-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 888: (S)-(4"-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 - fluorobiphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 889: (S)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenyl-4-yl)(3-hydroxypiperidin- 1 -yl)methanone

Compound 890 : (R)-(4'-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 - fluorobiphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 891: (S)-l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 892: (R)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 893 : (S)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 894: (S)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)bi phenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 895: (S)-l -(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2- fluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 896: (S)-l -(4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-2- yl)benzoyl)pyrrolidine-2-carboxamide

Compound 897: (R)-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) pyridin-2- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 898: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)pyridin-2- yl)-2-fluorobenzoyl)pyrrolidine-2-carboxamide

Compound 899: (S)-(4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-2-yl) - 2-fluorophenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 900: (R)-(4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-2- yl)-2 -fluorophenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 901: (S)-l-(3,3'-difluoro-4'-((l-((l- (trifluoromemyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bip henylcarbonyl)pyrrolidm carboxamide Compound 902: (R)-(3,3'-difluoro-4'-((l-((l-(trifluorometl yl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 903 : (R)-(3 ,3 '-difluoro-4'-(( 1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl )methanone

Compound 904: (S)-(3,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)me thyl)piperidin-

4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 905 : (S)-(3 ,3'-difluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 906: (S)-l-(5-(3-fluoro-4-((l-((l-(trifluoromethyl)cyclobutyl)met hyl)piperidin- 4-yl)methoxy)phenyl)picolinoyl)pyrrolidine-2-carboxamide

Compound 907: (R)-(5-(3-fluoro-4-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin- 4-yl)methoxy)phenyl)pyridin-2-yl)(3-hydroxypiperidin-l-yl)me thanone

Compound 908: (2,2'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl )piperidin-4- yl)methoxy)biphenyl-4-yl)((R)-2-(hydroxymethyl)pyrrolidin-l- yl)methanone

Compound 909: (2S)-l-(2,2'-difluoro-4*-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )biphenylcarbonyl)pyrrolidine-2- carboxamide

Compound 910: (2,2'-difluoro-4'-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)((R)-3 -hydroxypiperidin- 1 -yl)methanone

Compound 911 : (2,2'-difluoro-4 ^, -((l-((l-(irifluoromethyl)cyclobutyl)methyl)piperidin- 4- yl)methoxy)biphenyl-4-yl)((S)-3-hydroxypiperidin- 1 -yl)methanone

Compound 912: (R)-(2',3 -difluoro-4"-((l -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin-l-yl )methanone

Compound 913: (S)-l-(2',3-difluoro-4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)memoxy)bip henylcarbonyl)pyrrolidine-2- carboxamide

Compound 914: (R)-(2',3-difluoro-4'-(( 1 -((1 -(trifluoromethyl)cyclobutyl)methyI)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 915: (S)-(2',3-difluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- l-yl)methanone

Compound 916: (S)-(2',3-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)me thyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 917: (R)-(2-fluoro-4 ^, -((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin- 4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone Compound 918: (S)-l-(2-fluoro-4'-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 919: (R)-(2-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 920: (S)-(2-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 921 : (S)-(2-fluoro-4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 922: (S)-l -(4'-((l -((1 -fluorocyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 923: (R)-(4'-((l-((l-fluorocyclobutyl)methyl)piperidin-4-yl)metho xy)biphenyl- 4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 924: (S)-(4'-(( 1 -(( 1 -fluorocyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl- 4-yl)(3-hydroxypyrrolidin- 1 -yl)methanone

Compound 925: (R)-(4'-((l-((l-fluorocyclobutyl)methyl)piperidin-4-yl)metho xy)biphenyl-

4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 926: (R)-(3 -hydroxypiperidin- l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methylamin o)biphenyl-4-yl)methanone

Compound 927: (R)-(3-hydroxypiperidin-l-yl)(4'-((l-(3,3,3-trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methylamino)biphenyl-4-yl)meth anone

Compound 928: (R)-(3 -hydroxypiperidin- l-yl)(4'-(methyl((l-((l- (trifluoromemyl)cyclobutyl)methyl)piperidin-4-yl)methyl)amin o)biphenyl-4-yl)methanone

Compound 929 : (R)-(4'-(ethyl(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methyl)amino)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 930: (R)-(3 -hydroxypiperidin- l-yl)(4'-(methyl((l -(3,3,3 -trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methyl)amino)biphenyl-4-yl)met hanone

Compound 931: (2S,4R)-methyl 4-hydroxy-l-(4-(6-((l-((l- (trifluoromemyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyr idin-3-yl)benzoyl)pyrrolidine-2- carboxylate

Compound 932: (2S,4R)-methyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxyl ate

Compound 933: (2S,4R)-4-hydroxy-l-(4-(6-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridin-3-yl)benzoyl)pyrrolidine-2- carboxamide Compound 934: (2S,4R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxam ide

Compound 935 : (S)- 1 -(5-(2-fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinoyl)pyrrolidine-2-carboxamide

Compound 936:

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenylcarbonyl)piperazin-l- yl)ethanone

Compound 937: (S)- 1 -(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3 '- difluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 938: (S)-l-(3'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 939: (R)-3'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)-4'- (3 -hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 940: (R)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3'- difluorobiphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 941 : (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 ,3'- difluorobiphenyl-4-yl)(2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

Compound 942: (S)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3'- difluorobiphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 943 : (S)-(4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3*- difluorobiphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 944: (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyrazin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 945: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3-hydroxypiperidin-l-yl)meth anone

Compound 946: (S)-l -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- 3'-(hydroxymethyl)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 947: (S)-(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5'- (hydroxymethyl)biphenyl-4-yl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 948: (R)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyrazin-

2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 949: (S)-(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazin-2- yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone Compound 950: (S)-l-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyrazin-

2- yl)benzoyl)pyrrolidine-2-carboxamide

Compound 951 : (S)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyrazin-2- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 953: (S)- 1 -(4-(6-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridazin-

3- yl)benzoyl)pyrrolidine-2-carboxamide

Compound 954: (R)-(4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-3- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 955: (S)-(4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) pyridin-3- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 956: (R)-(4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-3- yl)-2-fluorophenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 957: (S)-(4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridin-3-yl) - 2-fluorophenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 963 : (R)-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4'-(3 - hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 964: (S)-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4'-(3 - hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 965 : (S)- 1 -(3 '-cyano-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 966: (S)-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4 '-(3- hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 967: (R)-2'-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4'- (3 -hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 968: (S)-2 ^, -fluoro-4-((l-(2-fluoro-2-methylρroρyl)piρeridin-4- yl)methoxy)-4 ^, -

(3 -hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 969: (S)-l-(3 ^, -cyano-2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperi din-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 970: (S)-(3-hydroxypyrrolidin-l-yl)(4-(2-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py rimidin-5-yl)phenyl)methanone

Compound 971: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4-(2-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py rimidin-5-yl)phenyl)methanone

Compound 972: (R)-(3 -hydroxypiperidin- l-yl)(4-(2-(( 1-((1- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py rimidin-5-yl)phenyl)methanone Compound 973 : (S)- 1 -(4-(2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 974: (S)-(3-fluoro-4-(2-((l-((l-(trifluoromethyl)cycIobutyl)methy l)piperidin-4- yl)memoxy)pyrimidin-5-yl)phenyl)(3-hydroxypyrrolidin-l-yl)me thanone

Compound 975 : (R)-(3-fluoro-4-(2-(( 1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)pyrimidin-5-yl)phenyl)(2-(hydroxymethyl)pyrr olidin-l-yl)methanone

Compound 976: (R)-(3-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin- 4-yl)methoxy)pyrimidin-5-yl)phenyl)(3-hydroxypiperidin-l-yl) methanone

Compound 977: (S)-l-(3-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)met hyl)piperidin- 4-yl)methoxy)pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxamid e

Compound 978: (S)-(2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin-4- yl)methoxy)pyrimidin-5-yl)phenyl)(3-hydroxypyrrolidin-l-yl)m ethanone

Compound 979: (R)-(2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin- 4-yl)methoxy)pyrimidin-5-yl)phenyl)(2-(hydroxymethyl)pyrroli din-l-yl)methanone

Compound 980: (R)-(2-fluoro-4-(2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

4-yl)methoxy)pyrimidin-5-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 981 : (S)-l-(2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)met hyl)piperidin- 4-yl)methoxy)pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxamid e

Compound 982: (R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3-hydroxypiperidin-l-yl)meth anone

Compound 983: (S)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3-hydroxypiperidin-l-yl)meth anone

Compound 984: (S)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 985: (R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin- l-yl)methanone

Compound 986: (S)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 987: (S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(3-hydroxypyrrolidin-l-yl)met hanone

Compound 988: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin- l-yl)methanone

Compound 989 : (S)- 1 -(4-(6-(( 1 -(2- fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazin-3-yl)benzoyl)pyrrolidine-2-carboxamide Compound 990: (R)-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazin-3 -yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 991: (S)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridazin-3 -yl)benzoyl)pyrrolidine-2-carboxamide

Compound 992: (R)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazin-3-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1000: (S)-l-(3'-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1001 : (R)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3'- fluoro-4'-(3- hydroxypiperidine-l-carbonyl)biphenyl-3-carbonitrile

Compound 1002: (R)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3'- fluoro-4 ^, -(2- (hydroxymethyl)pyrrolidine-l-carbonyl)biphenyl-3-carbonitril e

Compound 1003 : (S)-4-((l -(2-ethyl-2-fIuorobutyl)piperidin-4-yl)methoxy)-3'-fluoro-4' -(3- hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 1004: (S)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1005: (R)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-4'- (2- (hydroxymethyl)pyrrolidine-l-carbonyl)biphenyl-3-carbonitril e

Compound 1006: (S)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-4'- (3- hydroxypyrrolidine-l-carbonyl)biphenyl-3 -carbonitrile

Compound 1007: (R)-(2-(hydroxymethyl)pyrrolidin-l-yl)(4-(5-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py razin-2-yl)phenyl)methanone

Compound 1008: (R)-(3-hydroxypiperidin-l-yl)(4-(5-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py razin-2-yl)phenyl)methanone Compound 1009: (S)-l-(4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piper idin-4- yl)methoxy)pyrazin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 1010: (R)-(3-fluoro-4-(5-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)pyrazin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1011 : (S)-l-(3-fluoro-4-(5-((l-((l- (trifluoromemyl)cyclobutyl)methyl)pi

2-carboxamide

Compound 1012: (R)-(2-fluoro-4-(5-(( 1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)pyrazin-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidi n-l-yl)methanone Compound 1013: (R)-(2-fluoro-4-(5-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yI)methoxy)pyrazin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1014: (S)-l-(2-fluoro-4-(5-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidm^

2-carboxamide

Compound 1015: (R)-l-(3'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide

Compound 1016: (S)-3'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)-4'- (3 -hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 1017: (S)-3'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)-4'-

(3 -hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 1018: (S)-l -(4-(5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrazin-2- yl)benzoyl)pyrrolidine-2-carboxamide

Compound 1020: (S)-(3-hydroxypyrrolidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methylamin o)biphenyl-4-yl)methanone

Compound 1021: (S)- 1 -(4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1022: (S)-(3-hydroxypiperidin-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methylamin o)biphenyl-4-yl)methanone

Compound 1023: (R)-l-(4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in-4- yl)methylamino)biphenylcarbonyl)piperidine-2-carboxamide

Compound 1024: (S)-(3 -hydroxypyrrolidin- 1 -yl)(4'-(( 1 -(3 ,3 ,3 -trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methylamino)biphenyl-4-yl)meth anone

Compound 1025: (S)-l-(4'-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin- 4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1026: (S)-(3 -hydroxypiperidin- l-yl)(4'-((l -(3,3,3 -trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methylamino)biphenyl-4-yl)meth anone

Compound 1028: (S)-l-(2 ^, -cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperi din-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1029: (R)-3'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)-

4'-(3 -hydroxypiperidine- 1 -carbonyl)biphenyl-2-carbonitrile

Compound 1030: (R)-l-(2'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide Compound 1031 : (S)-l-(2'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1032 : (S)- 1 -(2-fluoro-4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 1033: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1034: (S)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1035 : (R)-(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 1036: (S)-l -(5-(3-cyano-4-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinoyl)pyrrolidine-2-carboxamide

Compound 1037: (R)-l -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 1038: (S)-l-(5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyrazine-2-carbonyl)pyrrolidine-2-carboxam ide

Compound 1051: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Compound 1052: (R)-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) pyrimidin- 2-yl)phenyl)(3 -hydroxypiperidin- l-yl)methanone

Compound 1053: (R)- 1 -(4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 1054: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-2-fluorobenzoyl)pyrrolidine-2-car boxamide

Compound 1055: (R)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-2-fluorobenzoyl)piperidine-2-carb oxamide

Compound 1056: (R)-(4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin- 2-yl)-3 -fluorophenyl)(3 -hydroxypiperidin- 1 -yl)methanone

Compound 1057: (R)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-3-fluorobenzoyl)piperidine-2-carb oxamide

Compound 1067: (2S,4R)-1 -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)-4-hydroxypyrrolidine-2-carb oxamide

Compound 1072: (S)-l -(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)benzoyl)pyrrolidine-2-carboxamide Compound 1073: (R)-l-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyrazin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 1076 : (R)- 1 -(4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3-yl)benzoyl)piperidine-2-carboxamide

Compound 1077: (R)-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridin-

3 -yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 1078 : (S)-(4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridin- 3 -yl)phenyl)(3 -hydroxypyrrolidin- 1 -yl)methanone

Compound 1079: (S)- 1 -(4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-3 -yl)benzoyl)piperidine-2-caxboxamide

Compound 1080: (R)- 1 -(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 1081 : (S)-l-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazin-2-yl)benzoyl)piperidine-2-carboxamide

Compound 1082: (S)-l-(5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)phenyl)pyrazine-2-carbonyl)pyrrolidine-2-carboxam ide

Compound 1097: (2S,4S)-4-fluoro-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl )piperidin- 4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carbonitrile

Compound 1098 : (2S,4R)- 1 -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carbonit rile

Compound 1099 : (2S,4S)-4-fluoro- 1 -(3 -fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1100: (2S,4R)-l-(3-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxam ide

Compound 1115: 3'-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4'-(4- hydroxypiperidine- 1 -carbonyl)biphenyl-2-carbonitrile

Compound 1119: (S)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl )methoxy)-2- fluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1120: (R)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl )methoxy)-2- fluorobiphenylcarbonyl)piperidine-2-carboxamide

Compound 1121: (S)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 ^, -fluoro-4 ^, -(3- hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

Compound 1123: (R)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 ^, -fluoro-4'-(3- hydroxypiperidine- 1 -carbonyl)biphenyl-3 -carbonitrile Compound 1124: (S)-l-(2'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Compound 1125 : (R)- 1 -(2'-cyano-4'-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxamide; and

Compound 1126: (R)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-4'- (3- hydroxypiperidine- 1 -carbonyl)biphenyl-2-carbonitrile.

Specific examples of more preferred compounds of formula 1 according to the present invention include:

Compound 770: (S)-l -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridin-2-yl)benzoyl)pyrrolidine-2-carboxamide;

Compound 896: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)pyridin-2- yl)benzoyl)pyrrolidine-2-carboxamide;

Compound 938: (S)-l-(3'-cyano-3-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide;

Compound 1028: (S)-l-(2'-cyano-3-fluoro-4'-((l-(2-fiuoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide; and

Compound 1032 : (S)- 1 -(2-fluoro-4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxamide.

The present invention also provides pharmaceutical composition comprising the piperidine derivative of the formula 1 , stereoisomers thereof, or pharmaceutically acceptable salts thereof; and pharmaceutically acceptable carriers thereof.

Preferably, the composition is used for treatment of a disease associated with GPRl 19 agonist.

Preferably, said disease associated with GPRl 19 agonist is diabetes mellitus, and more preferably, Type II diabetes mellitus.

Advantageous Effects

The present invention can provide a novel piperidine derivative, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In addition, the present invention can provide a novel piperidine derivative being able to control GPRl 19 activity with low adverse effect, stereoisomers thereof, and

pharmaceutically acceptable salts thereof. Synthetic Schemes The intermediate 5 can be synthesized according to the following reaction schemes 1 and 2.

[Reaction Scheme

1 2 3

As shown in the reaction scheme 1, Boc protecting group is introduced into the amine of compound 1. Hydroxyl group is activated with MsCl, and substituted with aryl alcohol of formula 4 to synthesize the desired compound of formula 5.

[Reaction Scheme 2]

As shown in the reaction scheme 2, bromo or chloro compound 6 is substituted with compound 2 to prepare compound 5.

The intermediate 8 can be synthesized according to the following reaction scheme 3. [Reaction Scheme 3]

7 8

As shown in the reaction scheme 3, compound 8 is prepared through the oxidation reaction of compound 7.

The intermediate 13 can be synthesized according to the following reaction schemes 4, Reaction Scheme 4]

As shown in the reaction scheme 4, compound 11 is prepared by amide bond formation of compound 9 with compound 10, and then subjected to reduction thereby to obtain compound 12. Finally, the intermediate 13 is prepared through the substitution reaction of compound 12.

[Reaction Scheme 5]

As shown in the reaction scheme 5, the protecting group of compound 5 is removed, and subjected to the formation of amide bond with compound 10 to prepare compound 15. Finally, compound 13 is prepared through reduction. Reaction Scheme 6]

As shown in the reaction scheme 6, compound 16 is prepared using compound 14 and oxirane compound 8, and then hydroxyl group of compound 16 is substituted with fluoride to prepare compound 13.

The compounds 21 and 23 that Q is -S(0) ₂ R _! in formula 1 can be synthesized according to the following reaction schemes 7, 8, 9, 10, 11 and 12. [Reaction Scheme 7]

As shown in the reaction scheme 7, compound 18 is prepared through the Suzuki coupling reaction of compound 5 with boronic acid compound 17. The protection group of compound 18 is removed using acid, and reacted with oxirane compound 8 to obtain compound 20. Finally, hydroxyl group of compound 20 is substituted with fluoride to prepare compound 21. Reaction Scheme 8]

As shown in the reaction scheme 8, compound 22 is prepared by amide bond formation of compounds 19 and 10, and then subjected to reduction to prepare compound 21.

[Reaction Scheme 9]

As shown in the reaction scheme 9, compound 19 is reacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate to obtain compound 23. Reaction Scheme 10]

As shown in the reaction scheme 10, compound 25 is prepared by amide bond formation of compounds 19 and 24, and subjected to the reduction to prepare compound 21. [Reaction Scheme 11]

As shown in the reaction scheme 11, compound 13 is subjected to Suzuki coupling reaction with boronic acid compound 17 to prepare compound 21. [Reaction Scheme 12]

As shown in the reaction scheme 12, boronic acid compound 26 is prepared using compound 13 as a starting compound, and then subjected to Suzuki coupling reaction with compound 27 to prepare compound 21.

The compound 29 that Q is -S(0) ₂ NHR ₁ or -S(0) ₂ NR ₂ R ₃ in formula 1 can be synthesized according to the following reaction scheme 13.

[Reaction Scheme 13]

As shown in the reaction scheme 13, compound 26 is subjected to Suzuki coupling reaction with compound 28 to prepare compound 29.

The compound 38 that the formula 1 can be synthesized according to the following reaction schemes 14 and 15. [Reaction Scheme 14]

46

(

As shown in the reaction scheme 14, compound 30 is subjected to Suzuki coupling reaction with compound 31 to prepare compound 32. Compound 33 is prepared through the substitution reaction of compound 32 with compound 3, and subjected to the oxidation and hydrogenation reactions to prepare compound 35. The protecting group of compound 35 is removed with acid, following with reaction with oxirane compound 8 to prepare compound 37. Finally, hydroxyl group of compound 37 is substituted with fluoride to obtain compound 38. Reaction Scheme 15]

As shown in the reaction scheme 15, compound 36 is reacted with 2,2,2-trifiuoroethyl trifluoromethanesulfonate to prepare compound 38.

The compound 44 that Q is -C(0)R _! in formula 1 can be synthesized according to the following reaction scheme 16.

Reaction Scheme 16]

As shown in the reaction scheme 16, compound 5 is subjected to Suzuki coupling reaction with compound 39 to prepare compound 40. The protecting group of compound 40 is removed using acid, following with the formation of amide bond with compound 10 to prepare compound 42. The carbonyl group of amide in compound 42 is removed through reduction, and then, in order to re-introducing the undesired reduced keton group, following with oxidation to obtain compound 44.

The intermediate 46 can be synthesized according to the following reaction schemes 17, 18, 19 and 20.

[Reaction Scheme 17]

As shown in the reaction scheme 17, compound 13 is subjected to Suzuki coupling reaction with boronic acid compound 45 to prepare compound 46.

As shown in the reaction scheme 18, compound 5 is subjected to Suzuki coupling reaction with boronic acid compound 31 to prepare compound 47. The protecting group is removed using acid, following with the formation of amide bond with compound 10 to prepare compound 49. Through the reduction, the removal of carbonyl group from amide and the reduction of ester group proceeds at the same time, and then the formed hydroxyl group is activated with triflate group to prepare compound 51. Finally, compound 46 is synthesized using palladium catalyst and CO gas.

[Reaction Scheme 19]

As shown in the reaction scheme 19, compound 52 is subjected to Suzuki coupling reaction with boronic acid compound 31 to prepare compound 53. Compound 53 is subjected to the substitution reaction with compound 3 to prepare compound 54. The protecting group of compound 54 is removed. The obtained compound 55 is reacted with oxirane compound 8 to prepare compound 56. Hydroxyl group of compound 56 is substituted with fluoride to obtained compound 46.

[Reaction Scheme 20]

As shown in the reaction scheme 20, compound 52 is subjected to Suzuki coupling reaction with boronic acid compound 57 to prepare compound 58. Using palladium and hydrogen, compound 53 is synthesized, and then subjected to the substitution reaction with compound 3 to prepare compound 54. After removal of the protecting group from compound 54, compound 55 is reacted with oxirane compound 8 to prepare compound 56. Hydroxyl group of compound 56 is substituted with fluoride to obtain compound 46.

The compound 61 that Q is -C(0)NHR _! or -C(0)NR ₂ R ₃ in formula 1 can be

synthesized according to the following reaction scheme 21.

[Reaction Scheme 21]

As shown in the reaction scheme 21, compound 46 is hydrolyzed to prepare compound 59. Finally, compound 59 is subjected to the formation of amide bond with amine compound 60 to prepare compound 61a or compound 61b.

The intermediate 68 can be synthesized according to the following reaction scheme 22 and 23.

[Reaction Scheme 22]

As shown in the reaction scheme 22, compound 62 is subjected to the reduction amination with compound 63 to prepare compound 64. Protecting group is introduced into the secondary amine of compound 64 to prepare compound 65. The protecting group of compound 65 is removed, following with the reaction with oxirane compound 8 to prepare compound 67. Finally, hydroxyl group of compound 67 is substituted with fluoride to prepare compound 68.

[Reaction Scheme 23]

As shown in the reaction scheme 23, compound 66 is subjected to the formation of amide bond with compound 10 to prepare compound 69, following with a reduction to obtain compound 68.

The compounds 72 and 73 that Q is -C(0)NHR ₁ or -C(0)NR ₂ R ₃ in formula 1 can be synthesized according to the following reaction schemes 24 and 25.

[Reaction Scheme 24]

As shown in the reaction scheme 24, compound 68 is subjected to Suzuki coupling reaction with boronic acid compound 45 to prepare compound 69. Secondary amine of compound 69 is removed to prepare compound 70. And then, compound 71 is prepared through the hydrolysis of compound 70, and subjected to the formation of amide bond with amine compound 60 to prepare compound 72.

[Reaction Scheme 25]

As shown in the reaction scheme 25, compound 72 is subjected to the reduction amination with an aldehyde to prepare compound 73.

The compound 77 that Q or -C(0)NR ₂ R ₃ m formula 1 can be synthesized according to the following reaction scheme 26

[Reaction Scheme 26]

As shown in the reaction scheme 26, compound 59 is subjected to the formation of amide bond with amine compound 74 to prepare compound 75. Compound 75 is hydrolyzed to prepare compound 76. And compound 76 is subjected to the formation of amide bond with amine compound 60 to prepare compound 77.

Abbreviations

The following abbreviations and terms have the indicated meanings throughout:

Ac = acetyl

Boc = t-butoxycarbonyl

BOP = benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate

Bu = butyl

DAST = diethylaminosulfur trifluoride

DCM = dichloromethane = methylene chloride = MC = CH ₂ C1 ₂

DIPEA = N,N-diisopropylethylamine

DME = dimethoxyethane

D F = N,N-dimethylformamide

D SO = dimethyl sulfoxide dppp = l,3-Bis(diphenylphosphino)propane EDC = l-ethyl-3-(3-dimethylaminopropyl) carbodiimide = EDCI Et = ethyl EtOAc = ethyl acetate = EA EtOH = ethanol HOBt = 1 -hydro xybenzotriazole HX = hexane

LAH = lithium aluminium hydride m-CPBA = meta-chloroperoxybenzoic acid Me = methyl MeCN = methyl cyanide = acetonitrile = ACN

MeOH = methanol

MsCl = methanesulfonyl chloride

Pd(dbpf)Cl ₂ = [1,1 '-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2 = [l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PyBOP = benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate t- or tert- = tertiary TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran

Best Mode for Carrying out the Invention

Preparation of Compounds and Preparing Method of Compounds

The compound of formula 1 can be prepared by the method known from various references. Hereinafter, the preparing method for compound of formula 1 will be described further detail with reaction scheme. Example 1. Compound 431:

l-(2-fluoro-2-methylpr '-(methyIsulfonyl)biphenyl-4-yloxy)methyl)piperidine

Step 1. t-butyl 4-(hydroxymethyl)piperidin-l-carboxylate: 4-Piperidinemethanol (10.00 g, 86.83 mmol) was dissolved in CH ₂ C1 ₂ 200 mL, and then cooled with ice bath. Di-t-butyl dicarbonate was added thereto, following with increasing temperature slowly to room temperature and stirring for 3 hours. The obtained reaction mixture was washed in order with water, saturated NH ₄ C1 aqueous solution and saturated aqueous brine solution. The washed reaction mixture was dried over MgS0 ₄ and filtered. After removing solid material, organic solvent was removed from the filtrate under reduced pressure to yield the title compound as white solid (18.35 g, 98%)

Step 2. t-butyl 4-((methylsulfonyloxy)methyl)piperidin- 1 -carboxylate: t-Butyl 4- (hydroxymethyl)piperidin-l -carboxylate (18.35 g, 85.24 mmol) was dissolved in CH ₂ C1 ₂ 200 mL. Et ₃ N (35.45 mL, 255.71 mmol) was added thereto, and then the mixture was cooled with ice bath. MsCl (9.83 mL, 127.86 mmol) was added dropwise slowly thereto, following with increasing temperature slowly to room temperature and stirring for 15 hours. The obtained reaction mixture was washed in order with 1 N HCl, saturated NaHC0 ₃ aqueous solution and saturated aqueous brine solution. The washed reaction mixture was dried over MgS0 ₄ and filtered. After removing solid material, organic solvent was removed from the filtrate under reduced pressure to yield the title compound as yellow solid (24.80 g, 99%).

Step 3. t-butyl 4-((4-bromophenoxy)methyl)piperidin- 1 -carboxylate: t-Butyl 4- ((methylsulfonyloxy)methyl)piperidin-l -carboxylate (13.63 g, 46.46 mmol) and 4-bromophenol (8.34 g, 46.46 mmol) were dissolved in DMF 100 mL, and then K ₂ C0 ₃ (19.26 g, 139.38 mmol) was added thereto, following with stirring at 80 °C for 15 hours. Sufficient amount of water was added thereto, following with filtering to obtain a solid. The obtained solid was recrystallized with MeOH to yield the title compound as white solid (11.31 g, 66%). The obtained filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10 % EtOAc/hexane) further to yield the title compound as white solid (2.38 g, 14%).

Step 4. t-butyl 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-l -carboxylate:

t-Butyl 4-((4-bromophenoxy)methyl)piperidin-l -carboxylate (3.00 g, 8.10 mmol) and 4- (methylsulfonyl)phenylboronic acid (1.78 g, 8.91 mmol) were dissolved in DME 15 mL, and then water 5 mL was added thereto. Pd(dbpf)Cl ₂ (528 mg, 0.81 mmol) and Cs ₂ C0 ₃ (3.96 g, 12.15 mmol) were added thereto, and refluxed with heating at 80 °C for a day. The reaction mixture was diluted with water, and extracted with EtOAc three times. The obtained organic layer was dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50 % EtOAc/hexane) to yield the title compound as yellow solid (2.50 g, 69%).

Stepjj. 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate:

t-Butyl 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-l -carboxylate (2.50 g, 5.61 mmol) was dissolved in CH ₂ C1 ₂ 8 mL, and then TFA 644 iL was added thereto, following with stirring at room temperature for 3 hours. The obtained reaction mixture was filtered to yield the title compound as white solid (2.40 g, 96%). Alternatively, 4-((4'-(methylsulfonyl)biphenyl- 4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate (3.78 g, 8.48 mmol) was dissolved in dioxane 20 mL, and then 4 M HC1 solution (14.85 mL, 59.39 mmol) was added thereto, following with stirring at room temperature for 1 hour. The reaction mixture was suspended in EtOAc, and then filtered to yield the title compound as white solid (3.15 g, 97%).

Step 6. 2-methyl- 1 -(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)propan-2- ol: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate (100 mg, 0.22 mmol) and K ₂ C0 ₃ (15 mg, 0.11 mmol) were suspended in EtOH 1 mL. Water 0.5 mL was added thereto, and then suspended with warming. 2,2-Dimethyl oxirane (0.19 mL, 2.18 mmol) was added thereto, and then the reaction was performed at 1 10 °C for 20 minutes with the radiation of micro-wave ray. A little of water was added thereto, and filtered to yield the title compound as white solid (90 mg, 99%).

Step 7. Compound 431 : 2-Methyl- 1 -(4-((4'-(methylsulfonyl)biphenyl-4- yloxy)methyl)piperidin-l-yl)propan-2-ol (50 mg, 0.12 mmol) was dissolved in CH ₂ C1 ₂ 2 mL, and then Deoxo-Fluor (24 \iL, 0.13 mmol) was added thereto. After stirring at room

temperature for 3 hours, a saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS04, and then filtered to remove the solid materials. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10% MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (40 mg, 79%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.02 - 7.96 (m, 2 H), 7.78 - 7.71 (m, 2 H), 7.59 - 7.54 (m, 2 H), 7.04 - 6.98 (m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.10 (s, 3 H), 3.00 (d, 2 H, J = 1 1.5 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.23 - 2.13 (m, 2 H), 1.88 - 1.75 (m, 3 H), 1.48 - 1.40 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 420 (M+

Example 2. Compound 596: 2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5- (4-(methyIsulfonyl)p

Step 1. t-butyl 4-((5-bromopyridirte-2-yloxy)methyl)piperidin-l-carboxylate: N-Boc-4- piperidinemethanol (500 mg, 2.32 mmol) was dissolved in DMF 10 mL. 2,5-bromopyridine (600 mg, 2.55 mmol) and 95 % NaH (83 mg, 3.48 mmol) were added thereto slowly at 0 °C, following with increasing the temperature and stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with EtOAc. The obtained organic layer was washed three times with saturated NH ₄ C1 aqueous solution and saturated aqueous brine solution. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-20 % EtOAc/hexane) to yield the title compound as white solid (67 mg, 78%).

Step 2. t-butyl 4-((5-(4-(methylsulfonyl)phenyl)pyridine-2-yloxy)methyl)pipe ridin-l - carboxylate: t-butyl 4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-carboxylate (0.65 g, 1.80 mmol) was dissolved in dioxane 20 mL and H ₂ 0 5 mL. 4-methylsulfonylphenylboronic acid (0.36 g, 1.80 mmol), Pd(dbpf)Cl ₂ (59 mg, 0.09 mmol) and Cs ₂ C0 ₃ (1.17 g, 3.61 mmol) was added thereto, and refluxed with stirring for 2 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The obtained filtrate was concentrated under reduced pressure. The obtained concentrate was dissolved in CH ₂ C1 ₂ , washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-50 % EtOAc hexane) to yield the title compound as white solid (0.67 g, 83%).

Step 3. 5-(4-(methylsulfonyl)phenyl)-2-(piperidin-4-ylmethoxy)pyridi ne hydrochloride:

t-butyl 4-((5-(4-(methylsulfonyl)phenyl)pyridine-2-yloxy)methyl)pipe ridin-l -carboxylate (0.2 g, 0.45 mmol) was dissolved in MeOH. 1.25 M HC1 in MeOH (2.24 mmol, 1.8 mL) was added thereto. The solvent was removed completely and the residue was washed with ether to yield the title compound as white solid (0.15 g, 88%). The product was used without further purification. Step 4. 2-methyl- 1 -(4-((5-(4-(methylsulfonyl)phenyl)pyridine-2-yloxy)methyl)pi peridin- 1 - yl)propan-2-ol: 5-(4-(methylsulfonyl)phenyl)-2-(piperidin-4-ylmethoxy)pyridi ne hydrochloride (0.20 g, 0.58 mmol) was dissolved in EtOH 3 mL and ¾0 3 mL. Isobutylene oxide (0.42 g, 5.77 mmol) and K ₂ C0 ₃ (0.40 g, 2.89 mmol) were added slowly thereto. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in CH ₂ C1 ₂ , and washed with water three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-5 % eOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (0.15 g, 62%).

Step 5. Compound 596 : 2-methyl- 1 -(4-((5-(4-(methylsulfonyl)phenyl)pyridine-2- yloxy)methyl)piperidin-l-yl)propan-2-ol (0.15 g, 0.36 mmol) was dissolved in CH ₂ C1 ₂ 2 mL, and then Deoxo-Fluor (0.34 mL, 1.80 mmol) was added slowly thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, the obtained CH ₂ C1 ₂ layer was washed several times with water, The organic layer was concentrated under reduced pressure. The organic layer was distilled under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-30 % EtOAc/hexane) to yield the title compound as white solid (0.1 g, 66%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.41 (d, 1 H, J - 2.5 Hz), 8.02 (d, 2 H, J = 12.0 Hz), 7.82 (dd, 1 H, J = 8.6, 2.6 Hz), 7.72 (d, 2 H, J = 8.4 Hz), 6.86 (d, 1 H, J = 8.6 Hz), 4.22 - 4.20 (m, 2 H), 3.10 (s, 3 H), 3.0 (bra, 2 H), 2.45 (d, 2 H, J = 24.0 Hz), 2.17 (brs, 2 H), 1.81 (brs, 3 H), 1.40 - 1.25 (m, 8 H); MS (ESI) m/z 421 (M+ + H).

Example 3. Compound 597: 5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-2- (4-(methylsulfonyl)phenyl)pyridine

Step 1. t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin- 1 -carboxylate:

N-Boc-4-piperidinemethanol (0.50 g, 2.32 mmol) was dissolved in CH ₂ C1 ₂ 5 mL, and then Et ₃ N

(0.48 mL, 3.48 mmol) and MsCl (0.32 g, 2.79 mmol) was added dropwise slowly thereto at 0

°C. The mixture was stirred for 30 minutes, following with increasing the temperature and stirring at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was washed with excess water three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid ( 0.68 g, 100%). The product was dissolved in DMF 10 mL.

K ₂ C0 ₃ (1.13 g, 3.48 mmol) and 2-chloro-5-hydroxypyridine (0.3 g, 2.32 mmol) were added thereto slowly. After increasing the temperature, the mixture was stirred with heating at 100 °C for 3 hours. After the completion of the reaction, the reaction mixture was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-30 % EtOAc/hexane) to yield the title compound as white solid (0.45 g, 59%).

Step 2. t-butyl 4-((6-(4-(methylsulfonyl)phenyl)pyridine-3 -yloxy)methyl)piperidin- 1 - carboxylate: t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-carboxylate (0.45 g, 1.37 mmol) was dissolved in dioxane 20 mL and H ₂ 0 5 mL. 4-Methylsulfonylphenylboronic acid (0.28 g, 1.38 mmol) and Pd(dbpf)Cl ₂ (45 mg, 0.07 mmol), Cs ₂ C0 ₃ (0.89 g, 2.75 mmol) was added thereto, and refluxed with stirring for 2 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The obtained filtrate was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-50 % EtOAc/hexane) to yield the title compound as white solid (0.45 g, 73%).

Step 3. 2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-ylmethoxy)pyridi ne hydrochloride:

t-butyl 4-((6-(4-(methylsulfonyl)phenyl)pyridine-3-yloxy)methyl)pipe ridin- 1 -carboxylate (0.45 g, 1.0 mmol) was dissolved in dioxane 10 mL. 4M HC1 in MeOH (1.26 mL, 5.0 mmol) was added thereto. The solvent was removed completely and the residue was washed with ether to yield the title compound as white solid (0.36 g, 93%). The product was used without further purification.

Step 4. 2-methyl- 1 -(4-((6-(4-(methylsulfonyl)phenyl)pyridine-3 -yloxy)methyl)piperidin- 1 - yl)propan-2-ol: 2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-ylmethoxy)pyridi ne

hydrochloride (0.15 g, 0.39 mmol) was dissolved in EtOH 5 mL and H ₂ 0 5 mL. Isobutylene oxide (0.28 g, 3.92 mmol) and K ₂ C0 ₃ (0.27 g, 1.96 mmol) were added slowly thereto. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in CH ₂ C1 ₂ , and washed with water three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (0.15 g, 92%).

Step 5. Compound 597: 2-methyl- 1 -(4-((6-(4-(methylsulfonyl)phenyl)pyridine-3- yloxy)methyl)piperidin-l-yl)propan-2-ol (0.15 g, 0.36 mmol) was dissolved in C¾C1 ₂ 10 mL. Deoxo-Fluor (0.34 mL, 1.79 mmol) was added slowly thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, the obtained CH ₂ C1 ₂ layer was washed several times with water. The organic layer was distilled under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-30 %

EtOAc/hexane) to yield the title compound as white solid (0.1 g, 66%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, 1 H, J = 12.0 Hz), 8.16 (d, 2 H, J = 1.6 Hz), 8.02 (d, 2 H, J = 8.5 Hz), 7.74 (d, 1 H, J = 8.7 Hz), 7.30 (s, 1 H), 3.91 (d, 2 H, J = 5.5 Hz), 3.09 (s, 3 H), 3.0 (bra, 2 H), 2.48 - 2.42 (m, 2 H), 2.25 - 2.15 (m, 2 H), 1.93 - 1.78 (m, 3 H), 1.47 - 1.35 (m, 8 H); MS (ESI) m/z 421 (M+ + H).

Example 4. Compound 789:

l-((l-fluorocyclohexyl)methyl)-4-((4'-(methylsulfonyl)bip henyl-4-yloxy)methyl)piperidine

Step 1. 1 -((4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)methyl)cyclohexanol: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine hydrochloride (0.04 g, 0.11 mmol) and K ₂ C0 ₃ (0.01 g, 0.06mmol) were suspended in EtOH (1 mL). Water (0.5 mL) was added thereto, and the mixture was suspended with a little heating. 1- oxaspiro[2,5]octane (0.13 g, 1.18 mmol) was added thereto. The reaction was performed in a microwave at 110 °C for 20 minutes. A little of water was added thereto, and filtered to yield the title compound as white solid (0.05 g, 87%).

Step 2. Compound 789: 1 -((4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)methyl)cyclohexanol (0.05 g, 0.10 mmol) was dissolved in CH ₂ C1 ₂ (2 mL), and then the temperature was lowered with dry ice / acetone. DAST (0.02 mL, 0.10 mmol)was added thereto little by little, and stirred for 4 hours, and then further stirred at room temperature for 1 hour. A saturated NaHC0 ₃ aqueous solution was added thereto, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g, ISU silica gel cartridge, 10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as brown solid (0.01 g, 27%). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.97 (d, 2 H, J = 8.5 Hz), 7.72 (d, 2 H, J = 8.5 Hz), 7.55 (d, 2 H, J = 8.8 Hz), 6.99 (d, 2 H, J = 8.8 Hz), 3.85 (d, 2 H, J = 5.8 Hz), 3.08 (s, 3 H), 2.98 (d, 2 H, J = 10.0 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.16 (t, 2 H, J = 11.3 Hz), 1.92 - 1.74 (m, 5 H), 1.68 - 1.55 (m, 4 H), 1.55 - 1.35 (m, 6 H); MS (ESI) m/z 460 (M+ + H).

Example 5. Compound 500: 4-((4'-(methylsulfonyI)biphenyl-4-yloxy)methyl)-l-((l- (trifluoromethyl)cyclopropyl)methyl)piperidine

Step 1. (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl) cyclopropyl)methanone: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine hydrochloride [the product of synthesis step 5 of compound 431; 74 mg, 0.20 mmol], 1- (trifluoromethyl)cyclopropan-l-carboxylic acid (30 mg, 0.20 mmol), and EDC (74 mg, 0.39 mmol) and HOBt (52 mg, 0.39 mmol) were dissolved in DMF 3 mL, and then DIPEA (173 iL, 0.97 mmol) was added thereto. At 80 °C, the reaction was performed for 16 hours. The reaction mixture was added with CH ₂ C1 ₂ , and washed with saturated NH ₄ C1 aqueous solution. The obtained organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (30 mg, 32%).

Step 2. Compound 500 : (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)(l-(trifluoromethyl)cyclopropyl)methanone (50 mg, 0.10 mmol) was dissolved in dry THF 2 mL, and then cooled with ice bath. LAH (1 M in THF, 0.21 mL, 0.21 mmol) was added dropwise slowly thereto, following with increasing the temperature to room temperature slowly and stirring for 4 hours. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20- 40 % EtOAc/hexane) to yield the title compound as white solid (26 mg, 54%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.99 - 7.96 (m, 2 H), 7.74 - 7.71 (m, 2 H), 7.56 - 7.52 (m, 2 H), 7.01 - 6.98 (m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.09 (s, 3 H), 3.06 - 2.96 (m, 4 H), 2.41 (t, 2 H, J = 10.9 Hz), 1.87 - 1.81 (m, 3 H), 1.56 (s, 2 H), 1.52 - 1.43 (m, 2 H); MS (ESI) m/z 468 (M+ + Example 6. Compound 542: 4-((4'-(methylsuIfonyl)biphenyl-4-yloxy)methyl)-l-((l- (trifluoromethyl)cyclobutyI)methyl)piperidine

Step 1. (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl) cyclobutyl)met anone: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2- trifluoroacetate [the product of synthesis step 5 of compound 431 ; 140 mg, 0.37 mmol], 1- (trifluoromethyl)cyclobutanecarboxylic acid (92 mg, 0.55 mmol), EDC (141 mg, 0.73 mmol) and HOBt (99 mg, 0.73 mmol) were dissolved in DMF 2 mL, and then DIPEA (95 mg, 0.73 mmol) was added thereto. At 60 °C, the reaction was performed for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50-60 % EtOAc/hexane) to yield the title compound as white solid (105 mg, 57%).

Step 2. Compound 542 : (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)( 1 - (trifluoromethyl)cyclobutyl)methanone (80 mg, 0.16 mmol) was dissolved in dry THF 6 mL, and then cooled with ice bath. LAH (1 in THF, 0.18 mL, 0.18 mmol) was added dropwise slowly thereto, following with increasing the temperature to room temperature slowly and stirring for 1 hour. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS04, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50 % EtOAc/hexane) to yield the title compound as white solid (9 mg, 11%).

1H NMR (400 MHz, CDC1 ₃ ) 5 7.97 (dd, 2 H, J = 6.7, 1.9 Hz), 7.73 (dd, 1 H, J = 6.7, 1.8 Hz), 7.55 (dd, 2 H, J = 6.8, 2.0 Hz), 7.00 (dd, 2 H, J - 6.3, 2.0 Hz), 3.85 (d, 2 H, J = 6.1 Hz), 3.08 (s, 3 H), 2.09 (m, 2 H), 2.53 (s, 2 H), 2.23 (m, 4 H), 1.92 (m, 7 H), 1.45 (m, 2 H).; MS (ESI) m/z 482 (M+ + H).

Example 7. Compound 546: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyI)-l-((l- (trifluoromethyl)cyclopentyI)methyl)piperidine

Step 1. (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)( 1 - (trifluoromethyl)cyclopentyl)methanone: 4-((4'-(methylsulfonyl)biphenyl-4- yloxy)methyl)piperidine 2,2,2-trifluoroacetate [the product of synthesis step 5 of compound 431; 150 mg, 0.39 mmol], l-(trifluoromethyl)cyclopentanecarboxylic acid (107 mg, 0.59 rnmol), EDC (151 mg, 0.79 mmol) and HOBt (106 mg, 0.79 mmol) were dissolved in DMF 2 mL, and then DIPEA (101 mg, 0.79 mmol) was added thereto. At 60 °C, the reaction was performed for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (50- 60 % EtOAc / hexane) to yield the title compound as white solid (90 mg, 45%).

Step 2. Compound 546 : (4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)(l-(trifluoromethyl)cyclopentyl)methanone (35 mg, 0.07 mmol) was dissolved in dry THF 4 mL, and then cooled with ice bath. LAH (1 M in THF, 0.18 mL, 0.18 mmol) was added dropwise slowly thereto, following with increasing the temperature to 60 °C slowly and stirring for a day. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by Prep. TLC (40 % EtOAc/hexane) to yield the title compound as white solid (5 mg, 14%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.97 (dd, 2 H, J = 6.8, 1.9 Hz), 7.72 (dd, 2 H, J = 6.8, 1.9 Hz), 7.54 (dd, 2 H, J = 6.8, 2.0 Hz), 6.99 (dd, 2 H, J = 6.8, 2.0 Hz), 3.84 (d, 2 H, J = 6.0 Hz), 3.08 (s, 3 H), 2.46 (s, 2 H), 2.26 (m, 2 H), 2.17 (s, 4 H), 1.81 (m, 4 H), 1.67 (m, 5 H), 1.40 (m, 2 H); MS (ESI) m/z 496 (M+ + H).

Example 8. Compound 547:

l-(2,2-difluoroprop '-(methylsuIfonyl)biphenyl-4-yloxy)methyl)piperidine

Step 1. 1 -(4-((4 ^, -(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 -yl)propan-2-one 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate (the product of synthesis step 5 of compound 431; 50 mg, 0.11 mmol) and l-chloropropan-2-one (13 ί, 0.16 mmol) were dissolved in MeCN 2 mL. K ₂ C0 ₃ (53 mg, 0.38 mmol) was added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was diluted with water, and extracted with CH ₂ C1 ₂ three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as pale gray solid (30 mg, 68%).

Step 2. Compound 547 : 1 -(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)propan-2-one (32 mg, 0.08 mmol) was dissolved in CH ₂ C1 ₂ 0.5 mL, and then Deoxo-Fluor (29 iL, 0.16 mmol) was added thereto. EtOH (1 uL, 0.02 mmol) was added thereto, following with increasing the temperature to room temperature and stirring for 15 hours. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid. The obtained product was purified again by silica gel column chromatography (0-50 %

EtOAc/Hexane) to yield the title compound as white solid (7 mg, 20%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.95 - 8.01 (m, 2 H), 7.77 - 7.69 (m, 2 H), 7.59 - 7.53 (m, 2 H), 7.03 - 6.97 (m, 2 H), 3.85 (d, 2 H, J = 5.8 Hz), 3.09 (s, 3 H), 3.00 (d, 2 H, J = 11.8 Hz), 2.68 (t, 2 H, J - 13.8 Hz), 2.26 (td, 2 H, J = 11.7, 1.9 Hz), 1.88 - 1.77 (m, 3 H), 1.65 (t, 3 H, J = 18.7 Hz), 1.46 - 1.42 (m, 2 H); MS (ESI) m/z 424 (M+ + H). Example 9. Compound 589: 5-(4-(methylsulfonyl)phenyl)-2-((l-((l- (trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)p yridine

Step 1. ethyl 1 -(1 -(trifluoromethyl)cyclopropanecarbonyl)piperidin-4-carboxyla te:

l-(trifluoromethyl)cyclopropanecarboxylic acid(500 mg, 3.25 mmol), ethyl piperidin-4- carboxylate (561 mg, 3.57 mmol), EDC (1.24 g, 6.49 mmol) and HOBt (877 mg, 6.49 mmol) were dissolved in CH ₂ C1 ₂ 10 mL, and then DIPEA (114 iL, 6.49 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH ₄ CI aqueous solution, and extracted with EtOAc. The obtained organic layer was dried over MgSC«4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 %

EtOAc/hexane) to yield the title compound as colorless oil (800 mg, 84%).

Step 2. ( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methanol : ethyl 1 -( 1 - (trifluoromethyl)cyclopropanecarbonyl)piperidin-4-carboxylat e (818 mg, 2.79 mmol) was dissolved in dry THF 20 mL. At 0°C, LAH (1 M in THF, 13.94 mL, 13.94 mmol) was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. The reaction was quenched by slow addition of MeOH at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (577 mg, 87%).

Step 3. 5-bromo-2-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)pyridine: ( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methanol (577 mg, 2.43 mmol) was dissolved in THF 10 mL. At 0 °C, NaH (87 mg, 3.65 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5-dibromopyridine (0.57 g, 2.43 mmol) in THF 5 mL was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (500 mg, 52%).

Step 4. Compound 589: 5-bromo-2-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin- 4-yl)methoxy)pyridine (100 mg, 0.25 mmol), 4-(methylsulfonyl)phenylboronic acid(76 mg, 0.38 mmol), Pd(dbpf)Cl ₂ (5 mg, 0.01 mmol), Cs ₂ C0 ₃ (247 mg, 0.76 mmol) were added into a microwave reactor, and then dioxane 6 mL and water 3 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10- 50 % EtOAc/hexane) to yield the title compound as white solid (38 mg, 32%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.40 (m, 1 H), 8.02 (dd, 2 H, J = 5.2, 3.4 Hz), 7.83 (dd, 1 H, J = 8.6, 2.6 Hz), 7.72 (dt, 2 H, J = 8.6, 1.9 Hz), 6.86 (dd, 1 H, J = 8.6, 0.6 Hz), 4.21 (d, 2 H, J = 6.0 Hz), 3.10 (s, 3 H), 2.98 (d, 2 H, J = 10.1 Hz), 2.54 (s, 2 H), 1.99 (m, 2 H), 1.81 (d, 2 H, J = 10.0 Hz), 1.41 (m, 2 H), 0.98 (s, 2 H), 0.65 (s, 2 H); MS (ESI) m/z 469 (M+ + H).

Example 10. Compound 676: 5-(4-(methylsuIfonyI)phenyl)-2-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridine

Step 1. ethyl 1 -(1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-carboxylat e:

l-(trifiuoromethyl)cyclobutanecarboxylic acid (500 mg, 2.97 mmol), ethyl piperidin-4- carboxylate (514 mg, 3.27 mmol), EDC (1.14 g, 5.94 mmol) and HOBt (803 mg, 5.95 mmol) was dissolved in CH ₂ C1 ₂ 10 mL. DIPEA (1.05 mL, 5.95 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH4CI aqueous solution, and extracted with EtOAc. The organic layer was dried over MgSC>4, and then filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as colorless oil (750 mg, 82%).

Step 2. ( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methanol : ethyl 1 -( 1 - (trifluoromethyl)cyclobutanecarbonyl)piperidin-4-carboxylate (759 mg, 2.47 mmol) was dissolved in dry THF 20 mL. At 0 °C, LAH (1 M in THF, 12.34 mL, 12.34 mmol) was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. The reaction was quenched by slow addition of MeOH at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (581 mg, 94%).

Step 3. 5-bromo-2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in-4-yl)methoxy) pyridine: (l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)met hanol ( 581 mg, 2.31 mmol) were dissolved in THF 10 mL. At 0 °C, NaH (83 mg, 3.47 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5- dibromopyridine (547 mg, 2.31 mmol) in THF 5 mL was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (500 mg, 53%).

Step 4. Compound 676: 5-bromo-2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in- 4-yl)methoxy)pyridine (500 mg, 0.12 mmol), 4-(methylsulfonyl)phenylboronic acid (27 mg, 0.13 mmol), Pd(dbpf)Cl ₂ (2 mg, 0.01 mmol), Cs ₂ C0 ₃ (119 mg, 0.37 mmol) were added into a microwave reactor, and then dioxane 2 mL and water 1 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10- 50 % EtOAc/hexane) to yield the title compound as white solid (20 mg, 34%).

1H NMR (400 MHz, CDC1 ₃ ) 6 8.41 (d, 1 H, J = 2.6 Hz), 8.02 (dd, 2 H, J = 8.5, 1.8 Hz), 7.83 (dd, 1 H, J = 8.7, 2.6 Hz), 7.72 (dd, 2 H, J = 6.6, 1.7 Hz), 6.87 (d, 1 H, J = 8.6 Hz), 4.22 (d, 2 H, J = 6.2 Hz), 3.10 (s, 3 H), 2.90 (d, 2 H, J = 11.4 Hz), 2.53 (s, 2 H), 2.24 - 2.18 (m, 4 H), 2.10 - 1.79 (m, 7 H), 1.47 - 1.43 (m, 2 H); MS (ESI) m/z 483 (M+ + H).

Example 11. Compound 714: l-(2-fluoro-2-methylpropyl)-4-((2-fluoro-4'- (methyIsulfonyl)biphenyl-4-yloxy)methyI)piperidine

4-((4-bromo-3-fluorophenoxy)methyl)-l-(2-fluoro-2-methylprop yl)piperidine (the product of synthesis step 4 of compound 704; 850 mg, 2.35 mmol), 4-(methylsulfonyl)phenylboronic acid (563 mg, 2.82 mmol), Pd(dbpf)Cl ₂ (77 mg, 0.12 mmol) and Cs ₂ C0 ₃ (1.53 g, 4.69 mmol) were added to water (2 mL)/l ,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. Water was poured thereto, and the reaction mixture was extracted with EtOAc, The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1/7) to yield the title compound as yellow solid (390 mg, 38%) .

1H NMR (400 MHz, CDC1 ₃ ) 6 8.01 - 7.98 (m, 2 H), 7.73 - 7.70 (m, 2 H), 7.39 - 7.27 (m, 1 H), 6.82 - 6.72 (m, 2 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.10 (s, 3 H), 3.02 (brs, 2 H), 2.49 - 2.44 (m, 2 H), 2.19 (brs, 2 H), 1.82 - 1.79 (m, 3 H), 1.45 - 1.36 (m, 8 H); MS (ESI) m/z 438 (M+ + H).

Example 12. Compound 617: 2-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phen -5-(methylsulfonyl)pyridine

Step 1. 4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenylborop ic acid:

4-((4-bromophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine (the product of synthesis step 3 of compound 498; 0.54 g, 1.57 mmol) was dissolved in dry THF 10 mL. At -78 °C, n- BuLi (1.6 M in hexane, 1.17 mL, 1.88 mmol) was added slowly thereto. The reaction was performed at -78 °C for 30 minutes. At -78 °C, triisopropyl borate (0.47 mL, 2.04 mmol) was added thereto. The reaction was performed at room temperature for 4 hours. At 0 °C, 1 M HCl 5 mL was added thereto, and the reaction was performed for 1 hour. The reaction mixture was added with EtOAc, and stirred. The resulting precipitate was filtered to yield the title compound as white solid (0.40 g, 83%).

Step 2. Compound 617: 4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl boronic acid (50 mg, 0.16 mmol), 2-bromo-5-(methylsulfonyl)pyridine (42 mg, 0.18 mmol),

Pd(dbpf)Cl ₂ (3 mg, 0.01 mmol), Cs ₂ C0 ₃ (104 mg, 0.32 mmol) were added into a microwave reactor, and then dioxane 2 mL and water 1 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-50 % EtOAc/hexane) to yield the title compound as white solid (30 mg, 44%).

1H NMR (400 MHz, CDC1 ₃ ) δ 9.14 (m, 1 H), 8.21 (dd, 1 H, J = 8.5, 2.4 Hz), 8.05 (dt, 2 H, J = 9.0, 2.5 Hz), 7.85 (dd, 1 H, J = 8.5, 0.8 Hz), 7.02 (dt, 2 H, J = 8.9, 2.4 Hz), 3.88 (d, 2 H, J = 5.9 Hz), 3.14 (s, 3 H), 3.07 (m, 2 H), 2.60 - 2.40 (m, 2 H), 2.22 (m, 2 H), 1.85 - 1.82 (m, 3 H), 1.47 - 1.37 (m, 8 H); MS (ESI) m/z 421 (M+ + H).

According to the above-described synthesis process of compound 617 (Step 2), the compounds of Table 2 were synthesized using 4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenylboronic acid and the reactant of Table 1.

Table 1.

Compound No. Reactant Yield (%)

618 5-bromo-2-(methylsulfonyl)pyridine 47 614 4-bromo-N,N-dimethylbenzenesulfonamide 43

615 l-(4-bromophenylsulfonyl)pyrrolidine 35

616 l-(4-bromophenylsulfonyl)piperidine 35

666 (S)- 1 -(4-bromophenylsulfonyl)pyrrolidine-3 -ol 27

667 (R)-( 1 -(4-bromophenylsulfonyl)pyrrolidine-2-yl)methanol 30

668 (S)- 1 -(4-bromophenylsulfonyl)pyrrolidine-2-carboxamide 34

669 (R)-l-(4-bromophenylsulfonyl)piperidin-3-ol 33

670 (S)- 1 -(4-bromophenylsulfonyl)piperidin-3-ol 31

674 4-bromobenzenesulfonamide 34

675 4-bromo-N-methylbenzenesulfonamide 37

Table 2.

ylsulfonyl)pyrrolidine-3 -ol

1H NMR (400 MHz, CDC1 ₃ ) 6 8.13 (dd, 2 H, J = 8.6, 1.9 Hz), 7.69 (dd, 2 H, J = 8.6, 1.9 Hz), 7.55 (dd, 2 H, J = 8.6, 1.9 Hz), 6.99 (dd, 2 H, J = 8.6, 1.9 Hz), 4.41 (m, 1 H), 3.86 (d, 2 H, J = 5.9 Hz), 3.44 (m, 3 H), 3.31 (m, 1 H), 3.20 - 3.02 (m, 2 H), 2.61 - 2.45 (m, 2 H), 2.38 - 2.20 (m, 2 H), 1.97 (m, 1 H), 1.88 - 1.83 (m, 4 H), 1.61 - 1.38 (m, 9 H); MS (ESI) m/z 491 (M+ + H).

(R)-( 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- ylsulfonyl)pyrrolidine-2-yl)methanol

1H NMR (400 MHz, CDC1 ₃ ) δ 7.88 (dd, 2 H, J - 8.6, 1.9 Hz), 7.71 (dd, 2 H, J =

667 8.6, 1.9 Hz), 7.56 (dd, 2 H, J = 8.6, 1.9 Hz), 6.99 (dd, 2 H, J = 8.6, 1.9 Hz), 3.86

(d, 2 H, J = 5.9 Hz), 3.71 (m, 3 H), 3.52 (m, 1 H), 3.31 (m, 1 H), 3.08 - 2.90 (m, 2 H), 2.84 (m, 1 H), 2.60 - 2.40 (m, 2 H), 2.30 - 2.10 (m, 2 H), 1.84 - 1.70 (m, 6 H), ί .52 - 1.36 (m, 9 H); MS (ESI) m/z 505 (M+ + H).

(S)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- ylsulfonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.88 (dd, 2 H, J = 8.6, 1.9 Hz), 7.73 (dd, 2 H, J =

668 8.6, 1.9 Hz), 7.56 (dd, 2 H, J = 8.6, 1.9 Hz), 7.00 (dd, 2 H, J = 8.6, 1.9 Hz), 6.93

(m, 1 H), 5.59 (m, 1 H), 4.13 (m, 1 H), 3.87 (d, 2 H, J = 5.9 Hz), 3.62 (m, 1 H), 3.23 (m, 1 H), 3.02 (m, 2 H), 2.55 - 2.40 (m, 2 H), 2.30 - 2.12 (m, 2 H), 1.82 (m, 4 H), 1.65 (m, 3 H), 1.45 - 1.37 (m, 7 H); MS (ESI) m/z 518 (M+ + H).

(R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)biphenyl-4- ylsulfonyl)piperidin-3 -ol

1H NMR (400 MHz, CDC1 ₃ ) δ 7.79 (dd, 2 H, J = 8.6, 1.9 Hz), 7.70 (dd, 2 H, J =

669 8.6, 1.9 Hz), 7.55 (dd, 2 H, J = 8.6, 1.9 Hz), 7.00 (dd, 2 H, J = 8.6, 1.9 Hz), 3.90 - 3.85 (m, 3 H), 3.37 (m, 1 H), 3.17 (m, 1 H), 3.02 (m, 2 H), 2.85 (m, 1 H), 2.77 (m, 1 H), 2.60 - 2.40 (m, 2 H), 2.30 - 2.18 (m, 2 H), 2.09 (m, 1 H), 1.85 - 1.60 (m, 6 H), 1.48 - 1.37 (m, 9 H); MS (ESI) m z 505 (M+ + H).

(S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)biphenyl-4- ylsulfonyl)piperidin-3 -ol

1H NMR (400 MHz, CDC1 ₃ ) δ 7.79 (dd, 2 H, J = 8.6, 1.9 Hz), 7.70 (dd, 2 H, J =

670 8.6, 1.9 Hz), 7.54 (dd, 2 H, J = 8.6, 1.9 Hz), 7.00 (dd, 2 H, J = 8.6, 1.9 Hz), 3.91 - 3.85 (m, 3 H), 3.36 (m, 1 H), 3.19 (m, 1 H), 3.01 (m, 2 H), 2.85 (m, 1 H), 2.77 (m, 1 H), 2.49 - 2.43 (m, 2 H), 2.18 (m, 2 H), 2.09 (m, 1 H), 1.86 - 1.60 (m, 6 H), 1.48 - 1.37 (m, 9 H); MS (ESI) m/z 505 (M+ + H).

4'-((l-(2-fluoro-2-methyIpropyl)piperidin-4-yl)methoxy)biphe nyl-4-sulfonamide 1H NMR (400 MHz, CDC1 ₃ ) δ 7.96 (dd, 2 H, J = 8.6, 1.9 Hz), 7.70 (dd, 2 H, J = 8.6, 1.9 Hz), 7.54 (dd, 2 H, J = 8.6, 1.9 Hz), 7.00 (dd, 2 H, J = 8.6, 1.9 Hz), 4.83

674

(m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.00 (d, 2 H, J = 9.7 Hz), 2.46 (d, 2 H, J = 23.2 Hz), 2.18 (m, 2 H), 1.82 (m, 3 H), 1.45 - 1.35 (m, 8 H); MS (ESI) m/z 421 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-me thylbiphenyl-4- sulfonamide

675 1H NMR (400 MHz, CDC1 ₃ ) δ 7.89 (dd, 2 H, J = 8.6, 1.9 Hz), 7.70 (dd, 2 H, J =

8.6, 1.9 Hz), 7.55 (dd, 2 H, J = 8.6, 1.9 Hz), 7.00 (dd, 2 H, J = 8.6, 1.9 Hz), 4.36 (m, 1 H), 3.86 (d, 2 H, J = 5.8 Hz), 3.00 (d, 2 H, J = 11.5 Hz), 2.72 (d, 3 H, J - 5.4 Hz), 2.46 (d, 2 H, J = 22.8 Hz), 2.18 (m, 2 H), 1.82 (d, 3 H, J

- 1.35 (m, 8 H); MS (ESI) m/z 435 (M+ + H).

Example 13. Compound 499:

4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)-l-(2,2,2-tri fluoroethyI)piperidine

4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine hydrochloride (the product of synthesis step 5 of compound 431 ; 50 mg, 0.13 mmol) was dissolved in DMSO 2 mL. 2,2,2- trifluoroethyl trifluoromethanesulfonate (30 mg, 0.13 mmol) and K ₂ C0 ₃ (91 mg, 0.66 mmol) were added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was added with EtOAc, and washed with water three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-40 % EtOAc/hexane) to yield the title compound as white solid (23 mg, 41%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.99 - 7.96 (m, 2 H), 7.74 - 7.71 (m, 2 H), 7.56 - 7.52 (m, 2 H), 7.01 - 6.98 (m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.09 (s, 3 H), 3.06 - 2.96 (m, 4 H), 2.41 (t, 2 H, J = 10.9 Hz), 1.87 - 1.81 (m, 3 H), 1.56 (s, 2 H), 1.52 - 1.43 (m, 2 H); MS (ESI) m/z 428 (M+ + H).

Example 14. Compound 524:

4-((4'-(methylsul piperidine

Step 1. 3 ,3 ,3 -trifluoro- 1 -(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin- 1 - yl)propan- 1 -one: 4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine hydrochloride (the product of synthesis step 5 of compound 431; 40 mg, 0.11 mol) and CF ₃ CH ₂ C0C1 (16 μΐ,, 0.16 mmol) were dissolved in CH ₂ C1 ₂ 2 mL. Et ₃ N (44 μί, 0.31 mmol) was added thereto, following with stirring for 5 hours at room temperature. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , filtered to remove solid, and then concentrated under reduced pressure The obtained concentrate was purified by silica gel column chromatography (20 % EtOAc/hexane) to yield the title compound as white solid (54 mg, 113%).

Step 2. Compound 524: 3,3,3-trifluoro-l -(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl) piperidin-l-yl)propan-l-one (46 mg, 0.10 mmol) was dissolved in dry THF 2 mL, and then cooled with ice bath. 1 M LAH in THF (0.20 mL, 0.20 mmol) was added dropwise slowly thereto, following with increasing the temperature to room temperature slowly and stirring for 4 hours. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgSC^, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-40 %

EtOAc/hexane) to yield the title compound as white solid (9 mg, 19%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.00 - 7.93 (m, 2 H), 7.77 - 7.69 (m, 2 H), 7.59 - 7.52 (m, 2 H), 7.03 - 6.95 (m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.08 (s, 3 H), 2.95 (d, 2 H, J = 11.5 Hz), 2.66 - 2.57 (m, 2 H), 2.41 - 2.26 (m, 2 H), 2.11 - 2.01 (m, 2 H), 1.93 - 1.81 (m, 3 H), 1.50 - 1.36 (m, 2 H); MS (ESI) m/z 468 (M+ + H).

Example 15. Compound 470: 5-(4-((l-(2-fluoro-2-methylpropyI)piperidin-4- yI)methoxy)phenyl)-2,3-dihydrobenzo [b] thiophene 1 , 1-dioxide

Step 1. 4-(benzo[b]thiophen-5-yl)phenol: 5-bromobenzo[b]thiophene (3.0 g, 14.08 mmol) and 4-hydroxyphenylboronic acid (2.91 g, 21.11 mmol) were dissolved in DME 40 mL. Water 10 mL was added thereto. Pd(dbpf)Cl ₂ (459 mg, 0.70 mmol) and Cs ₂ C0 ₃ (13.68 g, 42.24 mmol) were added thereto, and refluxed with heating at 90 °C for a day. The reaction mixture was filtered through Celite. The obtained filtrate was extracted with EtOAc three times, dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (15-20 % EtOAc/hexane) to yield the title compound as white solid (2.30 g, 72%).

Step 2. t-butyl 4-((4-(benzo[b]thiophen-5-yl)phenoxy)methyl)piperidin- 1 -carboxylate:

4-(benzo[b]thiophen-5-yl)phenol (1.30 g, 5.74 mmol) and t-butyl 4-((methylsulfonyloxy) methyl)piperidin-l -carboxylate (the product of synthesis step 2 of compound 431 ; 2.02 g, 6.89 mmol) were dissolved in ACN 10 mL. Cs ₂ C0 ₃ (3.74 g, 11.49 mmol) was added thereto, and refluxed with heating for a day. The reaction mixture was diluted with water, and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-30 % EtOAc/hexane) to yield the title compound as white solid (1.81 g, 74%).

Step 3. t-butyl 4-((4-(l , 1 -dioxidobenzo[b]thiophen-5-yl)phenoxy)methyl)piperidin-l - carboxylate: t-butyl 4-((4-(benzo[b]thiophen-5-yl)phenoxy)methyl)piperidin- 1 -carboxylate (1.8 g, 4.28 mmol) was dissolved in CHC1 ₃ 3t) mL. m-CPBA (1.85 g, 10.70 mmol) was added thereto, following with stirring for 1 hour. A saturated NaHC0 ₃ aqueous solution was added thereto, and then , and extracted with CH ₂ C1 ₂ . The obtained concentrate was purified by silica gel column chromatography (10-20 % EtOAc/CH ₂ Cl ₂ ) to yield the title compound as white solid (1.50 g, 77%).

Step 4. t-butyl 4-((4-(l ,1 -dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)phenoxy)methyl) piperidin- 1 -carboxylate: t-butyl 4-((4-(l , 1 -dioxidobenzo[b]thiophen-5-yl)phenoxy)methyl) piperidin-1 -carboxylate (700 mg, 1.54 mmol) was dissolved in THF 10 mL and EtOH 10 mL. 10% wt Pd/C (70 mg) was added thereto, following with hydrogen gas flowing and stirring at room temperature for two days. The reaction mixture was filtered through Celite to remove a solid. The obtained filtrate was concentrated. The obtained concentrate was purified by silica gel column chromatography (20-30 % EtOAc/CH ₂ Cl ₂ ) to yield the title compound as white solid (680 mg, 96%).

Step 5. 5-(4-(piperidin-4-ylmethoxy)phenyl)-2,3-dihydrobenzo[b]thiop hene 1,1 -dioxide 2,2,2- trifluoroacetate: t-butyl 4-((4-(l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)phenoxy) methyl)piperidin-l -carboxylate (800 mg, 1.75 mmol) was dissolved in CH ₂ C1 ₂ 6 mL. TFA 161 μΐ, was added thereto, following with stirring at room temperature for 2 hours. The reaction mixture was filtered, and a recrystallization was performed with ether to yield the title compound as white solid (740 mg, 93%).

Step 6. 5-(4-((l -(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)-2, 3- dihydrobenzo[b]thiophene 1 ,1-dioxide: 5-(4-(piperidin-4-ylmethoxy)phenyl)-2,3- dihydrobenzo[b]thiophene 1,1-dioxide 2,2,2-trifluoroacetate (50 mg, 0.13 mmol) and K ₂ C0 ₃ (35 mg, 0.25 mmol) were suspended in EtOH 0.5 mL. Water 0.5 mL was added thereto, and the mixture was suspended with a little heating. 2,2-dimethyl oxirane (35 mg, 1.27 mmol) was added thereto. With a microwave radiation, the reaction was performed at 1 10 °C for 20 minutes. The reaction mixture was diluted with water, and extracted with EtOAc. The obtained concentrate was purified by silica gel column chromatography (50-60 % EtOAc/Hexane) to yield the title compound as white solid (31 mg, 57%). Step 7. Compound 470 : 5-(4-(( 1 -(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy) phenyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (14 mg, 0.03 mmol) was dissolved in CH ₂ C1 ₂ 1 mL. Deoxo-Fluor (8 mg, 0.04 mmol) was added thereto at 0 °C, following with stirring at room temperature for 3 hours. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , filtered to remove solid, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50-60 % EtOAc/Hexane) to yield the title compound as white solid (1 1 mg, 78%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.76 (d, 1 H, J = 8.2 Hz), 7.63 (d, 1 H, J = 8.7 Hz), 7.49 (m, 3 H), 6.98 (dd, 2 H, J = 9.2, 2.4 Hz), 3.84 (d, 2 H, J = 6.0 Hz), 3.53 (m, 2 H), 3.42 (m, 2 H), 2.98 (m, 2 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (td, 2 H, J = 11.7, 1.6 Hz), 1.80 (m, 3 H), 1.40 (m, 5 H), 1.33 (s, 3 H); MS (ESI) m/z 432 (M+ + H).

Example 16. Compound 540: 5-(4-((l-(2,2,2-trifluoroethyl)piperidin-4-yl)methoxy) phenyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

5-(4-(piperidin-4-ylmethoxy)phenyl)-2,3-dihydrobenzo[b]th iophene 1 , 1 -dioxide 2,2,2- trifluoroacetate (the product of synthesis step 5 of compound 470; 50 mg, 0.11 mmol) was dissolved in DMSO 1 mL. 2,2,2-trifluoroethyl trifluoromethanesulfonate (26 mg, 0.1 1 mmol) and K C0 ₃ (76 mg, 0.55 mmol) were added thereto, and stirred at room temperature for 20 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove solid, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40-60 % EtOAc/Hexane) to yield the title compound as white solid (9 mg, 18%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.77 (d, 1 H, J = 8.2 Hz), 7.64 (m, 1 H), 7.51 (m, 3 H), 6.98 (dd, 2 H, J = 6.8, 2.0 Hz), 3.85 (d, 2 H, J = 5.9 Hz), 3.53 (m, 2 H), 3.42 (m, 2 H), 3.00 (m, 4 H), 2.40 (m, 2 H), 1.85 (m, 3 H), 1.31 (m, 2 H); MS (ESI) m/z 440 (M+ + H). Example 17. Compound 574: 4-(6-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyridine-3-yl)benzoic acid

Step 1. methyl 4-(6-((l -((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3 -yl)benzoate: 5-bromo-2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyridine (the product of synthesis step 3 of compound 676; 0.34 g, 0.85 mmol), 4-(methoxycarbonyl)phenylboronic acid (306 mg, 1.70 mmol), Pd(dbpf)Cl ₂ (55 mg, 0.09 mmol), Cs ₂ C0 ₃ (1.19 g, 3.68 mmol) were added into a microwave reactor, and then dioxane 5 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (15-20 % EtOAc/hexane) to yield the title compound as white solid (80 mg, 20%).

Step 2. Compound 574: methyl 4-(6-((l-((l-(trifluoromethyl)cyclobutyi)methyl)piperidin- 4-yl)methoxy)pyridine-3-yl)benzoate (135 mg, 0.29 mmol) was dissolved in the mixed solvents of THF 2 mL / MeOH 1 mL / water 0.5 mL. LiOH H ₂ 0 (24 mg, 0.58 mmol) was added thereto, and refluxed with heating and stirring for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HC1 5 mL thereto, the resulting precipitate was filtered. The obtained solid was purified by silica gel column chromatography (30-80 % EtOAc/hexane) to yield the title compound as white solid (80 mg, 62%).

1H NMR (400 MHz, DMSO) δ 8.53 (s, 1 H), 8.07 (d, 1 H, J = 7.8 Hz), 7.99 (d, 2 H, J = 7.6 Hz), 7.78 (d, 2 H, J = 7.7 Hz), 6.92 (d, 1 H, J = 8.5 Hz), 4.15 (m, 2 H), 2.94 (m, 2 H), 2.51 (m, 2 H), 2.12 (m, 7 H), 1.90 (m, 2 H), 1.71 (m, 2 H), 1.28 (m, 2 H); MS (ESI) m/z 449 (M+ + H). Example 18. Compound 575: l-(4*-((l-((l-(trifluoromethyI)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphe -4-yl)ethanone

Step 1. t-butyl 4-((4'-acetylbiphenyl-4-yloxy)methyl)piperidin- 1 -carboxylate: t-butyl 4-((4- bromophenoxy)methyl)piperidin-l -carboxylate (the product of synthesis step 3 of compound 431; 500 mg, 1.35 mmol) and 4-acetylphenylboronic acid(244 mg, 1.49 mmol) were dissolved in dioxane 4 mL. water 1.5 mL was added thereto. Pd(dbpf)Cl ₂ (88 mg, 0.14 mmol) and Cs ₂ C0 ₃ (660 mg, 2.03 mmol) were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was filtered through Celite, and the filtrate was dissolved in EtOAc. The solution was washed with saturated NaHC0 ₃ aqueous solution and water, dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (30-40 %

EtOAc/hexane) to yield the title compound as yellow solid (400 mg, 72%).

Step 2. l-(4'-(piperidin-4-ylmethoxy)biphenyl-4-yl)ethanone hydrochloride: t-butyl 4-((4'- acetylbiphenyl-4-yloxy)methyl)piperidin-l-carboxylate (400 mg, 0.98 mmol) was dissolved in CH ₂ C1 ₂ 4 mL. 4 M HC1 488 was added thereto, following with stirring at room

temperature for 2 hours. The obtained reaction mixture was filtered to yield the title compound as white solid (330 mg, 97%).

Step 3. 1 -(4'-(( 1 -( 1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy )biphenyl-4- yl)ethanone: l-(4'-(piperidin-4-ylmethoxy)biphenyl-4-yl)ethanone hydrochloride (380 mg, 1.10 mmol), l-(trifluoromethyl)cyclobutanecarboxylic acid (185 mg, 1.10 mmol), EDC (421 mg, 2.20 mmol) and HOBt (270 mg, 2.20 mmol) were dissolved in DMF 6 mL. DIPEA (284 mg, 2.20 mmol) was added thereto, and the reaction was performed at 60 °C for 3 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40 - 50 % EtOAc / hexane) to yield the title compound as yellow solid (350 mg, 69%).

Step 4. 1 -(4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)b iphenyl-4- yl)ethanol: l-(4'-((l-(l-(trifluoromethyl)cyclobutanecarbonyl)piperidin- 4-yl)methoxy) biphenyl-4-yl)ethanone (193 mg, 0.42 mmol) was dissolved in dry THF 10 mL, and then cooled with ice bath. LAH (1 M in THF, 0.13 mL, 0.13 mmol) was added dropwise slowly thereto, following with increasing the temperature to 50 °C and stirring for a day.. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (90 mg, 48%).

Step 5. Compound 575 : 1 -(4'-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)ethanol (27 mg, 0.06 mmol) was dissolved in CH ₂ C1 ₂ 2 mL. Dess- Martin periodinane (38 mg, 0.09 mmol) was added thereto. The reaction was performed at room temperature for 3 hours. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄₎ and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound as white solid (16 mg, 59%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.02 (d, 2 H, J = 8.4 Hz), 7.66 (d, 2 H, J = 8.3 Hz), 7.58 (d, 2 H, J = 8.7 Hz), 7.00 (d, 2 H, J = 8.7 Hz), 3.86 (d, 2 H, J = 6.0 Hz), 2.91 (d, 2 H, J = 11.3 Hz), 2.64 (s, 3 H), 2.54 (s, 2 H), 2.22 (m, 4 H), 2.01 (m, 4 H), 1.82 (m, 3 H), 1.43 (m, 2 H); MS (ESI) m/z 446 (M+ + H).

Example 19. Compound 593: l-(4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin - 4-yl)methoxy)pyridine-2-yl)phenyl)ethanone

Step 1. t-butyl 4-((6-(4-acetylphenyl)pyridine-3 -yloxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-l -carboxylate (the product of synthesis step 1 of compound 597; 500 mg, 1.53 mmol) and 4-acetylphenylboronic acid(276 mg, 1.68 mmol) were dissolved in dioxane 4 mL. water 1 mL was added thereto. Pd(dppf)Cl ₂ (63 mg, 0.08 mmol) and Na ₂ C0 ₃ (660 mg, 2.03 mmol) were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was filtered through Celite, and the obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution and water, dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (30-40 % EtOAc/CH ₂ Cl ₂ ) to yield the title compound as white solid (300 mg, 47%).

Step 2. 1 -(4-(5-(piperidin-4-ylmethoxy)pyridine-2-yl)phenyl)ethanone hydrochloride:

t-butyl 4-((6-(4-acetylphenyl)pyridine-3-yloxy)methyl)piperidin-l -carboxylate (300 mg, 0.73 mmol) was dissolved in CH ₂ C1 ₂ 3 mL. 4 M HC1 201 mL was added thereto, following with stirring at room temperature for 2 hours. The obtained reaction mixture was filtered to yield the title compound as white solid (250 mg, 98%).

Step 3. 1 -(4-(5-(( 1 -( 1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy )pyridine-

2-yl)phenyl)ethanone: l-(4-(5-(piperidin-4-ylmethoxy)pyridine-2-yl)phenyl)ethanone hydrochloride (250 mg, 0.72 mmol), l-(trifluoromethyl)cyclobutanecarboxylic acid (145 mg, 0.87 mmol), EDC (276 mg, 1.44 mmol) and HOBt (195 mg, 1.44 mmol) were dissolved in DMF 2 mL. DIPEA (186 mg, 1.44 mmol) was added thereto. At 50 °C, the reaction was performed for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40-50 % EtOAc/hexane) to yield the title compound as white solid (158 mg, 47%).

Step 4. 1 -(4-(5-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-2- yl)phenyl)ethanol: 1 -(4-(5-(( 1 -(1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4- yl)methoxy)pyridine-2-yl)phenyl)ethanone (148 mg, 0.32 mmol) was dissolved in dry THF 7 mL, and then cooled with ice bath. LAH (1 M in THF, 0.96 mL, 0.96 mmol) was added dropwise slowly thereto, following with increasing the temperature to 50 °C and stirring for 6 hours. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (110 mg, 76%).

Step 5. Compound 593: l-(4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin -4- yl)methoxy)pyridine-2-yl)phenyl)ethanol (96 mg, 0.21 mmol) was dissolved in CH ₂ C1 ₂ 2 mL. DMP (118 mg, 0.28 mmol) was added thereto. The reaction was performed at room

temperature for 3 hours. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane) to yield the title compound as white solid (78 mg, 81%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, 1 H, J = 2.9 Hz), 8.02 (s, 4 H), 7.74 (d, 1 H, J = 8.7 Hz), 7.29 (dd, 1 H, J = 8.8, 3.0 Hz), 3.91 (d, 2 H, J = 6.0 Hz), 2.94 (d, 2 H, J = 11.4 Hz), 2.65 (s, 3 H), 2.57 (s, 2 H), 2.21 (m, 4 H), 2.08 (m, 2 H), 1.99 (m, 1 H), 1.94 (m, 1 H), 1.89 (m, 3 H), 1.49 (m, 2 H); MS (ESI) m/z 447 (M+ + H).

Example 20. Compound 498:

methyl 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphe nyl-4-carboxylate

Step 1. 4-((4-bromophenoxy)methyl)piperidine hydrochloride: t-butyl 4-((4-bromophenoxyl) methyl)piperidin-l-carboxylate (the product of synthesis step 3 of compound 431; 5.00 g, 13.50 mmol) was dissolved in EtOAc 10 mL. 1 M HC1 30 mL was added thereto, following with stirring at room temperature for 15 hours and refluxing with heating and stirring for 2 hours. The reaction mixture was cooled to room temperature, and filtered to yield the title compound as white solid (4.01 g, 97%).

Step 2. 1 -(4-((4-bromophenoxy)methyl)piperidin- 1 -yl)-2-methylpropan-2-ol : 4-((4- bromophenoxy)methyl)piperidine hydrochloride (1.00 g, 3.26 mmol) and ₂ C0 ₃ (0.23 g, 1.63 mmol) were suspended in EtOH 10 mL. Water 5 mL was added thereto to make a solution. 2,2-dimethyl oxirane (2.90 mL, 32.61 mmol) was added thereto. With a microwave radiation, the reaction was performed at 110 °C for 20 minutes. A little of water was added thereto, following with removing EtOH under reduced pressure, and extracting with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was

concentrated under reduced pressure to yield the title compound as white solid (1.10 g, 98%).

Step 3. 4-((4-bromophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine:

l-(4-((4-bromophenoxy)methyl)piperidin-l-yl)-2-methylpropan- 2-ol(1.10 g, 3.21 mmol) was dissolved in CH ₂ C1 ₂ 10 mL. DAST (0.43 mL, 3.21 mmol) was added thereto, following with stirring with at room temperature for 1 hour. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The organic layer was dried over MgSC>4, and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (0.77 g, 70%).

Step 4. Compound 498: 4-((4-bromophenoxy)methyl)-l-(2-fluoro-2-methylpropyl)piperi dine (770 mg, 2.24 mmol) and 4-(methoxycarbonyl)phenylboronic acid (483 mg, 2.68 mmol) were dissolved in dioxane 3 mL. water 1 mL was added thereto. Pd(dbpf)Cl ₂ (44 mg, 0.07 mmol) and Cs ₂ C0 ₃ (2.18 g, 6.71 mmol) were added thereto. With a microwave radiation, the reaction was performed at 140°C for 15 minutes. The reaction mixture was diluted with water, and extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20 % EtOAc hexane) to yield the title compound as white solid (682 mg, 76%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.11 - 8.04 (m, 2 H), 7.66 - 7.60 (m, 2 H), 7.59 - 7.53 (m, 2 H), 7.02 - 6.94 (m, 2 H), 3.93 (s, 3 H), 3.84 (d, 2 H, J = 6.0 Hz), 2.99 (d, 2 H, J = 11.0 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 1.82 - 1.79 (m, 3 H), 1.49 - 1.37 (m, 1 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 400 (M+ + H). Example 21. Compound 548:

4'-((l-(2-fluoro-2-me boxylic acid

Methyl 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate (682 mg, 1.71 mmol) was dissolved in THF 6 mL. MeOH 2 mL and H ₂ 0 2 mL were added thereto. LiOH (358 mg, 8.53 mmol) was added thereto, following with stirring at room temperature and refluxing with heating and stirring for 15 hours. After acidification with 1 N HC1, the resulting precipitate was filtered. The obtained solid was dissolved in MeOH, following with filtering to remove insoluble material and concentrating under reduced pressure to yield the title compound as pale gray solid (625 mg, 95.1%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (d, 2 H, J = 8.3 Hz), 7.72 (d, 2 H, J = 8.3 Hz), 7.65 (d, 2 H, J = 8.7 Hz), 7.02 (d, 2 H, J = 8.7 Hz), 3.85 (d, 2 H, J = 5.8 Hz), 2.90 (d, 2 H, J = 11.2 Hz), 2.42 (s, 1 H), 2.36 (s, 1 H), 2.06 (t, 2 H, J = 11.4 Hz), 1.72 - 1.69 (m, 3 H), 1.30 (m, 2 H), 1.30 (s, 3 H), 1.25 (s, 3 H); MS (ESI) m/z 486 (M+ + H).

Example 22. Compound 515:

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphe nyl-4-carboxamide

4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid (compound 548, 15 mg, 0.04 mmol) and NH ₄ C1 (4 mg, 0.08 mmol) were dissolved in DMF 1 mL. EDC (15 mg, 0.08 mmol) and HOBt (11 mg, 0.08 mmol) were added thereto. Lastly, DIPEA (34 μϋ, 0.20 mmol) was added thereto, following with stirring at room temperature for 15 hours. The solvent was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (7 mg, 48%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.81 - 7.87 (m, 2 H), 7.64 - 7.58 (m, 2 H), 7.56 - 7.50 (m, 2 H), 6.99 - 6.93 (m, 2 H), 3.82 (d, 2 H, J = 6.0 Hz), 2.97 (d, 2 H, J = 11.8 Hz), 2.46 (s, 1 H), 2.40 (s, 1 H), 2.20 - 2.04 (m, 6 H), 1.84 - 1.72 (m, 3 H), 1.49 - 1.35 (m, 2 H), 1.38 (s, 3 H), 1.32 (s, 3 H); MS (ESI) m/z 385 (M+

Example 23. Compound 612: (R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yI)methoxy)biphenyI-4-yl)(3-hydroxypiperidin-l-yI)methanone

4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid (compound 548, 50 mg, 0.13 mmol) was suspended in CH ₂ C1 ₂ 1 mL, and then added with EDC (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol) and DIPEA (113 μΐ, 0.65 mmol), thereby being dissolved completely. Lastly, (R)-hydroxypiperidine hydrochloride (36 mg, 0.26 mmol) was added thereto, following with stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, dissolved in a little of MeOH, and then added with water. The resulting precipitate was filtered to obtain a solid. The obtained solid was purified by silica gel column chromatography (0-10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (45 mg, 73%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.56 - 7.50 (m, 2 H), 7.50 - 7.46 (m, 2 H), 7.02 - 6.95 (m, 2 H), 3.94 (brs, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.47 (br, 4 H), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J - 11.2 Hz), 1.97 (br, 2 H), 1.83 - 1.80 (m, 3 H), 1.67 (br, 2 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 469 (M+ + H).

According to the above-described synthesis process of compound 515, the compounds of Table 4 were synthesized using 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphe nyl-4- carboxylic acid and the reactant of Table 3.

Table 3.

Compound

Reactant Yield (%) No.

516 dimethylamine hydrochloride 73

517 morpholine 53

526 cyclopropylamine 69

527 cyclobutylamine 67

528 cyclopentylamine 73

529 cyclohexylamine 68 530 pyrrolidine 80

531 piperidine 66

533 4-aminobutan- 1 -ol 64

534 methylamine 67 ,

549 2-aminoethanol 77

550 3 -aminopropan- 1 -ol 74

551 2-(methylamino)ethanol 71

553 (R)-3 -pyrrolidinol 72

554 (S)-3-pyrrolidinol 76

555 (R)-prolinol 77

556 (S)-prolinol 66

557 (R)-2-(methoxymethyl)pyrrolidine 80

558 (S)-2-(methoxymethyl)pyrrolidine 69

559 2-(butylamino)ethanol 66

560 fur furyl amine 78

561 propylamine 70

562 benzylamine 74

563 N-ethylbenzylamine 80

564 (S)-2-trifluoromethylpyrrolidine 71

565 L-prolinamide 67

566 3-fluoropyrrolidine hydrochloride 76

567 4-piperidinemethanol 69

568 4-hydroxypiperidine 73

569 3-hydroxypiperidine hydrochloride 55

570 (R)-3-fluoropyrrolidine hydrochloride 76

571 · (S)-3-fluoropyrrolidine hydrochloride 72

594 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[ 1 ,2,4]triazolo[4,3 -ajpyrazine 52

598 N-methylethanamine 76

599 N-methylpropan-2-amine 74

600 azetidin-3-ol 73

601 3 ,3 -difluoroazetidine 67

602 t-butylamine 79

603 isopropylamine 98

604 diethylamine 89

605 2-amino-2-methyl- 1 -propanol 81

606 (S)-2-amino- 1 -propanol 83

607 (R)-2-amino- 1 -butanol 75

608 D-valinol 84

609 L-valinol 78

610 serinol 62

611 3 -amino- 1 ,2-propanediol 65 613 (S)-3 -hydroxypiperidine hydrochloride 79

619 (R)-methyl pyrrolidine-2-carboxylate ii48

622 (S)-methyl pyrrolidine-2-carboxylate 42

623 cyclopropyl(piperazin- 1 -yl)methanone 83

624 1 -(methylsulfonyl)piperazine 87

625 (S)-methyl pyrrolidine-2-carboxylate 23

626 t-butyl piperazin-l -carboxylate 62

627 1 -benzylpiperazine 51

628 1 -(piperazin- 1 -yl)ethanone 17

629 3,3-difluoro pyrrolidine 40

645 glycine methyl ester hydrochloride 82

646 3-oxetaneamine 77

647 β-alanine methyl ester 78

648 D-serine methyl ester hydrochloride 71

649 L-serine methyl ester hydrochloride 57

650 ethyl 4-amino-l-piperidinecarboxylate 83

651 amylamine 81

677 ethyl piperidin-2-carboxylate 72

678 ethyl piperidin-4-carboxylate 83

679 ethyl piperidin-3-carboxylate 85

680 1-ethylpiperazine 48

681 1 -isopropylpiperazine 42

685 1 -methylpiperazine 47

686 2,6-dimethylpiperazine 17

687 2,6-dimethylmo holine 58

790 piperazin-2-one 82

791 piperidin-4-carbonitrile 77

830 4-(2-aminoethyl)benzene- 1 ,2-diol 25

831 (R)-piperidin-2-carboxamide hydrochloride 65

832 (S)-piperidin-2-carboxamide hydrochloride 71

874 (S)-piperidin-3 -carboxamide hydrochloride 64

879 (R)-piperidin-3 -carboxamide hydrochloride 79

Table 4.

H), 1.85 - 1.75 (m, 3 H), 1.50 - 1.38 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 413 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)(morpholino)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.57 - 7.62 (m, 2 H), 7.55 - 7.50 (m, 2 H), 7.49 -

517 7.44 (m, 2 H), 7.00 - 6.95 (m, 2 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.81 - 3.45 (m, 8 H), 2.99 (d, 2 H, J = 11.8 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.21 - 2.12 (m, 2 H), 1.85 - 1.76 (m, 3 H), 1.49 - 1.38 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 455 (M+ + H).

N-cyclopropyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl- 4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.81 - 7.75 (m, 2 H), 7.62 - 7.57 (m, 2 H), 7.56 -

526 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 6.25 (s, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 2.99 (d, 2 H, J = 11.3 Hz), 2.95 - 2.89 (m, 1 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.19 - 2.14 (m, 2 H), 1.85 - 1.75 (m, 3 H), 1.47 - 1.39 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 0.93 - 0.85 (m, 2 H), 0.67 - 0.60 (m, 2 H); MS (ESI) m/z 425 (M+ + H).

N-cyclobutyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)biphenyl-4- carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.83 - 7.77 (m, 2 H), 7.63 - 7.58 (m, 2 H), 7.57 - 527 7.51 (m, 2 H), 7.01 - 6.95 (m, 2 H), 6.24 (d, 1 H, J = 8.0 Hz), 4.65 - 4.59 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 2.99 (d, 2 H, J = 11.3 Hz), 2.51 - 2.40 (m, 4 H), 2.17 (t, 2

H, J = 10.8 Hz), 2.04 - 1.91 (m, 2 H), 1.85 - 1.75 (m, 5 H), 1.49 - 1.37 (m, 2 H),

I.39 (s, 3H), 1.34 (s, 3 H); MS (ESI) m/z 439 (M+ + H).

N-cyclopentyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl- 4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.79 (d, 2 H, J = 8.5 Hz), 7.59 (d, 2 H, J = 8.3 Hz),

528 7.56 - 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 6.12 (d, 1 H, J = 7.3 Hz), 4.48 - 4.37 (m,

1 H), 3.84 (d, 2 H, J = 6.0 Hz), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.21 - 2.05 (m, 4 H), 1.86 - 1.60 (m, 7 H), 1.56 - 1.37 (m, 4 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 453 (M+ + H).

N-cyclohexyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)biphenyl-4- carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.80 (d, 2 H, J = 8.5 Hz), 7.60 (d, 2 H, J = 8.5 Hz),

529 7.56 - 7.51 (m, 2 H), 6.98 (d, 2 H, J = 8.8 Hz), 6.00 - 5.94 (m, 1 H), 4.07 - 3.94 (m,

1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.03 - 2.95 (m, 2 H), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.19 - 2.14 (m, 2 H), 2.10 - 2.00 (m, 2 H), 1.82 - 1.75 (m, 5 H), 1.51 - 1.37 (m, 4 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.31 - 1.20 (m, 4 H); MS (ESI) m/z 467 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)b iphenyl-4- yl)(pyrrolidine- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.57 (s, 4 H), 7.55 - 7.51 (m, 2 H), 7.00 - 6.95 (m, 2

530 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.67 (t, 2 H, J = 7.0 Hz), 3.50 (t, 2 H, J = 6.5 Hz), 2.98 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.21 - 2.11 (m, 2 H), 2.02 - 1.93 (m, 2 H), 1.92 - 1.87 (m, 2 H), 1.84 - 1.74 (m, 3 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 439 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(piperidin- l-yl)methanone

531 IH NMR (400 MHz, CDCI ₃ ) δ 7.59 - 7.55 (m, 2 H), 7.54 - 7.49 (m, 2 H), 7.47 - 7.41 (m, 2 H), 7.00 - 6.94 (m, 2 H), 3.84 (d, 2 H, J = 5 .8 Hz), 3.72 (br, 2 H), 3.41 (br, 2 H), 2.98 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (td, 2 H, J = 11.7, 2.0 Hz), 1.86 - 1.74 (m, 3 H), 1.74 - 1.50 (m, 6 H), 1.48 - 1.36 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 453 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(4 - hydroxybutyl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDCI3) δ 7.84 - 7.78 (m, 2 H), 7.64 - 7.58 (m, 2 H), 7.57 -

533 7.50 (m, 2 H), 7.01 - 6.94 (m, 2 H), 6.50 (t, 1 H, J = 5.6 Hz), 3.84 (d, 2 H, J = 5.8 Hz), 3.75 (t, 2 H, J = 6.0 Hz), 3.53 (q, 2 H, J = 6.5 Hz), 2.99 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.8 Hz), 1.86 ^" ^ 1.60 (m, 7 H), 1.49 - 1.37 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-me thylbiphenyl-4- carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.83 - 7.78 (m, 2 H), 7.64 - 7.58 (m, 2 H), 7.57 -

534 7.52 (m, 2 H), 7.01 - 6.94 (m, 2 H), 6.16 (d, 1 H, J = 4.3 Hz), 3.84 (d, 2 H, J = 6.0 Hz), 3.04 (d, 3 H, J = 4.8 Hz), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 1.85 - 1.75 (m, 3 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 399 (M+ + H).

4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(2- hydroxyethyl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.85 - 7.79 (m, 2 H), 7.62 - 7.56 (m, 2 H), 7.55 -

549 7.49 (m, 2 H), 7.00 - 6.93 (m, 2 H), 6.75 (t, 1 H, J = 5.4 Hz), 3.89 - 3.80 (m, 4 H), 3.69 - 3.61 (m, 2 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 1.86 - 1.74 (m, 3 H), 1.49 - 1.37 (m, 2 H), 1.41 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 429 (M+ + H).

4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(3 - hydroxypropyl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.85 - 7.79 (m, 2 H), 7.63 - 7.57 (m, 2 H), 7.56 -

550 7.49 (m, 2 H), 7.00 - 6.93 (m, 2 H), 6.78 (br, 1 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.73 (t, 2 H, J = 5.5 Hz), 3.65 (q, 2 H, J = 6.1 Hz), 2.99 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 1.85 - 1.73 (m, 5 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 443 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(2 -hydroxyethyl)-N- methylbiphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.63 - 7.45 (m, 6 H), 6.97 (d, 2 H, J = 8.8 Hz), 3.92

551 (br, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.75 (br, 2 H), 3.51 (br, 1H), 3.11 (br, 3 H) 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 1.86 - 1.73 (m, 3 H), 1.50 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 443 (M+ + H).

(R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(3- hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.47 (m, 6 H), 6.96 (d, 2 H, J = 8.8 Hz), 3.83

553

(d, 2 H, J = 5.8), 3.80 - 3.47 (m, 4 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 2.10 - 1.91 (m, 3 H), 1.86 - 1.73 (m, 3 H), 1.50 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 455 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(3- hydroxypyrrolidine- 1 -yl)methanone

554

1H NMR (400 MHz, CDC1 ₃ ) 8 7.60 - 7.46 (m, 6 H), 6.99 - 6.93 (m, 2 H), 3.83 (d, 2 H, J - 5.8 Hz), 3.80 - 3.45 (m, 4 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.22 - 2.11 (m, 2 H), 2.11 - 1.91 (d, 3 H, J = 3.5 Hz), 1.85 - 1.73 (m, 3 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 455 (M+ + H).

(R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(2- (hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.62 - 7.55 (m, 4 H), 7.54 - 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 4.43 (d, 1 H, J = 6.0 Hz), 3.87 - 3.71 (m, 4 H), 3.66 - 3.49 (m, 2 H), 2.98 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.20 - 2.13 (m, 3 H), 1.95 - 1.58 (m, 6 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 469 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(2- (hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.55 (m, 4 H), 7.54 - 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 4.48 - 4.38 (m, 1 H), 3.87 - 3.71 (m, 4 H), 3.66 - 3.48 (m, 2 H), 2.98 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.16 (m, 3 H), 1.94 - 1.58 (m, 6 H), 1.49 - 1.36 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 469 (M+ + H).

(R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)biphenyl-4-yl)(2- (methoxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (s, 4 H), 7.55 - 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 4.46 (br, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.74 - 3.47 (m, 4 H), 3.41 (s, 3 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.22 - 2.12 (m, 2 H), 2.12 - 1.90 (m, 3 H), 1.86 - 1.69 (m, 4 H), 1.50 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 483 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(2- (methoxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (s, 3 H), 7.55 - 7.49 (m, 2 H), 7.01 - 6.93 (m, 2 H), 4.46 (br, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.74 - 3.47 (m, 4 H), 3.41 (s, 3 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.22 - 2.12 (m, 2 H), 2.11 - 1.89 (m, 3 H), 1.85 - 1.72 (m, 4 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 483 (M+ + H).

N-butyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)-N-(2- hydroxyethyl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.0 Hz), 7.53 (d, 2 H, J = 8.8 Hz), 7.47 - 7.42 (m, 2 H), 7.01 - 6.94 (m, 2 H), 3.90 (br, 2 H), 3.84 (d, 2 H, J - 6.0 Hz), 3.72 (br, 2 H), 3.33 (br, 2 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.9 Hz), 1.86 - 1.73 (m, 3 H), 1.58 (br, 2 H), 1.50 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.28 - 1.14 (m, 2 H), 0.83 (br, 3 H); MS (ESI) m/z 485 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(f uran-2- ylmethyl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.86 - 7.80 (m, 2 H), 7.63 - 7.57 (m, 2 H), 7.56 - 7.50 (m, 2 H), 7.38 (dd, 1 H, J - 1.8, 0.8 Hz), 7.01 - 6.93 (m, 2 H), 6.49 (t, 1 H, J = 5.1 Hz), 6.37 - 6.29 (m, 2 H), 4.66 (d, 2 H, J = 5.5 Hz), 3.83 (d, 2 H, J = 6.0 Hz), 2.98 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.21 - 2.11 (m, 2 H), 1.86 - 1.70, (m, 3 H) 1.51 - 1.36, (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 465 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-pr opylbiphenyl-4- carboxamide IH NMR (400 MHz, CDC1 ₃ ) δ 7.88 - 7.78 (m, 2 Η), 7.66 - 7.59 (m, 2 H), 7.59 - 7.49 (m, 2 H), 7.05 - 6.93 (m, 2 H), 6.17 (t, 1 H, J = 5.8 Hz), 3.85 (d, 2 H, J = 6.0 Hz), 3.52 - 3.41 (m, 2 H), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, IH), 2.43 (s, IH), 2.18 (t, 2 H, J = 10.8 Hz), 1.88 - 1.73 (m, 3 H), 1.72 - 1.63 (m, 2 H), 1.52 - 1.41 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H), 1.02 (t, 3 H, J = 7.4 Hz); MS (ESI) m/z 427 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-pr opylbiphenyl-4- carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.85 (d, 2 H, J = 8.5 Hz), 7.62 (d, 2 H, J = 8.5 Hz),

562 7.59 - 7.50 (m, 2 H), 7.44 - 7.29 (m, 5 H), 7.04 - 6.93 (m, 2 H), 6.44 (t, 1 H, J = 5.5 Hz), 4.69 (d, 2 H, J = 5.5 Hz), 3.85 (d, 2 H, J = 5.8 Hz), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, IH), 2.43 (s, IH), 2.18 (t, 2 H, J = 10.9 Hz), 1.83 - 1.82 (d, 3 H), 1.48 - 1.41 (m, 2 H), 1.41 (s 3H), 1.35 (s, 3H); MS (ESI) m/z 475 (M+ + H).

N-benzyl-N-ethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.66 - 7.45 (m, 6 H), 7.43 - 7.17 (m, 5 H), 6.98 (d,

563 2 H, J = 7.8 Hz), 4.81 (br,l H), 4.59 (br, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.55 - 3.53 (m, 1 H), 3.29 (br, 1 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, IH), 2.43 (s, IH), 2.18 (t, 2 H, J = 11.2 Hz), 1.83 - 1.80 (m, 3 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.29 - 1.12 (m, 3H); MS (ESI) m/z 503 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-yl)(2- (trifluoromethyl)pyrrolidine- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.69 - 7.58 (m, 4 H), 7.57 - 7.52 (m, 2 H), 7.02 -

564 6.96 (m, 2 H), 5.18 (br, IH), 3.85 (d, 2 H, J = 6.0 Hz), 3.73 - 3.55 (m, 2 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.43 (m, 1 H), 2.26 - 2.03 (m, 5 H), 1.96 - 1.74 (m, 4 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 507 (M+ + H).

(S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.60 (s, 4 H) 7.53 (d, 2 H, J = 8.8 Hz) 7.07 (br, 1

565 H) 6.98 (d, 2 H, J = 8.5 Hz) 5.71 (br, 1 H) 4.82 (dd, 1 H, J = 7.4, 5.4 Hz) 3.84 (d, 2

H, J = 6.0 Hz) 3.70 - 3.53 (m, 2 H) 3.00 (d, 2 H, J = 11.5 Hz) 2.48 (s, 1 H), 2.46 -

2.39 (m, 1 H), 2.42 (s, 1 H) 2.23 - 1.96 (m, 4 H) 1.93 - 1.72 (m, 4 H) 1.52 - 1.38

(m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 482 (M+ + H).

(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - fluoropyrrolidine- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.66 - 7.50 (m, 6 H) 7.03 - 6.95 (m, 2 H) 5.30 (t, 1

566 H, 51.3 Hz) 4.04 - 3.61 (m, 6 H) 3.00 (d, 2 H, J = 11.5 Hz) 2.48 (s, 1 H), 2.43 (s, 1 H) 2.43 - 2.18 (m, 1 H) 2.18 (t, 2 H, J = 10.8 Hz) 2.13 - 1.91 (m, 1 H) 1.88 - 1.74 (m, 3 H) 1.53 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(4- (hydroxymethyl)piperidin- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.55 - 7.50 (m, 2 H), 7.47 -

567 7.42 (m, 2 H), 7.01 - 6.95 (m, 2 H), 4.76 (br, 1 H), 3.89 (br, IH), 3.84 (d, 2 H, J = 6.0 Hz), 3.53 (d, 2 H, J = 3.8 Hz), 3.03 (br, 1 H), 3.00 (d, 2 H, J - 11.5 Hz), 2.80 (br, 1 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.23 - 2.12 (m, 2 H), 1.95 - 1.67 (m, 7 H), 1.52 - 1.38 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.29 -1.19 (m, 2 H); MS (ESI) m/z 483 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(4- hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.55 - 7.50 (m, 2 H), 7.45 (d, 2 H, J = 8.5 Hz), 7.01 - 6.95 (m, 2 H), 4.23 (br, 1 H), 4.01 - 3.95 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.76 (br, 1 H), 3.48 - 3.15 (m, 2 H), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.0 Hz), 2.07 - 1.74 (m, 6 H), 1.71 - 1.38 (m, 4 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 469 (M+ + H).

(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.55 - 7.51 (m, 2 H), 7.48 (d, 2 H, J = 8.3 Hz,), 7.02 - 6.95 (m, 2 H), 3.94 (br, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.80 -3.16 (br, 3 H), 3.01 (d, 2 H, J = 10.8 Hz), 2.49 (s, 1 H), 2.44 (s, 1 H), 2.19 (t,

2 H, J = 11.0 Hz), 2.08 - 1.52 (m, 9 H), 1.51 - 1.39 (m, 2 H), 1.41 (s, 3 H), 1.36 (s,

3 H); MS (ESI) m/z 469 (M+ + H).

(R)-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - fluoropyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 6 7.66 - 7.57 (m, 4 H), 7.54 (d, 2 H, J = 8.5 Hz), 7.02 - 6.96 (m, 2 H), 5.45 - 5.14 (m, 1 H), 4.02 - 3.87 (m, 2 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.82 - 3.62 (m, 2 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.39 - 2.22 (m, 1 H), 2.22 - 2.13 (m, 2 H), 2.13 - 1.91 (m, 1 H), 1.87 - 1.74 (m, 3 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metli oxy)biphenyl-4-yl)(3- fluoropyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.66 - 7.57 (m, 4 H), 7.54 (d, 2 H, J = 8.5 Hz), 7.02 - 6.95 (m, 2 H), 5.45 - 5.14 (m, 1 H), 4.04 - 3.87 (m, 2 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.82 - 3.61 (m, 5 H), 3.00 (d, 5 H, J = 11.3 Hz), 2.48 (s, 3 H), 2.43 (s, 3 H), 2.40 - 2.23 (m, 1 H), 2.22 - 2.13 (m, 2 H), 2.12 - 1.92 (m, 1 H), 1.87 - 1.74 (m, 3 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3H), 1.35 (s, 8 H); MS (ESI) m/z 457 (M+ + H).

(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - (trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine -7(8H)-yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) 8 7.65 (d, 2 H, J = 6.7 Hz), 7.54 (d, 4 H, J = 8.6 Hz), 7.00 (d, 2 H, J = 8.8 Hz), 5.10 (s, 2 H), 4.27 (m, 2 H), 4.13 (m, 2 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.01 (m, 2 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.3 Hz), 1.82 (m, 2 H), 1.47 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 560 (M+ + H)

N-ethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)-N- methylbiphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J= 8.0 Hz), 7.53 (d, 2 H, J= 8.0 Hz), 7.46 (m, 2 H), 6.98 (d, 2 H, J= 8.5 Hz), 3.86 (d, 2 H, J= 5.6 Hz), 3.62 (brs, 1 H), 3.38 (brs, 1 H), 3.05 (m, 5 H), 2.47 - 2.38 (m, 4 H), 1.85 - 1.82 (m, 2 H), 1.53- 1.37 (m, 10 H), 1.28 - 1.15 (m, 3 H); MS (ESI) m/z 427 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-is opropyl-N- methylbiphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.0 Hz), 7.53 (d, 2 H, J = 8.6 Hz), 7.43 - 7.42 (m, 2 H), 6.98 (d, 2 H, J = 8.6 Hz), 4.16 (brs, 1H), 3.86 (d, 2 H, J = 5.8 Hz), 3.02 - 2.85 (m, 5H), 2.32 (brs, 2 H), 2.20 (brs, 2 H), 1.82 - 1.68 (m, 3 H), 1.53 - 1.37 (m, 8 H), 1.19 (s, 6 H); MS (ESI) m/z 441 (M+ + H). (4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - hydroxyazetidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.65 (d, 2 H, J = 7.8 Hz), 7.54 (dd, 4 H, J = 20.0,

600 8.0 Hz), 6.97 (d, 2 H, J = 8.1 Hz), 4.71 (brs, 1 H), 4.49 (brs, 2 H), 4.22 (brs, 2H), 3.84 (d, 2 H, J = 4.9 Hz), 3.53 (d, 1 H, J = 5.4 Hz), 3.03 (brs, 2 H), 2.49 (d, 2 H, J = 21.4 Hz), 2.21 (brs, 2 H), 1.84 - 1.82 (m, 3 H), 1.42 - 1.36 (m, 8 H); MS (ESI) m/z 441 (M+ + H)

(3,3-difluoroazetidin-l-yl)(4'-((l-(2-fluoro-2-methylpropyl) piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

601 1H NMR (400 MHz, CDC1 ₃ ) 6 7.70 (d, 2 H, J= 8.2 Hz), 7.63 (d, 2 H, J= 8.2 Hz), 7.55 (d, 2 H, J= 8.6 Hz), 6.99 (d, 2 H, J= 8.6 Hz), 4.58 (t, 4 H, J= 11.5 Hz), 3.86 (d, 2 H, J= 5.8 Hz), 3.03 (brs, 2 H), 2.52 - 2.45 (m, 2 H), 2.21 (brs, 2 H), 1.83 (d, 3 H, J= 10.0 Hz), 1.48 - 1.36 (m, 8 H); MS (ESI) m/z 461 (M+ + H).

N-t-butyl-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)b iphenyl-4- carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.79 - 7.74 (m, 2 H), 7.62 - 7.57 (m, 2 H), 7.56 -

602 7.51 (m, 2 H), 7.01 - 6.95 (m, 2 H), 5.96 (s, 1 H), 3.84 (d, 2 H, J = 5.8 Hz), 2.98 (d, 2 H, J = 11.8 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.19 - 2.14 (m, 2 H), 1.81 (d, 3 H, J = 11.5 Hz), 1.49 (s, 9 H), 1.38 - 1.46 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 441 (M+ + H).

4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-is opropylbiphenyl-4- carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.83 - 7.77 (m, 2 H), 7.63 - 7.58 (m, 2 H), 7.57 -

603 7.51 (m, 2 H), 7.01 - 6.95 (m, 2 H), 5.93 (d, 1 H, J = 8.0 Hz), 4.34 - 4.29 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 2.99 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.21 - 2.12 (m, 2 H), 1.82 - 1.79 (m, 3 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.28 (d, 6 H, J = 6.5 Hz); MS (ESI) m/z 427 (M+ + H).

N,N-diethyl-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)m ethoxy)biphenyl-4- carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 - 7.55 (m, 2 H), 7.55 - 7.50 (m, 2 H), 7.46 -

604 7.40 (m, 2 H), 7.01 - 6.94 (m, 2 H), 3.84 (d, 2 H, J = 5.8 Hz), 3.57 (br, 2 H), 3.32 (br, 2 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.9 Hz), 1.87 - 1.74 (m, 3 H), 1.52 - 1.37 (m, 2 H), 1.41 (s, 3 H), 1.34 (s, 3 H), 1.31 - 1.07 (m, 6 H); MS (ESI) m/z 441 (M+ +Ή).

4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-( 1 -hydroxy-2- methylpropan-2-yl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.81 - 7.74 (m, 2 H), 7.63 - 7.58 (m, 2 H), 7.57 -

605 7.50 (m, 2 H), 7.01 - 6.94 (m, 2 H), 6.26 (s, 1 H), 3.84 (d, 2 H, J = 5.8 Hz), 3.71 (s, 2 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.8 Hz), 1.81 (dd, 3 H, J = 8.8, 2.8 Hz), 1.45 - 1.39 (m, 2 H), 1.44 (s, 6 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

(S)-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-( 1 -hydroxypropan- 2-yl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.82 (d, 2 H, J = 8.5 Hz), 7.64 - 7.59 (m, 2 H), 7.57

606 - 7.51 (m, 2 H), 7.01 - 6.95 (m, 2 H), 6.34 (d, 1 H, J = 7.3 Hz), 4.37 - 4.27 (m, 1 H), 3.88 - 3.78 (m, 3 H), 3.68 (m, 1 H), 2.99 (d, 2 H, J = 11.0 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 11.8 Hz), 1.82 - 1.79 (m, 3 H), 1.51 - 1.38 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.32 (d, 3 H, J = 6.8 Hz); MS (ESI) m/z 443 (M+ + H). (R)-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-( 1 -hydroxybutan- 2-yl)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.85 - 7.79 (m, 2 H), 7.62 - 7.57 (m, 2 H), 7.56 -

607 7.50 (m, 2 H), 7.00 - 6.94 (m, 2 H), 6.39 (d, 1 H, J = 7.8 Hz), 4.14 - 4.16 (m, 1 H), 3.87 - 3.79 (m, 3 H), 3.76 - 3.69 (m, 1 H), 2.99 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.9 Hz), 1.86 - 1.58 (m, 5 H), 1.51 - 1.37 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.04 (t, 3 H, J = 6.0 Hz); MS (ESI) m/z 457 (M+ + H).

(R)-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)-N-(l-hydroxy-3- methylbutan-2-yl)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.86 - 7.80 (m, 2 H), 7.65 - 7.59 (m, 2 H), 7.57 -

608 7.51 (m, 2 H), 7.02 - 6.95 (m, 2 H), 6.36 (d, 1 H, J = 8.3 Hz), 4.01 - 3.94 (m, 1 H), 3.88 - 3.77 (m, 4 H), 2.99 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.8 Hz), 2.10 - 1.99 (m, 1 H), 1.86 - 1.75 (m, 3 H), 1.50 - 1.37 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.05 (t, 6 H, J = 6.4 Hz); MS (ESI) m/z 471 (M+ + H).

(S)-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)-N-(l-hydroxy-3- methylbutan-2-yl)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.86 - 7.81 (m, 2 H), 7.66 - 7.60 (m, 2 H), 7.57 -

609 7.51 (m, 2 H), 7.02 - 6.95 (m, 2 H), 6.35 (d, 1 H, J = 8.5 Hz), 4.03 - 3.93 (m, 1 H), 3.89 - 3.78 (m, 4 H), 2.99 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.22 - 2.12 (m, 2 H), 2.09 - 2.00 (m, 1 H), 1.83 - 1.80 (m, 3 H), 1.51 - 1.38 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.05 (t, 6 H, J = 6.4 Hz); MS (ESI) m/z 471 (M+ + H).

N-( 1 ,3 -dihydroxypropan-2-yl)-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.85 (d, 2 H, J = 8.5 Hz), 7.60 (d, 2 H, J = 8.5 Hz),

610 7.49 - 7.55 (m, 2 H), 7.21 (s, 1 H), 6.99 - 6.92 (m, 2 H), 4.12 - 4.03 (m, 1 H), 3.91 - 3.71 (m, 6 H), 2.97 (d, 2 H, J = 11.5 Hz), 2.46 (s, 1 H), 2.40 (s, 1 H), 2.15 (t, 2 H, J = 8.0 Hz), 1.80 - 1.77 (m, 3 H), 1.49 - 1.35 (m, 2 H), 1.38 (s, 3 H), 1.32 (s, 3 H); MS (ESI) m/z 459 (M+ + H).

N-(2,3-dihydroxypropyl)-4'-((l-(2-fluoro-2-methylpropyl)pipe ridin-4- yl)methoxy)biphenyl-4-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.85 (d, 2 H, J = 8.3 Hz), 7.62 (d, 2 H, J = 8.5 Hz),

611 7.57 - 7.51 (m, 2 H), 7.27 (t, 1 H, J = 4.0 Hz), 7.01 - 6.95 (m, 2 H), 3.90 - 3.82 (m, 3 H), 3.68 - 3.53 (m, 4 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.17 (t, 2 H, J = 11.3 Hz), 1.82 - 1.80 (m, 3 H), 1.37 - 1.51 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 459 (M+ + H).

(S)-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 - hydroxypiperidin- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.55 - 7.51 (m, 2 H), 7.50 -

613 7.46 (m, 2 H), 7.02 - 6.95 (m, 2 H), 4.07 - 3.89 (m, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.81 - 3.17 (m, 4 H), 3.00 (d, 2 H, J = 11.0 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.3 Hz), 1.96 (br, 2 H), 1.83 - 1.80 (m, 3 H), 1.67 (br, 2 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 469 (M+ + H).

(R)-methyl 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylate

IH NMR (400 MHz, CDC1 ₃ ) 6 7.63 - 7.50 (m, 6 H), 6.95 (d, 2 H, J= 6.1 Hz), 19

4.64 (m, 1 H), 3.82 (d, 2 H, J= 5.8 Hz), 3.77 (s, 3 H), 3.68 - 3.46 (m. 4 H), 2.99 (d,

2 H, J= 10.2 Hz), 2.48 - 2.41 (m, 2 H), 2.32 (m, 1 H), 2.18 -2.14 (m, 2 H), 2.02 -

2.00 (m, 2 H), 1.96 (brs, 1 H), 1.79 (d, 3 H, J= 10.5 Hz), 1.38 - 1.33 (m, 8 H); MS (ESI) m/z 497 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4- yl)thiazolidin-3 -yl)methanone

622 1H NMR (400 MHz, CDC1 ₃ ) 6 7.61 - 7.52 (m, 6 H), 6.98 (d, 2 H, J= 8.4 Hz), 4.65 (brs, 2H), 3.98 (brs, 2 H), 3.02 (brs, 4 H), 2.51 - 2.48 (m, 2 H), 2.20 (t, 2 H, J = 12.0 Hz), 1.82 (d, 3 H, J= 8.0 Hz), 1.48 - 1.45 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

(4-(cyclopropanecarbonyl)piperazin- 1 -yl)(4'-(( 1 -(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 6 7.61 (d, 2 H, J= 6.1 Hz), 7.53 (d, 2 H, J= 6.5

623 Hz), 7.48 (d, 2 H, J= 6.1 Hz), 6.99 (d, 2 H, J= 6.5 Hz), 3.86 (d, 2 H, J= 4.4 Hz),

3.76 - 3.69 (m, 8 H), 3.13 (brs, 2 H), 2.61 - 2.54 (m, 2 H), 2.29 (brs, 2 H), 1.87 -

1.84 (m, 3 H), 1.78 (brs, 1 H), 1.58 - 1.56 (brs, 2 H), 1.44 (s, 3 H), 1.39 (s, 3 H),

1.05 - 1.01 (m, 2 H), 0.82 - 0.81 (m, 2 H); MS (ESI) m/z 522 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(4- (methylsulfonyl)piperazin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 (d, 2 H, J = 6.2 Hz), 7.53 (d, 2 H, J = 6.6 Hz),

624

7.48 (d, 2 H, J = 6.2 Hz), 6.99 (d, 2 H, J = 6.5 Hz), 3.87 - 3.85 (m, 6 H), 3.28 (brs, 4 H), 3.13 (brs, 2 H), 2.82 (s, 3 H), 2.55 (brs, 2 H), 2.21 (brs, 2 H), 1.87 - 1.84 (m, 3 H), 1.42 - 1.37 (m, 8 H); MS (ESI) m z 532 (M+ + H).

(S)-methyl 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylate

1H NMR (400 MHz, CDC1 ₃ ) 6 7.66 - 7.52 (m, 6 H), 6.98 (d, 2 H, J= 12.0 Hz),

625 3.85 (d, 2 H, J= 5.9 Hz), 3.79 (s, 3 H), 3.83 - 3.62 (m, 2 H), 3.01 (d, 2 H, J= 11.9

Hz), 2.47 (d, 2 H, J= 24.0 Hz), 2.38 (m, 1 H), 2.51 - 2.44 (m, 2 H), 2.02 - 1.87 (m,

3 H), 1.82 (d, 3 H, J= 12.0 Hz), 1.47 - 1.36 (m, 8 H); MS (ESI) m/z 497 (M+ +

H).

t-butyl 4-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazin- 1 -carboxylate

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 (d, 2 H, J= 8.3 Hz), 7.54 (d, 2 H, J= 1.8

626

Hz), 7.46 (d, 2 H, J= 8.3 Hz), 6.98 (d, 2 H, J= 9.9 Hz), 3.86 (d, 2 H, J= 5.1 Hz), 3.83 - 3.49 (m, 8 H), 3.01 (brs, 2 H), 2.47 - 2.41 (m, 2 H), 2.19 (brs, 2 H), 1.83 (brs, 3 H). 1.48 (s, 9 H), 1.42 - 1.37 (m, 8 H); MS (ESI) m/z 554 (M+ + H).

(4-benzylpiperazin- 1 -yl)(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 8.19 (d, 2 H, J = 9.3 Hz), 7.63 (d, 2 H, J = 5.1 Hz),

627

7.57 (d, 2 H, J = 4.5 Hz), 6.99 (d, 2 H, J = 6.9 Hz), 3.86 (m, 4 H), 3.56 (m, 4 H), 2.96 (brs, 2 H), 2.54 - 2.43 (m, 6 H), 2.18 (brs, 2 H), 1.82 (brs, 3 H), 1.59 - 1.26 (m, 8 H); MS (ESI) m/z 544 (M+ + H).

1 -(4-(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazin- 1 -yl)ethanone

1H NMR (400 MHz, CDC1 ₃ ) 7.59 (d, 2 H, J = 8.1 Hz), 7.51 (d, 2 H, J = 8.6 Hz),

628

7.45 (d, 2 H, J = 9.9 Hz), 6.96 (d, 2 H, J = 8.7 Hz), 3.83 (d, 2 H, J = 5.8 Hz), 3.63 (brs, 4 H), 3.52 (brs, 4 H), 2.98 (brs, 2 H), 2.47 (d, 2 H, J = 22.5 Hz), 2.19 -2.12 (m, 5 H), 1.80 (m, 3 H), 1.39 - 1.33 (m, 8 H); MS (ESI) m/z 496 (M+ + H).

(3 ,3 -difluoropyrrolidine- 1 -yl)(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-

629

yl)methoxy)biphenyl-4-yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 7.62 - 7.52 (m, 6 H), 6.99 (d, 2 H, J= 6.5 Hz), 4.03 - 3.80 (m, 6 H), 3.10 - 3.01 (m, 2 H), 2.65 - 2.43 (m, 4 H), 2.19 - 2.05 (m, 2 H), 1.97 - 1.82 (m, 2 H), 1.59 - 1.41 (m, 2 H), 1.36 (s, 3 H), 1.27 (s, 3 H); MS (ESI) m/z 475 (M+ + H).

methyl 2-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- ylcarboxamido)acetate

1H NMR (400 MHz, CDC1 ₃ ) δ 7.91 - 7.85 (m, 2 H), 7.67 - 7.62 (m, 2 H), 7.59 -

645 7.53 (m, 2 H), 7.02 - 6.96 (m, 2 H), 6.68 (t, 1 H, J = 5.0 Hz), 4.29 (d, 2 H, J = 5.0 Hz), 3.86 (d, 2 H, J = 6.0 Hz), 3.83 (s, 3 H), 3.00 (d, 2 H, J = 11.0 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.2 Hz), 1.83 - 1.81 (m, 3 H), 1.38 - 1.51 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-(oxetane -3 - yl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.84 (d, 2 H, J = 8.5 Hz), 7.67 - 7.62 (m, 2 H), 7.59 - 7.53 (m, 2 H), 7.03 - 6.96 (m, 2 H), 6.65 (d, 1 H, J = 7.5 Hz), 5.35 - 5.24 (m, 1

646

H), 5.06 (t, 2 H, J = 7.2 Hz), 4.64 (t, 2 H, J = 6.5 Hz), 3.86 (d, 2 H, J = 5.8 Hz), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 10.8 Hz), 1.82 (d, 3 H, J = 11.5 Hz), 1.38 - 1.51 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 441 (M+ + H).

methyl 3-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)bi phenyl-4- ylcarboxamido)propanoate

1H NMR (400 MHz, CDC1 ₃ ) δ 7.86 - 7.79 (m, 2 H), 7.65 - 7.59 (m, 2 H), 7.58 -

647 7.52 (m, 2 H), 7.02 - 6.96 (m, 2 H), 6.87 (t, 1 H, J = 5.9 Hz), 3.85 (d, 2 H, J = 5.8 Hz), 3.80 - 3.75 (m, 2 H), 3.74 (s, 3 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.69 (t, 2 H, J = 5.9 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 10.8 Hz), 1.83 - 1.80 (m, 3 H), 1.38 - 1.52 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 471 (M+ + H).

(R)-methyl 2-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- ylcarboxamido)-3 -hydroxypropanoate

1H NMR (400 MHz, CDC1 ₃ ) 6 7.86 - 7.93 (m, 2 H), 7.61 - 7.67 (m, 2 H), 7.52 -

648 7.59 (m, 2 H), 7.14 (d, J = 6.8 Hz, 1 H), 6.95 - 7.02 (m, 2 H), 4.88 - 4.95 (m, 1 H), 4.11 (dd, J=3.5, 1.8 Hz, 2 H), 3.82 - 3.90 (m, 5 H), 3.00 (d, j=l 1.3 Hz, 2 H), 2.57 - 2.69 (m, 1 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, j=11.3 Hz, 2 H), 1.82 (d, j=11.8 Hz, 3 H), 1.38 - 1.53 (m, 5 H), 1.35 (s, 3 H); MS (ESI) m/z 487 (M+ + H).

(S)-methyl 2-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- ylcarboxamido)-3 -hydroxypropanoate

1H NMR (400 MHz, CDC1 ₃ ) δ 7.92 - 7.87 (m, 2 H), 7.67 - 7.61 (m, 2 H), 7.59 -

649 7.53 (m, 2 H), 7.15 (d, 1 H, J = 7.0 Hz), 6.99 (d, 2 H, J = 8.8 Hz), 4.94 - 4.89 (m, 1 H), 4.11 - 4.10 (m, 2 H), 3.89 - 3.83 (m, 5 H), 3.00 (d, 2 H, J = 11.0 Hz), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.0 Hz), 1.82 (d, 3 H, J = 11.8 Hz), 1.38 - 1.52 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 487 (M+ + H).

ethyl 4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)bi phenyl-4- ylcarboxamido)piperidin- 1 -carboxylate

1H NMR (400 MHz, CDC1 ₃ ) δ 7.84 - 7.78 (m, 2 H), 7.65 - 7.60 (m, 2 H), 7.58 - 7.52 (m, 2 H), 7.02 - 6.96 (m, 2 H), 6.02 (d, 1 H, J = 7.5 Hz), 4.27 - 4.10 (m, 5

650

H), 3.85 (d, 2 H, J = 6.0 Hz), 3.01 - 2.98 (m, 4 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.4 Hz), 2.08 (d, 2 H, J = 10.3 Hz), 1.83 - 1.80 (m, 3 H), 1.52 - 1.38 (m, 4 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.28 (t, 3 H, J = 7.2 Hz); MS (ESI) m/z 540 (M+ + H). 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-pe ntylbiphenyl-4- carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.84 - 7.79 (m, 2 H), 7.65 - 7.59 (m, 2 H), 7.58 -

651 7.52 (m, 2 H), 7.02 - 6.96 (m, 2 H), 6.15 (t, 1 H, J = 5.6 Hz), 3.85 (d, 2 H, J = 6.0 Hz), 3.52 - 3.44 (m, 2 H), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.0 Hz), 1.83 - 1.80 (m, 3 H), 1.70 - 1.60 (m, 3 H), 1.50 - 1.37 (m, 9 H), 1.35 (s, 3 H), 0.93 (t, 3 H, J = 7.1 Hz); MS (ESI) m/z 455 (M+ + H). ethyl 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-3-carboxylate

IH NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.3 Hz), 7.53 (d, 2 H, J = 8.8 Hz),

677 7.46 (d, 2 H, J = 8.3 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 4.22 - 4.07 (m, 2 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.13 - 3.05 (m, 1 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.24 - 2.10 (m, 3 H), 1.88 - 1.70 (m, 5 H), 1.50 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.31 - 1.17 (m, 3 H); MS (ESI) m/z 525 (M+ + H).

ethyl 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-4-carboxylate

IH NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.56 (m, 2 H), 7.53 (d, 2 H, J = 9.0 Hz), 7.46 (d, 2 H, J = 8.5 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 4.65 - 4.48 (m, 1 H), 4.18 (q, 2 H, J

678

= 7.2 Hz), 3.85 (d, 2 H, J = 6.0 Hz), 3.04 - 3.19 (m, 2 H), 3.00 (d, 2 H, J = 11.0 Hz), 2.64 - 2.54 (m, 1 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 11.3 Hz), 2.10 - 1.89 (m, 2 H), 1.76 - 1.64 (m, 5 H), 1.38 - 1.52 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.28 (t, 3 H, J = 7.0 Hz); MS (ESI) m/z 525 (M+ + H).

ethyl 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidine-2-carboxylate

IH NMR (400 MHz, CDC1 ₃ ) δ 7.64 - 7.39 (m, 6 H), 6.98 (d, 2 H, J = 8.8 Hz), 4.31 - 4.22 (m, 2 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.76 (d, 1 H, J = 13.6 Hz), 3.34 - 3.27

679

(m, 1 H), 3.00 (d, 2 H, J = 11.3 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.38 (d, 1 H, J = 13.3 Hz), 2.24 - 2.12 (m, 2 H), 1.88 - 1.72 (m, 5 H), 1.68 - 1.59 (m, 2 H), 1.53 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.37 - 1.26 (m, 2 H), 1.35 (s, 3 H); MS (ESI) m/z 525 (M+ + H).

(4-ethylpiperazin-l-yl)(4'-((l-(2-fluoro-2-methylpropyl)pipe ridin-4- yl)methoxy)biphenyl-4-yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.1 Hz), 7.53 (d, 2 H, J = 8.6 Hz),

680 7.46 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 9.1 Hz), 3.85 - 3.84 (m, 4 H), 3.58 (brs,

2 H), 3.02 (d, 2 H, J = 10.0 Hz), 2.55 - 2.44 (m, 8 H), 2.20 (t, 2 H, J = 11.5 Hz), 1.82 (d, 3 H, J = 11.0 Hz), 1.47 - 1.40 (m, 2 H), 1.35 (s, 3 H), 1.26 (s, 3 H), 1.13 (t,

3 H, J = 8.0 Hz); MS (ESI) m/z 482 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(4- isopropylpiperazin- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.0 Hz), 7.52 (d, 2 H, J = 8.0 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 8.0 Hz), 3.85 - 3.84 (m, 4 H), 3.58 (brs,

681

2 H), 3.03 (d, 2 H, J = 11.1 Hz), 3.03 (d, 2 H, J = 11.1 Hz), 2.67 (m, 1 H), 2.56 - 2.45 (m, 6 H), 2.20 (t, 2 H, J = 12.0 Hz), 1.82 (d, 3 H, J = 7.2 Hz), 1.48 - 1.41 (m, 2 H), 1.36 (s, 3 H), 1.26 (s, 3 H), 1.11 (d, 6 H, J = 6.4 Hz); MS (ESI) m/z 496 (M+ + H).

(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biph enyl-4-yl)(4-

685 methylpiperazin- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J - 6.0 Hz), 7.52 (d, 2 H, J - 8.0 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 8.5 Hz), 3.85 - 3.84 (m, 4 H), 3.55 (brs,

2 H), 3.02 (d, 2 H, J = 10.2 Hz), 2.50 - 2.45 (m, 6 H), 2.35 (s, 3 H), 2.20 (t, 2 H, J = 11.3 Hz), 1.82 (d, 3 H, J = 12.0 Hz), 1.47 - 1.44 (m, 2 H). 1.41 (s, 3 H), 1.35 (s,

3 H); MS (ESI) m/z 468 (M+ + H).

(3 ,5-dimethylpiperazin- 1 -yl)(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 (d, 2 H, J = 8.0 Hz), 7.54 (d, 2 H, J = 8.4 Hz), 7.46 (d, 2 H, J = 8.0 Hz), 6.99 (d, 2 H, J = 8.5 Hz), 4.64 (brs, 1 H), 3.85 (d, 2 H, J = 5.6 Hz), 3.01 - 3.00 (m, 2 H), 2.46 - 2.45 (m, 2 H), 2.19 (t, 2 H, J = 11.6 Hz), 1.82 (d, 3 H, J = 10.6 Hz), 1.48 - 1.35 (m, 8 H), 1.26 - 1.04 (m, 6 H); MS (ESI) m/z 482 (M+ + H)

(2,6-dimethylmorpholino)(4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 (d, 2 H, J = 6.8 Hz), 7.53 (d, 2 H, J = 7.1 Hz), 7.45 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 7.2 Hz), 3.85 (d, 2 H, J = 5.6 Hz), 3.64 (brs, 2 H), 3.02 (d, 2 H, J = 10.7 Hz), 2.48 - 2.47 (m, 2 H), 2.21 (t, 2 H, J = 7.5 Hz), 1.82 (d, 3 H, J = 10.5 Hz), 1.47 - 1.12 (m, 14 H); MS (ESI) m/z 483 (M+ + H)

4-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperazin-2-one

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.0 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 6.97 (d, 2 H, J = 8.8 Hz), 4.28 (s, 2 H), 3.84 (s, 2 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.44 (s, 2 H), 2.98 (d, 2 H, J = 11.5 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.16 (t, 2 H, J = 10.9 Hz), 1.85 - 1.72 (m, 3 H), 1.49 - 1.36 (m, 2 H), 1.39 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 468 (M+ + H).

1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-4-carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.5 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 7.44 (d, 2 H, J = 8.5 Hz), 6.97 (d, 2 H, J = 8.8 Hz), 3.84 (d, 2 H, J = 6.0 Hz), 3.74 (s, 4 H), 2.89 - 3.03 (m, 3 H), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.17 (t, 2 H, J = 10.9 Hz), 1.92 (s, 4 H), 1.74 - 1.84 (m, 3 H), 1.37 - 1.50 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 478 (M+ + H).

N-(3 ,4-dihydroxyphenethyl)-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.68 (d, 2 H, J = 8.0 Hz), 7.54 (d, 2 H, J = 7.5 Hz), 7.48 (d, 2 H, J = 8.0 Hz), 6.92 (d, 2 H, J = 7.5 Hz), 6.75 (d, 1 H, J = 7.5 Hz), 6.71 (s, 1 H), 6.56 (d, 1 H, J = 7.5 Hz), 3.80 (d, 2 H, J = 5.8 Hz), 3.59 (d, 2 H, J = 5.8 Hz), 2.98 (d, 2 H, J = 10.0 Hz), 2.76 (t, 2 H, J = 6.9 Hz), 2.52 - 2.37 (m, 2 H), 2.22 - 2.09 (m, 2 H), 1.78 (d, 3 H, J = 10.8 Hz), 1.53 - 1.34 (m, 2 H), 1.36 (s, 3 H), 1.31 (s, 3 H); MS (ESI) m/z 521 (M+ + H).

(R)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.65 - 7.41 (m, 6 H), 6.97 (d, 2 H, J = 8.5 Hz), 3.84 (d, 2 H, J = 5.8 Hz), 3.80 (s, 1 H), 3.11 (t, 1 H, J = 12.8 Hz), 3.00 (d, 2 H, J = 10.8 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.34 (d, 1 H, J = 12.5 Hz), 2.18 (t, 2 H, J = 11.5 Hz), 1.91 - 1.73 (m, 6 H), 1.71 - 1.50 (m, 4 H), 1.49 - 1.37 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H).

(S)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.65 - 7.41 (m, 6 H), 6.97 (d, 2 H, J = 8.5 Hz), 3.84 (d, 2 H, J = 5.8 Hz), 3.80 (s, 1 H), 3.11 (t, 1 H, J = 13.3 Hz), 3.00 (d, 2 H, J = 10.3 Hz), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.34 (d, 1 H, J = 12.3 Hz), 2.18 (t, 2 H, J = 11.2 Hz), 1.91 - 1.73 (m, 6 H), 1.72 - 1.51 (m, 3 H), 1.51 - 1.37 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

(S)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.0 Hz), 7.53 (d, 2 H, J = 8.8 Hz),

874 7.45 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 4.15 - 4.01 (m, 1 H), 3.85 (d, 3

H, J = 6.0 Hz), 3.02 (d, 2 H, J = 10.8 Hz), 2.60 (s, 1 H), 2.51 (s, 1 H), 2.45 (s, 1 H), 2.20 (t, 2 H, J = 11.4 Hz), 2.06 - 1.87 (m, 3 H), 1.86 - 1.76 (m, 4 H), 1.62 (s, 1 H),

I.55 - 1.43 (m, 3 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

(R)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 8.0 Hz), 7.53 (d, 2 H, J = 8.8 Hz),

879 7.45 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 4.01 - 4.10 (m, 1 H), 3.86 (d, 3

H, J = 6.0 Hz), 3.63 - 3.39 (m, 2 H), 2.65 - 2.40 (m, 3 H), 2.29 - 2.11 (m, 3 H),

I.98 - 1.79 (m, 5 H), 1.76 - 1.58 (m, 3 H), 1.56 - 1.46 (m, 2 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

Example 24. Compound 620: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyI)pyrroIidine-2-carboxylic acid

(R)-methyl 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl) pyrrolidine-2-carboxylate (compound 619, 53 mg, 0.11 mmol) was dissolved in THF 1.5 mL, H ₂ 0 0.5 mL and MeOH 0.5 mL. LiOH H ₂ 0 (25 mg, 0.53 mmol) was added slowly thereto, following with stirring at room temperature for 2 hours. After the completion of the

reaction, the reaction mixture was acidified to pH 5 by addition of 1 N HCl, following with adding excess amount of water. The resulting precipitate was filtered to yield the title compound as white solid (41 mg, 80%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 (d, 2 H, J = 10.2 Hz), 7.37 - 7.23 (m, 4 H), 6.65 (d, 2 H, J = 7.6 Hz), 3.82 (d, 2 H, J = 5.8 Hz), 3.72 - 3.50 (m, 6 H), 3.32 - 3.16 (m, 2 H), 2.70 (brs, 2 H), 2.32 (m, 1 H), 2.18 -2.14 (m, 2 H), 2.02 - 2.00 (m, 2 H), 1.96 (brs, 1 H), 1.79 (d, 3 H, J = 10.5 Hz), 1.38 - 1.33 (m, 8 H); MS (ESI) m/z 483 (M+ + H). Example 25. Compound 621: 2-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)-N-methylbiphenyl-4-ylcarboxamido)acetic acid

4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid (compound 548, 0.12 g, 0.31 mmol) and methyl 2-(methylamino)acetate (29 mg, 0.28 mmol) were dissolved in DMF 1 mL. EDC (0.12 g, 0.62 mmol) and HOBt (84 mg, 0.62 mmol) were added thereto. Lastly, DIPEA (0.27 mL, 1.56 mmol) was added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was added with EtOAc, and washed three times with water. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (10 % MeOH/CH Cl ₂ ) to yield the title compound as white solid (0.12 g, 82%). The obtained product (90 mg, 0.19 mmol) was dissolved in THF 1.5 mL, H ₂ 0 0.5 mL and MeOH 0.5 mL. LiOH H ₂ 0 (40 mg, 0.96 mmol) was added slowly thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was acidified to pH 5 by addition of 1 N HCl. Excess amount of water was added thereto. The resulting precipitate was filtered to yield the title compound as white solid (16 mg, 18%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 - 7.42 (m, 6 H), 6.92 - 6.89 (m, 2 H), 4.03 - 3.85 (m, 2 H), 3.80 - 3.79 (m, 2 H), 2.83 (brs, 5 H), 2.51 - 2.44 (m, 2 H), 2.20 - 2.18 (m, 2 H), 1.80 - 1.78 (m, 3 H), 1.45 - 1.42 (m, 2 H), 1.38 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 457 (M+ + H).

Example 26. Compound 630: (4'-((l-(2-fluoro-2-methyIpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(piperazin-l-yl)methanone

t-butyl 4-(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)piperazin- 1 -carboxylate (compound 626, 20 mg, 0.04 mmol) was dissolved in MeOH. trifluoroacetic acid (8 μί,, 0.11 mmol) was added slowly thereto, following with stirring at room temperature for 1 hour. After the completion of the reaction, the obtained reaction mixture was alkalinized with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over MgS0 ₄ to yield the title compound as white solid (5 mg, 31%).

1H NMR (400 MHz, CDC1 ₃ ) 5 7.59 (d, 2 H, J= 6.0 Hz), 7.53 (d, 2 H, J= 6.5 Hz), 7.46 (d, 2

H, J= 6.2 Hz), 6.98 (d, 2 H, J= 6.5 Hz), 3.85 (d, 2 H, J= 4.2 Hz), 3.79 (brs, 4 H), 3.01 (d, 2 H, J= 8.5 Hz), 2.93 (brs, 4 H), 2.50 - 2.44 (m, 2 H), 2.19 (t, 2 H, J= 8.3 Hz), 1.83 - 1.80 (m, 3 H).

I .49 - 1.40 (m, 2 H), 1.35 (s, 3 H), 1.26 (s, 3 H); MS (ESI) m/z 454 (M+ + H).

Example 27. Compound 682: (R)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

(R)- 1 -(4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)pyrrolidine-2- carboxylic acid (compound 620, 40 mg, 0.084 mmol) and NH ₄ C1 (6 mg, 0.12 mmol) were dissolved in DMF 1 mL. EDC (31 mg, 0.17 mmol) and HOBt (22 mg, 0.17 mmol) were added thereto. Lastly, DIPEA (72 μΐ,, 0.42 mmol) was added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was added with EtOAc, and washed three times with water. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (15 mg, 37%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 (s, 4 H), 7.53 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2 H, J = 8.0 Hz), 5.53 (s, 1 H), 4.83 (t, 1 H, J = 6.0 Hz), 3.85 (d, 2 H, J = 8.0 Hz), 3.66 - 3.58 (m, 2 H), 2.50 - 2.47 (m, 2 H), 2.20 - 2.06 (m, 4 H), 1.88 - 1.81 (m, 5 H), 1.42 - 1.26 (m, 8 H); MS (ESI) m/z 482 (M+ + H).

According to the above-described synthesis process of compound 682, the compounds of Table 6 were synthesized using 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphe nyl-4- carboxylic acid and the reactant of Table 5. Table 5.

Table 6.

Example 28. Compound 755: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

Step 1. 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)piperidin- 3-carboxylic acid: ethyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidine-3-carboxylate (compound 677, 0.07 g, 0.14 mmol) was dissolved in THF (1.5 mL). MeOH (0.5 mL) and H ₂ 0 (0.5 mL) were poured thereto. LiOH (0.3 g, 0.70 mmol) was added thereto, and refluxed with heating and stirring for 4 hours. The reaction mixture was acidified with 1 N HCl, and extracted with EtOAc and CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as yellow solid (0.070 g, 100%).

Step 2. Compound 755: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidin-3-carboxylic acid (0.07 g, 0.14 mmol), EDC (0.05 g, 0.28 mmol), HOBt (0.05 g, 0.28 mmol) and DIPEA (0.12 mL, 0.70 mmol) were dissolved in DMF (21 mL) completely. Lastly, NH ₄ C1 (0.02 g, 0.28 mmol) was added thereto, following with stirring at room temperature for 15 hours . Water (10 mL) was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g, ISCO silica gel cartridge, 0 - 10% MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (0.03 g, 51%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (d, 2 H, J = 8.3 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 7.43 (d, 2 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.8 Hz), 6.84 - 6.67 (m, 1 H), 5.65 (s, 1 H), 4.09 (s, 1 H), 3.83 (d, 2 H, J = 5.8 Hz), 3.69 - 3.80 (m, 1 H), 3.49 - 3.63 (m, 1 H), 3.47 - 3.32 (m, 1 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.57 (s, 1 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (t, 2 H, J = 1 1.0 Hz), 2.11 - 2.05 (m, 1 H), 1.92 (s, 1 H), 1.85 - 1.72 (m, 1 H), 1.61 (s, 1 H), 1.50 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

Example 29. Compound 756: l-(4'-((l-(2-fluoro-2-methyIpropyl)piperidin-4- yl)methoxy)biphe

Step 1. 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)piperidin- 4-carboxylic acid: ethyl 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidine-4-carboxylate (compound 678, 0.09 g, 0.17 mmol) was dissolved in THF (1.5 mL). MeOH (0.5 mL) and H ₂ 0 (0.5 mL) were poured thereto. LiOH (0.4 g, 0.87 mmol) was added thereto, and refluxed with heating and stirring for 4 hours. The reaction mixture was acidified with 1 N HC1, and extracted with EtOAc and CH ₂ C1 ₂ . The organic layer was dried over MgS0 , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as yellow solid (0.087 g, 100%).

Step 2. Compound 756: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidin-4-carboxylic acid (0.08 g, 0.17 mmol), EDC (0.06 g, 0.35 mmol), HOBt (0.05 g, 0.35 mmol) and DIPEA (0.11 mL, 0.87 mmol) were dissolved in DMF (21 mL) completely. Lastly, NH ₄ C1 (0.02 g, 0.35 mmol) was added thereto, following with stirring at room temperature for 15 hours . Water (10 mL) was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over

MgS04, and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g, ISCO silica gel cartridge, 0 - 10% MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (0.06 g, 70%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 - 7.54 (m, 2 H), 7.50 (d, 2 H, J = 8.8 Hz), 7.42 (d, 2 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.8 Hz), 5.82 (d, 2 H, J = 15.6 Hz), 4.78 - 4.55 (m, 1 H), 3.99 - 3.85 (m, 1 H), 3.83 (d, 2 H, J = 5.8 Hz), 3.11 - 2.83 (m, 2 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.48 - 2.40 (m, 1 H), 2.49 - 2.37 (m, 1 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.16 (t, 2 H, J = 11.0 Hz), 2.05 - 1.84 (m, 2 H), 1.84 - 1.65 (m, 6 H), 1.50 - 1.36 (m, 2 H), 1.39 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

Example 30. Compound 757: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

Step 1. 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)piperidin- 2-carboxylic acid: ethyl l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidine-2-carboxylate (compound 679, 0.09 g, 0.16 mmol) was dissolved in THF (1.5 mL). MeOH (0.5 mL) and H ₂ 0 (0.5 mL) were poured thereto. LiOH (0.3 g, 0.83 mmol) was added thereto, and refluxed with heating and stirring for 4 hours. The reaction mixture was acidified with 1 N HCl, and extracted with EtOAc and CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as yellow solid (0.082 g, 100%). Step 2. Compound 757: l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidin-2-carboxylic acid (0.08 g, 0.17 mmol), EDC (0.06 g, 0.33 mmol), HOBt (0.05 g, 0.33 mmol) and DIPEA (0.11 mL, 0.83 mmol) were dissolved in DMF (21 mL) completely. Lastly, NH ₄ C1 (0.02 g, 0.33 mmol) was added thereto, following with stirring at room temperature for 15 hours . Water (10 mL) was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over

MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g, ISCO silica gel cartridge, 0 - 10% MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (0.04 g, 46%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.64 - 7.40 (m, 6 H), 6.97 (d, 2 H, J = 8.5 Hz), 6.54 (s, 1 H), 3.84 (d, 2 H, J = 5.8 Hz), 3.79 (s, 1 H), 3.12 (t, 1 H, J = 13.8 Hz), 2.99 (d, 2 H, J = 11.0 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.33 (d, 1 H, J = 12.3 Hz), 2.17 (t, 2 H, J = 11.2 Hz), 1.89 - 1.72 (m, 5 H), 1.64 (s, 2 H), 1.61 - 1.51 (m, 2 H), 1.49 - 1.37 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 496 (M+ + H).

Example 31. Compound 932: (2S,4R)-methyl l-(4'-((l-(2-fluoro-2-methyIpropyI) piperidin-4-yI)methoxy)biphenylcarbonyl)-4-hydroxy yrrolidine-2-carbox Iate

4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid (compound 548; 300 mg, 0.78 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (212 mg, 1.17 mmol), EDC (298 mg, 1.56 mmol), HOBt (210 mg, 1.56 mmol) and DIPEA (0.28 mL, 1.56 mmol) were dissolved in DMF (5 mL) at room temperature. After stirring at

80 °C for 12 hours, the reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 5 % to 80 ·%), and concentrated to yield the title compound as white solid (240 mg, 60%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.63 - 7.50 (m, 6 H), 6.97 (m, 2 H), 4.87 (m, 1 H), 4.53 (m, 1 H), 3.89 - 3.79 (m, 5 H), 3.62 (m, 1 H), 3.11 (m, 2 H), 2.59 - 2.13 (m, 7 H), 1.86 (m, 4 H), 1.58 (m, 2 H), 1.41 (m, 6 H); MS (ESI) m/z 513 (M+ + H).

Example 32. Compound 934: (2S,4R)-l-(4*-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxam ide

Step 1. (2S,4R)- 1 -(4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)- 4-hydroxypyrrolidine-2-carboxylic acid: (2S,4R)-methyl l-(4'-((l-(2-fluoro-2- memylpropyl)piperidin-4-yl)memoxy)biphenylcarbonyl)-4-hyd

(400 mg, 0.78 mmol) and LiOH H ₂ 0 (65 mg, 1.56 mmol) were dissolved in THF (10 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at 60 °C for 10 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The obtained concentrate was added with 1 M-HC1 aqueous solution, and concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 2. Compound 934: (2S,4R)-l-(4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxyl ic acid (400 mg, 0.80 mmol), ammonium chloride (64 mg, 1.20 mmol), EDC (231 mg, 1.20 mmol), HOBt (163 mg, 1.20 mmol) and DIPEA (21 mg, 1.61 mmol) were dissolved in DMF (10 mL) at room temperature. The solution was stirred at 60 °C for 10 hours, the reaction mixture was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as brown solid (100 mg, 25%).

1H NMR (400 MHz, CDC1 ₃ + MeOD) δ 7.58 - 7.46 (m, 6 H), 7.22 (brs, 1 H), 6.91 (m, 2 H), 6.07 (br, 1 H), 4.76 (m, 1 H), 4.37 (m, 1 H), 3.81 - 3.73 (m, 3 H), 3.51 (m, 1 H), 3.95 (m, 2 H), 2.49 -.2.11 (m, 6 H), 1.76 (m, 3 H), 1.41 _r 1.31 (m, 8 H); MS (ESI) m/z 498 (M+ + H).

Example 33. Compound 749: (R)-(2-fluoro-4 ^, -((l-(2-fluoro-2-ir-ethylpropyl)piperidin- 4-yl)methoxy)biphenyI-4-yl)(3-hydroxypiperidin-l-yl)methanon e

Step 1. methyl 2-fiuoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 4-((4-bromophenoxy)methyl)-l -(2-fluoro-2-methylpropyl)piperidine (the product of synthesis step 3 of compound 498; 180 mg, 0.52 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (124 mg, 0.63 mmol), Pd(dppf)Cl ₂ (43 mg, 0.05 mmol and Cs ₂ C0 ₃ (341 mg, 1.05 mmol) were added to water (2 mL)/l,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (30 % EtOAc/hexane) to yield the title compound as white solid (114 mg, 52%).

Step 2. 2-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: methyl 2-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate (114 mg, 0.27 mmol) was dissolved in THF (10 mL)/water (5 mL). At room temperature, LiOH H ₂ 0 (57 mg, 1.36 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was acidified by the addition of IN HC1. The resulting precipitate was filtered, and dried to yield the title compound as white solid (90 mg, 81%).

Step 3. Compound 749: 2-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenyl-4-carboxylic acid (45 mg, 0.11 mmol), (R)-piperidin-3-ol hydrochloride (13 mg, 0.13 mmol), BOP (94 mg, 0.21 mmol) and Et ₃ N (30 μί, 0.21 mmol) were dissolved in DMF (1 mL).

At 60 °C, the reaction was performed for a day. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtOAc.

The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (18 mg, 33%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 - 7.43 (m, 3 H), 7.27 - 7.22 (m, 2 H), 7.00 - 6.96 (m, 2 H), 3.96 (brs, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.68 - 3.39 (m, 3 H), 3.04 - 3.02 (m, 2 H), 2.52 - 2.46 (m, 2 H), 2.35 - 2.21 (m, 2 H), 2.20 - 1.95 (m, 2 H), 1.84 - 1.82 (m, 4 H), 1.69 (brs, 2 H), 1.42 (m, 2 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 487 (M+ + H).

According to the above-described synthesis process of compound 749, the compounds of Table 8 were synthesized using 2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 7.

Table 7.

Table 8. Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(S)-l -(2-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-

750 yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

MS (ESI) m/z 500 (M+ + H).

Example 34. Compound 638: 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)-N,N-

Step 1. ethyl 3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 4-((4-bromophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine (the product of synthesis step 3 of compound 498; 450 mg, 1.31 mmol) and 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (305 mg, 1.44 mmol) were dissolved in dioxane 6 mL. Water 2 mL was added thereto. Pd(dbpf)Cl ₂ (43 mg, 0.07 mmol) and Cs ₂ C0 ₃ (851 mg, 2.61 mmol) were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was filtered through Celite. The filtrate was added with a saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (MeQH/CH ₂ Cl ₂ ) to yield the title compound as white solid (350 mg, 62%).

Step 2. 3-fluoro-4 ^, -((l-(2-fluoro-2 _T methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxy lic acid: ethyl 3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate (350 mg, 0.84 mmol) was dissolved in THF 2 mL. MeOH 1 mL and H ₂ 0 0.5 mL were added thereto. LiOH (70 mg, 1.68 mmol) was added thereto, and refluxed with heating and stirring for 5 hours. After acidification with 1 N HCl, the resulting precipitate was filtered to yield the title compound as white solid (300 mg, 88%).

Step 3. Compound 638: 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy) biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), dimethylamine hydrochloride (9 mg, 0.11 mmol) and PyBOP (58 mg, 0.11 mmol) were dissolved in CH ₂ C1 ₂ 1 mL. DIPEA (19 mg, 0.15 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (15 mg, 47%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (d, 2 H, J = 8.8 Hz), 7.39 (m, 2 H), 7.27 (s, 1 H), 6.97 (d, 2 H, J = 8.8 Hz), 3.84 (d, 2 H, J - 6.0 Hz), 3.15 (m, 3 H), 2.99 (m, 5 H), 2.52 (s, 1 H), 2.47 (s, 1 H), 2.22 (m, 2 H), 1.82 (m, 3 H), 1.44 (m, 5 H), 1.27 (m, 3 H); MS (ESI) m/z 431 (M+ + H).

Example 35. Compound 640: (S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphen

3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)m ethoxy)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), (S)-3-pyrrolidinol (10 mg, 0.11 mmol) and PyBOP (58 mg, 0.11 mmol) were dissolved in CH ₂ C1 ₂ 1 mL, following with stirring for 10 minutes. DIPEA (19 mg, 0.15 mmol) was added thereto, following with stirring at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove a solid, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (18 mg; 51%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.46 (m, 3 H), 7.35 (m, 1 H), 7.24 (m, 1 H), 6.96 (d, 2 H, J = 8.6 Hz), 4.57 (m, 0.5 H), 4.44 (m, 0.5 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.78 (m, 1 H), 3.75 (m, 2 H), 3.53 (m, 2 H), 3.13 (m, 2 H), 3.01 (m, 2 H), 2.50 (s, 1 H), 2.44 (s, 1 H), 2.20 (m, 2 H), 1.98 (m, 1 H), 1.40 (m, 5 H), 1.25 (s, 3 H); MS (ESI) m/z 473 (M+ + H). According to the above-described synthesis process of compound 638 (Step 3), the compounds of Table 10 were synthesized using 3-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 9.

Table 9.

642 3 -hydroxypiperidine 38

643 2-amino-2-methyl- 1 -propanol 53

644 L-prolinamide 45

700 (R)-piperidin-3-ol hydrochloride 46

701 (S)-piperidin-3-ol hydrochloride 30

702 (R)-pyrrolidine-3-ol 45

703 (S)-pyrrolidine-2-ylmethanol 41

792 piperidin-4-carboxamide hydrochloride 39

793 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a ]pyrazine 29

872 (R)-piperidin-2-carboxamide hydrochloride 63

875 (S)-piperidin-2-carboxamide hydrochloride 65

880 (R)-piperidin-3-carboxamide hydrochloride 63

1097 (2S,4S)-4-fluoropyrrolidine-2-carbonitrile hydrochloride 49

1098 (2S,4R)-4-hydroxypyrrolidine-2-carbonitrile hydrochloride 49

Table 10.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

N,N-diethyl-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperid in-4- yl)methoxy)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (d, 2 H, J = 8.8 Hz), 7.37 (m, 2 H), 7.27 (m, 1

639 H), 6.97 (d, 2 H, J = 8.8 Hz), 3.84 (d, 2 H, J = 6.0 Hz), 3.61 (m, 2 H), 3.27 (m, 2 H), 3.01 (m, 2 H), 2.51 (s, 1 H), 2.45 (s, 1 H), 2.20 (m, 2 H), 1.45 (m, 5 H), 1.35 (s, 3 H), 1.28 (t, 4 H, J = 7.1 Hz), 1.12 (t, 3 H, J = 7.1 Hz); MS (ESI) m/z 459 (M+ + H).

(R)-(3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.49 (m, 3 H), 7.39 (m, 1 H), 7.29 (d, 1 H, J = 9.8

641

Hz), 6.98 (d, 2 H, J = 8.8 Hz), 4.40 (m, 1 H), 3.75 (m, 4 H), 3.47 (m, 2 H), 3.01 (d, 2 H, J = 11.5 Hz), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.18 (m, 3 H), 1.76 (m, 6 H), 1.46 (m, 5 H), 1.40 (s, 3 H); MS (ESI) m/z 487 (M+ + H).

(3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (dd, 2 H, J = 8.8, 2.3 Hz), 7.39 (m, 2 H), 7.27

642 (m, 1 H), 6.98 (d, 2 H, J = 6.8 Hz), 4.41 (m, 1 H), 3.93 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.38 (m, 2 H), 3.14 (m, 2 H), 3.01 (d, 2 H, J = 1 1.5 Hz), 2.49 (s, 1 H), 2.44 (s, 1 H), 2.19 (m, 2 H), 1.82 (m, 5 H), 1.61 (m, 1 H), 1.43 (m, 5 H), 1.35 (s, 3 H); MS (ESI) m/z 487 (M+ + H).

3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-N-( 1 -hydroxy-

643 2-methylpropan-2-yl)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.09 (t, 1 H, J = 8.4 Hz), 7.54 (dd, 2 H, J - 6.9, 1.9 Hz), 7.46 (dd, 1 H, J = 8.2, 1.7 Hz), 7.30 (dd, 1 H, J = 13.9, 1.6 Hz), 6.99 (dd, 2 H, J = 6.9, 1.9 Hz), 6.88 (d, 1 H, J = 15.2 Hz), 4.73 (s, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.72 (s, 2 H), 3.00 (d, 2 H, J = 11.5 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.18 (td, 2 H, J = 11.7, 1.7 Hz), 1.80 (m, 3 H), 1.43 (s, 6 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 475 (M + H).

(S)- 1 -(3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

644 1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (m, 2 H), 7.47 (m, 1 H), 7.40 (m, 1 H), 7.29

(m, 1 H), 6.99 (d, 2 H, J = 8.7 Hz), 5.46 (s, 1 H), 4.83 (m, 1 H), 3.85 (d, 2 H, J =

5.9 Hz), 3.53 (m, 1 H), 3.43 (m, 1 H), 2.99 (m, 2 H), 2.48 (m, 3 H), 2.10 (m, 5 H),

1.95 (m, 4 H), 1.26 (m, 5 H), 1.20 (s, 3 H); MS (ESI) m/z 450 (M+ + H).

(R)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl-4-

700

yl)(3-hydroxypiperidin-l-yl)methanone MS (ESI) m/z 487 (M+ + H).

(S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl-4-

701 yl)(3 -hydroxypiperidin- 1 -yl)methanone

MS (ESI) m/z 487 (M+ + H).

(R)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl-4-

702 yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

MS (ESI) m/z 473 (M+ + H).

(S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 - 7.40 (m, 3 H), 7.39 - 7.30 (m, 1 H), 7.30 -

703 7.27 (m, 1 H), 6.98 - 6.95 (m, 2 H), 4.41 - 4.12 (m, 1 H), 3.88 - 3.82 (m, 2 H), 3.80 - 3.75 (m, 1 H), 3.49 - 3.45 (m, 2 H), 3.30 - 3.21 (m, 2 H), 2.78 - 2.73 (m, 2 H), 2.50 - 2.38 (m, 1 H), 2.23 - 2.19 (m, 1 H), 1.92 - 1.81 (m, 3 H), 1.79 - 1.70 (m, 4 H), 1.51 (s, 3 H), 1.43 (s, 3 H), 1.28 - 1.22 (m, 3 H); MS (ESI) m/z 487 (M+ + H).

1 -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (m, 2 H), 7.36 (m, 2 H), 7.24 (m, 1 H), 6.91

792

(m, 2 H), 5.50 (m, 2 H), 4.74 (m, 1 H), 3.84 (d, 2 H, J - 6.0 Hz), 3.71 (m, 2 H), 3.01 (m, 4 H), 2.41 (m, 3 H), 2.22 (m, 2 H), 2.02 (m, 1 H), 1.80 (m, 6 H), 1.55 (m,

2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 514 (M + H).

(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy)biphenyl-4- yl)(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]py razine-7(8H)- yl)methanone

793 1H NMR (400 MHz, CDC1 ₃ ) δ 7.69 (m, 4 H), 7.33 (d, 1 H, J = 11.3 Hz), 7.00 (d, 2 H, J = 8.5 Hz), 5.22 (s, 1 H), 4.94 (s, 1 H), 4.28 (m, 2 H), 3.87 (m, 2 H), 3.04 (m, 2 H), 2.87 (d, 1 H, J = 10.2 Hz), 2.50 (s, 1 H), 2.44 (s, 1 H), 2.19 (m, 2 H), 1.82 (m, 4 H), 1.40 (m, 5 H), 1.19 (s, 3 H).

(R)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.38 - 7.55 (m, 4 H), 7.32 - 7.28 (m, 1 H), 6.99 (d,

872 2 H, J = 8.8 Hz), 3.85 (d, 2 H, J = 6.0 Hz), 3.62 (d, 1 H, J = 12.0 Hz), 3.22 (t, 1 H, J = 12.5 Hz), 3.02 (d, 2 H, J = 9.8 Hz), 2.55 - 2.35 (m, 3 H), 2.20 (t, 2 H, J = 11.2 Hz), 1.88 - 1.70 (m, 6 H), 1.64 (d, 3 H, J = 12.5 Hz), 1.53 - 1.39 (m, 2 H), 1.41 (s,

3 H), 1.36 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

875 (S)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 - 7.37 (m, 4 H), 7.32 - 7.28 (m, 1 H), 6.99 (d, 1 H, J = 9.0 Hz), 3.85 (d, 2 H, J = 6.0 Hz), 3.62 (d, 1 H, J = 12.3 Hz), 3.22 (t, 1 H, J = 13.2 Hz), 3.02 (d, 2 H, J = 1 1.0 Hz), 2.50 (s, 1 H), 2.45 (s, 1 H), 2.42 - 2.35 (m, 1 H), 2.20 (t, 2 H, J = 11.3 Hz), 1.88 - 1.71 (m, 6 H), 1.70 - 1.54 (m, 3 H), 1.53 - 1.43 (m, 3 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

(R)- 1 -(3 -fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (d, 2 H, J = 8.5 Hz), 7.40 (d, 2 H, J = 3.5 Hz),

880 7.31 - 7.24 (m, 1 H), 6.98 (d, 2 H, J = 8.8 Hz), 3.86 (d, 2 H, J = 5.8 Hz), 3.82 - 3.74 (m, 1 H), 3.49 - 3.43 (m, 1 H), 3.37 - 3.31 (m, 1 H), 3.03 (s, 2 H), 2.62 - 2.56 (m, 1 H), 2.54 - 2.43 (m, 2 H), 2.28 - 2.04 (m, 3 H), 1.97 - 1.77 (m, 5 H), 1.74 - 1.60 (m, 4 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

(2S,4S)-4-fluoro-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpro pyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 - 7.45 (m, 4 H), 7.33 - 7.28 (m, 1 H), 7.00 (m,

1097

2 H), 5.45 - 5.32 (m, 1 H), 5.13 (m, 1 H), 3.88 - 3.77 (m, 4 H), 3.16 - 3.01 (m, 3 H), 2.82 - 2.42 (m, 6 H), 1.98 - 1.80 (m, 4 H), 1.47 - 1.29 (m, 6 H); MS (ESI) m/z 500.2 (M+ + H).

(2S,4R)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidi n-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypynOlidine-2-carbonitr ile

1H NMR (400 MHz, CDC1 ₃ ) 6 7.57 - 7.49 (m, 3 H), 7.41 - 7.38 (m, 1 H), 7.30 -

1098 7.27 (m, 1 H), 6.98 (m, 2 H), 5.04 (t, 1 H, J = 8.2 Hz), 4.58 (m, 1 H), 3.86 (m, 2

H), 3.80 - 3.76 (m, 1 H), 3.49 - 3.46 (m, 1 H), 3.15 (s, 2 H), 2.58 - 2.47 (m, 4 H),

2.38 (s, 2 H), 1.87 - 1.85 (m, 3 H), 1.49 - 1.27 (m, 9 H); MS (ESI) m/z 498.2 (M+

+ H).

Example 36. Compound 1099: ( S^SH-fluoro-l-iS-fluoro^'-^l-Ci-fluoro^- methylpropyl)piperidin-4-yl)methoxy)biphenyIcarbonyI)pyrroli dine"2-carboxamide

F

Step 1. (2S,4S -methvl 4-fluoro-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperid in-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxylate: 3 -fluoro-4'-(( 1 -(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (150 mg, 0.37 mmol), (2S,4S)-methyl 4-fluoropyrrolidine-2-carboxylate (55 mg, 0.37 mmol), EDC (107 mg, 0.56 mmol), HOBt (75 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.74 mmol) were dissolved in DMF (4 mL) at room temperature. The solution was stirred at 80 °C for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; ethyl acetate / hexane = 10 % to 50 %), and concentrated to yield the title compound as colorless oil (0.12 g, 61%).

Ste^ (2S,4S)-4-fluoro-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl )piperidin-4-yl)methoxy) biphenylcarbonyl)pyrrolidine-2-carboxylic acid: (2S,4S)-methyl 4-fluoro-l-(3-fluoro-4'-((l- (2-fluoro-2-methylpropyl)piperidin-4-yl)memoxy)biphenylcarbo nyl)pyrrolidine-2-carboxylate (120 mg, 0.23 mmol) and LiOH H ₂ 0 (19 mg, 0.45 mmol) were dissolved in THF (10 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at 60 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 3. Compound 1099: (2S,4S)-4-fluoro- 1 -(3-fluoro-4*-((l -(2-fluoro-2-methylpropyl) piperidin-4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carbox ylic acid (200 mg, 0.39 mmol), ammonium chloride (31 mg, 0.58 mmol), EDC (1 11 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol) and DIPEA (0.14 mL, 0.77 mmol) were dissolved in DMF (6 mL) at room temperature. The solution was stirred at 80 °C for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; ethyl acetate / hexane = 10 % to 90 %), and concentrated to yield the title compound as light- red solid (30 mg, 15%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.53 - 7.28 (m, 5 H), 7.00 - 6.96 (m, 2 H), 6.68 (s, 0.78 H), 6.35 (s, 0.16 H), 5.70 (m, 1 H), 5.33 - 5.20 (m, 1 H), 5.00 (m, 1 H), 3.92 - 3.83 (m, 3 H), 3.74 - 3.62 (m, 1 H), 3.18 - 2.89 (m, 3 H), 2.58 - 2.18 (m, 5 H), 1.85 (m, 3 H), 1.43 - 1.27 (m, 8 H); MS (ESI) m/z 518.2 (M+ + H).

Example 37. Compound 1100: (2S,4R)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl) piperidin-4-yl)methoxy)biphenylcarbonyI)-4-hydroxypyrrolidin e-2-carboxamide

Step 1. (2S,4R)-methyl l-(3- fluoro-4*-((l-(2- fluoro-2- methylpropyl) piperidin-4- yl)methoxy) biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxylate: 3-fluoro-4'-(( 1 -(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (100 mg, 0.25 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (45 mg, 0.25 mmol), EDC (71 mg, 0.37 mmol), HOBt (50 mg, 0.37 mmol) and DIPEA (0.09 mL, 0.50 mmol) were dissolved in DMF (4 mL) at room temperature. The solution was stirred at 80 °C for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; ethyl acetate / hexane = 10 % to 80 %), and concentrated to yield the title compound as colorless oil (70 mg, 53%).

Step 2. (2S,4R)- 1 -(3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid: (2S,4R)-methyl l-(3-fluoro- 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcar bonyl)-4- hydroxypyrrolidine-2-carboxylate (70 mg, 0.13 mmol) and LiOH H ₂ 0 (11 mg, 0.26 mmol) were dissolved in THF (6 mL) / H ₂ 0 (3 mL) at room temperature. The solution was stirred at 60 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 3. Compound 1100: (2S,4R)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidi n-4- yl)methoxy)biphenylcarbonyl)-4-hydroxypyrrolidine-2-carboxyl ic acid (100 mg, 0.19 mmol), ammonium chloride (16 mg, 0.29 mmol), EDC (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and DIPEA (0.07 mL, 0.39 mmol) were dissolved in DMF (5 mL) at room temperature. The solution was stirred at 80 °C for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge;

methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as light-red solid (15 mg, 15%).

1H NMR (400 MHz, CDCl ₃ +MeOD) S 7.57 - 7.44 (m, 3 H), 7.38 - 7.31 (m, 1 H), 7.28 - 7.27 (m, 1 H), 6.93 (m, 2 H), 4.79 (t, 1 H, J = 8.2 Hz), 4.41 (m, 1 H), 3.86 (m, 2 H), 3.72 - 3.68 (m, 2 H), 3.41 - 3.37 (m, 2H), 2.34 - 2.25 (m, 3 H), 2.01 - 1.90 (m, 4 H), 1.47 - 1.38 (m, 6 H), 1.37 - 1.21 (m, 4 H); MS (ESI) m/z 516.2 (M+ + H).

Example 38. Compound 758: (R)-(6-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyridine-3-yl)(3-hydroxypiperidin-l-yl)met hanone

Step 1. methyl 6-(4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)nico tinate:

Methyl 6-bromonicotinate (0.07 g, 46%) was dissolved in 1,4-dioxane 2 mL and H ₂ 0 1 mL.

4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nylboronic acid (the product of synthesis step 1 of compound 617; 0.1 g, 0.32 mmol), Pd(dbpf)Cl ₂ (O.Olg, 0.02 mmol) and

Cs ₂ C0 ₃ (0.21 g, 0.65 mmol) were added thereto. The mixture was stirred in a microwave at 1

°C for 30 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 0 - 20 % EtOAc/Hexane) to yield the title compound as yellow solid (0.06 g, 46%).

Step 2. 6-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl)nicotinic acid:

Methyl 6-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl)nicotinate (0.06 g, 0.15 mmol) were dissolved in THF 10 mL, H ₂ 0 3 mL and MeOH 3 mL. LiOH H ₂ 0 (0.03 g, 0.75 mmol) was added thereto, following with increasing the temperature slowly. The mixture was refluxed with stirring for 3 hours. After the completion of the reaction, HC1 was added thereto to acidify to pH 5. The resulting precipitate was filtered to yield the title compound as light-yellow solid (0.03 g, 55%).

Step 3. Compound 758: 6-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl) nicotinic acid (0.03 g, 0.08 mmol) and (R)-piperidin-3-ol (0.02 g, 0.15 mmol) were dissolved in DMF 2 mL. DIPEA (0.05 g, 0.38 mmol), EDCI (0.03 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added thereto slowly, following with stirring at room temperature for 3 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as brown solid (0.02 g, 61%). 1H NMR (400 MHz, CDC1 ₃ ) 6 8.70 (s, 1 H), 7.96 (d, 2 H, J = 8.4 Hz), 7.82 (d, 1 H, J = 6.8 Hz), 7.71 (d, 1 H, J = 8.4 Hz), 7.00 (d, 2 H, J = 8.8 Hz), 3.99 - 3.57 (m, 7 H), 3.00 (d, 2 H, J = 10.4 Hz), 2.48 - 2.43 (m, 2 H), 2.19 (t, 2 H, J = 11.2 Hz), 2.05 - 1.67 (m, 7 H), 1.55 - 1.35 (m, 8 H).

Example 39. Compound 759: (R)-(5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyI)pyridine-2-yl)(3-hydroxypiperidin-l-yl)met hanone

Step 1. methyl 5-(4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)pico linate: Methyl 5-bromopicolinate (0.10 g, 0.46 mmol) was dissolved in 1,4-dioxane 2 mL and H ₂ 0 1 mL. 4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl boronic acid (Synthesis step 1 of compound 617, 0.13 g, 0.42 mmol), Pd(dbpf)Cl ₂ (0.01 g, 0.02 mmol) and Cs ₂ C0 ₃ (0.27 g, 0.84 mmol) were added thereto. The mixture was stirred in a microwave at 110 °C for 30 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 0 - 20 % EtOAc/Hex) to yield the title compound as light-yellow solid (0.03 g, 18%).

Step 2. 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl) picolinic acid: methyl 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl) picolinate (0.03 g, 0.08 mmol) was dissolved in THF 10 mL, H ₂ 0 3 mL, MeOH 3 mL. LiOH H ₂ 0 (0.02 g, 0.38 mmol) was added thereto, following with increasing the temperature slowly and then refluxing with stirring for 3 hours. After the completion of the reaction, the reaction mixture was acidified to pH 5 by the addition of HC1. The resulting precipitate was filtered to yield the title compound as white solid (0.03 g, 97%).

Step 3. Compound 759: 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl) picolinic acid (0.03 g, 0.07 mmol) and (R)-piperidin-3-ol (0.01 g, 0.08 mmol) were dissolved in DMF. DIPEA (0.05 g, 0.36 mmol), EDCI (0.03 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added thereto slowly, following with stirring at room temperature for 3 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (0.01 g, 38%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.72 (s,< 1 H), 8.00 (d, 1 H, J = 6.1 Hz), 7.S4 (d, 1 H, J = 8.4 Hz), 7.53 (d, 2 H, J = 7.7 Hz), 7.02 (d, 2 H, J = 7.6 Hz), 5.84 (s, 1 H), 4.61 (d, 1 H, J - 12.8 Hz), 4.10 - 4.03 (m, 2 H), 3.86 (d, 2 H, J = 5.4 Hz), 3.27 (d, 1 H, J = 14.0 Hz), 3.01 - 2.91 (m, 3 H), 2.48 - 2.43 (m, 2 H), 2.21 - 1.98 (m, 4 H), 1.82 - 1.48 (m, 5 H), 1.46 - 1.26 (m, 8 H); MS (ESI) m/z 470 (M+ + H).

Example 40. Compound 1038: (S)-l-(5-(4-((l-(2-fIuoro-2-methylpropyl)piperidin-4- yl)methoxy)ph

Step 1. methyl 5-(4-hydroxymethyl)pyrazine-2-carboxylate: methyl 5-bromopyrazine-2- carboxylate (500 mg, 2.30 mmol), 4-hydroxyphenylboronic acid (381 mg, 2.77 mmol), methyl 5-bromopyrazine-2-carboxylate, Pd(dppf)Cl ₂ (188 mg, 0.23 mmol) and Cs ₂ C0 ₃ (1.50 g, 4.61 mmol) were added to water (2 mL) DME (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (30 % EtOAc hexane) to yield the title compound as brown solid (210 mg, 40%).

Step 2. methyl 5-(4-((l -(t-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)pyrazine-2- carboxylate: methyl 5-(4-hydroxymethyl)pyrazine-2-carboxylate(l 50 mg, 0.65 mmol) was dissolved in DMF(10 mL). At room temperature, K ₂ C0 ₃ (318 mg, 0.98 mmol) was added thereto. After 5 minutes, t-butyl 4-(hydroxymethyl)piperidin-l-carboxylate (229 mg, 0.78 mmol) was added thereto, following with stirring at 80 °C for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer v/as washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained material was.used without further purifying process. (170 mg, 61%).

Step 3. methyl 5-(4-(piperidin-4-ylmethoxy)phenyl)pyrazine-2-carboxylate hydrochloride: Methyl 5-(4-((l -(t-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)pyrazine-2- carboxylate (170 mg, 0.39 mmol) was dissolved in CH ₂ C1 ₂ (10 mL) . At room temperature, 4 M HC1 in 1,4- dioxane (1.99 mL, 7.95 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The resulting precipitate was filtered, and dried to yield the title compound as white solid (142 mg, 98%).

Step 4. methyl 5-(4-((l -(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)pyr azine-2- carboxylate: Methyl 5-(4-(piperidin-4-ylmethoxy)phenyl)pyrazine-2-carboxylate hydrochloride (142 mg, 0.39 mmol), 2,2-dimethyloxirane (352 μΐ,, 0.28 mmol) and K ₂ C0 ₃ (27 mg, 0.19 mmol) were dissolved in ethanol(10 mL), With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained material was used without further purifying process (117 mg, 100%).

Step 5. methyl 5-(4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)pyra zine-2- carboxylate: methyl 5-(4-((l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)ph enyl) pyrazine-2-carboxylate (117 mg, 0.29 mmol) was dissolved in CH ₂ C1 ₂ (15 mL). At room temperature, DAST (39 μΐ,, 0.29 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 , and concentrated under reduced pressure. The obtained material was used without further purifying process (100 mg, 85%).

Step 6. 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phe nyl)pyrazine-2- carboxylic acid: methyl 5-(4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl) pyrazine-2-carboxylate (100 mg, 0.24 mmol) was dissolved in THF (10 mL)/water (5 mL). At room temperature, LiOH H ₂ 0 (52 mg, 1.24 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The obtained solid was filtered, and dried to yield the title compound as white solid (75 mg, 78%).

Step 7. Compound 1038: 5-(4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) phenyl)pyrazine-2-carboxylic acid (35 mg, 0.09 mmol), (S)-pyrrolidine-2-carboxamide (21 mg, 0.18 mmol), EDC (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol) and DIPEA (32 0.18 mmol) were dissolved in CH ₂ C1 ₂ (1 mL), following with stirring at room temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (10 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (19 mg, 44%). 1H NMR (400 MHz, CDC1 ₃ ) δ 9.25 - 9.15 (m, 1 H), 8.93 - 8.87 (m, 1 H), 8.05 - 7.99 (m, 2 H), 7.05 - 6.99 (m, 2 H), 5.48 (brs, 1 H), 5.04 - 4.85 (m, 1 H), 4.12 - 4.06 (m, 1 H), 3.95 - 3.84 (m, 3 H), 3.04 (brs, 2 H), 2.50 - 2.41 (m, 3 H), 2.39 - 2.20 (m, 3 H), 2.18 - 1.97 (m, 3 H), 1.83 (brs, 3 H), 1.61 - 1.22 (m, 8 H); MS (ESI) m/z 484 (M+ + H).

Example 41. Compound 725: (S)-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy)biphenyI-4-yl)(3-hydroxypiperidin-l-yl)methanon e

Step 1. t-butyl 4-((4-bromo-2-fluorophenoxy)methyl)piperidin- 1 -carboxylate: t-butyl 4- ((methylsulfonyloxy)methyl)piperidin-l-carboxylate (the product of synthesis step 2 of compound 431 ; 4.50 g, 15.34 mmol) was dissolved in DMF. K ₂ C0 ₃ (4.24 g, 30.67 mmol) ; 2-fluoro-4-bromo phenol (1.85 mL, 16.87 mmol) were added thereto slowly, following with increasing the temperature and stirring at 60 °C for 3 hours. After the completion of the reaction, the reaction mixture was extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution three times, dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g ISCO silica gel cartridge, 0 - 20 % EtOAc/Hex) to yield the title compound as white solid (5.10 g, 86%).

Step 2. 4-((4-bromo-2-fluorophenoxy)methyl)piperidine hydrochloride: t-butyl 4-((4- bromo-2-fluorophenoxy)methyl)piperidin-l-carboxylate (5.60 g, 14.42 mmol) was dissolved in MeOH. And 1.25 M HC1 in MeOH (57.69 mL, 72.12 mmol) was added thereto. After the solvent was distilled Out completely, the residue was washed with ether to yield the title compound as white solid (4.1 g, 99%).

Step 3. 1 -(4-((4-bromo-2-fluorophenoxy)methyl)piperidin- 1 -yl)-2-methylpropan-2-ol:

4-((4-bromo-2-fluorophenoxy)methyl)piperidine hydrochloride (2.30 g, 7.98 mmol) was dissolved in EtOH 50 mL and H ₂ 0 50 mL. And 1 ,2-epoxy-2-methylpropane (5.76 g, 79.82 mmol) and K ₂ C0 ₃ (5.52 g, 39.91 mmol) were added slowly thereto. The mixture was stirred in a microwave at 120 °C for 20 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Excess amount of H ₂ 0 was added thereto, and then a little of MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as white solid (2.4 g, 86%).

Step 4. 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(2-fiuoro-2-methylpropyl)piperidine:

l-(4-((4-bromo-2-fluorophenoxy)methyl)piperidin-l-yl)-2-m ethylpropan-2-ol (4.88 g, 13.55 mmol) was dissolved in CH ₂ C1 ₂ . At 0 °C, DAST (1.97 mL, 14.90 mmol) was added slowly thereto, following with stirring with at 0 °C for 2 hours. The reaction mixture was neutralized with saturated NaHC0 ₃ aqueous solution to pH 7, and then washed with saturated aqueous brine solution three times. The organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column

chromatography (40 g ISCO silica gel cartridge, 0 ~ 40 % EtOAc/Hex) to yield the title compound as light-yellow solid (3.3 g, 67%).

Step 5. methyl 3 '-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine (0.62 g, 1.71 mmol) was dissolved in 1,4-dioxane 12 mL and H ₂ 0 3 mL. And then, 4- (methoxycarbonyl)phenylboronic acid (0.31 g, 1.71 mmol), Pd(dbpf)Cl ₂ (0.056 g, 0.086 mmol) and Cs ₂ C0 ₃ (1.12 g, 3.42 mmol) were added thereto, following with increasing the temperature slowly and stirring at 120 °C for 3 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na SC«4, and filtered. The filtrate was concentrated under reduced pressure. MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as white solid (0.23 g, 32%).

Step 6. 3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy)biphenyl-4- carboxylic acid: methyl 3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy) biphenyl-4-carboxylate (0.32 g, 0.77 mmol) was dissolved in THF 10 mL, H ₂ 0 3 mL and MeOH 3 mL. LiOH H ₂ 0 (0.26 g, 6.13 mmol) was added thereto, following with stirring at room temperature for 12 hours. After the completion of the reaction, The reaction mixture was acidified to pH 5 by the addition of HC1. The reaction mixture was extracted with CH ₂ C1 ₂ . The organic layer was washed with saturated aqueous brine solution three times, dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (0.12 g, 39%).

Step 7. Compound 725: 3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy) biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol) and (S)-piperidin-3-ol (0.02 g, 0.20 mmol) were dissolved in DMF 2 mL. DIPEA (0.06 g, 0.50 mmol), EDCI (0.04 g, 0.20 mmol) and HOBt (0.03 g, 0.20 mmol) were added thereto slowly, following with stirring at room temperature for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered, and then dissolved in CH ₂ C1 ₂ . The solution was concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (0.032 g, 68%).

1H NMR (400 MHz, CDC1 ₃ ) 5 7.50 (m, 4 H), 7.32 - 7.24 (m, 2 H), 7.00 (t, 1 H, J = 8.5 Hz),

3.89 (d, 2 H, J = 6.0 Hz), 3.44 - 2.98 (m, 6 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 - 1.65 (m, 9 H), 1.38 - 1.23 (m, 8 H); MS (ESI) m/z 487 (M+ + H).

According to the above-described synthesis process of compound 725, the compounds of Table 12 were synthesized using 3'-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 11.

Table 11. 727 (R)- pyrrolidine-2-ylmethanol 3

728 (S)-pyrrolidine-2-ylmethanol 27

729 (R)-pyrrolidine-3 -ol 28

799 piperidin-4-carboxamide 47

806 (R)-piperidin-2-carboxamide 47

807 (S)-piperidin-2-carboxamide 16

Table 12.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

726 1H NMR (400 MHz, CDC1 ₃ ) δ 7.53 - 7.44 (m, 4 H), 7.32 - 7.24 (m, 2 H), 7.00 (t, 1 H, J = 8.5 Hz), 3.89 - 3.44 (m, 6 H), 2.98 (d, 2 H, J = 9.6 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (t, 2 H, J = 11.1 Hz), 1.91 - 1.38 (m, 9 H), 1.32 (s, 3H), 1.23 (s, 3 H); MS (ESI) m/z 487 (M+ + H)

(R)-(3'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 5 7.66 - 7.19 (m, 5 H), 7.01 (t, 1 H, J = 8.5 Hz), 4.98

727 .

(brs, 1 H), 3.90 (d, 2 H, J = 5.9· Hz), 3.80 - 3.74 (m, 2 H), 3.58 - 3.50 (m, 3 H), 3.01 - 2.48 (m, 4 H), 2.19 - 1.60 (m, 9 H), 1.40 - 1.34 (m, 8 H);'MS (ESI) m/z 487 (M+ + H).

(S)-(3 '-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC13) δ 7.55 (brs, 4 H), 7.33 - 7.24 (m, 2 H), 7.01 (t, 1 H, J

728

= 8.5 Hz), 4.98 (brs, 1 H), 3.90 (d, 2 H, J = 5.9 Hz), 3.80 - 3.74 (m, 2 H), 3.58 - 3.50 (m, 3 H), 3.01 - 2^.48 (m, 4 H), 2.19 - 1.60 (m, 9 H), 1 .40 - 1.34 (m, 8 H); MS (ESI) m/z 487 (M+ + H).

(R)-(3'-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)b iphenyl-4- yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 - 7.50 (m, 4 H), 7.33 - 7.24 (m, 2 H), 7.00 (t, 1

729

H, J = 8.5 Hz), 4.60 (s, 0.5 H), 4.47 (s, 0.5 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.83 - 3.76 (m, 2 H), 3.68 - 3.45 (m, 2 H), 3.00 (brs, 2 H), 2.47 - 1.85 (m, 7 H), 1.44 - 0.83 (m, 8 H); MS (ESI) m z 473 (M+ + H).

l-(3'-fluoro-4'-((l-(2-fluoro-2-meth.ylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (d, 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0 Hz),

799

7.34 - 7.27 (m, 2 H), 7.03 (t, 1 H, J = 8.4 Hz), 5.58 (d, 2 H, J = 12.9 Hz), 3.91 - 3.90 (m, 4 H), 3.01 - 2.98 (m, 4 H), 2.48 - 2.42 (m, 3 H), 2.19 (t, 2 H, J = 11.4 Hz), 1.85 - 1.82 (m, 7 H), 1.47 - 1.26 (m, 8 H); MS (ESI) m/z 514 (M+ + H).

(R)- 1 -(3 '-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

806

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 (dd, 4 H, J = 28.0, 7.2 Hz), 7.35 - 7.27 (m, 2 H), 7.03 (t, 1 H, J = 8.5 Hz), 6.53 (brs, 1 H), 5.70 (brs, 1 H), 5.29 (brs, 1 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.79 (d, 1 H, J = 13.2 Hz), 3.14 (t, 1 H, J = 12.6 Hz), 2.99 (d, 2 H, J = 11.2 Hz), 2.47 (s, 1 H), 2.42 (s, 1 H), 2.34 (d, 1 H, J = 12.4 Hz), 2.18 (t, 2 H, J = 11.1 Hz), 1.88 - 1.53 (m, 8 H), 1.49 - 1.25 (m, 8 H); MS (ESI) m/z 514 (M+ + H).

(S)- 1 -(3 '-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 - 7.50 (m, 4 H), 7.35 - 7.27 (m, 1 H), 7.03 (t, 1

807 H, J = 8.4 Hz), 6.49 (brs, 1 H), 5.48 (brs, 1 H), 5.29 (brs, 1 H), 3.91 (d, 2 H, J = 5.2 Hz), 3.80 (d, 1 H, J = 13.2 Hz), 3.13 (t, 1 H, J = 12.2 Hz), 3.00 (d, 2 H, J = 11.2 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.35 (d, 1 H, J = 12.8 Hz), 2.19 (t, 2 H, J = 11.0 Hz), 1.89 - 1.44 (m, 8 H), 1.41 - 1.26 (m, 8 H); MS (ESI) m/z 514 (M+ + H).

Example 42. Compound 730: (S)-l-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl) piperidin-4-yl)methoxy)biphenylcarbonyl)pyrroUdine-2-carboxa mide

Step 1. methyl 3,3'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-carboxylate: 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl) piperidine (the product of synthesis step 4 of compound 725; 0.6 g, 1.66 mmol) was dissolved in 1 ,4-dioxane 12 mL and H ₂ 0 3 mL. 4-(ethoxycarbonyl)-3-fluorophenylboronic acid, Pd(dbpf)Cl ₂ (0.05 g, 0.08 mmol) and Cs ₂ C0 ₃ (1.07 g, 3.13 mmol) were added thereto, following with increasing the temperature, slowly and stirring at 120 °C for'3 hours. After the completion of the reaction, the reactioamixture was filtered through Celits. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as brown solid (0.5 g, 69%).

Step 2. 3 ,3 '-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: methyl 3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (0.5 g, 1.15 mmol) was dissolved in THF 10 mL, H ₂ 0 3 mL and MeOH 3 mL. LiOH H ₂ 0 (0.24 g, 5.74 mmol) was added thereto, following with stirring at room temperature for 12 hours. After the completion of the reaction, The reaction mixture was acidified to pH 5 by the addition of HCl. The reaction mixture was extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times, dried over Na ₂ S0 , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (0.37 g, 77%).

Step 3. Compound 730: 3,3 '-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol) and (S)-pyrrolidine-2-carboxamide (0.02 g, 0.19 mmol) were dissolved in DMF 1 mL. DIPEA (0.08 mL, 0.47 mmol), EDCI (0.04 g, 0.19 mmol) and HOBt (0.03 g, 0.19 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered to yield the title compound as brown solid (0.04 g, 75%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.24 - 7.21 (m, 5 H), 7.00 (t, 1 H, J = 8.4 Hz), 6.89 (brs, 1 H), 5.41 (brs, 1 H), 4.81 - 4.80 (m, 1 H), 3.91 (brs, 2 H), 3.53 - 3.41 (m, 2 H), 3.13 - 2.43 (m, 4 H), 2.21 - 1.86 (m, 3 H), 1.71 - 1.23 (m, 10 H); MS (ESI) m/z 518 (M+ + H).

According to the above-described synthesis process of compound 730, the compounds of Table 14 were synthesized using 3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 13.

Table 13.

Table 14.

Compound

Compound Name, Ή-NMR, MS (ESI)

No.

(S)-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin -4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

731 1H NMR (400 MHz, CDC1 ₃ ) δ 7.43 - 7.02 (m, 5 H), 6.99 (t, 1 H, J = 10.2 Hz), 3.89 (d, 2 H, J = 6.4 Hz), 3.56 - 3.08 (m, 4 H), 3.06 (brs, 2 H), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.28 - 1.54 (m, 9 H), 1.38 - 0.86 (m, 8 H); MS (ESI) m/z 505 (M+ + H).

(S)-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperi din-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidine- 1 -yl)methanone

732

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 - 7.46 (m, 1 H), 7.37 - 7.10 (m, 4 H), 7.04 - 7.00 (m, 1 H) 4.62 (s, 1 H), 4.50 (s, 1 H), 3.92 (d, 2 H, J = 4.6 Hz), 3.85 - 3.33 (m, 4 H), 3.02 (brs, 2 H), 2.49 (d, 2 H, J = 16.1 Hz), 2.30 - 1.84 (m, 7 H), 1.66 - 1.26 (m, 8 H); MS (ESI) m z 491 (M+ + H).

(R)-(3 ,3 '-difluoro-4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidine- 1 -yl)methanone

733 1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 - 7.46 (m, 1 H), 7.41 - 7.25 (m, 4 H), 7.03 (t,

1 H, J = 6.3 Hz), 4.62 (s, 0.5 H), 4.49 (s, 0.5 H), 3.92 (d, 2 H, J = 4.5 Hz), 3.85 - 3.03 (m, 4 H), 3.03 (brs, 2 H), 2.51 (s, 1 H), 2.47 (s, 1 H), 2.31 - 1.84 (m, 7 H), 1.69 - 1.36 (m, 8 H); MS (ESI) m/z 491 (M+ + H).

(R)-(3 ,3 '-difluoro-4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

734 1H NMR (400 MHz, CDC1 ₃ ) δ 7.41 (t, 1 H, J = 5.3 Hz), 7.34 - 7.20 (m, 4 H), 7.00 (t, 1 H, J = 6.3 Hz), 3.88 (d, 2 H, J = 4.6 Hz), 3.56 - 3.08 (m, 4 H), 2.98 (d, 2 H, J = 8.1 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (t, 2 H, J = 8.5 Hz), 1.98 - 1.59 (m, 7 H), 1.43 - 1.23 (m, 8 H); MS (ESI) m/z 505 (M+ + H).

l-(3,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

H NMR (400 MHz, CDC1 ₃ ) δ 7.59 - 7.27 (m, 5 H), 7.07 (t, 1 H, J = 8.3 Hz), 5.70

800

(brs, 2 H), 4.78 (d, 1 H, J = 12.9 Hz), 3.95 (d, 2 H, J = 5.9 Hz), 3.75 (d, 1 H, J = 12.8 Hz), 3.16 - 2.95 (m, 4 H), 2.51 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 11.2 Hz), 2.06 - 1.59 (m, 7 H), 1.48 - 0.92 (m, 8 H); MS (ESI) m z 532 (M+ + H).

(R)- 1 -(3 ,3 '-difluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.49 (t, 1 H, J = 7.4 Hz), 7.42 - 7.25 (m, 4 H), 7.03

816 (t, 1 H, J = 8.4 Hz), 6.32 (brs, 1 H), 5.68 (brs, 1 H), 5.44 (brs, 1 H), 3.91 (d, 2 H, J = 6.4 Hz), 3.60 (d, 1 H, J = 12.7 Hz), 3.22 (t, 1 H, J = 12.0 Hz), 2.99 (d, 2 H, J = 8.0 Hz), 2.48 - 2.42 (m, 3 H), 2.15 - 1.39 (m, 8 H), 1.34 - 1.26 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

(S)- 1 -(3 ,3 ' -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (t, 1 H, J = 6.0 Hz), 7.42 - 7.27 (m, 5 H), 7.03

817 (t, 1 H, J = 7.0 Hz), 6.31 (JOTS, ^' ji H), 5.52 (brs, 1 H), 5.45 (brs, 1 H), 3.92 (d, 2 H, J = 5.8 Hz), 3.61 (d, 1 H, J = 13.9 Hz), 3.21 (brs, 1 H), 3.00 (d, 2 H, J = 11.1 Hz), 2.48 - 2.42 (m, 3 H), 2.19 (t, 2 H, J = 11.6 Hz), 2.05 - 1.45 (m, 8 H), 1.40 - 1.25 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

Example 43. Compound 735: (S)-(2,3 '-difluoro-4 '-((l-(2-fluoro-2-methyIpropyl) piperidin-4-yl)methoxy)biphenyI-4-yl)(3-hydroxypiperidin-l-y I)methanone

Step 1. methyl 2,3 '-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-carboxylate: 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine (the product of synthesis step 4 of compound 725; 0.60 g, 1.66 mmol) was dissolved in 1,4- dioxane 12 mL and H ₂ 0 3 mL. 2-Fluoro-4-(methoxycarbonyl)phenylboronic acid (0.33 g, 1.66 mmol), Pd(dbpf)Cl ₂ (0.05 g, 0.08 mmol) and Cs ₂ C0 ₃ (1.07 g, 3.31 mmol) was added thereto. The mixture was stirred in a microwave at 120 °C for 30 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over a ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as light-yellow solid (0.35 g, 49%).

Step 2. 2,3 ' -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: methyl 2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (0.35 g, 0.80 mmol) was dissolved in THF 10 mL, H ₂ 0 3 mL and MeOH 3 mL. LiOH H ₂ 0 (0.17 g, 4.02 mmol) was added thereto, following with increasing the temperature slowly and then refluxing with stirring for 3 hours. After the completion of the reaction, The reaction mixture was acidified to pH 5 by the addition of HC1. The reaction mixture was extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (0.33 g, 97%).

Step 3. Compound 735: 2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol) and (S)-piperidin-3-ol (0.02 g, 0.19 mmol) were dissolved in DMF 2 mL. DIPEA (0.08 mL, 0.48 mmol), EDCI (0.04 g, 0.19 mmol) and HOBt (0.03 g, 0.19 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered, and dissolved in CH ₂ C1 ₂ . The solution was concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (0.02 g, 42%).

1H MR (400 MHz, CDC1 ₃ ) δ 7.40 (t, 1 H, J = 5.8 Hz), 7.29 - 7.21 (m, 4 H), 6.99 (t, 1 H, J = 6.4 Hz), 3.88 (d, 2 H, J = 4.6 Hz), 3.78 - 3.27 (m, 4 H), 2.97 (d, 2 H, J = 8.2 Hz), 2.45 (s, 1 H), 2.40 (s, 1 H), 2.16 (t, 2 H, J = 8.5 Hz), 1.91 - 1.65 (m, 7 H), 1.45 - 1.23 (m, 8 H); MS (ESI) m/z 505 (M+ + H).

According to the above-described synthesis process of compound 735, the compounds of Table 16 were synthesized using 2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 15.

Table 15.

Table 16.

H); MS (ESI) m/z 505 (M+ + H).

(S)- 1 -(2,3 ' -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

753 1H NMR (400 MHz, CDC1 ₃ ) δ 7.47 - 7.25 (m, 5 H), 7.02 (t, 1 H, J = 8.0 Hz), 6.96

(brs, 1 H), 5.81 (brs, 1 H), 4.76 - 4.75 (m, 1 H), 3.91 (d, 2 H, J = 5.6 Hz), 3.66 -

3.57 (m, 2 H), 3.00 (d, 2 H, J = 12.0 Hz), 2.48 - 2.37 (m, 2 H), 2.21 - 1.81 (m, 9

H), 1.44 - 1.25 (m, 8 H); MS (ESI) m/z 518 (M+ + H).

(R)-(2,3 '-difluoro-4 '-((1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

754 1H NMR (400 MHz, CDC1 ₃ ) δ 7.42 (t, 1 H, J = 8.8 Hz), 7.31 - 7.23 (m, 4 H), 7.02 (t, 1 H, J = 8.6 Hz), 3.91 - 3.35 (m, 7 H), 3.00 (d, 2 H, J = 11.2 Hz), 2.48 - 2.42 (m, 2 H), 2.18 (t, 2 H, J = 11.4 Hz), 1.93 - 1.41 (m, 7 H), 1.39 - 1.25 (m, 8 H); MS (ESI) m/z 505 (M+ + H).

l-(2,3'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 53.00 (d, 2 H, J = 11.1 Hz), 7.32 - 7.19 (m, 4 H),

818

7.03 (t, 1 H, J = 8.4 Hz), 5.59 (brs, 2 H), 4.73 (brs, 1 H), 3.92 - 3.90 (m, 3 H), 3.00

- 2.97 (m, 4 H), 2.49 - 2.42 (m, 3 H), 2.18 (t, 2 H, J = 11.0 Hz), 1.88 - 1.81 (m, 7

H), 1.47 - 1.26 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

(R)- 1 -(2,3 ' -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.46 - 7.44 (m, 1 H), 7.33 - 7.25 (m, 4 H), 7.03 (t,

819 1 H, J = 8.6 Hz), 6.45 (brs, 1 H), 5.56 (brs, 1 H), 5.27 (brs, 1 H), 3.92 (d, 2 H, J = 6.2 Hz), 3.78 - 3.73 (m, 1 H), 3.16 - 3.18 (m, 1 H), 3.01 (d, 2 H, J = 11.2 Hz), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.34 (d, 1 H, J = 12.0 Hz), 2.19 (t, 2 H, J = 11.2 Hz), 2.05 - 1.40 (m, 8 H), 1.34 - 1.24 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

(S)- 1 -(2,3 '-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 57.47 (t, 1 H, J = 7.6 Hz), 7.33 - 7.25 (m, 4 H), 7.03

820 (t, 1 H, J = 8.6 Hz), 6.41 (brs, 1 H), 5.56 (brs, 1 H), 5.26 (brs, 1 H), 3.92 (d, 2 H, J = 6.0 Hz), 3.78 (d, 1 H, J = 13.6 Hz), 3.17 (m, 1 H), 3.00 (d, 2 H, J = 11.2 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.34 (d, 1 H, J = 12.4 Hz), 2.19 (t, 2 H, J = 11.1 Hz), 2.05 - 1.43 (m, 8 H), 1.40 - 1.24 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

Example 44. Compound 782: (S)-l-(5-(3-fluoro-4-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)phenyl)picolinoyl)pyrrol idme-2-carboxamide

Step 1. methyl 5-(3-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl) picolinate: 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine

(the product of synthesis step 4 of compound 725; 1.0 g, 2.76 mmol) was dissolved in 1,4- dioxane 8 mL and H ₂ 0 2 mL. 6-(Methoxycarbonyl)pyridine-3-ylboronic acid (0.50 g, 2.76 mmol), Pd(dbpf)Cl ₂ (0.22 g, 0.28 mmol) and Cs ₂ C0 ₃ (1.80 g, 5.52 mmol) were added thereto. The mixture was stirred in a microwave at 110 °C for 30 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer was washed three times with saturated aqueous brine solution, dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as dark brown solid (0.1 g, 9%).

Step 2. 5-(3-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)phenyl)picolinic acid: methyl 5-(3-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl) picolinate (0.12 g, 0.29 mmol) was dissolved in THF 10 mL, H ₂ 0 3 mL and MeOH 3 mL. LiOH H ₂ 0 (0.06 g, 1.43 mmol) was added thereto, following with increasing the temperature slowly and then refluxing with stirring for 3 hours. After the completion of the reaction, The reaction mixture was acidified to pH 5 by the addition of HC1, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution three times, dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as dark brown solid (0.08 g, 69%).

Step 3. Compound 782: 5-(3-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinic acid (0.03 g, 0.07 mmol) and (S)-pyrrolidine-2-carboxamide (0.02 g, 0.15 mmol) was dissolved in DMF 1 mL. DIPEA (0.05 g, 0.37 mmol, EDCI (0.03 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered, and dissolved in CH ₂ C1 ₂ again. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (0.01 g, 38%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.77 (brs, 1 H), 8.14 - 7.93 (m, 2 H), 7.37 - 7.29 (m, 2 H), 7.07 - 7.05 (m, 1 H), 5.50 (brs, 1 H), 5.16 - 4.82 (m, 1 H), 3.93 - 3.89 (m, 5 H), 3.02 (d, 2 H, J = 12.5 Hz), 2.50 - 1.78 (m, 11 H), 1.47 - 1.26 (m, 8 H); MS (ESI) m/z 501 (M+ + H).

According to the above-described synthesis process of compound 782, the compounds of Table 18 were synthesized using 5-(3-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinic acid and the reactant of Table 17.

Table 17. Table 18.

Example 45. Compound 706: (S)-l-(2'-fluoro-4'-((l-(2-fluoro-2- methylpropyl)piperidm-4-yl)methoxy)biphenylcarbonyl)pyrrolid ine-2-carboxamide

Step 1. methyl 2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy)biphenyl-4- carboxylate: 4-((4-bromo-3-fluorophenoxy)methyl)-l-(2-fluoro-2-methylprop yl)piperidine (the product of synthesis step 4 of compound 704; 500 mg, 1.38 mmol), 4-(methoxycarbonyl) phenylboronic acid (298 mg, 1.57 mmol), Pd(dppf)Cl ₂ (56 mg, 0.07 mmol) and Cs ₂ C0 ₃ (341 mg, 1.05 mmol) were added to water (2 mL)/l,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1/7) to yield the title compound as white solid (210 mg, 36%).

Step 2. 2 ' -fluoro-4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: methyl 2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (210 mg, 0.50 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (106 mg, 2.52 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified by the addition of IN HCl. The resulting precipitate was filtered to yield the title compound as white solid (200 mg, 98%).

Step 3. Compound 706: 2' -fluoro-4 '-((1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (50 mg, 0.12 mmol), (S)-pyrrolidine-2-carboxamide (17 mg, 0.15 mmol), Bop (110 mg, 0.248 mmol) and Et ₃ N (34 μΐ,, 0.25 mmol) were dissolved in DMF. The reaction was performed at 60 °C for a day. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtOAc, The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 10/1) to yield the title compound as yellow solid (23 mg, 37%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.61 - 7.53 (m, 4 H), 7.37 - 7.27 (m, 1 H), 7.04 (brs, 1 H), 6.79 - 6.70 (m, 2 H), 5.53 (brs, 1 H), 4.85 - 4.82 (m, 1 H), 3.83 (d, 2 H, J = 5.8 Hz), 3.67 - 3.56 (m, 2 H), 3.01 (brs, 1 H), 2.50 - 2.39 (m, 2 H), 2.20 - 2.12 (m, 2 H), 2.10 - 2.06 (m, 2 H), 1.89 - 1.80 (m, 4 H), 1.42 - 1.37 (m, 8 H), 1.29 - 1.21 (m, 2 H); MS (ESI) m/z 500 (M+ + H).

According to the above-described synthesis process of compound 706, the compounds of Table 20 were synthesized using 2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 19.

Table 19.

Table 20.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl- 4-yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 - 7.53 (m, 4 H), 7.37 - 7.33 (m, 1 H), 6.79 -

707

6.69 (m, 2 H), 5.00 (brs, 1 H), 4.47 - 4.42 (m, 1 H), 3.84 - 3.61 (m, 3 H), 3.57 - 3.51 (m, 2 H), 3.04 - 3.02 (m, 2 H), 2.51 - 2.46 (m, 2 H), 2.28 - 2.18 (m, 3 H), 1.91 - 1.60 (m, 6 H), 1.42 - 1.27 (m, 8 H); MS (ESI) m/z 487 (M+ + H). (R)-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl- 4-yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.62 - 7.54 (m, 4 H), 7.37 - 7.27 (m, 1 H), 6.79 - 6.69 (m, 2 H), 4.62 - 4.49 (m, 1 H), 3.90 - 3.77 (m, 4 H), 3.71 - 3.68 (m, 1 H), 3.66 - 3.49 (m, 1 H), 3.03 (brs, 1 H), 2.57 (brs, 2 H), 2.26 (brs, 2 H), 2.16 - 2.06 (m, 2 H), 1.99 - 1.73 (m, 3 H), 1.55 - 1.44 (m, 6 H), 1.33 (s, 2 H), 0.91 - 0.86 (m, 1 H); MS (ESI) m/z 487 (M+ + H).

(R)-(2 ' -fluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

MS (ESI) m/z 487 (M+ + H).

(S)-(2 ' -fluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-yl)(3-hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 - 7.52 (m, 4 H), 7.49 - 7.32 (m, 1 H), 6.79 - 6.70 (m, 2 H), 3.99 (brs, 1 H), 3.83 (d, 2 H, J = 5.9 Hz), 3.51 (brs, 2 H), 3.03 (brs, 2 H), 2.51 - 2.46 (m, 2 H), 2.20 (brs, 2 H), 2.05 - 2.03 (m, 2 H), 1.97 - 1.67 (m, 4 H), 1.55 (brs, 2 H), 1.42 - 1.32 (m, 8 H), 1.26 - 1.20 (m, 1 H); MS (ESI) m/z 487 (M+ + H).

(S)-(2 ' -fluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 6 7.62 - 7.54 (m, 4 H), 7.34 (t, 1 H, J = 8.7 Hz), 6.78 - 6.69 (m, 2 H), 4.60 - 4.48 (m, 1 H), 3.87 - 3.81 (m, 4 H), 3.79 - 3.71 (m, 1 H), 3.69 - 3.49 (m, 1 H), 3.03 (brs, 2 H), 2.52 - 2.46 (m, 2 H), 2.21 - 2.18 (m, 2 H), 2.15 - 2.13 (m, 1 H), 2.12 - 2.00 (m, 2 H), 1.99 - 1.71 (m, 3 H), 1.57 - 1.54 (m, 1 H), 1.47 (s, 3 H), 1.42 (s, 3 H); MS (ESI) m/z 473 (M+ + H).

(S)-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl- 4-yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 - 7.55 (m, 4 H), 7.35 (t, 1 H, J = 8.8 Hz), 6.77 - 6.69 (m, 2 H), 4.97 - 4.95 (m, 1 H), 4.46 - 4.44 (m, 1 H), 3.87 - 3.75 (m, 4 H), 3.65 - 3.46 (m, 3 H), 2.24 - 2.22 (m, 1 H), 2.20 - 2.00 (m, 1 H), 1.97 - 1.92 (m, 2 H), 1.90 - 1.81 (m, 2 H), 1.70 - 1.32 (m, 10 H), 1.29 - 1.26 (m, 3 H); MS (ESI) m/z 487 (M+ + H).

l-(2'-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (d, 2 H, J = 7.6 Hz), 7.49 (d, 2 H, J = 7.7 Hz), 7.38 (t, 1 H, J = 8.6 Hz), 6.81 (d, 1 H, J = 8.4 Hz), 6.75 (d, 1 H, J = 12.7 Hz), 5.73 (d, 2 H, J = 19.0 Hz), 4.73 (brs, 1 H), 3.95 (brs, 1 H), 3.86 (d, 2 H, J = 5.6 Hz), 3.04 - 3.01 (m, 4 H), 2.51 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 11.4 Hz), 1.84 - 1.48 (m, 7 H), 1.44 - 0.89 (m, 8 H); MS (ESI) m/z 514 (M+ + H).

(R)- 1 -(2 ' -fluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.64 - 7.43 (m, 4 H), 7.35 (t, 1 H, J - 8.8 Hz), 6.82 - 6.67 (m, 2 H), 3.83 (d, 3 H, J = 6.0 Hz), 3.13 (t, 1 H, J = 13.3 Hz), 3.01 (d, 2 H, J = 11.3 Hz), 2.50 (s, 1 H), 2.44 (s, 1 H), 2.34 (d, 1 H, J = 12.5 Hz), 2.19 (t, 2 H, J = 11.2 Hz), 1.93 - 1.74 (m, 6 H), 1.72 - 1.52 (m, 3 H), 1.52 - 1.38 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

(S)- 1 -(2 ' -fluoro-4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.63 - 7.43 (m, 4 H), 7.35 (t, 1 H, J = 8.9 Hz), 6.82 - 6.67 (m, 2 H), 3.83 (d, 3 H, J = 5.8 Hz), 3.13 (t, 1 H, J = 12.8 Hz), 3.01 (d, 2 H, J = 11.3 Hz), 2.50 (s, 1 H), 2.44 (s, 1 H), 2.34 (d, 1 H, J = 12.3 Hz), 2.19 (t, 2 H, J = 11.5 Hz), 1.95 - 1.73 (m, 6 H), 1.73 - 1.52 (m, 3 H), 1.52 - 1.42 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

(R)-l-(2'-fluoro-4'-((l-(2-iluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 6 7.56 (d, 2 H, J = 7.0 Hz), 7.45 (d, 2 H, J = 8.3 Hz),

881

7.34 (t, 1 H, J = 8.8 Hz), 6.81 - 6.67 (m, 2 H), 3.84 (d, 3 H, J = 5.8 Hz), 3.57 (s, 1 H), 3.47 (s, 1 H), 3.03 (s, 2 H), 2.66 - 2.40 (m, 3 H), 2.21 (s, 2 H), 1.99 - 1.47 (m, 10 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 514 (M+ + H).

Example 46. Compound 704: (2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy)biphenyl-4-yl)((R)-2-(hydroxymethyl)pyrrolidine -l-yl)methanone

Step 1. t-butyl 4-((4-bromo-3-fluorophenoxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l -carboxylate (the product of synthesis step 2 of compound 431 ; 6.0 g, 20.45 mmol) was dissolved in DMF (60 mL). 4-Bromo-3- fluorophenol (3.91 g, 20.45 mmol) and K ₂ C0 ₃ (8.48 g, 61.35 mmol) were added thereto slowly, following with stirring at 80 °C for 5 hours. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtO Ac. The organic layer was dried over anhydrous MgS0 , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane 1/10) to yield the title compound as white solid (6.27g, 79%).

Step 2. 4-((4-bromo-3-fluorophenoxy)methyl)piperidine hydrochloride:

t-butyl 4-((4-bromo-3 -fluorophenoxy)methyl)piperidin- 1 -carboxylate (6.27 g, 16.15 mmol) was dissolved in CH ₂ C1 ₂ (70 mL). 4 M HC1 in 1 ,4-dioxane (80.74 mL, 322.97 mmol) was added thereto, following with stirring for 1 hour. The resulting precipitate was filtered to yield the title compound as white solid (5.03 g, 96%).

Step 3. 1 -(4-((4-bromo-3 -fluorophenoxy)methyl)piperidin- 1 -yl)-2-methylpropan-2-ol :

4-((4-bromo-3-fluorophenoxy)methyl)piperidine hydrochloride (5.32 g, 16.39 mmol) was dissolved in EtOH (5 mL) and H ₂ 0 (5 mL). 2,2-Dimethyloxirane (14.59 mL, 163.88 mmol) and K ₂ C0 ₃ (1.13 g, 8.19 mmol) were added thereto slowly. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtO Ac. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtO Ac/hexane = 1/4) to yield the title compound as white solid (5.2 g, 88%).

Step 4. 4-((4-bromo-3 -fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine:

l-(4-((4-bromo-3-fluorophenoxy)methyl)piperidin-l-yl)-2-m ethylpropan-2-ol (5.2 g, 14.43 mmol) was dissolved in CH ₂ C1 ₂ (15 mL). At 0 °C, DAST (1.91 mL, 14.43 mmol) was added slowly thereto. After stirring for 1 hour at room temperature, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtO Ac. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtO Ac/hexane = 1/7) to yield the title compound as yellow solid (2.50 g, 48%).

Step 5. methyl 2,2'-difiuoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl- 4-carboxylate: 4-((4-bromo-3-fluorophenoxy)methyl)-l-(2-fluoro-2-methylprop yl)piperidine (200 mg, 0.55 mmol), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (131 mg, 0.06 mmol), Pd(dppf)Cl ₂ (22 mg, 0.03 mmol) and Cs ₂ C0 ₃ (360 mg, 1.10 mmol) were added to water (2 mL)/l,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtO Ac. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column

chromatography (EtO Ac/hexane = 1/7) to yield the title compound as white solid (81 mg, 34%).

Step 6. 2,2 ' -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: methyl 2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (81 mg, 0.19 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (39 mg, 0.93 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified by the addition of IN HCl. The resulting precipitate was filtered to yield the title compound as white solid (60 mg, 77%).

Step 7. Compound 704: 2,2'-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol),(R)-pyrrolidine-2-ylmethanol (9 mg, 0.09 mmol), Bop (63 mg, 0.14 mmol) and Et ₃ N (20 iL, 0.14 mmol) were dissolved in

DMF, and at 60 °C. The reaction was performed at a day. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtO Ac. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 10/1) to yield the title compound as yellow solid (17 mg, 47%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 - 7.27 (m, 4 H), 6.77 - 6.70 (m, 2 H), 4.43 - 3.83 (m, 1 H), 4.12 - 3.83 (m, 3 H), 3.78 - 3.47 (m, 4 H), 3.05 - 2.81 (m, 2 H), 2.67 - 2.49 (m, 2 H), 2.22 - 2.21 (m, 1 H), 2.20 (s, 1 H), 2.06 - 1.85 (m, 5 H), 1.57 (s, 3 H), 1.51 (s, 3 H), 1.36 - 1.31 (m, 3 H); MS (ESI) m/z 505 (M+ + H).

According to the above-described synthesis process of compound 704, the compounds of Table 22 were synthesized using 2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 21.

Table 21.

Table 22.

4-yl)((R)-3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.40 - 7.27 (m, 4 H), 6.79 - 6.71 (m, 2 H), 4.63 - 4.51 (m, 1 H), 3.84 - 3.80 (m, 3 H), 3.77 - 3.66 (m, 1 H), 3.65 - 3.49 (m, 1 H), 3.03 (brs, 2 H), 2.52 - 2.46 (m, 2 H), 2.21 - 2.13 (m, 2 H), 2.09 - 2.02 (m, 3 H), 1.97 - 1.70 (m, 3 H), 1.69 - 1.26 (m, 8 H); MS (ESI) m/z 491 (M+ + H).

(2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl- 4-yl)((S)-3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.40 - 7.27 (m, 4 H), 6.79 - 6.71 (m, 2 H), 4.63 -

743

4.51 (m, 1 H), 3.84 - 3.80 (m, 3 H), 3.77 - 3.66 (m, 1 H), 3.65 - 3.49 (m, 1 H), 3.03 (brs, 2 H), 2.52 - 2.46 (m, 2 H), 2.21 - 2.13 (m, 2 H), 2.09 - 2.02 (m, 3 H), 1.97 - 1.70 (m, 3 H), 1.69 - 1.26 (m, 8 H); MS (ESI) m/z 491 (M+ + H).

(2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-y l)methoxy)biphenyl- 4-yl)((S)-2-(hydroxymethyl)pyrrolidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 - 7.27 (m, 4 H), 6.77 - 6.69 (m, 2 H), 4.43 -

744 4.41 (m, 1 H), 3.85 (d, 2 H ,J = 5.3 Hz), 3.78 - 3.74 (m, 1 H), 3.62 - 3.52 (m, 2 H), 3.24 (brs, 2 H), 2.72 - 2.67 (m, 2 H), 2.36 - 2.33 (brs, 2 H), 2.23 - 2.18 (m, 1 H), 1.94 - 1.81 (m, 5 H), 1.79 - 1.65 (m, 3 H), 1.63 (s, 3 H), 1.48 (s, 3 H), 1.26 - 1.21 (m, 1 H); MS (ESI) m/z 505 (M+ + H).

(2,2 ^> -difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl- 4-yl)((R)- 3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) $.7.39 (t, 1 H, J = 7.7 Hz), 7.31 - 7.22 (m, 3 H), 6.77

745 ^;

- 6.69 (m, 2 H), 4.14 - 4.12 (m, 1 H), 3.96 - 3.81 (m, 3 H), 3.79 - 3.46 (m, 5 H), 2.91 (brs, 2 H), 2.58 (brs, 2 H), 1.94 - 1.79 (m, 6 H), 1.69 (brs, 2 H), 1.56 (s, 3 H), 1.50 _. (s, 3 H), 1.31 - 1.23 (m, 1 H); MS (ESI) m z 505 (M+ + H).

l-(2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 6 7.46 (t, 1 H, J = 7.4 Hz), 7.34 - 7.23 (m, 3 H), 6.83

803

- 6.75 (m, 2 H), 5.51 (d, 2 H, J = 32.0 Hz), 4.73 (brs, 1 H), 3.96 (brs, 1 H), 3.87 (d, 2 H, J = 5.6 Hz), 3.05 - 3.02 (m, 4 H), 2.52 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 11.2 Hz), 2.09 - 1.66 (m, 7 H), 1.60 - 0.90 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

(2R)-l-(2,2'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.46 - 7.25 (m, 4 H), 6.80 - 6.71 (m, 2 H), 6.40

825 (brs, 1 H), 5.42 (brs, 1 H), 5.28 (brs, 1 H), 3.86 - 3.79 (m, 3 H), 3.16 - 3.13 (m, 1 H), 3.00 (d, 2 H, J = 11.2 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.35 (d, 1 H, J = 13.6 Hz), 2.18 (t, 2 H, J = 11.2 Hz), 1.86 - 1.55 (m, 8 H), 1.50 - 1.26 (m, 8 H); MS (ESI) m/z 532 (M+ + H).

(2S)-l-(2,6'-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperi din-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.45 - 7.24 (m, 4 H), 6.78 - 6.71 (m, 2 H), 6.46

860

(brs, 1 H), 5.69 (brs, 1 H), 5.28 (brs, 1 H), 3.83 - 3.77 (m, 3 H), 3.19 - 3.17 (m, 1

H), 3.00 (d, 2 H, J = 9.6 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.33 (d, 1 H, J = 12.4

Hz), 2.18 (t, 2 H, J = 11.0 Hz), 1.81 - 1.52 (m, 8 H), 1.48 - 1.25 (m, 8 H)

Example 47. Compound 710: (S)-l-(2',3-difluoro-4'-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenyIcarbonyl)pyrroli dine-2-carboxamide

Step 1. ethyl 2 ' ,3 -difluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 4-((4-bromo-3-fluorophenoxy)methyl)- 1 -(2-fluoro-2-methylpropyl)piperidine (the product of synthesis step 4 of compound 704; 500 mg, 1.38 mmol), 4-(ethoxycarbonyl)-3-

/

fluorophenylboronic acid (351 mg, 1.66 mmol), Pd(dppf)Cl ₂ (56 mg, 0.07 mmol) and Cs ₂ C0 ₃ (899 mg, 2.76 mmol) were added to water (2 mL)/l ,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 15 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1/7) to yield the title compound as white solid (287 mg, 46%).

Step_2. 2 ',3 -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: ethyl 2',3-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (287 mg, 0.64 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH ¾0 (134 mg, 3.19 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified by the addition of IN HCl. The resulting precipitate was filtered to yield the title compound as white solid (220 mg, 82%).

Step 3. Compound 710: 2',3-difluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (50 mg, 0.12 mmol), (S)-pyrrolidine-2-carboxamide (16 mg, 0.14 mmol), Bop (105 mg, 0.24 mmol) and Et ₃ N (33 \iL, 0.24 mmol) were dissolved in DMF. The reaction was performed at 60 °C for a day. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 10/1) to yield the title compound as yellow solid (19 mg, 31%).

1H NMR (400 MHz, CDC1 ₃ ) 6 7.49 - 7.45 (m, 1 H), 7.39 - 7.32 (m, 3 H), 6.95 (brs, 1 H), 6.80 - 6.70 (m, 2 H), 5.56 (brs, 1 H), 4.84 - 4.81 (m, 1 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.58 - 3.51 (m, 1 H), 3.47 - 3.52 (m, 1 H), 3.00 (brs, 2 H), 2.51 - 2.43 (m, 3 H), 2.20 (brs, 2 H), 2.18 - 2.04 (m, 2 H), 1.94 - 1.91 (m, 1 H), 1.89 - 1.82 (m, 3 H), 1.80 - 1.42 (m, 8 H); MS (ESI) m/z 518 (M+ + H). According to the above-described synthesis process of compound 710, the compounds of Table 24 were synthesized using 2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 23.

Table 23.

Table 24.

(S)-(2' ,3-difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 (t, 1 H, J = 7.6 Hz), 7.35 - 7.24 (m, 3 H), 6.76

746

- 6.67 (m, 2 H), 4.12 (brs, 1 H), 3.95 - 3.89 (m, 3 H), 3.75 - 3.58 (m, 2 H), 3.46 (brs, 1 H), 3.36 (brs, 1 H), 3.16 - 3.00 (m, 3 H), 2.68 (brs, 2 H), 2.10 - 1.89 (m, 7 H), 1.83 - 1.53 (m, 9 H); MS (ESI) m/z 505 (M+ + H).

(S)-(2 ' ,3 -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 - 7.48 (m, 1 H), 7.46 - 7.27 (m, 3 H), 6.79 -

747 6.70 (m, 2 H), 3.86 - 3.81 (m, 3 H), 3.79 - 3.60 (m, 2 H), 3.50 - 3.46 (m, 1 H), 3.38 - 3.35 (m, 1 H), 3.04 (brs, 2 H), 2.44 (brs, 2 H), 2.21 - 2.18 (m, 2 H), 2.14 (brs, 2 H), 1.89 - 1.81 (m, 4 H), 1.60 (brs, 1 H), 1.43 - 1.38 (m, 7 H); MS (ESI) m/z 491 (M+ + H).

(S)-(2 ',3 -difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidine-l-yl) methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (t, 1 H, J = 7.5 Hz), 7.38 - 7.17 (m, 3 H), 6.80

748 - 6.70 (m, 2 H), 4.83 - 4.81 (m, 1 H), 4.42 - 4.40 (m, 1 H), 3.86 - 3.78 (m, 4 H),

3.50 - 3.46 (m, 2 H), 3.01 (brs, 1 H), 2.48 (brs, 1 H), 2.23 - 2.18 (m, 2 H), 1.92 -

1.88 (m, 1 H), 1.87 - 1.71 (m, 4 H), 1.70 - 1.64 (m, 2 H), 1.42 - 1.24 (m, 8 H),

1.22 (brs, 1 H); MS (ESI) m/z 505 (M+ + H).

l-(2',3-difluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.47 - 7.30 (m, 4 H), 6.82 (d, 1 H, J = 8.4 Hz), 6.76

802 (d, 1 H, J = 12.6 Hz), 5.62 (d, 2 H, J = 24.5 Hz), 4.79 (d, 1 H, J = 12.9 Hz), 3.87 (d, 2 H, J = 5.5 Hz), 3.78 (d, 1 H, J = 13.0 Hz), 3.17 - 2.95 (m, 4 H), 2.52 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 11.5 Hz), 2.07 - 1.82 (m, 7 H), 1.48 - 0.92 (m, 6 H); MS (ESI) m/z 532 (M+ + H).

(R)- 1 -(2 ' ,3-difluoro-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.60 - 7.27 (m, 4 H), 6.80 - 6.68 (m, 2 H), 6.33

823 (brs, 1 H), 5.64 (brs, 1 H), 5.44 (brs, 1 H), 3.90 (brs, 2 H), 3.63 - 3.59 (m, 1 H),

3.25 - 3.19 (m, 1 H), 2.96 (d, 2 H, J = 26.4 Hz), 2.89 - 2.86

(m, 3 H), 2.73 - 2.70 (m, 2 H), 2.44 - 1.57 (m, 8 H), 1.27 - 1.14 (m, 8 H); MS

(ESI) m/z 532 (M+ + H)

(S)- 1 -(3 ,6 ' -difluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.45 - 7.24 (m, 4 H), 6.77 - 6.67 (m, 2 H), 6.28

861

(brs, 1 H), 5.71 (brs, 1 H), 5.42 (brs, 1 H), 3.80 (d, 2 H, J = 6.2 Hz), 3.61 - 3.58

(m, 1 H), 3.23 - 3.19 (m, 1 H), 2.97 (d, 2 H, J = 11.5 Hz), 2.45 - 2.40 (m, 3 H),

2.15 (t, 2 H, J = 11.0 Hz), 1.78 - 1.60 (m, 8 H), 1.42 - 1.32 (m, 8 H)

Example 48. Compound 1082: (S)-l-(5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy)phenyl)pyrazine-2-carbonyl)pyrrolidine-2-carbox amide

Step 1. methyl 5-(4-(benzoxy)-2-fluorophenyl)pyrazine-2-carboxylate: DME (8 mL) / H ₂ 0 (2 mL) was added to 4-(benzoxy)-2-fluorophenylboronic acid (1.00 g, 4.06 mmol), methyl 5- bromopyrazine-2-carboxylate (0.77 g, 4.47 mmol), Pd(dppf)Cl ₂ (0.16 g, 0.20 mmol) and

CS ₂ CO3 (2.64 g, 8.12 mmol). With a microwave radiation, the mixture was heated at 110 °C for 25 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NH ₄ CI aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.75 g, 54%).

Step 2. methyl 5-(2-fluoro-4-hydroxyphenyl)pyrazine-2-carboxylate: methyl 5-(4- (benzoxy)-2-fluorophenyl)pyrazine-2-carboxylate (0.750 g, 2.21 mmol) was dissolved in MeOH (10 mL) / THF (10 mL) at room temperature. 10 % wt Pd/C (150 mg) was added slowly thereto, and then following with stirring at the same temperature for 1 hour under hydrogen gas balloon. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was concentrated under reduced pressure. To the obtained concentrate, methanol (5 mL) and hexane (20 mL) were added thereto, following with stirring. The resulting precipitate was filtered, and dried to yield the title compound as green solid (0.19 g, 34%).

Step 3. methyl 5-(4-((l -(t-butoxycarbonyl)piperidin-4-yl)methoxy)-2-fluorophenyl)py razine-2- carboxylate: methyl 5-(2-fluoro-4-hydroxyphenyl)pyrazine-2-carboxylate (0.19 g, 0.76 mmol), t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate (0.22 g, 0.76 mmol) and ₂ C0 ₃ (0.15 g, 1.14 mmol) were dissolved in 70 °C for DMF (10 mL), following with stirring at the same temperature for 18 hours. The reaction mixture was added with saturated NH4CI aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.28 g, 82%, white solid).

Step 4. methyl 5-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)pyrazine-2-carbo xylate

hydrochloride: methyl 5-(4-((l-(t-butoxycarbonyl)piperidin-4-yl)methoxy)-2- fluorophenyl)pyrazine-2-carboxylate (0.28 g, 0.62 mmol) was dissolved in DCM (10 mL). At room temperature, HC1 (4.00M solution in dioxane, 0.62 mL, 2.51 mmol) was added thereto, following with stirring at the same temperature for 18 hours. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.14 g, 59%).

Step 5. methyl 5-(2-fluoro-4-((l-(2-hydroxy-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyrazine-2-carboxylate: EtOH (10 mL) was added to methyl 5-(2- fluoro-4-(piperidin-4-ylmethoxy)phenyl)pyrazine-2-carboxylat e hydrochloride (0.14 g, 0.29 mmol), 2,2-dimethyl oxirane (0.26 mL, 2.96 mmol) and K ₂ C0 ₃ (0.20 g, 1.48 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.12 g, 96%, red solid).

Step 6. methyl 5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyrazine-2-carboxylate: methyl 5-(2-fluoro-4-(( 1 -(2 -hydroxy-2- methylpropyl)piperidin-4-yl)methoxy)phenyl)pyrazine-2-carbox ylate (0.12 g, 0.28 mmol) and DAST (0.05 mL, 0.34 mmol) were dissolved in DCM (10 mL) at room temperature. The solution was stirred at the same temperature for 4 hours. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.09 g, 73%, yellow solid).

Step 7. 5-(2-fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)pyra zine-2- carboxylic acid: methyl 5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyrazine-2-carboxylate (0.09 g, 0.21 mmol) and LiOH ¾0 (0.04 g, 1.04 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (lmL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.06 g, 76%).

Step 8. Compound 1082: 5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)pyrazine-2-carboxylic acid (0.06 g, 0.14 mmol), (S)-pyrrolidine-2- carboxamide (0.01 g, 0.17 mmol), HOBt (0.04 g, 0.29 mmol), EDC (0.05 g, 0.29 mmol) and iPr ₂ NEt (0.05 mL, 0.29 mmol) were dissolved in DCM (2 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH ₄ CI aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.02 g, 35%).

1H NMR (400 MHz, CDC1 ₃ ) δ 9.18 - 9.19 (m, 1 H), 8.95 - 9.02 (m, 1 H), 8.06 (td, 1 H, J = 8.9, 2.5 Hz), 6.85 (td, 1 H, J = 8.4, 2.2 Hz), 6.68 - 6.74 (m, 1 H), 6.19 (s, 1 H), 5.44 (s, 1 H), 5.04 - 4.83 (m, 1 H), 4.83 - 4.86 (m, 1 H), 4.06 - 4.11 (m, 1 H), 3.88 - 3.96 (m, 1 H), 3.83 - 3.86 (m, 2 H), 2.97 - 3.00 (m, 2 H), 2.41 - 2.47 (m, 3 H), 2.13 - 2.21 (m, 3 H), 1.97 - 2.06 (m, 2 H), 1.77 - 1.80 (m, 3 H), 1.41 - 1.47 (m, 2 H), 1.39 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 502.3 (M+ + H).

Example 49. Compound 935: (S)-l-(5-(2-fluoro-4-((l-(2-fluoro-2- methyIpropyl)piperidin-4-yl)methoxy)phenyl)picolinoyl)pyrrol idme-2-carboxamide

Step 1. methyl 5-(2-fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinate: 4-((4-bromo-3-fluorophenoxy)methyl)- 1 -(2-fluoro-2- methylpropyl)piperidine (the product of synthesis step 4 of compound 704; 1.00 g, 2.76 mmol), 6-(methoxycarbonyl)pyridine-3-ylboro _^ hic acid (600 mg, 3.31 mmol), Pd(dppf)Cl ₂ (113 mg, 0.14 mmol) and Cs ₂ C0 ₃ (1.80 g, 5.52. mmol) were added to water (2 mL)/l,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1/7) to yield the title compound as white solid (200 g, 17%).

Step 2. 5-(2-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)phenyl)pico linic acid: methyl 5-(2-fluoro-4-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinate (200 mg, 0.48 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (100 g, 2.39 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified by the addition of IN HC1. The resulting precipitate was filtered to yield the title compound as white solid (145 mg, 75%).

Step 3. Compound 935: 5-(2-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinic acid (30 mg, 0.07 mmol), EDC (28 mg, 0.15 mmol) and HOBt (20 mg, 0.15 mmol) was added thereto, DIPEA (26 μL, 0.15 mmol) was dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (17 mg, 0.15 mmol) was added thereto, following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ CI aqueous solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (19 mg, 51%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.75 - 8.70 (m, 1 H), 8.10 - 7.91 (m, 2 H), 7.40 - 7.34 (m, 1 H), 6.95 (brs, 0.5 H), 6.84 - 6.73 (m, 2 H), 5.44 (brs, 0.5 H), 5.07 (d, 0.5 H, J = 7.1 Hz), 4.88 - 4.85 (m, 0.5 H), 3.84 (d, 2 H, J = 5.9 Hz), 3.01 (d, 2 H, J = 10.4 Hz), 2.49 - 2.41 (m, 2 H), 2.21 - 1.95 (m, 5 H), 1.82 - 1.61 (m, 7 H), 1.49 - 1.46 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 501 (M+ + H). Example 50. Compound 963: (R)-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)-4'-(3-

Step 1. methyl 3 '-cyano-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)r etoxy)biphenyl-4- carboxylate: DME (4 mL) / H ₂ Oj(l mL) was added to 5-bromo-2-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)benzonitrile (the product of synthesis step 4 of compound 938; 0.25 g, 0.67 mmol), 4-(methoxycarbonyl)phenylboronic acid (014 g, 0.81 mmol), Pd(dppf)Cl ₂ (0.02 g, 0.03 mmol) and Cs ₂ C0 ₃ (0.44 g, 1.35 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ CI aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.22 g, 78%).

Step 2. 3'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)biphenyl-4- carboxylic acid: Methyl 3'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)metoxy)biphenyl-4-carboxylate (0.22 g, 0.53 mmol) and LiOH H ₂ 0 (0.1 1 g, 2.65 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (2 mL) at room temperature. The solution was stirred at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.18 g, 86%).

Step 3. Compound 963 : 3 '-cyano-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.09 mmol), (R)-piperidin-3-ol (0.01 g, 0.11 mmol), HOBt (0.02 g, 0.19 mmol), EDC (0.03 g, 0.19 mmol) and DIPEA (0.02 g, 0.19 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 10 %), and concentrated to yield the title compound as red solid (0.02 g, 49%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.72 - 7.74 (m, 2 H), 7.53 (dd, 4 H, J = 14.7, 8.5 Hz), 7.04 (d, 1 H, J = 8.8 Hz), 3.95 - 4.01 (m, 3 H), 3.43 - 3.94 (m, 4 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.44 (s, 1 H), 2.17 - 2.23 (m, 2 H), 1.86 - 1.95 (m, 6 H), 1.63 - 1.72 (m, 2 H), 1.42 - 1.56 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 494.3 (M+ + H).

According to the above-described synthesis process of compound 963, the compounds of Table 26 were synthesized using 3 '-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 25.

Table 25.

Table 26.

(S)-l-(3'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.73 - 7.79 (m, 2 H), 7.63 (d, 2 H, J = 8.2 Hz), 7.57

965 (d, 2 H, J = 8.2 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.97 (s, 1 H), 5.56 (s, 1 H), 4.82 (dd,

1 H, J = 7.4, 5.0 Hz), 3.95 (d, 2 H, J = 6.4 Hz), 3.53 - 3.67 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.43 - 2.49 (m, 3 H), 2.10 - 2.22 (m, 2 H), 1.98 - 2.10 (m, 2 H), 1.78 - 1.92 (m, 5 H), 1.35 - 1.49 (m, 7 H); MS (ESI) m/z 507.3 (M+ + H).

(S)-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4 '-(3- hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 8.13 (d, 1 H, J = 7.9 Hz), 7.71 - 7.78 (m, 2 H), 7.53

966 - 7.64 (m, 3 H), 7.01 (t, 1 H, J = 8.8 Hz), 4.49 - 4.61 (m, 1 H), 3.96 (d, 2 H, J = 6.0 Hz), 3.51 - 3.83 (m, 2 H), 3.20 - 3.27 (m, 2 H), 2.68 (dd, 2 H, J = 22.7, 15.3 Hz), 2.32 - 2.40 (m, 2 H), 1.92 - 2.08 (m, 5 H), 1.47 - 1.66 (m, 2 H), 1.40 - 1.46 (m, 9 H); MS (ESI) m/z 480.3 (M+ + H).

Example 51. Compound 967: (R)-2'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yI)methoxy)-4'- -hydroxypiperidin-l-carbonyI)biphenyl-3-carbonitrile

Step 1. methyl 3 '-cyano-2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4 - yl)methoxy)biphenyl-4-carboxylate: DME (4 mL) / H ₂ 0 (1 mL) was added to 5-bromo-2- ((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzonit rile (the product of synthesis step 4 of compound 938; 0.25 g, 0.67 mmol),- 2-fluoro-4-(methoxycarbonyl)pb.enylboronic acid (0.14 g, 0.81 mmol), Pd(dppf)Cl ₂ (0.02 g, 0.03 mmol) and Cs ₂ C0 ₃ (0.44 g, 1.35 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.14 g, 49%).

Step 2. 3 '-cyano-2-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: Methyl 3'-cyano-2-fiuoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylate (0.14 g, 0.32 mmol) and LiOH H ₂ 0 (0.06 g, 1.63 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (2 mL) at room temperature. The solution was stirred at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.13 g, 95%).

Step 3. Compound 967: 3'-cyano-2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.093 mmol), (R)-piperidin-3-ol (0.01 g, 0.11 mmol), HOBt (0.02 g, 0.18 mmol), EDC (0.03 g, 0.18 mmol) and DIPEA (0.03 mL, 0.18 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 10 %), and concentrated to yield the title compound as yellow oil (0.02 g, 46%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.69 - 7.70 (m, 2 H), 7.42 (t, 1 H, J = 7.8 Hz), 7.24 - 7.30 (m, 2 H), 7.04 (d, 1 H, J = 8.8 Hz), 3.95 (d, 2 H, J = 6.4 Hz), 3.38 - 3.78 (m, 4 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.17 - 2.27 (m, 3 H), 1.85 - 1.95 (m, 5 H), 1.63 - 1.71 (m, 1 H), 1.42 - 1.56 (m, 3 H),1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 512.3 (M+ + H).

According to the above-described synthesis process of compound 967, the compounds of Table 28 were synthesized using 3'-cyano-2-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 27.

Table 27.

Table 28.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)-2 ' -fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4 ' -(3 - hydroxypiperidin- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.69 - 7.71 (m, 2 H), 7.42 (t, 1 H, J = 7.8 Hz),

968 7.24 - 7.30 (m, 2 H), 7.04 (d, 1 H, J = 8.8 Hz), 3.95 (d, 2 H, J = 6.4 Hz), 3.36 - 3.79 (m, 4 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.17 - 2.22 (m, 3 H), 1.91 - 2.11 (m, 6 H), 1.43 - 1.71 (m, 3 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 512.3 (M+ + H).

(S)- 1 -(3 ' -cyano-2-fluoro-4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-

969

yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide 1H NMR (400 MHz, CDC1 ₃ ) δ 7.70 - 7.75 (m, 2 H), 7.36 - 7.46 (m, 3 H), 7.05 (d, 1 H, J = 8.8 Hz), 6.87 (s, 1 H), 5.66 (s, 1 H), 4.77 - 4.80 (m, 1 H), 3.95 (d, 2 H, J = 6.4 Hz), 3.56 - 3.68 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.41 - 2.49 (m, 2 H), 2.07 - 2.33 (m, 5 H), 1.85 - 1.92 (m, 4 H), 1.42 - 1.48 (m, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 525.3 (M+ + H).

Example 52. Compound 938: (S)-l-(3'-cyano-3-fluoro-4'-((l-(2-fluoro-2- methylpropyl)piperidin-4-yI)methoxy)biphenylcarbonyl)pyrroIi dine-2-carboxamide

Step 1. t-butyl 4-((4-bromo-2-cyanophenoxy)methyl)piperidin-l-carboxylate: t-butyl 4- ((methylsulfonyloxy)methyl)piperidine-l-carboxylate (the product of synthesis step 2 of compound 431; 800 mg, 2.73 mmol) was dissolved in ACN (80 mL). At room temperature, 5- bromo-2-hydroxybenzonitrile (540 mg, 2.73 mmol) was added thereto, and stirred for 5 minutes. Cs ₂ C0 ₃ (1.33 g, 4.09 mmol) was added thereto, following with stirring at 80 °C for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 30 % ~ 70 %), and

concentrated to yield the title compound as white solid (655 mg, 60%).

Step 2. 5-bromo-2-(piperidin-4-ylmethoxy)benzonitrile hydroxychloride: t-butyl 4-((4- bromo-2-cyanophenoxy)methyl)piperidin-l-carboxylate (655 mg, 1.66 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). 4 M HC1 solution in 1,4-dioxane (414 μί, 1.66 mmol) was added thereto at room temperature. The mixture was stirred at the same temperature for 1 hour. The resulting precipitate was filtered, and dried to yield the title compound as white solid (540 mg, 98%).

Step 3. 5-bromo-2-(( 1 -(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)benzonitri le:

To 5-bromo-2-(piperidin-4-ylmethoxy)benzonitrile hydroxychloride (540 mg, 1.63 mmol), 2,2- dimethyl oxirane (1.45 mL, 16.3 mmol) and K ₂ C0 ₃ (112 mg, 0.81 mmol), EtOH (5 mL) / H ₂ 0 (5 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material, which is the title compound as white solid (440 mg, 73%), was used without further purification. Step 4. 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)benzonitrile:

5-bromo-2-((l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)me thoxy)benzonitrile (440 mg, 1.20 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). At 0 °C, DAST (158 μί, 1.20 mmol) was added thereto, following with stirring at room temperature for 1 hour. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 30 % ~ 70 %), and concentrated to yield the title compound as white solid (254 mg, 57%).

Step 5. ethyl 3'-cyano-3-fiuoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy) biphenyl-4-carboxylate: 5-bromo-2-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) benzonitrile (the product of synthesis step 4 of compound 963; 254 mg, 0.69 mmol), 4- (ethoxycarbony^-S-fluorophenylboroniCiacid (160 mg, 0.76 mmol), Pd(dppi)Cl ₂ (56 mg, 0.07 mmol) and Cs ₂ C0 ₃ (448 mg, 1.38 mmol);were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was ₅ added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (205 mg, 65%).

Step 6. 3 '-cyano-3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: Ethyl 3'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylate (205 mg, 0.45 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (94 mg, 2.25 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (120 mg, 62%).

Step 7. Compound 938: 3 '-cyano-3-fluoro-4'-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), EDC (27 mg, 0.14 mmol) and HOBt (19 mg, 0.14 mmol) was added thereto, DIPEA (25 μΐ,, 0.14 mmol) was dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (16 mg, 0.14 mmol) was added thereto, following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5%) to yield the title compound as white solid (21 mg, 57%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.77 - 7.71 (m, 2 H), 7.52 (t, 1 H, J = 7.5 Hz), 7.44 - 7.39 (m, 1 H), 7.37 - 7.23 (m, 1 H), 7.06 (d, 1 H, J = 8.9 Hz), 6.89 (brs, 1 H), 5.50 (brs, 1 H), 4.83 - 4.80 (m, 1 H), 3.96 (d, 2 H, J = 6.4 Hz), 3.56 - 3.39 (m, 2 H), 3.03 (brs, 2 H), 2.52 - 2.41 (m, 2 H), 2.22 - 2.14 (m, 2 H), 2.12 - 2.01 (m, 2 H), 1.94 - 1.87 (m, 4 H), 1.67 (brs, 2 H), 1.57 - 1.45 (brs, 1 H), 1.42 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 525 (M+ + H).

According to the above-described synthesis process of compound 938, the compounds of Table 30 were synthesized using 3'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 29.

Table 29.

Table 30.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-3 ' -fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4 '-(3 - hydroxypiperidin- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.76 - 7.70 (m, 2 H), 7.48 (t, 1 H, J = 7.3 Hz), 7.36 - 7.34 (m, 1 H), 7.27 - 7.22 (m, 1 H), 7.05 (d, 1 H, J = 8.8 Hz), 4.14 - 4.07 (m, 1

939

H), 3.96 (d, 2 H, J = 6.4 Hz), 3.58 - 3.52 (m, 1 H), 3.38 - 3.23 (m, 1 H), 3.16 - 3.13 (m, 2 H), 2.51 - 2.46 (m, 2 H), 2.22 - 2.17 (m, 2 H), 2.05 - 1.87 (m, 6 H), 1.76 - 1.71 (m, 3 H), 1.70 - 1.48 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 512 (M+ + H).

(R)-l-(3'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)pip eridin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.69 - 7.78 (m, 2 H), 7.50 - 7.54 (m, 1 H), 7.40 (dd, 1 H, J = 8.0, 1.5 Hz), 7.22 - 7.32 (m, 1 H), 7.06 (d, 1 H, J = 8.9 Hz), 6.28 (s, 1

1015

H), 5.31 (s, 1 H), 3.96 (d, 2 H, J = 6.4 Hz), 3.58 (d, 1 H, J = 13.0 Hz), 3.18 - 3.25 (m, 1 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.17 - 2.23 (m, 2 H), 1.86 - 1.92 (m, 3 H), 1.73 - 1.76 (m, 2 H), 1.53 - 1.66 (m, 5 H), 1.42 - 1.48 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 539.3 (M+ + H).

(S)-3'-fluoro-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl) methoxy)-4'-(3-

1016 hydroxypiperidin- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.75 - 7.76 (m, 1 H), 7.70 - 7.73 (m, 1 H), 7.48 (t, 1 H, J = 7.4 Hz), 7.32 - 7.37 (m, 1 H), 7.22 - 7.27 (m, 1 H), 7.05 (d, 1 H, J = 8.8 Hz), 4.06 - 4.10 (m, 1 H), 4.00 (d, 2 H, J = 6.3 Hz), 3.11 - 3.58 (m, 3 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.17 - 2.23 (m, 2 H), 1.81 - 2.05 (m, 5 H), 1.48 - 1.68 (m, 4 H), 1.42 - 1.46 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 512.3 (M+ + H).

(S)-3 ' -fluoro-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-4 ' -(3 - hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.76 - 7.77 (m, 1 H), 7.72 (dd, 1 H, J = 8.8, 1.6 Hz), 7.53 (dd, 1 H, J = 13.3, 7.4 Hz), 7.22 - 7.32 (m, 1 H), 7.05 (d, 2 H, J = 8.8

1017

Hz), 4.51 - 4.64 (m,l H), 3.95 (d, 2 H, J = 6.3 Hz), 3.33 - 3.85 (m, 4 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 - 2.22 (m, 3 H), 2.02 - 2.08 (m, 1 H), 1.85 - 1.91 (m, 2 H), 1.70 - 1.63 (m, 2 H), 1.42 - 1.49 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 498.3 (M+ + H).

Example 53. Compound 1036: (S)-l-(5-(3-cyano-4-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)phenyl)picolinoyl)pyrroI idme-2-carboxamide

Step 1. methyl 5-(3-cyano-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy)phenyl) picolinate: 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)benzonitrile (the product of synthesis step 4 of compound 938; 673 mg, 1.82 mmol), 6-(methoxycarbonyl) pyridine-3-ylboronic acid (330 mg, 1.82 mmol), Pd(dppf)Cl ₂ (59 mg, 0.09 mmol) and Cs ₂ C0 ₃ (1.19 g, 3.65 mmol) were added to water (2 mL)/l,4-dioxane (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as brown solid (150 mg, 19%).

Step 2. 5-(3-cyano-4-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)met hoxy)phenyl)picolinic acid: Methyl 5-(3-cyano-4-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinate (150 mg, 0.35 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (74 mg, 1.76 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (41 mg, 28%). Step 3. Compound 1036: 5-(3-cyano-4-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)phenyl)picolinic acid (30 mg, 0.07 mmol), (S)-pyrrolidine-2-carboxamide (22 mg, 0.19 mmol), EDC (37 mg, 0.19 mmol), HOBt (26 mg, 0.19 mmol) and DIPEA (34 μΐ., 0.19 mmol) were dissolved in CH ₂ C1 ₂ (1 mL), following with stirring at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (21 mg, 42%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.77 - 8.72 (m, 1 H), 8.14 - 8.12 (m, 0.4 H), 7.99 - 7.93 (m, 1.6 H), 7.82 - 7.75 (m, 2 H), 7.11 - 7.08 (m, 1 H), 6.39 (brs, 0.5 H), 6.39 (brs, 0.5 H), 5.43 (brs, 1 H), 4.87 - 4.86 (m, 0.5 H), 4.85 - 4.84 (m, 0.5 H), 4.06 - 3.87 (m, 4 H), 3.05 (brs, 2 H), 2.46 - 2.36 (m, 2 H), 2.21 - 2.15 (m, 2 H), 2.13 - 1.97 (m, 5 H), 1.64 (brs, 2 H), 1.58 - 1.39 (m, 6 H), 1.36 - 1.25 (m, 2 H); MS (ESI) m/z 508 (M+ + H).

Example 54. Compound 1031: (S)-l-(2'-cyano-4'-((l-(2-fluoro-2- methyIpropyl)piperidin-4-yl)methoxy)biphenylcarbonyl)pyrroli dine-2-carboxamide

Step 1. methyl 2'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)biphenyl-4- carboxylate: DME (4 mL) / H ₂ 0 (1 mL) was added to 2-bromo-5-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)benzonitrile (the product of synthesis step 4 of compound 1028; 0.30 g, 0.81 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.17 g, 0.97 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol) and Cs ₂ C0 ₃ (0.52 g, 1.62 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ CI aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0% to 40%), and concentrated to yield the title compound as white solid (0.05 g, 14%).

Step 2. 2 ' -cyano-4' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid: Methyl 2 ^, -cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (0.05 g, 0.11 mmol) and LiOH H ₂ 0 (0.02 g, 0.58 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (2 mL) at room temperature. The solution was stirred at the same temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.01 g, 20%).

Step 3. Compound 1031: 2'-cyano-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.03 g, 0.08 mmol), L-prolinamide (0.01 g, 0.10 mmol), HOBt (0.02 g, 0.17 mmol), EDC (0.03 g, 0.17 mmol) and DIPEA (0.02 mL, 0.17 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSC^, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%), and concentrated to yield the title compound as white solid (0.02 g, 64%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.65 (d, 2 H, J = 8.2 Hz), 7.59 (d, 2 H, J = 8.3 Hz), 7.42 (d, 1 H, J = 8.7 Hz), 7.25 (d, 1 H, J = 2.6 Hz), 7.19 (dd, 1 H, J = 8.7, 2.6 Hz), 7.01 (s, 1 H), 5.59 (s, 1 H), 4.83 (dd, 1 H, J = 7.4, 5.2 Hz), 3.86 (d, 2 H, J = 6.0 Hz), 3.57 - 3.68 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.43 - 2.50 (m, 3 H), 2.05 - 2.21 (m, 4 H), 1.78 - 1.92 (m, 4 H), 1.43 - 1.49 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 507.3 (M+ + H).

Example 55. Compound 1028: (S)-l-(2'-cyano-3-fluoro-4'-((l-(2-fluoro-2- methylpropyl)p boxamide

Step 1. t-butyl 4-(hydroxymethyl)piperidin- 1 -carboxylate:

Piperidin-4-ylmethanol (10.0 g, 86.8 mmol), (Boc) ₂ 0 (21.9 mL, 95.5 mmol) and TEA (14.4 mL, 104.1 mmol) were dissolved in DCM (50 mL) at room temperature. The solution was stirred at the same temperature for 1 hour. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized with ethyl acetate (10 mL) and hexane (150 mL) at 25 °C to yield the title compound as white solid (18.0 g, 96%).

Step 2. t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l -carboxylate:

t-butyl 4-(hydroxymethyl)piperidin-l-carboxylate (18.0 g, 83.6 mmol), MsCl (7.16 mL, 91.9 mmol) and TEA (13.9 mL, 100.3 mmol) were dissolved in DCM (50 mL) at 0 °C, following with stirring at room temperature for 2 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized with ethyl acetate (10 mL) and hexane (150 mL) at 25 °C to yield the title compound as white solid (16.0 g, 65%).

Step 3. t-butyl 4-((4-bromo-3-cyanophenoxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l -carboxylate ( 2.00 g, 6.81 mmol), 2-bromo-5- hydroxybenzonitrile (1.35 g, 6.87 mmol) and K ₂ C0 ₃ (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80 °C, following with stirring at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (1.90 g, 70%).

Step 4. 2-bromo-5-(piperidin-4-ylmethoxy)benzonitrile hydrochloride: t-butyl 4-((4- bromo-3-cyanophenoxy)methyl)piperidin- 1 -carboxylate (1.90 g, 4.80 mmol) and 4 M HC1 solution in 1,4-dioxane (6.00 mL, 24.03 mmol) were dissolved in CH ₂ C1 ₂ (15 mL) at room temperature. The solution was stirred at the same temperature for 2 hours. The resulting precipitate was filtered, and dried to yield the title compound as white solid (1.52 g, 95%).

Step 5. 2-bromo-5-((l-(2-hvdroxv-2-methvlpropyl)piperidin-4-yl)metho xy)benzonitrile:

EtOH (8 mL) / H ₂ 0 (2 mL) was added to 2-bromo-5-(piperidin-4-ylmethoxy)benzonitrile hydrochloride (1.72 g, 5.18 mmol), 2,2-dimethyl oxirane (4.61 mL, 51.86 mmol) and K ₂ C0 ₃ (3.58 g, 25.93 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (1.70 g, 89%, white solid).

Step 6. 2-bromo-5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzonitril e:

2-bromo-5-((l-(2-hydroxy-2-methylpropyl)piperidin-4-yl)me thoxy)benzonitrile (1.70 g, 4.62 mmol) was dissolved in CH ₂ C1 ₂ (20 mL). At 0 °C, DAST (0.72 mL, 5.55 mmol) was added thereto, following with stirring at the same temperature for 2 hours. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (1.10 g, 64%).

Step 7. ethyl 2 ' -cyano-3 -fluoro-4 '-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate: DME (4 mL) / H ₂ 0 (1 mL) was added to 2-bromo-5- ((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzonit rile (0.30 g, 0.81 mmol), 4- (ethoxycarbonyl)-3-fluorOphenylboronic acid (0.17 g, 0.97 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol) and Cs ₂ C0 ₃ (0.52 g, 1.62 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0 % to 40 %), and concentrated to yield the title compound as white solid (0.16 g, 43%).

Step 8. 2 ^, -cyano-3-fluoro-4 ^, -((l -(2-fluoro-2-methvlpropvl pipeiidin-4-vl)methoxy)biphenyl-4- carboxylic acid: Ethyl 2'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylate (0.16 g, 0.35 mmol) and LiOH H ₂ 0 (0.07 g, 1.75 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (2 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (15 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.15 g, 93%).

Step 9. Compound 1028: 2'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.21 mmol), EDC (0.04 g, 0.21 mmol) and DIPEA (0.03 mL, 0.21 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, added with saturated NH ₄ CI aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.05 g, 92%). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 - 7.56 (m, 1 H), 7.41 (dd, 2 H, J = 8.0, 1.7 Hz), 7.30 - 7.33 (m, 2 H), 7.19 - 7.22 (m, 1 H), 6.91 (s, 1 H), 5.45 (s, 1 H), 4.83 (dd, 1 H, J = 7.6, 3.9 Hz), 3.87 (d, 2 H, J = 6.0 Hz), 3.44 - 3.56 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.48 - 2.52 (m, 2 H), 2.43 (s, 1 H), 2.06 - 2.21 (m, 4 H), 1.91 - 1.94 (m, 2 H), 1.79 - 1.81 (m, 2H), 1.635 (s, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 525.3 (M+ + H).

According to the above-described synthesis process of compound 1028, the compounds of Table 32 were synthesized using 2'-cyano-3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 31.

Table 31.

Table 32.

1.32 (s, 3 H); MS (ESI) m/z 512.2 (M+ + H).

Example 56. Compound 691: (S)-l-(4-(5-((l-(2-fluoro-2-methylpropyI)piperidin-4- yl)methoxy)pyridine-2-yl)benzoyl)pyrrolidine-2-carboxamide

Step 1. t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin- 1 -carboxylate:

t-Butyl 4-((methylsulfonyloxy)methyl)piperidin-l -carboxylate (the product of synthesis step 2 of compound 431 ; 2.0 g, 6.82 mmol) was dissolved in ACN 10 mL. 6-chloropyridine-3-ol (1.06 g, 8.18 mmol), Cs ₂ C0 ₃ (3.33 g, 10.23 mmol) was added thereto, and refluxed with heating for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge,

EtOAc/Hexane) to yield the title compound as white solid (1.6 g, 72%).

Step 2. 2-chloro-5-(piperidin-4-ylmethoxy)pyridine hydrochloride:

t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin- 1 -carboxylate (1.6 g, 4.90 mmol) was dissolved in CH ₂ C1 ₂ 8 mL. 4 M HC1 1.47 mL was added thereto, following with stirring at room temperature for 2 hours. The reaction mixture was filtered, washed with hexane, and evaporated under reduced pressure to yield the title compound as white solid (1.25 g, 97%).

Step 3. 1 -(4-((6-chloropyridine-3 -ylox ,)methyl)piperidin- 1 -yl)-2-methylpropan-2-ol :

2-chloro-5-(piperidin-4-ylmethoxy)pyridine hydrochloride (1.25 g, 4.75 mmol) was dissolved in EtOH 6 mL. 2,2-dimethyloxirane (3.42 g, 47.5 mmol), K ₂ C0 ₃ (1.31 g, 9.5 mmol) and water 3 mL were added thereto. With a microwave radiation, the mixture was stirred at 110 °C for 20 minutes. After the completion of the reaction, EtOH was evaporated from the reaction mixture under reduced pressure, and then a little of water was added to thereto. The resulting precipitate was filtered, and dried under reduced pressure to yield the title compound as white solid (980 g, 69%).

Step 4. 2-chloro-5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine: 1 -(4-((6- chloropyridine-3-yloxy)methyl)piperidin-l-yl)-2-methylpropan -2-ol (980 mg, 3.28 mmol) was dissolved in CH ₂ C1 ₂ 6 mL. And then, DAST (793 mg, 4.92 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer washed with saturated aqueous brine solution, dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure to yield the title compound as yellow solid (460 mg, 46%).

Step 5. methyl 4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoate: 2-chloro-5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine (230 mg, 0.77 mmol), 4-(methoxycarbonyl)phenylboronic acid (165 mg, 0.92 mmol),

Pd(dppf)Cl ₂ (62 mg, 0.08 mmol), Na ₂ C0 ₃ (162 mg, 1.53 mmol) were dissolved in DME 6 mL and water 2 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (220 mg, 71 %).

Step 6. 4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoic acid: methyl 4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoate (220 mg, 0.55 mmol) was dissolved in THF:MeOH:Water = 2/1/0.5 mL. LiOH H ₂ 0 (46 mg, 1.10 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure to yield the title compound as yellow solid (210 mg, 98%).

Step 7. Compound 691 : 4-(5-(( 1 -(2-fiuoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine- 2-yl)benzoic acid (40 mg, 0.10 mmol), (S)-pyrrolidine-2-carboxamide (24 mg, 0.20 mmol) and BOP (91 mg, 0.21 mmol) were dissolved in DMF 1 mL. After stirring for 10 minutes at room temperature, TEA (31 mg, 0.31 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS04, and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (19 mg, 38%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 (d, 1 H, J = 2.9 Hz), 7.97 (d, 2 H, J = 8.2 Hz), 7.68 (d, 1 H, J = 8.7 Hz), 7.52 (d, 2 H, J = 8.2 Hz), 3.90 (d, 2 H, J = 6.0 Hz), 3.14 (m, 3 H), 3.02 (m, 5 H), 2.46 (m, 2 H), 2.04 (m, 2 H), 1.73 (m, 2 H), 1.46 (m, 2 H), 1.36 (m, 8 H); MS (ESI) m/z 469 (M + H). According to the above-described synthesis process of compound 691, the compounds of Table 34 were synthesized using 4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr idine- 2-yl)benzoic acid and the reactant of Table 33.

Table 33.

Table 34.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 2.7 Hz), 7.97 - 7.94 (m, 2 H), 7.68 - 7.59 (m, 3 H), 7.28 - 7.25 (m, 1 H), 4.59 - 4.46 (m, 1 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.85 - 3.81 (m, 2 H), 3.78 - 3.62 (m, 1 H), 3.56 - 3.46 (m, 1 H), 3.07 - 3.04 (m, 2 H), 2.53 - 2.48 (m, 2 H), 2.37 - 2.34 (m, 1 H), 2.26 - 2.20 (m, 2 H), 2.12 - 1.98 (m, 2 H), 1.84 - 1.82 (m, 3 H), 1.51 - 1.48 (m, 2 H), 1.42 (s, 3 H), 1.40 (s, 3 H); MS (ESI) m/z 456 (M+ + H).

(S)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine-2- yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 6 8.39 (d, 1 H, J = 2.9 Hz), 7.99 (d, 2 H, J = 8.2 Hz),

765 7.69 (d, 1 H, J = 8.7 Hz), 7.60 (d, 1 H, J = 8.2 Hz), 7.29 - 7.26 (m, 2 H), 4.95 - 4.93 (m, 1 H), 4.46 - 4.41 (m, 1 H), 3.90 (d, 2 H, J = 5.9 Hz), 3.85 - 3.74 (m, 2 H), 3.60 - 3.49 (m, 2 H), 3.03 (brs, 2 H), 2.51 - 2.46 (brs, 2 H), 2.27 - 2.18 (m, 2 H), 2.05 - 1.81 (m, 5 H), 1.78 - 1.63 (m, 2 H), 1.60 - 1.48 (m, 2 H), 1.42 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 470 (M+ + H).

(R)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine-2- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 2 H, J = 2.6 Hz), 7.97 (d, 2 H, J = 8.2 Hz),

766 7.68 (d, 1 H, J = 8.7 Hz), 7.51 (d, 2 H, J = 8.2 Hz), 7.28 - 7.25 (m, 1 H), 4.02 - 4.00 (m, 1 H), 3.91 (d, 2 H, J = 5.8 Hz), 3.80 - 3.46 (m, 3 H), 3.25 - 3.06 (m, 2 H), 2.67 - 2.49 (m, 2 H), 2.37 - 2.12 (m, 2 H), 2.05 - 1.94 (m, 2 H), 1.85 - 1.83 (m, 4 H), 1.71 - 1.66 (m, 3 H), 1.52 - 1.50 (m, 2 H), 1.43 (s, 3 H), 1.38 (s, 3 H); MS (ESI) m/z 471 (M+ + H).

1 -(4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.42 - 8.41 (m, 1 H), 8.00 (d, 2 H, J = 8.4 Hz),

804 7.71 (d, 1 H, J = 8.4 Hz), 7.51 (d, 2 H, J = 6.4 Hz), 7.29 - 7.28 (m, 1 H), 5.71 (d, 2 H, J = 30.8 Hz), 4.73 (brs, 1 H), 3.93 - 3.92 (m, 3 H), 3.05 - 3.02 (m, 4 H), 2.51 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 11.4 Hz), 1.98 - 1.83 (m, 7 H), 1.58 - 1.22 (m, 8 H); MS (ESI) m/z 497 (M+ + H)

(R)- 1 -(4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 - 8.38 (m, 1 H), 7.99 (d, 2 H, J = 8.0 Hz), 7.69 (d, 2 H, J = 8.7 Hz), 7.54 (d, 2 H, J = 7.6 Hz), 7.28 - 7.25 (m, 1 H), 6.52 (brs,

821

1 H), 5.53 (brs, 1 H), 5.29 (brs, 1 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.78 (d, 1 H, J = 12.7 Hz), 3.12 - 3.10 (m, 1 H), 3.01 (d, 2 H, J = 11.2 Hz), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.34 (d, 1 H, J = 13.2 Hz), 2.19 (t, 2 H, J = 11.0 Hz), 2.05 - 1.43 (m, 8 H), 1.40 - 1.24 (m, 8 H); MS (ESI) m/z 497 (M+ + H).

Example 57. Compound 696: (S)-l-(3-fluoro-4-(5-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)pyridme-2-yl)benzoyl)pyr rolidine-2-carboxamide

Step 1. methyl 3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)pyridine-2- yl)benzoate: 2-chloro-5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine (the product of synthesis step 5 of compound 691 ; 366 mg, 1.06 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (231 mg, 1.17 mmol), Pd(dppf)Cl ₂ (87 mg, 0.11 mmol), Na ₂ C0 ₃ (225 mg, 2.12 mmol) were dissolved in DME 6 mL and water 2 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (210 mg, 47%).

Step 2. 3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoic acid: Methyl 3 -fluoro-4-(5 -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoate (220 mg, 0.53 mmol) was dissolved in THF MeOH/H ₂ 0 = 2/1/0.5 mL. LiOH H ₂ 0 (44 mg, 1.05 mmol) was added thereto, and refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using IN HC1. The resulting precipitate was filtered to yield the title compound as white solid (195 mg, 91%).

Step 3. Compound 696: 3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoic acid (40 mg, 0.10 mmol), (R)-pyrrolidine-2-ylmethanol (23 mg, 0.20 mmol) and BOP (88 mg, 0.20 mmol) were dissolved in DMF 1 mL, following with stirring for 10 minutes at room temperature. TEA (30 mg, 0.30 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution,dried over MgS0 ₄ , filtered to rernpve the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (20 mg, 40%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, 1 H, J = 2.8 Hz), 8.05 (t, 1 H, J = 7.9 Hz), 7.78 (d, 1 H, J = 8.8 Hz), 7.38 (m, 2 H), 7.27 (m, 2 H), 6.92 (s, 1 H), 5.51 (s, 1 H), 4.79 (m, 1 H), 3.91 (d, 2 H, J = 5.9 Hz), 3.55 (m, 2 H), 3.01 (m, 2 H), 2.46 (m, 3 H), 2.13 (m, 2 H), 2.06 (m, 2 H), 1.92 (m, 4 H), 1.35 (m, 5 H), 1.26 (s, 3 H); MS (ESI) m/z 501 (M + H).

According to the above-described synthesis process of compound 696, the compounds of Table 36 were synthesized using 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoic acid and the reactant of Table 35.

Table 35. Compound No. Reactant Yield (%)

697 (R)-pyrrolidine-2-ylmethanol 47

698 (R)-piperidin-3-ol 39

699 (S)-pyrrolidine-3-ol 17

813 piperidin-4-carboxamide hydrochloride 39

815 (R)-pyrrolidine-3 -ol 52

Table 36.

Example 58. Compound 770: (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2- methylpropyl)piperidm-4-yl)methoxy)pyridine-2-yl)benzoyl)pyr roUdine-2-carboxamide

Step 1. t-butyl 4-(hydroxymethyl)piperidin-l-carboxylate: Piperidin-4-ylmethanol (33.0 g, 286.53 mmol) was dissolved in DCM (400 mL). TEA (47.9 mL, 343.84 mmol) was added thereto, (Boc) ₂ 0 (68.79 g, 315.18 mmol) was added thereto, following with stirring at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with DCM. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was recrystallized with HX : EA = (4 : 1) to yield the title compound as yellow solid (59.0 g, 96%). Step 2. t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate: t-butyl 4- (hydroxymethyl)piperidin-l-carboxylate (59.0 g, 274.05 mmol) was dissolved in DCM (400 mL). TEA (45.84 mL, 328.86 mmol) was added thereto. At 0 °C, MsCl (23.4 mL, 301.45 mmol) was added thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, reaction mixture was added with water, and extracted with DCM. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized with HX : EA = (4 : 1) to yield the title compound as white solid (70.0 g, 87%).

Step 3. t-butyl 4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-carboxylate:

t-butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate ( 3.00 g, 10.23 mmol) was dissolved in ACN (50 mL). Cs ₂ C0 ₃ (4.99 g, 15.34 mmol) was added thereto. And then, 6- chloropyridine-3-ol (1.32 g, 10.23 mmol) was added thereto, following with stirring for 5 hours at the reflux temperature. After the completion of the reaction, the reaction mixture was added with water, and then extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ ; hexane / EtOAc = 5/1) to yield the title compound as white solid (2.8 g, 83%).

Step 4. 2-chloro-5-(piperidin-4-ylmethoxy)pyridine hydrochloride: t-butyl 4-((6- chloropyridine-3-yloxy)methyl)piperidin-l-carboxylate (2.80 g, 8.57 mmol) was dissolved in DCM (70 mL) was added thereto, following with stirring for 5 minutes. And then, 4 M HC1 solution in 1,4-dioxane (42.84 mL, 171.35 mmol) was added dropwise slowly thereto, following with stirring for 1 hour at room temperature. After the completion of the reaction, the reaction mixture was filtered to yield the title compound as white solid (1.50 g, 77%). Step 5. l-(4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-yl)-2-met hylpropan-2-ol:

2-chloro-5-(piperidin-4-ylmethoxy)pyridine hydrochloride (1.50 g, 5.70 mmol), 2,2-dimethyl oxirane (5.07 mL, 57.0 mmol) and K ₂ C0 ₃ (0.39 g, 2.85 mmol) were dissolved in EtOH (5 mL) / H ₂ 0 (5 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 20 minutes. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ ; hexane / EtOAc = 4/1) to yield the title compound as white solid (1.3 g, 76%).

Step 6. 2-chloro-5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine:

l-(4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-yl)-2- methylpropan-2-ol (1.30 g, 4.35 mmol) was dissolved in CH ₂ C1 ₂ (15 mL). At 0 °C, DAST (0.57 mL, 4.35 mmol) was added thereto little by little. The reaction mixture was stirred for 1 hour at room temperature. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ ; hexane / EtOAc = 7/1) to yield the title compound as white solid (1.20 g, 92%).

Step 7. ethyl 2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoate: 2-chloro-5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine (0.60 g, 1.99 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (0.51 g, 2.39 mmol), Pd(dppf)Cl ₂ (0.08 g, 0.10 mmol) and Cs ₂ C0 ₃ (1.29 g, 3.98 mmol) were added to 1 ,4-dioxane (6 mL) / H ₂ 0 (2 mL). With a microwave radiation, the reaction was performed at 110 °C for 15 minutes. After the completion of the reaction, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ ;

hexane / EtOAc = 7/1) to yield the title compound as white solid (0.66 g, 76%).

Step 8. 2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoic acid: Ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoate (0.66 g, 0.35 mmol) was dissolved in THF (10 mL) / eOH (10 mL) / H ₂ 0 (5 mL). LiOH H ₂ 0 (0.32 g, 7.64 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified by the addition of IN HCl. The resulting precipitate was filtered to yield the title compound as white solid (0.60 g, 97%). Step 9. Compound 770: 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoic acid (0.08 g, 0.19 mmol), L-prolinamide (0.03 g, 0.24 mmol), BOP (0.17 g, 0.39 mmol) and TEA (0.06 mL, 0.39 mmol) were dissolved in DMF (1 mL). At 60 °C, the reaction was performed for a day. After the completion of the reaction, the reaction mixture was added with a saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ ; MC / MeOH = 10/1) to yield the title compound as yellow solid (0.03 g, 35%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 (m, 1 H), 7.78 - 7.75 (m, 2 H), 7.68 - 7.66 (m, 1 H), 7.50 (t, 1 H, J = 7.5 Hz), 7.29 - 7.26 (m, 1 H), 6.93 (brs, 1 H), 5.50 (brs, 1 H), 4.84 - 4.81 (m, 1 H),

3.90 (d, 2 H, J = 5.8 Hz), 3.55 - 3.40 (m, 2 H), 3.03 (brs, 2 H), 2.51 - 2.45 (m, 3 H), 2.21 - 2.19 (m, 2 H), 2.16 - 2.01 (m, 2 H), 1.93 - 1.90 (m, 1 H), 1.89 - 1.81 (m, 3 H), 1.57 - 1.48 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 501 (M+ + H). Example 59. Compound 694: (R)-(2-fluoro-4-(5-((l-(2-fluoro-2- methylpropyI)piperidin-4-yl)methoxy)pyridine-2-yl)phenyI)(2- (hydroxymethyl)pyrrolidine-l-yl)methanone

Step 1. ethyl 2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoate: 2-chloro-5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)pyridine (the product of synthesis step 5 of compound 691; 230 mg, 0.77 mmol), 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (195 mg, 0.92 mmol), Pd(dppf)Cl ₂ (62 mg, 0.08 mmol) and Na ₂ C0 ₃ (162 mg, 1.35 mmol) were dissolved in DME 6 mL and water 2 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (210 mg, 68%).

Step 2. 2-fluoro-4-( 5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-2- yl)benzoic acid: Ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoate (210 mg, 0.49 mmol) was dissolved in THF/MeOH/H ₂ 0 = 2/1/0.5 mL. ΠΟΗΉ ₂ Ο (41 mg, 0.97 mmol) was added thereto, and refluxed with heating and stirring for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure to yield the title compound as yellow solid (195 mg, 99%).

Step 3. Compound 694: 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoic acid (40 mg, 0.10 mmol), (R)-pyrrolidine-2-ylmethanol (20 mg, 0.20 mmol), and BOP (88 mg, 0.20 mmol) were dissolved in DMF 1 mL. After stirring for 10 minutes at room temperature, TEA (30 mg, 0.30 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (22 mg, 45%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 2.7 Hz), 7.75 (m, 2 H), 7.65 (m, 1 H), 7.49 (m, 1 H), 7.26 (m, 1 H), 4.78 (s, 1 H), 4.40 (m, 2 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.77 (m, 2 H), 3.43 (m, 2 H), 3.15 (m, 2 H), 3.00 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.19 (m, 2 H), 1.81 (m, 3 H), 1.68 (m, 1 H), 1.47 (m, 5 H), 1.34 (s, 3 H)

According to the above-described synthesis process of compound 694, the compounds of Table 38 were synthesized using 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoic acid and the reactant of Table 37.

Table 37.

Table 38.

Compound

Compound Name, Ή-NMR, MS (ESI)

No. (S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 2-yl)phenyl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 5 8.36 (m, 1 H), 7.72 (m, 2 H), 7.69 (m, 1 H), 7.48

695 (m, 1 H), 7.25 (m, 1 H), 4.57 (m, 0.5 H), 4.45 (m, 0.5 H), 3.89 (d, 2 H, J = 6.0 Hz),

3.73 (m, 3 H), 3.13 (m, 1 H), 3.02 (m, 2 H), 3.00 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.05 (m, 2 H), 1.99 (m, 2 H), 1.41 (m, 5 H), 1.35 (s, 3 H); MS (ESI) m/z 474 (M + H).

(S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 3.0 Hz), 7.76 - 7.71 (m, 2 H), 7.67 - 7.65 (m, 1 H), 7.48 - 7.44 (m, 1 H), 7.29 - 7.26 (m, 1 H), 4.12 - 3.90 (m, 3

767

H), 3.59 - 3.55 (m, 1 H), 3.49 - 3.46 (m, 1 H), 3.38 - 3.26 (m, 1 H), 3.25 - 3.02 (m, 1 H), 2.97 - 2.46 (m, 2 H), 2.21 - 2.28 (m, 2 H), 2.06 - 2.01 (m, 1 H), 1.98 - 1.91 (m, 1 H), 1.89 - 1.82 (m, 4 H), 1.68 - 1.62 (m, 4 H), 1.60 - 1.48 (m, 2 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 488(M+ + H).

(R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 2-yl)phenyl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 2.8 Hz), 7.76 - 7.72 (m, 2 H), 7.67 - 7.65 (m, 1 H), 7.54 - 7.49 (m, 1 H), 7.29 - 7.26 (m, 1 H), 4.62 - 4.49 (m, 1

768

H), 3.91 (d, 2 H, J = 5.8 Hz), 3.86 - 3.80 (m, 2 H), 3.79 - 3.61 (m, 2 H), 3.04 (brs, 2 H), 2.52 - 2.48 (m, 2 H), 2.29 - 2.18 (m, 2 H), 2.17 - 2.01 (m, 2 H), 1.99 - 1.83 (m, 4 H), 1.67 - 1.53 (m, 2 H), 1.43 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 474 (M+ + H).

(S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 2-yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 2.9 Hz), 7.77 - 7.73 (m, 2 H), 7.67 (d, 1 H, J = 8.7 Hz), 7.52 - 7.48 (m, 1 H), 7.28 - 7.26 (m, 1 H), 4.77 - 4.74

769

(m, 1 H), 4.41 - 4.39 (m, 1 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.83 - 3.77 (m, 2 H), 3.46 - 3.43 (m, 2 H), 3.02 (brs, 2 H), 2.51 - 2.45 (m, 2 H), 2.24 - 2.17 (m, 3 H), 1.91 - 1.87 (m, 1 H), 1.86 - 1.81 (m, 4 H), 1.79 - 1.71 (m, 1 H), 1.70 - 1.66 (m, 1 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 488 (M+ + H).

(R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, 1 H, J = 3.0 Hz), 7.76 - 7.71 (m, 2 H), 7.67 - 7.65 (m, 1 H), 7.48 - 7.44 (m, 1 H), 7.29 - 7.26 (m, 1 H), 4.12 - 3.90 (m, 3

771

H), 3.59 - 3.55 (m, 1 H), 3.49 - 3.46 (m, 1 H), 3.38 - 3.26 (m, 1 H), 3.25 - 3.02 (m, 1 H), 2.97 - 2.46 (m, 2 H), 2.21 - 2.28 (m, 2 H), 2.06 - 2.01 (m, 1 H), 1.98 - 1.91 (m, 1 H), 1.89 - 1.82 (m, 4 H), 1.68 - 1.62 (m, 4 H), 1.60 - 1.48 (m, 2 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 488 (M+ + H).

l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)pyridine-2- yl)benzoyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.41 - 8.40 (m, 1 H), 7.78 - 7.68 (m, 3 H), 7.47 (t,

805 1 H, J = 7.2 Hz), 7.31 - 7.29 (m, 1 H), 5.75 (d, 2 H, J = 21.6 Hz), 4.77 (d, 2 H, J =

13.2 Hz), 3.93 (d, 2 H, J = 6.0 Hz), 3.73 (d, 1 H, J = 14.0 Hz), 3.13 - 2.93 (m, 4 H), 2.52 - 2.46 (m, 3 H), 2.22 (t, 2 H, J = 1 1.6 Hz), 2.05 - 1.78 (m, 7 H), 1.59 - 0.90 (m, 8 H); MS (ESI) m/z 515 (M+ + H)

(R)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4-

822

yl)methoxy)pyridine-2-yl)benzoyl)piperidin-2-carboxamide 1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 - 8.38 (m, 1 H), 7.79 - 7.75 (m, 2 H), 7.68 (d,

1 H, J = 8.8 Hz), 7.50 (t, 1 H, J = 7.7 Hz), 7.29 - 7.26 (m, 2 H), 6.33 (brs, 1 H), 5.58 (brs, 1 H), 5.47 (brs, 1 H), 3.90 (d, 2 H, J = 6.0 Hz), 3.59 (d, 1 H, J = 14.4 Hz), 3.29 - 3.16 (m, 1 H), 3.01 (d, 2 H, J = 11.4 Hz), 2.48 - 2.43 (m, 3 H), 2.18 (t,

2 H, J = 12.0 Hz), 1.85 - 1.60 (m, 8 H), 1.49 - 1.24 (m, 8 H); MS (ESI) m/z 515 (M+ + H).

(S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridine-2-yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 - 8.35 (m, 1 H), 7.78 - 7.69 (m, 3 H), 7.60 (t,

824 1 H, J = 12.0 Hz), 7.36 - 7.25 (m, 1 H), 6.34 (brs, 1 H), 5.75 (brs, 1 H), 5.44 (brs,

1 H), 3.89 (d, 2 H, J = 4.0 Hz), 3.58 (d, 1 H, J = 12.8 Hz), 3.23 - 3.20 (m, 1 H),

3.00 (d, 2 H, J = 11.2 Hz), 2.48 - 2.37 (m, 3 H), 2.17 (t, 2 H, J = 11.0 Hz), 1.86 -

1.62 (m, 8 H), 1.59 - 1.29 (m, 8 H); MS (ESI) m/z 515 (M+ + H)

Example 60. Compound 1067: (2S,4R)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl) piperidin-4-yl)methoxy)pyridine-2-yl)benzoyl)-4-hydroxypyrro lidine-2-carboxamide

Step 1. (2S,4R)-methyl l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-2-yl)benzoyl)-4-hydroxypyrrolidine-2-car boxylate:

2-fluoro-4-(5-((l-(2-fluoro-2-memylpropyl)piperidin-4-yl) methoxy)pyridine-2-yl)benzoic acid (the product of synthesis step 2 of compound 694; 200 mg, 0.49 mmol), (2S,4R)-methyl 4- hydroxypyrrolidine-2-carboxylate hydrochloride (135 mg, 0.74 mmol), EDC (190 mg, 0.99 mmol), HOBt (134 mg, 0.99 mmol) and DIPEA (0.18 mL, 0.99 mmol) were dissolved in DMF (10 mL) at room temperature. The solution was stirred at 80 °C for 14 hours. The reaction mixture was added with water (20 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as red solid (230 mg, 88%).

Step 2. (2S,4R)- 1 -(2-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy) pyridine-2-yl)benzoyl)-4-hydroxypyrrolidine-2-carboxylic acid: (2S,4R)-methyl l-(2- fluoro-4-(5-((l-(2-fiuoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyridine-2-yl)benzoyl)-4- hydroxypyrrolidine-2-carboxylate(230 mg, 0.43 mmol) and LiOH H ₂ 0 (36 mg, 0.86 mmol) were dissolved in THF (20 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at 60 °C for 14 hours. The reaction mixture was concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 3. Compound 1067: (2S,4R)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperi din- 4-yl)methoxy)pyridine-2-yl)benzoyl)-4-hydroxypyrrolidine-2-c arboxylic acid (290 mg, 0.56 mmol), ammonium chloride (45 mg, 0.84 mmol), EDC (161 mg, 0.84 mmol), HOBt (114 mg, 0.84 mmol) and DIPEA (0.20 mL, 1.12 mmol) were dissolved in DMF (10 mL) at room temperature. The solution was stirred at 80 °C for 16 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as yellow solid (10 mg, 3%).

1H NMR (400 MHz, CDC1 ₃ + MeOD) δ 8.33 (m, 1 H), 7.72 - 7.64 (m, 3 H), 7.54 (m, 1 H), 7.26 (m, 1 H), 7.01 (br, 1 H), 5.99 (br, 1 H), 4.84 (m, 1 H), 4.42 (m, 1 H), 3.89 (m, 2 H), 3.68 (m, 1 H), 3.38 (m, 1 H), 2.99 (m, 2 H), 2.51 - 2.01 (m, 7 H), 1.80 (m, 2 H), 1.63 - 1.25 (m, 9 H); MS (ESI) m/z 517 (M+ + H).

Example 61.Synthesis of compound 652: (R)-(4-(6-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)pyridine-3-yl)phenyl)(2-

(hydroxymethyl)pyrrolidine-l-yl)methanone

Step_L 5-bromo-2-(piperidin-4-ylmethoxy)pyridine hydrochloride: t-butyl 4-((5- bromopyridine-2-yloxy)methyl)piperidiri- l-carboxylate (the product of synthesis step 1 of compound 596; 710 mg, 1.91 mmol) was dissolved in CH ₂ C1 ₂ 5 mL. 4 M HC1 526 μΐ, was added thereto. And then, the reaction mixture was stirred for 1 hour at room temperature. The obtained reaction mixture was filtered to yield the title compound as white solid (580 mg, 98%).

Step 2. l-(4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-yl)-2-meth ylpropan-2-ol:

5-bromo-2-(piperidin-4-ylmethoxy)pyridine hydrochloride (500 mg, 1.63 mmol) and K ₂ C0 ₃ (450 mg, 3.25 mmol) were suspended in EtOH 2 mL. Water 2 mL was added thereto, and the mixture was suspended with a little heating. 2,2-dimethyl oxirane (1.17 g, 16.25 mmol) was added thereto. With a microwave radiation, the reaction was performed at 110 °C for 20 minutes. The reaction mixture was added with water, and the resulting precipitate was filtered to yield the title compound as white solid (490 mg, 88%).

Step 3. 5-bromo-2-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine:

l-(4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-yl)-2-m ethylpropan-2-ol (490 mg, 1.43 mmol) was dissolved in CH ₂ C1 ₂ 4 mL. Deoxo-Fluor (347 mg, 1.57 mmol) was added thereto. After stirring for 3 hours at room temperature, A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS04, and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as yellow liquid (470 mg, 95%).

Step 4. methyl 4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-3- yl)benzoate: 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine (270 mg, 0.78 mmol) and 4-(methoxycarbonyl)phenylboronic acid (169 mg, 0.94 mmol) were dissolved in dioxane 2 mL. Water 0.5 mL was added thereto. Pd(dbpf)Cl ₂ (26 mg, 0.04 mmol) and Cs ₂ C0 ₃ (510 mg, 1.56 mmol) were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was filtered through Celite. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgSC>4, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (210 mg, 67%).

\Step 5. 4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-3- yl)benzoic acid: methyl 4-(6-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-3 -yl)benzoate (210 mg, 0.52 mmol) was dissolved in THF 2 mL. MeOH 1 mL and H ₂ 0 0.5 mL were poured therein. LiOH (44 mg, 1.05 mmol) was added thereto, and refluxed with heating and stirring for a day. After acidification with 1 N HC1, the resulting precipitate was filtered to yield the title compound as white solid (110 mg, 54%).

Step 6. Compound 652: 4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr idine- 3-yl)benzoic acid (35 mg, 0.09 mmol), (R)-pyrrolidine-2-ylmethanol (14 mg, 0.14 mmol) and PyBOP (71 mg, 0.14 mmol) were dissolved in DMF 1 mL. DIPEA (23 mg, 0.18 mmol) was added thereto. The reaction was performed at room temperature for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (23 mg, 54%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.36 (d, 1 H, J = 2.0 Hz), 7.78 (dd, 1 H, J = 8.6, 2.3 Hz), 7.56 (m,

4 H), 6.80 (d, 1 H, J = 8.6 Hz), 4.94 (s, 1 H), 4.41 (m, 2 H), 4.17 (d, 2 H, J = 6.1 Hz), 3.74 (m, 2 H), 3.55 (m, 2 H), 2.97 (d, 2 H, J = 11.2 Hz), 2.46 (s, 1 H), 2.40 (s, 1 H), 2.15 (m, 3 H), 1.76 (m,

5 H), 1.40 (m, 5 H), 1.23 (s, 3 H); MS (ESI) m/z 470 (M+ + H). According to the above-described synthesis process of compound 652, the compounds of Table 40 were synthesized using 4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr idine- 3-yl)benzoic acid and the reactant of Table 39.

Table 39.

Table 40.

3.48 (m, 1 H), 2.98 (d, 2 H, J = 11.6 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.19 - 2.13 (m, 2 H), 2.04 - 2.00 (m, 2 H), 1.81 - 1.78 (m, 4 H), 1.45 - 1.42 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 456 (M+ + H).

(S)-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine-3- yl)phenyl)(3-hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (s, 1 H), 7.81 - 7.78 (m, 1 H), 7.64 - 7.61 (m,

2 H), 7.59 - 7.54 (m, 2 H), 6.82 (d, 1 H, J = 8.4 Hz), 4.62 (brs, 0.5 H), 4.49 (brs,

1078

0.5 H), 4.19 (d, 2 H, J = 6.4 Hz), 3.86 - 3.76 (m, 2 H), 3.70 - 3.65 (m, 1 H), 3.60 - 3.48 (m, 1 H), 2.98 (d, 2 H, J = 11.6 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.19 - 2.13 (m, 2 H), 2.04 - 2.00 (m, 2 H), 1.81 - 1.78 (m, 4 H), 1.45 - 1.42 (m, 2 H), 1.39 (s,

3 H), 1.34 (s, 3 H); MS (ESI) m/z 456 (M+ + H).

(S)-l-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)pyridine-3- yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 6 8.38 (s, 1 H), 7.81 - 7.78 (m, 1 H), 7.59 - 7.52 (m, 4 H), 6.83 (d, 1 H, J = 8.4 Hz), 6.46 (brs, 1 H), 5.39 (brs, 1 H), 5.28 (brs, 1 H),

1079

4.19 (d, 2 H, J = 6.0 Hz), 3.79 (brs, 1 H), 3.12 (t, 1 H, J - 12.4 Hz), 2.98 (d, 2 H, J = 12.6 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.34 (d, 1 H, J = 13.6 Hz), 2.16 (t, 2 H, J = 10.8 Hz), 1.86 - 1.78 (m, 5 H), 1.67 - 1.55 (m, 4 H), 1.48 - 1.42 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 497 (M+ + H).

Example 62. Compound 862: (R)-l-(3-fluoro-4-(6-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)pyridine-3-yl)benzoyl)pi peridin-2-carboxainide

Step 1. methyl 3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)pyridine-3- yl)benzoate: 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine (the product of synthesis step 4 of compound 784; 0.5 g, 1.45 mmol) was dissolved in 1,4- dioxane 12 mL and H ₂ 0 3 mL. 2-Fluoro-4-(methoxycarbonyl)phenylboronic acid (0.29 g, 1.45 mmol), Pd(dbpf)Cl ₂ (0.05 g, 0.07 mmol) and Cs ₂ C0 ₃ (0.94 g, 2.90 mmol) were added thereto. With a microwave radiation, the mixture was heated at 120 °C for 45 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with C¾C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. MeOH was added and the resulting precipitate was filtered to yield the title compound as light-yellow solid (0.48 g, 79%).

Step 2. 3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)pyridine-3- yl)benzoic acid: Methyl 3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate (0.47 g, 1.12 mmol) was dissolved in THF 3 mL, H ₂ 0 1 mL and MeOH 1 mL. LiOH H ₂ 0 (0.24 g, 5.62 mmol) was added thereto, following with increasing the temperature slowly and stirring at 50 °C for a day. After the completion of the reaction, the solvent was distilled under reduced pressure. Excess amount of water was added thereto, and the resulting precipitate was filtered to yield the title compound as white solid (0.45 g, 99%).

Step 3. Compound 862: 3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid (0.05 g, 0.12 mmol) and (R)-piperidin-2-carboxamide (0.032 g, 0.25 mmol) were dissolved in DMF 2 mL. DIPEA (0.10 mL, 0.62 mmol), EDCI (0.05 g, 0.25 mmol) and HOBt (0.03 g, 0.25 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered, and dissolved in CH ₂ C1 ₂ again. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (0.016 g, 25%). 1H NMR (400 MHz, CDC1 ₃ ) δ 8.33 (s, 1 H), 7.79 - 7.77 (m, 1 H), 7.49 - 7.45 (m, 1 H), 7.32 - 7.27 (m, 2 H), 6.84 (d, 1 H, J = 8.6 Hz), 6.40 (brs, 1 H), 5.26 (bis, 1 H), 4.20 (d, 2 H, J = 6.4 Hz), 3.78 (d, 1 H, J = 12.8 Hz), 3.19 - 3.17 (m, 1 H), 2.99 (d, 2 H, J = 9.6 Hz), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.34 (d, 1 H, J = 13.2 Hz), 2.17 (t, 2 H, J = 11.2 Hz), 2.05 - 1.54 (m, 8 H), 1.48 - 1.24 (m, 8 H)

According to the above-described synthesis process of compound 862, the compounds of Table 42 were synthesized using 3-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 41.

Table 41.

Table 42.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(S)- 1 -(3 -fluoro-4-(6-(( 1 -(2-fmoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoyl)piperidin-2-carboxamide

863 1H NMR (400 MHz, CDC1 ₃ ) 5 8.32 (brs, 1 H), 7.83 - 7.76 (m, 1 H), 7.52 - 7.43

(m, 1 H), 7.28 - 7.27 (m, 1 H), 6.83 - 6.81 (m, 2 H), 6.48 (brs, 1 H), 6.78 (brs, 1

H), 5.32 (brs, 1 H), 4.19 (d, 2 H, J = 6.0 Hz), 2.98 (d, 2 H, J = 11.4 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.37 - 2.26 (m, 1 H), 2.17 (t, 2 H, J = 11.0 Hz), 1.80 - 1.78 (m, 8 H), 1.45 - 1.25 (m, 8 H)

1 -(3 -fluoro-4-(6-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-3 - yl)benzoyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.31 (s, 1 H), 7.77 (d, 1 H, J = 7.2 Hz), 7.44 (t, 1 H,

864 J = 7.8 Hz), 7.27 - 7.20 (m, 2 H), 6.82 (d, 1 H, J = 8.8 Hz), 5.74 (d, 2 H, J = 22.4 Hz), 4.63 (brs, 1 H), 4.18 (d, 2 H, J = 6.0 Hz), 3.87 (brs, 1 H), 3.17 - 2.96 (m, 4 H), 2.47 - 2.41 (m, 3 H), 2.17 (t, 2 H, J = 11.0 Hz), 2.02 - 1.77 (m, 7 H), 1.47 - 1.25 (m, 8 H)

Example 63. Compound 784: (R)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl) piperidin-4-yl)m thanone

Step 1. t-butvl 4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-carboxylate: t-Butyl 4- (hydroxymethyl)piperidin-l-carboxylate (the product of synthesis step 1 of compound 431; 7.0 g, 32.51 mmol) was dissolved in DMF. 2,5-bromopyridine (8.47 g, 35.77 mmol) and NaH (1.23 g, 48.77 mmol) were added thereto slowly, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g ISCO silica gel cartridge, 0 - 20 % EtOAc/hexane) to yield the title compound as white solid (11.8 g, 98%).

Step 2. 5-bromo-2-(piperidin-4-ylmethoxy)pyridine hydrochloride: t-butyl 4-((5- bromopyridine-2-yloxy)methyl)piperidin-l-carboxylate (22.0 g, 59.26 mmol) was dissolved in 1 ,4-dioxane 300 mL. 4 M HC1 in 1 ,4-dioxane (74.0 mL, 296.28 mmol) was added thereto. After the solvent was distilled out completely, the residue was washed with ether to yield the title compound as white solid (17.0 g, 93%).

Step 3. l-(4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-yl)-2-meth ylpropan-2-ol:

5-bromo-2-(piperidin-4-ylmethoxy)pyridine hydrochloride (4.5 g, 14.63 mmol) was dissolved in EtOH 50 mL and H ₂ 0 50 mL. l,2-epoxy-2-methylpropane (10.55 g, 146.29 mmol) and K ₂ C0 ₃ (10.11 g, 73.15 mmol) were added slowly thereto. The mixture was stirred in a microwave at 110 °C for 20 minutes. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, following with washing with H ₂ 0 three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (5.00 g, 99%).

Step 4. 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)pyridine:

l-(4-((5-bromopyridine-2-yloxy)methyl)piperidin-l-yl)-2-m ethylpropan-2-ol (10.20 g, 29.71 mmol) was dissolved in CH ₂ C1 ₂ 200 mL. DAST (4.32 mL, 32.69 mmol) was added dropwise slowly thereto at 0 °C, following with stirring at 0 °C for 2 hours. After the completion of the reaction, the reaction mixture was washed with a saturated NaHC0 ₃ aqueous solution several times. The CH ₂ C1 ₂ layer was distilled under reduced pressure. The concentrate was purified by column chromatography (4 g ISCO silica gel cartridge, 0 - 10 % EtOAc/hexane) to yield the title compound as white solid (5.80 g, 57%).

Step 5. ethyl 2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine-3- yl)benzoate: 5-bromo-2-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridine (0.5 g, 1.45 mmol) was dissolved in 1,4-dioxane 12 mL and H ₂ 0 3 mL. 4-(Ethoxycarbonyl)-3- fluorophenylboronic acid (0.31 g, 1.45 mmol), Pd(dbpf)Cl ₂ (0.05 g, 0.07 mmol) and Cs ₂ C0 ₃ (0.94 g, 2.90 mmol) were added thereto. The mixture was stirred in a microwave at 110 °C for 45 minutes. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. MeOH was added thereto. The resulting precipitate was filtered to yield the title compound as transparent oil (0.17 g, 27%).

Step 6. 2-fluoro-4-(6-((l -(2-fluoro-2-methvlpropvl)piperidin-4-vl)methoxy)pyridine-3- yl)benzoic acid: Ethyl 2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate (0.17 g, 0.39 mmol) was dissolved in THF (3 mL) / H ₂ 0 (1 mL) / MeOH 1 mL). LiOH H ₂ 0 (0.08 g, 1.97 mmol) was added thereto, following with increasing the temperature slowly, and then refluxing with stirring at 80 °C for 30 minutes. After the completion of the reaction, the solvent was distilled under reduced pressure. Excess amount of water was added thereto, and the resulting precipitate was filtered to yield the title compound as yellow solid (0.12 g, 76%).

Step 7. Compound 784: 2-fluoro-4-(6-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid (0.04 g, 0.10 mmol) and (R)-piperidin-3-ol(0.02 g, 0.19 mmol) were dissolved in DMF 2 mL. DIPEA (0.06 g, 0.47 mmol), EDCI (0.04 g, 0.19 mmol) and HOBt (0.03 g, 0.19 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered, and dissolved in CH ₂ C1 ₂ again. The concentrate was purified by column chromatography (40 g IS CO silica gel cartridge, 0 - 20 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as brown solid (0.02 g, 47%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.36 (s, 1 H), 7.78 (d, 1 H, J = 2.0 Hz), 7.49 - 7.24 (m, 4 H), 6.83 (d, 1 H, J = 8.6 Hz), 4.20 (d, 2 H, J = 6.0 Hz), 4.10 - 3.1 1 (m, 5 H), 3.01 (brs, 2 H), 2.49 - 2.44 (m, 2 H), 2.18 - 1.61 (m, 9 H), 1.41 - 1.26 (m, 8 H); MS (ESI) m/z 488 (M+ + H).

According to the above-described synthesis process of compound 784, the compounds of Table 44 were synthesized using 2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 43.

Table 43.

Table 44.

(S)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 3-yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.35 (s, 1 H), 7.76 (dt, 1 H, J = , 2.1 Hz), 7.49 (t, 1 H, J = 6.8 Hz), 7.36 (d, 1 H, J = 4.4 Hz), 7.26 (d, 1 H, J = 12.0 Hz), 6.82 (dd, 1 H,

787

J = 8.8, 1.2 Hz), 4.39 - 4.37 (m, 1 H), 4.19 - 4.17 (m, 2 H), 3.82 - 3.73 (m, 2 H), 3.45 (t, 2 H, J = 6.4 Hz), 2.98 (d, 2 H, J = 10.8 Hz), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.22 - 2.13 (m, 3 H), 1.91 - 1.67 (m, 6 H), 1.48 - 1.33 (m, 8 H); MS (ESI) m/z 488 (M+ + H).

(R)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridine-3-yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) 6 8.37 - 8.36 (m, 1 H), 7.79 - 7.76 (m, 1 H), 7.51 (t,

1 H, J = 7.6 Hz), 7.43 - 7.39 (m, 1 H), 6.84 (d, 1 H, J = 8.8 Hz), 6.31 (brs, 1 H),

854

5.65 (brs, 1 H), 5.44 (brs, 1 H), 4.20 (d, 2 H, J = 6.1 Hz), 3.60 (d, 1 H, J = 12.8 Hz), 3.23 - 3.21 (m, 1 H), 2.99 (d, 2 H, J = 11.2 Hz), 2.47 - 2.42 (m, 3 H), 2.17 (t,

2 H, J = 11.2 Hz), 1.80 - 1.63 (m, 8 H), 1.48 - 1.25 (m, 8 H); MS (ESI) m/z 515 (M+ + H).

(S)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridine-3-yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 - 8.36 (m, 1 H), 7.78 - 7.75 (m, 1 H), 7.51 (t, 1 H, J = 7.4 Hz), 7.41 - 7.39 (m, 1 H), 7.28 - 7.25 (m, 1 H), 6.83 (d, 1 H, J = 8.0

855

Hz), 6.33 (brs, 1 H), 5.74 (brs, 1 H), 5.48 (brs, 1 H), 4.19 (d, 2 H, J = 7.6 Hz), 3.60 (d, 1 H, J = 12.8 Hz), 3.32 - 3.21 (m, 1 H), 2.99 (d, 2 H, J = 1 1.2 Hz), 2.47 - 2.41 (m, 3 H), 2.17 (t, 2 H, J = 11.2 Hz), 1.80 - 1.62 (m, 8 H), 1.48 - 1.25 (m, 6 H); MS (ESI) m/z 515 (M+ + H).

l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)pyridine-3- yl)benzoyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.36 (d, 1 H, J = 4.0 Hz), 7.77 (dd, 1 H, J = 8.5, 2.4

856 Hz), 7.45 (t, 1 H, J = 7.4 Hz), 7.37 - 7.23 (m, 2 H), 6.83 (d, 1 H, J = 8.4 Hz), 5.61 (d, 2 H, J = 12.8 Hz), 4.74 (d, 1 H, J = 13.2 Hz), 4.19 (d, 2 H, J = 6.2 Hz), 3.72 (d, 1 H, J = 13.9 Hz), 3.13 - 2.92 (m, 4 H), 2.48 - 2.42 (m, 3 H), 2.18 (t, 2 H, J = 1 1.2 Hz), 2.04 - 1.78 (m, 7 H), 1.48 - 0.88 (m, 8 H); MS (ESI) m/z 515 (M+ + H).

(R)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin -4-yl)methoxy)pyridine- 3 -yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 6 8.35 (d, 1 H, J = 2.4 Hz), 7.76 (dd, 1 H, J = 7.4, 1.3 Hz), 7.50 (t, 1H, J = 7.5 Hz), 7.36 (dd, 1 H, J = 8.0, 1.5 Hz), 7.26 (dd, 1 H, J =

657

1 1.1, 1.6 Hz), 6.82 (d, 1 H, J = 8.6 Hz), 4.38 (m, 1 H), 4.18 (d, 2 H, J = 6.1 Hz), 3.76 (m, 2 H), 3.45 (m, 2 H), 2.97 (m, 2 H), 2.46 (s, 1 H), 2.41 (s, 1 H), 2.13 (m, 3 H), 1.87 (m, 1 H), 1.79 (m, 5 H), 1.44 (m, 5 H), 1.41 (s, 3 H); MS (ESI) m/z 488 (M + H).

(S)-l-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyridine-3-yl)benzoyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.36 (d, 1 H, J = 2.4 Hz), 7.77 (dd, 1 H, J = ^' 8.6, 1.3 Hz), 7.50 (t, 1H, J = 7.5 Hz), 7.38 (dd, 1 H, J = 7.9, 1.5 Hz), 7.28 (dd, 1 H, J =

658

10.8, 1.4 Hz), 6.92 (s, 1 H), 6.83 (d, 1 H, J = 8.6 Hz), 5.62 (s, 1 H), 4.80 (m, 1 H), 4.19 (d, 2 H, J = 6.2 Hz), 3.54 (m, 1 H), 3.43 (s, 1 H), 2.99 (m, 2 H), 2.45 (m, 2 H), 2.09 (m, 4 H), 1.93 (m, 1 H), 1.84 (m, 4 H), 1.46 (m, 5 H), 1.39 (s, 3 H); MS (ESI) m/z 501 (M + H).

659 (S)-(2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridine- 3 -yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.33 (t, 1 H, J = 2.7 Hz), 7.74 (m, 1 H), 7.43 (t, 1H, J = 7.4 Hz), 7.32 (m, 1 H), 7.21 (m, 1 H), 6.80 (d, 1 H, J = 8.6 Hz), 4.17 (d, 2 H, J = 6.2 Hz), 3.62 (m, 1 H), 3.37 (m, 2 H), 3.13 (m, 2 H), 2.98 (m, 2 H), 2.78 (s, 1 H), 2.45 (s, 1 H), 2.40 (s, 1 H), 2.15 (t, 2 H, J = 11.1 Hz), 1.86 (m, 2 H), 1.76 (m, 4 H), 1.58 (m, 1 H), 1.40 (m, 5 H), 1.32 (s, 3 H); MS (ESI) m/z 488 (M + H).

Example 64. Compound 946 :

(S)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)-3'- (hydroxymethyl)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. t-butyl 4-((4-bromo-2-formylphenoxy)methyl)piperidin-l-carboxylate: t-butyl 4- ((methylsulfonyloxy)methyl)piperidin-l-carboxylate (the product of synthesis step 2 of compound 431; 1.00 g, 3.41 mmol) was dissolved in DMF (80 mL). K ₂ C0 ₃ (1.67 g, 5.11 mmol) was added thereto, and stirred for 5 minutes. 5-bromo-2-hydroxybenzaldehyde (685 mg, 3.41 mmol)was added thereto, following with stirring at 80 °C for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column

chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (840 mg, 61%).

Step 2. 5-bromo-2-(piperidin-4-ylmethoxy)benzaldehyde hydrochloride:

t-butyl 4-((4-bromo-2-formylphenoxy)methyl)piperidin-l-carboxylate (840 mg, 2.11 mmol) was dissolved in CH ₂ C1 ₂ (20 mL). 4 M HC1 in 1,4-dioxane (1.06 mL, 4.22 mmol) was added thereto, following with stirring for 1 hour. The resulting precipitate was filtered to yield the title compound as white solid (500 mg, 70%).

Step 3. 5-bromo-2-((l-2-hydroxy-2-methylpropyl)piperidin-4-yl)methox y)benzaldehyde:

5-bromo-2-(piperidin-4-ylmethoxy)benzaldehyde hydrochloride(500 mg, 1.68 mmol) was dissolved in EtOH (5 mL) and H ₂ 0 (5 mL). 2,2-Dimethyloxirane (1.49 mL, 16.77 mmol) and 2C0 ₃ (116 mg, 0.84 mmol) were added thereto slowly. With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained material, which is the title compound as white solid (620 mg, 99%), was used without further purification.

Step 4. 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)benzaldehyde:

5-bromo-2-((l-2-hydroxy-2-methylpropyl)piperidin-4-yl)met hoxy)benzaldehyde (620 mg, 1.67 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). At 0 °C, DAST (221 μΐ., 1.67 mmol) was added slowly thereto. After stirring for 1 hour at room temperature, The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 40 % ~ 60 %) to yield the title compound as white solid (31C mg, 49%).

Step 5. (5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)phenyl)methanol: 5-bromo-2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methox y)benzaldehyde (310 mg, 0.83 mmol) was dissolved in THF (10 mL). At room temperature, NaBH ₄ (95 mg, 2.50 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS04, and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 50 %) to yield the title compound as white solid (200 mg, 64%).

Step 6. ethyl 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)-3 '- (hydroxymethyl)biphenyl-4-carboxylate: (5-bromo-2-(( 1 -(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)phenyl)methanol (200 mg, 0.534 mmol), 4- (ethoxycarbonyl)-3-fluorophenylboronic acid (125 mg, 0.59 mmol), Pd(dppf)Cl ₂ (44 mg, 0.05 mmol) and Cs ₂ C0 ₃ (348 mg, 1.07 mmol) were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 40 % ~ 60 %) to yield the title compound as white solid (146 mg, 59%).

Step_7. 3-fluoro-4 ^, -((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- 3'- (hydroxymethyl)biphenyl-4-carboxylic acid: Ethyl 3-fluoro-4'-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)-3 ' -(hydroxymethyl)biphenyl-4-carboxylate ( 146 mg, 0.32 mmol) was dissolved in THF (10 n L) and water (5 mL). LiOH H ₂ 0 (66 mg, 1.58 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered to yield the title compound as white solid (120 mg, 87%).

Step 8. Compound 946 : 3 -fluoro-4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)- 3'-(hydroxymethyl)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), (S)-pyrrolidine-2- carboxarnide (16 mg, 0.14 mmol), EDC (27 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol) and DIPEA (25 0.14 mmol) were dissolved in CH ₂ C1 ₂ (1 mL), following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH =

95 % ~ 5 %) to yield the title compound as white solid (21 mg, 42%).

1H NMR (400 MHz, CDCI3) δ 7.56 - 7.55 (m, 1 H), 7.49 - 7.41 (m, 3 H), 7.33 - 7.27 (m, 1 H), 6.96 - 6.94 (m, 1 H), 5.50 (brs, 1 H), 5.31 - 4.81 (m, 3 H), 3.93 (d, 2 H, J = 5.4 Hz), 3.57 - 3.40 , (m, 2 H), 3.03 (brs, 1 H), 2.51 - 2.43 (m, 3 H), 2.23 - 2.21 (m, 2 H), 2.16 - 2.03 (m, 3 H), 1.94 , - 1.80 (m, 4 H), 1.69 (brs, 2 H), 1.43 (s, 3 H), 1.38 (s, 3 H), 1.32 - 1.28 (m, 2 H); MS (ESI) m/z 530 (M+ + H). According to the above-described synthesis process of compound 946, the compounds of Table 46 were synthesized using 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth oxy)- 3'-(hydroxymethyl)biphenyl-4-carboxylic acid and the reactant of Table 45.

Table 45. Table 46.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl )methoxy)-5'- (hydroxymethyl)biphenyl-4-yl)(3-hydroxypynOlidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 (s, 1 H), 7.54 - 7.44 (m, 2 H), 7.38 (d, 1 H, J = 8.0 Hz), 7.30 - 7.26 (m, 1 H), 6.93 (d, 1 H, J = 8.6 Hz), 4.77 (d, 2 H, J = 6.0 Hz),

947

4.61 (brs, 0.5 H), 4.48 (brs, 0.5 H), 3.93 (d, 2 H, J = 5.4 Hz), 3.85 - 3.78 (m, 2 H), 3.73 - 3.57 (m, 2 H), 3.46 (brs, 0.5 Hz), 3.33 (brs, 0.5 H), 3.08 (brs, 2 H), 2.50 (brs, 2 H), 2.18 - 2.00 (m, 4 H), 1.99 - 1.81 (m, 4 H), 1.45 (s, 3 H), 1.40 (s, 3 H), 1.29 - 1.23 (m, 2 H); MS (ESI) m/z 503 (M+ + H). Example 65. Compound 948: (R)-(4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazi -2-yl)phenyl)(3-hydroxypiperidin-l-yl)methanone

Step 1. methyl 4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoate: To 2-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5-iodopyra zine (the product of synthesis step 4 of compound 944; 0.35 g, 0.89 mmol), 4-(methoxycarbonyl) phenylboronic acid (0.19 g, 1.06 mmol), Pd(dbpf)Cl ₂ (0.03 g, 0.04 mmol) and Cs ₂ C0 ₃ (0.58 g, 1.78 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.21 g, 59%).

Step 2. 4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoic acid: Methyl 4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoate (0.21 g, 0.52 mmol) and LiOH H ₂ 0 (0.11 g, 2.62 mmol) were dissolved in THF (2 mL) / H ₂ 0

/MeOH (3 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.16 g, 78%).

Step 3. Compound 948: 4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr azine- 2-yl)benzoic acid (0.04 g, 0.10 mmol), EDCI (0.04 g, 0.20 mmol), HOBt (0.02 g, 0.20 mmol) and DIPEA (0.09 mL, 0.51 mmol) were dissolved in DMF (2 ml). At room temperature, (R)- piperidin-3-ol (0.02 g, 0.20 mmol) was added thereto, following with stirring at 60 °C for 12 hours. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column chromatography (Si0 ₂ , 4 g cartridge;

methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as yellow solid (0.02 g, 49%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (s, 1 H), 8.26 (s, 1 H), 7.93 (d, 2 H, J - 8.4 Hz), 7.51 (d, 2 H, J = 8.0 Hz), 4.20 (d, 2 H, J = 6.1 Hz), 3.98 - 3.25 (m, 5 H), 2.97 (d, 2 H, J = 11.2 Hz), 2.45 (s, 1 H), 2.39 (s, 1 H), 2.18 - 1.67 (m, 9 H), 1.44 - 1.32 (m, 8 H); MS (ESI) m/z 471 (M+ + H). According to the above-described synthesis process of compound 948, the compounds of Table 48 were synthesized using 4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr azine- 2-yl)benzoic acid and the reactant of Table 47.

Table 47.

(ESI) m/z 498.3 (M+ + H).

(S)- 1 -(4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.51 (s, 1 H), 8.28 (s, 1 H), 7.89 - 8.01 (m, 2 H),

1081 7.54 - 7.56 (m, 2 H), 6.48 (s, 1 H), 5.50 (s, 1 H), 5.27 - 5.28 (m, 1 H), 4.21 (d, 2

H, J = 6.2 Hz), 3.74 - 3.78 (m, 1 H), 3.07 - 3.14 (m, 1 H), 2.97 - 2.99 (m, 2 H), 2.41 - 2.46 (m, 2 H), 2.31 - 2.35 (m, 1 H), 2.13 - 2.18 (m, 2 H), 1.76 - 1.87 (m, 5 H), 1.53 - 1.69 (m, 3 H), 1.43 - 1.48 (m, 2 H), 1.38 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 498.3 (M+ + H).

Example 66. Compound 982: (R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyI)piperidin- 4-yl)methoxy)pyr

Step 1. methyl 3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoate: To 2-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5-iodopyra zine (the product of synthesis step 4 of compound 944; 0.50 g, 1.27 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (0.29 g, 1.39 mmol), Pd(dppf)Cl ₂ (0.05 g, 0.06 mmol) and Cs ₂ C0 ₃ (0.82 g, 2.54 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.24 g, 45%).

Step 2. 3 -fluoro-4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoic acid: Methyl 3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoate (0.24 g, 0.57 mmol) and LiOH H ₂ 0 (0.12 g, 2.86 mmol) were dissolved in THF / MeOH (16 mL) / H ₂ 0 (4 mL) at room temperature. The solution was stirred at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.20 g, 86%).

Step 3. Compound 982: 3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy) pyrazine-2-yl)benzoic acid (0.04 g, 0.09 mmol), (R)-piperidin-3-ol (0.01 g, 0.11 mmol), HOBt (0.02 g, 0.19 mmol), EDC (0.03 g, 0.19 mmol) and DIPEA (0.03 mL, 0.19 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgSC , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by coltrmn chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.02 g, 41%).

1H NMR (400 MHz, CDCI ₃ ) δ 8.61 (s, 1 H), 8.32 (s, 1 H), 8.00 (t, 1 H, J = 7.8 Hz), 7.26 - 7.32 (m, 2 H), 4.23 (d, 2 H, J = 6.2 Hz), 3.27 - 3.95 (m, 5 H), 2.98 - 3.01 (m, 2 H), 2.42 - 2.48 (m, 2 H), 2.14 - 2.22 (m, 3 H), 1.77 - 2.05 (m, 4 H), 1.43 - 1.67 (m, 5 H), 1.40 (s, 3 H), 1.34 (s, 3 H); MS (ESI) m/z 489.2 (M+ + H).

According to the above-described synthesis process of compound 982, the compounds of Table 50 were sy thesized using 3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoic acid and the reactant of Table 49.

Table 49.

Table 50.

Compound

Compound Name, Ή-NMR, MS (ESI)

No.

(S)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(3-hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.62 (s, 1 H), 8.33 (s, 1 H), 8.01 (t, 1 H, J = 7.8

983 Hz), 7.22 - 7.34 (m, 2 H), 4.24 (d, 2 H, J = 6.3 Hz), 3.35 - 3.96 (m, 5 H), 2.97 - 3.01 (m, 2 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.15 - 2.20 (m, 2 H), 1.68 - 2.05 (m, 6 H), 1.49 - 1.56 (m, 2 H), 1.43 - 1.47 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 489.2 (M+ + H).

(S)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(3 -hydroxypyrrolidine- 1 -yl)methanone

984 1H NMR (400 MHz, CDC1 ₃ ) 6 8.63 (s, 1 H), 8.33 (s, 1 H), 8.03 (t, 1 H, J = 7.7 Hz), 7.36 - 7.53 (m, 2 H), 4.51 - 4.63 (m, 1 H), 4.24 (d, 2 H, J = 6.2 Hz), 3.75 - 3.87 (m, 2 H), 3.46 - 3.71 (m, 2 H), 2.99 - 3.01 (m, 2 H), 2.43 - 2.55 (m, 2 H), 1.93 - 2.21 (m, 4 H), 1.60 - 1.82 (m, 4 H), 1.44 - 1.47 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H); MS (ESI) m/z 475.2 (M+ + H).

(R)-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.63 (s, 1 H), 8.33 (s, 1 H), 8.04 (t, 1 H, J = 7.9 Hz), 7.42 (d, 1 H, J - 8.1 Hz), 7.36 (d, 1 H, J = 1 1.4 Hz), 5.31 (s, 1 H), 4.40 - 4.45

985

(m, 1 H), 4.24 (d, 2 H, J = 6.3 Hz), 3.74 - 3.85 (m, 2 H), 3.49 - 3.60 (m, 2 H), 2.98 - 3.01 (m, 2 H), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.14 - 2.23 (m, 3 H), 1.64 - 1.93 (m, 6 H), 1.43 - 1.50 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 489.2 (M+ + H).

(S)-l-(3-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyrazine-2-yl)benzoyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.60 (s, 1 H), 8.30 (s, 1 H), 8.02 (t, 1 H, J = 7.8

1072 Hz), 7.34 - 7.43 (m, 2 H), 6.87 (s, 1 H), 5.51 (s, 1 H), 4.77 (dd, 1 H, J = 7.4, 5.0

Hz), 4.21 (d, 2 H, J = 6.4 Hz), 3.51 - 3.64 (m, 2 H), 2.97 - 3.00 (m, 2 H), 2.41 -

2.47 (m, 2 H), 2.02 - 2.19 (m, 5 H), 1.75 - 1.90 (m, 4 H), 1.42 - 1.48 (m, 2 H),

1.37 (s, 3 H), 1.32 (s, 3 H); MS (ESI) m/z 502.2 (M+ + H).

(R)- 1 -(3-fluoro-4-(5-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.60 (s, 1 H), 8.30 (s, 1 H), 8.03 (t, 1 H, J = 8.0

1073 Hz), 7.26 - 7.33 (m, 2 H), 6.36 (s, 1 H), 5.41 (s, 1 H), 5.24 - 5.28 (m, 1 H),4.21 (d,

2 H, J = 6.0 Hz), 3.71 - 3.74 (m, 1 H), 3.09 - 3.16 (m, 1 H), 2.99 - 3.01 (m, 2 H),

2.43 - 2.48 (m, 2 H), 2.29 - 2.32 (m, 1 H), 2.14 - 2.20 (m, 2 H), 1.43 - 1.83 (m,

10 H), 1.38 (s, 3 H), 1.33 (s, 3 H); MS (ESI) m/z 516.2 (M+ + H). "

Example 67. Compound 944 : (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2- ^! methylpropyI)piperidin-4-yl)methoxy)pyrazme-2-yl)benzoyl)pyr rolidine-2-carboxamide ⁾ '

Step 1. t-butyl 4-((5- odopyrazine-2-y oxy)methyl)piperidin-l-carboxylate: t-butyl 4- (hydroxymethyl)piperidin-l-carboxylate (the product of synthesis step 1 of compound 431 ;

2.70 g, 12.54 mmol), 2-bromo-5-iodopyrazine (3.57 g, 12.54 mmol) and NaH (0.36 g, 15.05 mmol) were dissolved in 70 °C for THF (30 mL), following with stirring at the same

temperature for 6 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous

MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (4.04 g, 76%).

Step 2. 2-iodo-5-(piperidin-4-ylmethoxy)pyrazine hydrochloride: t-butyl 4-((5- iodopyrazine-2-yloxy)methyl)piperidin-l-carboxylate (4.00 g, 9.54 mmol) was dissolved in CH ₂ C1 ₂ (30 mL). At room temperature, 4 M HC1 solution in 1,4-dioxane (11.92 mL, 47.70 mmol) was added thereto, following with stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (3.20 g, 94%).

Step 3. l-(4-((5-iodopyrazine-2-yloxy)methyl)piperidin-l-yl)-2-methy lpropan-2-ol:

To 2-iodo-5-(piperidin-4-ylmethoxy)pyrazine hydrochloride (1.20 g, 3.37 mmol), 2,2-dimethyl oxirane (3.00 mL, 33.74 mmol) and K ₂ C0 ₃ (2.33 g, 16.87 mmol), EtOH (8 mL) / H ₂ 0 (2 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (1.30 g, 98%).

Step 4. 2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5-iod opyrazine: l-(4-((5- iodopyrazine-2-yloxy)methyl)piperidin-l-yl)-2-methylpropan-2 -ol (1.30 g, 3.32 mmol) and DAST (0.53 mL, 3.98 mmol) were dissolved in CH ₂ C1 ₂ (20 mL) at 0 °C, following with stirring at room temperature for 2 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (0.81 g, 62%).

Step 5. ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)pyrazine-2- yl)benzoate: To 2-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)-5-iod opyrazine (250 mg, 0.64 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (162 mg, 0.76 mmol),

Pd(dppf)Cl ₂ (26 mg, 0.03 mmol) and Cs ₂ C0 ₃ (414 mg, 1.27 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 0 % ~ 15 %) to yield the title compound as white solid (162 mg, 58%).

Step 6. 2-fluoro-4-(5-( ( 1 -(2-fluoro-2-methvlpropyl)piperidin-4-yl)methoxy)pyrazine-2- yl)benzoic acid: Ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoate (158 mg, 0.36 mmol) was dissolved in THF (10 mL) and H ₂ 0 (5 mL). At room temperature, LiOH H ₂ 0 (77 mg, 1.82 mmol) was added thereto, following with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (120 mg, 81%).

Step 7. Compound 944: 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoic acid (30 mg, 0.07 mmol), EDC (28 mg, 0.15 mmol) and HOBt (20 mg, 0.15 mmol) was added thereto, DIPEA (26 \xL, 0.15 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (17 mg, 0.15 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (20 mg, 53%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.50 (s, 1 H), 8.29 (s, 1 H), 7.78 - 7.51 (m, 2 H), 7.53 (t, 1 H, J = 7.5 Hz), 6.91 (s, 1 H), 5.54 (s, 1 H), 4.84 - 4.81 (m, 1 H), 4.33 (d, 2 H, J = 5.6 Hz), 3.85 - 3.81 (m, 2 H), 3.56 - 3.38 (m, 2 H), 3.26 - 3.21 (m, 2 H), 2.92 - 2.85 (m, 2 H), 2.51 - 2.46 (m, 1 H), 2.27 - 2.26 (m, 2 H), 2.18 - 2.06 (m, 6 H), 1.66 (s, 3 H), 1.60 (s, 3 H); MS (ESI) m/z 502 (M+ + H).

According to the above-described synthesis process of compound 944, the compounds of Table 52 were synthesized using 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoic acid and the reactant of Table 51.

Table 51.

Table 52.

Compound

Compound Name, Ή-NMR, MS (ESI)

No.

(R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine-

945

2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 8.50 (s, 1 H), 8.28 (s, 1 H), 7.75 - 7.69 (m, 2 H), 7.49 (t, 1 H, J = 7.2 Hz), 4.24 (d, 2 H, J = 6.2 Hz), 4.11 - 4.08 (m, 1 H), 3.94 (brs, 1 H), 3.58 - 3.55 (m, 1 H), 3.46 - 3.19 (m, 1 H), 3.14 - 2.96 (m, 2 H), 2.64 - 2.50 (m, 2 H), 2.18 (brs, 2 H), 2.01 - 1.81 (m, 6 H), 1.72 - 1.50 (m, 5 H), 1.43 (s, 3 H), 1.38 (s, 3 H); MS (ESI) m/z 489 (M+ + H).

(S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.51 (s, 1 H), 8.29 (s, 1 H), 7.70 - 7.76 (m, 2 H),

986 7.48 - 7.53 (m, 1 H), 4.23 (d, 2 H, J = 6.2 Hz), 3.74 - 4.12 (m, 2 H), 3.25 - 3.58 (m, 3 H), 3.10 - 3.15 (m, 2 H), 2.98 - 3.01 (m, 2 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.18 (t, 2 H, J = 10.9 Hz), 1.62 - 2.03 (m, 6 H), 1.43 - 1.56 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 489.2 (M+ + H).

(S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(3 -hydro xypyrrolidine- 1 -yl)methanol

1H NMR (400 MHz, CDC1 ₃ ) δ 8.51 (s, 1 H), 8.29 (s, 1 H), 7.70 - 7.76 (m, 2 H),

987 7.52 - 7.57 (m, 1 H), 4.51 - 4.63 (m, 1 H), 4.23 (d, 2 H, J = 6.2 Hz), 3.42 - 3.86

(m, 3 H), 3.33 - 3.36 (m, 1 H), 2.98 - 3.01 (m, 2 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.11 - 2.20 (m, 3 H), 2.01 - 2.07 (m, 3 H), 1.78 - 1.85 (m, 2 H), 1.43 - 1.63 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 475.2 (M+ + H).

(R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrazine- 2-yl)phenyl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.51 (s, 1 H), 8.28 (s, 1 H), 7.71 - 7.74 (m, 2 H),

988 7.53 (t, 1 H, J = 7.5 Hz), 4.39 - 4.41 (m, 1 H), 4.22 (d, 2 H, J = 6.2 Hz), 3.75 - 3.85 (m, 2 H), 3.43 - 3.46 (m, 2 H), 3.00 - 2.98 (m, 2 H), 2.48 (s, 1 H), 2.43 (s, 1 H), 2.14 - 2.24 (m, 3 H), 1.67 - 1.92 (m, 7 H), 1.40 (s, 3 H), 1.34 (s, 3 H), 1.21 - 1.31 (m, 2 H); MS (ESI) m z 489.2 (M+ + H).

Example 68. Compound 989: (S)-l-(4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoyl)pyrrolidine-2-carboxamide

Step 1. t-butyl 4-((6-chloropyridazine-3-yloxy)methyl)piperidin-l-carboxylat e: t-butyl 4- (hydroxymethyl)piperidin-l-carboxylate (the product of synthesis step 1 of compound 431; 3.00 g, 13.94 mmol) and NaH (0.50 g, 20.90 mmol) were dissolved in DMF (100 mL). At 0 °C, 3,6-dichloropyridazine (2.49 g, 16.72 mmol) was added thereto, following with stirring at room temperature for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 0 % to 50 %), and concentrated to yield the title compound as white solid (2.60 g, 56%). Step 2. 3-chloro-6-(piperidin-4-ylmethoxy)pyridazine hydrochloride: t-butyl 4-((6- chloropyridazine-3-yloxy)methyl)piperidin-l-carboxylate (2.60 g, 7.93 mmol) and 4.0 M solution in 1,4-dioxane (9.91 mL, 39.66 mmol) were dissolved in MeOH (30 mL) at room temperature. The solution was stirred at the same temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (1.80 g, 85%).

Step 3. l-(4-((6-chloropyridazine-3-yloxy)methyl)piperidin-l-yl)-2-m ethylpropan-2-ol:

To 3-chloro-6-(piperidin-4-ylmethoxy)pyridazine hydrochloride (0.60 g, 2.27 mmol), 2,2- dimethyloxirane (1.64 g, 22.71 mmol) and K ₂ C0 ₃ (0.63 g, 4.54 mmol), EtOH (4 mL) / H ₂ 0 (4 mL) was added. With a microwave radiation, the mixture was heated at 1 10 °C for 20 minutes, and then cooled to room temperature, following with concentrating under reduced pressure. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.44 g, 64%).

Step 4. 3-chloro-6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)pyridazine:

l-(4-((6-chloropyridazine-3-yloxy)methyl)piperidin-l-yl)- 2-methylpropan-2-ol (0.55 g, 1.84 mmol) was dissolved in CH ₂ C1 ₂ (8 mL). At 0 °C, DAST (0.26 mL, 2.02 mmol) was added thereto, following with stirring at room temperature for 5 hours. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.40 g, 72%, yellow oil).

Step 5. methyl 4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridazine- 3- yl)benzoate: To 3-chloro-6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)pyridazine (0.20 g, 0.66 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.13 g, 0.73 mmol), Pd(dppf)Cl ₂ (0.05 g, 0.07 mmol) and Na ₂ C0 ₃ (0.14 g, 1.33 mmol), DME (12 mL) / water (3 mL) was added. With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.17 g, 63%).

Step 6. 4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyr idazine-3-yl)benzoic acid: Methyl 4-(6-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridazine- 3 - yl)benzoate (0.17 g, 0.42 mmol) and LiOH H ₂ 0 (0.04 g, 0.85 mmol) were added in THF/MeOH (6/3 mL) / water (2 mL). The mixture was refluxed with heating for 8 hours, and then cooled to room temperature, following with concentrating under reduced pressure. The concentrate was added with water (2 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as yellow solid (0.12 g, 73%).

Step 7. Compound 989: 4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoic acid (0.03 g, 0.08 mmol), EDC (0.03 g, 0.16 mmol), HOBt (0.02 g, 0.16 mmol) and DIPEA (0.04 mL, 0.23 mmol) were dissolved in DMF (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.01 g, 0.12 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under r educed pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 5 %), and concentrated to yield the title compound as colorless oil (2 mg, 5%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.07 (d, 2 H, J = 8.3 Hz), 7.82 (d, 1 H, J = 9.2 Hz), 7.67 (d, 2 H, J - 8.3 Hz), 7.09 (d, 2 H, J = 8.3 Hz), 6.97 (s, 1 H), 5.52 (s, 1 H), 4.82 (m, 1 H), 4.48 (d, 2 H, J = 6.3 Hz), 3.60 (m, 3 H), 3.07 (m, 1 H), 2.44 (m, 4 H), 1.62 (m, 4 H), 1.45 (m, 9 H). According to the above-described synthesis process of compound 989, the compounds of Table 54 were synthesized using 4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoic acid and the reactant of Table 53.

Table 53. Table 54.

Example 69. Compound 991: (S)-l-(2-fluoro-4-(6-((l-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)pyridazine-3-yl)benzoyl) pyrrolidine-2-carboxamide

Step I. ethyl 2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridazine- 3- yl)benzoate: 3-chloro-6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridazine (the product of synthesis step 4 of compound 989; 0.20 g, 0.66 mmol), 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (0.16 g, 0.73 mmol), Pd(dppf Cl ₂ (0.05 g, 0.06 mmol) and Na ₂ C0 ₃ (0.14 g, 1.33 mmol) were dissolved in DME (12 mL) / water (3 raL) at 120 °C, following with stirring at the same temperature for 20 minutes. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.17 g, 59%).

Step 2. 2-fluoro-4-(6-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)pyridazine- 3- yl)benzoic acid: Ethyl 2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoate (0.17 g, 0.39 mmol) and LiOH ¾0 (0.03 g, 0.78 mmol) were added to THF/MeOH (6/3 mL) / water (2 mL). The mixture was refluxed with heating for 8 hours, and then cooled to room temperature, following with concentrating under reduced pressure. The concentrate was added with water (2 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as yellow solid (0.13 g, 81%).

Step 3. Compound 991 : 2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoic acid (0.03 g, 0.07 mmol), EDC (0.03 g, 0.15 mmol), HOBt (0.02 g, 0.15 mmol) and DIPEA (0.03 g, 0.22 mmol) were dissolved in DMF (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.01 g, 0.11 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 5 %), and concentrated to yield the title compound as colorless oil (2 mg, 5 %). According to the above-described synthesis process of compound 991, the compounds of Table 56 were synthesized using 2-fluoro-4-(6-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyridazine-3-yl)benzoic acid and the reactant of Table 55.

Table 55,

Table 56.

Example 70. Compound 1032 : (S)-l-(2-fluoro-4-(5-((l-(2-fluoro-2- methyIpropyl)piperidin-4-yl)methoxy)pyrinudin-2-yl)benzoyl)p yrrolidine-2-carboxamide

Step 1. t-butyl 4-((2-chloropyrimidin-5-yloxy)methyl)piperidin- 1 -carboxylate: t-butyl 4- ((methylsulfonyloxy)methyl)piperidin-l-carboxylate (the product of synthesis step 2 of compound 431 ; 2.00 g, 6.82 mmol) was dissolved in DMF (80 mL). K ₂ C0 ₃ (3.33 g, 10.23 mmol) was added thereto, and stirred for 5 minutes. 2-chloropyrimidin-5-ol (890 mg, 6.82 mmol) was added thereto, following with stirring at 80 °C for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ CI aqueous solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography

(EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (2.10 g, 94%).

Step 2. 2-chloro-5-(piperidin-4-ylmethoxy)pyrimidine hydrochloride: t-butyl 4-((2- chloropyrimidin-5-yloxy)methyl)piperidin-l -carboxylate (2.10 g, 6.41 mmol) was dissolved in CH ₂ C1 ₂ (50 mL). 4 M HC1 in 1,4-dioxane (32.03 mL, 128.12 mmol) was added thereto, following with stirring for 1 hour. The resulting precipitate was filtered to yield the title compound as white solid (1.50 g, 88%).

Step 3. l-(4-((2-chloropyrimidin-5-yloxy)methyl)piperidin-l-yl)-2-me thylpropan-2-ol:

2-chloro-5-(piperidin-4-ylmethoxy)pyrimidine hydrochloride (1.50 g, 5.68 mmol), 2,2- dimethyloxirane (5.06 mL, 56.79 mmol) and ₂ C0 ₃ (392 mg, 2.84 mmol) were dissolved in EtOH (5 mL) and H ₂ 0 (5 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgSC , and concentrated under reduced pressure. The obtained material, which is the title compound as white solid (1.70 g, 99%), was used without further purification.

Step 4. 2-chloro-5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)pyrimidine:

l-(4-((2-chloropyrimidin-5-yloxy)methyl)piperidin-l-yl)-2 -methylpropan-2-ol (1.70 g, 5.67 mmol) was dissolved in CH ₂ C1 ₂ (15 mL). At 0 °C, DAST (749 μΐ,, 5.67 mmol) was added slowly thereto. After stirring for 1 hour at room temperature, The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained material, which is the title compound as white solid (1.20 g, 70%), was used without further purification.

Step 5. ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)me thoxy)pyrimidin-2- yl)benzoate: 2-chloro-5-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)metho xy)pyrimidine (600 mg, 1.99 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (421 mg, 1.99 mmol), Pd(dppf)Cl ₂ (81 mg, 0.10 mmol) and Cs ₂ C0 ₃ (1.30 g, 3.98 mmol) were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column

chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (480 mg, 55%).

Step 6. 2-fluoro-4-( 5-( ( 1 -(2-fluoro-2-methvlpropyl)piperidin-4-yl)methoxy)pyrimidin-2 - yl)benzoic acid: Ethyl 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoate (480 mg, 1.1 1 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH-H ₂ 0 (232 mg, 5.54 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered to yield the title compound as white solid (360 mg, 80%).

Step 7. Compound 1032: 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoic acid (40 mg, 0.10 mmol), (S)-pyrrolidine-2-carboxamide (23 mg, 0.20 mmol), EDC (38 mg, 0.20 mmol) and HOBt (27 mg, 0.20 mmol) was added thereto., DIPEA (35 μί,, 0.20 mmol) was dissolved in CH ₂ C1 ₂ (1 mL), following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column

chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (21 mg, 42%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.46 (s, 2 H), 8.23 (d, 1 H, J = 6.6 Hz), 8.16 (d, 1 H, J - 10.2 Hz), 7.51 (t, 1 H, J = 7.4 Hz), 6.94 (brs, 1 H), 5.56 (brs, 1 H), 4.84 - 4.81 (m, 1 H), 3.96 (d, 2 H, J = 5.9 Hz), 3.55 - 3.49 (m, 1 H), 3.43 - 3.37 (m, 1 H), 3.03 (brs, 2 H), 2.51 - 2.45 (m, 2 H), 2.19 (brs, 2 H), 2.16 - 2.01 (m, 3 H), 1.96 - 1.81 (m, 4 H), 1.70 - 1.36 (m, 8 H); MS (ESI) m/z 502 (M+ + H). According to the above-described synthesis process of compound 1032, the compounds of Table 58 were synthesized using 2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)benzoic acid and the reactant of Table 57.

Table 57.

Table 58.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4-

1033 yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.46 (s, 2 H), 8.20 (d, 1 H, J = 8.0 Hz), 8.10 (d, 1 H, J = 10.8 Hz), 7.48 (t, 1 H, J = 7.4 Hz), 4.12 - 4.09 (m, 1 H), 3.96 (d, 2 H, J = 5.9 Hz), 3.58 - 3.54 (m, 1 H), 3.37 - 3.33 (m, 1 H), 3.25 - 3.20 (m, 1 H), 3.13 - 3.03 (m, 2 H), 2.56 - 2.45 (m, 2 H), 2.27 - 2.16 (m, 2 H), 2.05 - 1.81 (m, 6 H),

I.69 - 1.62 (m, 3 H), 1.47 (s, 3 H), 1.42 (s, 3 H), 1.37 - 1.28 (m, 2 H); MS (ESI) m/z 489 (M+ + H).

(S)-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.46 (s, 2 H), 8.20 (d, 1 H, J = 8.0 Hz), 8.10 (d, 1

1034 H, J = 10.8 Hz), 7.48 (t, 1 H, J = 7.4 Hz), 4.12 - 4.09 (m, 1 H), 3.96 (d, 2 H, J =

5.9 Hz), 3.58 - 3.54 (m, 1 H), 3.37 - 3.33 (m, 1 H), 3.25 - 3.20 (m, 1 H), 3.13 - 3.03 (m, 2 H), 2.56 - 2.45 (m, 2 H), 2.27 - 2.16 (m, 2 H), 2.05 - 1.81 (m, 6 H),

I.69 - 1.62 (m, 3 H), 1.47 (s, 3 H), 1.42 (s, 3 H), 1.37 - 1.28 (m, 2 H); MS (ESI) m/z 489 (M+ + H).

(R)-(2-fluoro-4-(5-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)phenyl)(3 -hydroxypyrrolidine- 1 -yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 8.46 (s, 2 H), 8.21 - 8.18 (m, 1 H), 8.13 - 8.08 (m,

1035 1 H), 7.55 - 7.49 (m, 1 H), 4.61 (brs, 0.5 H), 4.48 (brs, 0.5 H), 3.96 (d, 2 H, J = 5.8

Hz), 3.85 - 3.71 (m, 2 H), 3.65 - 3.55 (m, 1 H), 3.46 - 3.42 (m, 0.5 H), 3.34 - 3.31 (m, 0.5 H), 3.04 (brs, 2 H), 2.49 (brs, 2 H), 2.20 - 2.00 (m, 6 H), 1.99 - 1.85 (m, 3 H), 1.42 (s, 3 H), 1.37 (s, 3 H); MS (ESI) m/z 475 (M+ + H).

(R)-l-(2-fluoro-4-(5-((l-(2-fluoro-2-methylpropyl)piperidin- 4- yl)methoxy)pyrimidin-2-yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.52 - 8.42 (m, 2 H), 8.25 (d, 1 H, J = 8.0 Hz), 8.13 (d, 1 H, J - 11.1 Hz), 7.52 (t, 1 H, J = 7.5 Hz), 6.32 (brs, 1 H), 5.65 (brs, 1

1037

H), 5.46 (brs, 1 H), 3.96 (d, 2 H, J = 6.0 Hz), 3.58 (d, 1 H, J = 13.0 Hz), 3.22 - 3.21 (m, 1 H), 3.01 - 2.96 (m, 2 H), 2.49 - 2.44 (m, 3 H), 2.19 - 2.17 (m, 2 H), 1.83 - 1.74 (m, 5 H), 1.63 - 1.60 (m, 3 H), 1.46 (brs, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 516 (M+ + H).

Example 71. Compound 631 : N,N-dimethyl-4'-((l-((l-(trifluoromethyl)cyclobutyl) methyl)piperidin-4-yl)methoxy)biphenyl-4-carboxamide Step 1. t-butyl 4-((4'-hydroxybiphenyl-4-yloxy)methyl)piperidin-l-carboxylat e:

t-butyl 4-((4-bromophenoxy)methyl)piperidin-l-carboxylate (the product of synthesis step 3 of compound 431; 3.45 g, 9.32 mmol) and 4-hydroxyphenylboronic acid(1.41 g, 10.25 mmol) were dissolved in dioxane 12 mL. Water 3 mL was added thereto. Pd(dbpf)Cl ₂ (607 mg, 0.93 mmol) and CS2CO3 (6.07 g, 18.64 mmol) were added thereto, and refluxed with heating for a day. The reaction mixture was filtered through Celite, and the obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution and water, dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/CH ₂ Cl ₂ ), and then recrystallized with CH ₂ C1 ₂ and hexane to yield the title compound as white solid (2.50 g, 70%).

Step 2. 4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride: t-butyl 4-((4'- hydroxybiphenyl-4-yloxy)methyl)piperidin-l-carboxylate (2.50 g, 6.51 mmol) was dissolved in CH ₂ C1 ₂ 6 mL. 4 M HC1 1.79 mL was added thereto, following with stirring for 1 hour at room temperature. The obtained reaction mixture was filtered to yield the title compound as white solid (2.00 g, 96%).

Step 3. '-((l -(1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy )biphenyl-4-yl 1 -(trifluoromethyl)cyclobutanecarboxylate: 4 ' -(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride (1.50 g, 4.69 mmol), l-(trifluoromethyl)cyclobutanecarboxylic acid (946 mg, 5.63 mmol) and PyBOP (3.66 g, 7.04 mmol) were dissolved in DMF 4 mL. DIPEA (3.63 g, 28.14 mmol) was added thereto. At 50 °C, the reaction was performed for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgSC>4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (1.16 g, 42%).

Step_4. 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)b iphenyl-4-ol : 4'-((l-(l-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-y l)methoxy)biphenyl-4-yl 1- (trifluoromethyl)cyclobutanecarboxylate (1.16 g, 2.67 mmol) was dissolved in dry THF 15 mL, and then cooled with ice bath. LAH (1 M in THF, 8.03 mL, 8.03 mmol) was added dropwise slowly thereto, following with increasing the temperature to 50 °C and stirring for a day. Water was poured into the reaction mixture. The formed solid was removed by filtration, and the filtrate was extracted with EtOAc three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/Hexane) to yield the title compound as white solid (640 mg, 57%).

Step 5. 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)b iphenyl-4-yl trifluoromethanesulfonate: 4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-ol (640 mg, 1.53 mmol) was dissolved in CH ₂ C1 ₂ 6 mL. At 0 °C, pyridine (181 mg, 2.29 mmol) and trifluoromethanesulfonic anhydride (560 mg, 1.98 mmol) were added thereto, The reaction was performed at room temperature for 3 hours. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgSC>4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/Hexane) to yield the title compound as white solid (590 mg, 70%).

Step 6. methyl 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)b iphenyl- 4-carboxylate: 4'-((l -((1 -(trifluoromemyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl trifluoromethanesulfonate (200 mg, 0.36 mmol), Pd(OAc) ₂ (4 mg, 0.02 mmol) and dppp (9 mg, 0.02) were dissolved in DMSO 3 mL. MeOH 3 mL was added thereto, following with sufficient CO gas flowing. Lastly, TEA (184 mg, 1.81 mmol) was added thereto, following with stirring at 120 °C for 4 hours. The reaction mixture was filtered through Celite. The filtrate was added with water, and extracted with EtOAc. The obtained organic layer was concentrated under reduced pressure, and purified by silica gel column

chromatography (EtOAc/CH ₂ Cl ₂ ) to yield the title compound as pink solid (105 mg, 62%).

Step 7. 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)b iphenyl-4- carboxylic acid: Methyl 4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (105 mg, 0.23 mmol) was dissolved in THF 2 mL. MeOH 1 mL and H ₂ 0 0.5 mL were poured therein. LiOH (19 mg, 0.46 mmol) was added thereto, and refluxed with heating and stirring for 5 hours. After acidification with 1 N HC1, the resulting precipitate was filtered to yield the title compound as white solid (98 mg, 96%).

Step 8. Compound 631 : 4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), dimethylamine hydrochloride (11 mg, 0.13 mmol) and PyBOP (52 mg, 0.10 mmol) were dissolved in DMF 0.5 mL. DIPEA (43 mg, 0.34 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography

(Me0H/CH ₂ Cl ₂ ) to yield the title compound as white solid ( 16 mg, 50%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 (m, 6 H), 6.98 (d, 2 H, J - 6.8 Hz), 3.85 (d, 2 H, J = 6.0

Hz), 3.14 (s, 3 H), 3.05 (s, 3 H), 2.85 (m, 2 H), 2.53 (s, 2 H), 2.19 (m, 4 H), 2.01 (m, 3 H), 1.96 (m, 1 H), 1.83 (m, 3 H), 1.46 (m, 2 H); MS (ESI) m/z 475 (M+ + H).

Example 72. Compound 633: (R)-(2-(hydroxymethyl)pyrrolidine-l-yl)(4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyI-4-yI)methanone

4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl )methoxy)biphenyl-4-carboxylic acid (30 mg, 0.07 mmol), (R)-prolinol (14 mg, 0.13 mmol) and PyBOP (52 mg, 0.10 mmol) were dissolved in DMF 0.5 mL following with stirring for 10 minutes at room temperature. DIPEA (43 mg, 0.34 mmol) was added thereto, following with stirring at room temperature for 8 hours. Water was poured into the reaction mixture. The formed solid was filtered, and dried to yield the title compound as white solid (17 mg, 47%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (m, 6 H), 6.99 (d, 2 H, J = 8.7 Hz), 5.01 (d, 1 H, J = 8.7 Hz), 4.46 (m, 1 H), 3.77 (m, 4 H), 3.53 (m, 2 H), 2.90 (m, 2 H), 2.54 (s, 2 H), 2.22 (m, 5 H), 2.11 (m, 3 H), 1.92 (m, 6 H), 1.64 (m, 2 H), 1.48 (m, 2 H); MS (ESI) m/z 531 (M+ + H). According to the above-described synthesis process of compound 631 (Step 8), the compounds of Table 60 were synthesized using 4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 59.

Table 59.

Table 60.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)-(3-hydroxypyrrolidine-l -yl)(4'-((l -((1 -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )biphenyl-4- yl)methanone

632 1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (m, 6 H), 6.97 (d, 2 H, J = 8.8 Hz), 4.59 (m, 1 H), 3.79 (m, 4 H), 3.63 (m, 1 H), 3.55 (m, 1 H), 3.14 (m, 1 H), 2.90 (m, 2 H), 2.68 (s, 1 H), 2.54 (s, 2 H), 2.23 (m, 4 H), 2.04 (m, 4 H), 1.87 (m, 4 H), 1.31 (m, 2 H); MS (ESI) m/z 517 (M+ + H).

(3 -hydroxypiperidin- 1 -yl)(4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-

634

4-yl)methoxy)biphenyl-4-yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (m, 6 H), 6.98 (d, 2 H, J = 6.9 Hz), 3.85 (m, 5 H), 3.46 (m, 3 H), 2.89 (m, 2 H), 2.54 (s, 2 H), 2.22 (m, 4 H), 1.96 (m, 10 H), 1.46 (m, 3 H); MS (ESI) m/z 531 (M+ + H).

(S)- 1 -(4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

635 1H NMR (400 MHz, CDC1 ₃ ) δ 7.54 (m, 5 H), 6.98 (d, 2 H, J = 8.7 Hz), 5.64 (s, 1

H), 4.82 (m, 1 H), 3.85 (d, 2 H, J = 8.7 Hz), 2.89 (m, 2 H), 2.49 (s, 2 H), 2.43 (m, 1

H), 2.15 (m, 4 H), 2.11 (m, 5 H), 1.93 (m, 4 H), 1.41 (m, 2 H); MS (ESI) m/z 544

(M+ + H).

N-(2-hydroxyethyl)-4'-((l-((l-(trifluoromethyl)cyclobutyl)me thyl)piperidin-4- yl)methoxy)biphenyl-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.84 (d, 2 H, J = 8.4 Hz), 7.62 (d, 2 H, J = 8.4 Hz),

636

7.55 (d, 2 H, J = 8.8 Hz), 6.98 (d, 2 H, J = 8.7 Hz), 6.67 (t, 1 H, J = 5.3 Hz), 3.86 (m, 4 H), 3.66 (m, 2 H), 2.90 (m, 2 H), 2.73 (s, 1 H), 2.66 (s, 2 H), 2.24 (m, 4 H), 2.06 (m, 3 H), 1.88 (m, 4 H), 1.45 (m, 2 H); MS (ESI) m/z 491 (M+ + H).

N-(2-hydroxyethyl)-N-methyl-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxamide

637 1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (m, 6 H), 6.98 (d, 2 H, J = 8.7 Hz), 3.57 (m, 7 H), 3.12 (s, 3 H), 2.90 (m, 2 H), 2.54 (s, 4 H), 2.19 (m, 4 H), 2.04 (m, 3 H), 1.93 (m, 1 H), 1.83 (m, 3 H), 1.40 (m, 2 H); MS (ESI) m z 505 (M+ + H).

(R)-(3-hydroxypiperidin- 1 -yl)(4'-((l -((1-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )biphenyl-4- yl)methanone

794

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (m, 6 H), 6.98 (d, 2 H, J = 8.7 Hz), 3.85 (m, 4 H), 3.45 (m, 3 H), 2.90 (m, 2 H), 2.54 (m, 2 H), 2.21 (m, 4 H), 1.96 (m, 11 H), 1.46 (m, 3 H); MS (ESI) m/z 531 (M+ + H).

(S)-(3 -hydroxypiperidin- 1 -yl)(4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.1 Hz), 7.52 (d, 2 H, J = 8.6 Hz),

795

7.47 (d, 2 H, J = 8.0 Hz), 6.98 (d, ^' 2 H, J = 8.6 Hz), 3.86 (m, 4 H), 3.44 (m, 3 H), 2.90 (m, 2 H), 2.55 (s, 2 H), 2.23 (m, 4 H), 1.98 (m, 11 H), 1.44 (m, 3 H); MS (ESI) m/z 531 (M+ + H).

(R)-(3-hydroxypyrrolidine-l -yl)(4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)

796 piperidin-4-yl)methoxy)biphenyl-4-yl)methanone

MS (ESI) m/z 517 (M+ + H).

(S)-(2-(hydroxymethyl)pyrrolidine-l -yl)(4'-((l -((1 -(trifluoromethyl)cyclobutyl) methyl)piperidin-4-yl)methoxy)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 (m, 6 H), 6.97 (d, 2 H, J = 8.6 Hz), 4.57 (s, 0.5

797

H), 4.44 (s, 0.5 H), 3.79 (m, 4 H), 3.63 (m, 1 H), 3.54 (m, 1 H), 2.83 (m, 3 H), 2.54 (s, 2 H), 2.23 (m, 4 H), 1.92 (m, 10 H), 1.80 (m, 2 H); MS (ESI) m/z 531 (M+ + H).

I -(4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) biphenylcarbonyl)piperidin-4-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.2 Hz), 7.52 (d, 2 H, J = 8.7 Hz),

798

7.44 (d, 2 H, J = 8.1 Hz), 6.97 (d, 2 H, J = 8.7 Hz), 5.70 (m, 2 H), 4.69 (s, 1 H), 3.90 (m, 3 H), 2.71 (m, 4 H), 2.55 (s, 2 H), 2.42 (m, 1 H), 2.23 (m, 4 H), 1.96 (m,

I I H), 1.46 (m, 2 H); MS (ESI) m/z 558 (M+ + H). Example 73. Compound 917: (R)-(2-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrro Iidine-l-yl)methanone

Step 1. methyl 2-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromophenoxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclObutyl)methyl)piperidine (the product of synthesis step 2 of compound 842; 0.78 g, 1.92 mmol), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.45 g, 2.30 mmol), Pd(dppf)Cl ₂ (0.07 g, 0.09 mmol) and Cs ₂ C0 ₃ (1.25 g, 3.84 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 100 %), and concentrated to yield the title compound as white solid (0.54 g, 59%).

Step 2. 2-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) biphenyl-4-carboxylic acid: Methyl 2-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylate (0.54 g, 1.13 mmol) and LiOH H ₂ 0 (0.23 g, 5.68 mmol) were dissolved in THF / MeOH (16 mL) / H ₂ 0 (4mL) at room temperature. The solution was stirred at the same temperature for 1 hour. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.50 g, 94%).

Step 3. Compound 917: 2-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-carboxylic acid (0.07 g, 0.15 mmol), (R)-pyrrolidine-2-ylmethanol (0.01 g, 0.18 mmol), HOBt (0.04 g, 0.30 mmol), EDC (0.05 g, 0.30 mmol) and DIPEA (0.05 mL, 0.30 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , dichloromethane / methanol = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.05 g, 69%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.45 - 7.51 (m, 3 H), 7.31 - 7.37 (m, 2 H), 6.99 (d, 2 H, J = 8.6 Hz), 4.75 (s, 1 H), 4.40 - 4.45 (m, 1 H), 3.74 - 3.87 (m, 4 H), 3.51 - 3.65 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.20 - 2.28 (m, 5 H), 1.87 - 2.11 (m, 6 H), 1.72 - 183 (m, 4 H), 1.43 - 1.49 (m, 2 H); MS (ESI) m/z 549.2 (M+ + H).

According to the above-described synthesis process of compound 917, the compounds of Table 62 were synthesized using 2-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 61.

Table 61.

Table 62.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(S)- 1 -(2-fluoro-4' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.46 - 7.51 (m, 3 H), 7.33 - 7.39 (m, 2 H), 6.98 -

918 7.00 (m, 2 H), 6.92 (s, 1 H), 5.48 (s, 1 H), 4.81 (dd, 1 H, J = 7.4, 5.2 Hz), 3.86 (d, 2

H, J = 6.0 Hz), 3.56 - 3.69 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.46 - 2.52 (m, 1 H), 2.20 - 2.28 (m, 4 H), 1.91 - 2.16 (m, 5 H), 1.80 - 1.90 (m, 5 H),

I .40 - 1.49 (m, 2 H); MS (ESI) m/z 562.3 (M+ + H).

(R)-(2-fiuoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 5 7.43 - 7.50 (m, 3 H), 7.22 - 7.27 (m, 2 H), 6.97 -

919 7.01 (m, 2 H), 3.85 - 3.95 (m, 3 H), 3.37 - 3.62 (m, 3 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.20 - 2.28 (m, 4 H), 2.00 - 2.11 (m, 2 H), 1.90 - 1.99 (m, 4 H), 1.80 - 1.89 (m, 3 H), 1.57 - 1.78 (m, 4 H), 1.39 - 1.50 (m, 2 H); MS (ESI) m/z 549.3 (M+ + H).

(S)-(2-fluoro-4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 - 7.50 (m, 3 H), 7.22 - 7.27 (m, 2 H), 6.97 -

920 7.00 (m, 2 H), 3.79 - 3.95 (m, 3 H), 3.34 - 3.67 (m, 3 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.20 - 2.28 (m, 4 H), 2.00 - 2.15 (m, 2 H), 1.82 - 1.99 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.50 - 1.64 (m, 3 H), 1.40 - 1.49 (m, 2 H); MS (ESI) m/z 549.3 (M+ + H).

(S)-(2-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidine- 1 -yl)methanone

921 1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 - 7.53 (m, 3 H), 7.31 - 7.41 (m, 2 H), 6.97 - 7.01 (m, 2 H), 4.51 - 4.63 (m, 1 H), 3.77 - 3.87 (m, 4 H), 3.50 - 3.71 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.22 - 2.28 (m, 4 H), 2.11 - 2.21 (m, 6 H), 1.66 - 1.89 (m, 4 H), 1.40 - 1.49 (m, 2 H); MS (ESI) m/z 535.2 (M+ + H).

Example 74. Compound 842: (S)-(3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-y l)methanone

Step 1. (4-((4-bromophenoxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl)cyclobutyl)methanone: 4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 1 of compound 498; 2.00 g, 6.52 mmol) was dissolved in CH ₂ C1 ₂ (40 mL). EDC (2.50 g, 13.05 mmol), HOBt (1.76 g, 13.05 mmol), DIPEA (2.31 mL, 13.05 mmol), 1 -(trifluoromethyl) cyclobutanecarboxylic acid (1.09 g, 6.52 mmol) was added thereto, following with stirring at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic laysr was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1 / 4) to yield the title compound as white solid (2.10 g, 76%).

Step 2. 4-((4-bromophenoxy)methyl)- 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidine: (4-((4-bromophenoxy)methyl)piperidin-l -yl)(l -(trifluoromethyl)cyclobutyl)methanone (812 mg, 1.93 mmol) was dissolved in THF (10 mL). 2.0 M Borane dimethyl sulfide complex solution in THF (4.83 mL, 9.66 mmol) was added thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1 / 8) to yield the title compound as yellow solid (480 mg, 61%).

Step 3. methyl 3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piper idin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromophenoxy)methyl)-l-((l -(trifluoromethyl) cyclobutyl)methyl)piperidine (480 mg, 1.18 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (300 mg, 1.42 mmol), Pd(dppf)Cl ₂ (97 mg, 1.42 mmol) and Cs ₂ C0 ₃ (770 mg, 2.36 mmol), DME (6 mL)/ H ₂ 0 (2 mL) was added, and refluxed with heating for a day. After the completion of the reaction, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1 / 7) to yield the title compound as white solid (250 mg, 42%).

Step 4. 3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piper idin-4- yl)methoxy)biphenyl-4-carboxylic acid: Methyl 3-fluoro-4'-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-carboxylate (250 mg, 0.51 mmol) was dissolved in THF (10 mL) and H ₂ 0 (5 mL). At room temperature, LiOH H ₂ 0 (106 mg, 2.53 mmol) was added thereto, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was acidified with 1 N HC1. The resulting precipitate was filtered, and dried to yield the title compound as white solid (201 mg, 85%). Step 5. Compound 842 : 3 -fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-carboxylic acid (40 mg, 0.09 mmol), EDC (33 mg, 0.17 mmol) and HOBt (23 mg, 0.17 mmol) was added thereto, DIPEA (30 iL, 0.17 mmol) were dissolved in (S)-piperidin-3-ol hydrochloride (24 mg, 0.17 mmol) was dissolved in CH ₂ C1 ₂ (1 mL), following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over^ anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5%) to yield the title compound as yellow solid (24 mg, 50%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (d, 2 H, J = 8.6 Hz), 7.45 - 7.38 (m, 2 H), 7.27 - 7.26 (m, 1 H), 6.98 (d, 2 H, J = 8.6 Hz), 4.1 1 - 3.94 (m, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.62 - 3.50 (m, 1 H), 3.40 - 3.27 (m, 1 H), 2.90 (d, 2 H, J = 10.9 Hz), 2.54 (s, 2 H), 2.28 - 2.20 (m, 4 H), 2.1 1 - 2.01 (m, 10 H), 1.99 - 1.63 (m, 3 H), 1.49 - 1.34 (m, 3 H); MS (ESI) m/z 549 (M+ + H).

According to the above-described synthesis process of compound 842, the compounds of Table 64 were synthesized using 3-fluoro-4'-((l -((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 63.

Table 63.

Table 64. Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)- 1 -(3-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.53 - 7.45 (m, 2 H), 7.43 - 7.40 (m, 2 H), 7.32 -

843 7.29 (m, 1 H), 7.00 - 6.95 (m, 2 H), 5.52 (brs, 1 H), 4.84 - 4.81 (m, 1 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.56 - 3.53 (m, 1 H), 3.47 - 3.42 (m, 1 H), 2.90 (d, 2 H, J = 11.2 Hz), 2.54 (s, 2 H), 2.50 - 2.46 (m, 1 H), 2.28 - 2.19 (m, 4 H), 2.14 - 2.11 (m, 4 H), 2.09 - 2.01 (m, 1 H), 1.99 - 1.91 (m, 2 H), 1.89 - 1.81 (m, 3 H), 1.68 (brs, 1 H), 1.46 - 1.43 (m, 2 H); MS (ESI) m/z 562 (M+ + H).

(R)-(3 -fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidine-l-yl) methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.53 - 7.46 (m, 3 H), 7.42 - 7.39 (m, 1 H), 7.31 -

7.27 (m, 1 H), 6.98 (d, 2 H, J = 8.7 Hz), 4.79 (d, 1 H, J = 6.1 Hz), 4.42 - 4.40 (m, 1

844

H), 3.86 (d, 2 H, J = 6.0 Hz), 3.84 - 3.81 (m, 1 H), 3.49 - 3.46 (m, 2 H), 2.90 (d, 2

H, J = 11.2 Hz), 2.54 (s, 2 H), 2.28 - 2.20 (m, 5 H), 2.18 - 1.99 (m, 3 H), 1.96 -

I .86 (m, 2 H), 1.83 - 1.80 (m, 4 H), 1.77 - 1.66 (m, 2 H), 1.50 - 1.43 (m, 2 H); MS (ESI) m/z 549 (M+ + H).

(S)-(3 -fluoro-4 ' -(( 1 -(( 1 -(trifiuoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 - 7.45 (m, 3 H), 7.40 - 7.37 (m, 1 H), 7.30 -

845 7.25 (m, 1 H), 6.98 (d, 2 H, J = 8.1 Hz), 4.62 - 4.49 (m, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.79 - 3.61 (m, 1 H), 3.59 - 3.35 (m, 1 H), 2.91 (d, 2 H, J = 11.2 Hz), 2.55 (s, 2 H), 2.28 - 2.22 (m, 4 H), 2.19 - 2.01 (m, 5 H), 1.99 - 1.90 (m, 2 H), 1.89 - 1.81 (m, 4 H), 1.49 - 1.43 (m, 2 H); MS (ESI) m/z 535 (M+ + H).

(R)-(3-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (d, 2 H, J = 8.6 Hz), 7.45 - 7.38 (m, 2 H), 7.27

846 - 7.26 (m, 1 H), 6.98 (d, 2 H, J = 8.6 Hz), 4.11 - 3.94 (m, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.62 - 3.50 (m, 1 H), 3.40 - 3.27 (m, 1 H), 2.90 (d, 2 H, J = 10.9 Hz), 2.54 (s, 2 H), 2.28 - 2.20 (m, 4 H), 2.11 - 2.01 (m, 10 H), 1.99 - 1.63 (m, 3 H), 1.49 - 1.34 (m, 3 H); MS (ESI) m/z 549 (M+ + H).

Example 75. Compound 833: (S)-l-(2'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl) methyl)piperidi -4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. t-butyl 4-((2-fluoro-4'-hydroxybiphenyl-4-yloxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((4-bromo-3 -fluorophenoxy)methyl)piperidin- 1 -carboxylate (the product of synthesis step 1 of compound 704; 3.7 g, 9.53 mmol), 4-hydroxyphenylboronic acid (1.31 g, 9.53 mmol),

Pd(dppf)Cl ₂ (778 mg, 0.95 mmol), Na ₂ C0 ₃ (2.02 g, 19.06 mmol) were dissolved in DME 15 mL and water 5 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over gS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc Hexane) to yield the title compound as white solid (2.8 g, 73%).

Step 2. 2'-fluoro-4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride:

t-butyl 4-((2-fluoro-4'-hydroxybiphenyl-4-yloxy)methyl)piperidin-l-c arboxylate (2.8 g, 6.97 mmol) was dissolved in CH ₂ C1 ₂ 15 mL. 4 M HC1 2.09 mL was added thereto, following with stirring at room temperature for 2 hours. The reaction mixture was filtered, washed with EtOAc, and evaporated under reduced pressure to yield the title compound as white solid (2.3 g, 97%).

Step 3. 2 ' -fluoro-4 ' -(( 1 -( 1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4- yl)methoxy)biphenyl-4-yl l-(trifluoromethyl)cyclobutanecarboxylate:

2' -fluoro-4 '-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride (1.5 g, 4.44 mmol), 1- (trifluoromethyl)cyclobutanecarboxylic acid (1.12 g, 6.66 mmol) and BOP (3.93 g, 8.88 mmol) were dissolved in DMF 6 mL. After stirring for 10 minutes at room temperature, TEA (1.35 g, 13.32 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, EtOAc/hexane) to yield the title compound as white solid (580 mg, 29%).

Step 4. 2'-fluoro-4 ^, -((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin- 4- yl)methoxy)biphenyl-4-ol : 2 '-fluoro-4 ' -(( 1 -( 1 -(trifluoromethyl)cyclobutanecarbonyl) piperidin-4-yl)methoxy)biphenyl-4-yl l-(trifluoromethyl)cyclobutanecarboxylate (1.38 g, 2.23 mmol) was dissolved in dry THF 20 mL. At 0 °C, LAH (6.88 mmol) was added thereto, following with stirring at 60 °C for a day. After the completion of the reaction, the reaction mixture was added with a little of water, and then extracted with excess amount of EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 15 - 20 % EtOAc/hexane) to yield the title compound as white solid (980 mg, 97%).

Step 5. 2 '-fluoro-4 '-(( !-((!-( trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl trifluoromethanesulfonate: 2 '-fluoro-4 ' -(( 1 -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-ol (980 mg, 2.24 mmol) was dissolved in dry CH ₂ C1 ₂ 6 mL. Pyridine (266 mg, 3.36 mmol) was added thereto. And then, trifluoromethanesulfonic anhydride (266 mg, 3.36 mmol) was added thereto a t 0 °C, following with stirring at room temperature for 3 hours. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ twice. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column

chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (880 mg, 69%).

Step 6. methyl 2'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate: 2'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl) methyl)piperidin-4-yl)methoxy)biphenyl-4-yl trifluoromethanesulfonate (880 mg, 1.55 mmol), Pd(OAc) ₂ (17 mg, 0.08 mmol) and dppp (40 mg, 0.09 mmol) were dissolved in DMSO 6 mL. eOH 6 mL was added thereto, following with sufficient infusion of carbon monoxide (CO). And then, TEA (782 mg, 7.73 mmol) was added thereto, following with stirring at 120 °C for 6 hours. After filtering through Celite, the reaction mixture was diluted with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (470 mg, 63%).

Step 7. 2 ' -fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid: Methyl 2 '-fluoro-4 '-((1-((1 - (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-carboxylate (470 mg, 0.98 mmol) was dissolved in THF/MeOH/H ₂ 0 = 6/3/2 mL. LiOH H ₂ 0 (82 mg, 1.96 mmol) was added thereto, and refluxed with heating for 3 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, following with adjusting pH to below 6 using IN HC1. The resulting precipitate was filtered to yield the title compound as white solid (410 mg, 89%).

Step 8. Compound 833 : 2 ' -fluoro-4 '-((1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-carboxylic acid (40 mg, 0.09 mmol), (S)-pyrrolidine-2-carboxamide (15 mg, 0.13 mmol) and BOP (76 mg, 0.17 mmol) were dissolved in DMF 1 mL. After stirring for 10 minutes at room temperature, TEA (26 mg, 0.26 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (22 mg, 45%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.54 (m, 4 H), 7.35 (t, 1 H, J = 4.8 Hz), 6.99 (s, 1 H), 6.73 (m, 2 H), 5.50 (s, 1 H), 4.82 (t, 2 H, J = 2.1 Hz), 3.83 (d, 2 H, J = 5.9 Hz), 3.58 (m, 2 H), 2.90 (m, 2 H), 2.49 (m, 3 H), 2.30 (m, 4 H), 2.09 (m, 5 H), 1.89 (m, 5 H), 0.98 (m, 2 H)

According to the above-described synthesis process of compound 833, the compounds of Table 66 were synthesized using 2'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pipe ridin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 65.

Table 65.

Table 66.

- 6.68 (m, 2 H), 3.84 (d, 3 H, J = 5.8 Hz), 3.12 (t, 1 H, J = 13.1 Hz), 2.91 (d, 2 H, J = 10.0 Hz), 2.55 (s, 2 H), 2.35 (d, 1 H, J = 12.8 Hz), 2.30 - 1.35 (m, 19 H); MS (ESI) m/z 576 (M+ + H).

(S)- 1 -(2 ' -fluoro-4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.64 - 7.43 (m, 4 H), 7.35 (t, 1 H, J - 8.9 Hz), 6.83

878

- 6.67 (m, 2 H), 3.84 (d, 3 H, J = 6.0 Hz), 3.13 (t, 1 H, J = 12.7 Hz), 2.91 (d, 2 H, J = 9.5 Hz), 2.55 (s, 2 H), 2.35 (d, 1 H, J = 12.8 Hz), 2.30 - 1.37 (m, 19 H); MS (ESI) m/z 576 (M+ + H).

(R)- 1 -(2 '-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (d, 2 H, J = 6.8 Hz), 7.46 (d, 2 H, J = 8.3 Hz),

882

7.35 (t, 1 H, J = 8.8 Hz), 6.81 - 6.68 (m, 2 H), 3.84 (d, 3 H, J = 5.5 Hz), 3.62 - 3.52 (m, 1 H), 3.51 - 3.40 (m, 1 H), 2.89 (s, 2 H), 2.54 (s, 3 H), 2.32 - 1.36 (m, 20 H); MS (ESI) m/z 576 (M+ + H).

Example 76. Compound 908: (2,2'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl ) piperidin-4-yl)methoxy)biphenyI-4-yl)((R)-2-(hydroxymethyl)p yrrolidine-l-yl)methanone

Step 1. (4-((4-bromo-3-fluorophenoxy)methyl)piperidin-l -yl)(l -(trifluoromethyl)cyclobutyl) methanone: 4-((4-bromo-3 -fluorophenoxy)methyl)piperidine hydrochloride

(the product of synthesis step 2 of compound 704; 2.60 g, 8.00 mmol), DIPEA (2.77 mL, 16.01 mmol), HOBt (2.16 g, 16.01 mmol), EDC (3.07 g, 16.01 mmol) and 1- (trifluoromethyl)cyclobutanecarboxylic acid (1.61 g, 9.61 mmol) were dissolved in DMF (30 mL) at 60 °C, following with stirring at the same temperature for 18 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as yellow oil (2.83 g, 80%).

Step 2. 4-((4-bromo-3-fluorophenoxy)methyl)-l-((l-(trifluoromethyl)c yclobutyl)methyl) piperidine: (4-((4-bromo-3 -fluorophenoxy)methyl)piperidin- 1 -yl)( 1 - (trifluoromethyl)cyclobutyl)methanone (1.40 g, 3.33 mmol) was dissolved in THF (30 mL). At 0 °C, 2.0 M BH ₃ SMe ₂ in THF (8.3 mL, 16.66 mmol) was added thereto, following with stirring at 60 °C for 2 hours The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 5 % to 20 %), and concentrated to yield the title compound as white solid (1.84 g, 67%).

Step 3. methyl 2,2'-difluoro-4'-((4-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromo-3-fluorophenoxy)methyl)-l -((1 - (trifluoromethyl)cyclobutyl)methyl)piperidine (0.80 g, 1.89 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (0.44 g, 2.26 mmol), Pd(dppf)Cl ₂ (0.07 g, 0.09 mmol) and Cs ₂ C0 ₃ (1.23 g, 3.78 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (S1O ₂ , EtOAc / hexane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.39 g, 42%).

Step_4. 2,2 '-difluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid: Methyl 2,2 ' -difluoro-4 ' -((4-(( 1 -(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyl ate (0.39 g, 0.78 mmol) and Li0H H ₂ O (0.16 g, 3.92 mmol) were dissolved in THF/ MeOH (20 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at the same temperature for 1 hour. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.21 g, 55%).

Step 5. Compound 908: 2,2'-difluoro-4'-((l-((l-(trifiuoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.08 mmol), (R)-pyrrolidine-2- ylmethanol (0.01 g, 0.09 mmol), HOBt (0.02 g, 0.16 mmol), EDC (0.03 g, 0.16 mmol) and DIPEA (0.02 mL, 0.16 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g, methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.02 g, 57%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.43 (t, 1 H, J = 7.3 Hz), 7.27 - 7.37 (m, 3 H), 6.78 (dd, 1 H, J = 8.5, 2.5 Hz), 6.73 (dd, 1 H, J = 11.9, 2.4 Hz), 4.40 - 4.44 (m, 1 H), 3.74 - 3.84 (m, 4 H), 3.53 - 3.64 (m, 2 H), 2.89 -2.92 (m, 2 H), 2.54 (s, 2 H), 2.20 - 2.28 (m, 4 H), 1.65 - 2.11 (m, 10 H), 1.40 - 1.48 (m, 2 H), 1.25 - 1.26 (m, 2 H); MS (ESI) m/z 567.2 (M+ + H).

According to the above-described synthesis process of compound 908, the compounds of Table 68 were synthesized using 2,2'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 67.

Table 67.

Table 68.

Example 77. Compound 912: (R)-(2',3-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl) methyl)piperidin-4-yl)methoxy)biphenyl-4-yl)(2-(hydroxymethy l)pyrrolidine-l- yl)methanone

Step 1. ethyl 2',3-difluoro-4'-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromo-3-fluorophenoxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidine (the product of synthesis step 2 of compound 908; 0.80 g, 1.89 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (0.48 g, 2.26 mmol), Pd(dppf)Cl ₂ (0.07 g, 0.09 mmol) and Cs ₂ C0 ₃ (1.23 g, 3.78 mmol), DME (9 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.70 g, 75%).

Step 2. 2 ' ,3 -difluoro-4' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid: Ethyl 2 ',3 -difluoro-4 '-((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyl ate (0.70 g, 1.36 mmol) and LiOH H ₂ 0 (0.28 g, 6.84 mmol) were dissolved in THF/ MeOH (20 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at the same temperature for 1 hour. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.66 g, 99%).

Step 3. Compound 912: 2',3-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (0.07 g, 0.14 mmol), (R)-pyrrolidine-2- ylmethanol (0.01 g, 0.17 mmol), HOBt (0.03 g, 0.29 mmol), EDC (0.05 g, 0.29 mmol) and DIPEA (0.05 mL, 0.29 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title

compound as white solid (0.07 g, 90%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (t, 1 H, J = 7.5 Hz), 7.27 - 7.38 (m, 2 H), 6.78 (dd, 1 H, J =

8.6, 2.4 Hz), 6.72 (dd, 1 H, J = 12.7, 2.3 Hz), 4.78 - 4.79 (s, 1 H), 4.40 - 4.44 (m, 1 H), 3.75 3.84 (m, 4 H), 3.46 - 3.50 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.19 - 2.28 (m, 5 H), 2.01 - 2.11 (m, 3 H), 1.90 - 1.99 (m, 2 H), 1.82 - 1.89 (m, 4 H), 1.64 - 1.79 (m, 2 H), 1.42 - 1.48 (m, 2 H); MS (ESI) m/z 567.3 (M+ + H).

According to the above-described synthesis process of compound 912, the compounds of Table 70 were synthesized using 2',3-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 69.

Table 69.

Table 70.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(S)- 1 -(2 ' ,3 -difluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.38 - 7.50 (m, 1 H), 7.28 - 7.37 (m, 2 H), 6.96 (s, 1 H), 6.77 (dd, 1 H, J = 8.6, 2.3 Hz), 6.71 (dd, 1 H, J - -12.7, 2.3 Hz), 5.86 (s, 1 H),

913

4.80 (dd, 1 H, J = 8.0, 4.1 Hz), 3.95 - 4.12 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.41

- 3.58 (m, 1 H), 2.88 - 2.91 (m, 2 H), 2.54 (s, 2 H), 2.38 - 2.41 (m, 1 H), 2.21 - 2.27 (m, 5 H), 2.19 - 2.18 (m, 5 H), 1.78 -1.93 (m, 3 H), 1.41 - 1.48 (m, 2 H), 1.24

- 1.26 (m, 2 H); MS (ESI) m/z 580.3 (M+ + H).

(R)-(2 ' ,3 -difluoro-4' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 (t, 1 H, J = 7.4 Hz), 7.26 - 7.37 (m, 3 H), 6.78

914 (dd, 1 H, J = 8.6, 2.4 Hz), 6.72 (dd, 1 H, J - 12.7, 2.4 Hz), 3.95 - 4.12 (m, 1 H), 3.84 (d, 2 H, J = 6.0 Hz), 3.52 - 3.61 (m, 1 H), 3.11 - 3.37 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.19 - 2.28 (m, 4 H), 1.79 - 2.1 1 (m, 9 H), 1.42 - 1.48 (m, 2 H), 1.32 - 1.30 (m, 4 H); MS (ESI) m/z 567.3 (M+ + H).

(S)-(2 ' ,3 -difluoro-4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 (t, 1 H, J = 7.4 Hz), 7.26 - 7.37 (m, 3 H), 6.78

915 (dd, 1 H, J = 8.6, 2.4 Hz), 6.72 (dd, 1 H, J = 12.6, 2.3 Hz), 3.94 - 4.14 (m, 1 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.37 - 3.62 (m, 1 H), 3.14 - 3.29 (m, 2 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.19 - 2.28 (m, 4 H), 1.79 - 2.11 (m, 10 H), 1.40- 1.48 (m, 3 H), 1.26 - 1.28 (m, 2 H); MS (ESI) m/z 567.2 (M+ + H).

(S)-(2 ',3-difluoro-4 '-((1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

916

1H NMR (400 MHz, CDC1 ₃ ) δ 7.45 - 7.50 (m, 1 H), 7.25 - 7.36 (m, 3 H), 6.70- 6.79 (m, 2 H), 4.48 - 4.61 (m, 1 H), 3.78 - 3.84 (m, 3 H), 3.66 - 3.74 (m, 1 H), 3.57 - 3.61 (m, 1 H), 3.35 - 3.48 (m, 1 H), 2.89 - 2.92 (m, 2 H), 2.54 (s, 2 H), 2.22 - 2.30 (m, 5 H), 2.01 - 2.19 (m, 5 H), 1.86 - 1.99 (m, 1 H), 1.79 - 1.82 (m, 3 H), 1.39 - 1.48 (m, 2 H); MS (ESI) m/z 553.3 (M+ + H).

Example 78. Compound 883: (S)-(3'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl) methyl)piperidin- -yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-yl)methanone

Step 1. t-butyl 4-((3 -fluoro-4 ' -hydro ybiphenyl-4-yloxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((4-bromo-2-fluorophenoxy)methyl)piperidin-l -carboxylate (the product of synthesis step 1 of compound 725; 3.75 g, 9.67 mmol), 4-hydroxyphenylboronic acid (1.33 g, 9.67 mmol), Pd(dppf)Cl ₂ (789 mg, 0.97 mmol) and Na ₂ C0 ₃ (2.04 g, 19.32 mmol) were dissolved in DME 15 mL and water 5 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (2.90 g, 75%).

Step 2. 3 '-fluoro-4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride:

t-butyl 4-((3 -fluoro-4 '-hydroxybiphenyl÷4-yloxy)methyl)piperidin-l -carboxylate (2.90 g, 7.22 mmol) was dissolved in CH ₂ C1 ₂ 15 mL. 4 M HC1 2.17 mL was added thereto, following with stirring at room temperature for 2 hours. The reaction mixture was filtered, washed with EtOAc, and evaporated under reduced pressure to yield the title compound as white solid (2.40 g, 98%).

Step 3. 3 -fluoro-4' -(( 1 -( 1 -(trifluoromethyl)cyclobutanecarbonyl)piperidin-4- yl)methoxy)biphenyl-4-yl 1 -(rrifluoromethyl)cyclobutanecarboxylate:

3'-fiuoro-4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride (0.83 g, 2.46 mmol), 1- (trifluoromethyl)cyclobutanecarboxylic acid (0.62 g, 3.69 mmol) and BOP (2.17 g, 4.93 mmol) were dissolved in DMF 6 mL. After stirring for 10 minutes at room temperature, TEA (0.75 g, 7.39 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, EtOAc/hexane) to yield the title compound as white solid (500 mg, 45%).

Step 4. 3 '-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-ol: 3-fluoro-4'-((l-(l-(trifluoromethyl)cyclobutanecarbonyl) piperidin-4-yl)methoxy)biphenyl-4-yl l-(trifluoromethyl)cyclobutanecarboxylate (672 mg, 1.12 mmol) was dissolved in dry THF 15 mL. At 0 °C, LAH (3.35 mmol) was added thereto, following with stirring at 60 °C for a day. After the completion of the reaction, the reaction mixture was added with a little of water, and then extracted with excess amount of EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgSC^, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g ISCO silica gel cartridge, 15 - 20 % EtOAc/hexane) to yield the title compound as white solid (485 mg, 99%).

Step 5. 3 '-fJ.uoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl trifluoromethanesulfonate: 3 '-fluoro-4'-((l -((1 - (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-ol (485 mg, 1.11 mmol) was dissolved in dry CH ₂ C1 ₂ 6 mL. Pyridine (132 mg, 1.66 mmol) was added thereto. And then, trifluoromethanesulfonic anhydride (401 mg, 1.44 mmol) was added thereto at 0 °C, following with stirring at room temperature for 3 hours. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ twice. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column

chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (395 mg, 62%).

Step 6. methyl 3 '-fluoro-4'-((l -((1 -(trifluor0methyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) biphenyl-4-carboxylate: 3 ' -fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl trifluoromethanesulfonate (785 mg, 1.38 mmol), Pd(OAc) ₂ (16 mg, 0.07 mmol) and dppp (35 mg, 0.08 mmol) were dissolved in DMSO 3 mL. MeOH 2 mL was added thereto, following with sufficient infusion of carbon monoxide (CO). TEA (697 mg, 6.89 mmol) was added thereto, following with stirring at 120 °C for 4 hours. The reaction mixture was diluted with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/CH ₂ Cl ₂ ) to yield the title compound as white solid (380 mg, 57%).

Step 7. 2'-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) biphenyl-4-carboxylic acid: Methyl 3 '-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylate (420 mg, 0.88 mmol) was dissolved in THF/ MeOH/H ₂ 0 = 6/3/2 mL. LiOH H ₂ 0 (73 mg, 1.75 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using IN HC1. The resulting precipitate was filtered to yield the title compound as white solid (380 mg, 93%).

Step 8. Compound 883 : 2'-fluoro-4'-((l -((1 -(trifiuoromethyl)cyclobutyl)methyl)piperidin- 4-yl)methoxy)biphenyl-4-carboxylic acid (50 mg, 0.11 mmol), EDC (33 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol) and DIPEA (42 mg, 32 mmol) were dissolved in DMF 1 mL. After stirring for 10 minutes at room temperature, (S)-piperidin-3-ol (16 mg, 0.16 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgSC>4, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g ISCO silica gelr. cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (35 mg, 59%). ,

1H NMR (400 MHz, CDC1 ₃ ) δ 7.49 (m, 4 H), 7.29 (m, 2 H), 7.00 (t, 1 H, J = 8.5 Hz), 3.90 (m, u 4 H), 3.59 (m, 3 H), 2.88 (m, 2 H), 2.53 (s, 2 H), 2.21 (m, 4 H), 1.98 (m, 10 H), 1.24 (m, 3 H); · MS (ESI) m/z 549 (M + H). According to the above-described synthesis process of compound 883, the compounds of Table 72 were synthesized using 2'-fluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pipe ridin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 71

Table 71.

Table 72. Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)- 1 -(3 '-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

837 IH NMR (400 MHz, CDC1 ₃ ) δ 7.59 (m, 4 H), 7.33 (m, 2 H), 7.02 (m, 2 H), 5.57 (s,

1 H), 4.82 (t, 1 H, J = 6.2 Hz), 3.92 (d, 2 H, J = 6.2 Hz), 3.58 (m, 2 H), 2.91 (m, 2 H), 2.45 (m, 3 H), 2.25 (m, 4 H), 2.13 (m, 6 H), 1.98 (m, 4 H), 1.26 (m, 2 H).

(R)-(3 '-fluoro-4 '-((1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidine-l-yl) methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.47 (m, 4 H), 7.31 (m, 2 H), 7.03 (t, 1 H, J = 8.5

838

Hz), 4.94 (m, 1 H), 4.43 (m, 1 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.78 (m, 2 H), 3.55 (m, 2 H), 3.13 (s, 1 H), 3.04 (s, 1 H), 2.89 (m, 2 H), 2.25 (s, 2 H), 2.23 (m, 5 H), 1.98 (m, 8 H), 1.42 (m, 2 H).

(S)-(3 '-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3-hydroxypyrrolidine- 1 -yl)methanone

IH NMR (400 MHz, CDC1 ₃ ) δ 7.58 (m, 4 H), 7.30 (m, 2 H), 7.01 (t, 1 H, J = 8.5

839 Hz), 4.58 (s, 0.5 H), 4.45 (s, 0.5 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.91 (d, 2 H, J = 6.2

Hz), 3.64 (m, 2 H), 3.54 (m, 1 H), 3.52 (m, 1 H), 2.91 (d, 2 H, J = 1 1.0 Hz), 2.81

(s, 0.5 H), 2.72 (s, 0.5 H), 2.55 (s, 2 H), 2.23 (m, 4 H), 2.04 (m, 10 H), 1.46 (m, 2

H).

(R)-(3 ' -fluoro-4' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

840 IH NMR (400 MHz, CDC1 ₃ ) δ 7.53 (m, 4 H), 7.33 (m, 2 H), 7.02 (t, 1 H, J = 8.5 Hz), 3.92 (m, 4 H), 3.57 (m, 3 H), 3.16 (m, 2 H), 2.68 (m, 2 H), 2.24 (m, 4 H), 2.04 (m, 10 H), 1.85 (m, 2 H), 1.26 (m, 2 H).

(S)- 1 -(3 '-fluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.55 (d, 2 H, J = 8.1 Hz), 7.44 (d, 2 H, J = 8.3 Hz),

884

7.30 (m, 2 H), 7.01 (t, 1 H, J = 8.5 Hz), 6.75 (s, 1 H), 5.44 (s, 1 H), 4.12 (m, 1 H), 3.90 (d, 2 H, J = 6.2 Hz), 3.77 (m, 1 H), 3.55 (m, 1 H), 3.26 (m, 1 H), 2.90 (m, 2 H), 2.54 (m, 2 H), 2.54 - 1.46 (m, 16 H), 1.12 (m, 2 H).

(R)- 1 -(3 '-fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-3-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) θ 7.56 (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.1 Hz),

885

7.30 (m, 2 H), 7.02 (t, 1 H, J = 8.5 Hz), 6.80 (s, 1 H), 5.70 (s, 1 H), 4.16 (s, 1 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.63 (m, 1 H), 3.37 (m, 1 H), 2.90 (m, 2 H), 2.55 (s, 2 H), 2.22 - 1.62 (m, 16 H), 1.43 (m, 3 H).

(R)- 1 -(3 ' -fluoro-4 '-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

IH NMR (400 MHz, CDC1 ₃ ) δ 7.55 (d, 2 H, J = 8.1 Hz), 7.44 (d, 2 H, J = 8.3 Hz),

886

7.31 (m, 2 H), 7.01 (t, 1 H, J = 8.5 Hz), 6.75 (s, 1 H), 5.54 (s, 1 H), 4.12 (m, 1 H), 3.90 (d, 2 H, J = 6.2 Hz), 3.77 (m, 1 H), 3.55 (m, 1 H), 3.26 (m, 1 H), 2.90 (m, 2 H), 2.54 - 1.61 (m, 15 H), 1.20 (m, 3 H); MS (ESI) m/z 576 (M + H).

(S)- 1 -(3 ' -fluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

887

IH NMR (400 MHz, CDC1 ₃ ) δ 7.53 (m, 4 H), 7.31 (m, 2 H), 7.02 (t, 1 H, J = 8.5 Hz), 6.49 (s, 1 H), 5.51 (s, 1 H), 5.27 (s, 1 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.78 (m, 2 H), 3.11 (m, 1 H), 2.89 (m, 2 H), 2.54 (s, 2 H), 1.97 - 1.24 (m, 14 H); MS (ESI) m/z 576 (M + H).

Example 79. Compound 847: (S)-l-(2,3'-difluoro-4'-((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidm-4-yI)methoxy)biphenylcarbonyI)pyr rolidine-2-carboxamide

Step 1. (4-((4-bromo-2-fluorophenoxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl)cyclobutyl) methanone: 4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 2 of compound 725; 3.90 g, 12.01 mmol) was dissolved in CH ₂ C1 ₂ (50 mL). EDC (4.61 g, 24.03 mmol), HOBt (3.25 g, 24.03 mmol), DIPEA (4.25 mL, 24.03 mmol), 1- (trifluoromethyl)cyclobutanecarboxylic acid (2.02 g, 12.01 mmol) was added thereto, following with stirring at room temperature for a day. After the completion of the reaction, the reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was extracted with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column

chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (3.10 g, 58%).

Step 2. 4-((4-bromo-2-fluorophenoxy)methyl)-l-((l-(trifluoromethyl)c yclobutyl)methyl) piperidine: (4-((4-bromo-2-fluorophenoxy)methyl)piperidin- 1 -yl)(l -(trifluoromethyl) cyclobutyl)methanone (2.28 g, 5.20 mmol) was dissolved in THF (50 mL). At 0 °C, 2.0 M Borane dimethyl sulfide complex solution in THF (13.01 mL, 26.01 mmol) was added thereto, following with stirring at 50 °C for 5 hours. After the completion of the reaction, the reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 20 % ~ 80 %) to yield the title compound as white solid (1.50 g, 68%).

Step 3. methyl 2,3 ' -difluoro-4' -(( 1 -(( 1 -(trifiuoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidine (800 mg, 1.89 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (448 mg, 2.26 mmol), Pd(dppf)Cl ₂ (154 mg, 0.19 mmol) and Cs ₂ C0 ₃ (1.23 g, 3.77 mmol), DME (6 mL) / H ₂ 0 (2 mL) was added, With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (535 mg, 57%).

Step 4. 2,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid: Methyl 2,3 '-difluoro-4 ^, -((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyl ate (535 mg, 1.08 mmol) was dissolved in THF (10 mL) and H ₂ 0 (5 mL). At room temperature, LiOH H ₂ 0 (226 mg, 5.38 mmol) was added thereto, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (400 mg, 76%). Step 5. Compound 847: 2,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (50 mg, 0.10 mmol), EDC (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (37 μί,, 0.21 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). (S)-pyrrolidine-2-carboxamide (24 mg, 0.21 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (43i mg, 71%).

1H NMR (400 MHz, CDC1 ₃ ) 5 7.48 - 7.45 (m, 1 H), 7.40 - 7.27 (m, 4 H), 7.03 (t, 1 H, J = 8.6 Hz), 6.91 (brs, 1 H), 5.60 (brs, 1 H), 4.81 - 4.78 (m, 1 H), 3.92 (d, 2 H, J = 6.2 Hz), 3.68 - 3.54 (m, 2 H), 2.90 (d, 2 H, J = 11.3 Hz), 2.54 (s, 2 H), 2.49 - 2.42 (m, 1 H), 2.27 - 2.20 (m, 4 H), 2.16 - 1.98 (m, 5 H), 1.96 - 1.91 (m, 4 H), 1.90 - 1.73 (brs, 1 H), 1.48 - 1.42 (m, 2 H); MS (ESI) m/z 580(M+ + H).

According to the above-described synthesis process of compound 847, the compounds of Table 74 were synthesized using 2,3 '-difluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 73.

Table 73. 849 (R)-pyrrolidine-2-ylmethanol 68

850 (S)-piperidin-3-ol hydrochloride 64

851 (S)-pyrrolidine-3-ol 61

Table 74.

Example 80. Compound 901 : (S)-l-(3,3'-dinuoro-4'-((l-((l-(trifluoromethyl)cycIobutyl) methyl)piperid -4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. ethyl 3,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4- yl)methoxy)biphenyl-4-carboxylate: To 4-((4-bromo-2-fluorophenoxy)methyl)-l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidine (the product of synthesis step 2 of compound 847; 627 mg, 1.48 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (345 mg, 1.63 mmol), Pd(dppf)Cl ₂ (121 mg, 0.15 mmol) and Cs ₂ C0 ₃ (963 mg, 2.96 mmol), DME (6 mL) / H ₂ 0 (2 mL) was added, With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (580 mg, 76%).

Step 2. 3,3 '-difluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid: Ethyl 3,3'-difluoro-4'-((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyl ate (580 mg, 1.13 mmol) was dissolved in THF (10 mL) and H ₂ 0 (5 mL). At room temperature, LiOH H ₂ 0 (238 mg, 5.67 mmol) was added thereto, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (500 mg, 91%). Step 3. Compound 901 : 3,3 '-difluoro-4 '-((1 -((1 -(trifluoromethyl)cyclobutyljmethyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (60 mg, 0.12 mmol), EDC (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and DIPEA (44 μΐ,, 0.25 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). (S)-pyrrolidine-2-carboxamide(28 mg, 0.25 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (46 mg, 64%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (t, 1 H, J = 7.5 Hz), 7.41 - 7.27 (m, 4 H), 7.03 (t, 1 H, J = 8.5 Hz), 6.93 (brs, 1 H), 5.65 (brs, 1 H), 4.83 - 4.80 (m, 1 H), 3.91 (d, 2 H, J = 6.3 Hz), 3.55 - 3.53 (m, 1 H), 3.44 - 3.41 (m, 1 H), 2.90 (d, 2 H, J = 11.4 Hz), 2.54 (s, 2 H), 2.47 - 2.44 (m, 1 H), 2.27 - 2.19 (m, 4 H), 2.15 - 1.82 (m, 10 H), 1.46 - 1.42 (m, 2 H); MS (ESI) m/z 580 (M+ + H).

According to the above-described synthesis process of compound 901, the compounds of Table 76 were synthesized using 3,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 75.

Table 75.

Table 76.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-(3,3'-difluoro-4'-((l-((l-(trifluoromethyl)cyclobutyl)me thyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 (t, 1 H, J = 7.4 Hz), 7.38 - 7.23 (m, 4 H), 7.02

902 (t, 1 H, J = 8.5 Hz), 4.07 (brs, 1 H), 3.91 (d, 2 H, J = 6.3 Hz), 3.60 - 3.56 (m, 1 H), 3.37 - 3.26 (m, 1 H), 2.90 (d, 2 H, J = 11.4 Hz), 2.54 (s, 2 H), 2.27 - 2.20 (m, 4 H), 2.10 - 1.83 (m, 10 H), 1.70 - 1.62 (m, 2 H), 1.48 - 1.40 (m, 3 H); MS (ESI) m/z 567 (M+ + H).

(R)-(3,3 '-difluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidine-l-yl) methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (t, 1 H, J = 7.5 Hz), 7.39 - 7.29 (m, 1 H), 7.29

903 - 7.26 (m, 3 H), 7.03 (t, 1 H, J = 8.4 Hz), 4.77 (brs, 1 H), 4.41 - 4.39 (m, 1 H),

3.91 (d, 2 H, J = 6.3 Hz), 3.82 - 3.75 (m, 2 H), 3.48 - 3.44 (m, 2 H), 2.90 (d, 2 H, J

= 11.1 Hz), 2.54 (s, 2 H), 2.27 - 2.20 (m, 5 H ), 2.19 - 1.69 (m, 10 H), 1.46 - 1.43

(m, 2 H); MS (ESI) m/z 567 (M+ + H).

(S)-(3 ,3 '-difluoro-4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.44 (t, 1 H, J = 7.4 Hz), 7.38 - 7.23 (m, 4 H), 7.02

904 (t, 1 H, J = 8.5 Hz), 4.07 (brs, 1 H), 3.91 (d, 2 H, J = 6.3 Hz), 3.60 - 3.56 (m, 1 H), 3.37 - 3.26 (m, 1 H), 2.90 (d, 2 H, J = 11.4 Hz), 2.54 (s, 2 H), 2.27 - 2.20 (m, 4 H), 2.10 - 1.83 (m, 10 H), 1.70 - 1.62 (m, 2 H), 1.48 - 1.40 (m, 3 H); MS (ESI) m/z 567 (M+ + H).

(S)-(3,3 '-difluoro-4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(3 -hydroxypyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 - 7.46 (m, 1 H), 7.37 - 7.23 (m, 4 H), 7.02 (t,

905 1 H, J = 8.5 Hz), 4.62 - 4.51 (m, 1 H), 3.91 (d, 2 H, J = 6.2 Hz), 3.83 - 3.78 (m, 1 H), 3.73 - 3.58 (m, 1 H), 3.48 - 3.36 (m, 1 H), 2.90 (d, 2 H, J = 11.4 Hz), 2.54 (s,

2 H), 2.27 - 2.20 (m, 4 H), 2.19 - 1.83 (m, 9 H), 1.71 (brs, 1 H), 1.46 - 1.42 (m, 2 H); MS (ESI) m/z 553 (M+ + H).

1 -(4-(3 ,3 ' -difluoro-4' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-

936

yl)methoxy)biphenylcarbonyl)piperazin- 1 -yl)ethanone 1H NMR (400 MHz, CDC1 ₃ ) 5 7.50 - 7.46 (m, 1 H), 7.44 - 7.41 (m, 1 H), 7.39 - 7.26 (m, 3 H), 7.03 (t, 1 H, J = 8.5 Hz), 3.92 (d, 2 H, J - 6.3 Hz), 3.85 - 3.75 (m, 3 H), 3.71 - 3.60 (m, 2 H), 3.59 - 3.39 (m, 2 H), 2.90 (d, 2 H, J = 1 1.5 Hz), 2.54 (s, 2 H), 2.28 - 1.83 (m, 13 H), 1.67 (brs, 1 H), 1.48 - 1.42 (m, 2 H), 1.39 - 1.38 (m, 1 H); MS (ESI) m/z 594 (M+ + H).

Example 81. Compound 906 : (S)-l-(5-(3-fluoro-4-((l-((l-(trifluoromethyl)cyclobutyl) methyl)piper i -4-yl)methoxy)phenyl)picoUnoyl)pyrroIidine-2-carboxamide

Step 1. methyl 5-(3-fluoro-4-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin-4- yl)methoxy)phenyl)picolinate: To 4-((4-bromo-2-fluorophenoxy)methyl)- 1 -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidine (the product of synthesis step 2 of compound 847; 856 mg, 2.02 mmol), 6-methoxycarbonyl)pyridine-3-yl boronic acid (402 mg, 2.22 mmol), Pd(dppf)Cl ₂ (165 mg, 0.20 mmol) and Cs ₂ C0 ₃ (1.31 g, 4.04 mmol), DME (6 mL) / H ₂ 0 (2 mL) was added, With a microwave radiation, the mixture was heated at 1 10 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc hexane = 30 % ~ 70 %) to yield the title compound as white solid (80 mg, 8%).

Step 2. 5-(3-fluoro-4-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)metoxy)phenyl)picolinic acid: Methyl 5-(3-fluoro-4-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)ph enyl)picolinate (80 mg, 0.17 mmol) was dissolved in THF (10 mL) and H ₂ 0 (5 mL). At room temperature, LiOH H ₂ 0 (35 mg, 0.83 mmol) was added thereto, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (60 mg, 77%).

Step 3. Compound 906: 5-(3-fluoro-4-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)metoxy)phenyl)picolinic acid (60 mg, 0.12 mmol), EDC (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and DIPEA (44 iL, 0.25 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). (S)-pyrrolidine- 2-carboxamide (28 mg, 0.25 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgSC^, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (46 mg, 64%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.77 - 8.72 (m, 1 H), 8.09 - 7.91 (m, 2 H), 7.37 - 7.27 (m, 2 H), 7.07 (t, 1 H, J = 8.7 Hz), 6.94 (brs, 0.5 H), 6.53 (brs, 0.5 H), 5.53 (brs, 1 H), 5.06 - 5.05 (m, 0.5 H), 4.86 - 4.83 (m, 0.5 H), 4.07 - 3.82 (m, 3 H), 2.90 (d, 2 H, J = 1 1.4 Hz), 2.54 (s, 2 H), 2.41 - 2.37 (m, 1 H), 2.36 - 1.78 (m, 15 H), 1.48 - 1.40 (m, 2 H); MS (ESI) m/z 563 (M+ + H).

According to the above-described synthesis process of compound 906, the compounds of Table 78 were synthesized using 5-(3-fluoro-4-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)metoxy)phenyl)picolinic acid and the reactant of Table 77.

Table 77.

Table 78.

Example 82. Compound 576: N,N-dimethyl-4-(6-((l-((l-

(trifluoromethyl)cyclobutyI)methyl)piperidin-4-yl)methoxy )pyridine-3-yl)benzamide

4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid (the product of synthesis step 2 of compound 574; 20 mg, 0.05 mmol), dimethylamine (4 mg, 0.09 mmol), EDC (17 mg, 0.09 mmol) and HOBt (12 mg, 0.09 mmol) were dissolved in DMF 1 mL. DIPEA (1 1 mg, 0.09 mmol) was added thereto. The reaction was performed at room temperature for 16 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20- 70 % EtOAc/hexane) to yield the title compound as white solid (9 mg, 42%).

1H NMR (400 MHz, CDC1 ₃ ) 6 8.38 (d, 1 H, J = 2.5 Hz), 7.80 (dd, 1 H, J = 8.6, 2.6 Hz), 7.52 (m, 4 H), 6.83 (d, 1 H, J = 8.5 Hz), 4.20 (d, 2 H, J = 6.2 Hz), 3.14 (s, 3 H), 3.05 (s, 3 H), 2.88 (m, 2 H), 2.26 (s, 2 H), 2.06 (m, 4 H), 1.90 (m, 7 H), 1.43 (m, 2 H); MS (ESI) m/z 476 (M+ + H).

Example 83. Compound 578:(S)-(3-hydroxypyrrolidine-l-yl)(4-(6-((l-((l-(trifluorom ethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-3-yl)pheny l)methanone

4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-3 -yl)benzoic acid (the product of synthesis step 2 of compound 574; 30 mg, 0.07 mmol), (S)-pyrrolidine-3-ol (11 mg, 0.13 mmol) and BOP (59 mg, 0.13 mmol) were dissolved in DMF 1 mL. TEA (13 mg, 0.13 mmol) was added thereto. At 50 °C, the reaction was performed for 16 hours. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (5-10 %

MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (13 mg, 38%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (s, 1 H), 7.79 (m, 1 H), 7.62 (m, 2 H), 7.54 (m, 2 H), 6.82 (d, 1 H, J = 8.5 Hz), 4.58 (m, 1 H), 4.19 (d, 2 H, J = 6.2 Hz), 3.81 (m, 2 H), 3.63 (m, 1 H), 3.57 (m, 1 H), 2.99 (m, 2 H), 2.66 (s, 3 H), 2.63 (s, 3 H), 2.26 (s, 2 H), 2.20 (m, 2 H), 2.04 (m, 3 H), 1.79 (m, 2 H), 1.43 (m, 2 H); MS (ESI) m/z 518 (M+ + H).

Example 84. Compound 581 : (S)-l-(4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyridine-3-yl)benzoyl)pyrrolidine-2-c arboxamide

4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-3 -yl)benzoic acid (the product of synthesis step 2 of compound 574; 50 mg, 0.1 1 mmol), L-prolinamide (26 mg, 0.22 mmol), EDC (43 mg, 0.22 mmol) and HOBt (30 mg, 0.22 mmol) were dissolved in DMF 1 mL. DIPEA (29 mg, 0.22 mmol) was added thereto. At 60 °C, the reaction was performed for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water, and dried to yield the title compound as white solid (40 mg, 66%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 8.4, 2.3 Hz), 7.60 (dd, 4 H, J = 19.3, 8.3 Hz), 7.00 (m, 1 H), 6.83 (d, 1 H, J = 8.7 Hz), 5.54 (m, 1 H), 4.84 (m, 1 H), 4.21 (m, 2 H), 3.65 - 3.54 (m, 2 H), 2.88 - 2.65 (m, 2 H), 2.52 - 2.47 (m, 2 H), 2.22 - 1.79 (m, 15 H), 1.46 (m, 2 H); MS (ESI) m/z 545 (M+ + H).

According to the above-described synthesis process of compound 581, the compounds of Table 80 were synthesized using 4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)metho y)pyridine-3-yl)benzoic acid and the reactant of Table 79.

Table 79.

Table 80.

H).

(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyraz ine-7(8H)-yl)(4-(6-((l- (( 1 -(1rifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-3 - yl)phenyl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.40 (d, 1 H, J = 2.3 Hz), 7.81 (dd, 1 H, J = 8.6, 2.6

595

Hz), 7.60 (m, 4 H), 6.86 (d, 1 H, J = 8.6 Hz), 5.10 (s, 2 H), 4.28 (m, 2 H), 4.21 (m, 4 H), 2.90 (d, 2 H, J = 11.2 Hz), 2.53 (s, 2 H), 2.18 (m, 4 H), 2.02 (m, 2 H), 1.98 (m, 1 H), 1.92 (m, 1 H), 1.82 (m, 3 H), 1.47 (m, 2 H); MS (ESI) m z 623 (M+ + H).

(R)- 1 -(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoyl)pyrrolidine-2-carboxarnide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 8.4, 2.3 Hz), 7.60

671 (dd, 4 H, J = 19.3, 8.3 Hz), 6.99 (m, 1 H), 6.83 (d, 1 H, J = 8.7 Hz), 5.44 (m, 1 H),

4.84 (m, 1 H), 4.21 (m, 2 H), 3.64 - 3.57 (m, 2 H), 2.90 (m, 2 H), 2.53 - 2.49 (m, 3

H), 2.24 - 2.18 (m, 4 H), 2.1 1 - 2.00 (m, 5 H), 2.00 - 1.80 (m, 5 H), 1.46 (m, 2 H);

MS (ESI) m/z 545 (M+ + H).

(R)-(3 -hydroxypiperidin- 1 -yl)(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyridine-3-yl)phenyl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 8.4, 2.3 Hz), 7.53

672

(dd, 4 H, J = 19.3, 8.3 Hz), 6.83 (d, 1 H, J = 8.7 Hz), 4.20 (m, 2 H), 4.05 - 3.20 (m,

15 H), 2.89 (m, 2 H), 2.53 (m, 2 H), 2.24 - 2.19 (m, 4 H), 2.15 - 1.75 (m, 9 H),

1.75 - 1.60 (m, 2 H), 1.46 (m, 2 H); MS (ESI) m/z 532 (M+ + H).

(S)-(3-hydroxypiperidin-l-yl)(4-(6-((l-((l-(trifluoromethyl) cyclobutyl)methyl) piperidin-4-yl)methoxy)pyridine-3-yl)phenyl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 8.4, 2,3 Hz), 7.53

673

(dd, 4 H, J = 19.3, 8.3 Hz), 6.83 (d, 1 H, J = 8.7 Hz), 4.20 (m, 2 H), 4.05 - 3.20 (m,

15 H), 2.89 (m, 2 H), 2.53 (m, 2 H), 2.24 - 2.19 (m, 4 H), 2.15 - 1.75 (m, 9 H),

1.75 - 1.60 (m, 2 H), 1.46 (m, 2 H); MS (ESI) m/z 532 (M+ + H).

Example 85. Compound 931: (2S,4R)-methyl 4-hydroxy-l-(4-(6-((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-3-yl)benzo yl)pyrroIidine-2- carboxylate

4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-3 -yl)benzoic acid (the product of synthesis step 2 of compound 574; 300 mg, 0.67 mmol), (2S,4R)-methyl 4- hydroxypyrrolidine-2-carboxylate hydrochloride (182 mg, 1.00 mmol), EDC (257 mg, 1.34 mmol), HOBt (181 mg, 1.34 mmol) and DIPEA (0.24 mL, 1.34 mmol) were dissolved in DMF (5 mL) at room temperature. The solution was stirred at 80 °C for 12 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 5 % to 80 %), and concentrated to yield the title compound as white solid (250 mg, 65%).

1H NMR (400 MHz, CDC1 ₃ ) 5 8.34 (m, 1 H), 7.78 (m, 1 H), 7.63 (m, 2 H), 7.52 (m, 2 H), 6.80 (m, 1 H), 4.86 (m _s 1 H), 4.55 (m, 1 H), 4.18 (m, 2 H), 3.85 - 3.61 (m, 6 H), 3.02 (m, 2 H), 2.68 (m, 2 H), 2.40 - 2.11 (m, 8 H), 2.10 - 1.79 (m, 5 H), 1.57 (m, 2 H); MS (ESI) m/z 576 (M+ + H).

Example 86. Compound 933: (2S,4R)-4-hydroxy-l-(4-(6-((l-((l-(trifluoromethyl) cyclobutyl)methyI)piperidin-4-yl)methoxy)pyridine-3-yl)benzo yl)pyrrolidine-2- carboxamide

Step 1. (2S,4R)-4-hydroxy- 1 -(4-(6-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoyl)pyrrolidine-2-carboxylic acid: (2S,4R)-methyl 4-hydroxy- 1 -(4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yridine-3 - yl)benzoyl)pyrrolidine-2-carboxylate(400 mg, 0.70 mmol) and LiOH H ₂ 0 (58 mg, 1.39 mmol) were dissolved in THF (10 mL) / H ₂ 0 (5 mL) at room temperature. The solution was stirred at 60 °C for 10 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The concentrate was added with 1 M-HCl aqueous solution, and concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 2. Compound 933: (2S,4R)-4-hydroxy-l-(4-(6-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyridine-3-yl)benzoyl)pyrrolidine- 2-carboxylic acid (400 mg, 0.71 mmol), ammonium chloride (57 mg, 1.07 mmol), EDC (205 mg, 1.07 mmol), HOBt (144 mg, 1.07 mmol) and DIPEA (18 mg, 1.43 mmol) were dissolved in DMF (10 mL) at room temperature. The solution was stirred at 60 °C for 10 hours. The reaction mixture was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as brown solid (110 mg, 28%).

1H NMR (400 MHz, CDC1 ₃ + MeOD) δ 8.33 (m, 1 H), 7.79 (m, 1 H), 7.62 (m, 2 H), 7.54 (m, 2 H), 7.22 (br, 1 H), 6.80 (m, 1 H), 5.97 (br, 1 H), 4.86 (m, 1 H), 4.41 (m, 1 H), 4.18 (m, 2 H), 3.78 (m, 1 H), 3.55 (m, 1 H), 2.78 (m, 2 H), 2.60 - 1.65 (m, 16 H), 1.42 (m, 2 H); MS (ESI) m/z 561 (M+ + H),

Example 87. Compound 715:(S)-(3-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)m ethyl) piperidin-4-yl)methoxy)pyridme-3-yl)phenyl)(3-hydroxypyrroIi dine-l-yI)methanone

Step 1. ethyl l-(l-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-carbox ylate:

l-(trifluoromethyl)cyclobutanecarboxylic acid (500 mg, 2.97 mmol), ethyl piperidin-4- carboxylate (514 mg, 3.27 mmol), EDC (1.14 g, 5.94 mmol) and HOBt (803 mg, 5.95 mmol) were dissolved in CH ₂ C1 ₂ 10 mL. DIPEA (1.05 mL, 5.95 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The extracted organic layer was dried over MgS0 ₄ , and then filtered. The filtrate was purified by silica gel column

chromatography (10-30 % EtOAc/hexane) to yield the title compound as colorless oil (850 mg, 93%).

Step_2. (l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)met hanol:

Ethyl l-(l-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-carbox ylate(1.73 g, 5.63 mmol) was dissolved in dry THF 40 mL. At 0 °C, LAH (1 M in THF, 28.15 mL, 28.15 mmol) was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. The reaction was quenched by addition of MeOH slowly at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (1.4 g, 99%).

Step 3. 5-bromo-2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in-4-yl)methoxy) pyridine: (l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)met hanol(760 mg, 3.02 mmol) was dissolved in THF 10 mL. At 0 °C, NaH (109 mg, 4.54 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5- dibromopyridine(788 mg, 3.32 mmol) in THF was added slowly thereto. At 50 °C, the reaction was performed for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc hexane) to yield the title compound as white solid (1.10 g, 89%).

Step 4. methyl 3-fluoro-4-(6-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate: 5-bromo-2-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyridine (550 mg, 1.35 mmol), 2- fluoro-4-(methoxycarbonyl)phenylboronic acid(294 mg, 1.48 mmol), Pd(dbpf)Cl ₂ (26 mg, 0.04 mmol), Cs ₂ C0 ₃ (1.31 g, 4.05 mmol) were added into a microwave reactor, and then 1,4-dioxane 4 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed for 30 minutes at 1 10 °C. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and then extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 %

EtOAc/hexane) to yield the title compound as white solid (300 mg, 46%).

Step 5. 3-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin-4- yl)methoxy)pyridine-3-yl)benzoic acid: Methyl 3-fluoro-4-(6-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridine-3-yl)benzoate (488 mg, 1.02 mmol) was dissolved in the mixed solvents of THF 10 mL / water 10 mL. LiOH H ₂ 0 (85 mg, 2.03 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HC1 thereto, the resulting precipitate was filtered to yield the title compound as white solid (410 mg, 86%).

Step 6. Compound 715: 3-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyridine-3-yl)benzoic acid (50 mg, 0.1 1 mmol), (S)-pyrrolidine-3-ol (14 mg, 0.16 mmol), EDC (41 mg, 0.21 mmol) and HOBt (29 mg, 0.21 mmol) were dissolved in DMF 2 mL. DIPEA (0.04 mL, 0.21 mmol) was added thereto, the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as white solid (25 mg, 43%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.33 (s, 1 H), 7.79 (d, 1 H, J = 8.8 Hz), 7.47 - 7.33 (m, 3 H), 6.83 (dd, 1 H, J = 10.2, 3.6 Hz), 4.62 - 6.51 (m, 1 H), 4.21 (d, 2 H, J = 5.5 Hz), 3.87 - 3.49 (m, 4 H), 2.90 (m, 2 H), 2.54 (s, 2 H), 2.22 - 1.80 (m, 15 H), 1.26 (m, 2 H); MS (ESI) m/z 536 (M+ + H).

According to the above-described synthesis process of compound 715, the compounds of Table 82 were synthesized using 3-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 81. Table 81.

Table 82.

Example 88. Compound 720:(S)-(2-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)m ethyI) piperidin-4-yl)methoxy)pyridine-3-yl)phenyl)(3-hydroxypyrrol idine-l-yl)methanone

Step 1. ethyl 2-fluoro-4-(6-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate: 5-bromo-2-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyridine (the product of synthesis step 3 of compound 715; 250 mg, 0.61 mmol), 3-fluoro-4-(ethoxycarbonyl)phenylboronic acid (143 mg, 0.68 mmol), Pd(dbpf)Cl ₂ (12 mg, 0.02 mmol), Cs ₂ C0 ₃ (596 mg, 1.84 mmol) were added into a microwave reactor, and then 1,4-dioxane 3 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and then extracted with EtOAc. The obtained organic layer was dried over. MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (200 mg, 66%).

Step 2. 2-fluoro-4-(6-((l-((l-(trifluoromethvl)cvclobutyl)methyl)pip eridin-4- yl)methoxy)pyridine-3-yl)benzoic acid: Ethyl 2-fluoro-4-(6-((l-((l- (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)py ridine-3-yl)benzoate (533 mg, 1.08 mmol) was dissolved in the mixed solvents of THF 10 mL / water 10 mL. LiOH H ₂ 0 (90 mg, 2.16 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HC1 thereto, the resulting precipitate was filtered to yield the title compound as white solid (350 mg, 70%). Step 3. Compound 720: 2-fluoro-4-(6-((l-((l-

(trifluoromemyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) pyridine-3-yl)benzoic acid (50 mg, 0.11 mmol), (S)-pyrrolidine-3-ol (14 mg, 0.16 mmol), EDC (41 mg, 0.21 mmol) and HOBt (29 mg, 0.21 mmol) were dissolved in DMF 2 mL. DIPEA (0.04 mL, 0.21 mmol) was added thereto, and the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as white solid (21 mg, 37%).

Ή NMR (400 MHz, CDC1 ₃ ) δ 8.36 (t, 1 H, J= 1.8 Hz), 7.78 (dt, 1 H, J= 8.6, 1.3 Hz), 7. 1 (m, 1 H), 7.37 (dd, 1 H, J= 10.2, 3.6 Hz), 7.27 (m, 1 H), 6.83 (d, 1 H, J= 8.5 Hz), 4.60 (m, 1 H), 4.21 (d, 2 H, J= 5.8 Hz), 3.84 - 3.25 (m, 5 H), 2.88 (m, 2 H), 2.53 (m, 2 H), 2.21 - 1.79 (m, 14 H), 1.42 (m, 2 H); MS (ESI) m/z 536.1 (M ⁺ + H). According to the above-described synthesis process of compound 720, the compounds of Table 84 were synthesized using 2-fluoro-4-(6-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 83.

Table 83.

Table 84.

Example 89. Compound 970:(S)-(3-hydroxypyrrolidine-l-yl)(4-(2-((l-((l-(trifluorom ethyl) cyclobutyl)methyl)piperidm-4-yl)methoxy)pyrimidin-5-yl)pheny l)methanone

Step 1. 5-bromo-2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidine: (1 -((1 -(trifluorornethyl)cyclobutyl)methyl)piperidin-4-yl)methanol (760 mg, 3.02 mmol) was dissolved in THF (40 mL). At 0 °C, NaH (143 mg, 5.97 mmol) was added thereto, and stirred for 30 minutes. 5-bromo-2-iodopyrimidine (1.25 g, 4.38 mmol) was added thereto, following with stirring at 55 °C for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 2. methyl 4-(2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoate: 5-bromo-2-((l -((1 -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyrimidine (450 mg, 1.10 mmol), 4-(methoxycarbonyl)phenylboronic acid (218 mg, 1.21 mmol), Pd(dbpf)Cl ₂ (22 mg, 0.03 mmol) and Cs ₂ C0 ₃ (1.07 g, 3.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 110 °C for 45 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with dichloromethane. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (300 mg, 59%).

Step 3. 4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5- yl)benzoic acid: Methyl 4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoate (300 mg, 0.65 mmol) and LiOH H ₂ 0 (27 mg, 0.65 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 6 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (290 mg, 99%).

Step 4. Compound 970: 4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoic acid (50 mg, 0.11 mmol), (S)-pyrrolidine-3-ol (15 mg, 0.17 mmol), EDC (32 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIPEA (0.04 mL, 0.22 mmol) were dissolved in DMF (4 mL) at room temperature. The solution was stirred at 60 °C for 16 hours , added with saturated NH ₄ CI aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as white solid (20 mg, 35%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.72 (s, 2 H), 7.69 - 7.55 (m, 4 H), 4.63 - 4.48 (m, 1 H), 4.28 (m, 2 H), 3.88 - 3.45 (m, 4 H), 2.90 (m, 2 H), 2.52 (s, 2 H), 2.22 - 1.83 (m, 14 H), 1.46 (m, 2 H); MS (ESI) m/z 519 (M+ + H). According to the above-described synthesis process of compound 970, the compounds of Table 86 were synthesized using 4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoic acid and the reactant of Table 85.

Table 85.

Table 86.

Example 90. Compound 974:(S)-(3-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)m ethyl) piperidin-4-yl)methoxy)pyrimidin-5-yl)phenyl)(3-hydroxypyrro lidine-l-yl)methanone

Step 1. methyl 3 -fluoro-4-(2-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoate: 5-bromo-2-((l -((1 -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyrimidine (the product of synthesis step 1 of compound 970; 450 mg, 1.10 mmol), 2-fluoro-4-

(methoxycarbonyl)phenylboronic acid (240 mg, 1.21 mmol), Pd(dbpf)Cl ₂ (22 mg, 0.03 mmol) and Cs ₂ C0 ₃ (1.07 mg, 3.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 110 °C for 45 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous gS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (300 mg, 57%).

Step 2. 3-fluoro-4-(2-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoic acid: Methyl 3-fluoro-4-(2-((l-((l-

(trifluoromemyl)cyclobutyl)memyl)piperidin-4-yl)methoxy)p yrimidin-5-yl)benzoate (300 mg, 0.62 mmol) and LiOH H ₂ 0 (52 mg, 1.25 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 6 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (250 mg, 86%).

Step 3. Compound 974: 3-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrimidin-5-yl)benzoic acid (50 mg, 0.11 mmol), (S)-pyrrolidine-3-ol (14 mg, 0.16 mmol), EDC (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.21 mmol) were dissolved in DMF (4 mL) at room temperature. The solution was stirred at 60 °C for 16 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as white solid (20 mg, 35%). 1H NMR (400 MHz, CDC1 ₃ ) δ 8.71 (s, 2 H), 7.46 - 7.37 (m, 3 H), 4.63 - 4.52 (m, 1 H), 4.28 (m, 2 H), 3.88 - 3.47 (m, 4 H), 2.88 (m, 2 H), 2.52 (s, 2 H), 2.25 - 1.78 (m, 14 H), 1.47 (m, 2 H); MS (ESI) m/z 537 (M+ + H).

According to the above-described synthesis process of compound 974, the compounds of Table 88 were synthesized using 3-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrimidin-5-yl)benzoic acid and the reactant of Table 87.

Table 87.

Table 88.

Example 91. Compound 978:(S)-(2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)m ethyl) piperidm-4-yl)methoxy)pyrimidin-5-yl)phenyl)(3-hydroxypyrrol idine-l-yl)methanone

Step 1. ethyl 2-fluoro-4-(2-(( 1 -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrimidin-5-yl)benzoate: 5-bromo-2-(( 1 -(( 1 -

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyrimidine (the product of synthesis step 1 of compound 970; 450 mg, 1.10 mmol), 4-(ethoxycarbonyl)-3- fiuorophenylboronic acid (257 mg, 1.21 mmol), Pd(dbpf)Cl ₂ (22 mg, 0.03 mmol) and Cs ₂ C0 ₃ (1.07 mg, 3.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 45 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (300 mg, 55%).

Step 2. 2-fluoro-4-(2-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) pyrimidin-5-yl)benzoic acid: Ethyl 2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrimidin-5-yl)benzoate (300 mg, 0.61 mmol) and LiOH H ₂ 0 (51 mg, 1.21 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 6 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (280 mg, 99%).

Step 3. Compound 978: 2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrimidin-5-yl)benzoic acid (50 mg, 0.11 mmol), (S)-pyrrolidine-3-ol (14 mg, 0.16 mmol), EDC (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.21 mmol) were dissolved in DMF (4 mL) at room temperature. After stirring at 60 °C for 16 hours, the reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as white solid (20 mg, 35%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.71 (m, 2 H), 7.55 (m, 1 H), 7.37 (m, 1 H), 7.26 (m, 1 H), 4.62 - 4.51 (m, 1 H), 4.29 (m, 2 H), 3.84 - 3.32 (m, 4 H), 2.89 (m, 2 H), 2.53 (m, 2 H), 2.35 - 1.62 (m, 14 H), 1.48 (m, 2 H); MS (ESI) m/z 537 (M+ + H).

According to the above-described synthesis process of compound 978, the compounds of Table 90 were synthesized using 2-fluoro-4-(2-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrimidin-5-yl)benzoic acid and the reactant of Table 89.

Table 89.

Table 90.

Example 92. Compound 1007: (R)-(2-(hydroxymethyl)pyrrolidine-l-yl)(4-(5-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yI)methoxy )pyrazine-2~

yl)phenyl)methanone

Ste£j^ 2-iodo-5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidi n-4-yl)methoxy)pyrazine: (l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)met hanol(880 mg, 3.50 mmol) was dissolved in THF (30 mL). At 0 °C, NaH (126 mg, 5.25 mmol) was added thereto, and stirred for 30 minutes. 2-bromo-5-iodopyrazine (1.09 g, 3.85 mmol) was added thereto, following with stirring at 55 °C for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process.

Step 2. methyl 4-(5-((l -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy) pyrazine-2-yl)benzoate: 2-iodo-5-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine (350 mg, 0.77 mmol), 4-(methoxycarbonyl)phenylboronic acid (152 mg, 0.85 mmol), Pd(dbpf)Cl ₂ (15 mg, 0.02 mmol) and Cs ₂ C0 ₃ (747 mg, 2.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 45 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (210 mg, 59%).

Step 3. 4-(5-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)p yrazine-2- yl)benzoic acid: Methyl 4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoate (210 mg, 0.45 mmol) and LiOH H ₂ 0 (38 mg, 0.91 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 4 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (200 mg, 98%).

Step 4. Compound 1007: 4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoic acid (50 mg, 0.11 mmol), (R)-pyrrolidine-2-ylmethanol (17 mg, 0.17 mmol), EDC (32 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIPEA (0.04 mL, 0.22 mmol) were dissolved in DMF (2 mL) at room temperature. The solution was stirred at 60 °C for 16 hours. The concentrate was added with water (4 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as beige solid (25 mg, 42%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.52 (s, 1 H), 8.29 (s, 1 H), 7.98 (d, 2 H, J = 8.2 Hz), 7.63 (d, 2 H, J = 8.2 Hz), 4.91 (d, 1 H, J = 6.7 Hz), 4.44 (q, 1 H, J = 7.2 Hz), 4.24 (d, 2 H, J = 5.4 Hz), 3.81 (m, 2 H), 3.55 (m, 2 H), 2.89 (m, 2 H), 2.53 (s, 2 H), 2.25 - 1.62 (m, 15 H), 1.45 (m, 2 H); MS (ESI) m/z 533 (M+ + H). According to the above-described synthesis process of compound 1007, the compounds of Table 92 were synthesized using 4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoic acid and the reactant of Table 91.

Table 91.

Table 92.

Example 93. Compound 1010: (R)-(3-fluoro-4-(5-((l-((l-(trifluoromethyI)cyclobutyl) methyl)piperidin- -yl)methoxy)pyrazine-2-yl)phenyl)(3-hydroxypiperidin-l-yl)me thanone

Step 1. methyl 3-fluoro-4-(5-((l-((l -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoate: 2-iodo-5-((l-((l-

(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy )pyrazine (the product of synthesis step 1 of compound 1007; 350 mg, 0.77 mmol), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (167 mg, 0.85 mmol), Pd(dbpf)Cl ₂ (15 mg, 0.02 mmol) and Cs ₂ C0 ₃ (747 mg, 2.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 110 °C for 45 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (210 mg, 57%).

Step 2. 3-fluoro-4-(5- (l-( i-(trifluoromethy cvclobutvnmethvnpiperidin-4-yl)methoxy^ pyrazine-2-yl)benzoic acid: Methyl 3-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrazine-2-yl)benzoate (210 mg, 0.44 mmol) and LiOH H ₂ 0 (37 mg, 0.87 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 4 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (200 mg, 98%).

Step 3. Compound 1010: 3-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrazine-2-yl)benzoic acid (50 mg, 0.1 1 mmol), (R)-piperidin-3-ol hydrochloride (22 mg, 0.16 mmol), EDC (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.21 mmol) were dissolved in DMF (2 mL) at room temperature. The solution was stirred at 60 °C for 16 hours. The concentrate was added with water (4 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as beige solid (21 mg, 36%). 1H NMR (400 MHz, CDC1 ₃ ) δ 8.62 (s, 1 H), 8.33 (m, 1 H), 8.02 (t, 1 H, J = 7.8 Hz), 7.32 (m, 2 H), 4.33 (m, 2 H), 4.04 - 3.21 (m, 7 H), 2.90 (m, 2 H), 2.54 (s, 2 H), 2.35 - 1.44 (m, 16 H); MS (ESI) m/z 551 (M+ + H).

According to the above-described synthesis process of compound 1010, the compounds of Table 94 were synthesized using 3-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrazine-2-yl)benzoic acid and the reactant of Table 93.

Table 93.

Table 94.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)-l-(3-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)met hyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoyl)pyrrolidine-2-carboxamide

1011 1H NMR (400 MHz, CDC1 ₃ ) δ 8.63 (s, 1 H), 8.33 (s, 1 H), 8.05 (t, 1 H, J = 7.9

Hz), 7.43 (m, 2 H), 6.90 (s, 1 H), 5.53 (s, 1 H), 4.79 (dd, 1 H, J = 10.2, 3.6 Hz),

4.25 (d, 2 H, J = 6.0 Hz), 3.67 - 3.51 (m, 2 H), 2.90 (m, 2 H), 2.54 - 2.42 (m, 3 H), I 12.16 - 1.66 (m, 14 H), 1.47 (m, 2 H); MS (ESI) m/z 564 (M+ + H).

Example 94. Compound 1012:

(R)-(2-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methy l)piperidin-4- yl)methoxy)pyrazine-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin e-l-yl)methanone

Step 1. ethyl 2-fluoro-4-(5-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methoxy)pyrazine-2-yl)benzoate: 2-iodo-5-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrazine (the product of synthesis step 1 of compound 1007; 350 mg, 0.77 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (179 mg, 0.85 mmol), Pd(dbpf)Cl ₂ (15 mg, 0.02 mmol) and Cs ₂ C0 ₃ (747 mg, 2.31 mmol) were added to 1,4-dioxane (10 mL) / water (5 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 45 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc hexane = 5 % to 25 %), and concentrated to yield the title compound as white solid (300 mg, 79%).

Step 2. 2-fluoro-4-(5-((l-((l-(trifluoromethvl)cvclobutyl ^' )methyl)piperidin-4-yl)methoxy) pyrazine-2-yl)benzoic acid: Ethyl 2-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrazine-2-yl)benzoate (300 mg, 0.61 mmol) and LiOH H ₂ 0 (51 mg, 1.21 mmol) were dissolved in THF (10 mL) / water (5 mL) at room temperature. The solution was stirred at 60 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was added with 1M HC1 aqueous solution (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (280 mg, 99%).

Step 3. Compound 1012: 2-fluoro-4-(5-((l-((l-(trifluoromethyl)cyclobutyl)methyl)pip eridin- 4-yl)methoxy)pyrazine-2-yl)benzoic acid (50 mg, 0.11 mmol), (R)-pyrrolidine-2-ylmethanol (16 mg, 0.16 mmol), EDC (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.21 mmol) were dissolved in DMF (2 mL) at room temperature. The solution was stirred at 60 °C for 16 hours. The concentrate was added with water (4 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as beige solid (24 mg, 41%). 1H NMR (400 MHz, CDC1 ₃ ) δ 8.52 (m, 1 H), 8.29 (m, 1 H), 7.75 (m, 2 H), 7.53 (m, 1 H), 4.72 (m, 1 H), 4.40 (m, 1 H), 4.23 (d, 2 H, J = 5.4 Hz), 3.84 - 3.78 (m, 2 H), 3.45 (m, 2 H), 2.89 (m, 2 H), 2.54 (s, 2 H), 2.24 - 1.64 (m, 15 H), 1.45 (m, 2 H); MS (ESI) m/z 551 (M+ + H).

According to the above-described synthesis process of compound 1012, the compounds of Table 96 were synthesized using 2-fluoro-4-(5-((l -((l -(trifluoromethyl)cyclobutyl)methyl) piperidin-4-yl)methoxy)pyrazine-2-yl)benzoic acid and the reactant of Table 95.

Table 95.

Table 96.

Example 95. Compound 772:(S)-(3-hydroxypyrrolidine-l-yl)(4-(6-((l-((l-(trifluorom ethyl) cyclopentyl)me one

Step 1. ethyl 1 -(1 -(trifluoromethyl)cyclopentanecarbonyl)piperidin-4-carboxyla te:

l-(trifluoromethyl)cyclopentanecarboxylic acid(500 mg, 2.74 mmol), ethyl piperidin-4- carboxylate(518 mg, 3.29 mmol), EDC (1.05 g, 5.49 mmol) and HOBt (742 mg, 5.49 mmol) were dissolved in DMF 5 mL. DIPEA (0.97 mL, 5.49 mmol) was added thereto, and the reaction was performed at 60°C for 8 hours. The reaction mixture was added with saturated

NH ₄ CI aqueous solution, and extracted with EtOAc. The extracted organic layer was dried over MgS0 ₄ , and then filtered. The filtrate was purified by silica gel column chromatography (10- 30 % EtOAc/hexane) to yield the title compound as colorless oil (400 mg, 45%).

Step 2. ( 1 -(( 1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methanol : Ethyl 1 -( 1 - (trifluoromethyl)cyclopentanecarbonyl)piperidin-4-carboxylat e(1.06 g, 3.30 mmol) was dissolved in dry THF 20 mL. At 0°C, LAH (1 M in THF, 16.49 mL, 16.49 mmol) was added slowly thereto. The reaction was performed at 50 °C for 10 hours. The reaction was quenched by slow addition of MeOH at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (844 mg, 96%).

Step 3. 5-bromo-2-(( 1 -(( 1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4- yl)methoxy)pyridine: ( 1 -(( 1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methanol (844 mg, 3.18 mmol) was dissolved in THF 10 mL. At 0 °C, NaH (115 mg, 4.77 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5-dibromopyridine (829 mg, 3.50 mmol) in THF was added slowly thereto. The reaction was performed at 50 °C for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (900 mg, 67%).

Step 4. methyl 4-(6-((l -((1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate: 5-bromo-2-((l -((1 -

(trifluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methox y)pyridine (400 mg, 0.95 mmol), 4- (methoxycarbonyl)phenylboronic acid (188 mg, 1.04 mmol), Pd(dbpf)Cl ₂ (19 mg, 0.03 mmol), Cs ₂ C0 ₃ (922 mg, 2.85 mmol) were added into a microwave reactor, and then 1,4-dioxane 4 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and then extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (330 mg, 73%).

Step 5. 4-(6-((l -((1 -(trifluoromethyl)cyclopentyl)methyl)piperidin-4-yl)methoxy) pyridine-3- yl)benzoic acid: Methyl 4-(6-((l-((l-(trifluoromethyl)cyclopentyl)methyl)piperidin-4 - yl)methoxy)pyridine-3-yl)benzoate (330 mg, 0.69 mmol) was dissolved in the mixed solvents of THF 4 mL / water 4 mL. LiOH H ₂ 0 (58 mg, 1.38 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HC1 thereto, the resulting precipitate was filtered to yield the title compound as white solid (300 mg, 94%).

Step 6. Compound 772: 4-(6-((l-((l-(trifluoromethyl)cyclopentyl)methyl)piperidin-4 - yl)methoxy)pyridine-3-yl)benzoic acid (50 mg, 0.11 mmol), (S)-pyrrolidine-3-ol (14 mg, 0.16 mmol), EDC (41 mg, 0.22 mmol) and HOBt (29 mg, 0.22 mmol) were dissolved in DMF 2 mL. DIPEA (0.04 mL, 0.22 mmol) was added thereto, and the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as white solid (21 mg, 37%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (s, 1 H), 7.80 (dd, 1 H, J = 10.2, 3.6 Hz), 7.65 - 7.53 (m, 4 H), 6.83 (d, 1 H, J = 8.6 Hz), 4.62 - 4.50 (m, 1 H), 4.29 - 4.18 (m, 2 H), 3.87 - 3.48 (m, 5 H), 2.89 (m, 2 H), 2.47 (s, 2 H), 2.30 (t, 2 H, J = 11.2 Hz), 2.20 - 1.96 (m, 3 H), 1.87 - 1.76 (m, 10 H), 1.45 (m, 2 H); MS (ESI) m/z 532 (M+ + H).

According to the above-described synthesis process of compound 772, the compounds of Table 98 were synthesized using 4-(6-((l-((l-(trifluoromethyl)cyclopentyl)methyl)piperidin-4 - yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 97.

Table 97.

Table 98.

- 7.53 (m, 4 H), 6.98 (br, 1 H), 6.83 (d, 1 H, J = 8.6 Hz), 5.45 (br, 1 H), 4.84 (dd, 1

H, J = 10.2, 3.6 Hz), 4.31 - 4.19 (m, 2 H), 3.67 - 3.54 (m, 2 H), 3.23 (m, 1 H), 2.89 - 2.80 (m, 2 H), 2.52 - 2.47 (m, 3 H), 2.32 (m, 2 H), 2.16 (m, 4 H), 1.98 -

I.68 (m, 9 H), 1.42 (m, 2 H); MS (ESI) m/z 559 (M+ + H).

(R)-(3-hydroxypiperidin- 1 -yl)(4-(6-((l -((1 -(trifluoromethyl)cyclopentyl) methyl)piperidin-4-yl)methoxy)pyridine-3-yl)phenyl)methanone

775 1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, 1 H, J = 2.3 Hz), 7.80 (dd, 1 H, J = 10.2,

3.6 Hz), 7.56 (d, 1 H, J = 8.4 Hz), 7.51 (d, 1 H, J = 8.3 Hz), 6.82 (d, 1 H, J = 8.6

Hz), 4.25 - 3.20 (m, 9 H), 2.89 (m, 2 H), 2.47 (s, 2 H), 2.30 (t, 2 H, J = 11.0 Hz),

2.09 - 1.68 (m, 14 H), 1.42 (m, 2 H); MS (ESI) m/z 546 (M+ + H).

Example 96. Compound 776:(S)-(3-hydroxypyrroIidine-l-yl)(4-(6-((l-((l-(trifluorom ethyl) cyclohexyl)methyl)piperidin-4-yl)methoxy)pyridine-3-yl)pheny l)methanone

Step 1. ethyl l-(l-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-carbox ylate:

l-(trifluofomethyl)cyclohexanecarboxylic acid(500 mg, 2.55 mmol), ethyl piperidin-4- carboxylate (481 mg, 3.06 mmol), EDC (977 mg, 5.09 mmol) and HOBt (689 mg, 5.09 mmol) were dissolved in DMF 5 mL. DIPEA (0.90 mL, 5.09 mmol) was added thereto. The reaction was performed at 60 °C for 8 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution and extracted with EtOAcr The extracted organic layer was dried over MgS0 ₄ , and then filtered. The filtrate was purified, by silica gel column chromatography (10-30 % EtOAc/hexane) to yield the title compound as colorless oil (250 mg, 29%).

Step 2. ( 1 -(( 1 -(trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methanol :

Ethyl l-(l-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-carbox ylate (576 mg, 1.72 mmol) was dissolved in dry THF 10 mL. At 0 °C, LAH (1 M in THF, 8.59 mL, 8.59 mmol) was added slowly thereto. The reaction was performed at 50 °C for 10 hours. The reaction was quenched by slow addition of MeOH at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (430 mg, 90%).

Step_3. 5-bromo-2-((l-((l-(trifluoromethyl)cyclohexyl)methyl)piperid in-4- yl)methoxy)pyridine: (1 -((1 -(trifluoromethyl)cyclohexyl)methyl)piperidin-4- yl)methanol(430 mg, 1.54 mmol) was dissolved in THF 10 mL. At 0 °C, NaH (55 mg, 2.31 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5-dibromopyridine(401 mg, 1.69 mmol) in THF was added slowly thereto. The reaction was performed at 50 °C for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 %

EtOAc/hexane) to yield the title compound as white solid (380 mg, 57%).

Step 4. methyl 4-(6-((l -((1 -(trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methoxy) pyridine-3-yl)benzoate: 5-bromo-2-((l -((1 -(trifluoromethyl)cyclohexyl)methyl)piperidin-4- yl)methoxy)pyridine (380 mg, 0.87 mmol), 4-(methoxycarbonyl)phenylboronic acid(173 mg, 0.96 mmol), Pd(dbpf)Cl ₂ (17 mg, 0.03 mmol), Cs ₂ C0 ₃ (848 mg, 2.62 mmol) were added into a microwave reactor, and then 1,4-dioxane 4 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (250 mg, 58%).

Step 5. 4-(6-((l-((l-(trifluoromethvl)cvclohexvl)methvl)piperidin-4- vl)methoxv)pvridine-3- yl)benzoic acid: Methyl 4-(6-((l-((l-(trifluoromethyl)cyclohexyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate (250 mg, 0.51 mmol) was dissolved in the mixed solvents of THF 4 mL / water 4 mL. LiOH H ₂ 0 (43 mg, 1.02 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HC1 thereto, the resulting precipitate was filtered to yield the title compound as white solid (210 mg, 87%).

Step 6. Compound 776 : 4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclohexyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid (45 mg, 0.09 mmol), (S)-pyrrolidine-3-ol (12 mg, 0.14 mmol), EDC (36 mg, 0.19 mmol) and HOBt (26 mg, 0.19 mmol) were dissolved in DMF 2 mL. DIPEA (0.03 mL, 0.19 mmol) was added thereto, the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as white solid (24 mg, 47%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (s, 1 H), 7.80 (m, 1 H), 7.67 - 7.54 (m, 4 H), 6.81 (m, 1 H), 4.61 - 4.45 (m, 1 H), 4.28 - 4.17 (m, 2 H), 3.84 - 3.48 (m, 4 H), 2.87 (m, 2 H), 2.48 (s, 2 H), 2.32 - 2.00 (m, 5 H), 1.88 - 1.35 (m, 15 H); MS (ESI) m/z 546 (M+ + H).

According to the above-described synthesis process of compound 776, the compounds of Table 100 were synthesized using 4-(6-((l-((l-(trifluoromethyl)cyclohexyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 99.

Table 99.

Table 100.

Example 97. Compound 828: (S)-l-(4-(6-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidi n-

4-yl)methoxy)p

Step 1. ethyl l-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperidin-4-carboxy late: 3,3,3- trifluoro-2,2-dimethylpropanoic acid (500 mg, 3.20 mmol), ethyl piperidin-4-carboxylate (604 mg, 3.84 mmol), EDC (1.23 g, 6.41 mmol) and HOBt (866 mg, 6.41 mmol) were dissolved in DMF 15 mL. DIPEA (1.13 mL, 6.41 mmol) was added thereto, and the reaction was performed at 60 °C for 8 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution and extracted with EtOAc. The extracted organic layer was dried over MgS0 ₄ , and then filtered. The filtrate was purified by silica gel column chromatography (10-30 %

EtOAc hexane) to yield the title compound as colorless oil (300 mg, 36%).

Step 2. ( 1 -(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methanol: Ethyl 1 -(3 ,3 ,3 - trifluoro-2,2-dimethylpropanoyl)piperidin-4-carboxylate (260 mg, 0.88 mmol) was dissolved in dry THF 20 mL. At 0 °C, LAH (1 M in THF, 4.40 mL, 4.40 mmol) was added slowly thereto and the reaction was performed at 50 °C for 10 hours. The reaction was quenched by slow addition of MeOH at 0 °C. The reaction mixture was added with water, and then extracted with EtOAc. The obtained extracted organic layer was dried over MgS0 ₄ , and then filtered to yield the title compound as colorless oil (170 mg, 81%).

Step 3. 5-bromo-2-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin- 4-yl)methoxy)pyridine: (l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methan ol(170 mg, 0.71 mmol) was dissolved in THF 10 mL. At 0°C, NaH (26 mg, 1.07 mmol) was added slowly thereto. The reaction was performed at room temperature for 20 minutes. At 0 °C, 2,5-dibromopyridine (185 mg, 0.78 mmol) in THF was added slowly thereto, and the reaction was performed at 50 °C for 10 hours. After the completion of the reaction, the reaction mixture was added with ice water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as colorless oil (260 mg, 93%).

Step 4. methyl 4-(6-((l -(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methoxy) pyridine-3- yl)benzoate: 5-bromo-2-(( 1 -(3 ,3 ,3 -trifiuoro-2,2-dimethylpropyl)piperidin-4- yl)methoxy)pyridine (260 mg, 0.66 mmol), 4-(methoxycarbonyl)phenylboronic acid(130 mg, 0.72 mmol), Pd(dbpf)Cl ₂ (13 mg, 0.02 mmol), Cs ₂ C0 ₃ (640 mg, 1.97 mmol) were added into a microwave reactor, and then 1,4-dioxane 6 mL and water 3 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and then extracted with EtOAc. The obtained organic layer was dried over MgS0 , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (200 mg, 68%).

Step 5. 4-(6-(( 1 -(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methoxy)pyridin e-3 - yl)benzoic acid: Methyl 4-(6-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate (200 mg, 0.44 mmol) was dissolved in the mixed solvents of THF 10 mL / water 10 mL. LiOH H ₂ 0 (37 mg, 0.89 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HCl thereto, the resulting precipitate was filtered to yield the title compound as white solid (150 mg, 77%).

Step 6. Compound 828: 4-(6-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid (40 mg, 0.09 mmol), L-prolinamide (16 mg, 0.14 mmol), EDC (35 mg, 0.18 mmol) and HOBt (25 mg, 0.18 mmol) were dissolved in DMF 2 mL.

DIPEA (24 mg, 0.18 mmol) was added thereto, and the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as white solid (20 mg, 41 %).

1H NMR (400 MHz, CDC1 ₃ ) 6 8.38 (d, 1 H, J = 2.1 Hz), 7.81 (dd, 1 H, J = 10.2, 3.6 Hz), 7.64 - 7.56 (m, 4 H), 6.99 (s, 1 H), 6.83 (d, 1 H, J = 8.6 Hz), 5.56 (s, 1 H), 4.82 (dd, 1 H, J = 10.2, 3.6 Hz), 4.19 (d, 2 H, J = 4.8 Hz), 3.66 - 3.56 (m, 2 H), 2.83 (d, 2 H, J = 9.0 Hz), 2.47 - 2.30 (m, 4 H), 2.10 (m, 2 H), 1.90 - 1.70 (m, 5 H), 1.42 (m, 2 H), 1.11 (m, 6 H); MS (ESI) m/z 423 (M+ + H).

According to the above-described synthesis process of compound 828, the compounds of Table 102 were synthesized using 4-(6-((l -(3,3,3 -trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 101.

Table 101.

Table 102.

Example 98. Compound 809: (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin- yl)methoxy)biphenyl-4-yl)(3-hydroxypiperidin-l-yl)methanone

Step 1. 2,2-diethyloxirane: 3 -methyl enepentane (2 g, 23.76 mmol) and m-CPBA (6.56 g, 38.02 mmol) were dissolved in CH ₂ C1 ₂ 30 mL. At 0 °C, the reaction was performed for a day. The reaction mixture was added with saturated Na ₂ S0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer was washed with saturated aqueous brine solution, dried over

MgS04, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure to yield the title compound as colorless oil (1.8 g, 75%).

Step 2. 3 -((4-((4-bromophenoxy)methyl)piperidin- 1 -yl)methyl)pentane-3-ol :

4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 4 of compound 686; 500 mg, 1.85 mmol) was dissolved in EtOH 4 mL. 2,2-diethyloxirane (the product of synthesis step 1 of compound 809; 930 mg, 9.25 mmol), K ₂ C0 ₃ (512 mg, 3.70 mmol) and water 2 mL were added thereto, With a microwave radiation, the mixture was stirred at 110 °C for 20 minutes. After the completion of the reaction, EtOH was evaporated from the reaction mixture under reduced pressure, and then a little of water was added to thereto. The resulting precipitate was filtered, and dried under reduced pressure to yield the title compound as white solid (600 mg, 87%).

Step 3. 4-((4-bromophenoxy)methyl)- 1 -(2-ethyl-2-fluorobutyl)piperidine:

3- ((4-((4-bromophenoxy)methyl)piperidin-l-yl)methyl)pentane-3- ol (596 mg, 1.61 mmol) was dissolved in CH ₂ C1 ₂ 5 mL. DAST (285 mg, 1.77 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer washed with saturated aqueous brine solution, dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 15 - 20 %

EtOAc/Hexane) to yield the title compound as white solid (520 mg, 87%).

Step 4. methyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-ca rboxylate:

4- ((4-bromophenoxy)methyl)-l-(2-ethyl-2-fluorobutyl)piperidine (130 mg, 0.35 mmol), 4- (methoxycarbonyl)phenylboronic acid (69 mg, 0.38 mmol), Pd(dbpf)Cl ₂ (11 mg, 0.02 mmol) and Cs ₂ C0 ₃ (228 mg, 0.70 mmol) were dissolved in 1 ,4-dioxane 4 mL and water 1 mL. With a microwave radiation, the reaction was performed at 120 °C for 15 minutes. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge,

EtOAc/Hexane) to yield the title compound as white solid (105 mg, 70%).

Step 5. 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)bipheny l-4-carboxylic acid:

Methyl 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)bipheny l-4-carboxylate (105 mg, 0.25 mmol) was dissolved in THF:MeOH:water - 3/1.5/1 mL. LiOH H ₂ 0 (21 mg, 0.49 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using IN HC1. The resulting precipitate was filtered to yield the title compound as white solid (72 mg, 71%).

Step 6. Compound 809: 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)bipheny l-4- carboxylic acid (35 mg, 0.09 mmol), (R)-piperidin-3-ol (13 mg, 0.13 mmol) and BOP (75 mg, 0.17 mmol) were dissolved in DMF 1 mL. After stirring for 10 minutes at room temperature, TEA (26 mg, 0.26 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl2) to yield the title compound as white solid (17 mg, 40%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.49 (m, 6 H), 6.96 (d, 2 H, J = 6.8 Hz), 3.82 (m, 4 H), 3.42 (m, 3 H), 2.99 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 (m, 2 H), 1.71 (m, 11 H), 1.64 (m, 2 H), 0.89 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 497 (M + H). According to the above-described synthesis process of compound 809, the compounds of Table 104 were synthesized using 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)bipheny l-4- carboxylic acid and the reactant of Table 103.

Table 103.

Table 104.

Example 99. Compound 888: (S)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 - fluorobiphenyl-4-yl -hydroxypyrrolidine-l-yl)methanone

Step 1. ethyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3-fluorobiph enyl-4- carboxylate: 4-((4-bromophenoxy)methyl)- 1 -(2-ethyl-2-fluorobutyl)piperidine (the product of synthesis step 3 of compound 809; 130 mg, 0.35 mmol), 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (345 mg, 1.63 mmol), Pd(dppf)Cl ₂ (60 mg, 0.07 mmol) and Na ₂ C0 ₃ (313 mg, 2.95 mmol) were dissolved in DME 12 mL and water 3 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (390 mg, 54%). Step 2. 4' -((I -(2-ethyl-2-fluorobutyl)piperidm^

acid: Ethyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3-fluorobiph enyl-4- carboxylate (390 mg, 0.85 mmol) was dissolved in THF/MeOH/water = 6/3/2 mL. LiOH H ₂ 0 (71 mg, 1.70 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using 1 N HCl. The resulting precipitate was filtered to yield the title compound as white solid (340 mg, 92%).

Step 3. Compound 888: 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenyl-4-carboxylic acid (0.03 g, 0.07 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.14 mmol) and DIPEA (0.036 mL, 0.209 mmol) were dissolved in DMF (1 mL). At room temperature, (S)-pyrrolidine-3-ol (0.01 g, 0.10 mmol) was added thereto, following with stirring at 50 °C for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (22 mg, 63%).

1H NM (400 MHz, CDC1 ₃ ) δ 7.49 (m, 3 H), 7.39 (m, 1 H), 7.28 (m, 1 H), 6.98 (d, 2 H, J - 8.7 Hz), 4.62 (s, 0.5 H), 4.49 (s, 0.5 H), 3.86 (m, 2 H), 3.70 (m, 2 H), 3.46 (m, 1 H), 2.96 (m, 2 H), 2.43 (m, 2 H), 1.97 - 1.65 (m, 1 1 H), 0.91 (t, 6 H, J = 7.4 Hz); MS (ESI) m/z 501 (M + H).

According to the above-described synthesis process of compound 888, the compounds of Table 106 were synthesized using 4'-((l-(2-ethyl ⁱ 2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenyl-4-carboxylic acid and the reactant of Table 105.

Table 105.

Table 106.

Compound

Compound Name, 1H-NMR, MS (ESI)

No. (R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)rnethoxy)- 3-fluorobiphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

810 1H NMR (400 MHz, CDC1 ₃ ) δ 7.47 (m, 3 H), 7.33 (m, 2 H), 6.96 (m, 2 H), 5.74 (s, 1 H), .4.42 (m, 1 H), 3.84 (d, 2 H, J = 5.9 Hz), 3.74 (m, 2 H), 3.59 (m, 2 H), 2.98 (m, 2 H), 2.48 (s, 1 H), 2.42 (s, 1 H), 1.92 (m, 11 H), 1.72 (m, 11 H), 0.89 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 515 (M + H).

l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenylcarbonyl)piperidin-4-carboxamide

814 1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (m, 2 H), 7.32 (m, 2 H), 7.27 (m, 1 H), 6.98 (m, 2 H), 5.49 (m, 1 H), 4.73 (m, 1 H), 3.84 (m, 2 H), 3.72 (m, 1 H), 3.02 (m, 4 H), 2.46 (m, 3 H), 2.04 (m, 2 H), 1.83 (m, 1 H), 1.68 (m, 12 H), 0.91 (t, 6 H, J = 7.5 Hz)

(S)-l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) -3-

866 fluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

MS (ESI) m/z 528 (M + H).

(S)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 -fluorobiphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

889 1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (m, 2 H), 7.41 (m, 2 H), 7.27 (m, 1 H), 6.98 (d, 2 H, J = 8.7 Hz), 4.00 (m, 2 H), 3.85 (d, 2 H, J = 5.9 Hz), 3.36 (m, 1 H), 3.26 (m, 2 H), 2.95 (m, 2 H), 2.37 (m, 2 H), 2.16 (m, 2 H), 1.82 - 1.26 (m, 14 H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 515 (M + H).

(R)-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3 -fluorobiphenyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (m, 2 H), 7.42 (m, 2 H), 7.27 (m, 1 H), 6.98

890

(d, 2 H, J = 6.9 Hz), 4.01 (m, 2 H), 3.85 (d, 2 H, J = 5.9 Hz), 3.57 (m, 1 H), 3.33 (m, 2 H), 3.01 (m, 2 H), 2.48 (m, 2 H), 2.18 (m, 2 H), 1.94 - 1.48 (m, 14 H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 515 (M + H).

Ϊ !i

Example 100. Compound 895: (S)-l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)-2-fluorobiphenylcarbonyl)pyrrolidine-2-carboxami de

Step 1. methyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluorobiph enyl-4- carboxylate: 4-((4-bromophenoxy)methyl)-l-(2-ethyl-2-fluorobutyl)piperidi ne (the product of synthesis step 3 of compound 809; 550 mg, 1.48 mmol), 2-fluoro-4-(methoxycarbonyl) phenylboronic acid (322 mg, 1.63 mmol), Pd(dppf)Cl ₂ (60 mg, 0.07 mmol), Na ₂ C0 ₃ (313 mg, 2.95 mmol) were dissolved in DME 12 mL and water 3 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated

NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (350 mg, 53%).

Step_2. 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluo robiphenyl-4-carboxylic acid: Methyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluorobiph enyl-4- carboxylate (350 mg, 0.79 mmol) was dissolved in THF/MeOH/water = 6/3/2 mL. LiOH H ₂ 0 (66 mg, 1.57 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using 1 N HC1. The resulting precipitate was filtered to yield the title compound as white solid (310 mg, 91 %) .

Step 3. Compound 895: 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2- fluorobiphenyl-4-carboxylic acid (0.03 g, 0.07 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.14 mmol) and DIPEA (0.04 mL, 0.21 mmol) were dissolved in DMF (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (12 mg, 0.10 mmol) was added thereto, following with stirring at 50 °C for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (23 mg, 62%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.48 (m, 3 H), 7.35 (m, 2 H), 6.97 (d, 2 H, J = 8.7 Hz), 6.91 (s, 1 H), 5.56 (s, 1 H), 4.78 (m, 1 H), 3.84 (d, 2 H, J = 5.9 Hz), 3.61 (m, 2 H), 3.00 (m, 2 H), 2.44 (m, 2 H), 2.03 (m, 4 H), 1.89 - 1.44 (m, 12 H), 0.89 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 528 (M + H).

According to the above-described synthesis process of compound 895, the compounds of Table 108 were synthesized using 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2- fluorobiphenyl-4-carboxylic acid and the reactant of Table 107.

Table 107.

Table 108.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)-(4 ' -(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluorobiph enyl-4-

811

yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 7.49 (m, 3 H), 7.37 (m, 2 H), 7.28 (m, 1 H), 6.95 (m, 2 H), 4.78 (s, 1 H), 4.37 (m, 1 H), 3.78 (m, 4 H), 3.45 (m, 2 H), 2.98 (m, 2 H), 2.47 (s, 1 H), 2.41 (s, 1 H), 2.17 (m, 3 H), 1.87 (m, 1 H), 1.75 (m, 10 H), 0.89 (t, 6 H, J = 7.5 Hz)

(R)-(4 ' -(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluorobiph enyl-4- yl)(3 -hydroxypiperidin- 1 -yl)methanone

812 1H NMR (400 MHz, CDC1 ₃ ) δ 7.45 (m, 3 H), 7.21 (m, 2 H), 6.97 (m, 2 H), 3.91

(m, 4 H), 3.56 (m, 3 H), 2.99 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 (m, 2 H), 1.71 (m, 13 H), 0.89 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 515 (M + H).

Example 101. Compound 896: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyridi -2-yl)benzoyI)pyrrolidine-2-carboxamide

Step 1. 3-((4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-yl)methy l)pentane-3-ol:

2- chloro-5-(piperidin-4-ylmethoxy)pyridine hydrochloride (the product of synthesis step 2 of compound 691 ; 1.4 g, 5.32 mmol) was dissolved in EtOH 6 mL. 2,2-diethyloxirane (the product of synthesis step 1 of compound 809; 1.60 g, 15.96 mmol), K ₂ C0 ₃ (1.47 g, 10.64 mmol) and water 3 mL were added thereto, With a microwave radiation, the mixture was stirred at 110 °C for 20 minutes. Ethanol was evaporated from the reaction mixture under reduced pressure, and water was added thereto. The resulting precipitate was filtered, and dried under reduced pressure to yield the title compound as white solid (1.61 g, 92%).

Step 2. 2-chloro-5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine:

3- ((4-((6-chloropyridine-3-yloxy)methyl)piperidin-l-yl)methyl) pentane-3-ol (1.61 g, 4.93 mmol) was dissolved in CH ₂ C1 10 mL. DAST (873 mg, 5.42 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer washed with saturated aqueous brine solution, dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, 15 - 20 % Hexane/EtOAc) to yield the title compound as white solid (1.24 g, 76%).

Step 3. methyl 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-2-yl )benzoate: 2-chloro-5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyridine (550 mg, 1.67 mmol), 4- (methoxycarbonyl)phenylboronic acid (331 mg, 1.84 mmol), Pd(dppf)Cl ₂ (68 mg, 0.08 mmol) and Na ₂ C0 ₃ (354 mg, 3.35 mmol) were dissolved in DME 12 mL and water 3 mL, and then refluxed with heating and stirring for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column

chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (310 mg, 43%).

Step 4. 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-2-yl )benzoic acid: methyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-2-yl)benzoate (310 mg, 0.98 mmol) was dissolved in THF/MeOH/water = 6/3/2 mL. LiOH-H ₂ 0 (61 mg, 1.45 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using 1 N HC1. The resulting precipitate was filtered to yield the title compound as white solid (210 mg, 70%).

Step 5. Compound 896: 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine- 2-yl)benzoic acid (0.05 g, 0.12 mmol), EDC (0.05 g, 0.24 mmol), HOBt (0.03 g, 0.24 mmol) and DIPEA (0.06 mL, 0.36 mmol) were dissolved in CH ₂ C1 ₂ (3 mL). At room temperature, (S)- pyrrolidine-2-carboxamide (0.02 g, 0.18 mmol) was added thereto, following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (0.04 g, 61%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, 1 H, J = 2.6 Hz), 7.97 (d, 2 H, J = 8.2 Hz), 7.62 (m, 3 H), 7.26 (m, 1 H), 7.06 (s, 1 H), 5.78 (s, 1 H), 4.78 (m, 1 H), 3.88 (d, 2 H, J = 5.9 Hz), 3.61 (m, 2 H), 3.00 (d, 2 H, J = 10.7 Hz), 2.49 - 2.43 (m, 2 H), 2.38 (m, 1 H), 2.08 (m, 4 H), 1.80 (m, 8 H), 1.42 (m, 2 H), 0.88 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 511 (M + H).

According to the above-described synthesis process of compound 896, the compounds of Table 110 were synthesized using 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-2- yl)benzoic acid and the reactant of Table 109.

Table 109. Table 110.

Example 102. Compound 898: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyridine-2-yl)-2-fluorobenzoyl)pyrrolidine-2-carb oxamide

Step 1. ethyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-2-yl)-2- fluorobenzoate: 2-chloro-5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine (the product of synthesis step 2 of compound 896; 550 mg, 1.67 mmol), 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (390 mg, 1.84 mmol), Pd(dppf)Cl ₂ (68 mg, 0.08 mmol) and Na ₂ C0 ₃ (354 mg, 3.35 mmol) were dissolved in DME 12 mL and water 3 mL, and then refluxed with heating for a day. The reaction mixture was filtered through Celite. The filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as white solid (290 mg, 37%).

Step 2. 4-(5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-2-yl )-2-fluorobenzoic acid: Ethyl 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-2-yl )-2- fluorobenzoate (290 mg, 0.63 mmol) was dissolved in THF/MeOH/water = 6/3/2 mL.

LiOH H ₂ 0 (53 mg, 1.26 mmol) was added thereto. And then, the mixture was refluxed with heating for 3 hours. After the completion of the reaction, the solvent was dried under reduced pressure, following with adjusting pH to below 6 using 1 N HCl. The resulting precipitate was filtered to yield the title compound as white solid (220 mg, 80%).

Step 3. Compound 898: 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-2- yl)-2-fluorobenzoic acid (0.05 g, 0.12 mmol), EDC (0.05 g, 0.24 mmol), HOBt (0.03 g, 0.24 mmol) and DIPEA (0.06 mL, 0.36 mmol) were dissolved in CH ₂ C1 ₂ (3 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.02 g, 0.18 mmol) was added thereto, following with stirring with at the same temperature for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (0.04 g, 61%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, 1 H, J - 2.9 Hz), 7.75 (m, 2 H), 7.67 (d, 1 H, J = 8.8 Hz), 7.49 (t, 1 H, J = 7.6 Hz), 7.27 (dd, 1 H, J = 8.5, 3.1 Hz), 6.93 (s, 1 H), 5.64 (s, 1 H), 4.81 (m, 1 H), 3.89 (d, 2 H, J = 6.0 Hz), 3.50 (m, 1 H), 3.40 (m, 1 H), 3.00 (m, 2 H), 2.43 (m, 3 H), 2.08 (m, 4 H), 1.92 - 1.46 (m, 10 H), 0.89 (t, 6 H, J - 7.5 Hz); MS (ESI) m/z 529 (M + H).

According to the above-described synthesis process of compound 898, the compounds of Table 112 were synthesized using 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-2- yl)-2-fluorobenzoic acid and the reactant of Table 11 1.

Table 1 11.

Table 112.

Example 103. Compound 954: (R).(4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yI)methoxy)pyridin -3-yI)phenyl)(3-hydroxypiperidin-l-yI)methanone

Step 1. 3-((4-((5-bromopyridine-2-yloxy)methyl)piperidin- 1 -yl)methyl)pentane-3-ol:

To 5-bromo-2-(piperidin-4-ylmethoxy)pyridine hydrochloride (the product of synthesis step 3 of compound 784; 2.70 g, 8.77 mmol), 2,2-diethyloxirane (the product of synthesis step 1 of compound 809; 4.39 g, 43.88 mmol) and K ₂ C0 ₃ (2.42 g, 17.55 mmol), EtOH (6 mL) / H ₂ 0 (3 mL) was added. With a microwave radiation, the mixture was heated at 115 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (1.50 g, 46%, yellow oil).

Step 2. 5-bromo-2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) pyridine: 3-((4-((5- bromopyridine-2-yloxy)methyl)piperidin-l-yl)methyl)pentane-3 -ol (1.50 g, 4.04 mmol) was dissolved in CH ₂ C1 ₂ (8 mL). At 0 °C, DAST (0.58 mL, 4.44 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.95 g, 63%, yellow oil).

Step 3. methyl 4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-3-yl )benzoate: 5-bromo-2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) pyridine (0.30 g, 0.80 mmol), 4- (methoxycarbonyl)phenylboronic acid (0.17 g, 0.96 mmol), Pd(dppf)Cl ₂ (0.06 g, 0.08 mmol) and Na ₂ C0 ₃ (0.17 g, 1.60 mmol) were dissolved in DME (12 mL) / water (3 mL). With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NaHC0 ₃ aqueous solution was added thereto, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.21 g, 61%).

Step 4. 4-(6-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-3 -yl)-2-fluorobenzoic acid: Methyl 4-(6-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-3- yl)benzoate (0.18 g, 0.39 mmol) and LiOH H ₂ 0 (0.03 g, 0.78 mmol) were dissolved in THF / MeOH (6 mL / 3 mL) / water (2 mL). The mixture was refluxed with heating for 10 hours, and then cooled to room temperature, following with concentrating under reduced pressure. After the addition of water to the concentrate, the resulting precipitate was filtered, and dried to yield the title compound as yellow solid (0.15 g, 88%).

Step 5. Compound 954: 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-3- yl)-2-fluorobenzoic acid (0.04 g, 0.09 mmol), EDC (0.03 g, 0.19 mmol), HOBt (0.02 g, 0.19 mmol) and DIPEA (0.03 g, 0.28 mmol) were dissolved in DMF (1 mL). At room temperature, (R)-piperidin-3-ol (0.02 g, 0.15 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 5 %), and concentrated to yield the title compound as white solid (0.02 g, 31 %).

1H NMR (400 MHz, CDC1 ₃ ) 5 8.36 (d, 1 H, J,= 2.5 Hz), 7.78 (dd, 1 H, J = 8.6, 2.6 Hz), 7.52 (m, 4 H), 6.81 (d, 1 H, J = 8.6 Hz), 4.17 (d, 2 H, J = 6.2 Hz), 3.98 - 3.05 (m, 6 H) ₅ 2.96 (m, 2 H), 2.46 - 2.39 (m, 2 H), 2.11 (m, 2 H), 1.95 (m, 3 H), 1.69 (m, 8 H), 1.43 (m, 3 H), 0.88 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 498 (M + H).

According to the above-described synthesis process of compound 954, the compounds of Table 114 were synthesized using 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-3- yl)-2-fluorobenzoic acid and the reactant of Table 113.

Table 113.

Table 114.

fluorobutyl)piperidin-4-yl)methoxy)pyridine-2-yl)-2-fluoroph enyl)(3- hydroxypyrrolidine- 1 -yl)methanone

Example 104. Compound 956: (R)-(4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyridi -3-yl)-2-fluorophenyl)(3-hydroxypiperidin-l-yl)methanone

Step 1. ethyl 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-3-yl)-2- fluorobenzoate: To 5-bromo-2-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine (the product of synthesis step 2 of compound 954; 0.30 g, 0.80 mmol), 4-(ethoxycarbonyl)-3- fluorophenylboronic acid (0.18 g, 0.88 mmol), Pd(dppf)Cl ₂ (0.06 g, 0.08 mmol) and Na ₂ C0 ₃ (0.17 g, 1.60 mmol), DME (12 mL) / water (3 mL) was added. With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NaHC0 ₃ aqueous solution was added thereto, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.18 g, 48%).

Step 2. 4-(6-(( 1 -(2-ethvl-2-fluorobutyl ^' )piperidin-4-vl)methoxv)pyridine-3 -yl -2-fluorobenzoic acid: Ethyl 4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridine-3-yl )-2- fluorobenzoate (0.18 g, 0.39 mmol) and LiOH H ₂ 0 (0.03 g, 0.78 mmol) were dissolved in THF / MeOH (6 mL / 3 mL) / water (2 mL). The mixture was refluxed with heating for 10 hours, and then cooled to room temperature, following with concentrating under reduced pressure. After the addition of water to the concentrate, the resulting precipitate was filtered, and dried to yield the title compound as yellow solid (0.15 g, 88%).

Step 3. Compound 956: 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-3- yl)-2-fmorobenzoic acid (0.04 g, 0.08 mmol), EDC (0.03 g, 0.16 mmol), HOBt (0.02 g, 0.16 mmol) and DIPEA (0.03 g, 0.24 mmol) were dissolved in DMF (1 mL). At room temperature, (R)-piperidin-3-ol (0.01 g, 0.12 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 5 %), and concentrated to yield the title compound as white solid (17 mg, 40%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.34 (s, 1 H), 7.75 (m, 1 H), 7.44 (m, 1 H), 7.35 (m, 1 H), 7.24 (m, 1 H), 6.81 (d, 1 H, J = 8.6 Hz), 4.17 (d, 2 H, J = 6.1 Hz), 3.92 (m, 2 H), 3.33 (m, 3 H), 2.96 (m, 2 H), 2.46 - 2.40 (m, 2 H), 1.96 (m, 6 H), 1.69 (m, 8 H), 1.39 (m, 2 H), 0.88 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 516 (M + H).

According to the above-described synthesis process of compound 956, the compounds of Table 116 were synthesized using 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid ine-3- yl)-2-fluorobenzoic acid and the reactant of Table 115.

Table 1 15.

Table 116.

Example 105. Compound 953: (S)-l-(4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyridazine-3- l benzo l rrolidine-2-carboxamid

Step 1. t-butyl 4-((6-chloropyridazine-3-yloxy)methyl)piperidin- 1 -carboxylate:

t-butyl 4-(hydroxymethyl)piperidin-l -carboxylate (the product of synthesis step 1 of compound 686; 3.00 g, 13.94 mmol) and NaH (0.50 g, 20.90 mmol) were dissolved in DMF (100 ml). At 0 °C, 3,6-dichloropyridazine (2.49 g, 16.72 mmol) was added thereto, following with stirring at room temperature for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 0 % to 50 %), and concentrated to yield the title compound as white solid (2.60 g, 56%).

Step 2. 3-chloro-6-(piperidin-4-ylmethoxy)pyridazine: t-butyl 4-((6-chloropyridazine-3- yloxy)methyl)piperidin-l-carboxylate (2.60 g, 7.93 mmol) and HC1 in 1,4-dioxane (4 M solution in 1,4-dioxane, 9.91 mL, 39.66 mmol) were dissolved in MeOH (30 mL) at room temperature. The solution was stirred at the same temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (1.80 g, 85%).

Step 3. 3 -((4-((6-chloropyridazine-3 -yloxy)methyl)piperidin- 1 -yl)methyl)pentane-3 -ol :

3-chloro-6-(piperidin-4-ylmethoxy)pyridazine (1.20 g, 5.27 mmol) and Et ₃ N (7.31 mL, 52.70 mmol) were dissolved in EtOH (10 mL). 2,2-diethyloxirane (the product of synthesis step 1 of compound 809; 1.06 g, 10.54 mmol) was added thereto. With a microwave radiation, the mixture was heated at 1 10 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSG ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (0.30 g, 17%, white solid ).

Step 4. 3-chloro-6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyridazine:

3-((4-((6-chloropyridazine-3-yloxy)methyl)piperidin-l-yl) methyl)pentane-3-ol (0.30 g, 0.91 mmol) was dissolved in dichloromethane (20 mL). At 0 °C, DAST (0.16 g, 1.00 mmol) was added thereto, following with stirring at room temperature for 1 hour. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 50 %), and concentrated to yield the title compound as yellow solid (0.14 g, 46%).

Step 5. methyl 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid azine-3- yl)benzoate: 3-chloro-6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyridazine (0.14 g, 0.42 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.08 g, 0.42 mmol), Pd(dbpf)Cl ₂ (0.01 g, 0.02 mmol) and Cs ₂ C0 ₃ (0.27 g, 0.85 mmol) were added to 1,4-dioxane (12 mL) / H ₂ 0 (3 mL). With a microwave radiation, the mixture was heated at 115 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC>4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 80 %), and concentrated to yield the title compound as white solid (0.05 g, 37%).

Step 6. 4-(6-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrid azine-3-yl)benzoic acid: methyl 4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridazine-3- yl)benzoate (0.05 g, 0.12 mmol) and LiOH H ₂ 0 (0.02 g, 0.58 mmol) were dissolved in THF (2 mL) / H ₂ 0 /MeOH (3 mL) at room temperature. The solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as yellow solid (0.05 g, 93%).

Step 7. Compound 953 : 4-(6-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyridazine- 3-yl)benzoic acid (0.02 g, 0.05 mmol), EDCI (0.02 g, 0.10 mmol), HOBt (0.01 g, 0.10 mmol) and DIPEA (0.03 g, 0.24 mmol) were dissolved in DMF (2 mL). At room temperature, (S)- pyrrolidine-2-carboxamide (0.01 g, 0.10 mmol) was added thereto, following with stirring at 60 °C for 12 hours. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated yield the title compound as light-yellow solid (0.01 g, 44%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.05 (d, 2 H, J = 8.1 Hz), 7.79 (d, 1 H, J = 9.3 Hz), 7.64 (d, 2 H, J = 10.0 Hz), 7.04 (d, 2 H, J = 9.3 Hz), 6.95 (brs, 1 H), 4.81 - 4.80 (m, 1 H), 4,42 (d, 2 H, J = 6.4 Hz), 3.59 - 3.53 (m, 2 H), 2.96 (d, 2 H, J = 11.2 Hz), 2.44 - 2.38 (m, 3 H), 2.13 - 1.62 (m, 1 1 H), 1.46 - 1.23 (m, 3 H), 0.87 (t, 6 H, J = 7.4 Hz); MS (ESI) m/z 512 (M+ + H). Example 106. Compound 1004 : (S)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. methyl 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 5-bromo-2-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)benzonitrile

(the product of synthesis step 4 of compound 1000; 400 mg, 1.01 mmol), 4-

(methoxycarbonyl)phenylboronic acid (199 mg, 1.11 mmol), Pd(dppf)Cl ₂ (82 mg, 0.10 mmol) and Cs ₂ C0 ₃ (656 mg, 2.01 mmol) were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (184 mg, 40%).

Step 2. 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-ca rboxylic acid: Methyl 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate (184 mg, 0.41 mmol) was dissolved in THF (10 mL) and water (5 mL).

LiOH H ₂ 0 (85 mg, 2.03 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (158 mg, 88%).

Step 3. Compound 1004: 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (35 mg, 0.08 mmol), (S)-pyrrolidine-2-carboxamide (18 mg, 0.16 mmol), EDC (31 mg, 0.16 mmol) and HOBt (22 mg, 0.16 mmol) was added thereto, DIPEA (28 μΐ,, 0.16 mmol) was dissolved in CH ₂ C1 ₂ (1 mL). After stirring at room temperature for a day, the reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (22 mg, 51%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.79 - 7.70 (m, 2 H), 7.63 - 7.60 (m, 2 H), 7.54 - 7.52 (m, 2 H), 7.34 - 7.27 (m, 1 H), 7.02 - 6.99 (m, 1 H), 5.72 (brs, 1 H), 4.80 - 4.78 (m, 1 H), 3.94 (d, 2 H, J = 6.3 Hz), 3.66 - 3.63 (m, 1 H), 3.52 - 3.48 (m, 3 H), 3.00 (s, 1 H), 2.95 (s, 1 H), 2.71 - 2.60 (m, 2 H), 2.48 - 2.37 (m, 1 H), 2.10 - 1.99 (m, 5 H), 1.82 - 1.69 (m, 7 H), 0.87 - 0.83 (m, 6 H); MS (ESI) m/z 535 (M+ + H).

According to the above-described synthesis process of compound 1004, the compounds of Table 118 were synthesized using 3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 117.

Table 1 17. 1006 (S)-pyrrolidine-3 -ol 71

Table 118.

Example 107. Compound 1000 : (S)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)-3-fluorobiphenylcarbonyl)pyrroIidine-2-carboxami de

Step 1. 5-bromo-2-((l-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)methoxy )benzonitrile:

To 5-bromo-2-(piperidin-4-ylmethoxy)benzonitrile hydroxychloride (the product of synthesis step 2 of compound 938; 1.00 g, 3.39 mmol), 2,2-diethyloxirane (1.70 g, 16,94 mmol) and K ₂ C0 ₃ (937 mg, 6.78 mmol), EtOH (5 mL) / H ₂ 0 (5 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material, which is the title compound as white solid (1.33 g, 99%), was used without further purification.

Step 2. 5-bromo-2-((l-(2-ethyl-2-fiuorobutyl)piperidin-4-yl)methoxy) benzonitrile:

5-bromo-2-((l-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)meth oxy)benzonitrile (1.33 g, 3.36 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). At 0 °C, DAST (444 μί, 3.36 mmol) was added thereto, following with stirring at room temperature for 1 hour. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The obtained material, which is the title compound as yellow oil (800 mg, 59%), was used without further purification.

Step 3. ethyl 3 '-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )-3-fluorobiphenyl- 4-carboxylate: 5-bromo-2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) benzonitrile (400 mg, 1.01 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (235 mg, 1.1 1 mmol), Pd(dppf)Cl ₂ (82 mg, 0.10 mmol) and Cs ₂ C0 ₃ (656 mg, 2.01 mmol) were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 1 10 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (189 mg, 38%).

Step 4. 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3-fluorobiph enyl-4- carboxylic acid: Ethyl 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-3- fluorobiphenyl-4-carboxylate (189 mg, 0.39 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH-H ₂ 0 (82 mg, 1.95 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (161 mg, 90%).

Step 5. Compound 1000: 3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)- 3-fluorobiphenyl-4-carboxylic acid (35 mg, 0.08 mmol), (S)-pyrrolidine-2-carboxamide (18 mg, 0.15mmol), EDC (29 mg, 0.15 mmol) and HOBt (21 mg, 0.15 mmol) was added thereto, DIPEA (27 μΕ, 0.15 mmol) was dissolved in CH ₂ C1 ₂ (1 mL). After stirring at room temperature for a day, the reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (25 mg, 59%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.77 - 7.71 (m, 2 H), 7.51 (t, 1 H, J = 7.5 Hz), 7.38 (d, 1 H, J = 8.0 Hz), 7.30 - 7.26 (m, 1 H), 7.05 (d, 1 H, J = 8.8 Hz), 6.90 (brs, 1 H), 5.57 (brs, 1 H), 4.83 - 4.80 (m, 1 H), 3.96 (d, 2 H, J = 6.2 Hz), 3.56 - 3.39 (m, 2 H), 3.02 (brs, 2 H), 2.50 - 2.43 (m, 2 H), 2.18 - 2.03 (m, 4 H), 1.95 - 1.87 (m, 4 H), 1.74 - 1.68 (m, 5 H), 1.45 (brs, 2 H), 0.92 - 0.88 (m, 6 H); MS (ESI) m/z 553 (M+ + H). According to the above-described synthesis process of compound 1000, the compounds of Table 120 were synthesized using 3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)-3-fiuorobiphenyl-4-carboxylic acid and the reactant of Table 119.

Table 119.

Table 120.

Example 108. Compound 1124 : (S)-l-(2 ^, -cyano-4'-((l-(2-ethyl-2-fiuorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyI)pyrrolidine-2-carboxamide

Step 1. 2-bromo-5-(( 1 -(2-ethyl-2-hydroxybutyl)piperidin-4-yl)methoxy)benzonitrile :

5-bromo-2-(piperidin-4-ylmethoxy)benzonitrile hydroxychloride (the product of synthesis step 2 of compound 1028; 3.00 g, 9.05 mmol) was dissolved in EtOH 6 mL. 2,2-diethyloxirane (the product of synthesis step 1 of compound 809; 2.72 g, 27.14 mmol), K ₂ C0 ₃ (2.50 g, 18.09 mmol) and water 3 mL were added thereto, With a microwave radiation, the mixture was stirred at 110 °C for 15 minutes. Ethanol was evaporated from the reaction mixture under reduced pressure. After the addition of water thereto, the resulting precipitated was filtered, and dried under reduced pressure to yield the title compound as white solid (2.9 g, 81%).

Step 2. 2-bromo-5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)benzonitrile:

2-bromo-5-((l-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)meth oxy)benzonitrile (2.90 g, 7.34 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). At room temperature, DAST (1.30 g, 8.07 mmol) was added thereto, following with stirring at the same temperature for 3 hours. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material (yellow oil) was used without further purifying process (2.20 g, 75%).

Step 3. methyl 2'-cyano-4'-((l-(2-emyl-2-fluorobutyl)piperidin-4-yl)methoxy )biphenyl-4- carboxylate: 2-bromo-5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)benzonitrile (700 mg, 1.76 mmol), 4-(methoxycarbonyl)phenylboronic acid (381 mg, 2.1 1 mmol),

Pd(dbpf)Cl ₂ (57 mg, 0.09 mmol) and Cs ₂ C0 ₃ (1.15 g, 3.52 mmol) were dissolved in 1,4- dioxane (3 mL) / H ₂ 0 (1 mL). At 120 °C, the mixture was stirred for 15 minutes. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; ethyl acetate / hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.52 g, 65%).

Step 4. 2'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)biphenyl-4-carboxylic acid: Methyl 2'-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate (0.52 g, 1.15 mmol) and LiOH H ₂ 0 (0.10 g, 2.30 mmol) were dissolved in THF / MeOH (6 mL / 3 mL) / Water (2 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with a little of conc.HCl to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.45 g, 89%).

Step 5. Compound 1124: 2'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.60 g, 0.14 mmol), EDC (0.05 g, 0.27 mmol), HOBt (0.04 g, 0.27 mmol) and DIPEA (0.05 g, 0.41 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.02 g, 0.16 mmol) was added thereto, following with stirring at the same temperature for 8 hours. The reaction mixture was added with water, and extracted with dichloromethane. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (0.05 g, 61%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.66 (d, 2 H, J = 8.2 Hz), 7.58 (d, 2 H, J - 8.2 Hz), 7.41 (d, 1 H, J = 8.6 Hz), 7.20 (m, 2 Hz), 7.07 (s, 1 H), 5.82 (s, 1 H), 4.80 (m, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.66 (m, 2 H), 3.01 - 2.98 (m, 2 H), 2.48 (s, 1 H), 2.42 (s, 1 H), 2.40 (m, 1 H), 2.09 (m, 4 H), 1.88 - 1.65 (m, 8 H), 1.41 (m, 2 H), 0.90 (t, 6 H, J = 7.5 Hz) According to the above-described synthesis process of compound 1124, the compounds of Table 122 were synthesized using 2'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 121.

Table 121.

Table 122.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(R)- 1-(2 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 (m, 4 H), 7.39 (d, 1 H, J = 8.6 Hz), 7.15 (m, 2

1125 H), 6.53 (s, 1 H), 5.90 (s, 1 H), 5.28 (m, 1 H), 3.81 (m, 3 H), 3.15 (m, 1 H), 2.97 - 2.95 (m, 2 H), 2.45 (s, 1 H), 2.39 (s, 1 H), 2.29 (m, 1 H), 2.11 (t, 2 H, J = 11.0 Hz), 1.77 - 1.62 (m, 10 H), 1.43 (m, 4 H), 0.90 (t, 6H, J = 8.8 Hz) (R)-4-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-4 ' -(3 -hydroxypiperidin- 1 -carbonyl)biphenyl-2-carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 (m, 4 H), 7.38 (d, 1 H, J = 8.6 Hz), 7.22 (m, 1 H), 7.16 (dd, 1 H, J = 8.7, 2.6 Hz), 4.07 - 3.62 (m, 4 H), 3.60 - 3.01 (m, 4 H), 2.98 - 2.95 (m, 2 H), 2.45 (s, 1 H), 2.39 (s, 1 H), 2.11 (t, 2 H, J = 10.9 Hz), 1.92 - 1.62 (m, 11 H), 1.41 (m, 2 H), 0.90 (t, 6 H, J = 7.5 Hz)

Example 109. Compound 1119 : (S)-l-(3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)-2-fluorobiphenylcarbonyl)pyrrolidine-2-carboxami de

Step 1. methyl 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)2- fluorobiphenyl-4-carboxylate: 5-bromo-2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy) benzonitrile(the product of synthesis step 4 of compound 1000; 850 mg, 2.14 mmol), 2-fluoro- 4-(methoxycarbonyl)phenylboronic acid (508 mg, 2.57 mmol), Pd(dbpf)Cl2 (70 mg, 0.11 mmol) and Cs ₂ C0 ₃ (1.39 g, 4.28 mmol) were added to 1,4-dioxane (3 mL) / H ₂ 0 (1 mL). With a microwave radiation, the mixture was heated at 120 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was added with saturated NaHC0 ₃ aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; ethyl acetate/hexane = 20 % to 30 %), and concentrated to yield the title compound as white solid (0.71 g, 70%).

Step 2. 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2-fluorobiph enyl-4- carboxylic acid: Methyl 3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)2- fluorobiphenyl-4-carboxylate (710 mg, 1.51 mmol) and LiOH-¾0 (0.13 g, 3.02 mmol) were dissolved in THF / MeOH (6 mL / 3 mL) / water (2 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with a little of conc.HCl to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.62 g, 90%).

Step 3. Compound 1119: 3 '-cyano-4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)- 2-fluorobiphenyl-4-carboxylic acid (0.06 g, 0.13 mmol), EDC (0.05 g, 0.26 mmol), HOBt (0.04 g, 0.26 mmol) and DIPEA (0.05 g, 0.39 mmol) were dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.02 g, 0.16 mmol) was added thereto, following with stirring at the same temperature for 8 hours. The reaction mixture was added with water, and extracted with dichloromethane. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgSC , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 2 % to 5 %), and concentrated to yield the title compound as white solid (0.04 g, 53%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.72 (s, 1 H), 7.70 (d, 2 H, J = 8.9 Hz), 7.38 (m, 3 H), 7.03 (d, 1 H, J = 8.8 Hz), 6.90 (s, 1 H), 5.75 (s, 1 H), 4.75 (m, 1 H), 3.93 (d, 2 H, J = 6.4 Hz), 3.62 (m, 2 H), 3.54 (m, 2 H), 2.98 - 2.95 (m, 2 H), 2.38 (m, 2 H), 2.06 (m, 5 H), 1.88 (m, 4 H), 1.70 (m, 4 H), 1.41 (m, 2 H), 0.90 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 553 (M+ + H).

According to the above-described synthesis process of compound 1119, the compounds of Table 124 were synthesized using 3'-cyano-4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)-2-fluorobiphenyl-4-carboxylic acid and the reactant of Table 123.

Table 123.

Table 124.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(R)- 1 -(3 '-cyano-4' -((1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2- fluorobiphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.70 (m, 2 H), 7.37 (m, 3 H), 7.03 (d, 1 H, J = 8.8

1120

Hz), 4.82 (m, 1 H), 4.39 (m, 2 H), 3.92 (d, 2 H, J = 6.4 Hz), 3.73 (m, 2 H), 3.52 (m, 2 H), 2.98 - 2.95 (m, 2 H), 2.45 (s, 1 H), 2.39 (s, 1 H), 2.12 (m, 3 H), 1.90 - 1.61 (m, 10 H), 1.38 (m, 2 H), 0.91 (t, 6 H, J = 7.5 Hz)

(S)-4-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2'- fluoro-4'-(3- hydroxypyrrolidine- 1 -carbonyl)biphenyl-3 -carbonitrile

1H NMR (400 MHz, CDC1 ₃ ) δ 7.70 (m, 2 H), 7.37 (m, 3 H), 7.03 (d, 1 H, J = 8.8

1121

Hz), 4.60 - 4.48 (s, 1 H), 3.93 (d, 2 H, J = 6.4 Hz), 3.82 - 3.46 (m, 4 H), 2.98 - 2.96 (m, 2 H), 2.48 (m, 3 H), 2.03 (m, 4 H), 1.99 (m, 3 H), 1.71 (m, 4 H), 1.42 (m, 2 H), 0.90 (t, 6 H, J = 7.5 Hz)

(R)-4-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2 ' -fluoro-4 ' -(3 - hydroxypiperidin- 1 -carbonyl)biphenyl-3 -carbonitrile

1123

1H NMR (400 MHz, CDC1 ₃ ) δ 7.72 (m, 2 H), 7.42 (t, 1 H, J = 7.8 Hz), 7.30 (m, 2 H), 7.05 (d, 1 H, J = 8.8 Hz), 3.95 (m, 3 H), 3.82 - 3.25 (m, 5 H), 3.01 - 2.98 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 (m, 2 H), 1.88 (m, 5 H), 1.71 (m, 5 H), 1.43 (m, 2 H), 0.91 (t, 6 H, J - 7.5 Hz)

Example 110. Compound 1018: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrazi -2-yl)benzoyl)pyrrolidine-2-carboxamide

Step 1. 3-((4-((5-iodopyrazine-2-yloxy)methyl)piperidin-l-yl)methyl) pentane-3-ol:

To 2-iodo-5-(piperidin-4-ylmethoxy)pyrazine hydrochloride (the product of synthesis step 2 of compound 944 ; 1.00 g, 2.81 mmol), 2,2-diethyloxirane (1.01 g, 14.06 mmol) and ₂ C0 ₃ (1.94 g, 14.06 mmol), EtOH (8 mL) / H ₂ 0 (2 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgSC«4, and filtered. The filtrate was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (1.15 g, 97%).

Step 2. 2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-5-iodop yrazine:

3- ((4-((5-iodopyrazine-2-yloxy)methyl)piperidin-l-yl)methyl)pe ntane-3-ol (2.00 g, 5.44 mmol) was dissolved in CH ₂ C1 ₂ (20 mL). At 0 °C, DAST (0.87 mL, 6.53 mmol) was added thereto, following with stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.41 g, 17%).

Step 3. methyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyraz ine-2-yl)benzoate: To 2-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-5-iodop yrazine (0.40 g, 0.94 mmol),

4- (methoxycarbonyl)phenylboronic acid (0.20 g, 1.13 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol) and Cs ₂ C0 ₃ (0.61 g, 1.89 mmol), DME (3 mL) / H ₂ 0 (1 mL) was added. With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.08 g, 19%).

Step 4. 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrazine-2-yl )benzoic acid: Methyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyraz ine-2-yl)benzoate (0.08 g, 0.18 mmol) and LiOH H ₂ 0 (0.03 g, 0.93 mmol) were dissolved in THF / MeOH (8 mL) / H ₂ 0 (1 mL) at 60 °C, following with stirring at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.04 g, 54%).

Step 5. Compound 1018: 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyraz ine- 2-yl)benzoic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.20 mmol), EDC (0.03 g, 0.20 mmol) and DIPEA (0.03 mL, 0.20 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, the reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; dichloromethane / methanol = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.01 g, 34%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.53 (s, 1 H), 8.30 (s, 1 H), 7.98 (d, 2 H, J = 8.3 Hz), 7.65 (d, 2 H, J = 8.2 Hz), 6.69 (s, 1 H), 5.46 (s, 1 H), 4.83 (dd, 1 H, J = 7.4, 4.7 Hz), 4.22 (d, 2 H, J = 6.2 Hz), 3.54 - 4.03 (m, 2H), 2.98 - 3.00 (m, 2 H), 2.48 - 2.51 (m, 2 H), 2.43 (s, 1 H), 2.03 - 2.16 (m, 3 H), 1.65 - 1.89 (m, 7 H), 1.39 - 1.48 (m, 2 H), 1.26 - 1.31 (m, 2H), 0.90 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 512.3 (M+ + H).

Example 111. Compound 1051: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yI)methoxy)pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxamide

Step 1. 3-((4-((2-chloropyrimidin-5-yloxy)methyl)piperidin-l-yl)meth yl)pentane-3-ol:

EtOH (4 mL) / H ₂ 0 (1 mL) was added to 2-chloro-5-(piperidin-4-ylmethoxy)pyrimidine hydrochloride (the product of synthesis step 2 of compound 1032 ; 1.20 g, 4.54 mmol), 2,2- diethyloxirane (3.18 g, 31.80 mmol) and ₂ C0 ₃ (1.25 g, 9.08 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material was used without further purifying process (1.47 g, 98%, white solid ).

Step 2. 2-chloro-5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyrimidine:

3-((4-((2-chloropyrimidin-5-yloxy)methyl)piperidin-l-yl)m ethyl)pentane-3-ol (1.47 g, 4.48 mmol) was dissolved in CH ₂ C1 ₂ (20 mL). At 0 °C, DAST (0.70 mL, 5.38 mmol) was added thereto, following with stirring at room temperature for 3 hours. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution, dried over anhydrous

MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.71 g, 48%).

Step 3. methyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrim idin-2- yl)benzoate: DME (4 mL) / H ₂ 0 (1 mL) was added to 2-chloro-5-((l-(2-ethyl-2- fluorobutyl)piperidin-4-yl)methoxy)pyrimidine (0.20 g, 0.60 mmol), 4- (methoxycarbonyl)phenylboronic acid (0.13 g, 0.72 mmol), Pd(dppf)Cl ₂ (0.02 g, 0.03 mmol) and Cs ₂ C0 ₃ (0.39 g, 1.21 mmol). With a microwave radiation, the mixture was heated at

120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NH ₄ CI aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.20 g, 76%).

Step 4. 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methyloxy)pyrimidin-2 -yl)benzoic acid: Methyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrim idin-2-yl)benzoate (0.20 g, 0.46 mmol) and LiOH-H ₂ 0 (0.09 g, 2.32 mmol) were dissolved in THF (4 mL) / MeOH (4 mL) / H ₂ 0 (1 mL) at room temperature. The solution was stirred at the same temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (20 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.15 g, 77%). Step 5. Compound 1051 : 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methyloxy)pyr imidin- 2-yl)benzoic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.13 mmol), HOBt (0.02 g, 0.21 mmol), EDC (0.04 g, 0.21 mmol) and DIPEA (0.03 mL, 0.21 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSC>4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.05 g, 93%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (s, 2 H), 8.41 (d, 2 H, J = 8.4 Hz),7.64 (d, 2 H, J = 8.3 Hz), 7.08 (s, 1 H), 5.71 (s, 1 H), 4.82 (dd, 1 H, J = 7.3, 5.1 Hz), 3.95 (d, 2 H, J = 6.0 Hz), 3.50 - 3.66 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.40 - 2.49 (m, 3 H), 2.05 - 2.17 (m, 4 H), 1.65 - 1.91 (m, 4 H), 1.41 - 1.49 (m, 4 H), 1.20 - 1.26 (m, 2 H), 0.91 (t, 6 H, J - 7.5 Hz); MS (ESI) m/z 512.3 (M+ + H).

According to the above-described synthesis process of compound 1051, the compounds of Table 126 were synthesized using 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methyloxy)pyrimidin-2-yl)benzoic acid and the reactant of Table 125.

Table 125.

Table 126.

Compound

Compound Name, Ή-NMR, MS (ESI)

No.

(R)-(4-(5-((l-(2-ethyl-2-fiuorobutyl)piperidin-4-yl)methoxy) pyrimidin-2- yl)phenyl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDCI3) δ 8.48 (s, 2 H), 8.39 (d, 2 H, J = 8.3 Hz), 7.52 (d, 2

1052

H, J = 8.2 Hz), 3.95 - 4.01 (m, 3 H), 3.33 - 3.88 (m, 4 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 (t, 2 H, J = 11.0 Hz), 1.27 - 2.06 (m, 14 H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 499.3 (M+ + H).

(R)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methox y)pyrimidin-2- yl)benzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (s, 2 H), 8.42 (d, 2 H, J = 7.8 Hz), 7.56 (d, 2

1053

H, J = 8.0 Hz), 6.53 (s, 1 H), 5.63 (s, 1 H), 5.31 (s, 1 H), 3.96 (d, 2 H, J = 5.8 Hz), 3.75 - 3.78 (m, 1 H), 3.09 - 3.15 (m, 1 H), 2.99 - 3.02 (m, 2 H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.33 - 2.36 (m, 1 H), 2.15 (t, 2 H, J = 11.4 Hz), 1.19 - 2.06 (m, 14 H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 526.3 (M+ + H).

Example 112. Compound 1056: (R)-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyriim -2-yl)-3-fluorophenyl)(3-hydroxypiperidin-l-yI)methanone

Step 1. methyl 4-(5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin-2-y l)-3 - fluorobenzoate: To 2-chloro-5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyrimidine (the product of synthesis step 2 of compound 1051; 0.25 g, 0.75 mmol), 2-fluoro-4- (methoxycarbonyl)phenylboronic acid (0.16 g, 0.83 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.03 mmol) and Cs ₂ C0 ₃ (0.49 g, 1.51 mmol), DME (4 mL) / H ₂ 0 (1 mL) was added. With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.21 g, 61%).

Step 2. 4-(5-((l -(2-ethvl-2-fluorobutvnpiperidin-4-vl)methoxv)pvrimidin-2-yl )-3-fluorobenzoic acid: Methyl 4-(5-((l -(2-ethyl-2:-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin-2- yl)-3- fluorobenzoate (0.21 g, 0.46 mmol)' and LiOH H ₂ 0 (0.09 g, 2.34 mmol) were dissolved in THF (4 mL) / MeOH (4 mL) / H ₂ 0 (1 mL) at room temperature. The solution was stirred at the sane temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (30 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.14 g, 71%).

Step 3. Compound 1056: 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrim idin- 2-yl)-3-fluorobenzoic acid (0.04 g, 0.10 mmol), (R)-piperidin-3-ol hydrochloride(0.01 g, 0.12 mmol), HOBt (0.02 g, 0.20 mmol), EDC (0.04 g, 0.20 mmol) and DIPEA (0.02 g, 0.20 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.02 g, 42%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.53 (s, 2 H), 8.06 (t, 1 H, J = 7.8 Hz), 7.24 - 7.33 (m, 2H), 3.97 (d, 2 H, J = 6.0 Hz), 3.29 - 3.79 (m, 4H), 3.00 - 3.02 (m, 2H), 2.49 (s, 1 H), 2.43 (s, 1 H), 2.15 (t, 2 H, J = 11.0 Hz), 1.27 - 2.06 (m, 15 H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 517.3 (M† + H).

According to the above-described synthesis process of compound 1056, the compounds of . Table 128 were synthesized using 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-3-fluorobenzoic acid and the reactant of Table 127.

Table 127.

Table 128.

Example 113. Compound 1054: (S)-l-(4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-2-fluorobenzoyl)pyrrolidine-2-car boxamide

Step 1. ethyl 4-(5-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin-2-y l)-2- fluorobenzoate: DME (4 mL) / H ₂ 0 (1 mL) was added to 2-chloro-5-((l -(2-ethyl-2- fluorobutyl)piperidin-4-yl)methoxy)pyrimidine (the product of synthesis step 2 of compound 1051 ; 0.25 g, 0.75 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (0.17 g, 0.83 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.03 mmol) and Cs ₂ C0 ₃ (0.49 g, 1.51 mmol). With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The filtrate was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (0.26 g, 74%).

Step 2. 4-(5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin-2-y l)-2-fluorobenzoic acid: Ethyl 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrim idin-2-yl)-2- fluorobenzoate (0.26 g, 0.60 mmol) and LiOH H ₂ 0 (0.12 g, 3.02 mmol) were dissolved in THF (4 mL) / MeOH (4 mL) / H ₂ 0 (1 mL) at room temperature. The solution was stirred at the same temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (20 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.19 g, 72%).

Step 3. Compound 1054 : 4-(5-(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin- 2-yl)-2-fluorobenzoic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.20 mmol), EDC (0.04 g, 0.20 mmol) and DIPEA (0.03 mL, 0.20 mmol) were dissolved in CH ₂ C1 ₂ (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH ₄ C1 aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.05 g, 90%).

1H NMR (400 MHz, CDC1 ₃ ) 5 8.47 (s, 2 H), 8:23 (d, 1 H, J = 8.0 Hz), 8.14 (d, 1 H, J = 11.1 Hz), 7.52 (t, 1 H, J = 7.5 Hz), 6.96 (s, 1 H), 5.71 (s, 1 H), 4.81 - 4.84 (m, 1 H), 3.96 (d, 2 H, J = 6.0 Hz), 3.38 - 3.56 (m, 2 H), 3.03 - 3.00 (m, 2 H), 2.44 - 2.50 (m, 3 H), 1.26 - 2.18 (m, 14 H), 0.90 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 530.3 (M+ + H).

According to the above-described synthesis process of compound 1054, the compounds of Table 130 were synthesized using 4-(5-((l-(2-ethyl-2-fluorobutyl)piperidin-4- yl)methoxy)pyrimidin-2-yl)-2-fluorobenzoic acid and the reactant of Table 129

Table 129. Table 130.

Compound

Compound Name, 'H-NMR, MS (ESI)

No.

(R)-l-(4-(5-((l-(2-emyl-2-fluorobutyl)piperidin-4-yl)methoxy )pyrimidin-2-yl)-2- fluorobenzoyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (s, 2 H), 8.27 (d, 1 H, J = 8.0 Hz), 8.15 (d, 1

1055 H, J = 11.2 Hz), 7.54 (t, 1 H, J = 7.5 Hz), 6.33 (s, 1 H), 5.47 - 5.56 (m, 2 H), 3.97

(d, 2 H, J = 6.1 Hz), 3.57 - 3.61 (m, 1 H), 3.20 - 3.22 (m, 1 H), 3.02 - 3.05 (m, 2 H), 2.45 - 2.51 (m, 2 H), 2.08 (t, 2 H, J = 19.7 Hz), 1.20 - 1.83 (m, 15H), 0.91 (t, 6 H, J = 7.5 Hz); MS (ESI) m/z 544.3 (M+ + H).

Example 114. Compound 937:(S)-l-(4'-((l-(2-ethyl-2-fluorobutyl)piperidm-4-yt)metho xy)- 2,3'-difluorobiphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. 3-((4-((4-bromo-2-fluorophenoxy)methyl)piperidin- 1 -yl)methyl)pentane-3-ol:

EtOH (5 mL) / H ₂ 0 (5 mL) was added to 4-((4-bromo-2-fluorophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 2 of compound 725; 500 mg, 1.54 mmol), 2,2- diethyloxirane (771 mg, 7.70 mmol) and K ₂ C0 ₃ (426 mg, 3.08 mmol). With a microwave radiation, the mixture was heated at 110 °C for 20 minutes, and then cooled to room

temperature. The reaction mixture was added:with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained material, which is the title compound as white solid (542 mg, 90%), was used without further purification.

Step 2. 4-((bromo-2-fluorophenoxy)methyl)-l -(2-ethyl-2-fiuorobutyl)piperidine: 3-((4-((4- bromo-2-fluorophenoxy)methyl)piperidin-l-yl)methyl)pentane-3 -ol (524 mg, 1.40 mmol) was dissolved in CH ₂ C1 ₂ (10 mL). At 0 °C, DAST (184 μί, 1.40 mmol) was added thereto, following with stirring at room temperature for 1 hour. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was

concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (371 mg, 68%).

Step 3. ethyl 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3'-d ifluorobiphenyl-4- carboxylate: 4-((bromo-2-fluorophenoxy)methyl)- 1 -(2-ethyl-2-fluorobutyl)piperidine (371 mg, 0.95 mmol), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (188 mg, 0.95 mmol), Pd(dppf)Cl ₂ (78 mg, 0.10 mmol) and Cs ₂ C0 ₃ (619 mg, 1.90 mmol) were added to water (2 mL)/DME (6 mL). With a microwave radiation, the mixture was heated at 110 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAc/hexane = 30 % ~ 70 %) to yield the title compound as white solid (242 mg, 53%).

Step 4. 4 ' -(( 1 -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3 ' -difluorobiphenyl-4- carboxylic acid: Ethyl 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3 '- difiuorobiphenyl-4-carboxylate (242 mg, 0.51 mmol) was dissolved in THF (10 mL) and water (5 mL). LiOH H ₂ 0 (106 mg, 2.53 mmol) was added thereto little by little at room temperature, following with stirring for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was filtered, and dried to yield the title compound as white solid (200 mg, 87%).

Step 5. Compound 937: 4'-((l -(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3 '- difluorobiphenyl-4-carboxylic acid (40 mg, 0.09 mmol), EDC (34 mg, 0.18 mmol) and HOBt (24 mg, 0.18 mmol) was added thereto, DIPEA (32 μί, 0.18 mmol) was dissolved in CH ₂ C1 ₂ (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (20 mg, 0.18 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then . The organic layer was dried over anhydrous MgS0 ₄ , and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH ₂ C1 ₂ /MeOH = 95 % ~ 5 %) to yield the title compound as white solid (35 mg, 87%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.47 (t, 1 H, J = 7.8 Hz), 7.40 - 7.27 (m, 4 H), 7.03 (t, 1 H, J = 8.6 Hz), 6.89 (brs, 0.5 H), 5.47 (brs, 0.5 H), 4.82 - 4.79 (m, 1 H), 3.92 (d, 2 H, J = 6.2 Hz), 3.66 - 3.57 (m, 2 H), 3.00 (d, 2 H, J = 10.4 Hz), 2.49 - 2.43 (m, 2 H), 2.18 - 2.06 (m, 4 H), 1.92 - 1.66 (m, 10 H), 1.47 - 1.41 (m, 2 H), 0.92 (s, 3 H), 0.88 (s, 3 H); MS (ESI) m/z 546 (M+ + H).

According to the above-described synthesis process of compound 937, the compounds of Table 132 were synthesized using 4'-((l-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3'- difluorobiphenyl-4-carboxylic acid and the reactant of Table 131.

Table 131. Compound No. Reactant Yield (%)

940 (R)-piperidin-3-ol hydrochloride 71

941 (R)-pyrrolidine-2-ylmethanol 65

942 (S)-piperidin-3-ol hydrochloride 69

943 (S)-pyrrolidine-3-ol 67

Table 132.

Example 115. Compound 922: (S)-l-(4'-((l-((l-fluorocyclobutyl)methyl)piperidin-4- yI)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. 1 -((4-((4-bromophenoxy)methyl)piperidin- 1 -yl)methyl)cyclobutanol :

4-((4-bromophenoxy)methyl)piperidine (the product of synthesis step 4 of compound 686; 0.10 g, 0.33 mmol), l-oxaspiro[2,3]hexane (55 mg, 0.65 mmol) and Et ₃ N (0.23 μΐ,, 1.63 mmol) were dissolved in EtOH 2 mL. With a microwave radiation, the reaction was performed at 110 °C for 20 minutes. The reaction mixture was diluted with water, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was

concentrated under reduced pressure to yield the title compound as white solid (90 mg, 78%). Step_2. 4-((4-bromophenoxy)methyl)-l-((l-fluorocyclobutyl)methyl)pip eridine:

l-((4-((4-bromophenoxy)methyl)piperidin-l-yl)methyl)cyclo butanol (0.61 g, 1.72 mmol) was dissolved in CH ₂ C1 ₂ 10 mL. DAST (0.23 μΐ, 1.72 mmol) was added thereto. After stirring for 1 hour at room temperature, a saturated NaHC0 ₃ aqueous solution was added thereto, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (12 g, ISU silica gel cartridge, 0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (234 mg, 38%).

Step 3. methyl 4'-((l -((1 -fluorocyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylate: 4-((4-bromophenoxy)methyl)-l-((l-fluorocyclobutyl)methyl)pip eridine (234 mg, 0.66 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.14 g, 0.79 mmol), Pd(dbpf)Cl ₂ (13 mg, 0.02 mmol) and Cs ₂ C0 ₃ (0.64 g, 1.97 mmol) were added to the mixed solvents of 1 ,4- dioxane/H ₂ 0 3 mL/1 mL. With a microwave radiation, the mixture was heated at 140 °C for 15 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , filtered through Celite to remove a solid, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , methanol/dichloromethane = 0 % to 5 %), and concentrated to yield the title compound as light-yellow solid (194 mg, 72%).

Step 4. 4'-((l -((1 -fluorocyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-c arboxylic acid: Methyl 4'-((l -((1 -fluorocyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-c arboxylate (0.19 g, 0.47 mmol) and LiOH H ₂ 0 (0.1 g, 2.35 mmol) were dissolved in THF/MeOH/H ₂ 0 6 mL/2 mL/2 mL, and then refluxed with heating and stirring for 4 hours. The reaction mixture was cooled to room temperature, and added with water. The resulting precipitate was filtered, and dried to yield the title compound as light-brown solid (0.18 g, 94%).

Step 5. Compound 922 : 4 ' -(( 1 -(( 1 -fluorocyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl- 4-carboxylic acid (0.04 g, 0.10 mmol), EDCI (0.04 g, 0.20 mmol), HOBt (0.03 g, 0.20 mmol) and DIPEA (0.09 mL, 0.50 mmol) were dissolved in DMF (2 mL). At room temperature, (0.02 g, 0.20 mmol) was added thereto, following with stirring at 60 °C for 12 hours. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column chromatography (Si0 ₂ ; methanol/dichloromethane = 0 % to 10 %), and concentrated yield the title compound as light- yellow solid (0.03 g, 58%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 (s, 4 H), 7.53 (d, 2 H, J = 8.8 Hz), 7.04 (brs, 1 H), 6.98 (d, 2 H, J = 9.0 Hz), 5.65 (brs, 1 H), 4.81 (brs, 1 H), 3.85 (d, 2 H, J = 6.0 Hz), 3.63 - 3.59 (m, 2 H), 3.01 (d, 2 H, J = 11.4 Hz), 2.66 (s, 1 H), 2.60 (s, 1 H), 2.28 - 2.00 (m, 10 H), 1.87 - 1.81 (m, 3 H), 1.50 - 1.44 (m, 4 H); MS (ESI) m/z 494 (M+ + H) _:

According to the above-described synthesis process of compound 922, the compounds of Table 134 were synthesized using 4'-((l -((1 -fluorocyclobutyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 133.

Table 133.

Table 134.

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 - 7.45 (m, 6 H), 6.98 - 6.96 (m, 2 H), 4.02 - 3.41 (m, 7 H), 4.02 - 3.41 (m, 7 H), 3.01 (d, 2 H, J = 1 1.2 Hz), 2.66 (s, 1 H), 2.60 (s, 1 H), 2.34 - 2.03 (m, 7 H), 1.95 - 1.64 (m, 8 H), 1.55 - 1.41 (m, 4 H); MS (ESI) m/z 481 (M+ + H).

Example 116. Compound 760: (S)-l-(4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4- yl)methoxy)biphenyIcarbonyI)pyrrolidine-2-carboxamide

Step 1. l-((4-((4-bromophenoxy)methyl)piperidin-l-yl)methyl)cyclohex anol: 4-((4- bromophenoxy)methyl)piperidine hydrochloride (500 mg, 1.63 mmol), l-oxaspiro[2.5]octane (274 mg, 2.45 mmol) and K ₂ C0 ₃ (113 mg, 0.82 mmol) were added into a microwave reactor, and then ethanol 4 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 110 °C for 30 minutes. After removing ethanol, a little of water was added to the reaction mixture. The resulting precipitate was washed thoroughly with water, and dried to yield the title compound as white solid (520 mg, 83%).

Step 2. 4-((4-bromophenoxy)methyl)-l-((l-fluorocyclohexyl)methyl)pip eridine:

l-((4-((4-bromophenoxy)methyl)piperidin-l-yl)methyl)cyclo hexanol (400 mg, 1.05 mmol) was dissolved in CH ₂ C1 ₂ 10 ml. Deoxo-Fluor® (0.23 mL, 1.26 mmol) was added thereto. , following with stirring at room temperature for, 5 hours. A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-50 %

EtOAc/hexane) to yield the title compound as white solid (100 mg, 25%).

Step 3. methyl 4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4- carboxylate: 4-((4-bromophenoxy)methyl)- 1 -(( 1 -fluorocyclohexyl)methyl)piperidine (1 15 mg, 0.30 mmol), 4-(methoxycarbonyl)phenylboronic acid (60 mg, 0.33 mmol), Pd(dbpf)Cl ₂ (6 mg, 0.01 mmol), Cs ₂ C0 ₃ (291 mg, 0.90 mmol) were added into a microwave reactor, and then 1 ,4-dioxane 4 mL and water 2 mL were added thereto. With a microwave radiation, the reaction was performed at 1 10 °C for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was added with water, and then extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (100 mg, 76%). Step_4. 4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4-yl)methoxy)bi phenyl-4-carboxylic acid: Methyl 4' -(( 1 -(( 1 -fluorocyclohexyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-c arboxylate( 100 mg, 0.23 mmol) was dissolved in the mixed solvents of THF 2 mL / water 2 mL. LiOH H ₂ 0 (20 mg, 0.46 mmol) was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HCl thereto, the resulting precipitate was filtered to yield the title compound as white solid (95 mg, 98%).

Step 5. Compound 760: 4'-((l-((l-fluorocyclohexyl)methyl)piperidin-4-yl)methoxy)bi phenyl- 4-carboxylic acid(50 mg, 0.12 mmol), L-prolinamide (20 mg, 0.18 mmol), EDC (45 mg, 0.24 mmol) and HOBt (32 mg, 0.24 mmol) were dissolved in DMF 2 mL. DIPEA (30 mg, 0.24 mmol) was added thereto, and the reaction was performed at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and added with water. The formed solid was filtered, washed with water thoroughly, and dried to yield the title compound as yellow solid (15 mg, 25%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.62 - 7.52 (m, 5 H), 7.02 - 6.97 (m, 3 H), 5.42 (s, 1 H), 4.85 (t, 1 H, J = 6.2 Hz), 3.86 (s, 2 H), 3.61 (m, 2 H), 3.01 (m, 2 H), 2.53 (m, 3 H), 2.21 - 2.04 (m, 4 H), 1.85 (m, 6 H), 1.65 - 1.24 (m, 11 H); MS (ESI) m/z 522 (M+ + H).

According to the above-described synthesis process of compound 760, the compounds of Table 136 were synthesized using 4 ^, -((l-((l-fluorocyclohexyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid and the reactant of Table 135.

Table 135.

Table 136.

Example 117. Compound 857: (R)-l-(4'-((l-(2-fluoro-2-methyIpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)piperidin-2-carboxamide

Step 1. t-butyl 4-((4-bromophenylamino)methyl)piperidin-l-carboxylate:

4-bromobenzeneamine (4.00 g, 18.76 mmol) was dissolved in MeOH 100 mL. Acetic acid (1.03 mL, 18.76 mmol) and t-butyl 4-formylpiperidin-l-carboxylate (3.38 g, 19.69 mmol) were added thereto, following with stirring at room temperature for 5 hours. NaCNBH ₃ (1.17 g,

18.75 mmol) was added thereto slowly at 0 °C, following with stirring at room temperature for 3 hours and extracting with CH ₂ C1 ₂ . The obtained organic layer was washed with saturated aqueous brine solution three times. The obtained organic layer was dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (4 g ISCO silica gel cartridge, 0 - 30 % EtOAc/hexane) to yield the title compound as light-yellow solid (3.00 g, 43%).

Step 2. t-butyl 4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -carboxylate:

t-butyl 4-((4-bromophenylamino)methyl)piperidin-l -carboxylate (3.00 g, 8.12 mmol) and NaH

(0.39 g, 16.24 mmol) were dissolved in DMF (100 mL). At 0 °C, benzyl bromide (2.08 g, 12.18 mmol) was added thereto, following with stirring at room temperature for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (2.70 g, 72%).

Step 3. N-benzyl-4-bromo-N-(piperidin-4-ylmethyl)benzeneamine hydrochloride: t-butyl 4- ((benzyl(4-bromophenyl)amino)methyl)piperidin-l -carboxylate (5.20 g, 14.08 mmol) was dissolved in EtOAc (100 mL). At room temperature, HC1 in 1,4-dioxane (17.60 mL, 70.40 mmol) was added thereto, following with stirring at the same temperature for 2 hours. The resulting precipitate was filtered, and dried to yield the title compound as white solid (4.80 g, 86%).

Step 4. l-(4-((benzyl(4-bromophenyl)amino)methyl)piperidin-l-yl)-2 methylpropan-2-ol: N-benzyl-4-bromo-N-(piperidin-4-ylmethyl)benzeneamine hydrochloride (2.40 g, 6.70 mmol) and ₂ C0 ₃ (4.63 g, 33.51 mmol) were dissolved in EtOH (10 mL) / H ₂ 0 (10 mL). 1,2-epoxy- 2-methylpropane (5.95 mL, 67.02 mmol) was added thereto. With a microwave radiation, the mixture was heated at 1 10 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was used without further purification for the next step (2.00 g, 69%, colorless oil).

Step 5. N-benzyl-4-bromo-N-((l -(2-fluoro-2-methylpropyl)piperidin-2- yl)methyl)benzeneamine: 1 -(4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -yl)-2 methylpropan-2-ol (4.00 g, 9.27 mmol) was dissolved in CH ₂ C1 ₂ (100 mL). At 0 °C, DAST (1.64 g, 10.19 mmol) was added thereto. Following with stirring at the same temperature for 1 hour. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as colorless oil (2.87 g, 71%).

Step 6. methyl 4'-(benzyl((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl )amino)biphenyl- 4-carboxylate: N-benzyl-4-bromo-N-((l-(2-fluoro-2-methylpropyl)piperidin-2- yl)methyl)benzeneamine (1.00 g, 2.30 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.41 g, 2.30 mmol), Pd(dbpf)Cl ₂ (0.07 g, 0.11 mmol) and Cs ₂ C0 ₃ (1.50 g, 4.61 mmol) were added to 1,4-dioxane (12 mL) / ¾0 (3 mL). With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as yellow oil (0.89 g, 78%).

Step 7. methyl 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylamino)b iphenyl-4- carboxylate: Methyl 4'-(benzyl((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methyl)amino)biphenyl-4-carboxylate (0.89 g, 1.82 mmol) was dissolved in MeOH (3 mL) / EtOAc (5 mL). At room temperature, NH ₄ COOH (1.14 g, 18.21 mmol) was added thereto, following with stirring at 80 °C for 2 hours. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with dichloromethane.. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 30 %), and concentrated yield the title compound as light-yellow solid (0.40 g, 55%).

Step 8. 4'-(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methylamino)bipheny l-4-carboxylic acid: Methyl 4'-((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methylamino)bipheny l-4- carboxylate (0.40 g, 1.0 mmol) was dissolved in THF (3 mL) / H ₂ 0 /MeOH (2 mL). At room temperature, LiOH H ₂ 0 (0.21 g, 5.01 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.32 g, 84%).

Step 9. Compound 857: 4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid (0.10 g, 0.23 mmol), EDCI (0.09 g, 0.47 mmol), HOBt (0.06 g, 0.47 mmol) and DIPEA (0.15 g, 1.18 mmol) were dissolved in DMF (2 mL). At room temperature, (R)-piperidin-2-carboxamide (0.06 g, 0.47 mmol) was added thereto, following with stirring at 60 °C for 5 hours. The concentrate was added with water (6 mL), and stirred. The resulting precipitate was filtered, dried, and purified by column chromatography (Si0 ₂ , dichloromethane / methanol = 0 % to 5 %), and concentrated to yield the title compound as light-yellow solid (0.06 g, 51%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 - 7.27 (m, 6 H), 6.67 - 6.61 (m, 3 H), 5.92 (brs, 1 H), 5.28 (brs, 1 H), 3.83 (d, 1 H, J = 12.0 Hz), 3.13 - 2.94 (m, 5 H), 2.45 (s, 1 H), 2.39 (s, 1 H), 2.33 (d, 1 H, J = 12.0 Hz), 2.12 (t, 2 H, J = 11.4 Hz), 1.75 - 1.55 (m, 8 H), 1.38 - 1.23 (m, 8 H); MS (ESI) m/z 495 (M+ + H) According to the above-described synthesis process of compound 857, the compounds of Table 138 were synthesized using 4'-((l-(2-fiuoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid and the reactant of Table 137.

Table 137.

Table 138.

Compound

Compound Name, 1H-NMR, MS (ESI)

No.

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylam ino)biphenyl-4-

858

yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 - 7.50 (m, 4 H), 7.43 (d, 2 H, J = 8.0 Hz), 6.65 (d, 2 H, J = 8.5 Hz), 4.37 (m, 1 H), 3.75 - 3.57 (m, 4 H), 3.03 (d, 2 H, J = 6.4 Hz), 2.95 (d, 2 H, J = 1 1.6 Hz), 2.13 - 2.07 (m, 3 H), 1.73 - 1.70 (m, 6 H), 1.37 - 1.31 (m, 8 H); MS (ESI) m/z 468 (M+ + H).

(R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylam ino)biphenyl-4- yl)(2-(hydroxymethyl)pyrrolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 - 7.50 (m, 4 H), 7.42 (d, 2 H, J = 8.0 Hz), 6.65

859 (d, 2 H, J = 8.3 Hz), 4.38 - 4.36 (m, 1 H), 3.75 - 3.73 (m, 2 H), 3.58 - 3.53 (m, 2 H), 3.03 (d, 2 H, J = 6.4 Hz), 2.95 (d, 2 H, J = 1 1.6 Hz), 2.44 - 2.38 (m, 3 H), 2.13 - 2.07 (m, 3 H), 1.92 - 1.56 (m, 5 H), 1.36 - 1.31 (m, 8 H); MS (ESI) m/z 468 (M+ + H).

(R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylam ino)biphenyl-4-

867 yl)(3 -hydroxypiperidin- 1 -yl)methanone

; MS (ESI) m/z 468 (M+ + H).

(S)-l-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 - 7.52 (m, 4 H), 7.42 (d, 2 H, J = 8.2 Hz), 6.64

868

(d, 2 H, J = 8.2 Hz), 4.68 (t, 1 H, J = 6.9 Hz), 3.67 - 3.55 (m, 2 H), 3.02 (d, 2 H, J

= 6.5 Hz), 2.95 (d, 2 H, J = 11.4 Hz), 2.43 (s, 1 H), 2.38 (s, 1 H), 2.21 - 2.00 (m, 5

H), 1.72 - 1.69 (m, 4 H), 1.56 - 1.23 (m, 8 H); MS (ESI) m/z 482 (M+ + H).

(S)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylam ino)biphenyl-4- yl)(3-hydroxypyiTolidine- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.50 - 7.37 (m, 4 H), 7.36 (d, 2 H, J = 6.8 Hz), 6.60

869 (d, 2 H, J = 8.8 Hz), 4.43 - 4.26 (m, 1 H), 3.72 - 3.53 (m, 5 H), 2.97 (d, 2 H, J = 6.4 Hz), 2.90 (d, 2 H, J = 11.6 Hz), 2.39 (s, 1 H), 2.33 (s, 1 H), 2.06 - 1.87 (m, 4 H), 1.67 (d, 2 H, J = 12.4 Hz), 1.59 - 1.56 (m, 1 H), 1.33 - 1.25 (m, 8 H); MS (ESI) m/z 454 (M+ + H).

Example 118. Compound 870: (S)-l-(3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin- 4-yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

Step 1. ethyl 4'-(benzyl((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl )amino)-3- fluorobiphenyl-4-carboxylate: N-benzyl-4-bromo-N-(( 1 -(2-fluoro-2-methylpropyl)piperidin- 4-yl)methyl)benzeneamine (0.80 g, 1.84 mmol), 4-(ethoxycarbonyl)-3-fluorophenylboronic acid (0.36 g, 1.84 mmol), Pd(dbpf)Cl ₂ (0.06 g, 0.09 mmol) and Cs ₂ C0 ₃ (1.20 g, 3.69 mmol) were added to 1,4-dioxane (12 mL) / ¾0 (3 mL). With a microwave radiation, the mixture was heated at 120 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was added with saturated aqueous brine solution was added thereto, and then extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as yellow oil (0.74 g, 79%).

Step 2. ethyl 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth ylamino)biphenyl-4- carboxylate: Ethyl 4'-(benzyl((l -(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl)amino)- 3-fluorobiphenyl-4-carboxylate (0.74 g, 1.41 mmol) was dissolved in MeOH (3 mL) / EtOAc (5 mL). At room temperature, NH ₄ COOH (0.89 g, 14.15 mmol) was added thereto, following with stirring at 80 °C for 2 hours. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was diluted with water, and extracted with dichloromethane.. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as light-yellow solid (0.40 g, 67%).

Step 3. 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)meth ylamino)biphenyl-4- carboxylic acid: Ethyl 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylate (0.37 g, 0.88 mmol) was dissolved in THF (3 mL) / H ₂ 0 /MeOH (2 mL). At room temperature, LiOH H ₂ 0 (0.18 g, 4.44 mmol) was added thereto, following with stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The concentrate was added with water (10 mL), and stirred. The resulting precipitate was filtered, and dried to yield the title compound as white solid (0.35 g, 97%).

Step 4. Compound 870: 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid (0.06 g, 0.14 mmol), EDCI (0.05 g, 0.29 mmol), HOBt (0.04 g, 0.29 mmol) and DIPEA (0.13 mL, 0.74 mmol) were dissolved in DMF (2 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (0.03 g, 0.29 mmol) was added thereto, following with stirring at 60 °C for 5 hours. The concentrate was added with water (5 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column chromatography (Si0 ₂ , dichloromethane / methanol = 0 % to 10 %), and concentrated yield the title compound as light-yellow solid (0.04 g, 61%).

1H NMR (400 MHz, CDCI3) δ 7.57 - 7.37 (m, 4 H), 7.27 (t, 1 H, J = 5.6 Hz), 6.95 (brs, 1 H), 6.67 (d, 2 H, J = 8.8 Hz), 5.59 (brs, 1 H), 4.83 - 4.80 (m, 1 H), 3.55 - 3.42 (m, 2 H), 3.06 (d, 2 H, J = 6.8 Hz), 2.98 (d, 2 H, J = 11.2 Hz), 2.46 - 2.40 (m, 3 H), 2.15 - 1.86 (m, 5 H), 1.74 (d, 2 H, J = 12.4 Hz), 1.60 - 1.56 (m, 1 H), 1.39 - 1.26 (m, 8 H); MS (ESI) m/z 499 (M+ + H). According to the above-described synthesis process of compound 870, the compounds of Table 140 were synthesized using 3-fluoro-4'-((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid and the reactant of Table 139.

Table 139.

Table 140.

Example 119. Compound 1020: (S)-(3-hydroxypyrrolidine-l-yl)(4'-((l-((l- (trifluoromethyl)cycIobutyl)methyl)piperidin-4-yl)methyIaini no)biphenyl-4-yl)methanon

Step 1. (4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl) cyclobutyl)methanone: N-benzyl-4-bromo-N-(piperidin-4-ylmethyl)benzeneamine hydrochloride(the product of synthesis step 3 of compound 857; 0.80 g, 4.75 mmol), EDCI (1.82 g, 9.51 mmol), HOBt (1.28 g, 9.51 mmol) and DIPEA (4.15 mL, 23.79 mmol) were dissolved in DMF (20 mL). At room temperature, l-(trifluoromethyl)cyclobutanecarboxylic acid (1.97 g, 4.99 mmol) was added thereto, following with stirring at the same temperature for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and

concentrated to yield the title compound as yellow oil (1.30 g, 53%).

Step 2. N-benzyl-4-bromo-N-(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methyl)benzeneamine: (4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -yl)( 1 - (trifluoromethyl)cyclobutyl)methanone (1.30 g, 2.55 mmol) was dissolved in THF (15 mL) and then cooled to room temperature, following with concentrating under reduced pressure. The concentrate with heating and stirring for 1 hour, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS04, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.96 g, 75%).

Step 3. methyl 4'-(benzyl((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperid in-4- yl)methyl)amino)biphenyl-4-carboxylate: N-benzyl-4-bromo-N-((l -(( 1 - (trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methyl)ben zeneamine (0.96 g, 1.93 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.34 g, 1.93 mmol), Pd(dbpf)Cl ₂ (0.06 g, 0.09 mmol) and Cs ₂ C0 ₃ (1.26 g, 3.87 mmol) were added to 1,4-dioxane (12 mL) / H ₂ 0 (3 mL). With a microwave radiation, the mixture was heated at 1 15 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (0.80 g, 75%).

Step 4. methyl 4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl )methylamino) biphenyl-4-carboxylate: Methyl 4' -(benzyl (( ((l-(trifiuoromethyl)cyclobutyl)methyl) piperidin-4-yl)methyl)amino)biphenyl-4-carboxylate (0.80 g, 1.45 mmol) and 10% wt Pd/C (0.3 g), NH ₄ COOH (0.91 g, 14.52 mmol) were dissolved in MeOH (6 mL) / EtOAc (12 mL). The reaction mixture was refluxed with heating for 3 hours, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was diluted with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column

chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (0.44 g, 65%).

Step 5. 4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methylami no)biphenyl-4- carboxylic acid: Methyl 4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylate (0.44 g, 0.95 mmol) and LiOH H ₂ 0 (0.20 g, 4.77 mmol) were dissolved in THF (2 mL) / H ₂ 0 / MeOH (3 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (20 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.42 g, 98%).

Step 6. Compound 1020: 4'-((l-((l-(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid (0.05 g, 0.1 1 mmol), EDCI (0.04 g, 0.22 mmol), HOBt (0.03 g, 0.22 mmol) and DIPEA (0.09 mL, 0.56 mmol) were dissolved in DMF (2 mL). At room temperature, (S)-pyrrolidine-3-ol (0.02 g, 0.22 mmol) was added thereto, following with stirring at 60 °C for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as yellow solid (0.03 g, 64%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (d, 2 H, J = 7.2 Hz), 7.45 (d, 2 H, J = 8.4 Hz), 6.67 (d, 2 H, J = 8.5 Hz), 4.62 (brs, 0.5 H), 4.41 (brs, 0.5 H), 3.81 - 3.43 (m, 5 H), 3.07 (d, 2 H, J - 6.6 Hz), 2.88 (d, 2 H, J = 1 1.6 Hz), 2.23 - 1.73 (m, 12 H), 1.39 - 1.35 (m, 3 H)); MS (ESI) m/z 516 (M+ + H).

According to the above-described synthesis process of compound 1020, the compounds of Table 142 were synthesized using 4'-((l-((l-(trifiuoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid and the reactant of Table 141.

Table 141.

Table 142.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(R)-(3-hydroxypiperidin-l-yl)(4'-((l-((l-(trifluoromethyl)cy clobutyl)methyl)

926

piperidin-4-yl)methylamino)biphenyl-4-yl)methanone 1H NMR (400 MHz, CDC1 ₃ ) δ 7.54 (d, 2 H, J = 8.0 Hz), 7.42 (d, 4 H, J = 7.4 Hz), 6.65 (d, 2 H, J = 8.4 Hz), 3.87 - 3.22 (m, 5 H), 3.05 (d, 2 H, J = 6.4 Hz), 2.86 (d, 2 H, J = 10.8 Hz), 2.50 (s, 2 H), 2.25 - 1.58 (m, 15 H), 1.39 - 1.31 (m, 2 H); MS (ESI) m/z 530 (M+ + H).

(S)- 1 -(4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenylcarbonyl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (s, 4 H), 7.46 (d, 2 H, J = 8.4 Hz), 7.27 (brs, 1

1021

H), 6.67 (d, 2 H, J = 8.5 Hz), 5.59 (brs, 1 H), 4.82 (m, 1 H), 3.70 - 3.58 (m, 2 H),

3.07 (d, 2 H, J = 6.6 Hz), 2.88 (d, 2 H, J = 1 1.2 Hz), 2.52 (s, 2 H), 2.24 - 1.73 (m,

15 H), 1.39 - 1.35 (m, 2 H); MS (ESI) m/z 543 (M+ + H).

(S)-(3-hydroxypiperidin-l-yl)(4'-((l-((l-(trifiuoromethyl)cy clobutyl)methyl) piperidin-4-yl)methylamino)biphenyl-4-yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) 57.56 (d, 2 H, J = 8.2 Hz), 7.45 (d, 4 H, J = 8.8 Hz),

1022

6.67 (d, 2 H, J = 8.6 Hz), 3.91 - 3.31 (m, 5 H), 3.07 (d, 2 H, J = 6.6 Hz), 2.88 (d, 2 H, J = 11.4 Hz), 2.52 (s, 2 H), 2.24 - 1.76 (m, 15 H), 1.73 - 1.36 (m, 2 H); MS (ESI) m/z 530 (M+ + H).

(R)- 1 -(4'-((l -((1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenylcarbonyl)piperidin-2-carboxamide

1H NMR (400 MHz, CDC1 ₃ ) δ 7.59 - 7.58 (m, 2 H), 7.49 - 7.44 (m, 4 H), 6.68 (d,

1023

2 H, J = 8.4 Hz), 6.58 (brs, 1 H), 5.52 (brs, 1 H), 5.29 (brs, 1 H), 3.92 - 3.80 (m, 2

H), 3.08 - 3.06 (m, 3 H), 2.88 (d, 2 H, J = 1 1.2 Hz), 2.52 (s, 2 H), 2.23 - 1.57 (m,

16 H), 1.39 - 1.35 (m, 2 H); MS (ESI) m/z 557 (M+ + H).

Example 120. Compound 1024: (S)-(3-hydroxypyrrolidine-l-yl)(4'-((l-(3,3,3-trifluoro- 2,2-dimethylpropyl)piperidin-4-yl)methylamino)biphenyl-4-yl) methanone

Step 1. 1 -(4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -yl)-3 ,3 ,3 -trifluoro-2,2- dimethylpropan- 1 -one: N-benzyl-4-bromo-N-(piperidin-4-ylmethyl)benzeneamine hydrochloride (the product of synthesis step 3 of compound 857; 0.80 g, 5.12 mmol), EDCI (1.96 g, 10.25 mmol), HOBt (1.38 g, 10.25 mmol) and DIPEA (4.47 mL, 25.62 mmol) were dissolved in DMF (20 mL). At room temperature, 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.13 g, 5.38 mmol) was added thereto, following with stirring at the same temperature for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and

concentrated to yield the title compound as light-yellow solid (1.54 g, 60%).

Step 2. N-benzvl-4-bromo-N-((l-(3 ,3-trifluoro-2,2-dimethvlpropyl)piperidin-4- yl)methyl)benzeneamine: 1 -(4-((benzyl(4-bromophenyl)amino)methyl)piperidin- 1 -yl)- 3,3,3-trifluoro-2,2-dimethylpropan-l-one (1.54 g, 3.09 mmol) was dissolved in THF (15 mL) and then cooled to room temperature, following with concentrating under reduced pressure. The concentrate with heating for 1 hour, and then cooled to room temperature. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated NaHC0 ₃ aqueous solution. The organic layer was dried over anhydrous MgS04, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 40 g cartridge; EtOAc / hexane = 0 % to 10 %), and concentrated to yield the title compound as transparent oil (0.42 g, 28%).

Step 3. methyl 4'-(benzyl((l -(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methyl)amino)biphenyl-4-carboxylate: N-benzyl-4-bromo-N-((l-(3,3,3-trifiuoro-2,2- dimethylpropyl)piperidin-4-yl)methyl)benzeneamine (0.42 g, 0.86 mmol), 4- (methoxycarbonyl)phenylboronic acid (0.15 g, 0.86 mmol), Pd(dppf)Cl ₂ (0.02 g, 0.04 mmol) and Cs ₂ C0 ₃ (0.56 g, 1.73 mmol) were added to 1,4-dioxane (12 mL) / H ₂ 0 (3 mL). With a microwave radiation, the mixture was heated at 115 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (0.37 g, 79%).

Step 4. methyl 4'-((l -(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-yl)rnethyla mino) biphenyl-4-carboxylate: Methyl 4'-(benzyl((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin- 4-yl)methyl)amino)biphenyl-4-carboxylate (0.37 g, 0.68 mmol), 10% Pd/C (0.15 g) and

NH ₄ COOH (0.43 g, 6.86 mmol) were added to MeOH (3 mL) / EtOAc (6 mL). The mixture was refluxed with heating for 5 hours, and then cooled to room temperature. The reaction mixture was filtered through a Celite pad to remove a solid. The obtained filtrate was concentrated under reduced pressure. The obtained concentrate was diluted with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; EtOAc / hexane = 0 % to 20 %), and concentrated to yield the title compound as white solid (0.24 g, 77%).

Step 5. 4 '-(( 1 -(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methylamino)bip henyl-4- carboxylic acid: Methyl 4'-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylate (0.24 g, 0.53 mmol) and LiOH H ₂ 0 (0.11 g, 2.67 mmol) were dissolved in THF (2 mL) / H ₂ 0 / MeOH (3 mL) at room temperature. The solution was stirred at the same temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (20 mL) to be suspended, and filtered. The obtained solid was dried to yield the title compound as white solid (0.22 g, 94%).

Step 6. Compound 1024: 4'-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid (0.06 g, 0.13 mmol), EDCI (0.05 g, 0.27 mmol), HOBt (0.03 g, 0.27 mmol) and DIPEA (0.12 mL, 0.69 mmol) were dissolved in DMF (2 mL). At room temperature, (S)-pyrrolidine-3-ol (0.02 g, 0.27 mmol) was added thereto, following with stirring at 60 °C for 12 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH ₄ C1 aqueous solution, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si0 ₂ , 12 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as yellow solid (0.04 g, 67%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.55 - 7.53 (m, 4 H), 7.44 (d, 2 H, J = 8.4 Hz), 6.66 (d, 2 H, J = 8.5 Hz), 4.58 (brs, 0.5 H), 4.41 (brs, 0.5 H), 3.82 - 3.43 (m, 5 H), 3.05 (d, 2 H, J = 6.4 Hz), 2.82 (d, 2 H, J = 11.6 Hz), 2.39 (s, 2 H), 2.29 (t, 2 H, J = 1 1.0 Hz), 1.95 - 1.70 (m, 5 H), 1.37 - 1.31 (m, 2 H), 1.10 (s, 6 H); MS (ESI) m/z 504 (M+ + H).

According to the above-described synthesis process of compound 1024, the compounds of Table 144 were synthesized using 4'-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4- yl)methylamino)biphenyl-4-carboxylic acid and the reactant of Table 143.

Table 143.

Table 144.

7.07 (d, 2 H, J = 8.4 Hz), 3.87- 3.40 (m, 5 H), 3.04 (d, 2 H, J = 6.6 Hz), 2.81 - 2.78 (m, 2 H), 2.37 (s, 2 H), 2.28 (t, 2 H, J = 1 1.4 Hz), 1.93 - 1.52 (m, 7 H), 1.36 - 1.24 (m, 2 H), 1.08 (d, 6 H); MS (ESI) m/z 518 (M+ + H).

(S)-l-(4'-((l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperid in-4- yl)memylamino)biphenylcarbonyl)pyrrolidine-2-carboxarnide 1H NMR (400 MHz, CDC1 ₃ ) 5 7.52 (s, 4 H), 7.46 (d, 2 H, J = 8.0 Hz), 7.07 (brs, 1 H), 6.67 (d, 2 H, J = 8.4 Hz), 5.66 (brs, 1 H), 5.66 (brs, 1 H), 4.82 -

1025

7.80 (m, 1 H), 3.92 (brs, 1 H), 3.65 - 3.60 (m, 2 H), 3.06 (d, 2 H, J = 6.8 Hz), 2.82 (d, 2 H, J = 11.2 Hz), 2.43 - 2.38 (m, 3 H), 2.29 (t, 2 H, J = 1 1.4 Hz), 2.13 - 1.57 (m, 7 H), 1.37 - 1.26 (m, 2 H), 1.10 (s, 6 H); MS (ESI) m/z 531 (M+ + H).

(S)-(3-hydroxypiperidin-l-yl)(4'-((l-(3,3,3-trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methylamino)biphenyl-4-yl)meth anone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.56 (d, 2 H, J = 8.4 Hz), 7.45 (d, 4 H, J = 8.4

1026

Hz), 6.67 (d, 2 H, J = 8.4 Hz), 3.90 - 3.32 (m, 5 H), 3.06 (d, 2 H, J = 6.6 Hz),

2.82 (d, 2 H, J = 11.6 Hz), 2.39 (s, 2 H), 2.28 (t, 2 H, J = 12.2 Hz), 2.05 - 1.57

(m, 6 H), 1 :35 - 1.26 (m, 3 H), 1.10 (s, 6 H); MS (ESI) m/z 518 (M+ + H).

Example 121. Compound 852: (R)-(4'-(((l-(2-fluoro-2-methylpropyl)piperidin-4- yl)methyI)(methyl)amino)biphenyl-4-yI)(3-hydroxypiperidin-l- yl)methanone

(R)-(4 ' -(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methylamino)bipheny l-4-yl)(3 - hydroxypiperidin-l-yl)methanone (compound 867, 0.02 g, 0.05 mmol) was dissolved in acetonitrile 5 mL. Formaldehyde (0.01 mL, 0.27 mmol) and acetic acid (0.30 mL, 0.05 mmol) were added thereto, following with stirring for a day and then cooling the temperature. At 0 °C, NaCNBH ₃ (0.30 mg, 0.05 mmol) was added slowly thereto, following with increasing the temperature and stirring at room temperature for 2 hours. After the reaction was quenched by addition of a little of water, the reaction mixture was added with water, and then extracted with CH ₂ C1 ₂ . The obtained organic layer was washed several times with H ₂ 0, dried over anhydrous MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as yellow solid (0.01 g, 62%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (d, 2 H, J = 8.0 Hz), 7.47 (dd, 4 H, J = 20.7, 8.7 Hz), 6.74 (d, 2 H, J = 8.8 Hz), 3.98 (brs, 2 H), 3.24 (d, 2 H, J - 6.8 Hz), 3.02 - 2.96 (m, 5 H), 2.50 - 2.41 (m, 5 H), 2.13 - 1.65 (m, 9 H), 1.39 - 1.26 (m, 8 H); MS (ESI) m/z 482 (M+ + H).

According to the above-described synthesis process of compound 852, the compounds of Table 146 were synthesized using (R)-(4'-((l-(2-fluoro-2-methylpropyl)piperidin-4-yl)methylam ino) biphenyl-4-yl)(3-hydroxypiperidin-l -yl)methanone and the reactant of Table 145.

Table 145.

Table 146.

Compound

Compound Name,

No. Ή-NMR, MS (ESI)

(R)-(4 ' -(ethyl(( 1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl)amino)biphen yl- 4-yl)(3 -hydroxypiperidin- 1 -yl)methanone

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (d, 2 H, J = 8.4 Hz), 7.49 - 7.27 (m, 4 H),

853 6.73 (d, 2 H, J = 8.8 Hz), 4.21 - 3.87 (m, 3 H), 3.46 - 3.41 (m, 4 H), 3.18 (d, 2 H, J = 8.0 Hz), 2.97 (d, 2 H, J = 12.0 Hz), 2.46 (s, 1 H), 2.40 (s, 1 H), 2.12 - 1.96 (m, 6 H), 1. 72 - 1.69 (m, 3 H), 1.39 - 1.26 (m, 8 H), 1.17 (t, 3 H, J = 7.0 Hz); MS (ESI) m/z 496 (M+ + H).

Example 122. Compound 928: (R)-(3-hydroxypiperidin-l-yl)(4'-(methyl((l-((l- (trifluoromethyI)cycIobutyl)methyI)piperidin-4-yI)methyI)ain ino)biphenyI-4-yI)m

(R)-(3 -hydroxypiperidin- 1 -yl)(4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclobutyl)methyl)piperidin-4- yl)methylamino)biphenyl-4-yl)methanone (compound 926, 0.03 g, 0.05 mmol), formaldehyde (8 ]iL, 0.28 mmol) and AcOH (3 μϋ, 0.05 mmol) were dissolved in Acetonitrile (3 mL), following with stirring with at 12 hours at room temperature and cooling the temperature slowly to 0 °C. NaCNBH ₃ (4 mg, 0.05 mmol) was added thereto at 0 °C, following with stirring at room temperature for 1 hour. The concentrate was added with water (10 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column chromatography (Si0 ₂ , 12 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.02 g, 81 %).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.0 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 7.45 (d, 2 H, J = 8.0 Hz), 6.75 (d, 2 H, J = 8.8 Hz), 4.03 - 3.42 (m, 5 H), 3.25 (d, 2 H, J = 7.1 Hz), 3.02 (s, 3 H), 2.86 (d, 2 H, J = 1 1.2 Hz), 2.51 (s, 2 H), 2.24 - 1.65 (m, 15 H), 1.38 - 1.34 (m, 2 H); MS (ESI) m/z 544 (M+ + H). According to the above-described synthesis process of compound 928, the compounds of Table 148 were synthesized using (R)-(3-hydroxypiperidin-l-yl)(4'-((l-((l-(trifluoromethyl) cyclobutyl)methyl)piperidin-4-yl)methylamino)biphenyl-4-yl)m ethanone and the reactant of Table 147.

Table 147.

Table 148.

Example 123. Compound 930: (R)-(3-hydroxypiperidin-l-yl)(4'-(methyl((l-(3,3,3- trifluoro-2,2-dimethylpropyl)piperidm-4-yl)methyl)amino)biph enyI-4-yl)methanone

(R)-(3 -hydroxypiperidin- 1 -yl)(4' -(( 1 -(3 ,3 ,3 -trifluoro-2,2-dimethylpropyl)'piperidin-4- yl)methylamino)biphenyl-4-yl)methanone (the product of synthesis of compound 927; 0.03 g, 0.05 mmol), formaldehyde (8 μΐ,, 0.29 mmol) and AcOH (3 μί, 0.05 mmol) were dissolved in Acetonitrile (3 mL). At 0 °C, NaCNBH ₃ (4.00 mg, 0.05 mmol) was added thereto, , following with stirring at room temperature for 2 hours. The concentrate was added with water (8 mL) to be suspended, and filtered. The obtained solid was dried, and purified by column

chromatography (Si0 ₂ , 12 g cartridge; methanol / dichloromethane = 0 % to 10 %), and concentrated to yield the title compound as white solid (0.01 g, 48%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.58 (d, 2 H, J = 8.4 Hz), 7.48 (dd, 4 H, J = 20.3, 8.5 Hz), 6.74 (d, 2 H, J = 8.9 Hz), 4.17 - 3.42 (m, 5 H), 3.24 (d, 2 H, J = 7.2 Hz), 3.02 (s, 3 H), 2.80 (d, 2 H, J = 11.4 Hz), 2.37 (s, 2 H), 2.27 (t, 2 H, J = 5.9 Hz), 2.23 - 1.50 (m, 7 H), 1.37 - 1.24 (m, 2 H), 1.51 (s, 6 H); MS (ESI) m/z 532 (M+ + H). Example 124. Compound 552: N,N-dimethyl-4'-((l-((l-(trifluoromethyl)cyclopropyl) methyl)piperidin-4-yI)methoxy)biphenyl-4-carboxamide

Step 1. (4-((4-bromophenoxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl)cyclopropyl) methanone: 4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 1 of compound 498; 200 mg, 0.65 mmol) and l-(trifluoromethyl)cyclopropanecarboxylic acid (101 mg, 0.65 mmol) were dissolved in CH ₂ C1 ₂ 4 mL. EDC (250 mg, 1.31 mmol) and HOBt (176 mg, 1.31 mmol) were added thereto. Lastly, DIPEA (0.57 mL, 3.26 mmol) was added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was diluted with water, and extracted with CH ₂ C1 ₂ three times. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-50% EtOAc/Hexane) to yield the title compound as white solid (239 mg, 90%).

Step_2. 4-((4-bromophenoxy)methyl)-l-((l-(trifluoromethyl)cyclopropy l)methyl)piperidine: (4-((4-bromophenoxy)methyl)piperidin- 1 -yl)( 1 -(trifluoromethyl)cyclopropyl)methanone (239 mg, 0.59 mmol) was dissolved in dry THF 10 mL, and then cooled with ice bath. 1 M LAH in THF (1.77 mL, 1.77 mmol) was added dropwise slowly thereto, following with increasing the temperature to room temperature slowly and stirring for 1 hour. The reaction was quenched by addition of water. After the addition of EtOAc thereto, the resulting precipitate was filtered, and extracted with EtOAc. The organic layer was dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained

concentrate was purified by silica gel column chromatography (0-40 % EtOAc/hexane) to yield the title compound as colorless liquid (64 mg, 28%).

Step 3. methyl 4'-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy) biphenyl-4-carboxylate: 4-((4-bromophenoxy)methyl)-l-((l-(trifluoromethyl)cyclopropy l) methyl)piperidine (50 mg, 0.127 mmol) and 4-(methoxycarbonyl)phenylboronic acid(28 mg, 0.15 mmol) were dissolved in dioxane 1 mL. Water 0.3 mL was added thereto. Pd(dbpf)Cl ₂ (30 μg, 0.01 mmol) and Cs ₂ C0 ₃ (125 mg, 0.38 mmol) were added thereto. With a microwave radiation, the reaction was performed at 140 °C for 15 minutes. The reaction mixture was diluted with water, and extracted with CH ₂ C1 ₂ three times. The organic layer was dried over MgS0 ₄ , filtered through Celite to remove solid, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-40 %

EtOAc/Hexane) to yield the title compound as light-yellow solid (30 mg, 53%).

Step 4. 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy) biphenyl-4- carboxylic acid: Methyl 4 ' -(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylate (30 mg, 0.07 mmol) was dissolved in THF 2 mL. MeOH 1 mL and H ₂ 0 1 mL were added thereto. LiOH (14 mg, 0.34 mmol) was added thereto, following with stirring at room temperature for 15 hours. After acidification with 1 N HC1, the resulting precipitate was filtered to yield the title compound as white solid (28 mg, 97%).

Step 5. Compound 552: 4'-((l-((l-(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (28 mg, 0.07 mmol) and dimethylamine hydrochloride (11 mg, 0.13 mmol) were dissolved in DMF 1 mL. EDC (25 mg, 0.13 mmol) and HOBt (18 mg, 0.13 mmol) were added thereto. Lastly, DIPEA (57 μί, 0.26 mmol) was added thereto, following with stirring at room temperature for 15 hours. Water 5 mL was added thereto, and filtered to give a solid. The residue was purified by silica gel column chromatography (0-5 % MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (23 mg, 76%).

1H NMR (400 MHz, CDC1 ₃ ) 57.60 - 7.55 (m, 2 H), 7.55 - 7.50 (m, 2 H), 7.50 - 7.45 (m, 2 H), 7.00 - 6.93 (m, 2 H), 3.83 (d, 2 H, J = 6.0 Hz), 3.13 (s, 3 H), 3.04 (s, 3 H), 2.98 (d, 2 H, J = 11.3 Hz), 2.54 (s, 2 H), 2.03 - 1.94 (m, 2 H), 1.86 - 1.74 (m, 3 H), 1.40 (dd, 2 H, J = 12.2, 2.6 Hz), 1.02 - 0.95 (m, 2.H), 0.65 (s, 2 H); MS (ESI) m/z 461 (M+ + H).

Example 125. Compound 580: N,N-dimethyl-4-(6-((l-((l-(trifluoromethyl)cyclopropyl) methyl)piperidin-4-yl)methoxy)pyridine-3-yl)benzamide

Step 1. methyl 4-(6-((l -((1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy) pyridine-3-yl)benzoate: 5-bromo-2-((l-((l-(trifluoromethyl)cyclopropyl)methyl)piperi din- 4-yl)methoxy)pyridine (the product of synthesis step 3 of compound 589; 0.50 g, 1.27 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.25 g, 1.40 mmol), Pd(dbpf)Cl ₂ (24 mg, 0.04 mmol), Cs ₂ C0 ₃ (1.24 g, 3.81 mmol) were added into a microwave reactor, and then dioxane 6 mL and water 3 mL were added thereto. With a microwave radiation, the reaction was performed at 100 °C for 30 minutes. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (20-70 % EtOAc/hexane) to yield the title compound as white solid (0.40 g, 70%).

Step 2. 4-(6-((l -((1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy) pyridine-3- yl)benzoic acid : Methyl 4-(6-(( 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidin-4- yl)methoxy)pyridine-3-yl)benzoate (0.40 g, 0.89 mmol) was dissolved in THF 10 mL.

LiOH H ₂ 0 (0.07 g, 1.78 mmol) in water 10 mL was added thereto, and the reaction was performed at 60 °C for 4 hours. The solvent was concentrated under reduced pressure. After the addition of 1M HCl 5 mL thereto, the resulting precipitate was filtered to yield the title compound as white solid (0.37 g, 96%).

Step 3. Compound 580: 4-(6-((l-((l-(trifluoromethyl)cyclopropyl)methyl)piperidin-4 - yl)methoxy)pyridine-3-yl)benzoic acid (0.05 g, 0.12 mmol), dimethylamine hydrochloride(0.02 g, 0.23 mmol), EDC (0.04 g, 0.23 mmol) and HOBt (0.03 g, 0.23 mmol) were dissolved in DMF 2 mL. DIPEA (0.04 mL, 0.23 mmol) was added thereto, following with stirring at room temperature for 10 hours. The reaction mixture was added with saturated NH4CI aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (0.01 g, 19%).

1H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (s, 1 H), 7.80 (dd, 1 H, J = 8.4, 2.3 Hz), 7.54 (dd, 4 H, J = 19.3, 8.3 Hz), 6.83 (d, 1 H, J = 8.7 Hz), 4.26 - 4.19 (m, 2 H), 3.14 - 2.98 (m, 8 H), 2.54 (m, 2 H), 2.19 - 1.80 (m, 5 H), 1.52 - 1.26 (m, 2 H), 1.03 (m, 2 H), 0.66 (m, 2 H); MS (ESI) m/z 462.2 (M+ + H); MS (ESI) m/z 462 (M+ + H).

According to the above-described synthesis process of compound 580 (Step 3), the compounds of Table 150 were synthesized using 4-(6-((l-((l-(trifluoromethyl)cyclopropyl)methyl) piperidin-4-yl)methoxy)pyridine-3-yl)benzoic acid and the reactant of Table 149.

Table 149.

Table 150.

Example 126. Compound 688:

4'-((l-(2-fluoropropyl)piperidm-4-yl)methoxy)-N,N-dimethylbi phenyl-4-carboxarnide

Step 1. 1 -(4-((4-bromophenoxy)methyl)piperidin- 1 -yl)propan-2-ol :

4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 2 of compound 686; 200 mg, 0.65 mmol) was dissolved in EtOH 1 mL. 2-methyloxirane (379 mg, 6.52 mmol), K ₂ C0 ₃ (180 mg, 1.31 mmol) and water 1 mL were added thereto. With a microwave radiation, the mixture was stirred at 110 °C for 20 minutes. After the completion of the reaction, EtOH was evaporated from the reaction mixture under reduced pressure, and then a little of water was added to thereto. The resulting precipitate was filtered, and dried under reduced pressure to yield the title compound as red oil (190 mg, 88%).

Step 2. 4-((4-bromophenoxy)methyl)- 1 -(2-fluoropropyl)piperidine:

l-(4-((4-bromophenoxy)methyl)piperidin-l-yl)propan-2-ol (190 mg, 0.58 mmol) was dissolved in CH ₂ C1 ₂ 2 mL. Deoxo-fluor (141 mg, 0.64 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer washed with saturated aqueous brine solution, dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as yellow oil (180 mg, 94%).

Step 3. methyl 4'-((l -(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyla te:

4-((4-bromophenoxy)methyl)-l-(2-fluoropropyl)piperidine (190 mg, 0.58 mmol), 4-

(methoxycarbonyl)phenylboronic acid (124 mg, 0.69 mmol), Pd(dbpf)Cl ₂ (19 mg, 0.03 mmol) and Cs ₂ C0 ₃ (375 mg, 1.15 mmol) were dissolved in 1,4-dioxane 2 mL and water 0.5 mL. With a microwave radiation, the mixture was stirred at 120 °C for 20 minutes. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (87 mg, 39%).

Step 4. 4'-((l -(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyli c acid:

methyl 4'-((l-(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4-car boxylate (87 mg, 0.23 mmol) was dissolved in THF:MeOH: water =4:2: 1. LiOH H ₂ 0 (19 mg, 0.45 mmol) was added thereto, and refluxed with heating for 7 hours. After the reaction was complete, the solvent was evaporated under reduced pressure. After adjusting pH to below 6 using 1 N HC1, the resulting precipitate was washed with EtOAc thoroughly, and filtered to yield the title compound as gray solid (80 mg, 95%).

Step 5. Compound 688: 4'-((l -(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid (40 mg, 0.11 mmol), dimethylamine hydrochloride (18 mg, 0.22 mmol) and PyBOP (84 mg, 0.16 mmol) were dissolved in CH ₂ C1 ₂ 1 mL. After stirring at room temperature for 10 minutes, DIPEA (28 mg, 0.22 mmol) was added thereto, following with stirring at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EA) to yield the title compound as white solid (17 mg, 45%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.52 (m, 6 H), 6.98 (d, 2 H, J = 8.8 Hz), 4.71 (m, 0.5 H), 4.58 (m, 0.5 H), 3.86 (d, 2 H, J = 6.0 Hz), 3.01 (m, 6 H), 2.66 (m, 1 H), 2.47 (m, 1 H), 2.14 (m, 2 H), 1.81 (m, 3 H), 1.66 (m, 2 H), 1.57 (m, 2 H), 1.01 (t, 3 H, J = 7.5 Hz); MS (ESI) m z 413 (M+ + H).

According to the above-described synthesis process of compound 688, the compounds of Table 152 were synthesized using 4'-((l-(2-fluoropropyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid and the reactant of Table 151.

Table 151.

Table 152.

Example 127. Compound 690: (4'-((l-(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl- 4-yI)(3-hydroxypiperidin-l-yl)methanone

Step 1. 1 -(4-((4-bromophenoxy)methyl)piperidin- 1 -yl)butan-2-ol :

4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 2 of compound 686; 200 mg, 0.65 mmol) was dissolved in EtOH 1 mL. 2-ethyloxirane (470 mg, 6.52 mmol), K ₂ C0 ₃ (180 mg, 1.31 mmol) and water 1 mL were added thereto. With a microwave radiation, the mixture was stirred at 110 °C for 20 minutes. After the completion of the reaction, EtOH was evaporated from the reaction mixture under reduced pressure, and then a little of water was added to thereto. The resulting precipitate was filtered, and dried under reduced pressure to yield the title compound as red oil (134 mg, 88%).

Step 2. 4-((4-bromophenoxy)methyl)- 1 -(2-fluorobutyl)piperidine:

l-(4-((4-bromophenoxy)methyl)piperidin-l-yl)butan-2-ol (134 mg, 0.39 mmol) was dissolved in CH ₂ C1 ₂ 2 mL. Deoxo-fluor (95 mg, 0.43 mmol) was added thereto, following with stirring at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer washed with saturated aqueous brine solution, dried over MgS0 ₄ and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, EtOAc/Hexane) to yield the title compound as yellow oil (120 mg, 89%).

Step 3. methyl 4'-((l -(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-carboxylat e: 4-((4- bromophenoxy)methyl)- 1 -(2-fluorobutyl)piperidine (150 mg, 0.44 mmol), 4-(methoxycarbonyl) phenylboronic acid (94 mg, 0.52 mmol), Pd(dbpf)Cl ₂ (14 mg, 0.02 mmol), Cs ₂ C0 ₃ (284 mg, 0.87 mmol) was dissolved in 1,4-dioxane 2 mL and water 0.5 mL. With a microwave radiation, the mixture was stirred at 120 °C for 20 minutes. The reaction mixture was added with saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The obtained organic layer was dried over MgS0 ₄ , and filtered to remove the solid residue. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as yellow solid (30 mg, 17%).

Step 4. 4'-((l-(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-carb oxylic acid: Methyl 4'- ((l-(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-carboxy late (30 mg, 0.08 mmol) was dissolved in THF:MeOH: water =4:2: 1. LiOH H ₂ 0 (6 mg, 0.15 mmol) was added thereto, and refluxed with heating for 7 hours. After the reaction was complete, the solvent was evaporated under reduced pressure. After adjusting pH to below 6 using 1 N HC1, the resulting precipitate was washed with EtOAc thoroughly, and filtered to yield the title compound as gray solid (21 mg, 72%).

Step 5. Compound 690: 4'-((l-(2-fluorobutyl)piperidin-4-yl)methoxy)biphenyl-4-carb oxylic acid (21 mg, 0.05 mmol), piperidin-3-ol (11 mg, 0.11 mmol) and PyBOP (43 mg, 0.08 mmol) were dissolved in CH ₂ C1 ₂ 1 mL. After stirring at room temperature for 10 minutes, DIPEA (14 mg, 0.11 mmol) was added thereto, following with stirring at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgS0 ₄ , filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO silica gel cartridge, MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (14 mg, 54%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.53 (m, 6 H), 6.97 (d, 2 H, J = 6.8 Hz), 4.60 (m, 0.5 H), 3.86 (m, 0.5 H), 3.08 (m, 4 H), 3.45 (m, 2 H), 2.66 (m, 2 H), 2.53 (m, 1 H), 2.45 (m, 1 H), 2.13 (m, H), 1.82 (m, 6 H), 1.64 (m, 3 H), 1.59 (m, 3 H), 1.01 (t, 3 H, J = 7.4 Hz); MS (ESI) m/z 469 (M+ + H).

Example 128. Compound 655: (R)-(4'-((l-(2-fluoropentyl)piperidin-4- yl)methoxy)biphenyl-4-yl)(2-(hydroxymethyl)pyrrolidine-l-yl) methanone

Step 1. l-(4-((4-bromophenoxy)methyl)piperidin-l-yl)pentane-2-ol: 4-((4-bromophenoxy) methyl)piperidine hydrochloride (the product of synthesis step 1 of compound 498; 500 mg, 1.63 mmol) and K ₂ C0 ₃ (450 mg, 3.26 mmol) were suspended in EtOH 2 mL. Water 2 mL was added thereto, and the mixture was suspended with a little heating. 2-propyloxirane (1.40 g,

16.31 mmol) was added thereto. With a microwave radiation, the reaction was performed at 110 °C for 20 minutes. The reaction mixture was diluted with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as white solid (510 mg, 88%).

Step 2. 4-((4-bromophenoxy)methyl)-l-(2-fluoropentyl)piperidine:

l-(4-((4-bromophenoxy)methyl)piperidin-l-yl)pentane-2-ol (510 mg, 1.43 mmol) was dissolved in CH C1 ₂ 4 mL. Deoxo-Fluor (348 mg, 1.58 mmol) was added thereto. After stirring for 3 hours at room temperature, A saturated NaHC0 ₃ aqueous solution was added thereto, and the mixture was extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and filtered to remove a solid. The filtrate was concentrated under reduced pressure to yield the title compound as yellow oil (395 mg, 77%).

Step 3. methyl 4'-((l-(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4-car boxylate:

4-((4-bromophenoxy)methyl)-l-(2-fluoropentyl)piperidine(2 50 mg, 0.70 mmol) and 4- (methoxycarbonyl)phenylboronic acid (151 mg, 0.84 mmol) were dissolved in dioxane 2 mL. Water 0.5 mL was added thereto. Pd(dbpf)Cl ₂ (23 mg, 0.04 mmol) and Cs ₂ C0 ₃ (455 mg, 1.40 mmol) were added thereto. With a microwave radiation, the reaction was performed at 120 °C for 20 minutes. The reaction mixture was filtered through Celite. The filtrate was added with a saturated NaHC0 ₃ aqueous solution, and extracted with CH ₂ C1 ₂ . The organic layer was dried over MgS0 ₄ , and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ ) to yield the title compound as white solid (1 15 mg, 40%).

Step 4. 4'-((l -(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyli c acid:

Methyl 4'-((l-(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4-car boxylate (1 15 mg, 0.28 mmol) was dissolved in THF 2 mL. MeOH 1 mL and H ₂ 0 0.5 mL were added thereto. The mixture was added with LiOH H ₂ 0 (23 mg, 0.56 mmol), and then refluxed with heating and stirring for a day. After acidification with 1 N HCl, the resulting precipitate was filtered to yield the title compound as white solid (100 mg, 90%).

Step 5. Compound 655 : 4'-(( 1 -(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4-carboxyli c acid (40 mg, 0.10 mmol), (R)-pyrrolidine-2-ylmethanol (15 mg, 0.15 mmol) and PyBOP (78 mg, 0.15 mmol) were dissolved in DMF 1 mL. DIPEA (26 mg, 0.20 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgS0 ₄ , and filtered. The obtained concentrate was purified by silica gel column chromatography

(MeOH/CH ₂ Cl ₂ ) to yield the title compound as light-yellow solid (21 mg, 43%).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.57 (m, 4 H), 7.52 (d, 2 H, J = 8.7 Hz), 6.97 (d, 2 H, J = 8.7 Hz), 4.78 (m, 0.5 H), 4.64 (m, 0.5 H), 4.42 (m, 1 H), 3.75 (m, 4 H), 3.55 (m, 2 H), 3.16 (m, 2 H), 2.62 (m, 1 H), 2.53 (m, 1 H), 2.17 (m, 3 H), 1.80 (m, 5 H), 1.63 (m, 2 H), 1.47 (m, 3 H), 0.95 (t, 3 H, J = 7.1 Hz); MS (ESI) m/z 483 (M+ + H).

According to the above-described synthesis process of compound 655 (Step 5), the compounds of Table 154 were synthesized using 4'-((l-(2-fluoropentyl)piperidin-4-yl)methoxy)biphenyl-4- carboxylic acid and the reactant of Table 153.

Table 153.

Table 154.

The structural formulae are as following Tables 155-180.

Table 155.

Table 156.

Table 157.

Table 158.

Table 159.

Table 160.

Table 161.

Table 162.

Table 163.

Table 164.

Table 165.

Table 166.

Table 167.

Table 168.

Table 169.

Table 170.

Table 171.

Table 172.

Table 173.

Table 174.

Table 175.

Table 176.

Table 177.

Table 178.

Table 179.

Table 180.

Protocol of Experiment: Activity test of the compound of the present invention

Using the commercial product as a control group, the treatment activities of the compounds of formula 1 according to the present invention for type II diabetes were tested, and the safety of the compound of formula 1 was also tested. Experimental Example 1. Activity test for the GPR 119 receptor (in vitro)

1. Human GPRl 19 receptor cell

As a human GPRl 19 receptor expression cell for this test, the cell line "GeneBLAzerTM T-Rex GPR 119 CHO-K1 DA cells" that is commercially available from Invitrogen, was used. The cell was incubated in the DMEM media containing 1% dialyzed fetal bovine serum etc.. The cell incubator was kept at constant temperature and constant humidity of 37 °C, 5% C0 ₂ .

2. Activity test for human GPRl 19 receptor

The human GPRl 19 receptor expressing cell was used to this test. Each of test compounds was added to be final concentrations of 0.1, 1, 10 μΜ in 96 well and tested in duplicate. A fixed amount of cell was added to each well of 96 well separately, and then treated with the test compound for 5 hours. After treatment of color development agent for 2 hours, the fluorescence value was determined with plate reader. To the luminous wavelength of control well, which was not treated with the agonist sample, but in which only a vehicle (i.e., cell) was contained, the ratio of the luminous wavelength of test well, which was treated with the agonist sample, was calculated, and then converted to obtain % value.

3. Statistical processing

All the results were expressed as mean ± SD, and each test groups and the control group were compared using student's t-test to adjudge the effects of each test groups.

4. Result of activity test for human GPR119

Table 181. Result of activity test for human GPR1 19

10 379

0.1 227

1 288

10 297

0.1 138

1 210

10 257

0.1 199

1 229

10 269

0.1 265

1 305

10 239

0.1 167

1 220

10 246

0.1 213

1 295

10 294

0.1 289

1 248

10 311

0.1 160

1 228

10 262

0.1 198

1 269

10 261

0.1 162

1 260

10 313

0.1 228

1 280

10 310

0.1 256

1 296

10 252 0.1 257

1 313

10 303

0.1 251

1 296

10 306

0.1 164

1 241

10 246

0.1 180

1 291

10 310

0.1 191 1 232

10 307

0.1 145

999 1 264

10 365

0.1 311

1000 1 367

10 374

0.1 235

1009 1 314

10 340

0.1 410

1013 1 490

10 426

0.1 187

1028 1 348

10 402

0.1 321

1032 1 459

10 430

0.1 223

1037 1 478

10 439

0.1 407

1055 1 474

10 408

0.1 406

1119 1 428

10 482

In Table 181, "% activation" shows the extent that human GPRl 19 receptor is activated by test compounds of each concentration. The higher value of % activation means the more excellent activity. The maximum % activation of control compound (MBX-2982) is 200, and the most of the compounds of the present invention show more than 200 of % activation. The compounds 1013 and 1028 show the excellent activity with 490 and 402 of % activation respectively.

Experimental Example 2. Animal test of activity for the GPR 119 receptor in normal mouse (in vivo)

1. Method of glucose tolerance test

Male C57/6J Jms mice of 6-7 weeks of age were fasted for 16 hours before the start of gl tolerance test. The experimental animal groups consist of:

A. a vehicle group (10 % EtOH, 20 % HPBCD in saline),

B. a positive control group administered with MBX-2982 (10 mg/kg), and C. test groups administered with compound 516, 581, 586, 612, 640, 644 or etc. (10 mg/kg). Before compound administration, that is, at 0 hour, whole blood glucose level was determined using a Glucometer (ACCU-CHEK, Roche). At 30 minutes after compound administration, whole blood glucose level was determined once again, and 20 % glucose (2 g/ kg 10 mL) was administered orally. Whole blood glucose level was determined at 20, 40, 60, 80, and 120 minutes after 20 % glucose administration. Area under the curve (AUC) of whole blood glucose level was obtained using GraphPad Prism 5.0. The effect of glucose tolerance was adjudged with the corrected area under the curve (cAUC), on which the base value of glucose area under the curve was excluded.

2. Result of glucose tolerance test

In Table 182, "Decrease % of AUC" shows the extent that whole blood glucose level is decreased by the test compounds administrated after oral administration of glucose into normal mouse. The higher value of decrease % of AUC means the more excellent drop effect in blood glucose level. The control compound (MBX 2982) shows only 24% of the excellent drop effect in blood glucose level, and some of the compounds of the present invention show more than 40% of the excellent drop effect in blood glucose level. The compounds 612 and 1028 show the very excellent drop effect in blood glucose level with 50 and 46 % respectively.

Table 182. Result of glucose tolerance test

Decrease % of AUC at 10 mg kg

BX-2982 24

Compound 516 43

Compound 581 50

Compound 586 34

Compound 612 50

Compound 640 52

Compound 644 39

Compound 658 38

Compound 768 40

Compound 770 47

Compound 944 32

Compound 950 39

Compound 999 39

Compound 1000 38

Compound 1028 46

Experimental Example 3. Disease model animal test of activity for the GPR 119 receptor (DIO mouse) 1. Method of glucose tolerance test

Male C57BL/6J mice of 6.5 weeks of age were taken with high fat diet (60% kcal, Research Diets) for 12 weeks. The obtained male diet induced obesity (DIO) C57BL/6J mice of 18.5 weeks of age were fasted for 16 hours before the start of glucose tolerance test. The experimental animal groups consist of:

A. a vehicle group (10 % EtOH, 20 % HPBCD in D. W.),

B. a positive control group administered with Sitagliptin (30 mg/kg), and

C. test groups administered with compound 770 and Compound 1028 (10, 30 mg kg and combination administration with sitagliptin 30 mg/kg).

Each test compounds was administered at the-same time of every day for 2 weeks. Before the compound administration, whole blood glucose level was determined using a Glucometer

(ACCU-CHEK, Roche). At 30 minutes after compound administration, whole blood glucose level was determined once again, and 20 % glucose (2 g/ kg/ 10 mL) was administered orally.

Whole blood glucose level was determined at 20, 40, 60, 80, and 120 minutes after 20 % glucose administration. Area under the .curve (AUC) of whole blood glucose level was obtained using GraphPad Prism 5.0. The effect of glucose tolerance was adjudged with the corrected area under the curve (cAUC), on which the base value of glucose area under the curve was excluded.

2. Measurement of whole blood glucose level change

Whole blood glucose level was measured at about 1 hour after test compound administration from caudal vein of mice using Glucometer. Whole blood glucose level was determined three times totally, that is, (1) at prior to the start of drug administration, (2) after 1 week from the start of 2-weeks drug administration, and (3) after the termination of 2-weeks drug

administration. Each determination was started with 20 % glucose administration, and then perfomed at 20, 40, 60, 80, and 120 minutes after 20 % glucose administration.

3. Result of glucose tolerance test (DIO) Table 183 shows the extent that whole blood glucose level is decreased by the test compounds administrated after oral administration of glucose into disease model mouse (DIO mouse). The higher value means the more excellent drop effect in blood glucose level. The effect was tested, separately, after administration of test compound alone and after co-administration of test compound with Sitagliptin, which is a DPP IV inhibitor. As a result, the compounds alone of the present invention show more than 20% of the excellent drop effect in blood glucose level, and the co-administration of the compound of the present invention with Sitagliptin show also the excellent effect. The compound 1028 shows 28.5% for alone-administration and 32.3% for co-administration.

Table 183.