THAT ARALILULUKUUTUUS009776962B2 (12 ) United States Patent ( 10) Patent No. : US 9 ,776 , 962 B2 Aida et al. ( 45 ) Date of Patent: Oct. 3 , 2017 (54 ) AROMATIC COMPOUNDS WITH GPR40 ( 52 ) U .S . CI. AGONISTIC ACTIVITY CPC ...... C07D 211 /34 (2013 . 01 ) ; C07D 211 / 22 (2013 . 01 ) ; C07D 213 / 30 ( 2013 .01 ) ; C07D (71 ) Applicant: TAKEDA PHARMACEUTICAL 401/ 10 (2013 .01 ); CO7D 401 /12 (2013 . 01 ); COMPANY LIMITED , Osaka - shi, C07D 401/ 14 ( 2013. 01 ) ; C07D 405/ 12 Osaka (JP ) (2013 .01 ) ; C07D 405 / 14 ( 2013 .01 ) ; C07D ( 72 ) Inventors: Jumpei Aida, Fujisawa ( JP ) ; Yayoi 409 / 12 ( 2013 .01 ); CO7D 413 /10 (2013 . 01 ); Yoshitomi, Fujisawa ( JP ) ; Yuko CO7D 413 / 14 (2013 . 01 ) Hitomi, Fujisawa ( JP ); Naoyoshi (58 ) Field of Classification Search Noguchi, Fujisawa ( JP ) ; Yasuhiro CPC . CO7D 211/ 34 ; CO7D 211/ 22 ; C07D 213 /30 ; Hirata , Fujisawa (JP ) ; Hideki CO7D 401 / 10 ; C07D 401 / 12 ; CO7D Furukawa , Fujisawa ( JP ) ; Akito 401/ 14 ; CO7D 405 / 12 ; COZD 405 / 14 ; Shibuya , Fujisawa ( JP ) ; Koji CO7D 409 / 12 ; C07D 413 / 10 ; CO7D Watanabe, Fujisawa ( JP ) ; Yasufumi 413 / 14 Miyamoto , Fujisawa ( JP ) ; Tomohiro See application file for complete search history . Okawa , Fujisawa ( JP ) ; Nobuyuki Takakura , Fujisawa ( JP ) ; Seiji (56 ) References Cited Miwatashi, Tokyo ( JP ) U .S . PATENT DOCUMENTS ( 73 ) Assignee : TAKEDA PHARMACEUTICAL 7 ,968 ,552 B2 * 6 / 2011 Negoro ...... C07D 271/ 06 COMPANY LIMITED , Osaka ( JP ) 514 /256 ( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U .S .C . 154 (b ) by 0 days . WO WO 2007 / 123225 * 11/ 2007 ( 21 ) Appl. No. : 14 /898 , 633 * cited by examiner (22 ) PCT Filed : Aug . 8 , 2014 Primary Examiner — Sahar Javanmard (74 ) Attorney, Agent , or Firm — Nath , Goldberg & ( 86 ) PCT No. : PCT/ JP2014 /070972 Meyer; Joshua B . Goldberg ; Scott H . Blackman § 371 (C )( 1 ), (57 ) ABSTRACT (2 ) Date : Dec . 15 , 2015 Provided is a novel aromatic ring compound having a ( 87 ) PCT Pub . No. : WO2015 /020184 GPR40 agonist activity and a GLP - 1 secretagogue action . A PCT Pub . Date : Feb . 12 , 2015 compound represented by the formula : (65 ) Prior Publication Data R5 US 2016 /0115128 A1 Apr. 28, 2016 R3 R4 X R8 R9 (30 ) Foreign Application Priority Data R2 X OH Aug. 9 , 2013 ( JP ) ...... 2013 - 167065 R6 R7 © (51 ) Int. Ci. CO7D 211 / 34 ( 2006 .01 ) C07D 211 /22 ( 2006 . 01 ) CO7D 213 / 30 ( 2006 . 01 ) wherein each symbol is as described in the DESCRIPTION , C07D 401 / 10 ( 2006 . 01 ) or a salt thereof has a GPR40 agonist activity and a GLP - 1 C07D 401 / 12 (2006 .01 ) secretagogue action , is useful for the prophylaxis or treat CO7D 401 / 14 ( 2006 . 01 ) ment of cancer, obesity , diabetes, hypertension , hyperlipi C07D 405 / 12 ( 2006 . 01 ) demia , cardiac failure , diabetic complications , metabolic C07D 405 / 14 ( 2006 .01 ) syndrome, sarcopenia and the like, and affords superior C07D 409 / 12 ( 2006 .01 ) efficacy. C07D 413 / 10 ( 2006 . 01 ) CO7D 413 / 14 ( 2006 .01 ) 16 Claims, No Drawings US 9 ,776 , 962 B2 AROMATIC COMPOUNDS WITH GPR40 Patent document 4 describes the following compound . AGONISTIC ACTIVITY This is a National Phase Application filed under 35 U . S . C . 371 as a national stage of PCT/ JP2014 /070972 , filed Aug . 8 , 2014 , an application claiming the benefit of Japanese Appli R2 cation No. 2013 - 167065 , filed Aug . 9 , 2013, the content of each of which is hereby incorporated by reference in its entirety . 10 RII TECHNICAL FIELD 3 dado wherein each symbol is as described in patent document 4 . The present invention relates to a novel aromatic ring 15 Patent document 5 describes the following compound . compound having a GPR40 agonist activity and GLP - 1 secretagogue action . The Sequence Listing submitted in text format (. txt) filed on Dec. 15 , 2015 , named “ JPOXMLDOC01. txt ” , (created on Dec. 2 , 2015 , 2 KB ) , is incorporated herein by reference . 20 SëBACKGROUND OF THE INVENTION qarthy Patent document 1 describes the following compound . 25 wherein each symbol is as described in patent document 5 . Patent document 6 describes the following compound . Po3

W R 120 30 R2 R3 ZR 120 OH Rla Rl 0 Xa OH 35 R12a RS R7 aj R9 R10 .whereinDonex each symbol is as described in patent document 6 . However, no documents specifically disclose the com 40 pound of the present application . wherein each symbol is as described in patent document 1 . * Patent document 2 describes the following compound . DOCUMENT LIST Patent Documents 45 [patent document 1 ] WO 2009 / 048527 Ipatent document 2 ] US2009- 0012093 ( I - 1 ) [patent document 3 ] US2006 -0258722 ( patent document 4 ] US2007 -0149608 ( patent document 5 ] US2010 -0144806 ??. 50 (patent document 6 ] WO 2013 /122029 SUMMARY OF THE INVENTION CH2COOH Problems to be Solved by the Invention OrQRa 55 The present invention aims to provide a novel aromatic ring compound having a GPR40 agonist activity and GLP - 1 wherein each symbol is as described in patent document 2 . secretagogue action , and useful as an agent for the prophy Patent document 3 describes the following compound. laxis or treatment of diabetes and the like . 60 Means of Solving the Problems ( 1) The present inventors have conducted various intensive studies and found that the compound represented by the Xcor + DB - - X — COR ! following formula (I ) unexpectedly has a superior GPR40 1 00 = x -com 65 agonist activity and GLP - 1 secretagogue action , and pro vides a safe and useful medicament to be an agent for the wherein each symbol is as described in patent document 3 . prophylaxis or treatment of mammalian GPR40 receptor US 9 ,776 ,962 B2 related pathology or disease . Based on these findings, they optionally substituted by 1 to 3 halogen atoms, ( 5 ) a C6- 14 have completed the present invention . aryl group optionally substituted by 1 to 3 halogen atoms, That is , the present invention relates to ( 6 ) an aromatic heterocyclic group , ( 7 ) a nonaromatic het [ 1 ] a compound represented by the formula (I ) : erocyclic group , ( 8 ) a C1- 6 alkylsulfonyl group , ( 9 ) a mono or di- C1- 6 alkyl- amino group optionally substituted by 1 to 3 halogen atoms and ( 10 ) a halogen atom , or R5 P (ii ) an aromatic heterocyclic group optionally substituted by R3 R4 R8 R9 1 or 2 substituents selected from ( 1 ) cyano, ( 2 ) a halogen atom , ( 3 ) a C1- 6 alkyl group R2 OH 10 optionally substituted by 1 to 3 halogen atoms , ( 4 ) a C3- 10 { B cycloalkyl group , ( 5 ) a C1- 6 alkoxy group , (6 ) a nitrogen R6 R7 © containing heterocyclyl- carbonyl group and ( 7 ) a mono - or di- C -6 alkyl - carbamoyl group , or a salt thereof; 15 [ 6 ] the compound of any of the above -mentioned [ 1 ] - [ 5 ] , wherein R ”, R4, R®, R ? , R? and Rº are hydrogen atoms, or a wherein salt thereof; ring A is a further optionally substituted aromatic ring ; [ ? ] the compound of any of the above -mentioned [ 1 ]- [ 6 ], ring B is a further optionally substituted 4 - 6 -membered wherein Rº is a C3- 10 cycloalkyl group , or a salt thereof; nitrogen - containing saturated ring ; 20 [ 8 ] the compound of the above -mentioned [ 1 ] , wherein ring X is – N = or — CH = ; A is a benzene ring optionally further substituted by 1 or 2 R and R ’ are each independently a hydrogen atom or a substituents selected from substituent; (1 ) a C1- 6 alkylsulfonyl group ; R and R2 are optionally bonded to each other to form , (2 ) a carbamoyl group ; together with the adjacent nitrogen atom , an optionally 25 ( 3 ) a hydroxy group ; substituted 3 - to 10 -membered ring; (4 ) an C1- 6 alkoxy group optionally substituted by 1 to 3 R and R * are each independently a hydrogen atom , a halogen atoms; halogen atom or a C1- 6 alkyl group ; R , R ?, RS and Rº are each independently a hydrogen (5 ) a C1- 6 alkylthio group ; atom , a halogen atom , a C1- 6 alkyl group or a C1- 6 alkoxyogen 30 (Bahaloo6 ) a cyano group ; group ; Kuay 30 ( 7 ) a halogen atom ; and Rº is a halogen atom , an optionally substituted C1- 6 alkyl (8 ) a C1-6 alkyl group , group , an optionally substituted C1- 6 alkoxy group or an ring B is (1 ) an azetidine ring , (2 ) a pyrrolidine ring or (3 ) optionally substituted C3- 10 cycloalkyl group ; and a piperidine ring optionally further substituted by 1 or 2 R and R7 are optionally bonded to each other to formorm , 3535 substituentsSub selected from a halogen atom and a C1- 6 alkyl together with the adjacent carbon atom , an optionally sub group , stituted 3 - to 10 -membered ring, X is — N — , or a salt thereof (hereinafter sometimes to be referred to as R and R? are each independently compound ( I ) ) ; (i ) a C1- 8 alkyl group optionally substituted by 1 or 2 [ 2 ] the compound of the above -mentioned [ 1 ], wherein ring 40 substituents selected from A is a benzene ring optionally further substituted by 1 or 2 ( 1 ) cyano , ( 2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group option substituents selected from ally substituted by 1 to 3 substituents selected from a ( 1) a C1- 6 alkylsulfonyl group ; halogen atom and a C1- 6 alkyl group , ( 4 ) a C1- 5 alkoxy group ( 2 ) a carbamoyl group ; optionally substituted by 1 to 3 halogen atoms, ( 5 ) a C6- 14 ( 3 ) a hydroxy group ; 45 aryl group optionally substituted by 1 to 3 halogen atoms, ( 4) a C1- 6 alkoxy group optionally substituted by 1 to 3 (6 ) an aromatic heterocyclic group , (7 ) a nonaromatic het halogen atoms; erocyclic group , (8 ) a C1- 6 alkylsulfonyl group , (9 ) a mono ( 5 ) a C1- 6 alkylthio group ; or di- C1 - 6 alkyl -amino group optionally substituted by 1 to ( 6 ) a cyano group ; 3 halogen atoms and ( 10 ) a halogen atom , or ( 7 ) a halogen atom ; and 50 ( ii ) an aromatic heterocyclic group optionally substituted by ( 8 ) a C1- 6 alkyl group , 1 or 2 substituents selected from or a salt thereof; ( 1 ) cyano , ( 2 ) a halogen atom , ( 3 ) a C1- 6 alkyl group [ 3 ] the compound of the above -mentioned [ 1 ] or [ 2 ] , optionally substituted by 1 to 3 halogen atoms, ( 4 ) a C3- 10 wherein ring B is cycloalkyl group , (5 ) a C1- 6 alkoxy group , (6 ) a nitrogen ( 1 ) an azetidine ring , ( 2 ) a pyrrolidine ring or ( 3 ) a piperidine 55 containing heterocyclyl- carbonyl group and ( 7 ) a mono - or ring optionally further substituted by 1 or 2 substituents di- C1 - 6 alkyl- carbamoyl group , selected from a halogen atom and a C1- 6 alkyl group , R ” , R4 , R ", R ", R? and Rare hydrogen atoms, and or a salt thereof; Rº is a C3- 10 cycloalkyl group , [ 4 ] the compound of any of the above -mentioned [ 1 ] - [ 3 ], or a salt thereof; wherein X is — N — , or a salt thereof; 60 [ 9 ] (3S ) -3 -cyclopropyl - 3 -( 2 - ( (1 - ( 2 - (( 2 ,2 -dimethylpropyl ) (6 [ 5 ] the compound of any of the above -mentioned [ 1 ] - [ 4 ] , methylpyridin - 2 - yl ) carbamoyl) - 5 -methoxyphenyl ) piperi wherein Rl and R2 are each independently din - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid or a salt (i ) a C1- 8 alkyl group optionally substituted by 1 or 2 thereof; substituents selected from [10 ] ( 3S ) -3 -cyclopropyl - 3 -( 2 - ( (1 - ( 2 - (( 2 ,2 -dimethylpropyl ) ( 1) cyano , (2 ) hydroxy , (3 ) a C3- 10 cycloalkyl group option - 65 (4 ,6 -dimethylpyrimidin - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) ally substituted by 1 to 3 substituents selected from a piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid or a halogen atom and a C1- 6 alkyl group , (4 ) a C1-6 alkoxy group salt thereof; US 9 ,776 , 962 B2 [ 11 ] ( 3S ) - 3 - cyclopropyl- 3 -( 2 - ( ( 1 -( 2 - ( ( 2 , 2 -dimethylpropyl ) In the present specification , examples of the “ C2- 6 alkynyl (pyridin - 2 - yl ) carbamoyl ) -5 -methoxyphenyl )piperidin -4 - yl) group” include ethynyl , 1 -propynyl , 2 -propynyl , 1 -butynyl , methoxy ) pyridin - 4 - yl) propanoic acid or a salt thereof; 2 - butynyl, 3 -butynyl , 1 - pentynyl , 2 - pentynyl , 3 - pentynyl , [ 12 ] a medicament comprising the compound of [ 1 ] or a salt 4 -pentynyl , 1 -hexynyl , 2 -hexynyl , 3 -hexynyl , 4 -hexynyl , thereof; 5 5 -hexynyl and 4 -methyl - 2 -pentynyl . [ 13 ] the medicament of [12 ] above , which is a GPR40 In the present specification , examples of the “ C3- 10 cycloalkyl group ” include cyclopropyl, cyclobutyl, cyclo receptor1141 the medicamentfunction regulator of 1121; above , which is a prophylactic pentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [ 2. 2 .1 ] or therapeutic agent for diabetes; heptyl, bicyclo [ 2 . 2 . 2 ] octyl, bicyclo [ 3 . 2 . 1 ]octyl and adaman [ 15 ] a method of preventing or treating diabetes in a mam In the present specification , examples of the “ optionally mal, comprising administering an effective amount of the halogenated C3- 10 cycloalkyl group ” include a C3- 10 compound of the above- mentioned [ 1 ] or a salt thereof to the cycloalkyl group optionally having 1 to 7 , preferably 1 to 5 , mammal; halogen atoms. Specific examples thereof include cyclopro [ 16 ] a method of regulating GPR40 receptor functionon inin a 15 pyl, 2, 2 -difluorocyclopropyl , 2 , 3 - difluorocyclopropyl, mammal, comprising administering an effective amount of cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, the compound of the above- mentioned [ 1 ] or a salt thereof cycloheptylcycloheptyl and cyclooctyl. to the mammal; In the present specification , examples of the “ C3- 10 [ 17 ] use of the compound of the above -mentioned [ 1 ] or a cycloalkenyl group ” include cyclopropenyl , cyclobutenyl , salt thereof for the production of an agent for the prophylaxis 20 cyclopentenyl, cyclohexenyl, cycloheptenyl and cycloocte or treatment of diabetes ; nyl. [ 18 ] the compound of the above -mentioned [ 1 ] or a salt In the present specification , examples of the “ C6- 14 aryl thereof for use for the prophylaxis or treatment of diabetes ; group ” include phenyl, 1 -naphthyl , 2 -naphthyl , 1 - anthryl, and the like . 2 -anthryl and 9 -anthryl . 25 In the present specification , examples of the “ C7- 16 aralkyl Effect of the Invention group” include benzyl, phenethyl, naphthylmethyl and phe nylpropyl. Since compound ( I) has a superior GPR40 agonist activity In the present specification , examples of the “ C1- 4 alkoxy and GLP -1 secretagogue action , is superior in the property group ” include methoxy, ethoxy, propoxy , isopropoxy, as a pharmaceutical product such as stability and the like, 30 butoxy, isobutoxy, sec- butoxy , tert -butoxy , pentyloxy and and particularly shows high solubility , low toxicity , good hexyloxy . kinetics such as sustainability in blood and the like , it can In the present specification , examples of the " optionally provide a safe and useful agent for the prophylaxis or halogenated C1- 6 alkoxy group ” include a C1- 6 alkoxy group treatment ofmammalian GPR40 receptor -related pathology optionally having 1 to 7 , preferably 1 to 5 , halogen atoms. 35 Specific examples thereof include methoxy, difluo or disease . romethoxy, trifluoromethoxy, ethoxy , 2 , 2 , 2 -trifluoroethoxy , DETAILED DESCRIPTION OF THE propoxy, isopropoxy , butoxy , 4 ,4 ,4 - trifluorobutoxy , isobu INVENTION toxy, sec -butoxy , pentyloxy and hexyloxy . In the present specification , examples of the “ C3- 10 The present invention is explained in detail in the follow - 40 cycloalkyloxy group ” include cyclopropyloxy, cyclobuty ing . loxy, cyclopentyloxy , cyclohexyloxy, cycloheptyloxy and The definition of each substituent used in the present cyclooctyloxy . specification is described in detail in the following . Unless In the present specification , examples of the “ C1- 6 alky otherwise specified , each substituent has the following defi- Ithio group ” include methylthio , ethylthio , propylthio , iso nition . 45 propylthio , butylthio , sec- butylthio , tert - butylthio , pentyl In the present specification , examples of the “ halogen thio and hexylthio . atom ” include fluorine, chlorine, bromine and iodine . In the present specification , examples of the “ optionally In the present specification , examples of the “ C1- 6 alkyl halogenated C1- 6 alkylthio group ” include a C1- 6 alkylthio group ” include methyl, ethyl, propyl, isopropyl, butyl, group optionally having 1 to 7 , preferably 1 to 5 , halogen isobutyl, sec - butyl, tert - butyl, pentyl, isopentyl, neopentyl, 50 atoms. Specific examples thereof include methylthio , dif 1 - ethylpropyl , hexyl, isohexyl , 1 , 1 - dimethylbutyl, 2 , 2 - dim luoromethylthio , trifluoromethylthio , ethylthio , propylthio , ethylbutyl, 3 , 3 - dimethylbutyl and 2 - ethylbutyl. isopropylthio , butylthio , 4 , 4 , 4 - trifluorobutylthio , pentylthio In the present specification , examples of the “ optionally and hexylthio . halogenated C1- 6 alkyl group ” include a C1- 6 alkyl group In the present specification , examples of the “ C1- 6 alkyl optionally having 1 to 7 , preferably 1 to 5 , halogen atoms. 55 carbonyl group ” include acetyl, propanoyl, butanoyl, Specific examples thereof include methyl, chloromethyl, 2 -methylpropanoyl , pentanoyl , 3 -methylbutanoyl , 2 -meth difluoromethyl, trichloromethyl , trifluoromethyl, ethyl, ylbutanoyl, 2 ,2 -dimethylpropanoyl , hexanoyl and hep 2 -bromoethyl , 2 , 2 ,2 - trifluoroethyl, tetrafluoroethyl, penta tanoyl. fluoroethyl, propyl, 2 , 2 -difluoropropyl , 3 , 3 , 3 - trifluoropro - In the present specification , examples of the “ optionally pyl, isopropyl, butyl, 4 , 4 , 4 - trifluorobutyl, isobutyl, sec - bu - 60 halogenated C1- 6 alkyl- carbonyl group ” include a C1- 6 alkyl tyl, tert - butyl, pentyl, isopentyl , neopentyl, 5 , 5 , 5 - carbonyl group optionally having 1 to 7 , preferably 1 to 5 , trifluoropentyl, hexyl and 6 , 6 ,6 -trifluorohexyl . halogen atoms. Specific examples thereof include acetyl, In the present specification , examples of the “ C2- 6 alkenyl chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, group ” include ethenyl, 1- propenyl , 2 -propenyl , 2 -methyl - butanoyl, pentanoyl and hexanoyl. 1 -propenyl , 1 -butenyl , 2 -butenyl , 3 -butenyl , 3 -methyl - 2 - 65 In the present specification , examples of the “ C1- 6 alkoxy butenyl, 1- pentenyl , 2 -pentenyl , 3 -pentenyl , 4 -pentenyl , carbonyl group ” include methoxycarbonyl, ethoxycarbonyl, 4 -methyl - 3 -pentenyl , 1 -hexenyl , 3 -hexenyl and 5- hexenyl . propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , US 9 , 776 ,962 B2 isobutoxycarbonyl , sec -butoxycarbonyl , tert - butoxycarbo - ( 10 ) a 3 - to 14 -membered non -aromatic heterocyclyloxy nyl, pentyloxycarbonyl and hexyloxycarbonyl. group (e . g ., morpholinyloxy , piperidinyloxy ), In the present specification , examples of the “ C6- 14 aryl (11 ) a C1- 6 alkyl- carbonyloxy group ( e .g ., acetoxy, pro carbonyl group ” include benzoyl, 1 -naphthoyl and 2 -naph panoyloxy ) , thoyl . 5 ( 12 ) a C6- 14 aryl- carbonyloxy group ( e . g ., benzoyloxy , In the present specification , examples of the “ C7- 16 1 - naphthoyloxy, 2 - naphthoyloxy ) , aralkyl- carbonyl group ” include phenylacetyl and phenyl- ( 13 ) a C1- 6 alkoxy -carbonyloxy group ( e . g ., methoxycarbo propionyl. nyloxy , ethoxycarbonyloxy, propoxycarbonyloxy , butoxy In the present specification , examples of the “ 5 - to carbonyloxy ) , 14 -membered aromatic heterocyclylcarbonyl group ” 10 ( 14 ) a mono - or di -C1 - 6 alkyl- carbamoyloxy group ( e . g ., include nicotinoyl, isonicotinoyl , thenoyl and furoyl methylcarbamoyloxy, ethylcarbamoyloxy , dimethylcarbam In the present specification , examples of the “ 3 - to oyloxy, diethylcarbamoyloxy ) , 14 -membered non - aromatic heterocyclylcarbonyl group ” ( 15 ) a C6- 14 aryl - carbamoyloxy group ( e . g ., phenylcarbam include morpholinylcarbonyl, piperidinylcarbonyl and pyr - oyloxy, naphthylcarbamoyloxy ), rolidinylcarbonyl. 15 ( 16 ) a 5 - to 14 -membered aromatic heterocyclylcarbonyloxy In the present specification , examples of the “mono - or group ( e . g . , nicotinoyloxy ) , di- C1 - 6 alkyl - carbamoyl group ” include methylcarbamoyl, ( 17 ) a 3 - to 14 -membered non - aromatic heterocyclylcarbo ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and nyloxy group (e . g. , morpholinylcarbonyloxy , piperidinylcar N - ethyl- N -methylcarbamoyl . bonyloxy ) , In the present specification , examples of the “mono - or 20 ( 18 ) an optionally halogenated C1- 6 alkylsulfonyloxy group di- C7 - 16 aralkyl- carbamoyl group ” include benzylcarbamoyl ( e . g . , methylsulfonyloxy, trifluoromethylsulfonyloxy ), and phenethylcarbamoyl. ( 19 ) a C6- 14 arylsulfonyloxy group optionally substituted by In the present specification , examples of the “ C1- 6 alkyl a C1- 6 alkyl group ( e . g ., phenylsulfonyloxy, toluenesulfony sulfonyl group ” include methylsulfonyl, ethylsulfonyl, pro - loxy ), pylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec -butylsul - 25 (20 ) an optionally halogenated C1- 6 alkylthio group , fonyl and tert -butylsulfonyl . (21 ) a 5 - to 14 -membered aromatic heterocyclic group , In the present specification , examples of the “ optionally (22 ) a 3 - to 14 -membered non - aromatic heterocyclic group , halogenated C1- 6 alkylsulfonyl group ” include a C1- 6 alkyl ( 23 ) a formyl group , sulfonyl group optionally having 1 to 7 , preferably 1 to 5 , ( 24 ) a carboxy group , halogen atoms. Specific examples thereof include methyl - 30 ( 25 ) an optionally halogenated C1- 6 alkyl- carbonyl group , sulfonyl, difluoromethylsulfonyl , trifluoromethylsulfonyl, ( 26 ) a C6- 14 aryl- carbonyl group , ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfo ( 27 ) a 5 - to 14 -membered aromatic heterocyclylcarbonyl nyl, 4 , 4 , 4 - trifluorobutylsulfonyl, pentylsulfonyl and hexyl group , sulfonyl. (28 ) a 3 - to 14 -membered non -aromatic heterocyclylcarbo In the present specification , examples of the “ C6- 14 aryl - 35 nyl group , sulfonyl group ” include phenylsulfonyl, 1 -naphthylsulfonyl ( 29 ) a C1- 6 alkoxy -carbonyl group , and 2 -naphthylsulfonyl . ( 30 ) a C6- 14 aryloxy - carbonyl group ( e . g ., phenyloxycarbo In the present specification , examples of the “ substituent” nyl , 1- naphthyloxycarbonyl , 2 -naphthyloxycarbonyl ) , include a halogen atom , a cyano group , a nitro group , an ( 31 ) a C7- 16 aralkyloxy -carbonyl group ( e . g . , benzyloxycar optionally substituted hydrocarbon group , an optionally 40 bonyl, phenethyloxycarbonyl) , substituted heterocyclic group , an acyl group , an optionally (32 ) a carbamoyl group , substituted amino group , an optionally substituted carbam - (33 ) a thiocarbamoyl group , oyl group , an optionally substituted thiocarbamoyl group , an (34 ) a mono - or di- C1 - alkyl -carbamoyl group , optionally substituted sulfamoyl group , an optionally sub - ( 35 ) a C6- 14 aryl- carbamoyl group ( e . g . , phenylcarbamoyl) , stituted hydroxy group , an optionally substituted sulfanyl 45 (36 ) a 5 - to 14 -membered aromatic heterocyclylcarbamoyl (SH ) group and an optionally substituted silyl group . group ( e. g ., pyridylcarbamoyl, thienylcarbamoyl ) , In the present specification , examples of the “ hydrocarbon (37 ) a 3 - to 14 - membered non - aromatic heterocyclylcar group ” ( including “ hydrocarbon group” of “ optionally sub - bamoyl group ( e . g . , morpholinylcarbamoyl, piperidinylcar stituted hydrocarbon group ' ) include a C1-6 alkyl group , a bamoyl) , C2- 6 alkenyl group , a C2- 6 alkynyl group , a C3- 10 cycloalkyl 50 (38 ) an optionally halogenated C1- 6 alkylsulfonyl group , group , a C3- 10 cycloalkenyl group , a C6- 14 aryl group and a ( 39 ) a C6- 14 arylsulfonyl group , C7- 16 aralkyl group . ( 40 ) a 5 . to 14 -membered aromatic heterocyclylsulfonyl In the present specification , examples of the “ optionally group (e . g. , pyridylsulfonyl, thienylsulfonyl) , substituted hydrocarbon group ” include a hydrocarbon (41 ) an optionally halogenated C1-6 alkylsulfinyl group , group optionally having substituent( s ) selected from the 55 (42 ) a C6- 14 arylsulfinyl group (e . g. , phenylsulfinyl, 1 -naph following substituent group A . thylsulfinyl, 2 -naphthylsulfinyl ) , substituent group A ] (43 ) a 5 - to 14 -membered aromatic heterocyclylsulfinyl ( 1 ) a halogen atom , group ( e . g . , pyridylsulfinyl, thienylsulfinyl) , ( 2 ) a nitro group , ( 44 ) an amino group , ( 3 ) a cyano group, 60 (45 ) a mono - or di- C1- 6 alkylamino group ( e . g . , methyl ( 4 ) an oxo group , amino , ethylamino , propylamino , isopropylamino , buty (5 ) a hydroxy group , lamino , dimethylamino , diethylamino , dipropylamino , dibu (6 ) an optionally halogenated C1- 6 alkoxy group , tylamino , N -ethyl - N -methylamino ) , ( 7 ) a C6 - 14 aryloxy group ( e. g ., phenoxy, naphthoxy ), (46 ) a mono - or di- C6- 14 arylamino group ( e. g. , phe ( 8 ) a C7- 16 aralkyloxy group ( e . g ., benzyloxy ) , 65 nylamino ) , ( 9 ) a 5 - to 14 -membered aromatic heterocyclyloxy group (47 ) a 5 - to 14 -membered aromatic heterocyclylamino group ( e. g ., pyridyloxy ) , ( e . g . , pyridylamino ) , US 9 ,776 , 962 B2 10 (48 ) a C7 - 16 aralkylamino group (e . g . , benzylamino ), non - aromatic heterocyclic group ” ) include a 3 - to 14 -mem (49 ) a formylamino group , bered (preferably 4 - to 10 -membered ) non -aromatic hetero ( 50 ) a C1- 6 alkyl- carbonylamino group ( e . g . , acetylamino , cyclic group containing , as a ring -constituting atom besides propanoylamino , butanoylamino ) , carbon atom , 1 to 4 hetero atoms selected from a nitrogen (51 ) a ( C1- 6 alkyl) ( C1- 6 alkyl -carbonyl ) amino group ( e . g . , 5 atom , a sulfur atom and an oxygen atom . N -acetyl - N -methylamino ), Preferable examples of the “ non -aromatic heterocyclic (52 ) a C6- 14 aryl- carbonylamino group ( e. g ., phenylcarbo nylamino , naphthylcarbonylamino ) , group ” include 3 - to 8 -membered monocyclic non - aromatic (53 ) a C1- 6 alkoxy -carbonylamino group ( e. g. , methoxycar heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, bonylamino , ethoxycarbonylamino, propoxycarbonylamino , 10 azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahy butoxycarbonylamino , tert- butoxycarbonylamino ) , drofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl , imidazo (54 ) a C7- 16 aralkyloxy - carbonylamino group ( e . g . , benzy lidinyl, oxazolinyl , oxazolidinyl, pyrazolinyl , pyrazolidinyl, loxycarbonylamino ) , thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahy (55 ) a C1- 6 alkylsulfonylamino group ( e . g ., methylsulfo drooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, nylamino , ethylsulfonylamino ) , 15 tetrahydropyridinyl, dihydropyridinyl , dihydrothiopyranyl, ( 56 ) a C6- 14 arylsulfonylamino group optionally substituted tetrahydropyrimidinyl, tetrahydropyridazinyl , dihydropyra by a C1- 6 alkyl group ( e . g ., phenylsulfonylamino , toluene nyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, sulfonylamino ) , thiomorpholinyl, azepanyl , diazepanyl, azepinyl, oxepanyl , (57 ) an optionally halogenated C1- 6 alkyl group , azocanyl, diazocanyl and the like ; and 9 - to 14 -membered (58 ) a C2- 6 alkenyl group , 20 fused polycyclic (preferably bi or tricyclic ) non -aromatic (59 ) a C2- 6 alkynyl group , heterocyclic groups such as dihydrobenzofuranyl, dihyd (60 ) a C3- 10 cycloalkyl group , robenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothi (61 ) a C3- 10 cycloalkenyl group and azolyl, dihydrobenzisothiazolyl, dihydronaphtho [2 ,3 -b ] thie (62 ) a C6- 14 aryl group . nyl, tetrahydroisoquinolyl, tetrahydroquinolyl, The number of the above -mentioned substituents in the 25 4H - quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno [ 2 , " optionally substituted hydrocarbon group ” is , for example , 3 - c ]pyridinyl , tetrahydrobenzazepinyl, tetrahydroquinoxali 1 to 5 , preferably 1 to 3 . When the number of the substituents nyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, is two or more , the respective substituents may be the same hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahy or different. dronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinno In the present specification , examples of the “ heterocyclic 30 linyl , tetrahydrocarbazolyl, tetrahydro - ß - carbolinyl, tetrahy group ” ( including " heterocyclic group ” of “ optionally sub droacrydinyl, tetrahydrophenazinyl, stituted heterocyclic group ' ) include ( i ) an aromatic hetero - tetrahydrothioxanthenyl, octahydroisoquinolyl and the like . cyclic group , ( ii ) a non -aromatic heterocyclic group and (iii ) In the present specification , preferable examples of the “ 7 a 7 - to 10 -membered bridged heterocyclic group , each to 10 -membered bridged heterocyclic group ” include qui containing , as a ring -constituting atom besides carbon atom , 35 nuclidinyl and 7 - azabicyclo [2 . 2 .1 ]heptanyl . 1 to 4 hetero atoms selected from a nitrogen atom , a sulfur I n the present specification , examples of the “ nitrogen atom and an oxygen atom . containing heterocyclic group ” include a " heterocyclic In the present specification , examples of the " aromatic group ” containing at least one nitrogen atom as a ring heterocyclic group " ( including “ 5 - to 14 -membered aro - constituting atom . matic heterocyclic group ” ) include a 5 . to 14 -membered 40 In the present specification , examples of the “ optionally (preferably 5 - to 10 -membered ) aromatic heterocyclic group substituted heterocyclic group ” include a heterocyclic group containing , as a ring - constituting atom besides carbon atom , optionally having substituent ( s ) selected from the aforemen 1 to 4 hetero atoms selected from a nitrogen atom , a sulfur tioned substituent group A . atom and an oxygen atom . The number of the substituents in the " optionally substi Preferable examples of the " aromatic heterocyclic group ” 45 tuted heterocyclic group ” is , for example , 1 to 3 . When the include 5 - or 6 -membered monocyclic aromatic heterocyclic number of the substituents is two or more , the respective groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyra - substituents may be the same or different. zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, In the present specification , examples of the “ acyl group ” pyrazinyl, pyrimidinyl, pyridazinyl, 1 , 2 , 4 - oxadiazolyl, 1 , 3 , include a formyl group , a carboxy group , a carbamoyl group , 4 -oxadiazolyl , 1, 2 ,4 - thiadiazolyl, 1, 3 ,4 - thiadiazolyl, triaz- 50 a thiocarbamoyl group , a sulfino group , a sulfo group , a olyl, tetrazolyl , triazinyl and the like ; and 8 - to 14 -mem - sulfamoyl group and a phosphono group , each optionally bered fused polycyclic ( preferably bi or tricyclic ) aromatic having “ 1 or 2 substituents selected from a C1- 6 alkyl group , heterocyclic groups such as benzothiophenyl, benzofuranyl, a C2- 6 alkenyl group , a C3- 10 cycloalkyl group, a C3- 10 benzimidazolyl , benzoxazolyl, benzisoxazolyl, benzothiaz - cycloalkenyl group , a C6- 14 aryl group , a C7- 16 aralkyl group , olyl , benzisothiazolyl, benzotriazolyl, imidazopyridinyl, 55 a 5 - to 14 -membered aromatic heterocyclic group and a 3 thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolo to 14 -membered non - aromatic heterocyclic group , each of pyridinyl, oxazolopyridinyl , thiazolopyridinyl, imidazopy - which optionally has 1 to 3 substituents selected from a razinyl, imidazopyrimidinyl , thienopyrimidinyl, furopyrim - halogen atom , an optionally halogenated C1- 6 alkoxy group , idinyl, pyrrolopyrimidinyl , pyrazolopyrimidinyl, a hydroxy group , a nitro group , a cyano group , an amino oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, 60 group and a carbamoyl group ” . naphtho [ 2 ,3 -b ]thienyl , phenoxathiinyl, indolyl, isoindolyl, Examples of the “ acyl group ” also include a hydrocarbon 1H - indazolyl, purinyl, isoquinolyl , quinolyl , phthalazinyl, sulfonyl group , a heterocyclylsulfonyl group , a hydrocar naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, car bon - sulfinyl group and a heterocyclylsulfinyl group . bazolyl, ß - carbolinyl, phenanthridinyl, acridinyl, phenazi - Here, the hydrocarbon -sulfonyl group means a hydrocar nyl, phenothiazinyl, phenoxazinyl and the like . 65 bon group -bonded sulfonyl group , the heterocyclylsulfonyl In the present specification , examples of the " non - aro - group means a heterocyclic group -bonded sulfonyl group , matic heterocyclic group ” ( including “ 3 - to 14 -membered the hydrocarbon - sulfinyl group means a hydrocarbon group US 9 ,776 , 962 B2 12 bonded sulfinyl group and the heterocyclylsulfinyl group bonylamino group ( e . g ., nicotinoylamino , isonicotinoy means a heterocyclic group - bonded sulfinyl group . lamino ) , a mono - or di- 3 - to 14 - membered non - aromatic Preferable examples of the “ acyl group ” include a formy1 heterocyclylcarbonylamino group ( e . g ., piperidinylcarbo group , a carboxy group , a C1-6 alkyl- carbonyl group , a C2- 6 nylamino ), a mono - or di- C1 - 6 alkoxy - carbonylamino group alkenyl -carbonyl group ( e . g . , crotonoyl) , a C3- 10 cycloalkyl- 5 ( e . g . , tert - butoxycarbonylamino ) , a 5 - to 14 -membered aro carbonyl group (e . g. , cyclobutanecarbonyl, cyclopentan - matic heterocyclylamino group (e .g . , pyridylamino ), a car ecarbonyl , cyclohexanecarbonyl, cycloheptanecarbonyl ) , a bamoylamino group , a (mono - or di -C1 - 6 alkyl- carbamoyl ) Cz. 10 cycloalkenyl- carbonyl group ( e . g . , 2 - cyclohexenecar - amino group ( e . g . , methylcarbamoylamino ) , a (mono - or bonyl) , a C6- 14 aryl- carbonyl group , a C7- 16 aralkyl- carbonyl di- C7 - 16 aralkyl- carbamoyl ) amino group ( e .g ., benzylcar group , a 5 - to 14 -membered aromatic heterocyclylcarbonyl 10 bamoylamino ) , a C1- 6 alkylsulfonylamino group (e .g . ,meth group , a 3 - to 14 -membered non - aromatic heterocyclylcar- ylsulfonylamino , ethylsulfonylamino ), a C6- 14 arylsulfo bonyl group , a C1-6 alkoxy -carbonyl group , a C6- 14 aryloxy - nylamino group ( e. g ., phenylsulfonylamino ) , a (C1 - 6 alkyl) carbonyl group ( e . g ., phenyloxycarbonyl, naphthyloxycar (C1 - 6 alkyl - carbonyl) amino group ( e . g . , N - acetyl- N bonyl) , a C7- 16 aralkyloxy -carbonyl group ( e. g ., methylamino ) and a (Cl - , alkyl) (C6 - 14 aryl- carbonyl ) amino benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl 15 group (e . g. , N -benzoyl - N -methylamino ). group , a mono - or di- C1- 6 alkyl- carbamoyl group , a mono - In the present specification , examples of the “ optionally or di- C2 - 6 alkenyl- carbamoyl group ( e . g ., diallylcarbamoyl) , substituted carbamoyl group ” include a carbamoyl group a mono - or di- C3- 10 cycloalkyl- carbamoyl group ( e . g ., optionally having “ 1 or 2 substituents selected from a C1- 6 cyclopropylcarbamoyl) , a mono - or di -C6 - 14 aryl- carbamoyl alkyl group , a C2- 6 alkenyl group , a C3- 10 cycloalkyl group , group ( e . g . , phenylcarbamoyl) , a mono - or di- C7- 16 aralkyl- 20 a C6- 14 aryl group , a C7- 16 aralkyl group , a C1- 6 alkyl carbamoyl group , a 5 - to 14 -membered aromatic heterocy - carbonyl group , a C6- 14 aryl- carbonyl group , a C7- 16 aralkyl clylcarbamoyl group ( e . g ., pyridylcarbamoyl ), a thiocar - carbonyl group , a 5 - to 14 -membered aromatic heterocy bamoyl group , a mono - or di- C1- 6 alkyl- thiocarbamoyl clylcarbonyl group , a 3 - to 14 -membered non - aromatic group ( e . g ., methylthiocarbamoyl, N -ethyl - N -methylthio - heterocyclylcarbonyl group , a C1- 6 alkoxy -carbonyl group , a carbamoyl) , a mono - or di- C2 - 6 alkenyl- thiocarbamoyl 25 5 - to 14 -membered aromatic heterocyclic group , a carbam group ( e . g . , diallylthiocarbamoyl ) , a mono - or di- C3- 10 oyl group , a mono - or di- C1- 6 alkyl- carbamoyl group and a cycloalkyl -thiocarbamoyl group ( e . g ., cyclopropylthiocar mono - or di- C7 - 16 aralkyl- carbamoyl group , each of which bamoyl, cyclohexylthiocarbamoyl) , a mono - or di - C6 - 14 optionally has 1 to 3 substituents selected from substituent aryl- thiocarbamoyl group ( e . g . , phenylthiocarbamoyl) , a group A ” . mono - or di- C7- 16 aralkyl- thiocarbamoyl group ( e . g . , ben - 30 Preferable examples of the optionally substituted carbam zylthiocarbamoyl, phenethylthiocarbamoyl) , a 5 . to oyl group include a carbamoyl group , a mono - or di -C1 - 6 14 -membered aromatic heterocyclylthiocarbamoyl group alkyl- carbamoyl group , a mono - or di- C2 - 6 alkenyl- carbam ( e .g ., pyridylthiocarbamoyl) , a sulfino group , a C1- 6 alkyl- oyl group (e . g. , diallylcarbamoyl) , a mono - or di- C3 - 10 sulfinyl group (e . g. , methylsulfinyl, ethylsulfinyl) , a sulfo cycloalkyl- carbamoyl group ( e. g ., cyclopropylcarbamoyl, group , a C1- 6 alkylsulfonyl group , a C6- 14 arylsulfonyl 35 cyclohexylcarbamoyl) , a mono - or di- C6- 14 aryl- carbamoyl group , a phosphono group and a mono - or di- C1- 6 alkyl group ( e. g ., phenylcarbamoyl) , a mono - or di -C7 - 16 aralkyl phosphono group ( e . g ., dimethylphosphono , diethyl - carbamoyl group , a mono - or di- C1- 6 alkyl -carbonyl - car phosphono , diisopropylphosphono , dibutylphosphono ). bamoyl group ( e. g ., acetylcarbamoyl, propionylcarbamoyl) , In the present specification , examples of the “ optionally a mono - or di- C6 - 14 aryl - carbonyl- carbamoyl group ( e . g ., substituted amino group ” include an amino group optionally 40 benzoylcarbamoyl) and a 5 - to 14 -membered aromatic het having “ 1 or 2 substituents selected from a C1- 6 alkyl group , erocyclylcarbamoyl group ( e .g . , pyridylcarbamoyl) . a C2-6 alkenyl group , a C3- 10 cycloalkyl group , a C6- 14 aryl In the present specification , examples of the “ optionally group , a C7- 16 aralkyl group , a C1- 6 alkyl - carbonyl group , a substituted thiocarbamoyl group ” include a thiocarbamoyl C6- 14 aryl- carbonyl group , a C7- 16 aralkyl- carbonyl group , a group optionally having “ 1 or 2 substituents selected from a 5 - to 14 -membered aromatic heterocyclylcarbonyl group , a 45 C1- 6 alkyl group , a C2- 6 alkenyl group , a C3- 10 cycloalkyl 3 - to 14 -membered non - aromatic heterocyclylcarbonyl group , a C6- 14 aryl group , a C7- 16 aralkyl group , a C1- 6 group , a Cl. alkoxy -carbonyl group , a 5 - to 14 -membered alkyl- carbonyl group , a C6- 14 aryl - carbonyl group , a C7- 16 aromatic heterocyclic group , a carbamoyl group , a mono - or aralkyl - carbonyl group , a 5 - to 14 -membered aromatic het di- C1 - 6 alkyl- carbamoyl group , a mono - or di- C7 - 16 aralkyl erocyclylcarbonyl group , a 3 - to 14 -membered non -aromatic carbamoyl group , a C1- 6 alkylsulfonyl group and a C6- 14 50 heterocyclylcarbonyl group , a C1- 6 alkoxy -carbonyl group , a arylsulfonyl group , each of which optionally has 1 to 3 5 - to 14 -membered aromatic heterocyclic group , a carbam substituents selected from substituent group A ” . oyl group , a mono - or di- C1 - 6 alkyl- carbamoyl group and a Preferable examples of the optionally substituted amino mono - or di - C7- 16 aralkyl- carbamoyl group , each of which group include an amino group , a mono - or di- ( optionally optionally has 1 to 3 substituents selected from substituent halogenated C1- 6 alkyl) amino group ( e . g . , methylamino , 55 group A ” . trifluoromethylamino , dimethylamino , ethylamino , diethyl Preferable examples of the optionally substituted thiocar amino , propylamino , dibutylamino ), a mono - or di- C2- 6 bamoyl group include a thiocarbamoyl group , a mono - or alkenylamino group (e .g . , diallylamino ), a mono - or di- C3- 10 di- C1 - 6 alkyl- thiocarbamoyl group ( e .g ., methylthiocarbam cycloalkylamino group ( e . g . , cyclopropylamino, cyclohexy - oyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylth lamino ) , a mono - or di- C6 - 14 arylamino group ( e . g . , phe - 60 iocarbamoyl, N - ethyl - N -methylthiocarbamoyl ) , a mono - or nylamino ) , a mono - or di- C7- 16 aralkylamino group ( e .g ., di- C2 - 6 alkenyl- thiocarbamoyl group ( e . g . , diallylthiocar benzylamino , dibenzylamino ) , a mono - or di- (optionally bamoyl) , a mono - or di- C3 - 10 cycloalkyl- thiocarbamoyl halogenated C1- 6 alkyl) -carbonylamino group ( e . g . , acety - group ( e . g ., cyclopropylthiocarbamoyl, cyclohexylthiocar lamino , propionylamino ), a mono - or di- C6 - 14 aryl - carbo bamoyl) , a mono - or di- C6 - 14 aryl- thiocarbamoyl group nylamino group (e . g. , benzoylamino ), a mono - or di- C7 - 16 65 (e .g ., phenylthiocarbamoyl) , a mono - or di- C7 - 16 aralkyl aralkyl- carbonylamino group ( e . g ., benzylcarbonylamino ) , a thiocarbamoyl group ( e . g ., benzylthiocarbamoyl, pheneth mono - or di- 5 - to 14 -membered aromatic heterocyclylcar - ylthiocarbamoyl) , a mono - or di- C1- 6 alkyl - carbonyl- thio US 9 ,776 , 962 B2 13 14 carbamoyl group ( e. g. , acetylthiocarbamoyl, loxy ), a C1- 6 alkylsulfonyloxy group ( e. g ., methylsulfony propionylthiocarbamoyl ), a mono - or di -C6 - 14 aryl - carbo loxy, ethylsulfonyloxy ) and a C6- 14 arylsulfonyloxy group nyl- thiocarbamoyl group ( e . g ., benzoylthiocarbamoyl) and a (e . g. , phenylsulfonyloxy ). 5 - to 14 -membered aromatic heterocyclylthiocarbamoyl In the present specification , examples of the “ optionally group ( e . g ., pyridylthiocarbamoyl) . 5 substituted sulfanyl group ” include a sulfanyl group option In the present specification , examples of the " optionally ally having " a substituent selected from a Cl- alkyl group , substituted sulfamoyl group ” include a sulfamoyl group a C2- 6 alkenyl group , a C3- 10 cycloalkyl group , a C6- 14 aryl optionally having “ 1 or 2 substituents selected from a C1- 6 group , a C7- 16 aralkyl group , a C1- 6 alkyl- carbonyl group , a alkyl group , a C2- 6 alkenyl group , a C3- 10 cycloalkyl group , C6 -14 aryl- carbonyl group and a 5 - to 14 -membered aromatic a Cau aryl group , aC a ralkyl group . a C . , alkyl- 10 heterocyclic groungroup , paeach of which optionally has 1 to 3 carbonyl group , a C6- 14 aryl- carbonyl group , a C7- 16 aralkyl substituents selected from substituent group A ” and a halo carbonyl group , a 5 . to 14 -membered aromatic heterocy genated sulfanyl group . clylcarbonyl group , a 3 - to 14 -membered non -aromatic Preferable examples of the optionally substituted sulfanyl heterocyclylcarbonyl group , a C1- 6 alkoxy - carbonyl group , a 15 group include a sulfanyl ( SH ) group , a C1- 6 alkylthio 5 - to 14 -membered aromatic heterocyclic grouparbony , a carbamgroup , a- 15 groupthio , 2 , -pentenylthioa C2- 6 alkenylthio . 3- hexenylthio group (e .)g , . a, alkylthioc , cycloalkylthio , 2 -butenyl oyl group , a mono - or di- C1 - 6 alkyl- carbamoyl group and a group ( e .g ., cyclohexylthio ), a C6- 14 arylthio group ( e .g ., mono - or di- C7 - 16 aralkyl- carbamoyl group , each of which phenylthio , naphthylthio ), a C7- 16 aralkylthio group ( e . g ., optionally has 1 to 3 substituents selected from substituent benzylthio , phenethylthio ), a C , a alkyl- carbonylthio group group A ” . 20 (e .g . , acetylthio , propionylthio , butyrylthio , isobutyrylthio , Preferable examples of the optionally substituted sulfa - pivaloylthio ), a C6- 14 aryl - carbonylthio group ( e. g. , benzo moyl group include a sulfamoyl group , a mono - or di- C1- 6 ylthio ), a 5 . to 14 - membered aromatic heterocyclylthio alkyl- sulfamoyl group ( e . g ., methylsulfamoyl, ethylsulfa - group ( e . g ., pyridylthio ) and a halogenated thio group ( e . g . , moyl, dimethylsulfamoyl, diethylsulfamoyl, N - ethyl- N pentafluorothio ). methylsulfamoyl ), a mono - or di- C2 - 6 alkenyl- sulfamoyl 25 In the present specification , examples of the “ optionally group ( e . g . , diallylsulfamoyl) , a mono - or di- C3- 10 substituted silyl group ” include a silyl group optionally cycloalkyl - sulfamoyl group ( e . g ., cyclopropylsulfamoyl, having “ 1 to 3 substituents selected from a C1- 6 alkyl group , cyclohexylsulfamoyl) , a mono - or di- C6 - 14 aryl- sulfamoyl a C2- 6 alkenyl group , a C3- 10 cycloalkyl group , a C6- 14 aryl group ( e . g . , phenylsulfamoyl) , a mono - or di- C7- 16 aralkyl- group and a C7- 16 aralkyl group , each of which optionally sulfamoyl group ( e . g ., benzylsulfamoyl , phenethylsulfa - 30 has 1 to 3 substituents selected from substituent group A ” . moyl) , a mono - or di- C1- 6 alkyl- carbonyl - sulfamoyl group Preferable examples of the optionally substituted silyl ( e . g. , acetylsulfamoyl, propionylsulfamoyl) , a mono - or group include a tri -C1 - 6 alkylsilyl group ( e . g ., trimethylsilyl , di- C6- 14 aryl- carbonyl - sulfamoyl group ( e . g ., benzoylsulfa tert -butyl ( dimethyl ) silyl) . moyl) and a 5 - to 14 -membered aromatic heterocyclylsul In the present specification , examples of the “ hydrocarbon famoyl group ( e . g ., pyridylsulfamoyl) . 35 ring ” include a C6 -14 aromatic hydrocarbon ring , C3- 10 In the present specification , examples of the “ optionally cycloalkane , and C3- 10 cycloalkene . substituted hydroxy group ” include a hydroxyl group In the present specification , examples of the “ C6- 14 aro optionally having a substituent selected from a C1- 6 alkyl matic hydrocarbon ring ” include benzene and naphthalene . group , a C2- 6 alkenyl group , a C3- 10 cycloalkyl group , a C6- 14 In the present specification , examples of the “ C3- 10 aryl group , a C7- 16 aralkyl group , a C1- 6 alkyl- carbonyl 40 cycloalkane ” include cyclopropane , cyclobutane , cyclopen group , a C6- 14 aryl- carbonyl group , a C7- 16 aralkyl -carbonyl tane , cyclohexane , cycloheptane, and cyclooctane . group , a 5 - to 14 -membered aromatic heterocyclylcarbonyl In the present specification , examples of the “ C3- 10 group, a 3 - to 14 -membered non - aromatic heterocyclylcar - cycloalkene” include cyclopropene , cyclobutene, cyclopen bonyl group , a C1- 6 alkoxy - carbonyl group , a 5 - to 14 -mem tene , cyclohexene, cycloheptene , and cyclooctene . bered aromatic heterocyclic group , a carbamoyl group , a 45 In the present specification , examples of the " heterocycle ” mono - or di- C . , alkyl- carbamoyl group , a mono - or di- C , include aromatic heterocycle and non -aromatic heterocycle , 16 aralkyl- carbamoyl group , a C - 6 alkylsulfonyl group and each containing , as a ring - constituting atom besides carbon a C6 - 14 arylsulfonyl group , each of which optionally has 1 to atom , 1 to 4 hetero atoms selected from a nitrogen atom , a 3 substituents selected from substituent group A ” . sulfur atom and an oxygen atom . Preferable examples of the optionally substituted hydroxy 50 In the present specification , examples of the “ aromatic group include a hydroxy group , a C1- 6 alkoxy group , a C2- 6 heterocycle ” include 5 - to 14 -membered ( preferably 5 - to alkenyloxy group ( e. g ., allyloxy , 2 -butenyloxy , 2 -penteny - 10 -membered ) aromatic heterocycle containing , as a ring loxy , 3 -hexenyloxy ) , a C3- 10 cycloalkyloxy group ( e .g ., constituting atom besides carbon atom , 1 to 4 hetero atoms cyclohexyloxy ), a C6- 14 aryloxy group (e . g. , phenoxy , naph selected from a nitrogen atom , a sulfur atom and an oxygen thyloxy ) , a C7- 16 aralkyloxy group ( e . g . , benzyloxy , phen - 55 atom . Preferable examples of the “ aromatic heterocycle” ethyloxy ), a C1- 6 alkyl- carbonyloxy group ( e . g ., acetyloxy , include 5 - or 6 -membered monocyclic aromatic hetero propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy ), a cycles such as thiophene, furan , pyrrole , imidazole , pyra C6- 14 aryl- carbonyloxy group ( e . g ., benzoyloxy ) , a C7- 16 zole , thiazole , isothiazole , oxazole, isoxazole , pyridine , aralkyl- carbonyloxy group ( e . g ., benzylcarbonyloxy ), a 5 - to pyrazine, pyrimidine , pyridazine , 1 ,2 ,4 -oxadiazole , 1 , 3 , 4 14 -membered aromatic heterocyclylcarbonyloxy group 60 oxadiazole , 1 , 2 , 4 - thiadiazole , 1 , 3 , 4 - thiadiazole , triazole , tet ( e . g . , nicotinoyloxy ) , a 3 - to 14 -membered non - aromatic razole , triazine and the like; and 8 - to 14 - membered fused heterocyclylcarbonyloxy group ( e . g ., piperidinylcarbony - polycyclic ( preferably bi- or tricyclic ) aromatic heterocycles loxy ) , a C1- 6 alkoxy - carbonyloxy group ( e . g ., tert - butoxy - such as benzothiophene , benzofuran , benzimidazole , benzo carbonyloxy ) , a 5 - to 14 - membered aromatic heterocycly - xazole , benzoisoxazole , benzothiazole , benzoisothiazole , loxy group (e .g ., pyridyloxy ), a carbamoyloxy group , a C1- 6 65 benzotriazole , imidazopyridine , thienopyridine , furopyri alkyl- carbamoyloxy group ( e . g ., methylcarbamoyloxy ) a, d ine , pyrrolopyridine , pyrazolopyridine , oxazolopyridine , C7- 16 aralkyl- carbamoyloxy group ( e . g ., benzylcarbamoy - thiazolopyridine, imidazopyrazine , imidazopyrimidine , US 9 ,776 , 962 B2 15 16 thienopyrimidine, furopyrimidine , pyrrolopyrimidine, pyra " optionally further substituted 4 -6 -membered nitrogen - con zolopyrimidine , oxazolopyrimidine , thiazolopyrimidine , taining saturated ring” ) include the above -mentioned “ nitro pyrazolopyrimidine, pyrazolotriazine , naphtho [ 2 ,3 -b ] thio gen - containing heterocycle ” which is 4 - to 6 -membered and phene , phenoxathiine, indole , isoindole , 1H - indazole , saturated . purine , isoquinoline , quinoline , phthalazine , naphthyridine , 5 In the present specification , the “ 4 - 6 -membered nitrogen quinoxaline , quinazoline , cinnoline , carbazole , ß - carboline , phenanthridine , acridine, phenazine , phenothiazine, phenox containing saturated ring ” of the “ optionally further substi athiine and the like. tuted 4 - to 6 -membered nitrogen - containing saturated ring ” In the present specification , examples of the " non - aro preferably optionally has 1 to 5 , preferably 1 to 3 substitu matic heterocycle ” include a 3 - to 14 -membered ( preferably ents at substitutable position ( s ) . When the number of the 4 - to 10 -membered ) non - aromatic heterocycle containing , as 10 substituents is not less than 2 , the respective substituents a ring - constituting atom besides carbon atom , 1 to 4 hetero may be the same or different. atoms selected from a nitrogen atom , a sulfur atom and an In the present specification , examples of the “ 3 - to oxygen atom . Preferable examples of the “ non -aromatic 10 -membered ring” ( including the “ 3 - to 10 -membered ring ” heterocycle ” include 3 - to 8 -membered monocyclic non of the “ optionally substituted 3 - to 10 -membered ring " ) aromatic heterocycles such as aziridine , oxirane, thiirane , 15 include the above -mentioned “ hydrocarbon ring” and “ het azetidine , oxetane, thietane, tetrahydrothiophene , tetrahy erocycle ” which are 3 - to 10 -membered . drofuran , pyrroline , pyrrolidine, imidazoline , imidazolidine , In the present specification , the “ 3 - to 10 -membered ring ” oxazoline, oxazolidine, pyrazoline , pyrazolidine , thiazoline , of the " optionally substituted 3 - to 10 -membered ring ” thiazolidine , tetrahydroisothiazole , tetrahydrooxazole , tetra optionally has 1 to 5 , preferably 1 to 3, substituents , at hydroisoxazole , piperidine , piperazine , tetrahydropyridine , 20 substitutable position (s ). When the number of the substitu dihydropyridine, dihydrothiopyran , tetrahydropyrimidine , ents is not less than 2 , the respective substituents may be the tetrahydropyridazine, dihydropyran , tetrahydropyran , tetra - same or different. hydrothiopyran , morpholine, thiomorpholine, azepanine, The definition of each symbol in the formula ( I ) is diazepane , azepine, azocane, diazocane , oxepane and the described in detail in the following . like ; and 9 - to 14 -membered fused polycyclic the formula 25 Ring A is an optionally further substituted 6 -membered (preferably 2 - or tricyclic ) non - aromatic heterocycles such aromatic ring . as dihydrobenzofuran , dihydrobenzoimidazole , dihydroben - Preferred as the " aromatic ring ” of the " optionally further zooxazole , dihydrobenzothiazole , dihydrobenzoisothiazole , substituted aromatic ring ” for ring A is a C6 -14 aromatic dihydronaphto [ 2 , 3 - b ] thiophene , tetrahydroisoquinoline, tet - hydrocarbon ring ( e . g . , benzene ring ) or an aromatic het rahydroquinoline , 4H - quinolizine , indoline , isoindoline, tet - 30 erocycle ( e . g ., pyridine ring) , more preferably a benzene rahydrothieno [ 2 , 3 - c ]pyridine , tetrahydrobenzoazepine , tet - ring or a pyridine ring, particularly preferably a benzene rahydroquinoxaline , tetrahydrophenanthridine , ring . hexahydrophenothiazine , hexahydrophenoxazine , tetrahy - The " aromatic ring ” is optionally further substituted by drophthalazine, tetrahydronaphthyridine , tetrahydroqui- 1 - 4 (preferably 1 - 3 , more preferably 1 or 2 ) substituents nazoline , tetrahydrocinnoline , tetrahydrocarbazole , tetra - 35 other than a R ' R ? N - C130 ) group and O CR3R4 hydro -ß -carboline , tetrahydroacridine , tetrahydrophenazine , ring B - group , at substitutable position ( s) . tetrahydrothioxanthene, octahydroisoquinoline and the like. Such substituent is preferably In the present specification , examples of the “ nitrogen ( 1 ) a C1- 6 alkylsulfonyl group ( e . g ., methylsulfonyl) option containing heterocycle ” include a " heterocycle ” containing ally substituted by 1 to 3 halogen atoms; at least one nitrogen atom as a ring constituting atom . 40 ( 2 ) a carbamoyl group optionally mono - or di- substituted by In the present specification , examples of the " aromatic a C1- 6 alkyl group optionally substituted by 1 to 3 halogen ring” ( including " aromatic ring ” in the “ optionally further atoms; substituted aromatic ring ” ) include a C6- 14 aromatic hydro - ( 3 ) a hydroxy group ; carbon ring , and aromatic heterocycle . ( 4 ) a C1- 6 alkoxy group (e . g. , methoxy, ethoxy ) optionally In the present specification , the " aromatic ring ” of the 45 substituted by 1 to 3 substituents selected from " optionally further substituted aromatic ring” optionally has ( a ) a halogen atom ( e . g . , a fluorine atom ) , 1 to 5 , preferably 1 to 3 , substituents at substitutable (b ) a carboxy group , position ( s ) . When the number of the substituents is not less ( c ) a C1- 6 alkoxy group , than 2 , the respective substituents may be the same or ( d ) a C1- 6 alkoxy -carbonyl group optionally substituted by different. 50 1 to 3 C6 - 14 aryl groups , In the present specification , examples of the “ optionally ( e ) an amino group optionally mono - or di- substituted by substituted C1- 6 alkyl group ” include the “ optionally substi a substituent selected from a C1- 6 alkyl group and a C1- 6 tuted hydrocarbon group” wherein the hydrocarbon group is alkoxy - carbonyl group , and a “ C1- 6 alkyl group ” . ( f ) a C3- 10 cycloalkyl group ; In the present specification , examples of the “ optionally 55 (5 ) a C1- 6 alkylthio group (e . g. , methylthio ) optionally substituted C3- 10 cycloalkyl group ” include the “ optionally substituted by 1 to 3 substituents selected from substituted hydrocarbon group ” wherein the hydrocarbon ( a ) a halogen atom , and group is a “ C3- 10 cycloalkyl group ” . ( b ) a C - alkoxy -carbonyl group ; In the present specification , the “ C1- 6 alkoxy group " of the (6 ) a cyano group ; " optionally substituted C - alkoxy group ” optionally has 1 60 ( 7 ) a halogen atom ( e .g . , a fluorine atom , a chlorine atom , a to 5 , preferably 1 to 3 , substituents , at substitutable bromine atom ); or position ( s ). When the number of the substituents is not less ( 8 ) a C1- 6 alkyl group ( e . g . , methyl, ethyl) optionally sub than 2 , the respective substituents may be the same or stituted by 1 to 3 substituents selected from different . ( a ) a halogen atom , In the present specification , examples of the “ 4 - 6 - mem - 65 ( b ) a carboxy group , bered nitrogen - containing saturated ring” ( including the (c ) a hydroxy group , “ 4 - 6 -membered nitrogen - containing saturated ring” of the ( d ) a C1- 6 alkoxy -carbonyl group , US 9 , 776 ,962 B2 17 18 ( e ) a C1- 6 alkoxy group , and The “ 4 - to 6 -membered nitrogen - containing saturated (f ) an amino group optionally mono - or di- substituted by ring” is optionally further substituted by 1 -4 (preferably 1 - 3 , a C1- 6 alkyl group , more preferably 1 or 2 ) substituents other than a R 'R ? N — more preferably , C O ) ring A - group and a O CR®R + - group , at ( 1 ) a C1- 6 alkylsulfonyl group ( e . g ., methylsulfonyl) ; 5 substitutable position ( s ). ( 2 ) a carbamoyl group ; Such substituent is preferably a halogen atom (e .g . , a ( 3 ) a hydroxy group ; fluorine atom ) or a C1- 6 alkyl group ( e . g ., methyl) . ( 4 ) a C1- 6 alkoxy group ( e . g ., methoxy ) optionally substi Ring B is preferably an optionally further substituted tuted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) ; azetidine ring , an optionally further substituted pyrrolidine ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; 10 ( 6 ) a cyano group ; ring or an optionally further substituted piperidine ring , ( 7 ) a halogen atom ( e . g . , a fluorine atom , a chlorine atom , a more preferably an azetidine ring , a pyrrolidine ring or a bromine atom ) ; or piperidine ring , each of which is optionally further substi ( 8 ) a C1- 6 alkyl group ( e . g ., methyl , ethyl) . tuted by 1 -4 (preferably 1- 3 , more preferably 1 or 2 ) Ring A is preferably an optionally further substituted 15 substituents selected from a halogen atom ( e . g ., a fluorine benzene ring or an optionally further substituted pyridine atom ) and a C1- 6 alkyl group ( e . g . , methyl) , further prefer ring, more preferably , a benzene ring or a pyridine ring , each ably ( 1) an azetidine ring , (2 ) a pyrrolidine ring or ( 3) a ofwhich is optionally further substituted by 1 - 4 (preferably piperidine ring optionally further substituted by 1- 4 (pref 1 - 3 , more preferably 1 or 2 ) substituents selected from erably 1- 3 , more preferably 1 or 2 ) substituents selected ( 1 ) a C1- 6 alkylsulfonyl group ( e . g . , methylsulfonyl) ; 20 from a halogen atom ( e . g ., a fluorine atom ) and a C1- 6 alkyl ( 2 ) a carbamoyl group ; group ( e. g ., methyl) . ( 3 ) a hydroxy group ; Ring B is particularly preferably a piperidine ring . ( 4 ) a C1- 6 alkoxy group ( e . g ., methoxy ) optionally substi X is N = or — CH = . tuted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) ; X is preferably – N = . ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; 25 R and R ’ are each independently a hydrogen atom or a ( 6 ) a cyano group ; substituent . (7 ) a halogen atom ( e. g. , a fluorine atom , a chlorine atom , a The “ substituent” for R ' or R² is preferably an optionally bromine atom ); and substituted C1- 8 alkyl group ( e . g . , methyl, ethyl, propyl, ( 8 ) a C1- 6 alkyl group ( e .g ., methyl , ethyl) , isopropyl, butyl, isobutyl, 1 -methylpropyl , isopentyl , neo more preferably a benzene ring optionally further substituted 30 pentyl , 1 , 1 - dimethylpropyl, 1 , 2 - dimethylpropyl, 1 - ethylpro by 1 -4 (preferably 1 - 3 , more preferably 1 or 2 ) substituents pyl, 2 -methylbutyl , hexyl, neohexyl, 1 , 2 , 2 - trimethylpropyl , selected from 2 , 2 -dimethylbutyl , 1 - ethyl- 1 -methylbutyl ) , an optionally ( 1) a C1- 6 alkylsulfonyl group (e .g . , methylsulfonyl) ; substituted C3- 10 cycloalkyl group (e .g ., cyclopropyl, ( 2 ) a carbamoyl group ; cyclobutyl, cyclopentyl, cyclohexyl) , an optionally substi ( 3 ) a hydroxy group ; 35 tuted C6- 14 aryl group ( e . g . , phenyl) , an optionally substi ( 4 ) a C1- 6 alkoxy group (e . g ., methoxy ) optionally substi - tuted aromatic heterocyclic group (e . g. , pyrazolyl, oxazolyl, tuted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) ; pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) , an optionally (5 ) a C1- 6 alkylthio group (e .g ., methylthio ) ; substituted nonaromatic heterocyclic group ( e . g ., piperidi ( 6 ) a cyano group ; nyl, tetrahydrofuranyl , dihydropyridinyl, tetrahydropyranyl, ( 7 ) a halogen atom (e . g ., a fluorine atom , a chlorine atom , a 40 tetrahydrothiopyranyl, dihydroindenyl) , an optionally sub bromine atom ) ; and stituted C1- 6 alkylsulfonyl group (e . g. , neopentylsulfonyl) or ( 8 ) a C1- 6 alkyl group ( e. g ., methyl, ethyl) , or a pyridine ring an optionally substituted C1- 6 alkyl -carbonylamino group optionally further substituted by 1 - 4 ( preferably 1 - 3 , more ( e . g ., tert- butylcarbonylamino ) . preferably 1 or 2 ) substituents selected from The “ C1- 8 alkyl group ” of the “ optionally substituted C1- 8 ( 1 ) a C1- 6 alkoxy group ( e . g . , methoxy ) ; 45 alkyl group ” is optionally substituted by 1 - 5 ( preferably 1 - 3 , (2 ) a halogen atom ( e .g ., a chlorine atom ); and more preferably 1 or 2 ) substituents , at substitutable ( 3 ) a C1- 6 alkyl group ( e . g . , ethyl) . position ( s ). Ring A is particularly preferably a benzene ring optionally The substituent is preferably ( 1 ) cyano , ( 2 ) hydroxy, ( 3 ) a further substituted by 1 -4 (preferably 1 -3 , more preferably 1 C3- 10 cycloalkyl group ( e. g ., cyclopropyl, cyclobutyl, cyclo or 2 ) substituents selected from 50 hexyl, cycloheptyl, bicyclo [ 2 . 2 . 1 ]heptyl ) optionally substi ( 1 ) a C1- 6 alkylsulfonyl group ( e . g . , methylsulfonyl) ; tuted by 1 to 3 substituents selected from a halogen atom ( 2 ) a carbamoyl group ; ( e. g ., a fluorine atom ) and a C1- 6 alkyl group ( e. g ., methyl) , ( 3 ) a hydroxy group ; ( 4 ) a C -, alkoxy group ( e . g ., methoxy , ethoxy , isopropoxy ) ( 4 ) a C1- 6 alkoxy group (e . g ., methoxy) optionally substi optionally substituted by 1 to 3 halogen atoms ( a fluorine tuted by 1 to 3 halogen atoms ( e . g . , fluorine atom ) ; 55 atom ) , ( 5 ) a C6 - 14 aryl group ( e .g ., phenyl) optionally sub ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; stituted by 1 to 3 halogen atoms ( e . g ., a fluorine atom , a ( 6 ) a cyano group ; chlorine atom ) , (6 ) an aromatic heterocyclic group ( e . g . , ( 7 ) a halogen atom ( e. g . , fluorine atom , chlorine atom , pyridyl, pyrimidinyl) , ( 7 ) a nonaromatic heterocyclic group bromine atom ) ; and ( e . g . , piperidinyl, tetrahydropyranyl) , ( 8 ) a C1- 6 alkylsulfo ( 8 ) a C1- 6 alkyl group (e .g . , methyl, ethyl) . 60 nyl group ( e . g . , methylsulfonyl) , ( 9 ) a mono - or di -C1 - 6 Ring B is a further optionally substituted 4 - to 6 -mem - alkyl- amino group ( e . g ., ethylamino ) optionally substituted bered nitrogen - containing saturated ring . by 1 to 3 halogen atoms ( e .g . , a fluorine atom ) or ( 10 ) a The “ 4 - to 6 -membered nitrogen -containing saturated halogen atom ( e .g ., a fluorine atom ). ring” of the “ optionally further substituted 4 - to 6 -membered The “ C3- 10 cycloalkyl group ” of the “ optionally substi nitrogen - containing saturated ring ” for ring B is preferably 65 tuted C3- 10 cycloalkyl group ” is optionally substituted by 1 - 5 monocyclic and , for example , an azetidine ring , a pyrroli (preferably 1 - 3 , more preferably 1 or 2 ) substituents , at dine ring, and a piperidine ring can be mentioned . substitutable position ( s ) . US 9 , 776 , 962 B2 20 Examples of such substituent include the above- men - ably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) a tioned “ substituent” . When the number of the substituents is halogen atom ( e . g ., a fluorine atom , a chlorine atom ), ( 3 ) a not less than 2 , the respective substituents may be the same C1-6 alkyl group ( e .g ., methyl ) optionally substituted by 1 to or different. The substituent is preferably a halogen atom 3 halogen atoms ( e . g ., a fluorine atom ), ( 4 ) a C3- 10 ( e . g . , fluorine atom ) . 5 cycloalkyl group ( e . g . , cyclopropyl) , ( 5 ) a C - 6 alkoxy group The “ C6- 14 aryl group " of the “ optionally substituted C6- 14 (e . g. , methoxy ), (6 ) a nitrogen - containing heterocyclyl- car aryl group ” is optionally substituted by 1 - 5 ( preferably 1 - 3 , bonyl group ( e . g . , pyrrolidinylcarbonyl) and ( 7 ) a mono - or more preferably 1 or 2 ) substituents , at substitutable di- C1 - 6 alkyl- carbamoyl group ( e .g . , neopentylcarbamoyl) , position ( s ) . ( F ) a nonaromatic heterocyclic group ( e . g . , piperidinyl, The substituent is preferably ( 1 ) cyano , ( 2 ) a halogen 10 tetrahydrofuranyl, dihydropyridinyl , tetrahydropyranyl , tet atom (e . g. , a fluorine atom , a chlorine atom ) or (3 ) a C1- 6 rahydrothiopyranyl, dihydroindenyl) optionally substituted alkyl group ( e . g . , methyl) . by 1 - 5 (preferably 1 - 3 , more preferably 1 or 2 ) substituents The “ aromatic heterocyclic group ” of the “ optionally selected from ( 1 ) a C1- 6 alkyl group ( e . g . , ethyl) optionally substituted aromatic heterocyclic group ” is optionally sub substituted by 1 to 3 halogen atoms (e .g . , a fluorine atom ), stituted by 1 - 5 (preferably 1 - 3 , more preferably 1 or 2 ) 15 ( 2 ) a C7- 16 aralkyl group ( e . g ., benzyl) and ( 3 ) oxo , substituents , at substitutable position ( s ) . ( G ) a C1- 6 alkylsulfonyl group ( e . g. , neopentylsulfonyl) or The substituent is preferably ( 1 ) cyano , ( 2 ) a halogen ( H ) a C1- 6 alkyl- carbonylamino group (e . g. , tert -butylcarbo atom ( e . g . , a fluorine atom , a chlorine atom ), ( 3 ) a C1- 6 alkyl nylamino ) . group ( e . g ., methyl ) optionally substituted by 1 to 3 halogen Rl and R2 are more preferably atoms ( e .g ., a fluorine atom ), (4 ) a C3- 10 cycloalkyl group 20 (i ) a C1-8 alkyl group ( e. g ., methyl , ethyl, propyl, isopropyl, ( e . g . , cyclopropyl ) , (5 ) a Cl. alkoxy group ( e . g ., methoxy ) , butyl, isobutyl, 1 -methylpropyl , isopentyl , neopentyl, 1 , 1 ( 6 ) a nitrogen - containing heterocyclyl- carbonyl group ( e. g ., dimethylpropyl, 1 ,2 -dimethylpropyl , 1- ethylpropyl, 2 -meth pyrrolidinylcarbonyl) or (7 ) a mono - or di- C1 - 6 alkyl- car ylbutyl, hexyl , neohexyl, 1, 2 ,2 - trimethylpropyl , 2 ,2 -dimeth bamoyl group ( e . g . , neopentylcarbamoyl) . ylbutyl, 1 - ethyl- 1 -methylbutyl ) optionally substituted by 1 - 5 The “ nonaromatic heterocyclic group ” of the “ optionally 25 (preferably 1- 3 ,more preferably 1 or 2 ) substituents selected substituted nonaromatic heterocyclic group ” is optionally from ( 1 ) cyano , ( 2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group substituted by 1 - 5 (preferably 1 - 3 , more preferably 1 or 2 ) (e . g ., cyclopropyl, cyclobutyl , cyclohexyl, cycloheptyl , substituents , at substitutable position ( s ) . bicyclo [ 2 . 2 . 1 ]heptyl ) optionally substituted by 1 to 3 sub The substituent is preferably ( 1 ) a C - , alkyl group ( e . g . , stituents selected from a halogen atom ( e . g ., a fluorine atom ) ethyl) optionally substituted by 1 to 3 halogen atoms ( e . g ., 30 and a C1- 6 alkyl group ( e . g . ,methyl ) , ( 4 ) aC1- 6 alkoxy group a fluorine atom ), ( 2 ) a C7- 16 aralkyl group ( e . g ., benzyl ) or (e . g ., methoxy, ethoxy , isopropoxy ) optionally substituted ( 3 ) oxo . by 1 to 3 halogen atoms (a fluorine atom ), (5 ) a C6- 14 aryl Rl and R2 are preferably and each independently group (e .g . , phenyl) optionally substituted by 1 to 3 halogen ( A ) a hydrogen atom , atoms ( e . g ., a fluorine atom , a chlorine atom ) , (6 ) an ( B ) a C1- 8 alkyl group (e . g ., methyl, ethyl, propyl, isopropyl, 35 aromatic heterocyclic group (e . g. , pyridyl, pyrimidinyl) , (7 ) butyl, isobutyl, 1 -methylpropyl , isopentyl, neopentyl, 1 , 1 a nonaromatic heterocyclic group ( e . g ., piperidinyl , tetrahy dimethylpropyl , 1, 2 - dimethylpropyl, 1 -ethylpropyl , 2 -meth dropyranyl) , ( 8 ) a C1- 6 alkylsulfonyl group ( e . g ., methylsul ylbutyl, hexyl, neohexyl, 1 , 2 , 2 - trimethylpropyl, 2 , 2 - dimeth fonyl) , ( 9 ) a mono - or di- C1 - 6 alkyl- amino group ( e . g . , ylbutyl, 1 -ethyl - 1 -methylbutyl ) optionally substituted by 1 - 5 ethylamino ) optionally substituted by 1 to 3 halogen atoms (preferably 1 -3 , more preferably 1 or 2 ) substituents selected 40 (e . g ., a fluorine atom ) and (10 ) a halogen atom ( e. g ., a from ( 1 ) cyano , ( 2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group fluorine atom ), or ( e .g ., cyclopropyl, cyclobutyl , cyclohexyl , cycloheptyl, ( ii ) an aromatic heterocyclic group (e . g. , pyrazolyl, bicyclo [2 . 2 . 1 ]heptyl ) optionally substituted by 1 to 3 sub oxazolyl, pyridyl , pyrimidinyl, pyrazinyl, pyridazinyl) stituents selected from a halogen atom ( e . g . , a fluorine atom ) optionally substituted by 1 - 5 (preferably 1 - 3 , more prefer and a C1- 6 alkyl group ( e . g ., methyl ), ( 4 ) a C1- 6 alkoxy group 45 ably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) a (e . g . , methoxy , ethoxy , isopropoxy ) optionally substituted halogen atom ( e . g ., a fluorine atom , a chlorine atom ) , ( 3 ) a by 1 to 3 halogen atoms ( a fluorine atom ) , (5 ) a C6- 14 aryl C1- 6 alkyl group ( e . g . ,methyl ) optionally substituted by 1 to group ( e . g . , phenyl) optionally substituted by 1 to 3 halogen 3 halogen atoms ( e . g . , a fluorine atom ) , (4 ) a C3- 10 atoms ( e . g . , a fluorine atom , a chlorine atom ) , (6 ) an cycloalkyl group ( e . g ., cyclopropyl) , ( 5 ) a C1- 6 alkoxy group aromatic heterocyclic group ( e . g . , pyridyl, pyrimidinyl) , ( 7 ) 50 ( e . g . , methoxy ) , ( 6 ) a nitrogen - containing heterocyclyl- car a nonaromatic heterocyclic group ( e .g ., piperidinyl, tetrahy - bonyl group (e .g . , pyrrolidinylcarbonyl) and (7 ) a mono - or dropyranyl) , ( 8 ) a C1-6 alkylsulfonyl group ( e. g ., methylsul- di- C1 - 6 alkyl- carbamoyl group (e . g. , neopentylcarbamoyl) . fonyl) , ( 9 ) a mono - or di- C1- 6 alkyl- amino group ( e . g ., R and R ’ are particularly preferably ethylamino ) optionally substituted by 1 to 3 halogen atoms ( i ) a C1- 8 alkyl group ( e . g . , methyl, ethyl, propyl, isopropyl, ( e. g ., a fluorine atom ) and ( 10 ) a halogen atom ( e. g ., a 55 butyl , isobutyl , 1 -methylpropyl , isopentyl, neopentyl, 1, 1 fluorine atom ) , dimethylpropyl, 1, 2 -dimethylpropyl , 1- ethylpropyl, 2 -meth ( C ) a C3- 10 cycloalkyl group ( e . g ., cyclopropyl, cyclobutyl, ylbutyl, hexyl , neohexyl, 1 , 2 , 2 - trimethylpropyl, 2 , 2 - dimeth cyclopentyl , cyclohexyl ) optionally substituted by 1 - 5 (pref ylbutyl, 1 -ethyl - 1 -methylbutyl ) optionally substituted by 1 - 5 erably 1 - 3 , more preferably 1 or 2 ) halogen atoms ( e . g ., a (preferably 1 - 3 , more preferably 1 or 2 ) substituents selected fluorine atom ), 60 from ( D ) a C6- 14 aryl group (e .g . , phenyl) optionally substituted (1 ) cyano , ( 2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group ( e .g ., by 1 - 5 (preferably 1 - 3 , more preferably 1 or 2 ) substituents cyclopropyl, cyclobutyl , cyclohexyl, cycloheptyl , bicyclo selected from ( 1 ) cyano , (2 ) a halogen atom ( e. g ., a fluorine [2 .2 .1 ]heptyl ) optionally substituted by 1 to 3 substituents atom , a chlorine atom ) and ( 3 ) a C1- 6 alkyl group ( e .g ., selected from a halogen atom (e .g . , fluorine atom ) and a C1- 6 methyl) , ( E ) an aromatic heterocyclic group ( e . g ., pyrazolyl, 65 alkyl group ( e .g . , methyl) , ( 4 ) a C1- 6 alkoxy group ( e . g . , oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) methoxy, ethoxy, isopropoxy ) optionally substituted by 1 to optionally substituted by 1 - 5 ( preferably 1 - 3 , more prefer - 3 halogen atoms ( fluorine atom ), ( 5 ) a C6- 14 aryl group ( e . g . , US 9 ,776 , 962 B2 21 phenyl) optionally substituted 1 to 3 halogen atoms ( e . g ., R is further preferably a hydrogen atom . fluorine atom , chlorine atom ), (6 ) a 5 - or 6 -membered R ’ is preferably a hydrogen atom or a C1- 6 alkyl group monocyclic aromatic heterocyclic group ( e . g ., pyridyl, ( e. g ., methyl) , more preferably a hydrogen atom or methyl. 7 ) a 3 - to 8 -membered monocyclic nonaro - R ? is further preferably a hydrogen atom . matic heterocyclic group ( e . g ., piperidinyl, tetrahydropyra - 5 R8 and Rºare preferably hydrogen atoms. nyl) , ( 8 ) a C1- 6 alkylsulfonyl group (e . g. , methylsulfonyl) , In one embodiment of the present invention , R3, R4, RS, ( 9 ) a mono - or di -C1 - alkyl- amino group ( e . g ., ethylamino ) R7 R8 and R9 are preferably hydrogen atoms. optionally substituted by 1 to 3 halogen atoms ( e . g . , fluorine atom ) and ( 10 ) a halogen atom ( e . g . , fluorine atom ) , or R? is a halogen atom , an optionally substituted C1- 6 alkyl ( ii ) a 5 - or 6 -membered monocyclic aromatic heterocyclic 10 group , an optionally substituted C1- 6 alkoxy group or an group ( e . g . , pyrazolyl , oxazolyl, pyridyl, pyrimidinyl, " optionally substituted C3- 10 cycloalkyl group . pyrazinyl, pyridazinyl) optionally substituted by 1 - 5 (pref The “ C1- 6 alkyl group ” , “ C1- 6 alkoxy group” and “ C3- 10 erably 1 - 3 , more preferably 1 or 2 ) substituents selected cycloalkyl group ” are optionally substituted by 1- 5 (prefer from ( 1) cyano , ( 2 ) a halogen atom (e . g ., fluorine atom , ably 1 - 3 , more preferably 1 or 2 ) substituents , at substitut chlorine atom ) , ( 3 ) a C alkyl group ( e . g ., methyl) option - 15 able position (s ). ally substituted by 1 to 3 halogen atoms ( e . g ., fluorine atom ), The substituent is preferably a C1- 6 alkoxy group ( e. g . , ( 4 ) a C3 - 10 cycloalkyl group ( e . g ., cyclopropyl) , ( 5 ) a CL- 6 methoxy ) . alkoxy group ( e . g ., methoxy ) , (6 ) a nitrogen - containing Rº is preferably a C1- 6 alkyl group ( e . g ., methyl) option heterocyclyl- carbonyl group (e .g ., pyrrolidinylcarbonyl) and ally substituted by a C1- 6 alkoxy group ( e. g. , methoxy ), a (7 ) a mono - or di -C1 - 6 alkyl -carbamoyl group ( e. g ., neopen - 20 C1- 6 alkoxy group ( e .g ., methoxy, ethoxy ) or a C3- 10 tylcarbamoyl) . cycloalkyl group (e . g ., cyclopropyl) . R? is more preferably R and R are optionally bonded to each other to form an a C3- 10 cycloalkyl group ( e . g ., cyclopropyl ) . optionally substituted 3 - to 10 -membered ring together with Rº and R are optionally bonded to each other to form , the adjacent nitrogen atom . together with the adjacent nitrogen atom , an optionally Examples of the “ 3 - to 10 -membered ring ” of the " option - 25 substituted 3 - to 10 -membered ring. ally substituted 3 - to 10 -membered ring ” which Rl and R2 Here, as the “ 3 - to 10 -membered ring” , a 3 - to 10 -mem form include a 3 - to 10 -membered monocyclic non - aromatic bered monocyclic non - aromatic heterocycle ( e . g . , an oxet heterocycle ( e. g . , a pyrrolidine ring , a piperidine ring , a ane ring ) is preferable . piperazine ring , a morpholine ring ) , and a 3 - to 10 -mem - The “ 3 - to 10 -membered ring ” is optionally substituted by bered fused bicyclic non - aromatic heterocycle ( e . g . , a dihy - 30 1 - 5 (preferably 1 - 3 , more preferably 1 or 2 ) substituents , at droindole ring , a dihydrobenzoxazine ring ) . substitutable position ( s ) . The “ 3 - to 10 -membered ring ” is optionally substituted by The optionally substituted 3 - to 10 -membered ring , which 1 -5 (preferably 1 -3 , more preferably 1 or 2 ) substituents , at is formed by R and R7 bonded to each other together with substitutable position ( s ) . the adjacent carbon atom is preferably a 3 - to 10 -membered The substituent is preferably ( 1) cyano , ( 2 ) a halogen atom 35 monocyclic non - aromatic heterocycle ( e. g ., an oxetane ( e. g ., a fluorine atom ), (3 ) a C1- 6 alkyl group ( e. g ., methyl, ring ). propyl, isobutyl, tert - butyl) optionally substituted by 1 to 3 Preferable examples of compound ( 1) include the follow substituents selected from a halogen atom ( e . g ., a fluorine ing compounds. atom ) and a C6- 14 aryl group ( e . g ., phenyl) , ( 4 ) a C1- 6 alkoxy [Compound I - 1 ] group ( e. g. ,methoxy ) or (5 ) a C6- 14 aryl group (e .g ., phenyl) . 40 Compound (1 ) wherein ring A is an optionally further The optionally substituted 3 - to 10 -membered ring formed substituted benzene ring or an optionally further substituted by R7 and R , which are bonded to each other , together with pyridine ring ; the adjacent nitrogen atom , is preferably ( A ) a 3 - to Ring B is an optionally further substituted azetidine ring , 10 -membered monocyclic non -aromatic heterocycle ( e. g ., an optionally further substituted pyrrolidine ring or an pyrrolidine ring , piperidine ring, piperazine ring , morpho - 45 optionally further substituted piperidine ring ; line ring ) optionally substituted by 1 - 5 (preferably 1 - 3 , more R and R ? are each independently a hydrogen atom , an preferably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) optionally substituted Cl. alkyl group ( e . g ., methyl, ethyl , a halogen atom ( e . g ., a fluorine atom ) , ( 3 ) a C1- 6 alkyl group propyl , isopropyl, butyl , isobutyl, 1 -methylpropyl , isopen ( e . g . , methyl, propyl, isobutyl, tert -butyl ) optionally substi tyl, neopentyl, 1 , 1 - dimethylpropyl , 1 , 2 - dimethylpropyl, tuted by 1 to 3 substituents selected from a halogen atom 50 l - ethylpropyl , 2 -methylbutyl , hexyl, neohexyl , 1 ,2 , 2 -trim ( e . g ., a fluorine atom ) and a C6- 14 aryl group ( e . g ., phenyl) , ethylpropyl, 2 , 2 -dimethylbutyl , 1 - ethyl- 1 -methylbutyl ) , an ( 4 ) a C1- 6 alkoxy group ( e . g . , methoxy ) and ( 5 ) a C6 - 14 aryl optionally substituted C3 - 10 cycloalkyl group ( e . g . , cyclo group ( e . g . , phenyl ) or ( B ) a 3 - to 10 -membered fused propyl, cyclobutyl, cyclopentyl, cyclohexyl) , an optionally bicyclic non -aromatic heterocycle (e .g . , a dihydroindole substituted C6 - 14 aryl group ( e . g . , phenyl) , an optionally ring , a dihydrobenzoxazine ring ) . 55 substituted aromatic heterocyclic group (e . g. , pyrazolyl, R and R + are each independently a hydrogen atom , a oxazolyl, pyridyl , pyrimidinyl , pyrazinyl, pyridazinyl) , an halogen atom or a C1- 6 alkyl group . optionally substituted nonaromatic heterocyclic group ( e . g ., R and R * are preferably each independently a hydrogen piperidinyl, tetrahydrofuranyl , dihydropyridinyl, tetrahydro atom or a C1- 6 alkyl group ( e . g ., methyl) , more preferably , pyranyl, tetrahydrothiopyranyl, dihydroindenyl) , an option each independently a hydrogen atom or methyl. 60 ally substituted C1- 6 alkylsulfonyl group ( e . g . , neopentylsul R3 and R4 are particularly preferably hydrogen atoms. fonyl) or an optionally substituted C - alkyl- carbonylamino R®, R ?, R8 and R9 are each independently a hydrogen group ( e. g. , tert- butylcarbonylamino ) ; atom , a halogen atom , a C1- 6 alkyl group or a C1- 6 alkoxy or, R ' and R² are bonded to each other to form an group . optionally substituted 3 - to 10 -membered monocyclic non R is preferably a hydrogen atom or a halogen atom (e . g. , 65 aromatic heterocycle (e . g. , a pyrrolidine ring, a piperidine a fluorine atom ) , more preferably a hydrogen atom or a ring , a piperazine ring , a morpholine ring ) or an optionally fluorine atom . substituted 3 - to 10 -membered fused bicyclic non -aromatic US 9 ,776 ,962 B2 23 24 heterocycle ( e . g ., a dihydroindole ring , a dihydrobenzox methoxy, ethoxy ) or an optionally substituted C3- 10 azine ring ) together with the adjacent nitrogen atom ; cycloalkyl group ( e. g ., cyclopropyl) ; R3 and R4 are each independently a hydrogen atom or a R ' is a hydrogen atom or a C1- 6 alkyl group ( e . g ., methyl ) ; C1- 6 alkyl group (e . g. , methyl) ; or, RÓ and R7 are bonded to each other to form an R > is a hydrogen atom or a halogen atom ( e . g . , a fluorineorine 55 optionallyop substituted 3 - to 10 -membered monocyclic non atom ) ; aromatic heterocycle ( e. g ., an oxetane ring ) together with the Rº is an optionally substituted C1- 6 alkyl group ( e. g ., adjacentR8 and carbon Rº are atomhydrogen ; and atoms. methyl) , an optionally substituted C1- 6 alkoxy group ( e . g . , [Compound 1 - 31 methoxy , ethoxy) or an optionally substituted C3- 10 Compound (I ) wherein ring A is a benzene ring optionally cycloalkyl group ( e. g ., cyclopropyl) ; further substituted by 1- 4 (preferably 1- 3 ,more preferably 1 R ’ is a hydrogen atom or a C1- 6 alkyl group ( e .g . ,methyl ) ; or 2 ) substituents selected from or, Rº and R ’ are bonded to each other to form an ( 1 ) a C1- 6 alkylsulfonyl group ( e . g ., methylsulfonyl) ; optionally substituted 3 - to 10 -membered monocyclic non ( 2 ) a carbamoyl group ; (3 ) a hydroxy group ; aromatic heterocycle ( e . g ., an oxetane ring) together with the 15 (4 ) a C1- 6 alkoxy group ( e .g ., methoxy ) optionally substi adjacent carbon atom ; and tuted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) ; R $ and Rº is a hydrogen atom . ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; [ Compound I - 2 ] ( 6 ) a cyano group ; Compound ( 1 ) wherein ring A is a benzene ring or a ( 7 ) a halogen atom ( e . g . , a fluorine atom , a chlorine atom , a pyridine ring each optionally further substituted by 1 - 4 20 bromine atom ); and (preferably 1 - 3 , more preferably 1 or 2 ) substituents selected ( 8 ) a C1- 6 alkyl group ( e . g . , methyl, ethyl ) , or a pyridine ring from optionally further substituted by 1 - 4 (preferably 1 - 3 , more ( 1) a C1- 6 alkylsulfonyl group (e .g ., methylsulfonyl) ; preferably 1 or 2 ) substituents selected from ( 2 ) a carbamoyl group ; ( 1 ) a C1- 6 alkoxy group ( e . g ., methoxy ) ; 25 ( 2 ) a halogen atom ( e . g . , a chlorine atom ) ; and ( 3 ) a hydroxy group ; ( 3 ) a C1- 6 alkyl group ( e .g ., ethyl) ; (4 ) a C1- 6 alkoxy group (e .g ., methoxy ) optionally substi ring B is ( 1 ) an azetidine ring, ( 2 ) a pyrrolidine ring or ( 3 ) tuted by 1 to 3 halogen atoms ( e . g ., a fluorine atom ) ; a piperidine ring optionally further substituted by 1 - 4 (pref ( 5 ) a C1- 6 alkylthio group ( e. g ., methylthio ) ; erably 1 - 3 , more preferably 1 or 2 ) substituents selected (6 ) a cyano group ; from a halogen atom ( e . g ., a fluorine atom ) and a C1- 6 alkyl ( 7 ) a halogen atom ( e . g . , a fluorine atom , a chlorine atom , a s group ( e . g ., methyl) ; bromine atom ) ; and R ! and R2 are each independently ( 8) a C1- 6 alkyl group ( e .g ., methyl, ethyl) ; (A ) a hydrogen atom , ring B is an azetidine ring , a pyrrolidine ring or a ( B ) a C1- 8 alkyl group ( e . g . ,methyl , ethyl, propyl, isopropyl, butyl , isobutyl, 1- methylpropyl , isopentyl, neopentyl, 1, 1 piperidine ring each optionally further substituted by 1- 4 35 dimethylpropyl, 1 ,2 -dimethylpropyl , 1 -ethylpropyl , 2 -meth ( preferably 1 - 3 , more preferably 1 or 2 ) substituents selected ylbutyl, hexyl, neohexyl, 1 , 2 , 2 - trimethylpropyl , 2 , 2 - dimeth from a halogen atom ( e. g ., a fluorine atom ) and a Cl- , alkyl ylbutyl, 1 - ethyl- 1 -methylbutyl ) optionally substituted by 1 - 5 group ( e . g . , methyl) ; (preferably 1 - 3 , more preferably 1 or 2 ) substituents selected R and R ’ are each independently a hydrogen atom , an from ( 1 ) cyano , (2 ) hydroxy, ( 3 ) a Cz. 10 cycloalkyl group optionally substituted C1- 8 alkyl group ( e . g ., methyl, ethyl, 40 ( e . g ., cyclopropyl , cyclobutyl, cyclohexyl, cycloheptyl, propyl, isopropyl, butyl, isobutyl, 1 -methylpropyl , isopen bicyclo [ 2 . 2 . 1 ]heptyl ) optionally substituted by 1 to 3 sub tyl, neopentyl, 1 , 1 - dimethylpropyl, 1 , 2 - dimethylpropyl, stituents selected from a halogen atom ( e . g ., a fluorine atom ) 1 - ethylpropyl , 2 -methylbutyl , hexyl, neohexyl , 1 , 2 , 2 - trim and a C1- 6 alkyl group ( e . g ., methyl) , ( 4 ) a C1- 6 alkoxy group ethylpropyl, 2 , 2 - dimethylbutyl, 1 -ethyl - 1 -methylbutyl ) , an ( e. g ., methoxy, ethoxy , isopropoxy ) optionally substituted optionally substituted C3. 10 cycloalkyl group ( e . g . , cyclo - 45 by 1 to 3 halogen atoms ( a fluorine atom ), (5 ) a C6- 14 aryl propyl, cyclobutyl, cyclopentyl, cyclohexyl) , an optionally group ( e. g ., phenyl) optionally substituted by 1 to 3 halogen substituted C6. 14 aryl group ( e . g . , phenyl) , an optionally atoms ( e . g ., a fluorine atom , a chlorine atom ), (6 ) an substituted aromatic heterocyclic group ( e . g ., pyrazolyl, aromatic heterocyclic group ( e . g . , pyridyl, pyrimidinyl) , ( 7 ) oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) , an a nonaromatic heterocyclic group ( e . g ., piperidinyl, tetrahy optionally substituted nonaromatic heterocyclic group ( e . g ., 50 dropyranyl) , ( 8 ) a C - alkylsulfonyl group ( e . g ., methylsul piperidinyl , tetrahydrofuranyl, dihydropyridinyl, tetrahydro - fonyl) , ( 9 ) a mono - or di- C - 6 alkyl- amino group ( e . g . , pyranyl, tetrahydrothiopyranyl, dihydroindenyl) , a C1- 6 ethylamino ) optionally substituted by 1 to 3 halogen atoms alkylsulfonyl group (e . g. , neopentylsulfonyl) or a C1- 6 alkyl ( e . g. , a fluorine atom ) and (10 ) a halogen atom ( e .g . , a carbonylamino group ( e . g ., tert- butylcarbonylamino ); fluorine atom ), or, R and R² are bonded to each other to form an 55 ( C ) a C3- 10 cycloalkyl group ( e . g ., cyclopropyl, cyclobutyl, optionally substituted 3 - to 10 -membered monocyclic non - cyclopentyl, cyclohexyl) optionally substituted by 1 - 5 (pref aromatic heterocycle ( e . g ., a pyrrolidine ring , a piperidine erably 1 - 3 , more preferably 1 or 2 ) halogen atoms ( e . g . , a ring, a piperazine ring, a morpholine ring ) , or a 3 - to fluorine atom ), 10 -membered fused bicyclic non - aromatic heterocycle ( e . g ., ( D ) a C6- 14 aryl group ( e . g ., phenyl) optionally substituted a dihydroindole ring , a dihydrobenzoxazine ring ) , together 60 by 1 - 5 ( preferably 1 - 3 , more preferably 1 or 2 ) substituents with the adjacent nitrogen atom ; selected from ( 1 ) cyano , ( 2 ) a halogen atom ( e . g . , a fluorine R and R + are each independently a hydrogen atom or a atom , a chlorine atom ) and (3 ) a C1- 6 alkyl group (e .g ., C1- 6 alkyl group ( e. g ., methyl) ; methyl) , R is a hydrogen atom or a halogen atom ( e .g ., a fluorine ( E ) an aromatic heterocyclic group (e . g ., pyrazolyl, atom ) ; 65 oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl) R™ is an optionally substituted C1- 6 alkyl group ( e . g . , optionally substituted by 1 - 5 (preferably 1 - 3 , more prefer methyl) , an optionally substituted C1- 6 alkoxy group ( e . g ., ably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) a US 9 ,776 , 962 B2 25 26 halogen atom ( e . g ., a fluorine atom , a chlorine atom ), ( 3 ) a from a halogen atom ( e . g ., a fluorine atom ) and a C1- 6 alkyl C1- 6 alkyl group ( e . g ., methyl ) optionally substituted by 1 to group ( e . g ., methyl ) ; 3 halogen atoms ( e . g ., a fluorine atom ), ( 4 ) a C3- 10 R and R are each independently cycloalkyl group ( e . g . , cyclopropyl) , ( 5 ) a C - alkoxy group ( i ) a C1- 8 alkyl group ( e . g . , methyl, ethyl, propyl, isopropyl, ( e . g . , methoxy) , ( 6 ) a nitrogen - containing heterocyclyl- car - 5 butyl, isobutyl, 1 -methylpropyl , isopentyl, neopentyl, 1 , 1 bonyl group ( e . g ., pyrrolidinylcarbonyl) and ( 7 ) a mono - or dimethylpropyl, 1 , 2 -dimethylpropyl , 1 - ethylpropyl, 2 -meth di- C , alkyl- carbamoyl group ( e . g . , neopentylcarbamoyl) , ylbutyl, hexyl, neohexyl, 1 , 2 , 2 - trimethylpropyl, 2 , 2 - dimeth ylbutyl, 1 -ethyl - 1 -methylbutyl ) optionally substituted by 1 -5 ( F ) a nonaromatic heterocyclic group (e . g. , piperidinyl, (preferably 1 - 3 , more preferably 1 or 2 ) substituents selected tetrahydrofuranyl , dihydropyridinyl , tetrahydropyranyl, itedtet 10 from ( 1 ) cyano , ( 2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group rahydrothiopyranyl, dihydroindenyl) optionally substituted ( e .g ., cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, by 1- 5 (preferably 1 - 3 , more preferably 1 or 2 ) substituents bicyclo [ 2 . 2 . 1 ]heptyl ) optionally substituted by 1 to 3 sub selected from ( 1 ) a C1- 6 alkyl group ( e . g ., ethyl) optionally stituents selected from a halogen atom ( e . g . , a fluorine atom ) substituted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) , and a C1- 6 alkyl group (e . g. , methyl) , ( 4 ) a C1- 6 alkoxy group ( 2 ) a C7- 16 aralkyl group ( e . g ., benzyl) and ( 3 ) oxo , 15 ( e . g ., methoxy , ethoxy , isopropoxy ) optionally substituted ( G ) a C1- 6 alkylsulfonyl group (e .g . , neopentylsulfonyl) or by 1 to 3 halogen atoms ( a fluorine atom ) , ( 5 ) a C6- 14 aryl ( H ) a C1- 6 alkyl- carbonylamino group ( e .g ., tert -butylcarbo group ( e . g . , phenyl ) optionally substituted by 1 to 3 halogen nylamino ) ; atoms ( e . g . , a fluorine atom , a chlorine atom ) , (6 ) an or, R . and R are bonded to each other to form ( A ) a 3 - to aromatic heterocyclic group ( e .g ., pyridyl, pyrimidinyl) , (7 ) 10 -membered monocyclic non -aromatic heterocycle ( e . g ., 20 a nonaromatic heterocyclic group ( e .g ., piperidinyl, tetrahy pyrrolidine ring , piperidine ring, piperazine ring, morpho dropyranyl) , ( 8 ) a C1- 6 alkylsulfonyl group ( e . g . ,methylsul line ring ) optionally substituted by 1 - 5 (preferably 1 - 3 , more fonyl) , ( 9 ) a mono - or di- C1- 6 alkyl- amino group ( e . g . , preferably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) ethylamino ) optionally substituted by 1 to 3 halogen atoms a halogen atom ( e . g ., a fluorine atom ) , (3 ) a C - alkyl group ( e .g ., a fluorine atom ) and ( 10 ) a halogen atom ( e . g ., a ( e . g . , methyl, propyl, isobutyl, tert- butyl ) optionally substi - 25 fluorine atom ) , or tuted by 1 to 3 substituents selected from a halogen atom ( ii) an aromatic heterocyclic group (e . g . , pyrazolyl , ( e . g . , a fluorine atom ) and a Caw aryl group ( e . g . , phenyl) , oxazolyl , pyridyl, pyrimidinyl , pyrazinyl, pyridazinyl) ( 4 ) a C1- 6 alkoxy group ( e. g ., methoxy ) and (5 ) a C6 - 14 aryl optionally substituted by 1 - 5 (preferably 1 - 3 , more prefer group (e .g ., phenyl ) or (B ) a 3 - to 10 -membered fused ably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) a bicyclic non - aromatic heterocycle leg. a dihydroindole 30 halogen atom ( e . g . , a fluorine atom , a chlorine atom ) , ( 3 ) a ring, a dihydrobenzoxazine ring ), together with the adjacent C1- 6 alkyl group ( e . g . , methyl ) optionally substituted by 1 to 3 halogen atoms (e .g . , a fluorine atom ), (4 ) a C3- 10 nitrogen atom ; cycloalkyl group (e . g. , cyclopropyl) , (5 ) a C1- 6 alkoxy group R3 and R are each independently a hydrogen atom or ( e . g ., methoxy ) , (6 ) a nitrogen - containing heterocyclyl- car methyl; 35 bonyl group ( e . g ., pyrrolidinylcarbonyl) and ( 7 ) a mono - or R® is a hydrogen atom or a fluorine atom ; di- C1- 6 alkyl- carbamoyl group (e .g ., neopentylcarbamoyl) ; Rºis a C1- 6 alkyl group ( e . g ., methyl ) optionally substi - R3 and R4 are each independently a hydrogen atom or tuted by a C1- 6 alkoxy group ( e. g ., methoxy ) , a C1-6 alkoxy methyl; group ( e . g . , methoxy, ethoxy ) or a C1- 10 cycloalkyl group R is a hydrogen atom or a fluorine atom ; ( e .g ., cyclopropyl) ; 40 R™ is a C3- 10 cycloalkyl group ( e . g . , cyclopropyl) ; R ' is a hydrogen atom or methyl; R ' is a hydrogen atom or methyl; and or, Ró and R7 are bonded to each other to form a 3 - to R8 and Rº are hydrogen atoms. 10 -membered monocyclic non -aromatic heterocycle ( e. g ., [Compound 1- 5 ] an oxetane ring ) together with the adjacent carbon atom ; and Compound ( I ) wherein ring A is a benzene ring optionally R8 and Rºare hydrogen atoms. 45 further substituted by 1 - 4 ( preferably 1 - 3 ,more preferably 1 [ Compound 1 - 4 ] or 2 ) substituents selected from Compound ( I) wherein ring A is a benzene ring optionally ( 1 ) a C1- 6 alkylsulfonyl group ( e . g . , methylsulfonyl) ; further substituted by 1 -4 (preferably 1 - 3 , more preferably 1 (2 ) a carbamoyl group ; or 2 ) substituents selected from ( 3 ) a hydroxy group ; ( 1 ) a C1- 6 alkylsulfonyl group ( e . g . , methylsulfonyl) ; 50 ( 4 ) a C1- 6 alkoxy group ( e . g ., methoxy ) optionally substi ( 2 ) a carbamoyl group ; tuted by 1 to 3 halogen atoms ( e . g ., a fluorine atom ); ( 3 ) a hydroxy group ; ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; ( 4 ) a C1- 6 alkoxy group ( e . g . , methoxy ) optionally substi - (6 ) a cyano group ; tuted by 1 to 3 halogen atoms ( e . g . , a fluorine atom ) ; ( 7 ) a halogen atom ( e . g ., a fluorine atom , a chlorine atom , a ( 5 ) a C1- 6 alkylthio group ( e . g ., methylthio ) ; 55 bromine atom ) ; and ( 6 ) a cyano group ; ( 8 ) a C1- 6 alkyl group (e .g . , methyl, ethyl) ; ( 7 ) a halogen atom ( e . g . , a fluorine atom , a chlorine atom , a ring B is ( 1 ) an azetidine ring , ( 2 ) a pyrrolidine ring or ( 3 ) bromine atom ) ; and a piperidine ring optionally further substituted by 1 - 4 (pref ( 8 ) a C1- 6 alkyl group ( e. g ., methyl, ethyl) , or a pyridine ring erably 1- 3, more preferably 1 or 2 ) substituents selected optionally further substituted by 1 - 4 (preferably 1 -3 , more 60 from a halogen atom (e .g . , a fluorine atom ) and a C1- 6 alkyl preferably 1 or 2 ) substituents selected from group ( e . g . , methyl) ; ( 1) a C1- 6 alkoxy group (e . g. , methoxy ); X is — N = ; ( 2 ) a halogen atom ( e . g ., a chlorine atom ) ; and R1 and R2 are each independently ( 3 ) a C1- 6 alkyl group ( e . g . , ethyl) ; ( i ) a C1- 8 alkyl group ( e . g ., methyl, ethyl, propyl, isopropyl, ring B is ( 1 ) an azetidine ring, ( 2 ) a pyrrolidine ring or ( 3 ) 65 butyl, isobutyl, 1 -methylpropyl , isopentyl , neopentyl, 1 , 1 a piperidine ring optionally further substituted by 1 - 4 (pref - dimethylpropyl, 1 , 2 - dimethylpropyl, 1 - ethylpropyl, 2 -meth erably 1 -3 , more preferably 1 or 2 ) substituents selected ylbutyl, hexyl , neohexyl, 1, 2 ,2 - trimethylpropyl, 2 , 2 - dimeth US 9 ,776 , 962 B2 28 ylbutyl, 1- ethyl- 1- methylbutyl ) optionally substituted by 1 -5 methoxy , ethoxy, isopropoxy ) optionally substituted by 1 to (preferably 1- 3, more preferably 1 or 2) substituents selected 3 halogen atoms (fluorine atom ), (5 ) a C6- 14 aryl group ( e. g. , from ( 1 ) cyano , ( 2 ) hydroxy , ( 3 ) a C3 - 10 cycloalkyl group phenyl ) optionally substituted by 1 to 3 halogen atoms ( e . g . , ( e . g ., cyclopropyl , cyclobutyl, cyclohexyl, cycloheptyl, fluorine atom , chlorine atom ), (6 ) a 5 - or 6 -membered bicyclo [2 . 2 . 1 ]heptyl ) optionally substituted by 1 to 3 sub - 5 monocyclic aromatic heterocyclic group ( e. g ., pyridyl, stituents selected from a halogen atom (e . g ., a fluorine atom ) pyrimidinyl) , ( 7 ) a 3 - to 8 -membered monocyclic nonaro and a C1- 6 alkyl group (e . g. , methyl) , ( 4 ) a C1- 6 alkoxy group matic heterocyclic group ( e. g ., piperidinyl, tetrahydropyra ( e . g . , methoxy , ethoxy , isopropoxy ) optionally substituted nyl) , (8 ) a C1- 6 alkylsulfonyl group ( e. g ., methylsulfonyl) , by 1 to 3 halogen atoms ( a fluorine atom ) , ( 5 ) a C6- 14 aryl group (e .g ., phenyl ) optionally substituted by 1 to 3 halogen 10 ( 9 ) a mono - or di- C1 - 6 alkyl- amino group (e . g. , ethylamino ) atoms ( e . g . , a fluorine atom , a chlorine atom ), (6 ) an optionally substituted by 1 to 3 halogen atoms ( e . g ., fluorine aromatic heterocyclic group (e .g ., pyridyl, pyrimidinyl) , ( 7 ) atom ) and ( 10 ) a halogen atom ( e . g ., fluorine atom ) , or a nonaromatic heterocyclic group ( e . g ., piperidinyl, tetrahy ( ii ) a 5 - or 6 -membered monocyclic aromatic heterocyclic dropyranyl) , ( 8 ) a C1-6 alkylsulfonyl group ( e. g ., methylsul group ( e. g. , pyrazolyl, oxazolyl, pyridyl, pyrimidinyl, fonyl) , ( 9 ) a mono - or di- C1 -6 alkyl- amino group ( e. g ., 15is Pyrazpyrazinyl , pyridazinyl) optionally substituted by 1 - 5 ( pref ethylamino ) optionally substituted by 1 to 3 halogen atoms erably 1 - 3 , more preferably 1 or 2 ) substituents selected (eg a fluorine atom ) and ( 10 ) a halogen atom ( e . g . , a from ( 1 ) cyano , ( 2 ) a halogen atom ( e . g ., fluorine atom , fluorine atom ) or chlorine atom ), ( 3 ) a C1- 6 alkyl group ( e . g . , methyl) option ( ii ) an aromatic heterocyclic group ( e . g . , pyrazolyl, ally substituted by 1 to 3 halogen atoms ( e . g . , fluorine atom ) , oxazolyl, pyridyl , pyrimidinyl, pyrazinyl, pyridazinyl) 20 ( 4 ) a C3- 10 cycloalkyl group (e .g ., cyclopropyl) , ( 5 ) a C1- 6 optionally substituted by 1 - 5 (preferably 1 - 3 , more prefer - alkoxy group ( e . g . , methoxy ) , ( 6 ) a nitrogen -containing ably 1 or 2 ) substituents selected from ( 1 ) cyano , ( 2 ) a heterocyclyl- carbonyl group ( e . g . , pyrrolidinylcarbonyl) and halogen atom ( e . g ., a fluorine atom , a chlorine atom ) , ( 3 ) a ( 7 ) a mono - or di- C1 - 6 alkyl -carbamoyl group ( e . g ., neopen C1- 6 alkyl group ( e . g ., methyl ) optionally substituted by 1 to tylcarbamoyl) ; 3 halogen atoms ( e . g . , a fluorine atom ), ( 4 ) a C3- 10 25 R3 and R4 are hydrogen atoms; cycloalkyl group (e . g. , cyclopropyl) , (5 ) a C1- 6 alkoxy group R is a hydrogen atom ; ( e . g . , methoxy ) , (6 ) a nitrogen -containing heterocyclyl - car R® is a C3- 10 cycloalkyl group ( e . g ., cyclopropyl ) ; bonyl group ( e . g . , pyrrolidinylcarbonyl) and ( 7 ) a mono - or R ’ is a hydrogen atom ; and di- C1 - 6 alkyl- carbamoyl group ( e .g ., neopentylcarbamoyl) ; R8 and Rº are hydrogen atoms. R and R * are hydrogen atoms; RS is a hydrogen atom ; 30 Compound 1 -7 ] Rº is a C3- 10 cycloalkyl group (e .g ., cyclopropyl) ; The aforementioned ( compound 1 -6 ] wherein ring B is a R ' is a hydrogen atom ; and piperidine ring. R8 and Rºare hydrogen atoms. Specific examples of compound (I ) include the com [ Compound 1 -6 ] as pounds of Examples 1 - 287. Of these , Compound (I ) wherein ring A is a benzene ring optionally (3S )- 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( ( 2, 2 - dimethylpropyl) ( 6 further substituted by 1 - 4 ( preferably 1 - 3 , more preferably 1 methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi or 2 ) substituents selected from din - 4 - yl) methoxy )pyridin - 4 - yl) propanoic acid or a salt ( 1 ) a C1- 6 alkylsulfonyl group ( e . g . , methylsulfonyl) ; thereof (Example 245 ); ( 2 ) a carbamoyl group ; 40 (3S )- 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( ( 2, 2 -dimethylpropyl ) ( 4 ,6 ( 3 ) a hydroxy group ; dimethylpyrimidin - 2 - yl) carbamoyl) -5 -methoxyphenyl ) (4 ) a C1 -6 alkoxy group (e .g ., methoxy ) optionally substi piperidin - 4 - yl) methoxy )pyridin - 4 - yl ) propanoic acid or a tuted by 1 to 3 halogen atoms ( e . g ., fluorine atom ) ; salt thereof ( Example 246 ) ; and ( 5 ) a C1- 6 alkylthio group ( e. g ., methylthio ) ; ( 3S ) - 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) (pyri (6 ) a cyano group ; 45 din - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) ( 7 ) a halogen atom ( e. g. , fluorine atom , chlorine atom , methoxy )pyridin - 4 - yl) propanoic acid or a salt thereof bromine atom ) ; and (Example 247 ) ( 8 ) a C1- 6 alkyl group (e . g ., methyl, ethyl) ; are preferable . ring B is ( 1 ) an azetidine ring , ( 2 ) a pyrrolidine ring or ( 3 ) Examples of salts of compounds represented by the a piperidine ring optionally further substituted by 1- 4 (pref - 50 formula (1 ) include metal salt , ammonium salt , salt with erably 1 - 3 , more preferably 1 or 2 ) substituents selected organic base , salt with inorganic acid , salt with organic acid , from a halogen atom ( e . g . , fluorine atom ) and a C1- 6 alkyl salt with basic or acidic amino acid and the like. group ( e . g . , methyl) ; Preferable examples of the metal salt include alkali metal X is — N = ; salts such as sodium salt , potassium salt and the like ; Rl and R2 are each independently 55 alkaline earth metal salts such as calcium salt , magnesium ( i) a C1- 3 alkyl group ( e . g ., methyl, ethyl, propyl, isopropyl, salt, barium salt and the like ; aluminum salt and the like . butyl, isobutyl, 1 -methylpropyl , isopentyl, neopentyl, 1 , 1 - Preferable examples of the salt with organic base include dimethylpropyl , 1, 2 - dimethylpropyl, 1 -ethylpropyl , 2 -meth - salts with trimethylamine , triethylamine, pyridine , picoline, ylbutyl , hexyl, neohexyl , 1 , 2 , 2 -trimethylpropyl , 2 , 2 -dimeth - 2 ,6 -lutidine , ethanolamine, diethanolamine, trietha ylbutyl, 1 -ethyl - 1 -methylbutyl ) optionally substituted by 1 -5 60 nolamine, cyclohexylamine , dicyclohexylamine, N ,N ' (preferably 1 - 3 , more preferably 1 or 2 ) substituents selected dibenzylethylenediamine and the like . from Preferable examples of the salt with inorganic acid ( 1) cyano, (2 ) hydroxy, ( 3 ) a C3- 10 cycloalkyl group ( e. g. , include salt with hydrochloric acid , hydrobromic acid , nitric cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, bicyclo acid , sulfuric acid , phosphoric acid and the like. [ 2 . 2 . 1 ] heptyl) optionally substituted by 1 to 3 substituents 65 Preferable examples of the salt with organic acid include selected from a halogen atom ( e . g . , fluorine atom ) andC a s alts with formic acid , acetic acid , trifluoroacetic acid , alkyl group ( e . g . , methyl) , ( 4 ) a C1- 6 alkoxy group ( e . g ., phthalic acid , fumaric acid , oxalic acid , tartaric acid , maleic US 9 ,776 , 962 B2 29 30 acid , citric acid , succinic acid , malic acid , methanesulfonic The compound obtained in each step can also be used for acid , benzenesulfonic acid , p - toluenesulfonic acid and the the next reaction in the form of the reaction mixture or after like . obtaining as a crude product. Alternatively , the compound obtained in each step can be isolated and / or purified from the Preferable examples of the salt with basic amino acid reaction mixture by a separation means such as concentra include salts with arginine, lysine, ornithine and the like, and 5 tion , crystallization , recrystallization , distillation , solvent preferable examples of the salt with acidic amino acid extraction , fractionation , chromatography and the like include salts with aspartic acid , glutamic acid and the like . according to conventional methods . Among the above -mentioned salts, a pharmaceutically When the starting materials and reagent compounds in acceptable salt is preferable. each step are commercially available , such commercially Compound ( I ) may be a prodrug . available products can be directly used . A prodrug of compound ( I) means a compound which is In the reaction of each step , the reaction time may vary converted to compound ( I ) with a reaction due to an enzyme, dependingde on the reagent and the solvent to be used . Unless an gastric acid , etc . under the physiological condition in the particularly described , it is generally 1 min -48 hr, preferably 10 min - 8 hr. living body , that is , a compound which is converted to 15 In the reaction of each step , the reaction temperature may compound ( I) by oxidation , reduction , hydrolysis, etc . due to vary depending on the reagent and solvent to be used . Unless an enzyme; a compound which is converted to compound ( 1) particularly described , it is generally - 78° C . - 300° C ., by hydrolysis etc . due to gastric acid , etc . preferably - 78° C . - 150° C . Examples of the prodrug of compound (1 ) include a In the reaction of each step , the pressure may vary compound obtained by subjecting amino in compound (I ) to 20 depending on the reagent and solvent to be used . Unless an acylation , alkylation or phosphorylation ( e . g ., a com particularly described , it is generally 1 atm - 20 atm , prefer pound obtained by subjecting amino in compound ( I) to an ably 1 atm - 3 atm . eicosanoylation , alanylation , pentylaminocarbonylation , In the reaction of each step , for example , Microwave ( 5 -methyl - 2 -oxo - 1 , 3 - dioxolen - 4 - yl )methoxycarbonylation , synthesis apparatus such as Initiator manufactured by tetrahydrofuranylation , pyrrolidylmethylation , pivaloy - 25 Biotage and the like may be used . The reaction temperature loxymethylation or tert -butylation ) ; a compound obtained may vary depending on the reagent and solvent to be used . by subjecting hydroxy in compound (1 ) to an acylation , Unless particularly described , it is generally room tempera alkylation , phosphorylation or boration ( e . g . , a compound ture300° C ., preferably 50° C . - 250° C . While the reaction obtained by subjecting hydroxy in compound (I ) to an time varies depending on the reagent and solvent to be used , acetylation , palmitoylation , propanoylation , pivaloylation , 30 unless particularly described , it is generally 1 min -48 hr, succinylation , fumarylation , alanylation or dimethylamin - preferably 1 min - 8 hr. omethylcarbonylation ) ; a compound obtained by subjecting In the reaction of each step , unless particularly described , carboxy in compound ( I ) to an esterification or amidation a reagent is used in 0 .5 equivalents - 20 equivalents, prefer ( e . g . , a compound obtained by subjecting carboxy in com - ably 0 . 8 equivalents - 5 equivalents , relative to the substrate . pound ( I ) to a C - alkyl esterification , phenyl esterification , 35 When a reagent is used as a catalyst, the reagent is used in carboxymethyl esterification , dimethylaminomethyl esteri- 0 .001 equivalent- 1 equivalent, preferably 0 . 01 equivalent fication , pivaloyloxymethyl esterification , ethoxycarbony 0 . 2 equivalent, relative to the substrate . When a reagent also loxyethyl esterification , phthalidyl esterification , ( 5 -methyl - acts as a reaction solvent, the reagent is used in a solvent 2 -oxo - 1 , 3 -dioxolen - 4 - yl) methyl esterification , amount. cyclohexyloxycarbonylethyl esterification or methyl amida - 40 In the reaction of each step , unless particularly described , tion etc . ) and the like. Among these , compound ( I ) wherein the reaction is performed without solvent, or by dissolving carboxy is esterified by C . alkyl such as methyl, ethyl, or suspending in a suitable solvent. Specific examples of the tert - butyl and the like is preferably used . These compounds solvent include the solvents described in the Examples and can be produced from compound (I ) according to a method the following . known per se . 45 alcohols : methanol, ethanol , tert- butyl alcohol, A prodrug for compound ( 1 ) may also be one which is 2 -methoxyethanol and the like ; converted to compound (I ) under a physiological condition , ethers : diethyl ether , diphenyl ether , tetrahydrofuran , 1, 2 such as those described in IYAKUHIN no KAIHATSU , dimethoxyethane and the like ; Development of Pharmaceuticals , Vol. 7 , Design of Mol- aromatic hydrocarbons: chlorobenzene , toluene , xylene ecules, p . 163 - 198 , Published by HIROKAWA SHOTEN , 50 and the like; 1990 . saturated hydrocarbons: cyclohexane, hexane and the In the present specification , a prodrug may be in the form like ; of a salt . Examples of the salt include those exemplified as amides: N , N -dimethylformamide , N -methylpyrrolidone the salt of the compound represented by the aforementioned and the like ; formula ( I ) . 55 halogenated hydrocarbons : dichloromethane, carbon tet The production method of compound ( 1) is explained rachloride and the like ; below . nitriles: acetonitrile and the like ; The starting materials and reagents used and the com sulfoxides: dimethyl sulfoxide and the like ; pounds obtained in each step of the following production aromatic organic bases: pyridine and the like ; methods may form each salt . Examples of such salt include 60 acid anhydrides: acetic anhydride and the like ; those similar to the salts of the aforementioned compound organic acids: formic acid , acetic acid , trifluoroacetic acid ( I ) and the like . and the like ; When the compound obtained in each step is a free inorganic acids: hydrochloric acid , sulfuric acid and the compound , it can be converted to a desired salt by a method like ; known per se . Conversely , when the compound obtained in 65 esters : ethyl acetate and the like ; each step is a salt , it can be converted to a free form or other ketones : acetone , methyl ethyl ketone and the like ; desired kind of salt by a method known per se . water. US 9 ,776 ,962 B2 31 32 Two or more kinds of the above -mentioned solvents may and the like; high valent iodine reagents such as iodosyl be mixed at an appropriate ratio and used . benzene and the like; reagents having manganese such as When a base is used in the reaction of each step , for manganese dioxide , potassium permanganate and the like ; example, the bases shown below or the bases described in leads such as lead tetraacetate and the like ; reagents having the Examples are used . 5 chrome such as pyridinium chlorochromate (PCC ) , pyri inorganic bases: sodium hydroxide , magnesium hydrox dinium dichromate (PDC ) , Jones reagent and the like ; halo ide and the like; gen compounds such as N -bromosuccinimide (NBS ) and the basic salts : sodium carbonate , calcium carbonate , sodium like ; oxygen ; ozone ; sulfur trioxide -pyridine complex ; hydrogen carbonate and the like ; osmium tetraoxide ; selenium dioxide ; 2 , 3 -dichloro - 5 ,6 - di organic bases : triethylamine , diethylamine, pyridine. 4 - di - 10 cyano - 1 , 4 - benzoquinone (DDV ) and the like . When radical cyclization reaction is performed in each methylaminopyridine, N , N - dimethylaniline, 1 , 4 - diazabicy step , examples of the radical initiator to be used include azo clo [ 2 . 2 . 2 ] octane , 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] - 7 -undecene , imi compounds such as azobisisobutyronitrile ( AIBN ) and the dazole , piperidine and the like ; like ; water - soluble radical initiators such as 4 - 4 ' - azobis - 4 metal alkoxides: sodium ethoxide , potassium tert - butoxtox - 15 cyanopentanoic acid (ACPA ) and the like; triethylboron in ide and the like ; the presence of air or oxygen ; benzoyl peroxide and the like . alkali metal hydrides : sodium hydride and the like; Examples of the radical reagent to be used include tributyl metal amides: sodium amide, lithium diisopropylamide , stannane, tristrimethylsilylsilane , 1 , 1 , 2 , 2 - tetraphenyldisi lithium hexamethyldisilazide and the like ; lane, diphenylsilane , samarium iodide and the like . organic lithiums: n -butyllithium and the like . 20 When Wittig reaction is performed in each step , examples When an acid or an acidic catalyst is used in the reaction of the Wittig reagent to be used include alkylidenephospho of each step , for example , the acids and acidic catalysts ranes and the like . Alkylidenephosphoranes can be prepared shown below or the acids and acidic catalysts described in by a method known per se , for example , by reacting a the Examples are used . phosphonium salt and a strong base . inorganic acids : hydrochloric acid , sulfuric acid , nitric 25 When Horner - Emmons reaction is performed in each acid , hydrobromic acid , phosphoric acid and the like ; step , examples of the reagent to be used include phospho organic acids : acetic acid , trifluoroacetic acid , citric acid , noacetic acid esters such as methyl dimethylphosphonoac p - toluenesulfonic acid , 10 - camphorsulfonic acid and the etate , ethyl diethylphosphonoacetate and the like ; bases such like; as alkali metal hydrides , organic lithiums and the like . Lewis acid : boron trifluoride diethyl ether complex , zinc 30 When Friedel- Crafts reaction is performed in each step , iodide, anhydrous aluminum chloride , anhydrous zinc chlo - examples of the reagent to be used include Lewis acid , acid ride, anhydrous iron chloride and the like . chloride or alkylating agent ( e. g ., alkyl halides , alcohol, The reaction of each step is , unless otherwise specified , olefins and the like ). Alternatively , organic acid or inorganic performed by a method known per se , for example, the acid can also be used instead of the Lewis acid , and acid methods described in the Fifth Series of Experimental 35 anhydrides such as acetic anhydride and the like can also be Chemistry, vol . 13 - vol. 19 ( The Chemical Society of Japan used instead of acid chloride . ed . ) ; Experimental Chemistry , vol. 14 -vol . 15 ( The Chemi- When aromatic nucleophilic substitution reaction is per cal Society of Japan ed . ) ; Fine Organic Chemistry, rev. 2nd formed in each step , the reagent includes nucleophilic agent edition ( L . F . Tietze , Th . Eicher, NANKODO ) ; rev. Organic ( e . g . , amines , imidazole and the like ) and base ( e . g . , basic Name Reaction ( Hideo Togo , Kodansha) ; ORGANIC SYN - 40 salts , organic bases and the like ) . THESES Collective Volume I- VII (John Wiley & Sons Inc ); When nucleophilic addition reaction by carbanion , Modern Organic Synthesis in the Laboratory A Collection of nucleophilic 1 , 4 -addition reaction by carbanion (Michael Standard Experimental Procedures ( Jie Jack Li, OXFORD addition reaction ), or nucleophilic substitution reaction by UNIVERSITY ) ; Comprehensive Heterocyclic Chemistry carbanion is performed in each step , examples of the base to III , Vol. 1 - Vol. 14 (Elsevier Japan ) ; Strategic Applications of 45 be used for developing carbanion include organic lithium , Named Reactions in Organic Synthesis (Kiyoshi Tomioka , metal alkoxide , inorganic base , organic base and the like . supervisor of translation , KAGAKUDOJIN ); Comprehen - When Grignard reaction is performed in each step , sive Organic Transformations ( VCH Publishers Inc. ) 1989 examples of the Grignard reagent include arylmagnesium and the like , or the methods described in the Examples . halides such as phenyl magnesium bromide and the like; and When reduction reaction is performed in each step , 50 alkylmagnesium halides such as methyl magnesium bro examples of the reducing agent to be used include metal mide and the like . The Grignard reagent can be prepared by hydrides such as lithium aluminum hydride , sodium triac a method known per se , for example , by reacting alkyl halide etoxyborohydride , sodium cyanoborohydride , diisobutylalu - or aryl halide with metal magnesium using ether or tetra minum hydride (DIBAL - H ) , sodium borohydride , tetram - hydrofuran as a solvent. ethylammonium triacetoxyborohydride and the like ; boranes 55 When Knoevenagel condensation reaction is performed in such as borane tetrahydrofuran complex and the like ; Raney - each step , the reagent includes an active methylene com nickel; Raney cobalt ; hydrogen ; formic acid and the like . pound ( e . g ., malonic acid , diethyl malonate , malononitrile When carbon - carbon double bond or triple bond is reduced , and the like ) located between two electron -withdrawing a method using a catalyst such as palladium - carbon , Lindlar groups and a base ( e .g ., organic bases, metal alkoxides , catalyst and the like is available . 60 inorganic bases ) . When oxidation reaction is performed in each step , When Vilsmeier- Haack reaction is performed in each examples of the oxidant to be used include peracids such as step , the reagent includes phosphoryl chloride and amide m - chloroperbenzoic acid (MCPBA ), hydrogen peroxide , derivative (e . g. , N , N -dimethylformamide and the like ). t -butyl hydroperoxide and the like ; perchlorates such as When azidation reaction of alcohol, alkyl halide , sulfonic tetrabutylammonium perchlorate and the like ; chlorates such 65 acid ester is performed in each step , examples of the as sodium chlorate and the like ; chlorites such as sodium azidation agent to be used include diphenylphosphoryl azide chlorite and the like ; periodic acids such as sodium periodate (DPPA ), trimethylsilylazide , sodium azide and the like. For US 9 ,776 ,962 B2 33 34 example , when alcohols is azidated , a method using diphe - disulfide structure such as 2 , 4 - bis ( 4 -methoxyphenyl - 1 , 3 , 2 , nylphosphoryl azide and 1, 8 -diazabicyclo [ 5 ,4 , 0 ]undec -7 4 -dithiadiphosphetane - 2 , 4 - disulfide (Lowesson ' s reagent ) ene (DBU ) , a method using trimethylsilylazide and Lewis and the like may also be used . acid and the like are used . When Wohl- Ziegler reaction is performed in each step , When reductive amination reaction is performed in each 5 examples of the halogenating agent to be used include step , examples of the reducing agent to be used include N - succinimide , N - bromosuccinimide (NBS ) , N -chlorosuc sodium triacetoxyborohydride , sodium cyanoborohydride , cinimide (NCS ), bromine, sulfuryl chloride and the like . The hydrogen , formic acid and the like . When the substrate is an amine compound , the carbonyl compound to be used is 10 reactioninit can be accelerated by adding heat, light, a radical para - formaldehyde, aldehydes such as acetaldehyde and the 10 initiator such as benzoyl peroxide , azobisisobutyronitrile like , or ketones such as cyclohexanone and the like . When and the like to the reaction . the substrate is a carbonyl compound , the amine to be used When halogenation reaction of the hydroxy group is is primary amine such as ammonia , methylamine and the performed in each step , examples of the halogenating agent like ; secondary amine such as dimethylamine and the like , 15 to be used include acid halide of hydrohalic acid and or the like . inorganic acid , specifically , hydrochloric acid , thionyl chlo When Mitsunobu reaction is performed in each step , ride, phosphorus oxychloride and the like for chlorination , examples of the reagent include azodicarboxylates ( e . g . , and 48 % hydrobromic acid and the like for bromination . In diethyl azodicarboxylate (DEAD ) , diisopropyl azodicar - 20 addition , a method of obtaining a halogenated alkyl form boxylate (DIAD ) and the like ) and triphenylphosphine . from alcohol by reacting triphenylphosphine with carbon When esterification reaction , amidation reaction , or ure tetrachloride or carbon tetrabromide and the likemay also be ation reaction is performed in each step , examples of the used . Alternatively, a method of synthesizing a halogenated reagent to be used include halogenated acyl forms such as alkyl form by two - step reactions including converting alco acid chloride , acid bromide and the like; activated carbox - 25 hol to sulfonic acid ester and reacting same with lithium ylic acids such as acid anhydride , active ester form , sulfuric bromide, lithium chloride or sodium iodide may also be used . acid ester form and the like . As an activator of carboxylic When Arbuzov reaction is performed in each step , acid , carbodiimide condensing agents such as 1 - ethyl- 3 - ( 3 examples of the reagent to be used include alkyl halides such dimethylaminopropyl) carbodiimide hydrochloride (WSCD ) 30, as ethyl bromoacetate and the like ; phosphites such as and the like ; triazine condensing agents such as 4 -( 4, 6 triethylphosphite , tri ( isopropyl) phosphite and the like . dimethoxy - 1, 3 ,5 - triazin -2 -yl ) -4 -methylmorpholinium chlo When sulfonation reaction is performed in each step , ride - n -hydrate (DMT -MM ) and the like ; carbonate condens examples of the sulfonating agent to be used include meth ing agents such as 1 , 1 -carbonyldiimidazole (CDI ) and the sanesulfonyl chloride, p - toluenesulfonyl chloride, methane like ; diphenylphosphoryl azide (DPPA ); benzotriazol -1 - 35 sulfonic anhydride , p - toluenesulfonic anhydride and the yloxy - trisdimethylaminophosphonium salt (BOP reagent) ; like. 2 - chloro -1 -methyl - pyridinium iodide (Mukaiyama reagent) ; When hydrolysis reaction is performed in each step , thionyl chloride; lower alkyl haloformates such as ethyl examples of the reagent include acid or base . When acid chloroformate and the like ; O - 7 -azabenzotriazol - 1 - yl) - N , N ,. 40 hydrolysis of t -butyl ester is performed , formic acid , trieth N ', N -tetramethyluronium hexafluorophosphate (HATU ) ; ylsilane and the like may be added to reductively trap sulfuric acid ; or combination thereof and the like can be by - produced t - butyl cation . mentioned . When a carbodiimide condensing agent is used , When dehydrating reaction is performed in each step , additives such as 1 -hydroxybenzotriazole (HOBt ) , N -hy examples of the dehydrating agent to be used include droxysuccinimide (HOSu ), dimethylaminopyridine 45 sulfuric acid , phosphorus pentaoxide , phosphorus oxychlo (DMAP ) and the like may be further added to the reaction . ride, N , N -dicyclohexylcarbodiimide , alumina, polyphos When coupling reaction is performed in each step , phoric acid and the like . examples of the metal catalyst to be used include palladium In the present specification , the protecting group includes compounds such as palladium ( II ) acetate , tetrakis( triphenyl 50 protecting group of hydroxyl group of alcohol and the like phosphine )palladium (0 ), dichlorobis (triphenylphosphine ) and phenolic hydroxyl group , protecting group of carbonyl palladium (II ), dichlorobis ( triethylphosphine )palladium ( II ), group of aldehyde, protecting group of carbonyl group of tris (dibenzylideneacetone )dipalladium ( 0 ) 1, 1' - bis (diphe ketone, protecting group of carboxyl group , thiol- protecting nylphosphino ) ferrocene palladium ( II) chloride, palladium group, protecting group of amino group , protecting group of ( II) acetate and the like; nickel compounds such as tetrakis 55 aromatic8 hetero ring such as imidazole , pyrrole , indole and ( triphenylphosphine) nickel ( 0 ) and the like ; rhodium the like , and the like. compounds such as tris ( triphenylphosphine )rhodium ( III ) Here , ring A , ring B , R1, R², R3, R4, RS, R " , R7, RS, Rº chloride and the like ; cobalt compound ; copper compounds and X in the formulas in the following reaction schemes are such as copper oxide, copper ( I ) iodide and the like; platinumhe 60 as defined above. compound and the like . A base may be further added to the In any step of the production methods shown below , reaction , and examples of such base include inorganic bases , substituent on ring A can be converted to a desired functional basic salts and the like . group by combining chemical reactions known per se in When thiocarbonylation reaction is performed in each each production method . The substituent on ring A is not step , representative example of the thiocarbonylating agent 65 limited as long as it does not influence the reaction . is diphosphorus pentasulfide. Besides diphosphorus penta - Examples of the chemical reaction include oxidation reac sulfide , a reagent having a 1 ,3 , 2, 4 -dithiadiphosphetane - 2, 4 - tion , reduction reaction , alkylation reaction , acylation reac US 9 ,776 , 962 B2 35 36 tion , ureation reaction , hydrolysis reaction , amination reac -continued tion , esterification reaction , coupling reaction , condensation reaction , deprotection reaction and the like. These reactions are performed according to a method known per se . Examples of such method include the methods described in 5 ORGANIC FUNCTIONAL GROUP PREPARATIONS, R3 R4 x x R8 R9 2nd edition , Academic Press ( Academic Press Inc. ) , 1989 , or R2- = 0 Comprehensive Organic Transformations: A Guide to Func OH tional Group Preparations, 2nd edition , Wiley - VCH , 1999 10 and the like , and the like . R6 R7 © Compound (I ) can be produced from compound (IV ) by the method shown in reaction scheme 1 . @ [ reaction scheme 1 ] 15

HOO R3 R4 X R8 R9 R2 RIN R10 ( III) yoxd R6 R7 © amidation 20 reaction wherein R10 is an optionally substituted C1- 6 alkyl group or an optionally substituted C7- 16 aralkyl group , and other (IV ) R5 symbols are as defined above . R3 R4 X R2 PSRS 25 In the present specification, the “ optionally substituted R10 hydrolysis C7 -16 aralkyl group” is an “ optionally substituted hydrocar R6 R7 © reaction bon group” wherein the hydrocarbon group is a “ C7- 16 hox = 30 aralkyl group ” . ( II ) Compound ( II ) can be produced from compound ( IV ) by the method shown in reaction scheme 2 .

reaction scheme 2 ] RI ps R3 R4 X R8 R9 R3 R4 Xy R8 R9 H - 1 R2 - y ! R2 - * R 10 (VI ) - R 10 NB alkylation NB1 R6 R7 0 reaction R6 R7 © olexxe( II - 1 ) (II )

amidation reactionH H ( V )

HO 20 R3 R4 X R8 R9

NB RIO R6 R7 0 pokok(IV ) US 9 ,776 , 962 B2 37 38 wherein Yl is a leaving group ( e . g ., a halogen atom or OSO ,Me , OSO , ( 4 - tolyl) , OSO , CF , and the like ) , and other symbols are as defined above . Compound ( V ) and compound (VI ) can be produced by a method known per se . Compound ( II ) can be produced by, for example , an alkylation reaction of compound ( II - 1 ) with compound (VI ) . This reaction is performed in the presence of a base in an inert solvent. Examples of the base include alkali metal hydride , inorganic base , basic salt , alkali metal alkoxide , organic base , organic lithium , metal amide and the like . 10 Compound ( II ) can be produced from compound (XI ) by the method shown in reaction scheme 3 . [ reaction scheme 31

R8 R9 R ? izes R10 R3 P4 HOVH R3 R4 X R8 R9 R2- R6 R7 -- Yy2 ( VII) | Mitsunobu reaction or R6 R7 yox alkylation reaction yoxlaya ( IX ) ( II ) R3 R4 aromatic nucleophilic x y2 substitution reaction or coupling reaction R3 R4 X R8 R9 NB RIO Loa H vaR6 R7 0 N . R2 ( VIII ) aromatic nucleophilic substitution reaction or coupling reaction wherein Y ? is an optionally protected hydroxyl group or a 45 Compound ( II ) wherein Y ? is a leaving group can be leaving group ( e . g . , a halogen atom or — OSO2Me, OSO2 produced by, for example , an alkylation reaction of com ( 4 - tolyl) , - OSO , CF , and the like ), and other symbols are as defined above . In the present specification , the optionally pound ( IX ) with compound (VII ) . Alkylation reaction can be protected hydroxyl group is , for example , a hydroxyl group performed according to the method shown in reaction optionally protected by the below -mentioned hydroxy - pro - scheme 2 , or according thereto . tecting group . Compound (X ) and compound (XII ) can be produced by Compound (IV ) can be produced from compound (XIV ) a method known per se . by the method shown in reaction scheme 4 . ?reaction scheme 41 RS HO . R3 R4 X R : R9

N B RIO R6 R7 © foxes(IV ) oxidation reaction US 9, 776 , 962 B2

- continued R8 R9 R3 R4 HO ORRIO10 R3 R4 XXDPS R8 R9 H O R6 R7 © HO 20 (VII ) N B R10 Mitsunobu reaction or R6 R7 © alkylation reaction For( XIII ) y Jokes( XII) R3 R4 | aromatic nucleophilic X Y2 substitution reaction NB or coupling reaction R3 R4 X R8 R9 NR R10 R6 R7 ch(VIII ) aromatic nucleophilic substitution reaction or coupling (XIV ) reaction

wherein the symbols are as defined above . Compound (XIV ) can be produced by a method known per se . Alkylation reaction can be performed according to the 35 Compound (IV ) can be produced from compound (XVII ) method shown in reaction scheme 2 , or according thereto . by the method shown in reaction scheme 5 .

[ reaction scheme 51

HO 20 R3 R4 X R8 R9 R10 Yox R6 R7 0 (IV ) deprotection

R8 R9 R 10 R4 HO O - RIO R3 R4 X RIC R3 R4 R6 R7 © RIC R8 R9 (VII ) Y RIOR10 Mitsunobu reaction or alkylation reaction R6 R7 ©

Foxy(XVI ) Forest(XV ) US 9 ,776 ,962 B2 41 42 - continued

R R + aromatic nucleophilic D . substitution reaction - or coupling reaction R3 R4 X R8 R9 wox = NB RIO R6 R7 ] R1 O xox ( VIII ) aromatic nucleophilic substitution reaction or coupling (XVII ) reaction

25 wherein Rll is an optionally substituted C1- 6 alkyl group or Compound (XVII ) can be produced by a method known an optionally substituted C7- 16 aralkyl group , and other per se . symbols are as defined above . Compound (IX ) can be produced from compound (XIII ) Alkylation reaction can be performed according to the or compound (XVI ) by the method shown in reaction method shown in reaction scheme 2 , or according thereto . scheme 6 .

[ reaction scheme 6 ]

H 20 R3 R4 R3 R4 R2 R3 R4 92 N B1 Z oxidation R2 H reaction ( III ) amidation reaction Foxe(XIII ) for(XVIII ) your( IX )

deprotection

RR22 - V? H ( III) R3 R4 amidation R11 – 0 reaction NB

(XVI )

wherein the symbols are as defined above . US 9 ,776 , 962 B2 43 44 Compound ( IX - 1 ) and compound ( IX - 2 ) can be produced from compound (IX -6 ) or compound (IX - 8 ) by the method shown in reaction scheme 7 . Compound (IX - 1 ) is compound ( IX ) wherein Y2 is a hydroxyl group .

[ reaction scheme 71

HO 20 x y Ho HO . 1 y } R2??? H (XIX ) ( III) aromatic nucleophilic oxidation amidation substitution reaction reaction reaction or coupling reaction ( IX - 6 ) (IX -5 ) ( IX - 4 ) Garot = Foteledeprotection

R1- O NB R1- O ( XIX ) aromatic nucleophilic substitution reaction or coupling reaction ( IX - 8 ) ( IX - 7 )

per R2

( IX - 3 ) Grignard reduction reaction reaction R3 – MgX PI => / p lami R3 R4 R Z R2 X OH OH

( IX - 1 ) ( IX - 2 ) 60 wherein Y² is hydrogen , an optionally substituted C1- 6 alkyl Compound ( IX - 6 ) , compound (IX - 8 ) and compound group , an optionally substituted C1- 6 alkoxy group or a (XIX ) can be produced by a method known per se. hydroxyl group , and other symbols are as defined above . Compound (IX - 1 ) can also be produced by the reaction of Compound (VII ), compound (VIII ) and compound (XX ) compound ( IX - 2 ) with an alkyllithium reagent and the like . 65 can be produced by the method shown in reaction scheme 8 Examples of the alkyllithium reagent include methyllithium or a method analogous thereto or the method exemplified in and the like . WO 2009 /048527 or a method analogous thereto . US 9 ,776 , 962 B2 45 46

10R

R10 R9R8 R6R7© OH R8R9 (VIII) RÓR7© X (VII) R8R9 R6R7© R4XR3 (XX) tehtyR RS X

HO X se|hydrolysis RIO deprotection

Ö deprotection RIO R6R70 OHOH (XXI-8) alkylation reactionof hydroxylgroup (XXI-12) R8R9 R6R7© (XXI) , reduction reaction FORS* reactionby O-R10 ROO [reactionscheme81 reactionby 1,4-addition carboanion nucleophilicaddition ela,0-R10 carboanion © bycarboanionor couplingreaction 1,4-additionreaction (XXI-11) O (XXI-3) RÓ© R6 ORIO (XIII-10) R6R70 ROR? PS (XXI-6) mo RS XXI)-7( O R?

=B O Knoevenagel reaction Wittig reaction Wittig condensation O (XXI-5) reaction (XXI-9) RS 20R? R6 (XXI-2) 1,4-additionreaction carboanionby TEX y4 =Grignard reaction R6JMgx Knoevenagel condensation reaction

(XXI-4) RS (XXI-1) zote 94 US 9 ,776 , 962 B2 47 48 wherein Y4 is a halogen atom (e .g ., fluorine , chlorine , bromine , iodine ), an optionally substituted C1- 6 alkyl group , reaction scheme 101 an optionally substituted C1- 6 alkoxy group , or an optionally protected hydroxyl group , and other symbols are as defined above . Compound (XXI ) can be produced by , for example , ??? converting the meldrum ’ s acid moiety of compound (XXI - 6 ) and compound ( XXI- 12 ) to an ester. This reaction is per oxidation formed by reacting methanol or ethanol in an inert solvent R 15 reaction R 15 such as DMF and the like. 10 ( III - 5 ) (III - 4 ) Compound (XXI ) can be produced by, for example , alkylation of the hydroxyl group of compound (XXI - 8 ). This reaction is performed by reacting alkyl halide in an inert H . solvent such as toluene and the like in the presence of silver 15 oxide and the like . Compound (XXI - 1) , compound (XXI - 4 ) , compound ( XXI- 7 ) and compound (XXI - 9 ) can be produced by a ( III- 3 ) method known per se . Compound ( III ), compound ( III - 1 ) and compound ( III -2 ) 20 wherein R15 is a substituent, and other symbols are as can be produced from compound ( V ) by the method shown defined above . in reaction scheme 9 . Compound ( III- 3 ) can be produced by the reaction of compound ( III- 4 ) with compound ( V ) . The reaction is per formed in the presence of phosphate represented by bro [ reaction scheme 91 25 motris (pyrrolidino )phosphonium hexafluorophosphate (Py Brop ) and a base . Examples of the base include alkali metal R ! H R2 _ y1 R R2 hydride, inorganic base , basic salt , alkali metal alkoxide , N ( VI) ' N organic base , organic lithium , metal amide and the like . ys alkylation Compound (III -5 ) can be produced by a method known reaction 30 per se . ( V - 1 ) ( III- 1 ) Compound (XIX - 1 ) can be produced from compound (XIX - 2 ) by the method shown in reaction scheme 11 , or protection deprotection according thereto . Compound (XIX - 1 ) is compound (XIX ) R2 - yl RI R2 wherein ring B is an optionally further substituted piperidine ( VI) 35 ring. H KV on reaction [ reaction scheme 11 ] R12 R13 D 12 (XXII ) 40 reductive amination reaction R 13 B reduction HN . amidation reaction reaction ( III - 1 ) R 16 R16 pada45 reduction RI (XIX - 2 ) (XIX - 1 ) reaction N R 14 - H wherein R16 is a substituent, and other symbols are as ( III- 2 ) defined above . (XXIII ) 50 Compound ( XIX - 2 ) can be produced by a method known per se . Compound (XXIV ) can be produced from compound wherein Y? is a protecting group , R12, R 13 and R 14 are each (XXIV - 3 ) by the method shown in reaction scheme 12 , or a hydrogen atom , an optionally substituted C , alkyl group , themethod described in J . Org . Chem ., 2010 , vol. 75 , pages an optionally substituted C7- 16 aralkyl group or an optionally 55 929 - 932 or a method analogous thereto . substituted C6- 14 aryl group . Alkylation reaction can be performed according to the method shown in reaction scheme 2 , or according thereto . [reaction scheme 121 Compound (XXII ) can be produced by a method known 60 y13 per se . Compound ( III -3 ) can be produced from compound (III R 18YRR20 R1919 5 ) by themethod shown in reaction scheme 10 , for example , the method described in Organic Letters, 2010 , 22 ( vol. 12 ) , R17 Ó pages 5254 - 5257 , or according thereto . Compound (III - 3S ) isis 65 NoneNC compound (III ) wherein R2 is an optionally further substi ( XXIV -3 ) coupling reaction tuted 2 -pyridyl group . US 9 , 776 , 962 B2 49 50 -continued drofuranyl group , a substituted silyl group ( e . g . , trimethyl R17 silyl, triethylsilyl, dimethylphenylsilyl, tert - butyldimethyl NC reduction silyl, tert -butyldiethylsilyl ) , a C2- 6 alkenyl group ( e .g ., reaction 1 - allyl) , and the like . These groups are optionally substituted R18 - 0 5 by 1 to 3 substituents selected from a halogen atom , a C1- 6 RPO R19 alkyl group , a C1- 4 alkoxy group and a nitro group . Examples of the carbonyl- protecting group include a (XXIV -2 ) cyclic acetal ( e . g ., 1 , 3 - dioxane ), a non - cyclic acetal ( e . g . , a R17 R17 di- C1- 6 alkylacetal) and the like . B reduction JB Y 10 Examples of the mercapto -protecting group include a C1- 6 reaction alkyl group , a phenyl group , a trityl group , a C7- 10 aralkyl HN . group ( e . g . , benzyl) , a C1- 6 alkyl - carbonyl group , a benzoyl R20 R20 IRR20 RTO19 group , a C7- 10 aralkyl - carbonyl group ( e . g . , benzylcarbonyl) , (XXIV ) a C1- 6 alkoxy - carbonyl group , a C6- 14 aryloxy - carbonyl (XXIV - 1) 15 group ( e . g . , phenyloxycarbonyl ) , a C7- 14 aralkyloxy - carbo nyl group ( e. g ., benzyloxycarbonyl, 9 - fluorenylmethoxycar bonyl) , a 2 -tetrahydropyranyl group , a C1- 6 alkylamino wherein R18 is an optionally substituted C1- 6 alkyl group or carbonyl group ( e . g ., methylaminocarbonyl, an optionally substituted C7- 16 aralkyl group , R1 , R19 and ethylaminocarbonyl) and the like. These groups are option R20 are eachcach a halogen atomatom ( e .. g ., , muorinefluorine , chlorine , bro - 20 allyallu substituted by 1 to 3 substituents selected from a mine, iodine) , an optionally substituted alkyl group , an halogen atom , a C1- 6 alkyl group , a C1- 6 alkoxy group and a optionally substituted alkoxy group , or an optionally pro nitro group . tected hydroxyl group , and other symbols are as defined The above -mentioned protecting groups can be removed above. by a method known per se , for example , the method Compound (XXIV - 2 ) can be produced by a method using 25 described in Protective Groups in Organic Synthesis , John a coupling reaction of compound (XXIV - 3 ) and compound Wiley and Sons ( 1980 ) and the like . Specifically , a method (XXV ) , or a method analogous thereto . The coupling reac - using acid , base , ultraviolet rays , hydrazine , phenylhydra tion can be performed by , for example , according to a zine , sodium N -methyldithiocarbamate , tetrabutylammo method including reacting compound (XXIV - 3 ) with com - nium fluoride , palladium acetate , trialkylsilyl halide ( e . g . , pound (XXV ) generally in the presence of a base and a 30 trimethylsilyl iodide, trimethylsilyl bromide ) and the like , a catalyst ( e . g . , palladium catalyst , copper catalyst, nickel reduction method and the like can be mentioned . catalyst and the like ) and an appropriate ligand ( e . g ., tetram In compound ( I ) obtained by each of the above -mentioned ethylethylenediamine ( TMEDA ) ) . production methods, a functional group in a molecule can Compound (XXIV - 3 ) and compound ( XXV ) can be pro also be converted to a desired functional group by a com duced by a method known per se . 35 bination of chemical reactions known per se . Examples of In each of the aforementioned reactions , when the starting the chemical reaction include oxidation reaction , reduction compound has an amino group , a carboxy group , a hydroxy reaction , alkylation reaction , acylation reaction , ureation group , a carbonyl group or a mercapto group as a substitu - reaction , hydrolysis reaction , amination reaction , esterifica ent, a protecting group generally used in the peptide chem tion reaction , aryl coupling reaction , deprotection reaction istry and the like may be introduced into these groups , and 40 and the like. the object compound can be obtained by eliminating the Compound ( I ) obtained by each of the above -mentioned protecting group as necessary after the reaction . production methods can be isolated and purified by a known Examples of the amino -protecting group include a formyl means such as concentration , concentration under reduced group ; a C1- 6 alkyl- carbonyl group , a C1- 6 alkoxy - carbonyl pressure, solvent extraction , crystallization , recrystalliza group , a benzoyl group , a C7- 13 aralkyl -carbonyl group ( e . g ., 45 tion , phase transfer, chromatography and the like . In addi benzylcarbonyl ) , a C7- 14 aralkyloxy - carbonyl group ( e . g ., tion , the starting compounds used for each of the above benzyloxycarbonyl , 9 - fluorenylmethoxycarbonyl) , a trityl mentioned production methods can be isolated and purified group , a phthaloyl group , an N , N - dimethylaminomethylene by a known means similar to the aforementioned methods. group , a substituted silyl group ( e . g . , trimethylsilyl, trieth - These starting compounds may be used in the form of a ylsilyl, dimethylphenylsilyl, tert - butyldimethylsilyl, tert- bu - 50 reaction mixture without isolation , as a starting material for tyldiethylsilyl ), a C2- 6 alkenyl group ( e .g ., 1 -allyl ) and the the next step . like . These groups are optionally substituted by 1 to 3 When compound ( 1 ) contains an isomer such as an optical substituents selected from a halogen atom , a C - alkoxy isomer, a stereoisomer, a regioisomer or a rotamer, any one group and a nitro group . of them and a mixture thereof are also encompassed in Examples of the carboxyl- protecting group include a C1- 6 55 compound ( I ) . For example , when compound (1 ) contains an alkyl group , a C71, aralkyl group ( e . g ., benzyl) , a phenyl optical isomer, an optical isomer resolved from racemate is group , a trityl, a substituted silyl group ( e . g . , trimethylsilyl, also encompassed in compound ( I ) . Each of these isomers triethylsilyl, dimethylphenylsilyl, tert -butyldimethylsilyl , can be obtained as a single product by a synthesis means, tert- butyldiethylsilyl ) , a C2- 6 alkenyl group ( e . g ., 1 - allyl) and separation means ( e . g ., concentration , solvent extraction , the like . These groups are optionally substituted by 1 to 3 60 column chromatography , recrystallization etc . ), optical reso substituents selected from a halogen atom , a C - , alkoxy l ution means ( e . g ., fractional recrystallization method , chiral group and a nitro group . column method , diastereomer method etc . ) and the like, Examples of the hydroxy -protecting group include a C1-6 which are known per se . alkyl group , a phenyl group , a trityl group , a C7- 10 aralkyl Compound ( 1) may be a crystal, and the crystal form may group (e .g ., benzyl) , a formyl group , a C1- 6 alkyl- carbonyl 65 be single or a mixture of crystal forms, both of which are group , a benzoyl group , a C7- 10 aralkyl- carbonyl group ( e . g . , encompassed in compound ( 1 ) . The crystal can be produced benzylcarbonyl ) , a 2 -tetrahydropyranyl group , a 2 - tetrahy - by a crystallization method known per se . US 9 ,776 , 962 B2 51 52 Compound ( 1 ) may be a pharmaceutically acceptable To be specific , the compound of the present invention is cocrystal or cocrystal salt. Here , the cocrystal or cocrystal useful as an agent for the prophylaxis or treatment of salt means a crystalline substance consisting of two or more diabetes ( e . g . , type 1 diabetes , type 2 diabetes , gestational particular substances which are solids at room temperature, diabetes, obese diabetes) , an insulin secretagogue, a pancre each having different physical properties ( e . g . , structure , 5 atic ß cell protector, a GLP - 1 secretion promoter, a GIP melting point, heat of melting , hygroscopicity , solubility, secretion promoter, an agent for the prophylaxis or treatment stability etc . ) . The cocrystal and cocrystal salt can be pro - of impaired glucose tolerance ( IGT) and an agent for pre duced by cocrystallization method known per se . venting progression of impaired glucose tolerance to diabe In the present specification , the melting point means that tes. measured using, for example , a micromelting point appara - 10 Particularly , the compound of the present invention is tus ( Yanako , MP - 500D or Buchi, B -545 ) , a DSC ( differen - useful as blood glucose level- dependent insulin secret tial scanning calorimetry ) device (SEIKO , EXSTAR6000 ) agogues based on the GPR40 agonist activity thereof. That or the like . is different from sulfonylureas , the compound of the present In general, the melting points vary depending on the invention is useful as insulin secretagogues that do not cause measurement apparatuses, the measurement conditions and 15 hypoglycemia . the like . The crystal in the present specification may show Furthermore , the compound of the present invention can different values from the melting point described in the be used as an agent for the prophylaxis or treatment of present specification , as long as they are within each of a obesity , hyperlipidemia ( e . g ., hypertriglyceridemia , hyperc general error range . holesterolemia , high LDL -cholesterolemia , hypo HDL - cho The crystal of the present invention is superior in physi - 20 lesterolemia , postprandial hyperlipidemia ) , hypertension , cochemical properties ( e . g . , melting point, solubility , stabil - cardiac failure , diabetic complications [ e . g . , neuropathy, ity ) and biological properties (e . g. , pharmacokinetics ( ab - nephropathy, diabetic retinopathy, diabetic cardiomyopathy, sorption , distribution , metabolism , excretion ), efficacy cataract, macroangiopathy , osteopenia , hyperosmolar dia expression ), and thus it is extremely useful as a medicament. betic coma, infections ( e . g . , respiratory infection , urinary Compound ( 1 ) may be a solvate ( e . g ., hydrate etc . ) , or a 25 tract infection , gastrointestinal infection , dermal soft tissue non - solvate ( e. g . , non -hydrate etc . ) , and both are encom - infections , inferior limb infection ) , diabetic gangrene , xero passed in compound ( I) . stomia , hypacusis , cerebrovascular disorder, peripheral A compound labeled with an isotope ( e . g . , PH , 13C , 14C , blood circulation disorder ], metabolic syndrome ( according 18F , 35S , 1251 etc . ) and the like is also encompassed in to the diagnostic criteria for Japanese people as reported in compound (I ) . 30 2005 by the Japan Society for the Study of Obesity and the Compound ( I) also encompasses a deuterium conversion like , the metabolic syndrome refers to males having an form wherein ' H is converted to ? H ( D ) . abdominal circumference of 85 cm or above and females Compound ( 1 ) labeled or substituted with an isotope can having an abdominal circumference of 90 cm or above and be used as, for example , a tracer (PET tracer) used for satisfying two items out of three items of: systolic blood Positron Emission Tomography (PET ) , and is useful in the 35 pressure of not less than 130 or diastolic blood pressure of fields of medical diagnosis and the like . not less than 85 mmHg, neutral triglyceride not less than 150 Compound (I ) and a prodrug thereof (hereinafter , these mg/ dl or HDLc less than 40 mg/ dl , and fasting blood sugar are collectively abbreviated as the compound of the present level ( venous plasma glucose concentration ) not less than invention ) have a GPR40 receptor function modulating 110 mg/ dl) and the like . action , particularly, a GPR40 agonist activity. GPR40 ago - 40 For diagnostic criteria of diabetes, Japan Diabetes Society nist activates GPR40 expressed in pancreatic B cells to reported diagnostic criteria in 1999 . promote insulin secretion , and activates GPR40 expressed in According to this report, diabetes is a condition showing the intestine to promote glucagon - like peptide - 1 ( glucagon any of a fasting blood glucose level ( glucose concentration like peptide - 1 ; GLP - 1 ) secretion . That is , the compound of of intravenous plasma ) of not less than 126 mg/ dl , a 75 g oral the present invention has a hypoglycemic action , an insulin 45 glucose tolerance test (75 g OGTT ) 2 h level ( glucose secretagogue action , a GLP - 1 secretagogue action and a concentration of intravenous plasma ) of not less than 200 pancreatic ß cell protecting action . The GLP - 1 secretagogue mg/ dl, and a non - fasting blood glucose level ( glucose con action of the compound of the present invention can be centration of intravenous plasma ) of not less than 200 mg/ dl. measured using , for example , an ELISA kit containing a A condition not falling under the above -mentioned diabetes GLP - 1 antibody . Moreover, the compound of the present 50 and different from " a condition showing a fasting blood invention may have a glucose - dependent insulinotropic glucose level (glucose concentration of intravenous plasma ) polypeptide (GIP ) secretagogue action , a food ingestion of less than 110 mg/ dl or a 75 g oral glucose tolerance test suppressive action and a glucagon secretion suppressive (75 g OGTT) 2 h level ( glucose concentration of intravenous action . plasma ) of less than 140 mg/ d1 ” (normal type) is called a The compound of the present invention shows low tox - 55 “ borderline type” . icity ( e . g . , acute toxicity , chronic toxicity , genetic toxicity . In addition , ADA ( American Diabetes Association ) and reproductive toxicity , cardiotoxicity , carcinogenicity , cyto - WHO reported diagnostic criteria of diabetes . toxicity ) and can be safely administered a mammal ( e . g ., According to these reports , diabetes is a condition show mouse , rat , hamster, rabbit , cat , dog , bovine , sheep , monkey, ing a fasting blood glucose level ( glucose concentration of human ) directly or as a pharmaceutical composition by 60 intravenous plasma ) of not less than 126 mg/ dl, or a 75 g oral mixing same with a pharmacologically acceptable carrier glucose tolerance test 2 h level ( glucose concentration of and the like . intravenous plasma ) of not less than 200 mg/ dl . The compound of the present invention is useful as According to the above -mentioned reports by ADA and modulators of physiological function in which GPR40 WHO , impaired glucose tolerance is a condition showing a receptor is involved or as agents for the prophylaxis or 65 75 g oral glucose tolerance test 2 h level (glucose concen treatment of pathology or disease in which GPR40 receptor tration of intravenous plasma ) of not less than 140 mg/ dl and is involved . less than 200 mg/ dl . According to the report of ADA , a US 9 ,776 , 962 B2 53 54 condition showing a fasting blood glucose level (glucose Since the compound of the present invention has a pan concentration of intravenous plasma ) of not less than 110 creatic ß cell protection action , it can be used for the mg/ dl and less than 126 mg/ dl is called IFG ( Impaired prognosis improvement in pancreatic islet transplantation . Fasting Glucose ) . According to the report of WHO , among The compound of the present invention can also be used the IFG ( Impaired Fasting Glucose ), a condition showing a 5 for decreasing the visceral fat, suppressing visceral fat fasting blood glucose level ( glucose concentration of intra accumulation , improving sugar metabolism , improving lipid venous plasma ) of not less than 110 mg/ dl and less than 126 metabolism , insulin sensitizing, suppressing oxidized LDL mg/ dl is called IFG (Impaired Fasting Glycemia ) . production , improving lipoprotein metabolism , improving coronary metabolism , preventing or treating cardiovascular The compound of the present invention can also be used 10 complication , preventing or treating heart failure complica as an agent for the prophylaxis or treatment of diabetes , tion , decreasing blood remnant, preventing or treating ano borderline type, impaired glucose tolerance , IFG ( Impaired vulation , preventing or treating hirsutism , preventing or Fasting Glucose ) and IFG ( Impaired Fasting Glycemia ), as treating hyperandrogenism and the like . determined according to the above -mentioned diagnostic The compound of the present invention can also be used criteria . Moreover, the compound of Thethe presentpresent inventioninvention 1515 for the secondary prevention and the suppression of pro can prevent progress of borderline type , impaired glucose gression of the above -mentioned various diseases ( e . g . , tolerance , IFG (Impaired Fasting Glucose ) or IFG (Impaired cardiovascular event such as myocardial infarction and the Fasting Glycemia ) into diabetes . like ) . The compound of the present invention is also useful as A medicament containing the compound of the present a therapeutic agent for diabetes with sulfonylurea secondary 20 invention can be safely administered solely to a mammal or failure and affords a superior insulin secretion effect and a by mixing with a pharmacologically acceptable carrier hypoglycemic effect for diabetic patients for whom sulfo according to a method known per se ( e . g ., the method nylurea compounds and fast -acting insulin secretagogues described in the Japanese Pharmacopoeia etc . ) as the pro fail to provide an insulin secretion effect, and therefore , fail duction method of a pharmaceutical preparation , and in the to provide a sufficient hypoglycemic effect . 25 form of, for example , tablet ( including sugar - coated tablet , As the sulfonylurea compound here , a compound having film - coated tablet , sublingual tablet, orally disintegrating a sulfonylurea skeleton or a derivative thereof ( e . g . , tolbu - tablet, buccal tablet and the like ), pill, powder, granule , tamide , glibenclamide , gliclazide , chlorpropamide , tolaz - capsule ( including soft capsule, microcapsule ) , troche , amide , acetohexamide, glyclopyramide, glimepiride , glipiz - syrup , liquid , emulsion , suspension , release control prepa ide , glybuzole and the like ) can be mentioned . 30 ration ( e . g . , immediate -release preparation , sustained -re As the fast -acting insulin secretagogue , a compound that lease preparation , sustained - release microcapsule ), aerosol, promotes insulin secretion from pancreatic B cell in the film ( e . g ., orally disintegrating film , oral mucosa -adhesive same manner as a sulfonylurea compound , though it does film ) , injection ( e . g . , subcutaneous injection , intravenous nothave a sulfonylurea skeleton , such as glinide compounds injection , intramuscular injection , intraperitoneal injection ) , ( e . g . , repaglinide , senaglinide , nateglinide , mitiglinide or a 35 drip infusion , transdermal absorption type preparation , oint calcium salt hydrate thereof etc . ) , and the like , can be ment, lotion , adhesive preparation , suppository ( e . g ., rectal mentioned . suppository , vaginal suppository ), pellet, nasal preparation , The compound of the present invention can also be used pulmonary preparation ( inhalant) , eye drop and the like , as an agent for the prophylaxis or treatment of, for example , orally or parenterally ( e . g ., intravenous, intramuscular, sub cognitive impairment, osteoporosis , cachexia ( e . g . , cancer - 40 cutaneous , intraorgan , intranasal, intradermal, instillation , ous cachexia , tuberculous cachexia , diabetic cachexia , intracerebral, intrarectal, intravaginal, intraperitoneal and hemopathic cachexia , endocrinopathic cachexia , infectious intratumor administrations, administration to the vicinity of cachexia or cachexia induced by acquired immunodefi - tumor , and direct administration to the lesion ) . ciency syndrome) , fatty liver , polycystic ovary syndrome, During production of an oral preparation , coating may be renal disease ( e . g . , diabetic nephropathy, glomerulonephri- 45 applied as necessary for the purpose of masking of taste , tis , glomerulosclerosis , nephrotic syndrome, hypertensive enteric property or durability . nephrosclerosis , end - stage renal disorder ), muscular dystro - Examples of the coating base to be used for coating phy, myocardial infarction , angina pectoris , cerebrovascular include sugar coating base , aqueous film coating base , disorder ( e . g ., cerebral infarction , cerebral apoplexy ) , insu - enteric film coating base and sustained -release film coating lin resistance syndrome, syndrome X , hyperinsulinemia , 50 base . perception disorder in hyperinsulinemia , tumor (e . g ., leuke - As the sugar coating base , sucrose is used . Moreover, one mia , breast cancer, prostate cancer , skin cancer ) , irritable or more kinds selected from talc , precipitated calcium car bowel syndrome, acute or chronic diarrhea , inflammatory bonate , gelatin , gum arabic , pullulan , carnauba wax and the disease ( e . g ., arteriosclerosis ( e . g ., atherosclerosis ) , rheuma- like may be used in combination . toid arthritis , spondylitis deformans, osteoarthritis , lumbago , 55 Examples of the aqueous film coating base include cel gout, postoperative or post- traumatic inflammation , swell - lulose polymers such as hydroxypropyl cellulose, hydroxy ing, neuralgia , pharyngolaryngitis , bladder inflammation , propylmethyl cellulose , hydroxyethyl cellulose, methylhy hepatitis ( including nonalcoholic steatohepatitis ) , pneumo - droxyethyl cellulose etc . ; synthetic polymers such as nia , pancreatitis , inflammatory colitis , ulcerative colitis , polyvinylacetal diethylaminoacetate, aminoalkyl methacry chronic obstructive pulmonary diseases (COPD ) ) , visceral 60 late copolymer E ?Eudragit E ( trade name ) ], polyvinylpyr fat syndrome, foot ulcer, sepsis , psoriasis and the like . rolidone etc . ; and polysaccharides such as pullulan etc . In addition , the compound of the present invention can Examples of the enteric film coating base include cellu also be used for the improvement of the symptoms of lose polymers such as hydroxypropylmethyl cellulose abdominal pain , nausea , vomiting, uncomfortable feeling in phthalate, hydroxypropylmethyl cellulose acetate succinate , the upper abdomen and the like , which are associated with 65 carboxymethylethyl cellulose , cellulose acetate phthalate peptic ulcer , acute or chronic gastritis , biliary dyskinesia , etc . ; acrylic polymers such as methacrylic acid copolymer L cholecystitis and the like, and the like . [Eudragit L (trade name) ], methacrylic acid copolymer LD US 9 ,776 , 962 B2 55 56 [Eudragit L - 30D55 (trade name) ] , methacrylic acid copoly As the isotonic agent, for example , glucose , D - sorbitol, mer S [Eudragit S ( trade name) ] etc . ; and naturally occurring sodium chloride, glycerin , D -mannitol and the like can be substances such as shellac etc . mentioned . Examples of the sustained - release film coating base As the buffer, for example, buffers such as phosphates , include cellulose polymers such as ethyl cellulose etc . ; and 5 acetates , carbonates , citrates and the like , and the like can be acrylic polymers such as aminoalkyl methacrylate copoly mentioned . mer RS [ Eudragit RS ( trade name) ], ethyl acrylate -methyl As the soothing agent, for example, benzyl alcohol and methacrylate copolymer suspension [Eudragit NE (trade the like can be mentioned . naname ) ] etc . As the preservative , for example , p - hydroxybenzoates , The above -mentioned coating bases may be used after 10 chlorobutanol, benzyl alcohol, phenethyl alcohol, dehy mixing with two or more kinds thereof at appropriate ratios. droacetic acid , sorbic acid and the like can be mentioned . For coating, for example , a light shielding agent such as As the antioxidant, for example , sulfites , ascorbic acid , titanium oxide , red ferric oxide and the like can be used . a - tocopherol and the like can be mentioned . The content of the compound of the present invention in As the colorant , for example, water -soluble edible tar a pharmaceutical preparation is about 0 .01 to about 100 % by 15 pigments ( e . g ., food colors such as Food Color Red Nos . 2 weight relative to the whole preparation . While the dose of and 3 , Food Color Yellow Nos. 4 and 5, Food Color Blue the compound of the present invention varies depending on Nos . 1 and 2 and the like ) , water insoluble lake pigments the administration subject, administration route , diseases, ( e . g ., aluminum salt of the aforementioned water- soluble condition and the like , for example , the compound of the edible tar pigment and the like ) , natural pigments ( e . g . , present invention (as an active ingredient) can be orally 20 ß -carotene , chlorophil, ferric oxide red etc .) and the like can administered to a patient with diabetes (body weight about be mentioned . 60 kg) in about 0 .01 to about 30 mg/kg body weight per day, As the sweetening agent , for example , saccharin sodium , preferably about 0 . 1 to about 20 mg/ kg body weight per day, dipotassium glycyrrhizinate , aspartame, stevia and the like more preferably about 1 to about 20 mg/ kg body weight per can be mentioned . day , which may be given at once or in several portions ( e . g . , 25 Moreover , the compound of the present invention can be 1 - 3 portions) a day. used in combination with drugs other than the compound of As the above -mentioned pharmacologically acceptable the present invention . carrier, various organic or inorganic carrier substances con - As the drugs that can be used in combination with the ventionally used as a preparation material can be mentioned . compound of the present invention (hereinafter sometimes For example , excipient, lubricant, binder and disintegrant 30 to be abbreviated as a concomitant drug ) , for example , for solid preparations; solvent, solubilizing agents , suspend therapeutic agents for diabetes , therapeutic agents for dia ing agent, isotonic agent, buffer and soothing agent for liquid betic complications, therapeutic agents for hyperlipidemia , preparations and the like can be mentioned . Where neces antihypertensive agents , antiobesity agents , diuretics , che sary , conventional additives such as preservatives, antioxi motherapeutic agents , immunotherapeutic agents , antiin dants , colorants , sweetening agents , adsorbing agents , wet - 35 flammatory agents , antithrombotic agents, therapeutic ting agents and the like can be used . agents for osteoporosis , vitamins, antidementia agents , erec As the excipient, for example , lactose , sucrose , D -man tile dysfunction improving drugs , therapeutic agents for nitol, starch , corn starch , crystalline cellulose , light anhy - pollakiuria or urinary incontinence , therapeutic agents for drous silicic acid and the like can be mentioned . dysuria and the like can be mentioned . Specifically , the As the lubricant, for example , magnesium stearate , cal - 40 following agents can be mentioned . cium stearate , talc , colloidal silica and the like can be Examples of therapeutic agents for diabetes include insu mentioned . lin preparations ( e . g . , animal insulin preparations extracted As the binder, for example , crystalline cellulose , sucrose , from pancreas of bovine or swine; human insulin prepara D -mannitol , dextrin , hydroxypropylcellulose , hydroxypro tions genetically synthesized using Escherichia coli or yeast ; pylmethylcellulose , polyvinylpyrrolidone, starch , sacchar - 45 zinc insulin ; protamine zinc insulin ; fragment or derivative ose , gelatin , methylcellulose, carboxymethylcellulose of insulin ( e . g ., INS - 1 ) , oral insulin preparation ) , insulin sodium and the like can be mentioned . sensitizers ( e . g ., pioglitazone or a salt thereof (preferably As the disintegrant, for example, starch , carboxymethyl - hydrochloride ) , rosiglitazone or a salt thereof (preferably cellulose , carboxymethylcellulose calcium , carboxymethyl- maleate ) , Metaglidasen , AMG - 131, Balaglitazone , MBX starch sodium , L -hydroxypropylcellulose and the like can be 50 2044 , Rivoglitazone , Aleglitazar , Chiglitazar , Lobeglita mentionedm zone , PLX - 204 , PN - 2034 , GFT -505 , THR -0921 , the com As the solvent, for example , water for injection , alcohol, pound described in WO 2007 /013694 , WO 2007/ 018314 , propylene glycol, macrogol, sesame oil , corn oil , olive oil WO 2008/ 093639 and WO 2008 /099794 ), a - glucosidase and the like can be mentioned . inhibitors ( e. g ., voglibose, acarbose , miglitol, emiglitate ), As the solubilizing agents , for example , polyethylene 55 biguanides ( e . g . , metformin , buformin or a salt thereof ( e . g . , glycol, propylene glycol, D -mannitol , benzyl benzoate , hydrochloride , fumarate , succinate ) ) , insulin secretagogues ethanol, trisaminomethane, cholesterol, triethanolamine , ( sulfonylurea ( e . g ., tolbutamide , glibenclamide , gliclazide , sodium carbonate , sodium citrate and the like can be men - chlorpropamide , tolazamide , acetohexamide , glyclopyra tioned . mide , glimepiride, glipizide , glybuzole ) , repaglinide, nateg As the suspending agent , for example , surfactants such as 60 linide, mitiglinide or calcium salt hydrate thereof ) , dipepti stearyltriethanolamine , sodium lauryl sulfate , lauryl amino - dyl- peptidase IV inhibitors ( e . g ., Alogliptin or a salt thereof propionate , lecithin , benzalkonium chloride , benzethonium ( preferably benzoate ) , Vildagliptin , Sitagliptin , Saxagliptin , chloride, glycerol monostearate and the like ; hydrophilic B11356 , GRC8200 , MP -513 , PF - 00734200 , PHX1149 , polymers such as polyvinyl alcohol, polyvinylpyrrolidone , SK -0403 , ALS2 -0426 , TA -6666 , TS -021 , KRP - 104 , Trela carboxymethylcellulose sodium , methylcellulose , 65 gliptin or a salt thereof (preferably , succinate )) , B3 agonist hydroxymethylcellulose , hydroxyethylcellulose, hydroxy ( e. g ., N -5984 ) , GPR40 agonist ( e . g ., Fasiglifam or a hydrate propylcellulose and the like, and the like can be mentioned thereof (preferably , 0 .5 hydrate ), the compound described in US 9 ,776 ,962 B2 57 58 WO 2004 /041266 , WO 2004 / 106276 , WO 2005 / 063729 , dipine, cilnidipine and the like ) , ß blockers ( e . g . ,metoprolol , WO 2005 / 063725 , WO 2005 /087710 , WO 2005 /095338 , atenolol, propranolol, carvedilol, pindolol and the like ) , WO 2007 /013689 and WO 2008 /001931 ) , GLP- 1 receptor clonidine and the like . agonists ( e. g ., GLP - 1, GLP - 1MR agent, Liraglutide, Examples of the antiobesity agent include monoamine Exenatide, AVE - 0010 , BIM -51077 , Aib ( 8 ,35 )hGLP - 1 ( 7 , 37 ) 5 uptake inhibitors ( e . g . , phentermine , sibutramine , mazindol, NH2, CJC -1131 , Albiglutide) , amylin agonists (e .g ., pram fluoxetine , tesofensine ), serotonin 2C receptor agonists ( e. g ., lintide ), phosphotyrosine phosphatase inhibitors ( e .g ., lorcaserin ), serotonin 6 receptor antagonists , histamine H3 receptor modulator, GABA modulator ( e . g ., topiramate ) , sodium vanadate ) , gluconeogenesis inhibitors ( e . g ., glyco neuropeptide Y antagonists ( e . g . , velneperit ) , cannabinoid gen phosphorylase inhibitors , glucose - 6 -phosphatase T2inhibi ( s . 10 receptor antagonists ( e. g. , rimonabant, taranabant) , ghrelin tors , glucagon antagonists , FBPase inhibitors ), SGLT2 ( so antagonists , ghrelin receptor antagonists , ghrelin acylation dium - glucose cotransporter 2 ) inhibitors ( e . g ., enzyme inhibitors , opioid receptor antagonists ( e .g ., GSK Depagliflozin , Canagliflozin , Empagliflozin , Ipragliflozin , 1521498 ) , orexin receptor antagonists , melanocortin 4 Tofogliflozin , PF -04971729 , TS - 071 ) , SGLT1 inhibitor, receptor agonists, 113 -hydroxysteroid dehydrogenase 11B -hydroxysteroid dehydrogenase inhibitors (e . g. , BVT 15 inhibitors ( e . g ., AZD - 4017 ) , pancreatic lipase inhibitors 3498 , INCB - 13739 ), adiponectin or agonist thereof, IKK ( e . g ., orlistat, cetilistat) , B3 agonists ( e . g . , N - 5984 ) , diacyl inhibitors ( e . g . , AS - 2868) , leptin resistance improving glycerol acyltransferase 1 (DGAT1 ) inhibitors, acetylCOA drugs, somatostatin receptor agonists , glucokinase activators carboxylase ( ACC ) inhibitors, stearoyl- CoA desaturated ( e . g . , Piragliatin , AZD1656 , AZD6370 , TTP - 355 , the com - enzyme inhibitors, microsomal triglyceride transfer protein pound described in WO 2006 / 112549 , WO 2007 /028135 , 20 inhibitors ( e . g ., R - 256918 ) , Na- glucose cotransporter inhibi WO 2008 / 047821, WO 2008 /050821 ,WO 2008 / 136428 and tors (e . g. , JNJ -28431754 , remogliflozin ), NFK inhibitors WO 2008 / 156757 ) , GIP (Glucose -dependent insulinotropic ( e . g ., HE - 3286 ) , PPAR agonists ( e . g . , GFT- 505 , DRF peptide ), GPR119 agonists (e . g ., PSN821 , MBX -2982 , 11605 ), phosphotyrosine phosphatase inhibitors (e . g. , APD597) , FGF21, FGF analogue and the like . sodium vanadate , Trodusquemin ) , GPR119 agonists ( e . g . , Examples of the therapeutic agents for diabetic compli - 25 PSN821 , MBX - 2982 , APD597 ) , glucokinase activators cations include aldose reductase inhibitors ( e . g ., Tolrestat , ( e . g ., AZD - 1656 ) , leptin , leptin derivatives ( e . g . , metrelep Epalrestat, Zopolrestat, Fidarestat, CT- 112 , ranirestat ( AS tin ) , CNTF ( ciliary neurotrophic factor ), BDNF (brain 3201 ), Lidorestat) , neurotrophic factors and increasing derived neurotrophic factor ), cholecystokinin agonists , glucagon - like peptide- 1 (GLP - 1 ) preparations ( e . g . , animal drugs thereof (e . g ., NGF , NT- 3, BDNF , neurotrophin pro37230 GLP - 1 preparations extracted from the pancreas of bovine or duction - secretion promoters described in W001/ 14372 30 swine ; human GLP - 1 preparations genetically synthesized (e .g ., 4 -( 4 - chlorophenyl) - 2 -( 2 -methyl - 1 - imidazolyl ) -5 - [3 using Escherichia coli or yeast ; fragments or derivatives of (2 -methylphenoxy )propyl ]oxazole ), compound described in GLP - 1 ( e . g . , exenatide , liraglutide ) ) , amylin preparations WO 2004 /039365 ) , PKC inhibitors ( e . g ., ruboxistaurin ( e . g . , pramlintide , AC - 2307 ) , neuropeptide Y agonists ( e . g ., mesylate ) , AGE inhibitors ( e . g ., ALT - 946 , N -pnenactmphenacylthi - 35 PYY3- 36 , derivatives of PYY3- 36 , obineptide, TM - 30339, azolium bromide (ALT - 766 ), EXO -226 , Pyridorin , Pyridox TM - 30335 ) , oxyntomodulin preparations: FGF21 prepara amine ), GABA receptor agonists ( e . g ., gabapentin , Pregaba - tions ( e . g ., animal FGF21 preparations extracted from the lin ), serotonin . noradrenaline reuptake inhibitors ( e . g . , pancreas of bovine or swine ; human FGF21 preparations duloxetine ) , sodium channel inhibitors ( e . g ., Lacosamide ), genetically synthesized using Escherichia coli or yeast ; active oxygen scavengers (e .g . , thioctic acid ) , cerebral vaso - 40 fragments or derivatives of FGF21 ), anorexigenic agents dilators ( e . g ., tiapuride , mexiletine ), somatostatin receptor ( e . g . , P -57 ) and the like . agonists (BIM23190 ), apoptosis signal regulating kinase -1 Examples of the diuretics include xanthine derivatives (ASK - 1 ) inhibitors and the like . ( e . g . , sodium salicylate and theobromine, calcium salicylate Examples of the therapeutic agent for hyperlipidemia and theobromine ) , thiazide preparations ( e . g ., ethiazide , include HMG -CoA reductase inhibitors ( e . g . , pravastatin , 45 cyclopenthiazide , trichloromethiazide, hydrochlorothiazide , simvastatin , lovastatin , atorvastatin , fluvastatin , rosuvasta - hydroflumethiazide, benzylhydrochlorothiazide , penflutiz tin , pitavastatin or a salt thereof ( e .g . , sodium salt , calcium ide , polythiazide , methyclothiazide ), antialdosterone prepa salt ) ) , squalene synthase inhibitors ( e . g . , compound rations ( e . g . , spironolactone , triamterene ) , carbonate dehy described in W097 /10224 , for example , N - [[ (3R ,5S )- 1 -( 3 dratase inhibitors (e . g. , acetazolamide ), acetoxy - 2 ,2 - dimethylpropyl) - 7 - chloro - 5 - ( 2 , 3 - dimethoxy - 50 chlorobenzenesulfonamide preparations ( e . g ., chlortalidone , phenyl) - 2 -oxo - 1 , 2 , 3 , 5 - tetrahydro - 4 , 1 -benzoxazepin - 3 - yl] mefruside , indapamide ), azosemide , isosorbide , etacrynic acetyl] piperidine - 4 -acetic acid ), fibrate compounds ( e . g ., acid , piretanide , bumetanide , furosemide and the like . bezafibrate , clofibrate , simfibrate , clinofibrate ), anion Examples of the chemotherapeutic agents include alky exchange resins ( e. g. , colestyramine ), probucol, nicotinic lating agents ( e. g ., cyclophosphamide, ifosfamide ), meta acid drugs ( e . g . , nicomol, niceritrol, niaspan ) , ethyl icosa - 55 bolic antagonists ( e . g . , methotrexate , 5 - fluorouracil ) , antitu pentate, phytosterol ( e . g ., soysterol , gamma oryzanol) , cho - mor antibiotics ( e . g ., mitomycin , adriamycin ), plant- derived lesterol absorption inhibitors ( e. g ., Zetia ) , CETP inhibitors antitumor agents (e . g ., vincristine, vindesine , Taxol) , cispla ( e . g . , dalcetrapib , anacetrapib ) , w - 3 fatty acid preparations tin , carboplatin , etoposide and the like . Of these , Furtulon or ( e. g ., W - 3 -acid ethyl esters 90 ) and the like . NeoFurtulon , which are 5 - fluorouracil derivatives, and the Examples of the antihypertensive agent include angio - 60 like are preferable . tensin converting enzyme inhibitors ( e. g. , captopril, enal Examples of the immunotherapeutic agents include april , delapril and the like ) , angiotensin II antagonists ( e . g ., microorganism or bacterial components ( e . g ., muramyl candesartan cilexetil , candesartan , losartan , losartan potas dipeptide derivatives, Picibanil) , polysaccharides having sium , eprosartan , valsartan , telmisartan , irbesartan , tasosar - immunity potentiating activity ( e . g . , lentinan , schizophyllan , tan , olmesartan , olmesartan medoxomil , azilsartan , azilsar - 65 krestin ) , cytokines obtained by genetic engineering tech tan medoxomil and the like ) , calcium antagonists ( e . g . , niques ( e . g ., interferon , interleukin ( IL ) ) , colony stimulating manidipine, nifedipine, amlodipine , efonidipine , nicar factors ( e . g ., granulocyte colony stimulating factor , eryth US 9 ,776 ,962 B2 59 60 ropoietin ) and the like , with preference given to interleukins glimepiride ), mitiglinide or calcium salt hydrate thereof, such as IL - 1 , IL - 2 , IL - 12 and the like . nateglinide , a dipeptidyl peptidase IV inhibitor (preferably Examples of the antiinflammatory agents include non - alogliptin or benzoate thereof , trelagliptin or succinate steroidal antiinflammatory agents such as aspirin , acet- thereof) , SGLT2 inhibitor, GLP - 1 receptor agonist and the aminophen , indomethacin and the like . 5 like . For enhancing the food ingestion suppressive action , a Examples of the antithrombotic agents include heparin combined use with a dipeptidyl peptidase IV inhibitor ( e . g . , heparin sodium , heparin calcium , enoxaparin sodium , (preferably , alogliptin or a salt thereof) is more preferable . dalteparin sodium ) , warfarins ( e . g ., warfarin potassium ) , Two or more kinds of the above -mentioned concomitant anti - thrombin drugs ( e . g . , argatroban , dabigatran )) , FXa drugs may be used in combination at an appropriate ratio . inhibitors ( e . g . , rivaroxaban , apixaban , edoxaban , YM150 , 10 When the compound of the present invention is used in the compounds described in WO02 / 06234 , WO 2004 / combination with a concomitant drug , the amounts thereof 048363 , WO 2005 /030740 , WO 2005 /058823 and WO can be increased or decreased within the safe range in 2005 /113504 ), thrombolytic agents (e . g. , urokinase, tisoki- consideration of the counter effect thereof. Particularly , the nase, alteplase , nateplase , monteplase , pamiteplase ) , platelet doses of insulin sensitizer, dipeptidyl peptidase IV inhibitor, aggregation inhibitors ( e . g . , ticlopidine hydrochloride , 15 a - glucosidase inhibitor, biguanide , insulin secretagogue , clopidogrel, prasugrel, E5555 , SHC530348, cilostazol, ethyl SGLT2 inhibitor and GLP - 1 receptor agonist can be reduced icosapentate , beraprost sodium , sarpogrelate hydrochloride ) from the general doses . Therefore , the counter effects that and the like. will be caused by these agents can be prevented safely . In Examples of the therapeutic agents for osteoporosis addition , the doses of therapeutic agents for diabetic com include alfacalcidol, calcitriol, elcatonin , calcitonin salmon , 20 plications, therapeutic agents for hyperlipidemia , and anti estriol, ipriflavone , pamidronate disodium , alendronate hypertensive agents can be reduced and, as a result , the sodium hydrate , incadronate disodium , risedronate disodium counter effects that will be caused by these agents can be and the like . prevented effectively . Examples of the vitamins include vitamin B1, vitamin B12 By combining the compound of the present invention with and the like . 25 a concomitant drug , superior effects such as Examples of the antidementia drugs include tacrine, done - (1 ) decreased dose of the compound of the present invention pezil , rivastigmine , galanthamine and the like . or a concomitant drug as compared to single administration Examples of the erectile dysfunction improving drug of the compound of the present invention or a concomitant include apomorphine, sildenafil citrate and the like . drug, Examples of the therapeutic agents for pollakiuria or 30 (2 ) possible setting of a long treatment period by selecting urinary incontinence include flavoxate hydrochloride , oxy - a concomitant drug having different action and mechanism butynin hydrochloride , propiverine hydrochloride and the from those of the compound of the present invention , like . ( 3 ) possible designing of a sustained treatment effect by Examples of the therapeutic agents for dysuria include selecting a concomitant drug having different action and acetylcholine esterase inhibitors ( e . g . , distigmine ) and the 35 mechanism from those of the compound of the present like . invention , Furthermore , drugs having a cachexia - improving action ( 4 ) a synergistic effect afforded by a combined use of the established in animalmodels and clinical situations, such as compound of the present invention and a concomitant drug , cyclooxygenase inhibitors ( e . g . , indomethacin ) , progester- and the like can be achieved one derivatives ( e . g ., megestrol acetate ) , glucosteroids ( e . g . , 40 When the compound of the present invention and a dexamethasone ) , metoclopramide agents , tetrahydrocan - concomitant drug are used in combination , the administra nabinol agents , fat metabolism improving agents ( e . g ., tion time of the compound of the present invention and the eicosapentanoic acid ) , growth hormones, IGF - 1 , or antibod - concomitant drug is not restricted , and the compound of the ies to a cachexia - inducing factor such as TNF - a , LIF , IL - 6 , present invention and the concomitant drug may be admin oncostatin M and the like , can be used in combination with 45 istered simultaneously , or may be administered at staggered the compound of the present invention . times , to an administration subject . The dosage of the Furthermore , glycosylation inhibitors (e . g. , ALT -711 ) , concomitant drug may be determined according to the dose nerve regeneration promoting drugs ( e. g ., Y - 128, VX853, clinically used , and can be appropriately selected depending prosaptide ), antidepressants ( e . g . , desipramine , amitrip - on an administration subject, administration route , disease , tyline, imipramine ) , antiepileptics ( e . g ., lamotrigine , Trilep - 50 combination and the like. tal, Keppra , Zonegran , Pregabalin , Harkoseride , carbam As the administration mode of the compound of the azepine ), antiarrhythmic agents ( e . g . , mexiletine ) , present invention and the concomitant drug, the following acetylcholine receptor ligands ( e . g ., ABT- 594 ) , endothelin methods can be mentioned : ( 1 ) The compound of the present receptor antagonists ( e . g ., ABT- 627 ) , monoamine uptake invention and the concomitant drug are simultaneously inhibitors (e . g ., tramadol) , narcotic analgesics ( e . g . , mor - 55 formulated to give a single preparation which is adminis phine) , GABA receptor agonists ( e . g . , gabapentin , gabapen - tered . ( 2 ) The compound of the present invention and the tin MR agent) , A2 receptor agonists (e . g ., clonidine ) , local concomitant drug are separately formulated to give two analgesics ( e . g ., capsaicin ) , antianxiety drugs ( e . g . , benzo - kinds of preparations which are administered simultane thiazepines ), phosphodiesterase inhibitors ( e. g ., sildenafil ), ously by the same administration route . ( 3 ) The compound dopamine receptor agonists ( e . g . , apomorphine) , midazo - 60 of the present invention and the concomitant drug are lam , Ketoconazole and the like can also be used in combi - separately formulated to give two kinds of preparations nation with the compound of the present invention . which are administered by the same administration route at The concomitant drug is preferably an insulin preparation , staggered times. ( 4 ) The compound of the present invention am insulin sensitizer ( preferably pioglitazone or its hydro - and the concomitant drug are separately formulated to give chloride ) , an a - glucosidase inhibitor (preferably voglibose ) , 65 two kinds of preparations which are administered simulta a biguanide (preferably metformin or hydrochloride neously by the different administration routes . ( 5 ) The thereof) , a sulfonylurea (preferably glibenclamide, compound of the present invention and the concomitant drug US 9 ,776 ,962 B2 62 are separately formulated to give two kinds of preparations method , ESI ( ElectroSpray Ionization ) method , or APCI which are administered by the different administration ( Atomospheric Pressure Chemical Ionization ) method was routes at staggered times ( e . g . , the compound of the present used . As the ionization mode , both or either one of the invention and the concomitant drug are administered in this positive mode ( ESI + ) and negative mode (ESI - ) were/ was order , or in the reverse order ) , and the like . 5 used and either data are described . The data indicates those found . Generally , molecular ion peak is observed ; however, EXAMPLES a peak derived from isotope is sometimes observed (e . g ., compound having a bromine atom ). Moreover, when the The present invention is explained in detail in the follow compound has a tert- butoxycarbonyl group (- Boc ) , a peak ing by referring to Examples, Experimental Examples and 10 after elimination of a tert- butoxycarbonyl group or tert -butyl Formulation Examples. However, the examples do not limit group may be observed as a fragment ion . When the the present invention and the present invention can be compound has a hydroxyl group ( OH ), a peak after modified within the scope of the present invention . elimination of H2O may be observed as a fragment ion . In The “ room temperature " in the following Examples is the case of a salt, a molecular ion peak or fragment ion peak generally about 10° C . to about 35° C . The ratio for a mixed 15 of free form is generally observed . solvent is , unless otherwise specified , a volumemixing ratio and % means wt % unless otherwise specified . Example 1 In silica gel column chromatography, the indication of NH means use of aminopropylsilane -bonded silica gel . In HPLC 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - (methyl ( 2 (high performance liquid chromatography ), the indication of 20 methylpropyl) carbamoyl) phenyl ) piperidin -4 -yl ) C18 means use of octadecyl- bonded silica gel. The ratio of methoxy ) phenyl) propanoic acid elution solvents is , unless otherwise specified , a volume mixing ratio . In the mobile phase , the description of “ water / Step 1 ) 2 - fluoro - 4 -methoxy -N -methyl - N - (2 -methyl acetonitrile ( 0 . 1 % TFA - containing system ) ” and the like means that water and acetonitrile containing 0 . 1 % by vol- 25 propyl) benzamide ume of TFA were mixed at an appropriate ratio and used . To a solution of 2 - fluoro - 4 -methoxybenzoic acid ( 3 . 0 g ) in Description of the columns used for SFC (supercritical fluid THF ( 50 mL ) was added oxalyl chloride ( 1 . 7 mL ) at room chromatography ) is provided . The ratios of elution solvents temperature , one drop of DMF was added and the mixture are volumemixing ratios, unless otherwise specified . In the was stirred for 10 min . The reaction mixture was concen mobile phase , the description of " carbon dioxide/ methanol / 30 trated and the residue was dissolved in THF ( 5 mL ) , and diethylamine” and the like means that carbon dioxide, added to a solution of N , 2 -dimethylpropan - 1 - amine ( 1 .69 g ) methanol and diethylamine were mixed at an appropriate and triethylamine ( 4 .9 mL ) in THF (50 mL ). The mixture ratio and used . was stirred for 30 min . To the reaction mixture was added In the following Examples , the following abbreviations water , and the mixture was extracted with ethyl acetate . The are used . 35 extract was washed with water and saturated brine , and dried THF : tetrahydrofuran over anhydrous magnesium sulfate . The solvent was evapo DMF: dimethylformamide rated under reduced pressure to give a crude product ( 4 . 26 DME : 1 , 2 -dimethoxyethane g ) of the title compound as a colorless oil . This compound DMSO : dimethyl sulfoxide was used for the next step without further purification . ' H NMR proton nuclear magnetic resonance ( spectrum ) 40 MS ( ESI + ) : [ M + H1+ 240 . 3 . was measured by Fourier - transform type NMR . The chemi cal shift of ' H NMR spectrum is described in d unit (ppm ) Step 2 ) 2 - [ 4 - ( hydroxymethyl) piperidin - 1 - yl) - 4 using TMS (tetramethylsilane ) as an internal standard sub methoxy - N -methyl - N - ( 2 -methylpropyl ) benzamide stance and taking the peak of internal standard substance as O ppm , and the coupling constant is described in hertz (Hz ) . 45 A mixture of 2 - fluoro - 4 -methoxy - N -methyl - N - ( 2 -meth For the analysis , ACD /SpecManager ( trade name) and the ylpropyl) benzamide ( 4 .26 g ), piperidin - 4 -ylmethanol ( 1 . 37 like were used . Peaks with very mild protons such as g ) , cesium carbonate ( 7 . 7 g ) , tetrabutylammonium iodide carboxy group , hydroxyl group , amino group and the like (438 mg ) and DMF ( 100 mL ) was stirred at 110° C . for 3 are not described in some cases . days. To the reaction mixture was added water at room Other abbreviations used in the specification mean the 50 temperature , and the mixture was extracted with ethyl following acetate . The extract was washed with water and saturated s : singlet brine , and dried over anhydrous magnesium sulfate . The d : doublet solvent was evaporated under reduced pressure , and the t : triplet residue was purified by silica gel column chromatography q : quartet 55 ( ethyl acetate /hexane ) to give the title compound (400 mg) quin : quintet as a pale -yellow oil. m : multiplet MS (ESI + ) : [ M + H ] * 335 . 4 . br: broad J : coupling constant Step 3 ) methyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy Hz : Hertz 60 2 -( methyl ( 2 -methylpropyl ) carbamoyl ) phenyl )piperi CDC1z : deuterated chloroform din -4 - yl)methoxy )phenyl ) propanoate DMSO - do: dimethyl sulfoxide -do CD ,OD : deuterated methanol To a solution of 2 - ( 4 - (hydroxymethyl ) piperidin - 1 - yl) -4 ' H - NMR : proton nuclear magnetic resonance methoxy - N -methyl - N - ( 2 -methylpropyl ) benzamide ( 180 TFA : trifluoroacetic acid 65 mg ) and triethylamine ( 113 uL ) in THF (5 mL ) was added MS (mass spectrum ) was measured by LC /MS (liquid methanesulfonyl chloride (50 ÎL ) , and the mixture was chromatography mass spectrometer ). As the ionization stirred at room temperature for 30 min . To the reaction US 9 , 776 , 962 B2 63 64 mixture was added water at room temperature , and the piperidin - 4 - ylmethanol ( 6 . 17 g ) and benzyl 2 - fluoro - 4 mixture was extracted with ethyl acetate . The extract was methoxybenzoate ( 20 . 9 g ) . washed with water and saturated brine , and dried over anhydrous magnesium sulfate . The solvent was evaporated MS ( ESI + ): [ M + H ]* 356 . 3 . under reduced pressure to give a residue . To a solution of 5 methyl 3 - cyclopropyl- 3 - ( 3 - hydroxyphenyl) propanoate ( 119 Step 3 ) benzyl 2 -( 4 -( ( 3 -( 1- cyclopropyl- 3 -methoxy mg) in DMF ( 5 mL ) was added sodium hydride ( oily ) (22 3 -oxopropyl ) phenoxy )methyl ) piperidin -1 -yl ) - 4 mg) , and the mixture was stirred at room temperature for 10 methoxybenzoate (1 ) and benzyl 2 - (4 - (( 3 -( 1 -cyclo min . To the mixture was added the obtained residue , and the propyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) mixture was stirred at 100° C . for 1 hr . To the reaction 10 piperidin - 1 - yl) - 4 -methoxybenzoate (2 ) mixture was added water at room temperature , and the mixture was extracted with ethyl acetate . The extract was washed with water and saturated brine , and dried over By a method similar to that in Example 1 , step 3 , the title anhydrous magnesium sulfate. The solvent was evaporated compound ( 1 ) (4 .32 g ) was obtained as a colorless oil and under reduced pressure , and the residue was purifieded hyby 15is the" title compound ( 2 ) ( 0 . 75 g ) was obtained as a colorless silica gel column chromatography (ethyl acetate /hexane ) to oil from benzyl 2 - ( 4 - (hydroxymethyl )piperidin - 1- yl) - 4 give the title compound ( 158 mg) as a pale - yellow oil. methoxybenzoate ( 4 . 26 g ) and methyl 3 -cyclopropyl - 3 - ( 3 MS ( ESI + ): [ M + H ] * 537 .7 . hydroxyphenyl) propanoate (3 .14 g ) . MS ( ESI + ): [M + H ]* 572. 3 . ( 1) , 558 .3 . (2 ) Step 4 ) 3 -cyclopropyl - 3 -( 3- (( 1 -( 5 -methoxy -2 20 (methyl ( 2 -methylpropyl ) carbamoyl ) phenyl ) piperi Step 4 ) 2 - ( 4 -( ( 3 - ( 1 -cyclopropyl - 3 - ethoxy -3 -oxopro din - 4 - yl) methoxy )phenyl ) propanoic acid pyl) phenoxy )methyl ) piperidin - 1 -yl ) -4 -methoxyben zoic acid To a solution of methyl 3 -cyclopropyl - 3 -( 3 -( ( 1- ( 5 - 25 methoxy - 2 - (methyl ( 2 -methylpropyl ) carbamoyl) - phenyl) pi peridin -4 -yl ) methoxy )phenyl ) propanoate ( 150 mg) in THF Benzyl 2 -[ 4 -( ( 3 -( 1 -cyclopropyl - 3 -ethoxy - 3- oxopropyl ) ( 2 mL ) and methanol ( 2 mL ) was added 1N aqueous sodium phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoate ( 751 hydroxide solution (1 mL ) , and the mixture was stirred at mg) was dissolved in a mixed solution of ethanol (17 .5 mL ) room temperature for 15 hr. To the reaction mixture was 30 and THF ( 8 . 76 mL ) , and reaction was performed in H -Cube added IN hydrochloric acid ( 1 mL ) , and the mixture was provided with a 10 % palladium / carbon (70 mm ) cartridge at extracted with ethyl acetate . The extract was washed with a flow rate of 1 mL /min at room temperature for 2 hr. The water and saturated brine , and dried over anhydrous mag - solvent was evaporated under reduced pressure , and the nesium sulfate . The solvent was evaporated under reduced residue was purified by silica gel column chromatography pressure , and the residue was purified by silica gel column 35 (ethyl acetate /hexane ) to give the title compound (492 mg) chromatography ( ethyl acetate/ hexane ) to give the title com as a colorless oil . pound (92 mg) as a white amorphous powder. MS (ESI +) : [M + H ]* 482 .5 . MS ( ESI+ ): [M + H ] * 523. 3 . Step 5 ) ethyl 3 -cyclopropyl - 3 -( 3- ( ( 1- (2 - (( 2 ,2 -dim Example 2 40 ethylpropyl )carbamoyl ) - 5 -methoxyphenyl ) piperidin 4 -yl )methoxy ) phenyl) propanoate 3 - cyclopropyl- 3 - (3 - (( 1 -( 2 -( ( 2 ,2 -dimethylpropyl ) carbamoyl) -5 -methoxyphenyl ) piperidin - 4 -yl ) To a solution of 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxo methoxy ) phenyl) propanoic acid 45 propyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (62 . 4 mg) in DMF ( 1. 30 mL ) were added 2 , 2 -dimeth Step 1 ) benzyl 2 - fluoro -4 -methoxybenzoate ylpropanamine ( 30 . 5 ul) , 2 - ( 7 - aza -1H -benzotriazol - 1 - yl) - 1 , 1 , 3 , 3 - tetramethyluronium hexafluorophosphate (HATU ) Under a nitrogen atmosphere , to a solution of 2 - fluoro - ( 76 . 9 mg ) and N - ethyldiisopropylamine (33 . 9 ul) at room 4 -methoxybenzoic acid ( 15 . 1 g ) in DMF ( 356 mL ) were 50 temperature , and the mixture was stirred for 20 hr. Ice water adadded potassium carbonate ( 18 . 4 g ) and benzyl bromide was poured into the reaction mixture , and the mixture was ( 11 .6 mL ) at room temperature, and the mixture was stirred extracted with ethyl acetate . The extract was washed with for 8 hr. Ice water was poured into the reaction mixture , and saturated brine , and dried over anhydrous sodium sulfate . the mixture was extracted with ethyl acetate . The extractwas The solvent was evaporated under reduced pressure , and the washed with saturated brine , and dried over anhydrous 55 residue was purified by silica gel column chromatography sodium sulfate . The solvent was evaporated under reduced pressure , and the residue was purified by silica gel column (ethyl acetate /hexane ) to give the title compound (59 .4 mg) chromatography ( ethyl acetate / hexane ) to give the title com as a colorless oil. pound ( 22 . 7 g ) as a colorless oil. MS ( ESI +) : [M + H ] * 551. 7 . MS (ESI + ): [ M + H ] * 260 . 9 . 60 Step 6 ) 3 -cyclopropyl - 3 - (3 - ( 1- (2 - (( 2, 2 -dimethyl Step 2 ) benzyl 2 - ( 4 -( hydroxymethyl ) piperidin - 1 - yl ) propyl) carbamoyl ) - 5 -methoxyphenyl ) piperidin -4 -yl ) 4 -methoxybenzoate methoxy )phenyl ) propanoic acid 65 By a method similar to that in Example 1 , step 2 , the title By a method similar to that in Example 1 , step 4 , the title compound (4 . 26 g ) was obtained as a pale -yellow oil from compound ( 46 . 6 mg) was obtained as a white amorphous US 9 ,776 , 962 B2 65 66 powder from ethyl 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth Example 8 ylpropyl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy )phenyl ) propanoate (59 . 4 mg ) . 3 -cyclopropyl - 3 - (3 - (( 1 -( 2 -( (3 - fluorophenyl) ( methyl ) MS ( ESI + ) : [ M + H ] * 523 . 4 . carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) Example 3 5 methoxy )phenyl ) propanoic acid 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - (morpholin - 4 In the same manner as in Example 2 , step 5 and Example ylcarbonyl) phenyl ) piperidin -4 -yl ) methoxy )phenyl ) 1 , step 4 , the title compound ( 86 mg) was obtained as a white propanoic acid amorphous powder from 3 - fluoro -N -methylaniline (71 mg ). 10 MS ( ESI+ ) : [ M + H ] * 561. 3 . By a method similar to that in Example 2 , step 5 and Example 1 , step 4 , the title compound ( 46 . 0 mg) was Example 9 obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 cyclopropyl - 3 - ethoxy - 3 -oxopropyl )phenoxy )methyl )piperi 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 -( ( 2 - fluorophenyl) (methyl ) din - 1 - yl) - 4 -methoxybenzoic acid (62 . 4 mg) and morpholine 15 carbamoyl) - 5 -methoxyphenyl )piperidin - 4 -yl ) (22 . 5 ul) . methoxy ) phenyl) propanoic acid MS ( ESI+ ): [ M + H ] * 523 .3 . In the samemanner as in Example 2 , step 5 and Example Example 4 1 , step 4 , the title compound (44 mg ) was obtained as a white 3 -cyclopropyl - 3 -( 3 -( 1 -( 2 -( 2, 3 -dihydro -1H - indol -1 20 amorphous powder from 2 - fluoro - N -methylaniline (53 . 5 ylcarbonyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) mg ). methoxy ) phenyl) propanoic acid MS ( ESI +) : [ M + H ]* 561. 3 . By a method similar to that in Example 2 , step 5 and 25 Example 10 Example 1 , step 4 , the title compound (43 . 8 mg ) was obtained as a colorless oil from 2 - ( 4 - ( 3 - ( 1 - cyclopropyl - 3 3 - (3 -( (1 - (2 - (( 4 -chlorophenyl ) ( methyl ) carbamoyl ) - 5 ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 -yl ) -4 methoxyphenyl) piperidin - 4 - yl) methoxy ) phenyl) - 3 methoxybenzoic acid (50 . 4 mg) and indoline ( 23 . 4 ul) . cyclopropylpropanoic acid MS (ESI + ) : [ M + H ] * 555 . 3 . 30 In the samemanner as in Example 2 , step 5 and Example Example 5 1 , step 4 , the title compound ( 36 mg ) was obtained as a white amorphous powder from 4 -chloro -N -methylaniline (60 .6 3 - cyclopropyl - 3 - ( 3 - ( ( 1 -( 2 - ( ( cis - 2 ,6 - dimethylmorpho mg) . lin - 4- yl )carbonyl ) -5 -methoxyphenyl ) piperidin -4 -yl ) MS (ESI + ): [ M + H ] * 577 . 2 . methoxy ) phenyl) propanoic acid 35 Example 11 By a method similar to that in Example 2 , step 5 and Example 1 , step 4 , the title compound (43 . 4 mg) was 3 -cyclopropyl - 3 - ( 3 - (( 1 - (2 -( ethyl( pyridin - 2 - yl) car obtained as a pale -yellow amorphous powder from 2 - ( 4 - ( ( 3 bamoyl) - 5 -methoxyphenyl ) piperidin -4 -yl ) methoxy ) ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) pip - 40 phenyl) propanoic acid eridin - 1 -yl ) -4 -methoxybenzoic acid (55 .4 mg) and cis -2 , 6 dimethylmorpholine ( 28 . 5 ul) . In the same manner as in Example 2 , step 5 and Example MS ( ESI+ ): [ M + H ] * 551 .3 . 1 , step 4 , the title compound ( 10 mg) was obtained as a white amorphous powder from N - ethylpyridin - 2 - amine (52 . 3 mg) . Example 6 45 MS (ESI + ) : [ M + H ]* 558 . 3 . 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - cyanoethyl) (phenyl ) carbamoyl) - 5 Example 12 methoxyphenyl) piperidin - 4 -yl ) methoxy )phenyl ) - 3 cyclopropylpropanoic acid 3 -( 3 -( 1 - (2 - (( 2 -chlorophenyl ) ( methyl ) carbamoyl ) - 5 50 methoxyphenyl) piperidin -4 - yl)methoxy )phenyl ) - 3 By a method similar to that in Example 2 , step 5 and cyclopropylpropanoic acid Example 1 , step 4 , the title compound (38 mg) was obtained as a white amorphous powder from 3 - anilinopropanenitrile In the same manner as in Example 1 , step 1 and Example ( 34 . 4 mg) . 1, step 4 , the title compound ( 13. 6 mg) was obtained as a MS (ESI + ): [ M + H ] * 582. 3 . 55 pale -yellow oil from 2 -( 4 - (( 3 - (1 -cyclopropyl - 3 -methoxy - 3 oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxyben Example 7 zoic acid (100 mg) and 2 - chloro - N -methylaniline (53 UL ) . 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( 4 - fluorophenyl )( methyl ) MS ( ESI + ) : [ M + H ] * 577 . 2 . carbamoyl) -5 -methoxyphenyl ) piperidin -4 - yl) 60 Example 13 methoxy ) phenyl) propanoic acid 3 - cyclopropyl- 3 - (3 - (( 1 -( 5 -methoxy - 2 -( methyl ( pyri In the same manner as in Example 2 , step 5 and Example din - 4 -yl ) carbamoyl )phenyl )piperidin - 4 - yl) methoxy ) 1 , step 4 , the title compound (68 mg ) was obtained as a white phenyl) propanoic acid amorphous powder from 4 - fluoro - N -methylaniline ( 29. 4 65 mg ) . In the samemanner as in Example 2 , step 5 and Example WWWWWMS (ESI + ) : [ M + H ] * 561 . 3 . 1 , step 4 , the title compound (72 .9 mg) was obtained as a US 9 ,776 ,962 B2 67 68 pale - yellow amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 - cyclopro phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid pyl- 3 -methoxy - 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 ( 100 mg) . yl) - 4 -methoxybenzoic acid ( 100 mg) and N -methylpyridin MS (ESI + ): [M + H ]* 578. 3 . 4 -amine (46 . 3 mg) . MS ( ESI + ) : [ M + H ] * 544 . 2 . Example 16 Example 14 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 4 -methylpip erazin - 1 - yl) carbonyl) phenyl) piperidin - 4 -yl ) methoxy ) 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( [ 4 - ( 2 , 2 , 3 , 3 , 3 phenyl) propanoic acid pentafluoropropyl) piperazin - 1 - yl) carbonyl) phenyl ) 10 piperidin -4 -yl ) methoxy ) phenyl) propanoic acid In the samemanner as in Example 2 , step 5 and Example 1 , step 4 , the title compound (42 mg) was obtained as a colorless amorphous powder from 1 -methylpiperazine ( 43 Step 1 ) tert -butyl 4 - ( 2 , 2 , 3 , 3 , 3 - pentafluoropropyl ) mg) and 2 - ( 4 - ( 3 - ( 1 -cyclopropyl - 3 -methoxy - 3 -oxopropyl ) piperazine - 1- carboxylate 15 phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid A mixture of tert -butyl piperazine -1 - carboxylate ( 1. 48 g ), ( 100 mg) . 2 , 2 , 3 , 3 , 3 - pentafluoropropyl trifluoromethanesulfonate ( 3 . 36 MS (ESI + ): [M + H ]* 536 .3 . g ) , triethylamine ( 2 . 22 mL ) and acetonitrile ( 5 mL ) was Example 17 stirred at 70° C . for 18 hr. The solvent was evaporated under 20 reduced pressure , and the residue was purified by silica gel 3 -cyclopropyl - 3 - (3 - (( 1 -( 5 -methoxy -2 -( methyl ( pyri column chromatography (ethyl acetate /hexane ) to give the din - 3 - yl) carbamoyl ) phenyl ) piperidin - 4 - yl )methoxy ) title compound ( 2 . 45 g ) as a colorless oil. phenyl) propanoic acid IH NMR (300 MHz, CDC13 ) d 1 .46 (9H , s ), 2 .55 -2 .64 (4H , m ) , 2 . 92 - 3 . 06 ( 2H , m ) , 3 .40 - 3 .47 (4H , m ) . 25 In the samemanner as in Example 2 , step 5 and Example 1, step 4 , the title compound ( 12 .3 mg) was obtained as a Step 2 ) 1 - ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl ) piperazine pale - yellow oil from 2 - ( 4 - ( 3 - ( 1 - cyclopropyl- 3 -methoxy - 3 di- hydrochloride oxopropyl ) phenoxy )methyl ) piperidin - 1 - yl ) - 4 -methoxyben zoic acid ( 100 mg) and N -methylpyridin - 3 - amine ( 44 uL ) . To a solution of tert - butyl 4 - ( 2 , 2 , 3 , 3 , 3 - pentafluoropropyl ) 30 MS (ESI + ): [ M + H ] * 544. 2 . piperazine - 1 -carboxylate ( 2 .45 g ) in ethyl acetate ( 15 mL ) and methanol (15 mL ) was added 4N hydrogen chloride Example 18 ethyl acetate solution ( 20 mL ) , and the mixture was stirred at room temperature for 18 hr . The reaction mixture was os 3 - ( 3 - ( ( 1 -( 2 - (( 3 - chlorophenyl) (methyl ) carbamoyl ) - 5 diluted with hexane , and the resultant precipitate was col 35 methoxyphenyl) piperidin -4 - yl)methoxy ) phenyl) - 3 lected by filtration , washed with ethyl acetate , and dried cyclopropylpropanoic acid under reduced pressure to give the title compound ( 2 .00 g ) In the samemanner as in Example 2 , step 5 and Example as a colorless solid . 1 , step 4 , the title compound ( 27 .6 mg) was obtained as a ' H NMR (300 MHz, DMSO -do ) 8 2 .77 - 2. 91 (4H , m 340) , 40 colorless oil from 2 - ( 4 - ( 3 - ( 1 -cyclopropyl - 3 -methoxy - 3 2 .97 - 3 . 11 ( 4H , m ), 3 . 34 ( 2H , td , J = 16 . 3 , 1 . 1 Hz ), 7 . 21 - 9 .58 oxopropyl) phenoxy )methyl ) piperidin - 1 -yl ) - 4 -methoxyben ( 3H , m ). zoic acid ( 100 mg) and 3 - chloro - N -methylaniline ( 52 uL ). Step 3 ) 3- cyclopropyl- 3 - (3 - (( 1 -( 5 -methoxy - 2- ( 4 -( 2 , MS ( ESI +) : [M + H ] * 577 .2 . 2 ,3 ,3 , 3 -pentafluoropropyl ) piperazine -1 -carbonyl ) 4545 Example 19 phenyl) piperidin - 4 - yl) methoxy )phenyl ) propanoic acid 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - fluorobenzyl) (methyl ) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl ) In the same manner as in Example 2 , step 5 and Example methoxy ) phenyl) propanoic acid 1 , step 4 , the title compound (74 mg) was obtained as a 50 colorless amorphous powder from 1 - ( 2 , 2 , 3 , 3 , 3 -pentafluoro By a method similar to that in Example 2 , step 5 and propyl) piperazine di- hydrochloride ( 125 mg) and 2 - ( 4 - ( ( 3 - Example 1 , step 4 , the title compound ( 112 mg) was ( 1 -cyclopropyl - 3 -methoxy - 3 -oxopropyl ) phenoxy )methyl ) obtained as a red amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 mg) . cyclopropyl - 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperi 55 din - 1 - yl) - 4 -methoxybenzoic acid ( 109 .3 mg) and 2 - fluoro MS (ESI + ): [M + H ]* 654. 3 . N -methylbenzylamine (60 . 3 ul) . Example 15 MS (ESI + ) : [ M + H ]* 575 . 3 . Example 20 3 - ( 3 - ( ( 1 - ( 2 - ( ( 4 - tert - butylpiperazin - 1 -yl )carbonyl ) - 5 - 60 methoxyphenyl) piperidin - 4 - yl) methoxy ) phenyl) - 3 3 -cyclopropyl - 3 - (3 - (( 1- ( 2 -( (3 - fluorobenzyl) ( methyl ) cyclopropylpropanoic acid carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) phenyl) propanoic acid In the same manner as in Example 2 , step 5 and Example 1 , step 4 , the title compound ( 55 mg) was obtained as a 65 By a method similar to that in Example 2 , step 5 and colorless amorphous powder from 1 - tert- butylpiperazine (61 Example 1 , step 4 , the title compound (92 mg) was obtained mg) and 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 -methoxy - 3 - oxopropyl) as a red amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl US 9 ,776 , 962 B2 69 70 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 obtained as a white amorphous powder from 2 - [ 4 - ( ( 3 -( 1 methoxybenzoic acid (109 . 3 mg) and 3 - fluoro - N -methyl cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi benzylamine (61 . 5 ul) . din - 1 - yl) -4 -methoxybenzoic acid ( 116 . 3 mg) and 3 -chloro MS ( ESI + ) : [ M + H ] * 575 . 3 . N -methyl - benzenemethanamine (70 .1 ul) . Example 21 5 MS ( ESI+ ) : [ M + H ] * 591. 2 . 3 -cyclopropyl - 3 - (3 - (( 1- ( 2 -( (4 - fluorobenzyl )( methyl ) Example 25 carbamoyl) -5 -methoxyphenyl ) piperidin -4 -yl ) methoxy ) phenyl) propanoic acid 3 - cyclopropyl- 3 - (3 -( ( 1 - (5 -methoxy - 2 - (methyl ( 6 10 methylpyridin - 2 -yl ) carbamoyl )phenyl ) piperidin - 4 Step 1 ) 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl - 3 -methoxy - 3 - oxo yl) methoxy )phenyl ) propanoic acid propyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxy benzoic acid Step 1 ) ethyl 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 ( 6 -methylpyridin - 2 -yl ) carbamoyl ) phenyl ) piperidin By a method similar to that in Example 2 , step 4 , the title 15 compound ( 3 .74 g ) was obtained as a colorless oil from 4 - yl) methoxy )phenyl ) propanoate benzyl 2 - [ 4 - ( ( 3 - ( 1 - cyclopropyl - 3 -methoxy - 3 - oxopropyl ) phenoxy )methyl ) piperidin - 1 - yl) - 4 - methoxybenzoate ( 5 . 29 In the same manner as in Example 2 , step 5 , the title g ) . compound (82 .5 mg) was obtained as a white solid from 202- ( 4 - ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl ) phenoxy ) MS ( ESI + ): [ M + H ]* 468 .4 . methyl ) piperidin - 1 - yl ) - 4 -methoxybenzoic acid ( 100 mg) Step 2 ) 3 -cyclopropyl - 3 - (3 - (( 1 -( 2 -( ( 4 - fluorobenzyl) and 6 -methylpyridin - 2 -amine ( 112 mg ). (methyl ) carbamoyl) -5 -methoxyphenyl ) piperidin - 4 ' H NMR ( 400 MHz, DMSO - d . ) 8 0 . 07 - 0 . 17 ( 1H , m ) , yl) methoxy )phenyl )propanoic acid 0 . 18 - 0 .27 ( 1H , m ), 0 .28 - 0 . 38 ( 1H , m ), 0 .44 - 0 .57 ( 1H , m ) , By a method similar to that in Example 2 , step 5 and 25 0 . 97 - 1 .05 ( 1H , m ) , 1. 07 (3H , t , J = 7 . 1 Hz ) , 1 .79 - 2 .04 ( 4H , Example 1 , step 4 , the title compound (94 mg ) was obtained m ) , 2 . 19 - 2 . 29 ( 1H , m ) , 2 . 39 (3H , s ), 2 .64 - 2 .80 (4H , m ) , as a white amorphous powder from 2 -( 4 -( (3 - ( 1 -cyclopropyl 2 .87 - 2 . 99 ( 2H , m ), 3 . 16 (2H , d , J = 11 . 8 Hz ), 3 .85 ( 3H , s ) , 3 -methoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 3 . 90 -4 .01 ( 3H , m ), 6 .79 (1H , d , J = 8 .4 Hz ), 6 .81 -6 .88 (2H , methoxybenzoic acid ( 102 . 1 mg) and 4 - fluoro - N -methyl - m ) , 6 . 92 ( 1H , dd , J = 8 . 9 , 2 . 4 Hz ) , 6 . 94 - 7 .00 (2H , m ) , 7 . 20 benzylamine (57 . 9 ul) . 30 (1H , t , J = 7 . 7 Hz) , 7 .69 ( 1H , t, J = 7 . 8 Hz) , 8 .07 (2H , t , J = 7 . 9 MS (ESI + ) : [ M + H ] * 575 . 3 . Hz ), 13. 14 ( 1H , s ) . Example 22 Step 2 ) ethyl 3 -cyclopropyl - 3 -( 3 -( 1 -( 5 -methoxy - 2 (methyl ( 6 -methylpyridin - 2 - yl) carbamoyl) phenyl) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - (methyl ( pyri - 35 piperidin - 4 - yl )methoxy )phenyl ) propanoate din -2 - ylmethyl) carbamoyl ) phenyl) piperidin -4 -yl ) methoxy )phenyl ) propanoic acid Under a nitrogen atmosphere , to a solution of ethyl 3 - cyclopropyl- 3 -( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( 6 -methylpyridin - 2 By a method similar to thatlat in Example 2 ,: step 5 and yl) carbamoyl) phenyl) piperidin - 4 - yl) methoxy ) phenyl) pro Example 1 , step 4 , the title compound (45 . 3 mg) was 40 panoate (82 . 5 mg ) and iodomethane (45 . 0 uL ) in DMF ( 1 . 5 obtained as a pale - yellow amorphous powder from 2 - ( 4 - ( ( 3 mL ) was added 60 % sodium hydride ( oily ) ( 17 .3 mg) at 0° ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) pip C ., and the mixture was stirred at room temperature for 3 hr. eridin - 1 -yl ) - 4 -methoxybenzoic acid ( 105. 3 mg) and methyl The reaction mixture was added to water at 0° C . , and the ( pyridin - 2 - ylmethyl) amine (53 . 7 ul) . mixture was extracted with ethyl acetate. The extract was MS ( ESI + ) : [ M + H ] + 558 . 3 . 45 washed with water, saturated aqueous sodium hydrogen Example 23 carbonate solution and saturated brine , and dried over anhy drous magnesium sulfate . The solvent was evaporated under 3 - cyclopropyl -3 - (3 - (( 1 -( 5 -methoxy - 2- ( methyl ( pyri reduced pressure , and the residue was purified by silica gel din - 3 - ylmethyl) carbamoyl) phenyl ) piperidin - 4 - yl) column chromatography (ethyl acetate/ hexane ) to give the methoxy )phenyl ) propanoic acid 50 title compound ( 77 . 5 mg) as a colorless oil . ' H NMR (400 MHz, DMSO -do ) 8 0 . 06 - 0. 17 (1H , m ), By a method similar to that in Example 2 , step 5 and 0 .18 - 0 . 26 ( 1H , m ), 0 .27 - 0 .37 ( 1H , m ) , 0 .43 -0 . 56 (1H , m ), Example 1 , step 4, the title compound (74 . 2 mg) was 0 .98 - 1. 08 ( 1H , m ), 1 .08 (3H , t , J= 7. 0 Hz ), 1 .70 (3H , d , J= 9. 7 obtained as a white powder from 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- Hz ), 2 . 24 (1H , q , J = 8 . 0 Hz) , 2 . 38 ( 3H , s ) , 2 . 46 - 2 .62 ( 5H , m ) , 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 - 55 2 .62 - 2 . 80 ( 3H , m ) , 3 .41 ( 3H , s ) , 3 . 74 (3H , s ) , 3 .81 ( 2H , d , methoxybenzoic acid ( 112 . 0 mg) and N -methyl ( pyridin - 3 J = 5 . 8 Hz) , 3 . 90 - 4 . 00 (2H , m ) , 6 . 28 ( 1H , brs ), 6 .60 ( 2H , dd , yl) methanamine ( 56 . 8 ul) . J = 8 . 4 , 2 . 0 Hz) , 6 .76 ( 1H , d , J = 7 . 5 Hz) , 6 . 80 -6 . 86 ( 2H , m ) , MS ( ESI + ) : [ M + H ] * 558 . 3 . 6 . 90 ( 1H , d , J = 7 . 5 Hz ), 7 . 18 ( 1H , t , J = 8 . 0 Hz ), 7 .28 ( 1H , d , J = 8 . 4 Hz) , 7 .37 ( 1H , t, J = 7 . 4 Hz ) . Example 24 60 Step 3 ) 3 -cyclopropyl - 3 -( 3 -( ( 1 -( 5 -methoxy - 2 3 - ( 3 - ( ( 1 - ( 2 - ( ( 3 -chlorobenzyl ) (methyl ) carbamoyl) - 5 (methyl (6 -methylpyridin - 2 - yl) carbamoyl) phenyl) methoxyphenyl) piperidin - 4 -yl ) methoxy )phenyl ) - 3 piperidin - 4 - yl) methoxy ) phenyl) propanoic acid cyclopropylpropanoic acid 65 In the same manner as in Example 1 , step 4 , the title By a method similar to that in Example 2 , step 5 and compound (70 . 0 mg) was obtained as a white amorphous Example 1 , step 4 , the title compound (109 mg) was powder from ethyl 3 - cyclopropyl- 3 -( 3 - (( 1 -( 5 -methoxy -2 US 9 ,776 ,962 B2 71 72 (methyl ( 6 -methylpyridin - 2 - yl) carbamoyl) phenyl ) piperidin powder from 2 - ( 4 - ( ( 3 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopro 4 - yl) methoxy ) phenyl) propanoate ( 77 . 5 mg) . pyl ) phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic MS ( ESI + ) : [ M + H ] * 558 . 3 acid ( 100 mg) and 3 -aminobenzonitrile (123 mg) . Example 26 'H NMR (400 MHz , DMSO -d .) 8 0 .12 ( 1H , dt, J = 9. 2 , 4 .7 5 Hz ) , 0 . 17 - 0 . 26 ( 1H , m ) , 0 .27 - 0 .38 (1H , m ), 0 .45 - 0 .56 ( 1H , 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - (methyl ( 4 m ) , 0 . 96 - 1 . 06 ( 1H , m ) , 1 . 07 (3H , t , J = 7 . 1 Hz ) , 1 . 47 - 1 . 62 methylpyridin - 2 - yl) carbamoyl) phenyl) piperidin - 4 ( 2H , m ) , 1 . 83 - 1 . 97 (3H , m ), 2 . 18 - 2 .29 ( 1H , m ) , 2 .63 - 2 . 78 yl )methoxy ) phenyl ) propanoic acid (2H , m ), 2 . 85 (2H , t , J = 10 . 9 Hz ), 3 .21 ( 2H , d , J = 11. 3 Hz) , 3 .84 ( 3H , s ) , 3 . 88 (2H , d , J = 5 . 3 Hz ) , 3 . 92 - 3 . 99 ( 2H , m ) , 6 .76 Step 1 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - 10 ( 1H , d , J = 9 . 3 Hz) , 6 . 80 - 6 . 90 (4H , m ) , 7 . 18 ( 1H , t, J = 7 . 8 Hz) , ( (4 -methylpyridin - 2 -yl ) carbamoyl ) phenyl ) piperidin 7 .50 - 7 .62 (2H , m ) , 7 . 86 (1H , d , J = 8 . 5 Hz) , 7 . 91 (1H , d , J = 8 . 0 4 -yl ) methoxy )phenyl ) propanoate Hz) , 8 . 37 ( 1H , s ) , 11. 91 (1H , s ) . In the same manner as in Example 2 , step 5 , the title compound ( 74 . 5 mg) was obtained as a white solid from 15 Step 2) ethyl 3 -( 3 -( ( 1 - (2 -( ( 3 -cyanophenyl ) ( methyl ) 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy ) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 mg) methoxy ) phenyl) -3 -cyclopropylpropanoate and 4 -methylpyridin - 2 -amine ( 112 mg) . H NMR (400 MHz, DMSO - d . ) 8 0 .08 - 0 . 17 ( 1H , m ) , In the same manner as in Example 25 , step 2 , a crude 0 . 18 - 0 . 27 ( 1H , m ) , 0 . 28 - 0 .40 ( 1H , m ) , 0 .45 - 0 . 58 ( 1H , m ) , m product of the title compound was obtained as a colorless oil 1 . 00 - 1 . 06 ( 1H , m ), 1 .08 ( 3H , t , J = 7 . 1 Hz ) , 1 . 73 - 1 . 98 (5H , - from ethyl 3 - ( 3 - ( ( 1 - ( 2 - ( ( 3 -cyanophenyl ) carbamoyl ) - 5 m ) , 2 . 19 - 2 . 29 ( 1H , m ), 2 .34 (3H , s ) , 2 .72 ( 2H , t , J = 8 . 0 Hz ) , methoxyphenyl) piperidin - 4 - yl) methoxy )phenyl ) - 3 - cyclo 2 . 86 - 2 . 98 (2H , m ) , 3 . 16 ( 2H , d , J = 11 . 8 Hz ) , 3 . 85 ( 3H , s ) , 3 . 91 ( 2H , d , J = 5 . 8 Hz ) , 3 . 94 - 4 . 01 (2H , m ) , 6 . 73 - 6 . 87 (3H , propylpropanoate (102 mg) . This compound was used for m ) , 6 .89 - 7 .00 ( 3H , m ), 7 . 20 ( 1H , t , J = 7 . 8 Hz) , 8 .06 ( 1H , d , the next step without further purification . J = 8 .8 Hz ), 8 .15 ( 1H , s ), 8 .20 (1H , d , J = 5 . 0 Hz ), 12 .86 ( 1H , 25 s ). Step 3 ) 3 - ( 3 - ( ( 1 - ( 2 - ( ( 3 -cyanophenyl ) (methyl ) car Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 bamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) (methyl ( 4 -methylpyridin - 2 - yl) carbamoyl) phenyl) phenyl) - 3 - cyclopropylpropanoic acid piperidin - 4 -yl ) methoxy )phenyl ) propanoate 30 In the same manner as in Example 1 , step 4 , the title In the same manner as in Example 25 , step 2 , the title compound (85 . 5 mg) was obtained as a white amorphous compound (69 . 7 mg) was obtained as a colorless oil from powder from a crude product of ethyl 3 - ( 3 - ( ( 1 - ( 2 - ( 3 -cya ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 4 -methylpyri - nophenyl) (methyl ) carbamoyl) - 5 -methoxyphenyl ) piperidin din - 2 - yl ) carbamoyl) phenyl) piperidin - 4 - yl )methoxy )phenyl ) 4 -yl )methoxy )phenyl ) - 3 -cyclopropylpropanoate (entire propanoate (74 . 5 mg ) . 35 amount) . 'H NMR (400 MHz , DMSO - do ) 8 0 .04 -0 . 17 (1H , m ), 0 . 17 - 0 . 26 ( 1H , m ), 0 . 27 - 0 .38 (1H , m ) , 0 .43 - 0 .56 ( 1H , m ) , MS (ESI + ): [M + H ] * 568. 3 . 0 .97 - 1 . 06 (1H , m ) , 1 .08 ( 3H , t , J = 7 . 1 Hz) , 1 . 72 (3H , brs ) , 2 . 08 ( 3H , s ) , 2 . 20 - 2 . 30 ( 1H , m ), 2 . 45 - 2 .63 ( 5H , m ), 2 .64 Example 28 2 .80 ( 3H , m ) , 3 .39 ( 3H , s ) , 3 .74 (3H , s ), 3 . 80 ( 2H , d , J = 6 . 0 40 Hz ), 3 . 90 - 4 .02 (2H , m ) , 6 .30 ( 1H , brs ) , 6 .60 ( 1H , dd , J = 8 . 5 , 3 -cyclopropyl - 3 - (3 - (( 1 -( 2 -( ( 2 ,2 -dimethylpropyl ) ( 2 2 . 1 Hz ) , 6 .66 - 6 .79 ( 2H , m ) , 6 . 79 - 6 . 86 ( 2H , m ) , 6 . 90 ( 1H , d , methylpropyl) carbamoyl) - 5 -methoxyphenyl ) piperi J = 4 . 6 Hz ), 7 . 18 ( 1H , t , J = 8 . 0 Hz ) , 7 . 26 ( 1H , d , J = 8 . 4 Hz) , din -4 - yl)methoxy )phenyl ) propanoic acid 8 . 19 (1H , d , J = 5 .1 Hz ). Step 3 ) 3 - cyclopropyl- 3 -( 3 - ( ( 1 - ( 5 -methoxy - 2 45 By a method similar to that in Example 2 , step 5 and (methyl ( 4 -methylpyridin - 2 -yl ) carbamoyl )phenyl ) Example 1 , step 4 , the title compound ( 77. 0 mg) was piperidin -4 -yl ) methoxy )phenyl ) propanoic acid obtained as a white amorphous powder from 2- (4 -( ( 3 -( 1 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi In the same manner as in Example 1 , step 4 , the title - din - 1 -yl ) - 4 -methoxybenzoic acid ( 104 . 2 mg ) and 2 , 2 - dim compound (61 . 9 mg) was obtained as a white amorphous - ethyl- N -( 2 -methylpropyl ) propan - 1 -amine (62 .0 mg ). powder from ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 MS (ESI + ) : [ M + H ] * 579 . 3 . (methyl ( 4 -methylpyridin - 2 - yl) carbamoyl) phenyl) piperidin 4 - yl) methoxy ) phenyl) propanoate (69 . 7 mg) . Example 29 MS ( ESI + ) : [ M + H ] * 558 . 3 . 55 Example 27 3 - cyclopropyl- 3 -( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylmorpholin 3 - ( 3 - ( ( 1 - ( 2 -( ( 3 - cyanophenyl) (methyl ) carbamoyl) - 5 4 - yl) carbonyl) -5 -methoxyphenyl ) piperidin -4 -yl ) methoxyphenyl) piperidin -4 - yl)methoxy ) phenyl) - 3 methoxy )phenyl ) propanoic acid cyclopropylpropanoic acid By a method similar to that in Example 2 , step 5 and Step 1 ) ethyl 3 - ( 3 - ( ( 1 - ( 2 - ( ( 3 - cyanophenyl) carbam Example 1 , step 4 , the title compound (71 . 0 mg) was oyl) - 5 -methoxyphenyl ) piperidin - 4 -yl )methoxy )phe obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 nyl) - 3 - cyclopropylpropanoate cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi 65 din - 1 - yl) - 4 -methoxybenzoic acid ( 104 . 2 mg) and 2 , 2 - dim In the same manner as in Example 2 , step 5 , the title ethylmorpholine (49 . 8 mg ). compound (102 mg) was obtained as a white amorphous MS (ESI + ): [M + H ]+ 551 . 3 . US 9 ,776 , 962 B2 73 74 Example 30 eridin - 1 -yl ) -4 -methoxybenzoic acid (112 . 7 mg) in THF ( 2 .34 mL ) was added 1 -chloro - N , N - 2 - trimethylpropylamine 3 - ( 3 -( ( 1 - ( 2 - ( (2 -tert -butylpyrrolidin - 1 - yl) carbonyl) -5 ( 37 . 2 ul) at 0° C . After stirring at room temperature for 30 methoxyphenyl) piperidin - 4 - yl) methoxy ) phenyl) - 3 min , N -( 2 ,2 - dimethylpropyl) - 6 -methylpyridin - 2 -amine (83 cyclopropylpropanoic acid 5 mg) and triethylamine ( 42 . 4 qul ) were added at 0° C ., and the mixture was stirred at room temperature for 20 hr. The By a method similar to that in Example 2 , step 5 and reaction mixture was poured into water at room temperature , Example 1 , step 4 , the title compound ( 108 mg) was and the mixture was extracted with ethyl acetate . The extract obtained as a white amorphous powder from 2 - ( 4 - ( 3 - ( 1 was washed with saturated brine , and dried over anhydrous cyclopropyl -3 - ethoxy -3 -oxopropyl )phenoxy )methyl ) piperi - " sodium sulfate . The solvent was evaporated under reduced din - 1- yl) -4 -methoxybenzoic acid ( 104 .2 mg) and 2 -( tert pressure , and the residue was purified by silica gel column butyl) pyrrolidine ( 55 . 1 mg) . chromatography (NH , ethyl acetate /hexane ) to give the title MS (ESI + ): [ M + H ] * 563 . 3 . compound (54 . 3 mg) as a colorless oil . MS (ESI + ) : [ M + H ] * 642. 6 . Example 31 15 Step 3 ) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl propyl) ( 6 -methylpyridin - 2 - yl) carbamoyl) - 5 3 - cyclopropyl - 3 - ( 3 -( ( 1 -( 5 -methoxy - 2 - (( (3R ) - 3 - ( 2 methoxyphenyl) piperidin - 4 - yl) methoxy ) phenyl) pro methylpropyl) morpholin - 4 - yl) carbonyl) phenyl) pip panoic acid eridin - 4 -yl ) methoxy ) phenyl) propanoic acid 20 By a method similar to that in Example 1 , step 4 , the title By a method similar to that in Example 2 , step 5 and compound (27 .5 mg) was obtained as a white solid from Example 1 , step 4 , the title compound ( 103 mg) was ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 -dimethylpropyl ) (6 obtained as a white amorphous powder from 2 - (4 -( ( 3 - ( !1 - methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi- 25 din - 4 - yl) methoxyphenyl ) propanoate (54 . 3 mg ) . din - 1 - yl) - 4 -methoxybenzoic acid ( 106 . 1 mg) and ( R )- 3 - ( 2 methylpropyl )morpholine hydrochloride ( 79 mg) . MS (ESI + ): [ M + H ] * 614 .4 . MS ( ESI + ): [M + H ] * 579 .3 . Example 33 Example 32 30 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) ( 4 methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) 3 - cyclopropyl- 3 -( 3 -( ( 1 -( 2 -( (2 , 2 -dimethylpropyl ) ( 6 piperidin -4 -yl ) methoxy )phenyl ) propanoic acid methylpyridin -2 - yl) carbamoyl ) -5 -methoxyphenyl ) piperidin -4 - yl)methoxy ) phenyl) propanoic acid By a method similar to that in Example 32, step 2 and 35 Example 1 , step 4 , the title compound ( 118 mg) was Step 1 ) obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 N -( 2 , 2 -dimethylpropyl )- 6 -methylpyridin - 2 -amine cyclopropyl- 3 -ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi din - 1 -yl ) -4 -methoxybenzoic acid (110 .0 mg) and N -( 2, 2 Under a nitrogen atmosphere , 2 , 2 -dimethylpropanoylu dimethylpropyl ) - 4 -methylpyridin - 2 - amine (81 mg) . chloride (8 . 53 mL ) was added to a solution of 6 -methyl 40 MS ( ESI + ) : [ M + H ] * 614 . 4 . pyridin - 2 - amine ( 5 . 00 g ) in DMA ( 25 mL ) at room tem Example 34 perature , and the mixture was stirred at room temperature for 48 hr. Saturated aqueous sodium hydrogen carbonate solu 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) tion was added to the reaction mixture , and the mixture was 45 (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperi extracted with ethyl acetate . The extract was washed with din - 4 - yl)methoxy ) phenyl) propanoic acid water and saturated brine, dried over anhydrous magnesium sulfate , and the solvent was evaporated under reduced By a method similar to that in Example 32 , step 2 and pressure . Under a nitrogen atmosphere , the obtained residue Example 1 , step 4 , the title compound ( 129 mg) was was added to a suspension of lithium aluminum hydride 50 obtained as a white amorphous powder from 2 - (4 -( (3 - (1 ( 8 . 78 g ) in THF ( 100 mL ) at 0° C ., and the mixture was cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperi heated under reflux for 1 hr. Water and aqueous sodium d in - 1 - yl) - 4 -methoxybenzoic acid ( 114 . 4 mg) and N - ( 2 , 2 hydroxide solution were added to the reaction mixture , and dimethylpropyl) pyridin - 2 -amine (78 mg ) . the resultant white precipitate was filtered off . The solvent in MS ( ESI + ) : [ M + H ] * 600 .3 . the filtrate was evaporated under reduced pressure to give 55 the title compound (7 .24 g ) as a colorless oil . Example 35 1H NMR ( 400 MHz, DMSO -d6 ) 8 0 . 90 ( 9H , s ), 2 . 22 ( 3H , s ), 3 .07 ( 2H , d , J = 6 . 1 Hz ) , 6 .15 ( 1H , t, J = 5 . 7 Hz) , 6 .27 (1H , 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methoxy d , J = 7 . 2 Hz ), 6 .32 ( 1H , d , J = 8 . 4 Hz) , 7 . 20 ( 1H , t, J = 7 . 7 Hz) . 2 -methylpropyl ) (pyridin - 2 -yl ) carbamoyl ) phenyl) 60 piperidin - 4 - yl) methoxy ) phenyl) propanoic acid Step 2) ethyl 3 -cyclopropyl - 3 -( 3 -( ( 1 -( 2 -( ( 2 ,2 -dim ethylpropyl ) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 Step 1) ethyl 2 -( pyridin -2 -ylamino hacetate methoxyphenyl) piperidin - 4 - yl) methoxy )phenyl ) pro panoate Under a nitrogen atmosphere , 40 % glyoxal aqueous solu 65 tion ( 10 . 7 mL ) and ethanol ( 80 mL ) were added to a mixture Under a nitrogen atmosphere , to a solution of 2 - ( 4 - ( ( 3 - of 2 - aminopyridine ( 8 . 00 g ) and 70 % aqueous perchloric ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) pip acid solution ( 19 . 0 mL ) at room temperature , and the US 9 ,776 , 962 B2 75 76 mixture was heated under reflux for 16 hr. The reaction H NMR (400 MHz, CDC1Z) 8 0 . 11 - 0 .21 ( 1H , m ) , 0 . 24 mixture was neutralized with saturated aqueous sodium 0 . 35 ( 1H , m ), 0 . 38 -0 .49 ( 1H , m ) , 0 .52 - 0 .64 ( 1H , m ) , 0 . 97 hydrogen carbonate solution , and extracted with ethyl 1 . 08 ( 1H , m ) , 1 . 12 - 1 . 23 (9H , m ) , 1 . 71 - 1 . 91 ( 3H , m ) , 2 .27 acetate . The extract was washed with water and saturated 2 . 79 (4H , m ) , 2 .29 - 2 . 39 ( 1H , m ), 2 .73 ( 3H , tt , J = 14 . 6 , 7 . 4 he 5 Hz) , 2 .83 (3H , s ), 3. 40 ( 1H , brs ), 3 .75 (3H , s) , 3 . 83 (2H , d , brine , and dried over anhydrous magnesium sulfate . The 5 J = 6 . 0 Hz) , 3 . 98 - 4 . 12 ( 2H , m ) , 4 . 22 -4 .63 (2H , m ), 6 .20 ( 1H , solvent was evaporated under reduced pressure, and the s ) , 6 . 47 ( 1H , dd , J = 8 . 4 , 2 . 3 Hz ), 6 . 57 ( 1H , brs ) , 6 .73 -6 . 92 residue was purified by silica gel column chromatography (AH4H , m ), 7 . 21 (2H , t, J= 7 .8 Hz) , 7 .24 - 7 .32 ( 1H , m ), 8. 35 ( 1H , (ethyl acetate / hexane ) to give the title compound ( 9 .01 g ) as dd. J = 4 . 8 . 1 . 2 Hz) . a colorless oil. ' H NMR ( 400 MHz , CDC13 ) d 1 .29 ( 3H , t, J = 7 . 1 Hz ), Step 5 ) 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 4 .14 (2H , d , J = 5 . 5 Hz ), 4 .24 (2H , 4 , J = 7 . 1 Hz) , 4 . 89 (1H , methoxy -2 -methylpropyl ) (pyridin -2 -yl ) carbamoyl ) brs ), 6 . 46 ( 1H , d , J = 8 . 3 Hz) , 6 .61 ( 1H , dd , J = 6 . 8 , 5 . 4 Hz) , phenyl) piperidin -4 -yl ) methoxy ) phenyl) propanoic 7 .36 - 7 . 49 ( 1H , m ) , 8 . 10 ( 1H , d , J = 4 . 9 Hz ) . acid Sten 22- methyl 1 - pyridin 2 - ylaminopropan - 2 -01 15 In the same manner as in Example 1 , step 4 , the title Step 2 ) 2 -methyl - 1 - (pyridin - 2 -ylamino ) propan - 2 - 01 compound (77 . 9 mg) was obtained as a white amorphous Under a nitrogen atmosphere. 10 M methylmagnesium powder from ethyl 3 -cyclopropyl - 3 -( 3 - (( 1 -( 5 -methoxy - 2 bromide ( 44 . 4 mL ) was added to a solution of ethyl 2 - (pyri nuri - 14(( 2 - methoxy - 2 -methylpropyl ) (pyridin - 2 - yl) carbamoyl) phe din -2 - ylamino ) acetate (2 . 0 g ) in THF (30 mL ) at 0° C ., and 20 nyl) piperidin - 4 - yl) methoxy ) phenyl) propanoate ( 85 . 0 mg) . the mixture was stirred at 0° C . for 20 min . Saturated 20 MS (ESI + ): [M + H ]* 616 .3 . aqueous ammonium chloride solution was added to the Example 36 reaction mixture , and the mixture was extracted with ethyl acetate . The extract was washed with water and saturated 3 -cyclopropyl - 3 - (3 - (( 1 -( 2 - (( cyclopropylmethyl ) (4 brine , and dried over anhydrous magnesium sulfate . The 25 methylpyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) solvent was evaporated under reduced pressure , the residue piperidin - 4 -yl ) methoxy )phenyl ) propanoic acid was purified by silica gel column chromatography ( ethyl acetate /hexane ) , and the obtained pale -orange solid was Step 1 ) washed with diisopropyl ether to give the title compound N -( cyclopropylmethyl )- 4 -methylpyridin -2 -amine (508 mg ) as a white solid . 30 ' H NMR (400 MHz , CDC1z) 8 1 . 26 (6H , s ), 3 . 36 ( 2H , d , To a solution ( 20 mL ) of 4 -methylpyridin - 2 -amine ( 2 . 89 J = 6 . 0 Hz) , 4 . 74 (1H , brs ) , 4 . 91 ( 1H , brs ), 6 .46 ( 1H , d , J = 8 . 4 g ) and cyclopropanecarbaldehyde ( 1 mL ) in acetic acid was Hz) , 6 .57 (1H , dd , J= 6 .6 , 5 .6 Hz ), 7. 39 (1H , td , J = 7 .8 , 1 .9 added sodium triacetoxyborohydride ( 7. 09 g ) at 0° C . , and Hz) , 8 .02 ( 1H , d , J = 5 . 1 Hz) . the mixture was stirred at room temperature for 3 hr. 35 Aqueous sodium hydroxide solution ( 8 N ) was added to the Step 3 ) reaction mixture , and the mixture was vigorously stirred and N -( 2- methoxy - 2 -methylpropyl ) pyridin -2 -amine extracted with ethyl acetate . The extract was washed with saturated brine , and dried over anhydrous magnesium sul Under a nitrogen atmosphere , to a solution of 2 -methyl fate . The solvent was evaporated under reduced pressure, 1 - (pyridin - 2 -ylamino )propan - 2 -ol (250 mg) in DMF ( 5 mL ) 40 and the residue was purified by silica gel column chroma was added 60 % sodium hydride (oily ) (66 .2 mg) at 0° C ., tography (ethyl acetate /hexane ) to give the title compound and the mixture was stirred for 5 min . Iodomethane ( 188 uL ) ( 1. 11 g) as a pale - yellow oil. MS ( ESI + ): [M + H ] * 163 . 0 . was added to the reaction mixture at 0° C . , and the mixture was stirred for 30 min . Water was added to the reaction Step 2 ) 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( cyclopropylm mixture at 0° C . , and the mixture was extracted with ethyl 45 ethyl) ( 4 -methylpyridin - 2 -yl ) carbamoyl) - 5 -methoxy acetate . The extract was washed with water and saturated phenyl) piperidin - 4 -yl ) methoxy )phenyl ) propanoic brine , and dried over anhydrous magnesium sulfate . The acid solvent was evaporated under reduced pressure , and the residue was purified by silica gel column chromatography In the same manner as in Example 32 , step 2 and Example (NH , ethyl acetate /hexane ) to give the title compound ( 150 50 1 , step 4 , the title compound ( 133 mg) was obtained as a mg) as a colorless oil . white amorphous powder from 2 - [ 4 - ( ( 3 - ( 1 - cyclopropyl- 3 ' H NMR (300 MHz, CDC13 ) d 1. 24 (6H , s ), 3 .23 ( 3H , s) , ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 -yl ) -4 3 .33 (2H , d , J = 5 . 4 Hz) , 4 .72 ( 1H , brs ) , 6 .40 ( 1H , dt, J = 8 . 4 , methoxybenzoic acid (150 mg) and N - (cyclopropylmethyl ) 0 .8 Hz) , 6 .53 (1H , ddd , J = 7 .1 , 5. 1 , 0 .8 Hz) , 7 .38 ( 1H , ddd , 4 -methylpyridin - 2 - amine (101 mg) . J = 8 . 5 , 6 . 9 , 1 . 9 Hz ), 7 .97 - 8 . 15 ( 1H , m ) . 55 MS (ESI + ): [ M + H ]* 598 .3 . Step 4 ) ethyl 3 -cyclopropyl - 3 - ( 3 - (( 1 - (5 -methoxy - 2 Example 37 ( ( 2 -methoxy - 2 -methylpropyl ) (pyridin - 2 -yl ) carbam oyl) phenyl) piperidin - 4 -yl ) methoxy )phenyl )propano 3 -( 3 -( (1 - ( 2 - (( 4 -cyano - 4 -methylpiperidin -1 - yl )carbo ate nyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) phe nyl) - 3 -cyclopropylpropanoic acid In the same manner as in Example 32 , step 2, the title compound ( 85 . 0 mg) was obtained as a colorless oil from Step 1 ) 4 -methylpiperidine - 4 - carbonitrile ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 -( pyridin - 2 - yl( 2 , 2 , 2 hydrochloride trifluoroethyl) carbamoyl) phenyl ) piperidin -4 - yl)methoxy ) 65 phenyl) propanoate (100 mg) and N -( 2 -methoxy -2 -methyl - A solution ( 1 M , 2. 85 mL ) of lithium hexamethyldisila propyl) pyridin - 2 -amine ( 55 . 1 mg) . zane in THF was added to a solution ( 5 mL ) of tert- butyl US 9 , 776 , 962 B2 77 78 4 -cyanopiperidine - 1 -carboxylate (300 mg) in THF at -78° mL ) at room temperature , and the mixture was stirred for 1 . 5 C . , and the mixture was stirred at - 78° C . for 20 min . hr. The reaction mixture was added dropwise to an ice Iodomethane (5 mL ) was added dropwise to the reaction cooled mixture of saturated aqueous sodium hydrogen car mixture at - 78° C . The mixture was allowed to gradually bonate solution and ethyl acetate , and the mixture was extracted with ethyl acetate . The extract was washed with warm from - 78° C . to room temperature , and stirred for 21 saturated brine , and dried over anhydrous magnesium sul hr. Water was added to the reaction mixture , and the mixture fate . The solvent was evaporated under reduced pressure , was extracted with ethyl acetate . The extract was washed and the residue was purified by silica gel column chroma with saturated brine , and dried over anhydrous magnesium tography (ethyl acetate /hexane ) to give the title compound sulfate . A solution ( 4 N , 5 mL ) of hydrochloric acid in ethyl ( 160 mg) as a colorless oil. acetate was added to the residue , and the mixture was stirred H NMR ( 300 MHz, CDC1z ) / 1 . 42 (6H , d , J = 21 . 6 Hz) , at room temperature for 1 . 5 hr. The solvent of the reaction 3 .56 (2H , dd , J = 21 . 2 , 5 . 9 Hz ) , 4 .67 ( 1H , brs ), 6 . 40 - 6 . 46 ( 1H , mixture was evaporated under reduced pressure to give a m ), 6 .56 ( 1H , ddd , J = 7 . 1 , 5 .1 , 0 . 8 Hz ) , 7 .39 ( 1H , ddd , J = 8 . 6 , crude product of the title compound ( 195 mg ) as an orange 7 . 0 , 1 . 9 Hz ) , 8 . 03 - 8 . 11 ( 1H , m ) . solid . This compound was used for the next step without further purification . 15 Step 2 ) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -meth ylpropyl) ( pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphe Step 2 ) 3 -( 3 - ( (1 - ( 2 - (( 4 -cyano - 4 -methylpiperidin - 1 nyl) piperidin - 4 - yl) methoxy ) phenyl) propanoic acid yl) carbonyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl) In the same manner as in Example 32 , step 2 and Example methoxy ) phenyl) -3 -cyclopropylpropanoic acid 20 1 , step 4 , the title compound ( 189 mg ) was obtained as a In the same manner as in Example 32 , step 2 and Example colorless amorphous powder from N - (2 - fluoro - 2 -methyl 1 , step 4 , the title compound ( 153 mg) was obtained as a propyl) pyridin - 2 - amine ( 140 mg) and 2 - ( 4 - ( ( 3 - ( 1 - cyclopro yellow amorphous powder from 2 - [ 4 -( ( 3 -( 1 -cyclopropyl - 3 pyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 -yl ) -4 4 -methoxybenzoic acid (200 mg) . methoxybenzoic acid ( 150 mg) and 4 -methylpiperidine - 4 - 25 MS ( ESI + ) : [ M + H ] * 604 . 4 . carbonitrile hydrochloride ( 100 mg) . Example 40 MS (ESI + ) : [ M + H ] * 560 . 3 . 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( cyclopropylmethyl) Example 38 (pyridin - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) piperi 30 din - 4 - yl)methoxy ) phenyl) propanoic acid 3 - ( 3 - ( ( 1 - ( 2 - ( ( 4 - cyano - 4 - ( 2 -methylpropyl ) piperidin 1 -yl ) carbonyl ) -5 -methoxyphenyl ) piperidin - 4 -yl ) Step 1 ) N - ( cyclopropylmethyl) pyridin - 2 - amine methoxy ) phenyl) - 3 -cyclopropylpropanoic acid In the same manner as in Example 36 , step 1 , the title Step 1 ) 4 - ( 2 -methylpropyl ) piperidine - 4 -carbonitrile 35 compound ( 1 .46 g ) was obtained as a colorless liquid from hydrochloride cyclopropanecarbaldehyde ( 1 .21 mL ) and 2 - aminopyridine (3 . 03 g ). In the same manner as in Example 37 , step 1 , the title ' H NMR (400 MHz, DMSO -do ) 0 . 11 - 0 . 27 (2H , m ) , compound ( 153 mg) was obtained as a pale - yelloww solid 0 .33 - 0 .53 ( 2H , m ) , 0 .91 - 1 . 11 ( 1H , m ), 3 .09 (2H , t , J = 6 . 1 Hz ) , from tert- butyl 4 -cyanopiperidine - 1 - carboxylate ( 300 mgo ) 4040 6 .26 - 6 .59 ( 3H , m ) , 7 .32 ( 1H , ddd , J = 8 . 5 , 6 . 9 , 2 . 0 Hz ) , and 1 -bromo - 2 -methylpropane ( 156 uL ). This compound 7 . 83 - 8 .00 ( 1H , m ) . was used for the next step without further purification . Step 2 ) ethyl 3 - cyclopropyl- 3 -( 3 - ( 1 - ( 2 - ( ( cyclopro pylmethyl) (pyridin - 2 -yl ) carbamoyl ) - 5 -methoxyphe Step 2 ) 3 - ( 3 - ( ( 1 - ( 2 - ( ( 4 - cyano - 4 - ( 2 -methylpropyl ) nyl) piperidin - 4 - yl )methoxy ) phenyl) propanoate piperidin - 1 - yl) carbonyl) - 5 -methoxyphenyl ) piperi 45 din - 4 - yl) methoxy ) phenyl) - 3 - cyclopropylpropanoic In the same manner as in Example 32 , step 2 , the title acid compound (116 mg) was obtained as a colorless oil from 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy ) In the samemanner as in Example 32 , step 2 and Example methyl) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 100 mg ) 1 , step 4 , the title compound ( 134 mg) was obtained as a 50 and N - (cyclopropylmethyl ) pyridin - 2 -amine (77 mg) . white amorphous powder from 2 - ( 4 - ( 3 - ( 1 -cyclopropyl - 3 H NMR (400 MHz, CDC1 ) 8 0 . 08 - 0 .23 (3H , m ) , 0 .24 ethoxy -3 - oxopropyl) phenoxy )methyl ) piperidin -1 - yl) - 4 0 . 32 (1H , m ) , 0 . 37 ( 2H , d , J = 8 . 0 Hz) , 0 . 40 - 0 .48 ( 1H , m ) , methoxybenzoic acid ( 150 mg ) and 4 - ( 2 -methylpropyl ) pip 0 .53 - 0 .64 ( 1H , m ), 0 . 94 - 1 .09 ( 1H , m ) , 1 . 10 - 1 . 21 ( 1H , m ) , eridine - 4 - carbonitrile hydrochloride (126 mg) . 1 .18 (4H , t , J = 7 . 1 Hz) , 1 . 43 - 1 .61 ( 2H , m ) , 1 .67 - 1 .89 ( 3H , MS ( ESI + ) : [ M + H ] * 602 . 3 . 55 m ) , 2 . 29 - 2 . 39 ( 1H , m ), 2 .56 ( 2H , brs ) , 2 .64 - 2 . 83 (3H , m ) , 3 . 78 ( 3H , s ), 3 .81 (2H , d , J = 6 . 3 Hz) , 3 . 99 - 4 . 11 (4H , m ) , 6 .21 Example 39 ( 1H , s ) , 6 .53 ( 1H , dd , J = 8 . 4 , 2 . 3 Hz ) , 6 .67 ( 1H , brs ) , 6 .73 - 6 .76 ( 1H , m ) , 6 .78 ( 1H , s ) , 6 . 82 ( 1H , d , J = 7 . 7 Hz ) , 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -methylpro 6 .88 - 6 .95 ( 1H , m ) , 7 . 21 (1H , t , J = 7 . 8 Hz) , 7 .24 - 7 .34 (1H , pyl )( pyridin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) 60 m ), 7 .42 (1H , d , J = 8. 4 Hz ), 8 .32 -8 .44 ( 1H , m ). piperidin -4 -yl ) methoxy ) phenyl) propanoic acid Step 3) 3 -cyclopropyl - 3 - (3 - (( 1 -( 2 -( (cyclopropylm Step 1 ) N - ( 2 - fluoro - 2 -methylpropyl ) pyridin - 2 - amine ethyl) ( pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) phenyl) propanoic acid To a solution of 2 -methyl - 1 - (pyridin - 2 - ylamino ) propan - 65 2 - ol ( 390 mg) obtained in Example 35 , step 2 , in toluene ( 4 In the same manner as in Example 1 , step 4 , the title mL ) was added N ,N -diethylaminosulfur trifluoride ( 0 .78 compound (94 .6 mg) was obtained as a white amorphous US 9 ,776 , 962 B2 79 80 powder from ethyl 3- cyclopropyl -3 - (3 -( ( 1- (2 - (( cyclopropy - H NMR (400 MHz, CDC13 ) 8 1. 25 (6H , s ), 3. 73 (3H , s) , Imethyl) (pyridin -2 -yl ) carbamoyl) - 5 -methoxyphenyl ) piperi 3 .85 ( 2H , s) , 7 .72 (2H , dd , J = 5 .3 , 3 . 1 Hz ), 7 .84 (2H , dd , din - 4 - yl) methoxy ) phenyl) propanoate ( 116 mg) . J = 5 . 4 , 3 . 0 Hz) . MS ( ESI + ) : [ M + H ] * 584 . 3 . 5 Step 2 ) methyl 3 -amino - 2 , 2 -dimethylpropanoate Example 41 Under a nitrogen atmosphere, hydrazine monohydrate 3 -cyclopropyl - 3 - (3 - (( 1 -( 5 -methoxy - 2 -( ( 2 -methylpro (4 .92 mL ) was added to a solution of methyl 3 -( 1 ,3 - diox pyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl) phenyl) piperi oisoindolin - 2 - yl) - 2 , 2 -dimethylpropanoate ( 5 . 3 g ) in metha din - 4 - yl) methoxy )phenyl ) propanoic acid 10 nol ( 100 mL ) at room temperature, and the mixture was stirred at 60° C . for 1 hr. The reaction mixture was diluted By a method similar to that in Example 32 , step 2 and with diethyl ether, and the resultant white precipitate was Example 1 , step 4 , the title compound ( 98 mg ) was obtained removed by filtration . The solvent was evaporated under as a white amorphous powder from 2 -( 4 - ( 3 - ( 1 -cyclopropyl - reduced pressure to give a crude product of the title com 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 - 15 pound ( 2 .42 g ) as a pale -yellow oil . methoxybenzoic acid ( 111. 8 mg ) and 6 -methyl - N - ( 2 -meth ' H NMR (400 MHz, DMSO -d ) 8 1. 06 (6H , s ), 1. 35 (2H , ylpropyl) pyridin - 2 - amine ( 76 mg) . brs ) , 2 .59 ( 2H , s ) , 3 . 58 ( 3H , s ). MS (ESI + ) : [ M + H ] * 600 . 3 . Step 3) methyl Example 42 20 2 ,2 - dimethyl- 3 -( pyridin- 2 - ylamino ) propanoate 3 -cyclopropyl - 3 - (3 - (( 1 -( 5 -methoxy - 2 -( ( 2- methylpro In the same manner as in Example 135, step 1 , the title pyl ) ( 4 -methylpyridin - 2 -yl ) carbamoyl ) phenyl )piperi compound ( 744 mg) was obtained as a pale - yellow oil from din - 4 - yl) methoxy )phenyl )propanoic acid methyl 3 -amino -2 ,2 -dimethylpropanoate (1 .00 g ) and pyri 25 dine N -oxide ( 1 . 81 g ) . Step 1 ) ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 H NMR ( 400 MHz, CDC13 ) d 1 . 26 (6H , s ) , 3 . 49 ( 2H , d , (( 2 -methylpropyl ) ( 4 -methylpyridin - 2 -yl ) carbamoyl) J = 6 .4 Hz ), 3 .68 (3H , s ), 4 .78 ( 1H , brs ), 6 .39 ( 1H , d , J = 8 .4 phenyl) piperidin - 4 - yl )methoxy ) phenyl) propanoate Hz ), 6 .53 ( 1H , dd , J= 6 .6 , 5 . 6 Hz ), 7 . 32 -7 .44 (1H , m ), 8. 05 ( 1H , d , J = 4 .8 Hz ). In the same manner as in Example 32 , step 2 , the title 30 compound (86 mg) was obtained as a colorless oil from Step 4 ) 2 -( 4 -( (3 - (1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy ) 2 , 2 - dimethyl- 3 - ( pyridin - 2 -ylamino )propanamide methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid (120 mg ) and 4 -methyl - N -( 2- methylpropyl )pyridin - 2- amine (82 . 0 A 28 % solution of sodium methoxide in methanol ( 3 .62 mg) . 35 mL ) was added to a solution of methyl 2 , 2 -dimethyl - 3 MS ( ESI + ) : [ M + H ] * 628 .5 . ( pyridin - 2 - ylamino )propanoate (744 mg ) and formamide ( 1 . 42 mL ) in DMF ( 10 mL ) at room temperature , and the Step 2 ) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 mixture was stirred at 70° C . for 30 min . Water was added methylpropyl) (4 -methylpyridin - 2 - yl) carbamoyl) to the reaction mixture , and the mixture was extracted with phenyl) piperidin - 4 -yl ) methoxy ) phenyl) propanoic 40 ethyl acetate . The extract was washed with water and acid saturated brine, and dried over anhydrous magnesium sul fate . The solvent was evaporated under reduced pressure to In the same manner as in Example 1 , step 4 , the title give a crude product of the title compound as a pale -yellow compound (41 . 0 mg) was obtained as a grayish white solid oil . This compound was used for the next step without from ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -meth - 45 further purification . ylpropyl) ( 4 -methylpyridin - 2 -yl ) carbamoyl) phenyl) piperi din -4 - yl) methoxy ) phenyl) propanoate ( 86 mg) . Step 5 ) MS ( ESI + ) : [ M + H ] * 600 .3 . 2, 2 -dimethyl - 3 - (pyridin - 2 - ylamino )propanenitrile Example 43 50 Trifluoroacetic anhydride ( 1 .51 mL ) was added to a solution of 2 , 2 -dimethyl - 3 - ( pyridin - 2 - ylamino ) propanamide 3 - ( 3 - ( ( 1 -( 2 - ( ( 2 -cyano - 2 -methylpropyl ) (pyridin - 2 - yl) ( entire amount) in pyridine (10 mL ) at room temperature, carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) and the mixture was stirred at room temperature for 5 min . methoxy )phenyl ) - 3 - cyclopropylpropanoic acid Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate . The extract was washed Step 1 ) methyl 3 - ( 1 , 3 -dioxoisoindolin - 2 - yl) - 2 , 2 with water and saturated brine , dried over anhydrous mag dimethylpropanoate nesium sulfate and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in Under a nitrogen atmosphere , a 2 . 2 M solution of diethyl methanol ( 10 mL ) was added potassium carbonate ( 1 .48 g ) azodicarboxylate in toluene (12 . 4 mL ) was added to a 60 at room temperature , and the mixture was stirred at 60° C . solution of phthalimide ( 4 .01 g ) , methyl 3 -hydroxy - 2 , 2 for 5 min . Water was added to the reaction mixture , and the dimethylpropanoate ( 3 .00 g ) and triphenylphosphine ( 7 . 14 mixture was extracted with ethyl acetate . The extract was g ) in THF (30 mL ) at room temperature , and the mixture was washed with water and saturated brine , and dried over stirred at room temperature for 16 hr. The solvent was anhydrous magnesium sulfate . The solvent was evaporated evaporated under reduced pressure, and the residue was 65 under reduced pressure , and the residue was purified by purified by silica gel column chromatography ( ethyl acetatel silica gel column chromatography ( ethyl acetate /hexane ) to hexane) to give the title compound ( 5 . 3 g ) as a white solid . give the title compound ( 203 mg) as a yellow oil. US 9 ,776 , 962 B2 82 ' H NMR (400 MHz, CDC13 ) 8 1 .40 (6H , s ), 3 .62 (2H , d , Step 2 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - (5 -methoxy - 2 J = 6 . 8 Hz ) , 4 .64 ( 1H , brs ) , 6 . 46 ( 1H , d , J = 8 . 3 Hz ) , 6 .60 ( 1H , ( ( 2 -methylpropyl ) ( 6 -oxo - 1 , 6 -dihydropyridin - 2 -yl ) dd , J = 6 . 7 , 5 . 5 Hz) , 7 .32 - 7 . 48 ( 1H , m ) , 8 .07 ( 1H , d , J = 4 . 1 carbamoyl) phenyl ) piperidin - 4 -yl ) methoxy )phenyl ) Hz) . propanoate 5 Step 6 ) ethyl 3 - ( 3 - ( ( 1 - ( 2 - (( 2 - cyano - 2 - methylpropyl ) Under a nitrogen atmosphere , a mixture of ethyl 3 - cyclo (pyridin - 2 -yl ) carbamoyl ) -5 -methoxyphenyl ) piperi propyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methylpropyl ) ( 6 din - 4 - yl) methoxy ) phenyl) - 3 - cyclopropylpropanoate methoxypyridin - 2 -yl ) carbamoyl ) phenyl) piperidin - 4 - yl ) methoxy )phenyl ) propanoate ( 153 mg) , pyridinium chloride In the same manner as in Example 32 , step 2 , the title (274 mg) and DMF ( 0 .2 mL ) was stirred at 130° C . for 16 compound (108 mg) was obtained as a white amorphous hr. 1N Hydrochloric acid was added to the reaction solution powder from 2 - ( 4 - ( 3 - ( 1 - cyclopropyl- 3 -ethoxy - 3 - oxopro at room temperature, and the mixture was extracted with pyl) phenoxy )methyl ) piperidin - 1- yl) -4 -methoxybenzoic ethyl acetate . The extract was washed with water and acid ( 100 mg) and 2 , 2 -dimethyl - 3 - ( pyridin - 2 - ylamino ) pro saturated brine , and dried over anhydrous magnesium sul panenitrile (91 . 0 mg) . fate . The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chroma ' H NMR (400 MHz, CDC13 ) 8 0 . 12 - 0 .21 ( 1H , m ), 0 .23 tography ( ethyl acetate / hexane ) to give the title compound 0 .32 ( 1H , m ) , 0 . 38 - 0 .49 ( 1H , m ), 0 . 53 - 0 .64 ( 1H , m ), 0 . 96 (32 .0 g ) as a yellow oil . 1 . 10 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 2 Hz) , 1 . 39 (6H , brs ) , ' H NMR (400 MHz , CDC1z ) : 0 .10 - 0 .21 (1H , m ), 0 .22 1 .38 - 1 .68 ( 2H , m ) , 1 .69 - 1 . 92 ( 3H , m ), 2 . 30 - 2 .39 ( 1H , m ) , 20 032 ( 11 . m ) 0 . 37 - 0 .48 ( 11 . m ) , 0 .53 - 0 .63 ( 1H , m ) , 0 . 88 2 . 35 - 2 . 71 (3H , m ) , 2 .67 - 2 . 80 (2H , m ) , 3 . 14 - 3 .42 (1H , m ) , 1 .08 ( 7H , m ) , 1. 18 (3H , t, J = 7 . 1 Hz) , 1 .50 - 1 .69 ( 2H , m ), 1 . 93 3 .78 ( 3H , s) , 3 . 82 (2H , d , J = 6 .3 Hz) , 4 .00 - 4 . 12 (2H , m ), ( 4H , dd , J = 13 . 4 , 6 . 5 Hz ), 2 . 34 ( 1H , 9 , J = 7 . 9 Hz ) , 2 . 49 - 3 . 01 4 .33 - 4 . 86 ( 2H , m ), 6 .20 ( 1H , d , J = 2 . 1 Hz) , 6 .54 ( 2H , dd , (4H , m ) , 3 . 17 - 3 . 81 ( 4H , m ), 3 .77 (3H , s ) , 3 .81 (2H , d , J = 5 . 4 J = 8 . 4 , 2 . 3 Hz ), 6 .70 - 6 .88 (3H , m ) , 6 . 90 - 7 .01 (1H , m ), Hz ) , 4 . 00 - 4 . 11 ( 2H , m ) , 5 . 80 ( 1H , d , J = 7 . 2 Hz ) , 6 .25 ( 1H , d , 7 . 18 - 7 . 25 ( 2H . m ), 7 . 37 ( 1H , d , J = 8 .4 Hz) , 8 . 40 ( 1H , d , J = 3 . 6 25 J = 9 , 0 Hz ) , 6 .48 - 6 . 58 ( 2H , m ), 6 .71 ( 1H , d , J = 8 . 0 Hz ), 6 . 77 Hz ). ( 1H , s) , 6 .82 ( 1H , d , J = 7 .5 Hz ) , 7 .09 (1H , d , J = 8 .3 Hz ), 7. 14 -7 . 24 (2H , m ), 10 .51 (1H , br. s ). Step 7 ) 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - cyano - 2 -methylpropyl ) (pyri din -2 - yl) carbamoyl )- 5 -methoxyphenyl ) piperidin - 4 Step 3 ) 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 yl) methoxy ) phenyl) - 3 - cyclopropylpropanoic acid 30 methylpropyl) (6 -oxo - 1 ,6 - dihydropyridin - 2 -yl ) car bamoyl) phenyl ) piperidin -4 - yl) methoxy )phenyl ) pro In the same manner as in Example 1 , step 4 , the title panoic acid compound (98 .0 mg) was obtained as a white amorphous In the same manner as in Example 1, step 4 , the title powder from ethyl 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - cyano - 2 -methylpropyl ) 35a compound (7 .70 mg) was obtained as a white solid from ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methylpro methoxy )phenyl ) -3 -cyclopropylpropanoate ( 108 mg ). pyl) ( 6 -oxo - 1 ,6 -dihydropyridin -2 -yl ) carbamoyl ) phenyl ) pip MS ( ESI+ ) : [ M + H ]* 611 .2 . eridin - 4 - yl) methoxy )phenyl ) propanoate ( 32 .0 mg ) . MS (ESI + ): [ M + H ] * 602. 2 . Example 44 40 Example 45 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methylpro 3 -cyclopropyl - 3 -( 3 -( ( 1- ( 2 -( 2, 2 -dimethylpropyl ) pyl) ( 6 -oxo - 1, 6 -dihydropyridin - 2 -yl ) carbamoyl ) phe (pyrimidin - 2 - yl) carbamoyl ) - 5 - ethylphenyl) piperidin nyl) piperidin - 4 -yl )methoxy )phenyl ) propanoic acid 4545 4 - yl) methoxy ) phenyl) propanoic acid Step 1) ethyl 3 -cyclopropyl - 3 - (3 - (( 1 - (5 -methoxy - 2 Step 1) 4 -bromo - 2 -( 4 -( hydroxymethyl ) piperidin - 1 ( ( 2 -methylpropyl ) ( 6 -methoxypyridin - 2 - yl) carbam yl) benzaldehyde oyl) phenyl) piperidin - 4 - yl) methoxy ) phenyl) propano ate 50 In the same manner as in Example 1 , step 2 , the title compound ( 8 . 33 g ) was obtained as a yellow oil from In the same manner as in Example 32, step 2 , the title 4 -bromo - 2 - fluorobenzaldehyde ( 10 g ) . compound (153 mg) was obtained as a colorless oil from ? H NMR (400 MHz, DMSO - d ) 1 .29 - 1 . 43 (2H , m ) , 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 1 .45 - 1 .60 ( 1H , m ) , 1 .77 ( 2H , d , J = 12 . 9 Hz) , 2 .87 ( 2H , t , yl) oxy )methyl ) piperidin - 1- yl )noxy - 4 -methoxybenzoic - 3 - oxopropyi pyridin acid (- 4150 - 55 J = 11 . 0 Hz ), 3 . 20 - 3 . 45 (4H , m ), 7 . 28 ( 1H , d , J = 8 . 3 Hz) , 7 . 33 mg) and 6 -methoxy - N - ( 2 -methylpropyl ) pyridin - 2 - amine (1H , d , J = 1 .5 Hz ), 7 .58 ( 1H , d , J = 8 . 2 Hz) , 10 .06 (1H , s) . ( 140 mg ) . Step 2 ) 4 - bromo- 2 - ( 4 - ( ( ( tert- butyldiphenylsilyl ) oxy ) ' H NMR (400 MHz, CDC12 ) 8 0 .09 - 0 .21 ( 1H , m ), 0 . 23 methyl) piperidin - 1 -yl ) benzaldehyde 0 .35 ( 1H , m ) , 0 . 38 - 0 .49 ( 1H , m ) , 0 .52 - 0 .64 ( 1H , m ), 0 . 89 60 (6H , d , J= 5 . 5 Hz ), 0 .98 - 1 .07 (1H , m ) , 1 . 18 (3H , t , J = 7 . 1 Hz) , To a solution of 4 -bromo - 2 -( 4 -( hydroxymethyl ) piperidin 1. 22 - 1 . 52 (2H , m ), 1 .69 - 1 . 99 ( 4H , m ) , 2 .27 - 2 .40 ( 1H , m ) , 1 - yl )benzaldehyde (8 .33 g ) and imidazole ( 5 .71 g ) in DMF 2 .42 - 2 .84 (5H , m ) , 3 . 20 - 3 . 46 ( 1H , m ) , 3 .74 - 3 .85 (2H , m ) , (50 mL ) was added tert -butyldiphenylchlorosilane (8 . 72 3 .78 ( 3H , s ) , 3 . 80 ( 3H , s ) , 3 . 98 - 4 . 12 (4H , m ) , 6 .25 ( 2H , brs ) , mL ) , and the mixture was stirred at room temperature for 1 6 . 35 ( 1H , d , J = 8 . 2 Hz ), 6 .51 ( 1H , d , J = 8 . 7 Hz) , 6 .74 ( 1H , d , 65 hr. Water was added to the reaction mixture , and the mixture J = 8 . 0 Hz) , 6 . 77 ( 1H , s ), 6 .82 (1H , d , J = 7 . 5 Hz) , 7 .15 - 7 . 24 was extracted with ethyl acetate . The extract was washed ( 2H , m ) , 7 . 34 ( 1H , d , J = 8 . 3 Hz ) . with water and saturated brine , and dried over anhydrous US 9 ,776 ,962 B2 83 84 magnesium sulfate . The solvent was evaporated under ( 2H , s ), 5 . 35 (1H , d , J = 10 . 9 Hz) , 5 .91 (1H , d , J = 17 . 7 Hz) , reduced pressure to give a crude product of the title com 6 .73 (1H , dd , J= 17 .6 , 11. 0 Hz) , 7. 06 -7 .14 (2H , m ), 7. 30 - 7 .42 pound as a yellow gummy substance. This compound was (3H , m ) , 7 .43 -7 .51 (2H , m ), 7 .57 (1H , d , J = 7 .9 Hz ). used for the next step without further purification . Step 6 ) benzyl 2 -( 4 -( ( 3 - ( 1 -cyclopropyl - 3 - ethoxy - 3 Step 3 ) 4 - bromo- 2 -( 4 - ( (( tert - butyldiphenylsilyl) oxy ) oxopropyl) phenoxy )methyl ) piperidin - 1- yl ) - 4 -vinyl methyl) piperidin - 1 - yl) benzoic acid benzoate In the same manner as in Example 262 , step 2 , the title Under a nitrogen atmosphere , to a solution of benzyl compound (13 .1 g ) was obtained as a white solid from a 10 2 -( 4 -( hydroxymethyl ) piperidin -1 - yl) -4 -vinylbenzoate (3 . 1 crude product of 4 -bromo - 2 - (4 - ( ( ( tert- butyldiphenylsilyl ) g ) and ethyl 3 - cyclopropyl- 3 - ( 3 -hydroxyphenyl ) propanoate oxy )methyl ) piperidin - 1 - yl) benzaldehyde ( entire amount ) . ( 2 .50 g ) in toluene ( 15 mL ) was added a 0 . 7 M solution ( 20 IH NMR (300 MHz, DMSO - do) 8 1 .03 ( 9H , s ) , 1 . 36 - 1 .56 mL ) of 2 - ( tributylphosphoranylidene )acetonitrile in toluene ( 2H , m ), 1 .74 - 1. 95 (3H , m ), 2 .97 - 3 . 19 (4H , m ), 3 .61 (2H , d , at room temperature , and the mixture was stirred at 100° C . J = 5 . 5 Hz) , 7 . 40 - 7 .51 ( 6H , m ), 7 .56 (1H , dd , J = 8 . 5 , 1 . 6 Hz ) , 15 for 30 min . The solvent was evaporated under reduced 7 .60 - 7 .68 ( 4H , m ), 7 . 84 - 7 .93 ( 2H , m ) . pressure , and the residue was purified by silica gel column chromatography ( ethyl acetate /hexane ) to give the title com Step 4 ) benzyl 4 - bromo - 2 - ( 4 - ( ( ( tert- butyldiphenylsi pound ( 3 . 39 g ) as a yellow oil . lyl) oxy )methyl ) piperidin - 1 -yl ) benzoate 1H NMR ( 300 MHz, DMSO - do) d 0 . 07 - 0 . 17 ( 1H , m ), 20 0 . 18 - 0 .27 ( 1H , m ) , 0 . 28 - 0 .40 ( 1H , m ) , 0 .43 - 0 . 59 ( 1H , m ) , Under a nitrogen atmosphere, to a solution of 4 -bromo 0 .97 - 1 . 07 ( 1H , m ), 1 .08 (3H , t. J = 7 . 1 Hz) , 1 .25 - 1. 43 ( 2H , 2 - ( 4 - ( ( ( tert -butyldiphenylsilyl )oxy )methyl ) piperidin - 1 - yl) m ), 1 .68 - 1 .84 ( 3H , m ), 2 . 17 - 2 .31 ( 1H , m ), 2 .65 - 2 .81 (4H , benzoic acid (13 . 0 g ) and DMF ( 180 °L ) in THF (130 mL ) m ) , 3 .21 - 3 .29 (2H , m ), 3 .79 ( 2H , d , J = 6 .0 Hz ) , 3 . 92 - 4 .01 was added oxalyl chloride ( 3 . 10 mL ) at 0° C ., and the (2H , m ), 5 . 30 ( 2H , s ) , 5 . 36 ( 1H , d , J = 11 . 7 Hz ) , 5 . 92 ( 1H , d , mixture was stirred at 0° C . for 20 min . To the reaction 25 J = 17 . 0 Hz ) , 6 .66 - 6 .79 ( 2H , m ), 6 . 80 - 6 . 85 ( 2H , m ) , 7 .08 - 7 . 15 solution was added benzylalcohol ( 4 . 88 mL ) at 0° C . , and (2H , m ) , 7 . 16 - 7 . 22 ( 1H , m ), 7 . 31 - 7 .42 ( 3H , m ) , 7 . 45 - 7 . 50 the mixture was stirred at 0° C . for 15 min . Saturated ( 2H , m ) , 7 .60 ( 1H , d , J = 7 . 9 Hz ) . aqueous sodium hydrogen carbonate solution was added to the reaction mixture , and the mixture was extracted with Step 7 ) 2 - [ 4 - ( ( 3 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro ethyl acetate . The extract was washed with water and 30 pyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 - ethylbenzoic saturated brine , and dried over anhydrous magnesium sul acid fate . The solvent was evaporated under reduced pressure , and the residue was purified by silica gel column chroma In the same manner as in Example 2 , step 4 , the title tography (NH , ethyl acetate /hexane ) to give the title com compound ( 2 . 76 g ) was obtained as a colorless oil from pound ( 14 . 9 g ) as a colorless oil . 35 benzyl 2 - ( 4 - ( 3 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) phe H NMR ( 400 MHz, DMSO - do) 8 1 .01 (9H , s ) , 1 .55 - 1 .70 n oxy )methyl )piperidin - 1 -yl ) - 4 - vinylbenzoate ( 3 . 39 g ) . ( 3H , m ) , 2 .68 ( 2H , t , J = 11 . 4 Hz ) , 3 . 19 (2H , d , J = 11. 9 Hz ), H NMR ( 300 MHz, DMSO - d . ) 8 0 .08 - 0 . 17 ( 1H , m ) , 3 . 26 - 3 . 31 (2H , m ) , 3 .46 ( 2H , d , J = 5 .6 Hz ) , 5 .28 ( 2H , s ) , 7 . 14 0 . 18 - 0 .27 ( 1H , m ) , 0 .28 - 0 .38 ( 1H , m ), 0 .44 - 0 .57 ( 1H , m ) , ( 1H , dd , J = 8 . 3 , 1. 3 Hz) , 7 . 18 (1H , s) , 7 .24 -7 .37 (3H , m ), 0 .97 - 1 .07 ( 1H , m ), 1 .09 (3H , t, J= 7 . 1 Hz) , 1 .21 (3H , t , J = 7 .6 7 . 40 - 7 .56 ( 9H , m ), 7 .58 - 7 .70 ( 4H , m ) . 40 Hz) , 1 .42 - 1 . 64 ( 2H , m ) , 1 . 95 - 2 . 13 (3H , m ), 2 . 18 - 2 .31 ( 1H , m ), 2 .62 - 2 .79 (4H , m ) , 3 . 11 (4H , brs ) , 3 . 90 - 4 .01 ( 4H , m ) , Step 5 ) benzyl 2 - (4 - hydroxymethyl) piperidin - 1 -yl ) 6 .75 - 6 .89 ( 3H , m ) , 7 .20 (1H , t, J = 7 . 8 Hz ), 7 .28 ( 1H , d , J = 8 . 1 4 - vinylbenzoate Hz ) , 7 .60 ( 1H , s ) , 7 . 96 ( 1H , d , J = 8 . 0 Hz ) . Under a nitrogen atmosphere , a mixture of benzyl 45 Step 8 ) N -( 2 , 2 - dimethylpropyl) pyrimidin - 2 - amine 4 -bromo - 2 - ( 4 -( (( tert - butyldiphenylsilyl ) oxy )methyl ) piperi din -1 -yl )benzoate (14 . 7 g ), vinyltrimethylsilane (9 . 95 mL ), Under a nitrogen atmosphere, to a solution of 2 -chloro palladium acetate (256 mg) , tris ( 2 -methylphenyl ) phosphine pyrimidine ( 3 .00 g ) and 2 , 2 - dimethylpropan - 1 -amine ( 4 .62 ( 1 . 04 g ) and triethylamine ( 9 .55 mL ) was stirred in a DMF mL ) in DMF (30 mL ) was added diisopropylethylamine ( 50 mL ) solvent at 130° C . for 1 hr. To the reaction mixture 50 ( 13 . 7 mL ) at room temperature , and the mixture was stirred was added water, and the mixture was extracted with ethyl at 130° C . for 2 hr. To the reaction mixture was added water , acetate . The extract was washed with water and saturated and the mixture was extracted with ethyl acetate. The extract brine , dried over anhydrous magnesium sulfate and the was washed with water and saturated brine, and dried over solvent was evaporated under reduced pressure . The anhydrous magnesium sulfate . The solvent was evaporated obtained residue was dissolved in THF (50 mL ) , 1 M 55 under reduced pressure , and the residue was purified by tetrabutylammonium fluoride THF solution (45 . 7 mL ) was silica gel column chromatography ( ethyl acetate /hexane ) to added , and the mixture was stirred at 70° C . for 30 min . To give the title compound ( 1 . 91 g ) as a white solid . the reaction mixture was added water , and the mixture was H NMR (400 MHz, DMSO - d . ) 8 0 .88 (9H , s ) , 3 . 16 ( 2H , extracted with ethyl acetate . The extract was washed with d , J = 6 .3 Hz ), 6 .50 ( 1H , t, J = 4 .8 Hz ), 7. 01 (1H , brs ), 8. 22 water and saturated brine , and dried over anhydrous mag - 60 ( 2H , d , J = 4 . 6 Hz ). nesium sulfate . The solvent was evaporated under reduced pressure , and the residue was purified by silica gel column Step 9 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 -dim chromatography ( ethyl acetate/ hexane ) to give the title com ethylpropyl) ( pyrimidin - 2 - yl) carbamoyl) - 5 - ethylphe pound ( 3 . 1 g ) as a yellow oil . nyl) piperidin - 4 - yl) methoxy ) phenyl) propanoate ' H NMR ( 400 MHz , DMSO - da ) d 1 .09 - 1 . 25 ( 2H , m ) , 65 1 . 35 - 1 .51 ( 1H , m ) , 1 .64 (2H , d , J = 11 . 3 Hz) , 2 .67 ( 2H , t , In the same manner as in Example 32 , step 2 , the title J= 11. 1 Hz) , 3 .17 -3 .27 (4H , m ) , 4 .43 (1H , t, J= 5 .2 Hz) , 5. 29 compound (20 .3 mg ) was obtained as a colorless oil from US 9 ,776 , 962 B2 85 86 2 -( 4 -( (3 - (1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy ) Example 47 methyl) piperidin - 1 - yl ) - 4 - ethylbenzoic acid ( 100 mg ) and N -( 2 ,2 -dimethylpropyl ) pyrimidin -2 - amine (86 mg ). 3 -cyclopropyl - 3 -( 3 -( ( 1 -( 2 -( ( 2 ,2 -dimethylpropyl ) (4 ' H NMR ( 400 MHz, CDC13 ) 8 0 . 11 - 0 .21 ( 1H , m ) , 0 . 23 methylpyridin - 2 - yl) carbamoyl ) - 5 -ethylphenyl ) pip 0 .33 ( 1H , m ) , 0 . 38 - 0 .48 ( 1H , m ) , 0 .52 - 0 .63 ( 1H , m ), 0 . 87 5 eridin - 4 -yl ) methoxy )phenyl ) propanoic acid ( 9H , s ) , 0 . 98 - 1 .09 ( 1H , m ) , 1. 15 - 1 . 22 (6H , m ) , 1 . 46 - 1 .61 ( 2H , m ), 1 .67 - 1 . 88 ( 3H , m ) , .30 - 2 . 40 ( 1H , m ), 2 . 40 - 2 .65 By a method similar to that in Example 32 , step 2 and (4H , m ), 2 .56 (2H , q , J = 7 .6 Hz ) , 2 .66 -2 .80 (2H , m ), 3. 82 Example 1 , step 4 , the title compound (100 mg) was (2H , d , J = 5 . 9 Hz ), 4 .01 - 4 .11 ( 2H , m ) , 4 .29 ( 2H , s ), 6 .44 (1H , obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 s ), 6 .72 -6 .90 (5H , m ), 7 .22 ( 1H , t, J= 7 .8 Hz) , 7. 40 (1H , d , cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi J = 7 . 8 Hz) , 8 . 30 ( 2H , d , J = 4 . 8 Hz) . din - 1 - yl) - 4 - ethylbenzoic acid ( 108 . 7 mg) and 4 -methyl - N Step 10 ) 3 -cyclopropyl - 3 - (3 - ( 1- (2 - (( 2, 2 -dimethyl ( 2 , 2 - dimethylpropyl) pyridin - 2 - amine (81 mg) . propyl) ( pyrimidin - 2 - yl) carbamoyl ) - 5 - ethylphenyl) MS (ESI + ): [M + H ] * 612. 4 . piperidin - 4 -yl ) methoxy ) phenyl) propanoic acid 15 Example 48 In the same manner as in Example 1 , step 4 , the title compound ( 9 . 2 mg) was obtained as a white amorphous 3 -( 3 -( (1 -( 2 -( (3 - chlorophenyl) (2 , 2- dimethylpropyl ) powder from ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( 2 , 2 -dimeth carbamoyl) - 5 - ethylphenyl) piperidin - 4 - yl) methoxy ) ylpropyl )( pyrimidin - 2 - yl ) carbamoyl) -5 - ethylphenyl )piperi - 20 phenyl) - 3 -cyclopropylpropanoic acid din - 4 - yl) methoxy ) phenyl) propanoate (20 . 3 mg) . MS ( ESI + ) : [ M + H ] * 599 . 4 . Step 1 ) 3 -chloro -N -( 2 ,2 -dimethylpropyl ) aniline Example 46 In the same manner as in Example 32 , step 1 , the title 25 compound ( 1 . 38 g ) was obtained as a pale -yellow oil from 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - (5 - ethyl- 2 - (pyridin - 2 - yl( 2 , 2 , 3 - chloroaniline ( 4 .00 g ) . 2 - trifluoroethyl ) carbamoyl) phenyl ) piperidin -4 - yl) ' H NMR ( 300 MHz, CDC1z ) 8 0 . 98 (9H , s ) , 2 .87 (2H , d , methoxy )phenyl ) propanoic acid J = 5 .9 Hz ), 3. 71 (1H , brs ), 6 .47 (1H , ddd , J = 8 .2 , 2 .3 , 0 .8 Hz ), 6 .55 - 6 .65 ( 2H , m ) , 7 .04 ( 1H , t , J = 8 . 0 Hz ). Step 1) N -( 2 ,2 , 2 - trifluoroethyl )pyridin - 2 -amine 30 Step 2 ) 3 - ( 3 - ( ( 1 - ( 2 -( ( 3 - chlorophenyl) ( 2 , 2 - dimethyl In the same manner as in Example 32 , step 1 , the title propyl) carbamoyl ) - 5 - ethylphenyl) piperidin - 4 - yl) compound ( 1 .25 g ) was obtained as white crystals from methoxy ) phenyl) - 3 - cyclopropylpropanoic acid 2 - aminopyridine ( 1 . 0 g ) . ' H NMR ( 300 MHz, DMSO - do) 8 4 . 14 ( 2H , qd , v = 9 . 9 , 6 . 7 35 In the same manner as in Example 32 , step 2 and Example Hz) , 6 . 56 -6 .65 (2H , m ), 7 .08 ( 1H , t, J= 6 .3 Hz ), 7. 40 - 7 .47 1 , step 4 , the title compound ( 101 mg) was obtained as a ( 1H , m ) , 7 . 98 - 8 .04 ( 1H , m ) . colorless amorphous powder from 3 - chloro - N - ( 2 , 2 - dimeth ylpropyl) aniline ( 103 mg ) and 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 Step 2 ) ethyl 3 -cyclopropyl - 3 - ( 3 -( ( 1 -( 5 - ethyl- 2 ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 -yl ) -4 - eth (pyridin - 2 - yl( 2 , 2 , 2 - trifluoroethyl) carbamoyl) phenyl) 40 ylbenzoic acid (100 mg) . piperidin - 4 - yl) methoxy )phenyl ) propanoate MS (ESI + ) : [ M + H ] * 631. 3 . In the same manner as in Example 32, step 2 , the title Example 49 compound (97 . 8 mg) was obtained as a colorless oil from 2 -( 4 - ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy ) 45 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -ethyl - 2 - ( ( 2 , 2 , 3 , 3 , 3 -penta methyl) piperidin - 1 - yl) - 4 - ethylbenzoic acid ( 100 mg) and fluoropropyl) ( tetrahydro - 2H -pyran - 4 -yl ) carbamoyl ) N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 2 - amine (92 . 0 mg ) . phenyl) piperidin - 4 - yl) methoxy ) phenyl) propanoic ' H NMR (400 MHz, DMSO - d . ) 8 0 .08 - 0 . 17 ( 1H , m ) , acid 0 . 17 - 0 . 26 ( 1H , m ) , 0 . 28 - 0 . 37 ( 1H , m ), 0 . 45 - 0 . 55 ( 1H , m ), 1 . 00 - 1 . 09 ( 1H , m ), 1 .09 ( 3H , t, J = 7 . 2 Hz ) , 1 . 14 ( 3H , t , J = 7 . 4 50 Step 1 ) N - ( 2 ,2 , 3 , 3 , 3 -pentafluoropropyl ) tetrahydro Hz ), 1 .61 - 1 . 84 ( 3H , m ) , 2 . 18 - 2 .30 ( 1H , m ), 2 .42 - 2 .62 ( 8H , 2H - pyran - 4 - amine m ) , 2 .61 - 2 . 82 ( 2H , m ) , 3 . 83 (2H , d , J = 6 . 1 Hz ), 3 . 91 - 4 .01 ( 2H , m ) , 4 . 97 ( 2H , brs ), 6 .65 ( 1H , s ) , 6 .71 ( 1H , brs ), In the same manner as in Example 14 , step 1, the title 6 . 75 - 6 .91 ( 4H , m ) , 7 .04 - 7 . 13 ( 1H , m ), 7 . 19 ( 1H , t , J= 7 . 8 compound ( 1 . 43 g ) was obtained as a colorless oil from Hz ) , 7 .23 ( 1H , d , J= 7 . 8 Hz ), 7 .47 ( 1H , t, J = 7 . 3 Hz) , 8 .39 ( 1H , 55 tetrahydro - 2H - pyran - 4 - amine ( 800 mg) . d , J = 3 . 8 Hz ) . ' H NMR (300 MHz, CDC13) 8 1 . 14 ( 1H , brs ), 1 . 32 - 1 . 48 ( 2H , m ), 1 .78 - 1 .89 ( 2H , m ) , 2 . 72 - 2 . 85 (1H , m ) , 3 . 25 (2H , t , Step 3 ) 3 -cyclopropyl - 3 - (3 - ( 1 -( 5 - ethyl- 2 -( pyridin J = 15 . 4 Hz ), 3 .40 (2H , td , J= 11. 5 , 2 .3 Hz ) , 3 .98 (2H , dt , 2 -yl ( 2 , 2 , 2 - trifluoroethyl )carbamoyl ) phenyl )piperi J = 11. 6 , 3. 7 Hz) . din -4 -yl ) methoxy ) phenyl) propanoic acid 60 Step 2 ) 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - ( ( 2 , 2 , 3 , 3 , In the same manner as in Example 1, step 4 , the title 3 -pentafluoropropyl ) ( tetrahydro -2H -pyran - 4 -yl )car compound (82 . 9 mg) was obtained as a white amorphous bamoyl) phenyl ) piperidin - 4 -yl ) methoxy ) phenyl) pro powder from ethyl 3 - cyclopropyl- 3 -( 3 - ( 1 -( 5 - ethyl- 2 - (pyri panoic acid din - 2 -yl ( 2 ,2 ,2 - trifluoroethyl) carbamoyl )phenyl ) piperidin -4 - 65 yl) methoxy ) phenyl) propanoate ( 97 . 8 mg) . In the same manner as in Example 32 , step 2 and Example MS ( ESI + ) : [ M + H ] * 610 . 3 . 1 , step 4 , the title compound ( 140 mg) was obtained as US 9 ,776 ,962 B2 87 88 colorless amorphous powder from N - ( 2 , 2 , 3 , 3 , 3 -pentafluo Example 52 ropropyl) tetrahydro - 2H -pyran - 4 - amine ( 122 mg) and 2 - ( 4 ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - (methyl ( 1 -methyl piperidin - 1 -yl ) - 4 -ethylbenzoic acid ( 100 mg ). 1H -pyrazol - 4 - yl) carbamoyl) phenyl) piperidin - 4 -yl ) MS ( ESI + ) : [ M + H ] * 667. 4 . methoxy )phenyl ) propanoic acid Example 50 Step 1 ) ethyl 3 -( 3 - (( 1 - ( 2 - (( 1H -pyrazol - 4 -yl ) carbam oyl) - 5 - ethylphenyl) piperidin - 4 - yl) methoxy ) phenyl) 3 - cyclopropyl- 3 - (3 - (( 1 -( 5 - ethyl- 2 -( ( 2 ,2 ,3 , 3 ,3 -penta 3 -cyclopropylpropanoate fluoropropyl) ( tetrahydrofuran - 3 -yl ) carbamoyl )phe 10 nyl) piperidin - 4 - yl) methoxy ) phenyl) propanoic acid In the same manner as in Example 2 , step 5 , the title compound (81 . 7 mg) was obtained as a white amorphous Step 1 ) N - ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl ) tetrahydro powder from 2 - [ 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopro furan -3 - amine 15 pyl) phenoxy )methyl )piperidin - 1 - yl ) -4 -ethylbenzoic acid ( 100 mg) and 1H -pyrazol - 4 -amine (87 mg) . In the same manner as in Example 14 . step 1 , the title H NMR (400 MHz, DMSO - d . ) 8 0 .07 - 0 . 18 ( 1H , m ) , compound ( 1 . 16 g ) was obtained as a colorless oil from 0 . 18 - 0 .26 ( 1H , m ) , 0 .29 - 0 . 38 ( 1H , m ), 0 .44 - 0 .56 ( 1H , m ) , tetrahydrofuran - 3 -amine (730 mg) . 1 . 00 - 1 . 08 ( 1H , m ) , 1 . 08 ( 3H , t , J = 7 . 2 Hz ) , 1 .21 ( 3H , t , J = 7 . 5 ' H NMR ( 300 MHz, CDC13 ) d 1 . 23 - 1 .39 ( 1H , m ), 1 .67 - 20 Hz ) , 1 . 52 - 1 .70 ( 2H , m ), 1 . 84 - 1 . 98 ( 3H , m ), 2 . 17 - 2 . 30 ( 1H , 1 .81 ( 1H , m ), 2 .05 - 2 . 19 ( 1H , m ) , 3 . 22 (2H , t , J = 15 . 2 Hz) , m ), 2 .61 - 2 . 79 (4H , m ) , 2 .87 ( 2H , t , J = 11 . 3 Hz) , 3 . 15 (2H , d , 3 .45 - 3 . 55 ( 1H , m ), 3 .56 - 3 .64 ( 1H , m ) , 3 . 73 - 3 . 86 ( 2H , m ), J = 11 . 3 Hz ) , 3 .88 - 4 . 01 ( 4H , m ) , 6 .77 - 6 . 86 ( 2H , m ) , 6 . 88 ( 1H , 3 .88 - 4 . 00 (1H , m ) . s ) , 7 . 09 ( 1H , d , J = 7 . 9 Hz ) , 7 . 14 - 7 .25 ( 2H , m ) , 7 . 73 ( 1H , brs ) , 7 .86 ( 1H , d , J = 8 .0 Hz) , 8 . 06 ( 1H , brs ), 12. 03 ( 1H , s ) , 12. 65 Step 2 ) 3 -cyclopropyl - 3 - (3 - (( 1 -( 5 -ethyl - 2 -( ( 2 ,2 ,3 , 3, 25 (1H , brs ). 3 - pentafluoropropyl) ( tetrahydrofuran - 3 - yl) carbam oyl) phenyl) piperidin - 4 -yl ) methoxy )phenyl ) pro Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 panoic acid (methyl ( 1 -methyl - 1H -pyrazol - 4 - yl) carbamoyl) phe nyl )piperidin - 4 - yl) methoxy ) phenyl) propanoate In the samemanner as in Example 32 , step 2 and Example 30 1 , step 4 , the title compound (91 mg) was obtained as a In the same manner as in Example 25, step 2 , the title colorless amorphous powder from N - ( 2, 2 ,3 ,3 ,3 -pentafluo compound (73 .2 mg) was obtained as a colorless oil from ropropyl) tetrahydrofuran - 3 - amine ( 114 mg) and 2 - ( 4 - ( ( 3 - ( 1 ethyl 3 -( 3 - (( 1 - ( 2 - ( (1H -pyrazol - 4 -yl ) carbamoyl ) - 5 - ethylphe cyclopropyl- 3 -ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperi - nyl) piperidin - 4 -yl )methoxy )phenyl ) - 3 -cyclopropylpropano din - 1 - yl) - 4 - ethylbenzoic acid ( 100 mg) . ate (81 .7 mg) . MS (ESI + ) : [ M + H ] * 653 .4 . MS (ESI + ) : [ M + H ]* 573. 5 . Example 51 Step 3 ) 3 - cyclopropyl- 3 - (3 - (( 1- (5 - ethyl- 2- (methyl ( 1 40 methyl- 1H -pyrazol - 4 -yl ) carbamoyl ) phenyl) piperi 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - (( 2 , 2 , 3 , 3 , 3 - penta din - 4 - yl) methoxy ) phenyl) propanoic acid fluoropropyl) (pyridin -2 - yl) carbamoyl) phenyl ) piperi din - 4 -yl ) methoxy ) phenyl) propanoic acid In the same manner as in Example 1, step 4 , the title compound (59 .3 mg) was obtained as a white amorphous 45 powder from ethyl 3 - cyclopropyl- 3 -( 3 -( ( 1 - (5 - ethyl- 2 Step 1 ) (methyl ( 1 -methyl - 1H - pyrazol- 4 - yl) carbamoyl ) phenyl ) pip N -( 2, 2 ,3 ,3 , 3 -pentafluoropropyl ) pyridin -2 -amine eridin - 4 - yl) methoxy ) phenyl ) propanoate ( 73 . 2 mg) . In the same manner as in Example 32, step 1, the title MS (ESI + ): [ M + H ] * 545 . 3 . compound (530 mg ) was obtained as a colorless solid from pyridin - 2 - amine ( 300 mg) . 50 Example 53 ' H NMR ( 300 MHz, CDC13 ) 8 4. 09 -4 .27 (2H , m ), 4 .52 3 - cyclopropyl - 3 - ( 3 - (( 1 -( 2 - ( ( ( 2 , 2 - dimethylpropyl) ( 1H , brs ), 6 .49 ( 1H , dt, J = 8 . 3 , 0 . 8 Hz ), 6 .67 (1H , ddd , J = 7 . 2 , sulfonyl) carbamoyl ) - 5 - ethylphenyl) piperidin - 4 - yl) 5 . 1 , 0 . 8 Hz) , 7 .40 - 7 .50 ( 1H , m ), 8 .12 (1H , ddd , J = 5 . 0 , 1 . 8 , methoxy )phenyl ) propanoic acid 0 .8 Hz ). 55 Step 2 ) 3 -cyclopropyl -3 - (3 -( (1 - (5 - ethyl- 2 - (( 2, 2, 3, 3 , Step 1 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( ( 2 , 2 -dim 3- pentafluoropropyl )( pyridin - 2 -yl ) carbamoyl) phe ethylpropyl) sulfonyl) carbamoyl) - 5 - ethylphenyl) pip nyl) piperidin - 4 -yl ) methoxy )phenyl ) propanoic acid eridin -4 - yl )methoxy )phenyl )propanoate 60 To a solution (3 mL ) of 2 -( 4 - ( 3 - ( 1 -cyclopropyl - 3 -ethoxy In the samemanner as in Example 32 , step 2 and Example 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 - yl) - 4 - ethylben 1 , step 4 , the title compound ( 150 mg ) was obtained as a zoic acid ( 176 mg) in acetonitrile were added 2 , 2 - dimeth colorless amorphous powder from N -( 2 ,2 ,3 , 3 ,3 -pentafluo - ylpropane - 1 -sulfonamide (83 mg) , triethylamine (153 uL ), ropropyl) pyridin - 2 - amine (130 mg) and 2 - ( 4 -( ( 3 -( 1 - cyclo - 2 -methyl - 6 - nitrobenzoic anhydride ( 190 mg) and dimethyl propyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy )methyl ) piperidin - 1 - 65 aminopyridine (67 . 2 mg) , and the mixture was stirred at yl) - 4 - ethylbenzoic acid ( 110 mg) . room temperature for 17 . 5 hr. To the reaction mixture was MS ( ESI + ) : [ M + H ] * 660 . 3 . added water, and the mixture was extracted with ethyl US 9 , 776 , 962 B2 89 90 acetate . The extract was washed with saturated brine, and 2 - ( 4 - ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy ) dried over anhydrous magnesium sulfate . The solvent was methyl) piperidin - 1 - yl) - 4 -ethylbenzoic acid ( 105 mg) . evaporated under reduced pressure, and the residue was MS (ESI + ): [ M + H ] * 625 . 3 . purified by silica gel column chromatography ( ethyl acetate / hexane) to give the title compound ( 173 mg) as a colorless 5 Example 55 oil. 3 - cyclopropyl- 3 - (3 - ( (1 -( 2 -( ( 2 ,2 -dimethylpropyl ) (6 MS ( ESI + ) : [ M + H ] * 613 . 3 . methylpyridin - 2 -yl ) carbamoyl ) - 5 -ethylphenyl )pip eridin -4 - yl) methoxy ) phenyl) propanoic acid Step 2 ) 3 - cyclopropyl- 3 - ( 3 -( ( 1 -( 2 - ( (( 2 , 2 - dimethyl 1010 By a method similar to that in Example 32 , step 2 and propyl) sulfonyl) carbamoyl) - 5 - ethylphenyl) piperidin Example 1 , step 4 , the title compound (68 . 1 mg) was 4 - yl) methoxy ) phenyl) propanoic acid obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 cyclopropyl - 3 - ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperi In the same manner as in Example 1 , step 4 , the title din - 1 - yl) - 4 - ethylbenzoic acid ( 113 . 4 mg) and N - ( 2 , 2 - dim compound ( 170 mg ) was obtained as a pale -vellow amor - 13 ethylpropyl) - 6 -methylpyridin - 2 -amine ( 84 mg ). phous powder from ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( ( 2 , 2 MS ( ESI + ) : [ M + H ] * 612 .3 . dimethylpropyl) sulfonyl ) carbamoyl ) -5 -ethylphenyl ) piperi din - 4 -yl ) methoxy )phenyl )propanoate (173 mg) . Example 56 MS (ESI + ): [ M + H ] * 585 .3 . 20 3 -cyclopropyl - 3 - ( 3 - (( 1 -( 2 -( ( 2, 2 -dimethylpropyl ) (pyridin - 2 - yl) carbamoyl ) -5 -ethylphenyl ) piperidin -4 Example 54 yl)methoxy )phenyl ) propanoic acid By a method similar to that in Example 32 , step 2 and 25 Example 1 , step 4 , the title compound ( 105 mg) was 3 - cyclopropyl- 3 - ( 3 - (( 1 - (5 - ethyl- 2 - ( ( 2 , 2 , 3 , 3 , 3 -penta obtained as a white amorphous powder from 2 - ( 4 - ( ( 3 - ( 1 fluoropropyl) (propan - 2 -yl ) carbamoyl) phenyl) piperi cyclopropyl- 3 - ethoxy - 3 - oxopropylphenoxymethyl) piperi din - 4 - yl) methoxy ) phenyl) propanoic acid din - 1 -yl ) -4 - ethylbenzoic acid ( 116 . 3 mg) and N -( 2 ,2 - dim ethylpropyl) pyridin - 2 - amine (80 mg) . Step 1 ) N -benzyl - 2 ,2 , 3 ,3 , 3 -pentafluoro - N - (propan 3020 . MS (ESI + ): [M + H ]* 598 . 4 . 2 -yl ) propan - 1 -amine Example 57 In the same manner as in Example 14 , step 1 , the title 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - (methyl ( 1 , 3 -ox compound ( 2 . 10 g ) was obtained as a colorless oil from azol- 2 -yl ) carbamoyl ) phenyl ) piperidin - 4 -yl ) methoxy ) N -benzylpropan - 2 -amine (2 .00 g ). phenyl )propanoic acid 'H NMR (300 MHz, CDC13 ) 8 1 .00 (6H , d , J= 6 .6 Hz) , 2 . 93 (1H , dt, J = 13 . 3 , 6 .6 Hz) , 3 .07 (2H , td , J = 15 . 4 , 1 . 1 Hz) , Step 1) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - ( 1 , 3 3 .77 (2H , s ), 7 .19 -7 .38 (5H , m ). oxazol- 2 - ylcarbamoyl) phenyl) piperidin - 4 - yl) methoxy ) phenyl) propanoate 40 Step 2 ) 2 ,2 ,3 , 3, 3 -pentafluoro - N -( propan - 2 -yl ) pro In the same manner as in Example 2 , step 5 , the title pan - 1 - amine hydrochloride compound (27 . 7 mg) was obtained as a colorless oil from 2 - ( 4 - (( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phenoxy ) Under a hydrogen atmosphere , a solution of N -benzyl - 2 , methyl) piperidin - 1 - yl) - 4 - ethylbenzoic acid ( 100 mg) and 2 , 3 , 3 ,3 -pentafluoro - N - (propan - 2 -yl ) propan - 1- amine (2 .10 45 1, 3 - oxazol- 2 - amine (88 mg) . g ) and 20 % palladium hydroxide ( containing water ( 50 % ), H NMR (400 MHz, CDC1 . ) 8 0 . 12 - 0 .22 ( 1H , m ) , 0 . 23 315 mg ) in methanol ( 20 mL ) was stirred at room tempera - 0 . 33 ( 1H , m ), 0 . 38 - 0 . 49 ( 1H , m ) , 0 .54 - 0 .64 ( 1H , m ), 0 . 96 ture for 18 hr. The reaction mixture was filtered through 1 . 10 ( 1H , m ) , 1 . 18 ( 3H , t , J = 7 . 2 Hz ), 1 . 25 - 1 . 32 (3H , m ) , celite , 4N hydrogen chloride ethyl acetate solution ( 3. 73 1. 71 - 1 .89 ( 2H , m ), 1. 97 - 2 . 14 ( 3H , m ), 2 .31 - 2 .40 (1H , m ), mL ) was added to the obtained filtrate , and the solvent was 50 2 .66 - 2 .82 ( 4H , m ) , 2 .95 ( 2H , t , J = 11 . 0 Hz ), 3 . 24 (2H , d , evaporated under reduced pressure . The residue was sus - J = 11 . 8 Hz) , 3 . 93 (2H , d , J = 5 . 9 Hz) , 4 . 01 - 4 . 12 (2H , m ) , pended in ethyl acetate and hexane , and the resultant pre - 6 .72 - 6 .89 ( 3H , m ) , 7 .04 ( 1H , s ) , 7 . 14 - 7 . 19 (2H , m ) , 7 . 20 cipitate was collected by filtration , washed with ethyl 7 . 25 ( 1H , m ), 7 . 46 ( 1H , s ) , 8 . 27 ( 1H , d . J = 8 . 5 Hz ) , 14 . 34 acetate , and dried under reduced pressure to give the title ( 11 . s ). compound ( 1 .33 g ) as a colorless solid . 55 'H NMR (300 MHz, DMSO - d .) 8 1 .32 (6H , d, J =6 . 5 Hz) , Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 3 .58 - 4 .19 (3H , m ) , 9 .92 ( 2H , brs ). (methyl ( 1 , 3 - oxazol - 2 - yl) carbamoyl) phenyl) piperi din -4 -yl ) methoxy )phenyl ) propanoate Step 3 ) 3 -cyclopropyl - 3 - (3 - ( (1 -( 5 -ethyl - 2 -( ( 2 ,2 ,3 , 3, 6060 InIn the same manner as in Example 25 , step 2 , the title 3 -pentafluoropropyl ) (propan - 2 - yl) carbamoyl ) phe compound ( 14 . 8 mg) was obtained as a colorless oil from nyl) piperidin - 4 -yl ) methoxy )phenyl ) propanoic acid ethyl 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 - ethyl- 2 - ( 1 , 3 - oxazol- 2 - yl carbamoyl) phenyl) piperidin - 4 - yl) methoxy )phenyl ) propano In the samemanner as in Example 32 , step 2 and Example ate (27 . 7 mg) . 1 , step 4 , the title compound ( 97 mg) was obtained as a 65 ' H NMR (400 MHz , CDC13 ) 8 0 . 10 - 0 .21 ( 1H , m ), 0 .23 colorless amorphous powder from 2 ,2 , 3 ,3 , 3 -pentafluoro - N - 0 .32 (1H , m ), 0 .38 - 0 .49 ( 1H , m ), 0 .52 -0 .63 ( 1H , m ), 0 . 96 ( propan - 2 -yl ) propan -1 -amine hydrochloride ( 100 mg) and 1 .09 (1H , m ), 1. 18 (3H , t, J= 7. 2 Hz ), 1 .23 (3H , t, J = 7 .6 Hz ), US 9 ,776 , 962 B2 91 92 1. 30 (2H , d , J = 18 .2 Hz ), 1 .73 - 1 .89 ( 3H , m ), 2 . 29 - 2 . 40 ( 1H , Step 4 ) benzyl 2 ,6 -dichloronicotinate m ) , 2 .63 (4H , q , J = 7 . 5 Hz ), 2 .69 - 2 .81 (2H , m ) , 2 .86 - 3 . 10 (2H , m ), 3 .57 ( 3H , s ), 3 .81 (2H , d , J = 6 .0 Hz ), 3 .97 -4 . 14 ( 2H , To a solution ( 50 mL ) of 2 , 6 -dichloronicotinic acid ( 5 . 00 m ), 6 .68 (1H , s ), 6 .73 - 6 . 80 ( 2H , m ) , 6 .82 ( 1H , d , J= 7 .7 Hz) , g ) in DMF were added (bromomethyl ) benzene (4 mL ) and 6 .88 ( 1H , s ), 6 . 92 (1H , d , J= 7 .8 Hz) , 7 .17 (1H , s) , 7 .21 ( 1H , 5 potassium carbonate ( 5 .04 g ) at room temperature , and the t , J = 7 . 8 Hz ), 7 .42 ( 1H , d , J = 7 . 8 Hz) . mixture was stirred for 3 . 5 hr. Water was added to the Step 3 ) 3 - cyclopropyl -3 - (3 - ( (1 - (5 - ethyl- 2 - methyl( 1, reaction mixture , and the mixture was extracted with ethyl 3 - oxazol- 2 - yl ) carbamoyl) phenyl) piperidin - 4 - yl) methoxy ) phenyl) propanoic acid acetate . The extract was washed with saturated brine , and 10 dried over anhydrous magnesium sulfate . The solvent was In the same manner as in Example 1 , step 4 , the title evaporated under reduced pressure , and the residue was compound (59 . 3 mg) was obtained as a white amorphous purified by silica gel column chromatography (ethyl acetate / powder from ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 -( 5 - ethyl- 2 - hexane ) to give the title compound ( 7 . 14 g ) as a yellow oil . (methyl ( 1 ,3 -oxazol - 2 - yl) carbamoyl ) phenyl) piperidin -4 - yl) MS ( ESI + ) : [ M + H ] * 282 . 0 . methoxyphenyl) propanoate ( 14 . 8 mg ) . 15 Step 5) benzyl 6 - chloro -2 -( 4 -( ( 3 -( 1- cyclopropyl - 3 MS (ESI + ) : [ M + H ] * 532 . 3 . ethoxy - 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) Example 58 nicotinate 3 - cyclopropyl- 3 - (3 - ( (1 -( 2 - (( (2 , 2 -dimethylpropyl ) sulfonyl) (methyl )carbamoyl )- 5 -ethylphenyl ) piperi 2010To a solution (40 20 MLmL ) 01of benzyl 2 ,6 -dichloronicotinate din - 4 - yl )methoxy ) phenyl) propanoic acid ( 1 . 00 g ) in THF were added ethyl 3 - cyclopropyl- 3 - ( 3 ( piperidin - 4 - ylmethoxy ) phenyl) propanoate ( 1 .41 g ) and tri In the samemanner as in Example 25, step 2 and Example ethylamine ( 988 uL ) at room temperature, and the mixture 1 , step 4 , the title compound (68 .3 mg) was obtained as a was stirred at 80° C . for 8 hr. To the reaction mixture was pale - yellow oil from ethyl 3 -cyclopropyl - 3 - (3 - ( ( 1 - ( 2 - ( ( ( 2 , 2 - 25 added water . and the mixture was extracted with ethyl dimethylpropyl) sulfonyl) carbamoyl) - 5 - ethylphenyl) piperi acetate . The extract was washed with saturated brine , and din -4 - yl)methoxy ) phenyl) propanoate (175 mg) obtained in dried over anhydrous magnesium sulfate . The solvent was Example 53 , step 1 . evaporated under reduced pressure , and the residue was MS (ESI + ) : [ M + H ] * 599. 3 . purified by silica gel column chromatography ( ethyl acetate ! Example 59 30 hexane ) to give the title compound ( 1 . 56 g ) as a colorless oil . 3 -( 3 -( ( 1 - (6 -chloro - 3 -( ( 2 ,2 -dimethylpropyl ) ( pyridin MS ( ESI + ) : [ M + H ] * 577 .2 . 2 - yl) carbamoyl) pyridin - 2 - yl) piperidin - 4 -yl ) Step 6 ) 6 -chloro - 2 - (4 - (( 3 -( 1 -cyclopropyl - 3 -ethoxy methoxy )phenyl ) - 3 - cyclopropylpropanoic acid 3 - oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) nico 35 Step 1) tert -butyl 4 -( ( 3 -( 1 -cyclopropyl - 3 - ethoxy -3 tinic acid oxopropyl) phenoxy )methyl ) piperidine - 1 - carboxylate Under a hydrogen atmosphere , to a solution (30 mL ) of To a solution of ethyl 3 - cyclopropyl - 3 - ( 3 -hydroxyphenyl ) benzyl 6 -chloro - 2 -( 4 - (3 - ( 1 -cyclopropyl - 3 -ethoxy -3 - oxo propanoate ( 543 mg) in toluene ( 23 . 2 mL ) were added 40 propyl ) phenoxy )methyl ) piperidin - 1 - yl ) nicotinate ( 1 . 56 g ) in tert- butyl 4 - hydroxymethyl) piperidine - 1 - carboxylate (499 THF was added 10 % palladium carbon ( 100 mg) , and the mg) and cyanomethylenetri - n - butylphosphorane ( 1823 ul) at mixture was stirred at room temperature for 3 hr. The room temperature , and the mixture was stirred at 100° C . for reaction mixture was filtered through celite , and the solvent 1 hr. The reaction mixture was cooled to room temperature , in the filtrate was evaporated under reduced pressure to give the solvent was evaporated under reduced pressure , and the 45 a crude product of the title compound ( 1 .37 g ) as a pale residue was purified by silica gel column chromatography yellow oil . This compound was used for the next step ( ethyl acetate / hexane ) to give the title compound (811 mg) without further purification . as a pale - yellow oil . MS (ESI + ) : [ M + H ] * 487. 2 . MS (ESI + ) . found : 376 . 3 . 50 Step 7 ) ethyl 3 - ( 3 - ( ( 1 -( 6 - chloro - 3 - ( ( 2 , 2 -dimethyl Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 3 - (piperidin - 4 - yl propyl )( pyridin - 2- yl ) carbamoyl) pyridin -2 -yl ) piperi methoxy ) phenyl) propanoate hydrochloride din -4 - yl) methoxy ) phenyl) - 3 -cyclopropylpropanoate To a solution of tert -butyl 4 - ( 3 -( 1 -cyclopropyl - 3 -ethoxy 3 -oxopropyl ) phenoxy )methyl ) piperidine - 1 - carboxylate In the same manner as in Example 32 , step 2 , the title (811 mg) in ethyl acetate ( 0 .2 mL ) was added 4N hydro 55 compound was obtained as a pale -yellow oil ( 152 mg) from chloric acid - ethyl acetate solution ( 4 . 7 mL ) at room tem 6 - chloro - 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) perature , and the mixture was stirred for 4 hr. The solvent phenoxy )methyl ) piperidin - 1 -yl )nicotinic acid (150 mg) and was evaporated under reduced pressure to give the title N - ( 2 , 2 -dimethylpropyl ) pyridin - 2 -amine ( 152 mg ) . MS ( ESI + ) : [ M + H ] * 633 . 3 . compound (691 mg) as a pale -white solid . 60 MS (ESI + ): [ M + H ] * 332 . 3 . Step 8 ) 3 -( 3 -( ( 1- ( 6 -chloro -3 -( ( 2 , 2 -dimethylpropyl ) Step 3 ) N - ( 2 , 2 - dimethylpropyl) pyridin - 2 - amine (pyridin - 2 -yl ) carbamoyl) pyridin - 2 -yl ) piperidin - 4 -yl ) methoxy ) phenyl) - 3 - cyclopropylpropanoic acid In the same manner as in Example 32 , step 1 , the title compound ( 3 . 13 g ) was obtained as a white solid from 65 In the same manner as in Example 1 , step 4 , the title pyridin - 2 - amine ( 5 .00 g ) . compound ( 149 mg ) was obtained as a white amorphous MS (ESI + ) : [ M + H ] * 165 . 1 . powder from ethyl 3 - ( 3 - ( ( 1 - ( 6 -chloro - 3 - ( ( 2 , 2 - dimethylpro US 9 ,776 , 962 B2 93 94 pyl) (pyridin - 2 - yl ) carbamoyl) pyridin - 2 - yl) piperidin - 4 - yl) Example 61 methoxy )phenyl ) -3 -cyclopropylpropanoate ( 152 mg) . 3 -cyclopropyl -3 - (3 -( (1 - (2 -( (2 - (2 ,2 -dimethylpro MS (ESI + ): [M + H ] * 605. 3 . panoyl )hydrazino ) carbonyl) - 5 -methoxyphenyl ) pip eridin - 4 - yl )methoxy ) phenyl) propanoic acid Example 60 Step 1 ) methyl 2 -( 4 - hydroxymethyl) piperidin - 1 yl) - 4 -methoxybenzoate 3 -cyclopropyl - 3 -( 3 -( (1 -( 3 -( ( 2 ,2 -dimethylpropyl ) (pyridin - 2 -yl ) carbamoyl ) -6 -ethylpyridin - 2 -yl ) piperi In the same manner as in Example 1 , step 1 , the title 1010 compound was obtained as a pale -yellow oil ( 3 .77 g ) from din - 4 - yl) methoxy )phenyl ) propanoic acid methyl 2 - fluoro - 4 -methoxybenzoate . MS (ESI + ) : [ M + H ] * 280 . 2 . Step 1 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 - dim ethylpropyl ) (pyridin - 2 - yl) carbamoyl) - 6 - vinylpyri Step 2 ) methyl 4 -methoxy - 2 -( 4 -( (methoxymethoxy ) din - 2 -yl ) piperidin - 4 - yl) methoxy )phenyl ) propanoate 15 methyl) piperidin - 1 -yl ) benzoate A solution of chloromethyl methyl ether ( 0 .84 mL ), Under a nitrogen atmosphere , to a solution ( 2 mL) of ethyl methyl 2 - ( 4 - hydroxymethyl ) piperidin - 1 - yl )- 4 -methoxy 3 - ( 3 - ( ( 1 - (6 - chloro - 3 - ( ( 2 , 2 -dimethylpropyl ) (pyridin - 2 -yl ) benzoate ( 1 .03 g ) and diisopropylamine ( 2 . 58 mL ) in THF carbamoyl) pyridin - 2 - yl) piperidin - 4 - yl )methoxy )phenyl ) - 3 - 20 (10 mL ) was stirred at room temperature overnight. The cyclopropylpropanoate obtained in Example 59 , step 7 , in reaction mixture was added to water, and the mixture was DME were added tetrakistrinhenylphosphinepalladium extracted with ethyl acetate . The extract was washed with water and saturated brine , and dried over anhydrous mag ( 38 .1 mg) , aqueous sodium carbonate solution ( 2 M , 495 uL ) nesium sulfate . The solvent was evaporated under reduced and 4 , 4 , 5 , 5 - tetramethyl - 2 -vinyl - 1 , 3 , 2 -dioxaborolane (153 25 pressure to give a crude product of the title compound as a mg) , and the mixture was stirred at 80° C . for 7 . 5 hr. 25 colorless oil. This compound was used for the next step Tetrakistriphenylphosphinepalladium (38 . 1 mg ) was added , without further purification . and the mixture was further stirred at 80° C . for 16 hr. To the MS ( ESI + ) : [ M + H ] * 324 . 1 . reaction mixture was added water, and the mixture was extracted with ethyl acetate . The extract was washed with Step 3 ) 4 -methoxy - 2 - ( 4 - ( (methoxymethoxy )methyl ) saturated brine , and dried over anhydrous magnesium sul piperidin - 1 - yl) benzohydrazide fate. The solvent was evaporated under reduced pressure, A solution ofmethyl 4 -methoxy -2 - (4 -( (methoxymethoxy ) and the residue was purified by silica gel column chroma methyl) piperidin - 1 - yl) benzoate ( entire amount ) and hydra tography ( ethyl acetate /hexane ) to give the title compound zine monohydrate ( 1 . 84 g ) in ethanol ( 9 . 2 mL ) was stirred (181 mg) as a pale -yellow oil. overnight under heated reflux . The reaction mixture was MS (ESI + ) : [ M + H ]* 625 .4 . concentrated under reduced pressure , the residue was added to water , and the mixture was extracted with ethyl acetate . The extract was washed with water and saturated brine , and Step 2 ) ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 -dim dried over anhydrous magnesium sulfate . The solvent was ethylpropyl ) (pyridin -2 -yl ) carbamoyl) - 6 - ethylpyri 40 evaporated under reduced pressure , and the residue was din - 2 - yl) piperidin - 4 - yl) methoxy )phenyl ) propanoate purified by silica gel column chromatography (ethyl acetate ! hexane and methanol/ ethyl acetate ) to give the title com Under a hydrogen atmosphere ( 1 atmosphere ) , to a solu pound ( 1 .04 g ) as a white solid . tion ( 4 mL ) of ethyl 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 - dimeth MS (ESI + ): [ M + H ] * 324 . 1 . ylpropyl) ( pyridin -2 - yl )carbamoyl )- 6 - vinylpyridin - 2 -yl ) pip - 45 Step 4 ) N '- (2 , 2 - dimethylpropanoyl) -4 -methoxy -2 eridin - 4 - yl) methoxy ) phenyl )propanoate (181 mg) in ethyl ( 4 - ( (methoxymethoxy )methyl ) piperidin - 1 - yl) benzo acetate was added 10 % palladium carbon ( 20 mg) , and the hydrazide mixture was stirred at room temperature for 20 min . The reaction mixture was filtered through celite , the solvent in To a solution of 4 -methoxy -2 -( 4 -( (methoxymethoxy ) the filtrate was evaporated under reduced pressure , and the 30 methyl) piperidin - 1 - yl) benzohydrazide (400 mg ) and trieth ylamine ( 0 .517 mL ) in THF ( 4 mL ) was added 2 , 2 - dimeth residue was purified by silica gel column chromatography ylpropanoyl chloride ( 0 .305 mL ) at 0° C ., and the mixture ( ethyl acetate /hexane ) to give the title compound (173 mg) was stirred for 30 min . The reaction mixture was added to as a pale -yellow oil. water, and the mixture was extracted with ethyl acetate . The MS (ESI + ) : [ M + H ]* 627. 4 . 55 extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate . The solvent was evapo Step 3 ) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 - dimethyl rated under reduced pressure to give a crude product (499 . 5 propyl) (pyridin - 2 - yl) carbamoyl ) -6 -ethylpyridin - 2 - yl) mg ) of the title compound as a white solid . This compound piperidin - 4 - yl) methoxy ) phenyl) propanoic acid was used for the next step without further purification . 60 MS ( ESI + ) : [ M + H ] * 408 . 2 . In the same manner as in Example 1 , step 4 , the title Step 5 ) 1 -( 2 -( 5 -tert -butyl - 1, 3 ,4 -oxadiazol - 2 -yl ) -5 compound ( 163 mg) was obtained as a white amorphous methoxyphenyl) - 4 - ( (methoxymethoxy )methyl ) pip powder from ethyl 3 -cyclopropyl - 3 -( 3 -( ( 1 -( 3 - ( (2 , 2 -dimeth ylpropyl) (pyridin - 2 -yl ) carbamoyl) - 6 - ethylpyridin - 2 - yl) pip - 65 eridine eridin -4 -yl ) methoxy ) phenyl) propanoate ( 173 mg) . A solution of N -( 2, 2 -dimethylpropanoyl ) - 4 -methoxy -2 MS (ESI + ) : [M + H ] * 599. 4 . (4 - ( (methoxymethoxy )methyl ) piperidin - 1 -yl ) benzohydraz US 9 ,776 ,962 B2 95 96 ide (250 mg) obtained in step 4 and 3 , 3 , 3 -triethyl - 1 - amorphous powder from methyl 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 (methoxycarbonyl )diazathian -3 -ium - 1- ide 2, 2 -dioxide (292 m ethoxy -2 - (pyridin -2 -ylcarbamoyl ) phenyl ) piperidin -4 - yl ) mg ) in THF ( 4 mL ) was stirred at 60° C . for 2 hr . The methoxy )phenyl ) propanoate (170 mg) . reaction mixture was evaporated under reduced pressure, MS (ESI + ) : [ M + H ] * 586 . 4 . and the residue was purified by silica gel column chroma- 5 tography (ethyl acetate /hexane ) to give the title compound Example 63 (119 . 6 mg) as a pale - yellow oil . MS (ESI + ) : [ M + H ] * 390 .2 . 3 - ( 3 - ( ( 1 - ( 2 - ( ( cycloheptylmethyl ) carbamoyl) - 5 methoxyphenyl) piperidin -4 - yl) methoxy ) phenyl) - 3 Step 6 ) ethyl 3 - cyclopropyl - 3 - ( 3 - (( 1 - ( 2 - ( ( 2 - ( 2 , 2 10 cyclopropylpropanoic acid dimethylpropanoyl) hydrazino ) carbonyl) - 5 -methoxy phenyl )piperidin - 4 - yl) methoxy ) phenyl) propanoate To a solution of 2 - (4 - (3 - ( 1- cyclopropyl -3 -methoxy -3 oxopropyl) phenoxy )methyl ) piperidin - 1 - yl) - 4 -methoxyben Concentrated hydrochloric acid ( 0 .256 mL ) was added to zoic acid (37 . 4 mg) in DMF (500 uL ) were added cyclo a solution of 1 - ( 2 - ( 5 - tert - butyl- 1 , 3 , 4 -oxadiazol - 2 - yl) - 5 - heptylmethanamine ( 20 . 36 mg) , N - ethyldiisopropylamine methoxyphenyl) - 4 - ( (methoxymethoxy )methyl ) piperidine (27 . 9 ul) and O - ( 7 - azabenzotriazol- 1 -yl ) - N , N , N ', N ' -tetram (119 . 6 mg ) in methanol ( 2 mL) at room temperature, and the ethyluronium hexafluorophosphate (60 . 8 mg) , and the mix mixture was stirred at 60° C . for 1 hr. The reaction mixture ture was stirred at room temperature overnight. To the was neutralized with saturated aqueous sodium hydrogen reaction solution were added aqueous sodium hydrogen carbonate solution , and extracted with ethyl acetate . The extractwas washed with water and saturated brine , and dried mixture was stirred . The organic layer was extracted , and the over anhydrous magnesium sulfate . To a solution of the solvent was evaporated by Multi - sample solvent extraction residue in toluene ( 2 mL ) were added ( tributylphosphora system with solvent recovery ( Soltrapper, The Institute of nylidene )acetonitrile ( 0 . 161 mL ) and ethyl 3 -cyclopropyl Creative Chemistry Co . , Ltd . ) . The residue was purified by 3 - ( 3 -hydroxyphenyl ) propanoate ( 94 mg) , and thehe mixture 25 HPLC (column : YMC Triart C18 , mobile phase : acetoni was stirred at 100° C . for 2 hr under a nitrogen atmosphere . trile / 10 mM aqueous ammonium hydrogen carbonate solu The reaction mixture was concentrated under reduced pres tion ) , and the solvent was evaporated by Multi - sample sure , and the residue was purified by silica gel column solvent extraction system with solvent recovery . To the chromatography ( ethyl acetate/ hexane ) to give the title com residue were added methanol ( 500 UL ) , tetrahydrofuran (500 pound (20 . 9 mg) as a colorless oil . 30 uL ) and 2 M aqueous sodium hydroxide solution (500 UL ) , and the mixture was stirred at 60° C . overnight. The solvent MS (ESI + ): [M + H ] * 580. 4 . was evaporated by Multi - sample solvent extraction system with solvent recovery . The residue was purified by HPLC Step 7 ) 3 - cyclopropyl- 3 - ( 3 - (( 1 - ( 2 - ( ( 2 - ( 2 , 2 - dimethyl ( column : YMC Triart C18 , mobile phase : acetonitrile / 10 propanoyl) hydrazino )carbonyl ) -5 -methoxyphenyl ) 35 mM aqueous ammonium hydrogen carbonate solution ), and piperidin -4 -yl ) methoxy )phenyl ) propanoic acid the solvent was evaporated by Multi -sample solvent extrac tion system with solvent recovery to give the title compound In the same manner as in Exampleample 1 , step 4 , the title (21 . 3 mg) . compound ( 18 . 9 mg) was obtained as a white amorphous powder from ethyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 - ( 2 , 2 -dim - 40 Examples 64 - 108 ethylpropanoyl) hydrazino )carbonyl ) -5 -methoxyphenyl ) pip eridin - 4 -yl ) methoxy )phenyl )propanoate ( 20 . 9 mg) . The compounds shown in the following Tables were MS ( ESI+ ): [M + H ]* 552 .3 . produced by a method similar to that in Example 63 . Example 62 45 TABLE 1 - 1 | MS 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - (5 -methoxy - 2 - ( ( 2 -methylpro Ex. compound name (ESI + ) M . W . pyl )( pyridin -2 - yl) carbamoyl) phenyl )piperidin - 4 -yl ) 3 - ( 3 - ( ( 1 - ( 2 - ( (cycloheptylmethyl ) 563 . 3 562 .7 methoxy ) phenyl) propanoic acid 50 carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 yl) methoxy ) phenyl )- 3 -cyclopropylpropanoic acid Step 1 ) methyl 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 -cyclohexylethyl ) 563 . 3 562. 7 2 - (pyridin - 2 - ylcarbamoyl ) phenyl) piperidin - 4 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 methoxy )phenyl ) propanoate yl) methoxy ) phenyl )- 3 -cyclopropylpropanoic 5555 acid 65 3 - ( 3 - ( ( 1 - ( 2 - ( ( ( 1R ) - 1 - cyclohexylethyl) 563 . 3 562. 7 In the same manner as in Example 2 , step 5 , the title carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 compound (520 mg ) was obtained as white crystals from yl) methoxy )phenyl ) - 3 - cyclopropylpropanoic acid 2 - aminopyridine ( 403 mg) . 66 3 - ( 3 -( ( 1 - ( 2 - ( (( 1S, 4R )- bicyclo [ 2 . 2 . 1 ] hept 561. 3 560 . 7 MS (ESI + ): [ M + H ]* 544 . 5 . 2 -ylmethyl )carbamoyl ) - 5 -methoxyphenyl ) 60 piperidin - 4 -yl ) methoxy )phenyl )- 3 cyclopropylpropanoic acid Step 2 ) 3 -cyclopropyl - 3 -( 3 -( ( 1- ( 2- (( 2 -methylpropyl ) 3 - cyclopropyl- 3 - ( 3 - (( 1 - ( 2 - ( 2, 3 -dihydro - 1H 569 . 3 568. 7 (pyridin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) piperi inden - 5 - ylcarbamoyl) - 5 -methoxyphenyl ) din - 4 -yl ) methoxy )phenyl ) propanoic acid piperidin - 4 - yl )methoxy )phenyl ) propanoic acid 3 - cyclopropyl- 3 -( 3 - ( ( 1 - ( 2 - (bis ( 2 565 . 4 564. 8 og og methylpropyl) carbamoyl) - 5 -methoxyphenyl ) In the samemanner as in Example 25 , step 2 and Exampleole piperidin - 4 - yl )methoxy )phenyl ) propanoic acid 1 , step 4, the title compound (50 mg ) was obtained as a white US 9 ,776 , 962 B2 97 98 TABLE 1 -1 -continued TABLE 1 - 4 MS MS Ex . compound name ( ESI+ ) M . W . Ex . compound name (ESI + ) M .W . 5 3 -cyclopropyl - 3 -( 3 -( ( 1- ( 5- methoxy - 2 529 . 2 528 . 6 (phenylcarbamoyl ) phenyl) piperidin - 4 69 3 - cyclopropyl- 3 -( 3 -( ( 1 - ( 2 -( ( cyclopropyl 583. 4 582 . 7 yl)methoxy )phenyl ) propanoic acid (phenyl ) methyl ) carbamoyl ) - 5 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 3 523. 3 522 . 7 . methylbutan - 2 - yl) carbamoyl) methoxyphenyl) piperidin -4 phenyl) piperidin - 4 yl) methoxy )phenyl ) propanoic acid 10 yl)methoxy )phenyl ) propanoic acid 3 - cyclopropyl- 3 -( 3 -( ( 1 -( 5 -methoxy -2 - ( ( 2 543. 3 542 . 7 methylphenyl) carbamoyl ) phenyl ) piperidin - 4 yl) methoxy )phenyl )propanoic acid 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 543 . 3 542 . 7 TABLE 1 - 2 15 (methyl (phenyl )carbamoyl ) phenyl) piperidin 4 - yl) methoxyphenyl ) propanoic acid MS 3 - ( 3 - ( ( 1 - ( 2 - ( (cyclobutylmethyl ) carbamoyl) 521 . 3 520 . 7 Ex . compound name (ESI + ) M . W . 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) 70 3 - ( 3 - ( ( 1 - ( 2 - ( ( cyclohexylmethyl) carbamoyl ) 549 . 3 548 . 7 phenyl) - 3 - cyclopropylpropanoic acid 5 -methoxyphenyl ) piperidin - 4 -yl )methoxy ) 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 547 . 2 546 . 6 phenyl) - 3 - cyclopropylpropanoic acid 20 fluorophenyl) carbamoyl) - 5 3 - cyclopropyl- 3 -( 3 -( ( 1 -( 5 - methoxy -2 - ( ( 2 571. 4 570 . 7 methoxyphenyl) piperidin - 4 phenylpropyl )carbamoyl ) phenyl ) piperidin -4 yl)methoxy )phenyl ) propanoic acid yl) methoxy )phenyl )propanoic acid 3 -( 3 -( ( 1- ( 2- ( butyl ( methyl ) carbamoyl) - 5 523 . 3 522. 7 72 3 - cyclopropyl - 3 - ( 3 - (( 1 - ( 2 - (hexyl (methyl ) 551 . 4 550 . 7 methoxyphenyl )piperidin - 4 - yl )methoxy ) carbamoyl) - 5 -methoxyphenyl ) piperidin -4 phenyl) - 3 -cyclopropylpropanoic acid yl )methoxy )phenyl ) propanoic acid 25 73 3 -cyclopropyl - 3 - (3 - ( ( 1 - ( 2 - ( ( 3 ,3 537. 3 536. 7 dimethylbutyl) carbamoyl ) - 5 methoxyphenyl) piperidin - 4 yl) methoxy )phenyl ) propanoic acid TABLE 1 - 5 74 3 - cyclopropyl - 3 - ( 3 - (( 1 - ( 2 - ( 2 , 3 - dihydro - 1H 569. 3 568. 7 30 MS inden - 1 - ylcarbamoyl) - 5 Ex . compound name (ESI + ) M . W . methoxyphenyl) piperidin - 4 yl )methoxy )phenyl ) propanoic acid 91 3 -cyclopropyl -3 - (3 - (( 1 - (2 - ([ ( 2S )- 1 553 . 3 552 . 7 75 3 -cyclopropyl - 3 - ( 3 - ( 1 - ( 5 -methoxy - 2 585 . 3 584 . 7 hydroxy -4 -methylpentan - 2 - yl) carbamoyl ) - 5 (methyl ( 3- phenylpropyl ) methoxyphenyl) piperidin - 4 carbamoyl )phenyl ) piperidin - 4 yl) methoxy )phenyl ) propanoic acid 35 92 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ethyl( 2 , 2 , 2 563 . 3 562 . 6 yl) methoxy )phenyl )propanoic acid trifluoroethyl) carbamoyl ) - 5 76 3 - cyclopropyl- 3 -( 3 -( ( 1- ( 5 -methoxy - 2 557 . 3 556 . 7 methoxyphenyl )piperidin -4 (( ( 1R )- 1- phenylethyl ) carbamoyl) yl) methoxy )phenyl )propanoic acid phenyl) piperidin -4 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 1 539 . 3 538 . 7 yl )methoxy )phenyl ) propanoic acid methoxybutan - 2 -yl ) carbamoyl) 40 phenyl) piperidin - 4 yl) methoxy ) phenyl) propanoic acid 94 3 -cyclopropyl - 3 -( 3 - ( ( 1 - ( 2 - (ethyl ( pyridin 572 . 4 571 . 7 4 - ylmethyl) carbamoyl) - 5 TABLE 1 - 3 methoxyphenyl) piperidin - 4 MS yl) methoxy )phenyl )propanoic acid 45 95 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 521 . 3 520 . 7 Ex. compound name (ESI + ) M .W . ( piperidin - 1- ylcarbonyl )phenyl ) piperidin 77 3 - ( 3 - ( ( 1 - ( 2 - ( benzyl( methyl ) carbamoyl ) - 5 557 . 3 556 . 7 4 -yl )methoxy )phenyl ) propanoic acid methoxyphenyl) piperidin - 4 -yl )methoxy ) 96 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 2 509. 3 508 . 7 phenyl) - 3 -cyclopropylpropanoic acid (diethylcarbamoyl ) -5 -methoxyphenyl ) 78 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 523 . 3 552 . 7 piperidin - 4 -yl ) methoxy ) phenyl ) propanoic ( ( ( 2S ) - 2 -methylbutylcarbamoyl ) 50 acid phenyl )piperidin - 4 97 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 553 . 3 552 . 7 yl )methoxy )phenyl ) propanoic acid ( tetrahydro - 2H -thiopyran - 4 553. 3 79 3 - ( 3 - (( 1 - ( 2 - (benzylcarbamoyl ) - 5 543 . 3 542. 7 ylcarbamoyl) phenyl ) piperidin - 4 methoxyphenyl) piperidin - 4 - yl) methoxy ) yl) methoxy )phenyl )propanoic acid phenyl) - 3 -cyclopropylpropanoic acid 80 3 - cyclopropyl- 3 -( 3 -( ( 1- ( 5 -methoxy - 2 571. 4 570 .7 55 (methyl ( 2 - phenylethyl) carbamoyl) phenyl )piperidin - 4 TABLE 1 - 6 yl) methoxy )phenyl )propanoic acid 81 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 523 . 3 522. 7 MS (pentan - 3 - ylcarbamoyl) phenyl) piperidin - 4 compound name ( ESI + ) M . W . yl) methoxy )phenyl )propanoic acid Ex. 82 3 - ( 3 - ( ( 1 - ( 2 - (cyclohexyl (methyl ) carbamoyl ) - 549. 3 548. 7 98 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 2 - ( ( ( 2S ) - 1 539 . 3 538 . 7 5 -methoxyphenyl ) piperidin - 4 hydroxy - 3 -methylbutan - 2 - yl) carbamoyl ) - 5 yl) methoxy ) phenyl ) - 3 - cyclopropylpropanoic methoxyphenyl )piperidin -4 acid yl) methoxyphenyl ) propanoic acid 83 3 - ( 3 - ( ( 1 - ( 2 - (cyclopentyl ( ethyl ) carbamoyl ) 549 . 3 548 . 7 3 -cyclopropyl - 3 -( 3 -( ( 1- ( 2- ( (3 -hydroxy - 2 , 2 539 . 3 538 . 7 5 -methoxyphenyl ) piperidin - 4 -yl )methoxy ) dimethylpropyl ) carbamoyl) - 5 phenyl) - 3 -cyclopropylpropanoic acid 65 methoxyphenyl) piperidin - 4 yl) methoxy )phenyl ) propanoic acid US 9 ,776 ,962 B2 99 100 TABLE 1 - 6 -continued C . , ice water was added , and the mixture was extracted with ethyl acetate . The extract was washed with saturated brine , MS and dried over anhydrous sodium sulfate . The solvent was Ex. compound name ( ESI + ) M . W . evaporated under reduced pressure, and the residue was 100 3 - cyclopropyl- 3 - ( 3 - (( 1 - ( 5 -methoxy - 2 ( (pyridin - 4 - ylmethyl) carbamoyl ) 544 .2 543. 7 5 purified by silica gel column chromatography ( ethyl acetate / phenyl) piperidin - 4 hexane ) to give the title compound ( 379mg ) as a white solid . yl) methoxy )phenyl ) propanoic acid MS ( ESI + ) : [ M + H ] * 329 . 3 . 101 3 -cyclopropyl - 3 - ( 3 - (( 1 - ( 5 -methoxy - 2 531. 2 530 . 6 (pyrimidin - 5 - ylcarbamoyl) phenyl) piperidin Step 3 ) N - ( 2 , 2 - dimethylpropyl) - 4 - ethyl- 2 - ( 4 - ( hy 4 - yl) methoxyphenyl ) propanoic acid 1010 102 3 -cyclopropyl - 3 - ( 3 - (( 1 - ( 5 -methoxy - 2 544 . 2 543 . 7 droxymethyl ) piperidin - 1 - yl) - N - ( 6 -methylpyridin - 2 (methyl (pyridin - 2 yl )benzamide yl) carbamoyl) phenyl) piperidin - 4 yl) methoxyphenyl ) propanoic acid 103 3 - ( 3 - ( ( 1 - ( 2 - (( 2 - cyanoethyl) 520 . 3 519 . 6 By a method similar to that in Example 1 , step 2 , the title (methyl ) carbamoyl ) - 5 -methoxyphenyl ) compound ( 107 mg) was obtained as a colorless oil from piperidin - 4 - yl) methoxy )phenyl ) - 3 4 - ethyl- 2 - fluoro - N - (6 -methylpyridin - 2 - yl) - N - ( 2 , 2 - dimeth cyclopropylpropanoic acid 104 3 -cyclopropyl - 3 - (3 - (( 1 - ( 2 - (( 2 ,2 537. 3 536 . 7 ylpropyl) benzamide (375 .6 mg ) . dimethylpropyl) (methyl ) carbamoyl ) - 5 MS ( ESI + ) : [ M + H ] * 424 . 3 . methoxyphenyl )piperidin - 4 yl)methoxy )phenyl ) propanoic acid Step 4 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl 20 propyl) (6 -methylpyridin - 2 - yl) carbamoyl) - 5 - ethyl phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro TABLE 1 -7 panoic acid MS 25 By a method similar to that in Example 45 , step 6 and Ex . compound name ( ESI+ ) M . W . 2 Example 1 , step 4 , the title compound (93 mg) was obtained 105 3 -cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 - ( (4 - 551. 3 550 . 7 as a white amorphous powder from N - ( 2 , 2 -dimethylpropyl ) methoxypiperidin - 1 yl) carbonyl) phenyl ) piperidin - 4 4 - ethyl- 2 - (4 - hydroxymethyl) piperidin - 1 -yl ) -N -( 6 -methyl yl )methoxy ) phenyl) propanoic acid pyridin - 2 - yl) benzamide ( 106 . 4 mg) and ethyl 3 -cyclopro 106 3 - cyclopropyl- 3 - ( 3 - (( 1 - ( 5 -methoxy - 2 545 . 2 544 . 6 30 pyl- 3 - (2 -hydroxypyridin -4 -yl ) propanoate (65 . 0 mg) . ( (pyrimidin - 2 545. 2 544 .6 ylmethyl )carbamoyl )phenyl )piperidin - 4 MS (ESI + ) : [ M + H ] * 613 . 4 . yl) methoxy )phenyl ) propanoic acid 107 3 -cyclopropyl - 3- ( 3- (( 1 -( 5 -methoxy - 2 -( (2 564 . 3 563. 7 Example 110 (piperidin - 1 - yl ) ethyl )carbamoyl ) phenyl )piperidin - 4 35 yl) methoxy )phenyl )propanoic acid 35 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 -dimethylpropyl ) (6 108 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 5 -methoxy - 2 573 . 3 572. 7 methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) (methyl ( 2 - (methylsulfonyl ) ethyl ) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoic acid carbamoyl) phenyl ) piperidin - 4 yl) methoxy )phenyl ) propanoic acid Step 1) N - ( 2, 2 -dimethylpropyl ) - 2 - fluoro - 4 40 methoxy - N - (6 -methylpyridin - 2 - yl ) - benzamide Example 109 By a method similar to that in Example 1 , step 1 , the title compound ( 1 .65 g ) was obtained as a white solid from 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) (6 15 2 -fluoro - 4 -methoxybenzoic acid ( 2 . 16 g ) and N - ( 2 , 2 - dim methylpyridin - 2 - yl ) carbamoyl) - 5 - ethylphenyl) pip ethylpropyl) - 6 -methylpyridin - 2 - amine ( 1 . 13 g ) . eridin -4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid MS (ESI + ) : [ M + H ] * 331. 3 . Step 1 ) 4 - bromo- N - ( 2 , 2 - dimethylpropyl) - 2 - fluoro Step 2 ) N - ( 2 , 2 -dimethylpropyl ) - 2 - ( 4 - (hydroxym N - ( 6 -methylpyridin - 2 - yl) benzamide 5050 ethyl) piperidin - 1 -yl ) - 4 -methoxy - N -( 6 -methylpyri din - 2 - yl) benzamide By a method similar to that in Example 1 , step 1 , the title compound (464 mg) was obtained as a white solid from By a method similar to that in Example 1, step 2, the title 4 - bromo - 2 - fluorobenzoic acid ( 593 mg) and N - ( 2 , 2 - dimeth compound ( 1 .08 g ) was obtained as a white powder from ylpropyl ) - 6 -methylpyridin - 2 - amine ( 241. 2 mg) . 55 N - ( 2 , 2 -dimethylpropyl ) - 2 -fluoro -4 -methoxy - N -( 6 -methyl MS (ESI + ) . found : 379 . 1 , 381 . 2 . pyridin - 2 - yl) benzamide ( 1 .65 g ) . Step 2 ) N - (2 , 2 - dimethylpropyl) - 4 - ethyl- 2 - fluoro - N MS (ESI + ): [ M + H ] * 426 . 4 . (6 -methylpyridin - 2 -yl ) benzamide Step 3 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl 60 propyl) ( 6 -methylpyridin -2 - yl ) carbamoyl) - 5 Under a nitrogen atmosphere, to a solution of 4 -bromo methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 N - ( 2 , 2 - dimethylpropyl) - 2 - fluoro - N - ( 6 -methylpyridin - 2 - yl) yl) propanoic acid benzamide (459 . 5 mg) in DMF (8 mL ) were added potas YP sium carbonate (419 mg) , diethyl zinc ( 1817 ul) and [ 1, 1 ' By a method similar to that in Example 45 , step 6 and bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( II) 65 Example 1 , step 4 , the title compound ( 167 mg) was (22 . 0 mg ) at room temperature , and the mixture was stirred obtained as a pale - yellow amorphous powder from N - ( 2 , 2 at 80° C . for 1 . 5 hr. The reaction mixture was cooled to 0° dimethylpropyl ) - 2 - ( 4 - (hydroxymethyl ) piperidin - 1 -yl ) - 4 US 9 ,776 , 962 B2 101 102 methoxy - N - ( 6 -methylpyridin - 2 -yl ) benzamide (212 . 3 mg) as a pale -yellow amorphous powder from 2 -( 4 - (( ( 4 - ( 1 -cy and ethyl 3 -cyclopropyl - 3 -( 2 -hydroxypyridin -4 - yl )propano clopropyl- 3 -ethoxy -3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) ate ( 129 mg ) . piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 101. 0 mg) and MS (ESI + ) : [M + H ]* 615. 3 . N - ( 2 -methylpropyl ) pyridin - 2 - amine (62 . 9 mg) . Example 111 5 MS (ESI + ): [ M + H ]* 587. 3 . 3 - cyclopropyl- 3 - (2 - ( (1 -( 2 -( (2 , 2 -dimethylpropyl ) Example 114 (pyridin - 2 -yl ) carbamoyl) -5 -methoxyphenyl ) piperi din - 4 -yl ) methoxy ) pyridin - 4 - yl) propanoic acid 10 3 -cyclopropyl - 3 - (2 - ( (1 -( 5 -methoxy - 2 -( (( 1 -methylcy Step 1 ) benzyl 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 clopropyl) methyl ) (pyridin - 2 -yl ) carbamoyl) phenyl) oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid 4 -methoxybenzoate Step 1 ) By a method similar to that in Example 45 , step 6 , the title 15 N -( ( 1- methylcyclopropyl ) methyl ) pyridin - 2- amine compound ( 153 mg) was obtained as a colorless oil from benzyl 2 -( 4 - hydroxymethyl) piperidin - 1 -yl ) - 4 -methoxyben In the same manner as in Example 32 , step 1 , the title zoate ( 164. 1 mg) and ethyl 3 - cyclopropyl- 3 - ( 2 - hydroxypyri compound ( 2 . 88 g ) was obtained as a colorless solid from din - 4 - yl) propanoate (119 mg) . 20 pyridin - 2 -amine ( 4 . 20 g ) and 1 -methylcyclopropanecarbox MS ( ESI + ): [M + H ] * 573 .5 . ylic acid (4 . 11 g ). Step 2 ) 2 - [ 4 -( (( 4 -( 1 - cyclopropyl- 3 - ethoxy -3 -oxopro H NMR ( 300 MHz , CDC12 ) d 0 .31 - 0 . 39 (2H , m ), 0 .43 pyl) pyridin - 2- yl ) oxy )methyl ) piperidin - 1- yl ) - 4 0 . 50 (2H , m ), 1 . 16 (3H , s ), 3 . 12 ( 2H , d , J = 5 .5 Hz ), 4 . 54 ( 1H , methoxybenzoic acid brs ) , 6 . 36 ( 1H , dt, J = 8 . 4 , 0 . 8 Hz) , 6 .54 ( 1H , ddd , J = 7 . 1 , 5 . 1 , 25 0 . 9 Hz ), 7 .40 ( 1H , ddd , J = 8 . 5 , 7 . 0 , 1 . 9 Hz) , 8 .02 - 8 . 10 ( 1H , By a method similar to that in Example 2 , step 4 , the title m ) . compound ( 845 mg ) was obtained as a colorless oil from benzyl 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( ( 1 pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzo methylcyclopropyl) methyl ) (pyridin - 2 - yl) carbamoyl ) ate ( 1. 06 g ). 30 phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro MS (ESI + ): [ M + H ] * 483 . 4 . panoic acid Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl propyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) In the same manner as in Example 32, step 2 and Example piperidin - 4 - vl) methoxy ) pyridin - 4 -ylpropanoic acid 35 1 , step 4 , the title compound ( 59 mg) was obtained as a colorless amorphous powder from N - ( ( 1 - methylcyclopro By a method similar to that in Example 32 . step 2 and pyl) methyl ) pyridin - 2 -amine ( 101 mg) and 2 - ( 4 - { [ ( 4 - ( 1 - cy F clopropyl- 3 -ethoxy -3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopro - piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 mg) . pyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl )oxy )methyl ) piperi - 40 MS (ESI + ) : [ M + H ] * 599 . 3 . din - 1 - yl) - 4 -methoxybenzoic acid ( 109. 4 mg) and N - ( 2 , 2 dimethylpropyl) pyridin -2 -amine (74 .5 mg) . Example 115 MS ( ESI + ) : [ M + H ] * 601 . 3 . Example 112 45 3 -cyclopropyl - 3 -( 2 -( ( 1 - (5 -methoxy - 2 -( ( 2- methylpro pyl) ( 5 -methylpyridin -2 - yl) carbamoyl ) phenyl ) piperi 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 -dimethylpropyl ) ( 4 din - 4 - yl )methoxy )pyridin -4 - yl) propanoic acid methylpyridin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 50 Step 1 ) By a method similar to that in Example 32 , step 2 and 5 -methyl - N -( 2 -methylpropyl ) pyridin - 2 - amine Example 1 , step 4 , the title compound ( 100 mg) was obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - 1 In the same manner as in Example 32 , step 1 , the title cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy ) compound ( 386 mg) was obtained as a pale - yellow solid methyl) piperidin - 1- yl) -4 -methoxybenzoic acid ( 101. 0 mg ) 55 from 2 -methylpyridin - 2 -amine (500 mg) . and N -( 2, 2 -dimethylpropyl )- 4- methylpyridin -2 -amine (74 .6 MS (ESI + ): [M + H ] * 165 .1 . mg) . MS (ESI + ) : [M + H ] * 615 . 3 . Step 2 ) 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 5 -methoxy - 2- (( 2 Example 113 60 methylpropyl) ( 5 -methylpyridin - 2 - yl) carbamoyl) phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) pro 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - (5 -methoxy - 2 - ( ( 2 -methylpro panoic acid pyl) (pyridin - 2 -yl ) carbamoyl) phenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 - yl ) propanoic acid In the same manner as in Example 32 , step 2 and Example 65 1, step 4, the title compound ( 171 mg ) was obtained as a By a method similar to that in Example 32, step 2 and white amorphous powder from 2 - ( 4 - ( ( (4 -( 1 - cyclopropyl- 3 Example 1, step 4 , the title compound (99 mg) was obtained ethoxy - 3 -oxopropyl ) pyridin -2 -yl ) oxy )methyl ) piperidin - 1 US 9 ,776 ,962 B2 103 104 yl) -4 -methoxybenzoic acid ( 167 mg) and 5 -methyl - N -( 2 powder from ethyl 3 - cyclopropyl- 3 - ( 2 - (( 1 - ( 2 - ( ( cyclopropy methylpropyl) pyridin - 2 - amine ( 114 mg) . Imethyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi MS (ESI + ) : [M + H ]* 601. 3 . din - 4 - yl) methoxy ) pyridin - 4 - yl) propanoate ( 120 mg) . MS (ESI +) : [ M + H ]* 585. 3 . Example 116 Example 118 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( pyridin - 2 - yl 3 - ( 2 - ( ( 1 -( 2 - ( ( cyclobutylmethyl) (pyridin - 2 - yl )car ( 2 , 2 , 2 -trifluoroethyl ) carbamoyl ) phenyl) piperidin - 4 bamoyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) yl) methoxy ) pyridin - 4 - yl) propanoic acid 10 pyridin - 4 - yl) - 3 -cyclopropylpropanoic acid Step 1 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 (pyridin - 2 - yl( 2 , 2 , 2 - trifluoroethyl) carbamoyl) phenyl) Step 1) N -( cyclobutylmethyl ) pyridin - 2 - amine piperidin - 4 - yl)methoxy ) pyridin - 4 - yl) propanoate In the same manner as in Example 32 , step 1 , the title 15 compound ( 1 . 82 g ) was obtained as a white solid from In the same manner as in Example 32, step 2 , the title 2 -aminopyridine ( 1. 50 g ) and cyclobutanecarboxylic chlo compound (111 mg) was obtained as a colorless oil from ride (2 .73 mL ). 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - ' H NMR (400 MHz, DMSO - do) d 1 .60 - 1 .74 (2H , m ) , yl) oxy )methyl )piperidin - 1- yl) - 4 -methoxybenzoic acid ( 100 1. 77 - 1. 89 (2H , m ), 1. 94 - 2 .06 (2H , m ), 2 .48 -2 .58 ( 1H , m ), mg) and N - ( 2 , 2 , 2 -trifluoroethyl ) pyridin - 2 - amine (91 . 0 mg) . 20 3 . 18 - 3 . 27 ( 2H , m ), 6 .27 - 6 . 50 ( 3H , m ) , 7 .20 - 7 . 38 ( 1H , m ) , MS (ESI + ) : [M + H ] * 641. 2 . 7 .92 ( 1H , d , J = 4 . 3 Hz ). Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (pyri Step 2 ) ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclobutylmethyl) (pyri din - 2 - yl( 2 , 2 , 2 -trifluoroethyl ) carbamoyl ) phenyl) pip din -2 - yl) carbamoyl) -5 -methoxyphenyl ) piperidin - 4 eridin - 4 - yl) methoxy )pyridin - 4 - yl) propanoic acid 2525 yl) methoxy )pyridin -4 -yl ) - 3 -cyclopropylpropanoate In the same manner as in Example 32 , step 2 , the title In the same manner as in Example 1 , step 4 , the title compound ( 106 mg) was obtained as a colorless oil from compound ( 96 .4 mg) was obtained as a white amorphous 2 -( 4 -( (( 4 -( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin -2 powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 3 -methoxy - 2 - 30 vloxylmethylpiperidin - 1 - v1) - 4 -methoxybenzoic acid ( 100 ( pyridin - 2 - yl( 2 ,2 , 2 - trifluoroethyl) carbamoyl) phenyl) piperi mg) and N - ( cyclobutylmethyl )pyridin - 2 - amine ( 84 . 0 mg) . din -4 - yl )methoxy ) pyridin -4 -yl ) propanoate ( 111 mg) . TH NMR (400 MHz, CDC1z ) 8 0 . 06 - 0 .24 (1H , m ), 0 .25 MS (ESI + ) : [ M + H ] * 613 . 2 . 0 . 36 (1H , m ) , 0 . 37 - 0 . 53 ( 1H , m ) , 0 .55 - 0 .68 ( 1H , m ), 0 . 90 1 . 07 ( 1H , m ) , 1 . 19 (3H , t , J = 7 . 1 Hz ) , 1 .45 - 1 . 96 ( 13H , m ) , Example 117 35 2 .23 - 2 .35 ( 1H , m ) , 2 .47 - 2 .73 (4H , m ), 2 .65 - 2 . 82 ( 2H , m ), 3 . 76 (3H , s ) , 4 .02 - 4 . 13 ( 2H , m ) , 4 . 16 (2H , d , J = 6 . 5 Hz) , 4 .23 (2H , d , J = 6 .8 Hz ), 6 .20 ( 1H , brs ), 6 .50 ( 1H , dd , J = 8 . 5 , 2 . 2 3 -cyclopropyl -3 -( 2 -( (1 - (2 -( (cyclopropylmethyl ) Hz ), 6 .62 ( 2H , s ) , 6 . 76 ( 1H , d , J = 5 . 3 Hz) , 6 . 83 - 6 . 93 ( 1H , m ) , (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperi 7 . 35 ( 1H , d , J= 8 . 4 Hz ) , 8 .07 (1H , d , J = 5 .4 Hz) , 8. 36 (1H , d , din - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoic acid 40 J = 4 .5 Hz ). Step 1 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopro Step 3 ) 3 - ( 2 - ( ( 1 - ( 2 - (( cyclobutylmethyl ) ( pyridin - 2 pylmethyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphe yl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl) nyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoate methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid 45 In the same manner as in Example 32 , step 2 , the title In the same manner as in Example 1 , step 4 , the title compound (120 mg) was obtained as a colorless oil from compound ( 94 . 1 mg) was obtained as a white amorphous 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - powder from ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclobutylmethyl) ( pyridin yl) oxy )methyl ) piperidin - 1- yl ) - 4 -methoxybenzoic acid (100 2 -yl ) carbamoyl ) -5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) mg) and N - ( cyclopropylmethyl) pyridin -2 - amine (77 . 0 mg) . 50 pyridin - 4 -yl ) - 3 -cyclopropylpropanoate ( 106 mg) . H NMR ( 400 MHz, CDC1z ) 8 0 .07 - 0 . 24 ( 3H , m ) , 0 . 24 MS (ESI + ): [ M + H ] * 599. 3 . 0 .33 ( 1H , m ) , 0 . 36 ( 2H , d , J = 8 . 2 Hz ) , 0 . 42 - 0 .51 ( 1H , m ) , 0 .55 - 0 .65 ( 1H , m ), 0 . 98 ( 1H , tt, J = 12 . 8 , 4 . 8 Hz) , 1 .09 - 1 . 22 Example 119 ( 1H , m ), 1. 19 (3H , t, J = 7 . 1 Hz ) , 1 .55 (4H , s) , 1. 67 -1 . 91 (3H , m ) , 2 . 25 - 2 . 36 ( 1H , m ) , 2 . 56 (2H , brs ) , 2 .64 - 2 . 80 ( 2H , m ), 55 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 -hydroxy - 2 -methylpro 3 .77 (3H , s ), 4 . 00 - 4 .11 (4H , m ) , 4 . 14 (3H , d , J = 6 . 7 Hz) , 6 .21 pyl) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) ( 1H , S ) , 6 . 52 ( 1H , dd , J = 8 . 4 , 2 . 1 Hz) , 6 .62 ( 1H , S ) , 6 . 66 ( 1H , piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid brs ), 6 . 76 ( 1H , d , J = 5 . 3 Hz ), 6 . 86 - 6 .93 (1H , m ) , 7 .42 (1H , d , Step 1 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 -hy J = 8 .4 Hz ), 8. 06 (1H , d , J = 5 .3 Hz ), 8. 36 (1H , d , J = 3 .4 Hz ). droxy - 2 -methylpropyl ) (pyridin - 2 -yl ) carbamoyl ) -5 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 Step 2 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( (cyclopropylm yl) propanoate ethyl) (pyridin -2 -yl ) carbamoyl ) -5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoic acid In the same manner as in Example 32, step 2 , the title 65 compound (262 mg) was obtained as a colorless oil from In the same manner as in Example 1 , step 4 , the title 2 -( 4 - ( (( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopropyl) pyridin - 2 compound (106 mg) was obtained as a white amorphous yl) oxy )methyl ) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 200 US 9 ,776 ,962 B2 105 106 mg) and 2 -methyl - 1 - (pyridin - 2 - ylamino ) propan - 2 -ol ( 172 tography ( ethyl acetate /hexane ) to give the title compound mg) obtained in Example 35 , step 2 . ( 180 mg) as a colorless solid . IH NMR ( 400 MHz. DMSO - d ) 8 0 . 12 - 0 . 21 ( 1H . m ) . ' H NMR ( 300 MHz, CDC1z ) 8 0 .88 - 1 . 01 (6H , m ), 1 . 13 0 . 22 - 0 .30 (1H , m ), 0 .30 - 0 .40 (1H , m ), 0 .43 - 0 .58 ( 1H , m ), (3H , d , J = 6 . 5 Hz) , 1 .69 - 1 . 91 ( 1H , m ) , 3 . 53 - 3 .69 ( 1H , m ) , 1 . 01 (6H , brs ) , 1 . 05 - 1 . 14 ( 1H , m ) , 1 . 07 ( 3H , t , J = 7 . 3 Hz ), 5 4 .23 - 4 .53 ( 1H , m ) , 6 . 34 ( 1H , d , J = 8 . 5 Hz ), 6 .51 ( 1H , ddd , 1 .59 - 1 .86 ( 3H , m ), 2 . 17 - 2 .29 ( 1H , m ), 2 .35 - 2 .68 (6H , m ) , J= 7 .1 , 5 .1 , 0 . 9 Hz ), 7 .38 (1H , ddd , J = 8 .6 , 7 .0 , 1 .9 Hz ), 2 .75 (2H , d , J = 7 . 5 Hz) , 3 .69 ( 3H , s ), 3 . 89 - 4 . 01 ( 2H , m ) , 7 .99 - 8 . 10 ( 1H , m ). 4 .02 - 4 .40 (2H , m ), 4 . 12 ( 2H , d , J = 6 . 7 Hz ), 4 .60 ( 1H , s ) , 6 . 24 Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 3 ( 1H , s ) , 6 . 48 - 6 . 59 ( 1H , m ) , 6 . 72 ( 2H , s ) , 6 . 91 ( 1H , d , J = 5 . 3 methylbutan - 2 - yl) (pyridin - 2 -yl ) carbamoyl) phenyl ) Hz) , 6 . 96 - 7 . 04 ( 1H , m ) , 7 . 16 ( 1H , d , J = 8 . 4 Hz ) , 7 . 41 ( 1H , t , 10 piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid J = 7 . 5 Hz) , 7 .90 (1H , d , J = 5 . 0 Hz ) , 8 .04 ( 1H , d , J = 5 . 4 Hz) , 8 . 32 ( 1H , d , J = 3 . 5 HZ ) . In the samemanner as in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 157 mg) was obtained as a Step 2 ) 3 - cyclopropyl - 3 - ( 2 - (( 1 - ( 2 - ( ( 2 - hydroxy - 2 colorless amorphous powder from N - (3 -methylbutan - 2 -yl ) methylpropyl) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxy - 15 pyridin - 2 - amine ( 112 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 phenyl) piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) pro ethoxy -3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 panoic acid yl) -4 -methoxybenzoic acid ( 150 mg) . MS (ESI + ): [ M + H ]* 601. 3 . In the same manner as in Example 1 , step 4 , the title compound (13 .7 mg) was obtained as a white amorphous 20 Example 122 powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - hydroxy 2 -methylpropyl ) ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphe 3 -cyclopropyl - 3 - (2 - (( 1 -( 5 -methoxy - 2 - ( (2 -methylpro nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoate (31 pyl) ( 6 -methylpyridin - 2 - yl) carbamoyl ) phenyl) piperi mg ) . din - 4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid MS ( ESI + ): [ M + H ]* 603 . 3 . 25 By a method similar to that in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 82 mg ) was obtained Example 120 as a pale - yellow amorphous powder from 2 -( 4 - ( (( 4 -( 1 -cy clopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -methylpro piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 106 . 7 mg) and pyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) 30 6 -methyl - N - ( 2 -methylpropyl ) pyridin - 2 -amine ( 72 . 6 mg) . piperidin -4 - yl)methoxy )pyridin -4 - yl) propanoic acid MS (ESI + ): [ M + H ] * 601 .3 . In the samemanner as in Example 32, step 2 and Example Example 123 1 , step 4 , the title compound ( 151 mg) was obtained as a colorless amorphous powder from N -( 2 - fluoro - 2 -methyl - 35 3 -cyclopropyl - 3 - ( 2 -( ( 1- ( 5 -methoxy - 2 -( (2 -methylpro propyl) pyridin -2 -amine ( 105 mg) obtained in Example 39 , pyl) ( 4 -methylpyridin - 2 -yl ) carbamoyl ) phenyl )piperi step 1 and 2 - ( 4 - ( (( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) din - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (150 mg ). In the samemanner as in Example 32 , step 2 and Example MS ( ESI + ) : [ M + H ] * 605. 3 . 40 1 , step 4 , the title compound ( 117 mg) was obtained as a grayish white solid from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy Example 121 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) -4 methoxybenzoic acid ( 132 mg ) and 4 -methyl - N - (2 -methyl 3 -cyclopropyl - 3 - ( 2 - (( 1 - (5 -methoxy - 2 -( (3 -methylbu propyl) pyridin - 2 -amine ( 90 mg ) . ) (pyridin - 2 -yl ) carbamoyl ) phenyl ) piperidin - 45 MS (ESI + ) : [ M +H1 + 601. 3 . 4 -yl )methoxy )pyridin -4 - yl) propanoic acid Example 124 Step 1 ) N - (3 -methylbutan - 2 -yl ) pyridin - 2- amine 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( (cyclopropylmethyl ) (6 A solution of pyridin - 2 - amine ( 2 .00 g ) and 3 -methylbu - 50 methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) tan - 2 - one ( 3 .66 g ) in acetic acid ( 10 mL ) was stirred at 70° piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid C . for 10 min , sodium triacetoxyborohydride (6 . 76 g ) was added , and the mixture was further stirred for 2 hr. The Step 1 ) solvent was evaporated under reduced pressure , saturated N -( cyclopropylmethyl )- 6 -methylpyridin -2 -amine aqueous sodium hydrogen carbonate solution was added to 55 the residue , and the mixture was extracted with ethyl acetate . In the same manner as in Example 36 , step 1 , the title The extract was washed with saturated brine , dried over compound ( 1 . 16 g ) was obtained as a pale - yellow oil from anhydrous magnesium sulfate , and the solvent was evapo 6 -methylpyridin - 2 -amine ( 2 . 89 g ) . rated under reduced pressure. The obtained residue was MS (ESI + ) : [ M + H ] * 163. 1 . dissolved in methanol ( 15 mL ), sodium borohydride ( 0 . 804 60 g ) was added , and the mixture was stirred at 70° C . for 1 hr . Step 2 ) 3 -cyclopropyl - 3 - (2 - ( 1 - ( 2 - ( ( cyclopropylm To the reaction mixture was added saturated aqueous ammo ethyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 -methoxy nium chloride solution at room temperature , and the mixture phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) pro was extracted with ethyl acetate . The extract was washed panoic acid with saturated brine , and dried over anhydrous magnesium 65 sulfate . The solvent was evaporated under reduced pressure , In the samemanner as in Example 32 , step 2 and Example and the residue was purified by silica gel column chroma - 1 , step 4 , the title compound ( 110 mg) was obtained as a US 9 ,776 ,962 B2 107 108 white amorphous powder from 2 -( 4 - ( ( (4 -( 1 - cyclopropyl - 3 - 60° C ., and the mixture was stirred at 110° C . for 16 hr. ethoxy - 3 - oxopropyl) pyridin - 2 - yl ) oxy )methyl ) piperidin - 1 Water was added to the reaction mixture at room tempera yl) - 4 -methoxybenzoic acid ( 167 mg) and N - ( cyclopropyl ture , and the mixture was extracted with ethyl acetate . The methyl) - 6 -methylpyridin - 2 - amine ( 112 mg) . extract was washed with saturated brine , dried over anhy MS (ESI + ) : [ M + H ] * 599. 3 . 5 drous magnesium sulfate , and the solvent was evaporated under reduced pressure. The residue was purified by silica Example 125 gel column chromatography ( ethyl acetate /hexane ) to give the title compound (71 mg ) as a colorless oil . 3 -cyclopropyl - 3 -( 2 -( ( 1- ( 2- ( ( cyclopropylmethyl )( 4 ' H NMR ( 300 MHz, CDC1z) / 1 . 22 (3H , t , J = 7 . 0 Hz ) , methylpyridin -2 -yl ) carbamoyl ) -5 -methoxyphenyl ) U 1 .51 (9H , s ), 3 . 97 (2H , q , J = 7 .0 Hz ), 6 .99 ( 1H , ddd , J = 5 . 8 , piperidin - 4 -yl )methoxy )pyridin - 4 -yl ) propanoic acid 4 . 9 , 2 .5 Hz ), 7 . 55 - 7 .64 ( 2H , m ) , 8 . 34 - 8 .41 ( 1H , m ). Step 1) Step 3 ) N -( 2, 2 -difluoropropyl ) pyridin - 2 -amine N - ( cyclopropylmethyl) - 4 -methylpyridin - 2 - amine hydrochloride 1515 In the same manner as in Example 36 , step 1 , the title To a solution of tert -butyl ( 2 , 2 - difluoropropyl) (pyridin - 2 compound ( 1 . 11 g ) was obtained as a pale -yellow oil from yl) carbamate (71 mg) in ethyl acetate ( 2 mL ) was added 4N 4 -methylpyridin - 2 -amine (2 . 89 g ). hydrogen chloride ethyl acetate solution ( 2 mL ) , and the MS ( ESI + ) : [ M + H ] * 163 .0 . 20 mixture was stirred at room temperature for 6 hr. The solvent Step 2 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 2 - (( cyclopropylm was evaporated under reduced pressure to give a crude ethyl) (4 -methylpyridin - 2 -yl ) carbamoyl) - 5 -methoxy product of the title compound as a colorless amorphous phenyl) piperidin - 4 - yl) methoxy )pyridin -4 - yl) pro powder . This compound was used for the next step without panoic acid further purification . 25 MS ( ESI+ ) : [ M + H ] * 173 .0 . In the same manner as in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 125 mg) was obtained as a Step 4 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( 1 - ( 2 - ( ( 2 , 2 - difluo white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 ropropyl) (pyridin -2 -yl ) carbamoyl ) - 5 -methoxyphe ethoxy - 3 - oxopropyl )pyridin - 2 - yl) oxy )methyl ) piperidin - 1 nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoate yl) - 4 -methoxybenzoic acid ( 168 mg) and N - ( cyclopropyl - 30 methyl) - 4 -methylpyridin - 2 - amine ( 113 mg) . In the same manner as in Example 32, step 2, the title MS ( ESI + ) : [ M + H ] * 599 . 3 . compound (8 mg) was obtained as a colorless oil from N -( 2 ,2 -difluoropropyl ) pyridin - 2 -amine hydrochloride ( 0 .26 Example 126 mmol) obtained in step 3 and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 3 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 ,2 -difluoropropyl ) (pyri ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl )piperidin - 1 din - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 yl) - 4 -methoxybenzoic acid ( 151 mg) . yl) methoxy )pyridin - 4 - yl ) propanoic acid MS (ESI + ) : [ M + H ] * 637 . 3 . Step 5 ) 3 - cyclopropyl- 3 - ( 2 - (( 1 - ( 2 - ( ( 2 , 2 - difluoropro Step 1 ) 2 ,2 - difluoropropyl methanesulfonate 40 pyl) (pyridin - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) 2 ,2 - Difluoropropan - 1 -ol (297 mg) and methanesulfonyl piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid chloride ( 0 . 263 mL ) were dissolved in THF (15 mL ) , and triethylamine ( 0 .646 mL ) was added at room temperature . In the same manner as in Example 1 , step 4 , the title After stirring for 20 min , saturated aqueous ammonium 45 compound (35 mg) was obtained as a colorless amorphous chloride solution was added to the reaction mixture at room powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 -difluoro temperature , and the mixture was extracted with ethyl propyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi acetate . The extract was washed with saturated brine, dried din - 4 - yl) methoxy ) pyridin - 4 - yl) propanoate ( 90 mg) . over anhydrous magnesium sulfate , and the solvent was MS ( ESI + ): [ M + H ] * 609 .2 . evaporated under reduced pressure to give a crude product 50 (540 mg) of the title compound as a colorless oil. This Example 127 compound was used for the next step without further puri fication . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methoxy IH NMR ( 300 MHz , CDC1z ) 8 1 . 72 (3H , t , J = 18 .6 Hz ) , pyridin - 4 - yl) ( 2 -methylpropyl ) carbamoyl) phenyl ) 3 . 10 ( 3H , s ), 4 .31 ( 2H , t, J = 11 .4 Hz) . 55 piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid Step 2 ) tert- butyl ( 2, 2 -difluoropropyl )pyridin -2 -yl Step 1 ) carbamate 2 -methoxy - N - ( 2 -methylpropyl ) pyridin - 4 - amine To a solution of tert -butyl pyridin - 2 - ylcarbamate ( 300 60 In the same manner as in Example 36 , step 1 , the title mg) in DMF ( 4 mL ) was added sodium hydride (60 % in oil, compound ( 227 mg) was obtained as colorless liquid from 124 mg) at 0° C . , and the mixture was stirred for 10 min . A 2 -methylpropanal ( 366 uL ) and 2 -methoxypyridin - 4 -amine solution of 2 , 2 -difluoropropyl methanesulfonate (540 mg) ( 1. 00 g ). obtained in step 1 in DMF ( 1. 5 mL ) was added thereto , and ' H NMR (400 MHz, CDC13 ) 8 0 .97 (6H , d , J = 6 .7 Hz) , the mixture was stirred at room temperature for 1 hr. The 65 1 . 75 - 1 . 97 ( 1H , m ) , 2 . 93 ( 2H , t , J = 6 . 3 Hz ), 3 . 88 (3H , s ) , mixture was allowed to warm to 60° C . and further stirred 4 . 01 - 4 .27 ( 1H , m ), 5 . 82 ( 1H , d , J = 1 . 9 Hz ) , 6 . 12 ( 1H , dd , for 16 hr. Then , cesium carbonate (1006 mg ) was added at J = 5 . 8 , 2 .1 Hz ), 7 .77 ( 1H , d , J= 5 .9 Hz ) . US 9 ,776 , 962 B2 109 110 Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 1. 52 - 1 .58 (2H , m ), 1 .68 - 1 . 99 (4H , m ), 2 .23 - 2 . 36 ( 1H , m ), (( 2 -methoxypyridin - 4 -yl ) ( 2 -methylpropyl ) carbam 2 . 42 - 2 .68 ( 3H , m ) , 2 . 65 - 2 . 81 ( 2H , m ) , 3 . 03 - 3 .53 ( 1H , m ) , oyl) phenyl) piperidin - 4 -yl ) methoxy ) pyridin - 4 - yl ) 3 .77 ( 3H , s ), 3 .81 ( 3H , s ), 3 . 94 -4 .20 (6H , m ), 6 .25 ( 2H , brs ), 6 . 34 ( 1H , d , J = 8 . 2 Hz ), 6 . 50 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz ) , 6 .61 propanoate 5 ( 1H , s ) , 6 .76 ( 1H , d , J = 5 .4 Hz ) , 7 . 13 - 7 . 23 ( 1H , m ), 7 . 34 ( 1H , In the same manner as in Example 32 , step 2 , the title d , J = 8 . 4 Hz ), 8 .05 ( 1H , d , J = 5 . 3 Hz ). compound (22 . 2 mg) was obtained as a colorless oil from Step 3 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 6 2 - ( 4 - ( ( [ 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 methoxypyridin - 2 -yl ) ( 2 -methylpropyl ) carbamoyl ) yl) oxy )methyl ) piperidin - 1- yl ) - 4 -methoxybenzoic acid ( 100 phenyl) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) pro mg) and 2 -methoxy - N - ( 2 -methylpropyl ) pyridin - 4 - amine 10 panoic acid ( 93 .0 mg) . H NMR ( 400 MHz, CDC12 ) 8 0 . 12 - 0 .22 ( 1H , m ), 0 . 25 In the same manner as in Example 1 , step 4 , the title 0 . 36 ( 1H , m ) , 0 . 41 - 0 .53 ( 1H , m ) , 0 .55 - 0 .67 ( 1H , m ), 0 . 89 compound (97 . 1 mg) was obtained as a white amorphous (6H , d , J = 6 . 7 Hz ), 0 .92 - 1 .07 (1H , m ) , 1 . 19 (3H , t , J = 7 . 1 Hz) , powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - (5 - methoxy - 2 1 .43 ( 2H , brs ) , 1 .77 - 1 . 95 ( 4H , m ) , 2 .24 - 2 .37 ( 1H , m ), 15 ( ( 6 -methoxypyridin - 4 - yl) ( 2 -methylpropyl ) carbamoyl) phe 2 . 39 - 2 .70 (3H , m ), 2 .65 - 2 .81 ( 2H , m ) , 3 . 23 - 3 .68 (2H , m ) , nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoate ( 107 3 .76 (3H , s ) , 3 . 83 ( 3H , s ) , 3 . 99 - 4 . 13 ( 3H , m ), 4 . 18 ( 2H , d , mg ) . J = 6 . 1 Hz) , 6 . 30 ( 1H , d , J = 1 . 8 Hz) , 6 . 41 ( 1H , s ) , 6 .45 ( 1H , d , MS (ESI + ): [ M + H ]* 617 .3 . J = 4 . 4 Hz) , 6 .51 (1H , dd , J = 8 . 5 , 2 . 2 Hz ) , 6 .64 ( 1H , s ) , 6 .72 - 6 . 83 ( 1H , m ) , 7 . 22 - 7 . 26 ( 1H , m ), 7 . 84 ( 1H , d , J = 5 . 6 20 Example 129 Hz ), 8 . 07 ( 1H , d , J = 5 . 3 Hz ) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( 2 , 2 , 3 , 3 , 3 Step 3 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 pentafluoropropyl) carbamoyl ) phenyl ) piperidin -4 -yl ) methoxypyridin - 4 - yl) ( 2 -methylpropyl ) carbamoyl) methoxy ) pyridin -4 -yl ) propanoic acid phenyl) piperidin - 4 - yl) methoxy )pyridin -4 - yl) pro 25 Step 1) ethyl 3 -cyclopropyl - 3 - (2 - ( (1 -( 5 -methoxy - 2 panoic acid ( ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl )carbamoyl ) phenyl) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoate In the same manner as in Example 1, step 4 , the title compound ( 18 . 0 mg) was obtained as a white amorphous In the samesame manner as in Example 32 , step 2 , the title powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - 30 compound (238 mg ) was obtained as a colorless oil from ( ( 2 -methoxypyridin - 4 -yl ) ( 2 -methylpropyl ) carbamoyl ) phe - 2 , 2 , 3 ,3 , 3 -pentafluoropropan - 1 - amine (201 mg) and 2 - ( 4 nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoate (22 . 2 ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl ) mg ) . oxy )methyl )piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 260 MS (ESI + ): [ M + H ] * 617 . 3 . mg) . 35 H NMR ( 300 MHz, CDC1z ) : 0 . 10 - 0 . 22 ( 1H , m ) , 0 . 24 Example 128 0 . 36 (1H , m ) , 0 .40 - 0 . 52 ( 1H , m ) , 0 .55 - 0 .67 ( 1H , m ), 0 .92 1 . 06 ( 1H , m ) , 1 . 19 (3H , t , J = 6 . 9 Hz ), 1 . 47 - 1 .66 ( 2H , m ) , 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( (6 -methoxy 1 . 92 - 2 .10 (3H , m ), 2 .25 - 2 .37 ( 1H , m ) , 2 .64 -2 .88 (4H , m ), pyridin - 2 - yl) ( 2 -methylpropylcarbamoyl ) phenyl ) 3 . 11 -3 .21 ( 2H , m ) , 3 .85 (3H , s ), 4 .01 - 4 . 11 (2H , m ), 4 . 13 piperidin -4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid 40 4 .28 (4H , m ), 6 .59 -6 .65 ( 1H , m ), 6 .74 -6 .87 (3H , m ), 8 .07 ( 1H , d , J = 5 . 3 Hz ) , 8 .24 ( 1H , d , J = 8 . 7 Hz ), 10 . 90 ( 1H , t , J = 5 . 9 Step 1 ) Hz ) . 6 -methoxy - N - ( 2 -methylpropyl ) pyridin - 2 - amine Step 2 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , In the same manner as in Example 32 , step 1 , the title 45 3 , 3 , 3 -pentafluoropropyl ) carbamoyl) phenyl )piperi compound ( 1 . 28 g ) was obtained as a colorless oil from din -4 - yl)methoxy )pyridin -4 - yl) propanoic acid 6 -methoxypyridin - 2 - amine ( 1 . 00 g ) and 2 -methylpropionyl chloride ( 2 . 16 mL ) . In the same manner as in Example 1 , step 4 , the title ' H NMR (400 MHz, CDC1z ) 8 0 . 98 (6H , d , J = 6 . 7 Hz ) , compound ( 135 mg) was obtained as a colorless amorphous 1 .89 ( 1H , dt , J = 13 . 4 , 6 . 7 Hz ), 3 . 06 ( 2H , t , J = 6 . 3 Hz) , 3 . 84 50 powder from ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 ( 3H , s ) , 4 . 44 ( 1H , brs) , 5 . 91 ( 1H , d , J = 7 . 9 Hz) , 5 . 99 ( 1H , d , (( 2 ,2 ,3 , 3, 3 -pentafluoropropyl ) carbamoyl )phenyl ) piperidin J = 7 . 8 Hz ), 7 . 33 ( 1H , t , J = 7 . 8 Hz) . 4 - yl) methoxy ) pyridin - 4 - yl) propanoate ( 140 mg) . Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 MS (ESI + ) : [ M + H ] * 586 . 2 . ( (6 -methoxypyridin -2 -yl ) (2 -methylpropyl ) carbam 55 Example 130 oyl )phenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoate 3 - cyclopropyl- 3 - ( 2 - (( 1 - ( 5 -methoxy - 2 - (methyl ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl ) carbamoyl ) phenyl ) piperidin In the same manner as in Example 32, step 2 , the title 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid compound ( 107 mg ) was obtained as a colorless oil from 60 2 - ( 4 - ( ( [ 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 Step 1 ) ethyl 3 -cyclopropyl -3 - (2 -( (1 - (5 -methoxy - 2 yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 (methyl ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl ) carbamoyl) mg) and 6 -methoxy -N - ( 2 -methylpropyl )pyridin - 2 - amine phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro ( 93 . 0 mg) . panoate 'H NMR (400 MHz, CDC1z ) 8 0 . 11 -0 .21 (1H , m ) , 0 . 24 - 65 0 .33 ( 1H , m ) , 0 . 40 - 0 . 50 ( 1H , m ) , 0 .55 - 0 .66 ( 1H , m ) , 0 .89 Ethyl 3 -cyclopropyl - 3 - ( 2 -( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , 3 , 3 , 3 ( 6H , d , J = 5 . 5 Hz) , 0 .93 - 1 .04 ( 1H , m ) , 1 . 19 ( 3H , t, J = 7 . 2 Hz) , pentafluoropropyl ) carbamoyl) phenyl ) piperidin - 4 - yl) US 9 ,776 , 962 B2 111 112 methoxy ) pyridin - 4 - yl) propanoate ( 105 mg) obtained in Example 132 Example 129, step 1, was dissolved in DMF (3 mL ), and sodium hydride (60 % in oil, 34 . 2 mg) was added at room 3 - ( 2 -( ( 1 -( 2 -( ( 3 -cyanophenyl ) ( 2 -methylpropyl )car temperature . The mixture was stirred at room temperature bamoyl) - 5 -methoxyphenyl ) piperidin - 4 -yl )methoxy ) for 10 min , iodomethane ( 0 . 107 mL ) was added , and the 5 pyridin - 4 -yl ) - 3 -cyclopropylpropanoic acid mixture was stirred at room temperature overnight. Water was added to the reaction mixture at room temperature, and Step 1 ) 3 -( ( 2- methylpropyl ) amino )benzonitrile the mixture was extracted with ethyl acetate . The extract was washed with saturated brine , dried over anhydrous magne In the same manner as in Example 36 , step 1 , the title sium sulfate , and the solvent was evaporated under reduced 10 compound (386 mg ) was obtained as a pale -yellow oil from pressure . The residue was purified by silica gel column 3 - aminobenzonitrile ( 1 .29 g ). chromatography ( ethyl acetate /hexane ) to give the title com - MS (ESI + ): IM + H1+ 163. 0 . pound ( 125 mg) as a colorless oil. MS (ESI + ) : [ M + H ] * 628 . 5 . 15 Step 2 ) 3 - ( 2 - ( ( 1 - ( 2 - ( ( 3 -cyanophenyl ) ( 2 -methylpro Step 2 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 pyl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) (methyl ( 2 , 2 , 3 , 3 , 3 - pentafluoropropyl) carbamoyl) methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) pro In the samemanner as in Example 32 , step 2 and Example panoic acid 20 . 1 , step 4 , the title compound ( 108 mg ) was obtained as a In the same manner as in Example 1 . step 4 . the title white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 compound ( 89 mg) was obtained as a colorless amorphous ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxV - 2 - yl) - 4 -methoxybenzoic acid ( 165 mg) and 3 - ( ( 2 -methylpro (methyl ( 2 ,2 ,3 ,3 ,3 -pentafluoropropyl carbamoyl) phenyl) pi- pyl) amino )benzonitrile ( 119 mg) . peridin -4 - yl) methoxy ) pyridin - 4 - yl) propanoate (125 mg) . 25 MS (ESI + ): [M + H ] * 611. 2 . MS (ESI + ): [ M + H ] * 600 . 2 . Example 133 Example 131 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methylpro 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methoxy - 30 pyl) (phenyl )carbamoyl ) phenyl ) piperidin - 4 -yl ) 2 -methylpropyl ) (pyridin - 2 - yl) carbamoyl ) phenyl ) methoxy )pyridin - 4 - yl) propanoic acid piperidin -4 -yl )methoxy )pyridin -4 - yl) propanoic acid Step 1 ) N - ( 2 -methylpropyl ) aniline Step 1 ) ethyl 3 -cyclopropyl - 3 - (2 - ( 1 -( 5 -methoxy - 2 (( 2 -methoxy -2 -methylpropyl ) ( pyridin -2 - yl ) carbam - 35 In the same manner as in Example 32, step 1 , the title oyl) phenyl )piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) compound ( 1 .51 g ) was obtained as a pale -yellow oil from propanoate aniline ( 1 mL ) . ' H NMR ( 300 MHz, CDC13 ) d 0 . 98 (6H , d , J = 6 .7 Hz) , In the same manner as in Example 32 , step 2 , the title 1. 89 ( 1H , dquin , J= 13 . 4 , 6 .7 Hz ), 2 . 93 (2H , d , J = 6 . 8 Hz) , compound ( 90 . 0 mg) was obtained as a colorless oil from 40 3 .68 ( 1H , brs ) , 6 .50 - 6 .63 ( 2H , m ) , 6 .63 - 6 .71 ( 1H , m ) , 2 -( 4 - (( (4 -( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl )pyridin -2 - 7 .09 - 7. 22 (2H , m ). yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 100 mg) and N - ( 2 -methoxy - 2 -methylpropyl ) pyridin - 2 - amine Step 2 ) 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 5 -methoxy - 2- ( ( 2 ( 93 . 0 mg) obtained in Example 35 , step 3 . methylpropyl) (phenyl ) carbamoyl) phenyl) piperidin IH NMR (400 MHz, CDC1 , ) & 0 . 12 - 0 . 22 ( 1H , m ) , 0 .25 - 45 4 - yl )methoxy )pyridin - 4 -yl ) propanoic acid 0 . 35 ( 1H , m ) , 0 .40 - 0 .53 ( 1H , m ), 0 .55 - 0 .66 (1H , m ), 0 .91 1 .06 ( 1H , m ) , 1 . 13 - 1 . 22 (3H , m ), 1 .19 (6H , s ) , 1 .27 - 1 . 94 In the same manner as in Example 32 , step 2 and Example (5H , m ) , 2 . 27 - 2 . 35 ( 1H , m ), 2 . 36 - 2 . 75 ( 3H , m ), 2 .66 - 2 .79 1 , step 4 , the title compound ( 182 mg) was obtained as a (2H , m ) , 2 . 83 (3H , s ), 3 .28 - 3 .54 ( 1H , m ), 3 .75 (3H , s ) , white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1- cyclopropyl- 3 4 . 02 - 4 . 12 ( 2H , m ) , 4 . 17 ( 2H , d , J = 6 . 7 Hz ), 4 .24 - 4 . 59 (2H , 50 ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 m ), 6 . 20 ( 1H , s ), 6 . 46 ( 1H , dd , J = 8 . 3 , 1 . 9 Hz) , 6 .58 ( 1H , brs ), yl) - 4 -methoxybenzoic acid ( 171 mg) and N -( 2 -methylpro 6 .63 (1H , s ) , 6 . 76 (1H , d , J = 5 . 3 Hz ), 6 .82 - 6 .89 ( 1H , m ) , 7 . 20 pyl) aniline ( 106 mg) . ( 1H , t , J = 8 . 2 Hz) , 7 .24 - 7 . 27 ( 1H , m ) , 8 . 07 ( 1H , d , J = 5 . 1 Hz) , MS (ESI + ) : [ M + H ] * 586 . 3 . 8 . 34 ( 1H , d , J = 3 . 9 Hz) . 55 Example 134 Step 2 ) 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 5 -methoxy - 2 -( (2 methoxy - 2 -methylpropyl ) (pyridin - 2 -yl ) carbamoyl) 3 - (2 -( ( 1- ( 2 -( (2 -cyano -2 -methylpropyl ) ( pyridin -2 -yl ) phenyl) piperidin -4 - yl) methoxy ) pyridin -4 -yl ) pro carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) panoic acid methoxy )pyridin - 4 -yl ) -3 -cyclopropylpropanoic acid 60 In the same manner as in Example 1 , step 4 , the title Step 1 ) ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - cyano - 2 -methylpropyl ) compound (82 . 6 mg) was obtained as a white amorphous ( pyridin - 2 - yl ) carbamoyl) - 5 -methoxyphenyl ) piperi powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 din - 4 - yl) methoxy ) pyridin - 4 - yl) - 3 - cyclopropylpro ( (2 -methoxy - 2 -methylpropyl ) (pyridin - 2 -yl ) carbamoyl ) phe panoate nyl) piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) propanoate (90 .0 65 mg) . In the same manner as in Example 32 , step 2 , the title MS (ESI + ): [ M + H ] * 617 . 3 . compound ( 115 mg) was obtained as a white amorphous US 9 ,776 , 962 B2 113 114 powder from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro Example 136 pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 - methoxy benzoic acid ( 100 mg) and 2 , 2 -dimethyl - 3 - (pyridin - 2 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 5 -methoxy -2 -( ( 2 -methoxy ylamino )propanenitrile (91 . 0 mg) obtained in Example 43 , pyridin - 3 - yl ) ( 2 -methylpropyl ) carbamoyl) phenyl) step 5 . piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 'H NMR (400 MHz , CDC12 ) 8 0 . 11 - 0 .21 (1H , m ), 0 . 25 0 .34 ( 1H , m ) , 0 .41 - 0 .52 ( 1H , m ), 0 .54 - 0 .65 ( 1H , m ), 0 .91 In the same manner as in Example 32 , step 2 and Example 1 .05 (1H , m ), 1. 19 ( 3H , t, J= 7 .2 Hz ), 1. 27 - 1. 43 ( 2H , m ), 1. 38 1, step 4 , the title compound (94 mg) was obtained as a ( 6H , brs ) , 1 .62 - 1 . 92 (4H , m ) , 2 . 26 - 2 . 36 ( 1H , m ), 2 .37 - 2 .66 grayish white solid from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy ( 3H , m ), 2 .65 - 2 .79 ( 2H , m ), 3 . 19 - 3 . 40 ( 1H , m ) , 3 . 77 ( 3H , s ), 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) -4 4 .01 - 4 . 11 ( 2H , m ) , 4 .16 (2H , d , J = 6 . 7 Hz) , 4 .30 -4 .79 (2H , methoxybenzoic acid (119 mg) and 2 -methoxy - N - ( 2 -meth m ) , 6 . 19 (1H , d , J = 1 .6 Hz) , 6 .53 (2H , dd , J = 8 . 5 , 2 . 2 Hz) , ylpropyl) pyridin - 3 -amine (89 mg) . 6 .63 ( 1H , s ), 6 .76 ( 1H , d , J = 5 .3 Hz ) , 6 .94 ( 1H , dd , J = 7 . 1, 5 .0 MS (ESI + ): [ M + H ] * 617 .3 . Hz ), 7. 36 ( 1H , d , J = 8 .5 Hz ), 8. 07 (1H , d , J = 5 .3 Hz) , 8 .39 15 ( 1H , d , J = 3 . 5 Hz) . Example 137 3 - cyclopropyl- 3 - (2 - ( (1 -( 2 -( ( 2 ,2 -difluoroethyl ) (pyri Step 2 ) 3 - ( 2 - (( 1 -( 2 - ( ( 2 - cyano - 2 -methylpropyl )( pyri din - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 din - 2 -yl ) carbamoyl ) -5 -methoxyphenyl ) piperidin -4 yl) methoxy ) pyridin -4 -yl ) propanoic acid yl) methoxy ) pyridin - 4 - yl) - 3 - cyclopropylpropanoic 20 acid Step 1 ) N - ( 2 , 2 -difluoroethyl ) pyridin - 2 - amine In the same manner as in Example 1, step 4 , the title In the same manner as in Example 135 , step 1 , the title compound ( 100 mg) was obtained as a white amorphous compound (210 mg ) was obtained as a colorless oil from powder from ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - cyano - 2 -methylpropyl ) 25 pyridine 1 -oxide ( 200 mg ) and 2 . 2 - difluoroethanamine ( 213 ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) mg ). methoxy )pyridin - 4 - yl) - 3 - cyclopropylpropanoate ( 115 mg) . ? H NMR ( 300 MHz, CDC12 ) 8 3 .78 (2H , tdd , J = 14 .6 , 6 .5 , MS ( ESI + ) : [ M + H ] * 612 . 3 . 4 . 3 Hz ) , 4 .56 ( 1H , brs) , 6 .46 ( 1H , dt, J = 8 . 3 , 0 . 8 Hz) , 6 .64 (1H , ddd , J = 7 . 1 , 5 . 1 , 0 . 9 Hz) , 7 . 38 - 7 .46 ( 1H , m ), 8 . 06 - 8 . 14 Example 135 30 (1H , m ). 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 5 -methoxy - 2 -( ( 4 -methoxy Step 2 ) 3 - cyclopropyl- 3 -( 2 - ( 1 - ( 2 - ( ( 2 , 2 - difluoro pyridin - 2 -yl ) ( 2 -methylpropyl ) carbamoyl ) phenyl ) ethyl) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid 35 Step 1 ) In the same manner as in Example 32 , step 2 and Example 4 -methoxy -N - (2 -methylpropyl ) pyridin -2 -amine 1, step 4 , the title compound (88 mg) was obtained as a colorless amorphous powder from N - ( 2 , 2 - difluoroethyl) To a solution of 2 -methylpropanamine ( 207 ul) in THF pyridin - 2 - amine ( 105 mg) and 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 ( 6 .65 mL ) were added N - ethyldiisopropylamine ( 1 .09 mL ), 40 ethoxy -3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl )piperidin - 1 4 -methoxypyridine 1 - oxide ( 208 . 1 mg ) and bromotris ( pyr yl) - 4 -methoxybenzoic acid ( 146 mg) . rolidino phosphonium hexafluorophosphate ( 1 .01 g ) at MS ( ESI + ) : [ M + H ] * 595. 2 . room temperature , and the mixture was stirred for 3 . 5 hr. To Example 138 the reaction mixture was added saturated aqueous sodium 45 hydrogen carbonate solution at 0° C . , and the mixture was 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - (5 -methoxy - 2 -( pyridin - 2 -yl extracted with ethyl acetate . The extract was washed with ( 2 , 2 , 3 , 3 - tetrafluoropropyl) carbamoyl ) phenyl) piperi saturated brine , and dried over anhydrous sodium sulfate , din -4 - yl)methoxy )pyridin -4 - yl) propanoic acid and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography 50 Step 1 ) N - benzyl- 2 , 2 , 3 , 3 - tetrafluoropropan - 1 - amine (NH , ethyl acetate / hexane) to give the title compound (215 mg) as a pale -brown oil . In the same manner as in Example 14 , step 1 , the title MS ( ESI + ) : [M + H ] * 181 .1 . compound (6 . 3 g ) was obtained as a colorless oil from 1 -phenylmethanamine (3 . 0 g ) and 2 ,2 , 3 ,3 - tetrafluoropropyl Step 2 ) 3- cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 - ( (4 55 trifluoromethanesulfonate ( 7. 39 g ). methoxypyridin - 2 -yl ) ( 2 -methylpropyl ) carbamoyl ) 'H NMR (300 MHz, CDC1z ) 1. 42 - 1. 58 ( 1H , m ), 3 .14 phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) pro (2H , tt , J = 14 . 3 , 1 . 7 Hz ) , 3 . 87 ( 2H , s ) , 5 .79 - 6 .21 ( 1H , m ) , panoic acid 7 .24 - 7. 39 (5H , m ). By a method similar to that in Example 32 , step 2 and 60 Step 2 ) 2 , 2 , 3 , 3 -tetrafluoropropan - 1 -amine Example 1 , step 4 , the title compound ( 132 .6 mg) was hydrochloride obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy ) Under a hydrogen atmosphere , a solution of N -benzyl - 2 , methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 133. 9 mg) 2 , 3 , 3 - tetrafluoropropan - 1 - amine (6 . 3 g ) and 20 % palladium and 4 -methoxy - N - ( 2 -methylpropyl ) pyridin - 2 -amine ( 100 65 hydroxide ( containing water ( 50 % ), 800 mg) in ethanol ( 50 mg) . mL ) was stirred at room temperature overnight. The reaction MS ( ESI + ): [M + H ]* 617 . 3 . mixture was filtered through celite , 4N hydrogen chloride US 9 ,776 ,962 B2 115 116 ethyl acetate solution ( 14 . 2 mL ) was added to the obtained grayish white solid from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy filtrate , and the solvent was evaporated under reduced pres 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1- yl ) - 4 sure. The residue was suspended in ethyl acetate and hexane , methoxybenzoic acid (115 mg) and 6 -methoxy - N - ( 2 -meth and the resulting precipitate was collected by filtration , ylpropyl) pyridin - 3 -amine ( 86 mg) . washed with ethyl acetate , and dried under reduced pressure 5 MS (ESI + ): [ M + H ] * 617. 3 . to give the title compound ( 3 . 74 g ) as a colorless solid . IH NMR ( 300 MHz, DMSO - d . ) 83 .62 ( 2H , t, J = 16 . 8 Hz) , Example 141 6 .47 -6 . 95 (1H , m ), 9. 02 ( 3H , s) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopropylmethyl) Step 3 ) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi N -( 2 , 2 , 3 , 3 - tetrafluoropropyl )pyridin - 2 - amine 10 din -4 - yl)methoxy )pyridin -4 - yl) propanoic acid In the same manner as in Example 135, step 1, the title Step 1 ) 2 - ( 4 - ( (( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopro compound ( 100 mg) was obtained as a colorless oil from pyl )pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 pyridine 1 - oxide ( 200 mg ) and 2 , 2 , 3 , 3 - tetrafluoropropan - 1 methoxybenzoic acid amine hydrochloride (458 mg) . 15 ' H NMR (300 MHz, CDC1z ) 3 . 99 - 4 . 14 (2H , m ), 4 . 54 Racemate ( 500 mg) of 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 ( 1H , brs ) , 5 .67 - 6 .09 ( 1H , m ), 6 . 49 ( 1H , d , J = 8 . 3 Hz ) , 6 .67 ethoxy -3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 (1H , ddd , J = 7 .2 , 5 . 1, 0. 9 Hz) , 7. 40 -7 .49 (1H , m ), 8 .12 ( 1H , yl) - 4 -methoxybenzoic acid was fractionated by SFC ( col dd , J = 5 . 1 , 1. 1 Hz) . umn : CHIRALPAK AS - H , 20 mmIDx250 mmL , Step 4 ) 3 - cyclopropyl- 3 - (2 - (( 1- (5 -methoxy - 2 -( pyri 20 manufactured by Daicel Corporation , mobile phase : CO2! din - 2 - yl( 2 , 2 , 3 , 3 - tetrafluoropropyl) carbamoyl) phe ethanol= 740 / 260 ) to give the title compound (176 mg) nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic having a shorter retention time. acid Step 2 ) ethyl 3 - cyclopropyl- 3 -( 2 - ( 1 - ( 2 - ( ( cyclopro In the samemanner as in Example 32 , step 2 and Example 25 pylmethyl) ( pyridin -2 -yl ) carbamoyl ) - 5 -methoxyphe 1 , step 4 , the title compound (69 mg) was obtained as a nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoate colorless amorphous powder from N - ( 2 , 2 , 3 , 3 - tetrafluoro propyl) pyridin - 2 -amine ( 100 mg) and 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopro In the same manner as in Example 32, step 2 , the title pyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperi compound ( 12 . 0 mg ) was obtained as a colorless oil from din - 1 - yl ) - 4 -methoxybenzoic acid ( 142 mg) . 30 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 MS ( ESI + ) : [ M + H ] * 645 . 3 . yl )oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (176 mg) having a shorter retention time and N - ( cyclopropylm Example 139 ethylpyridin - 2 - amine ( 135 mg ) . ' H NMR (300 MHz, CDC13 ) 8 0 .07 - 0 .23 (3H , m ), 0 .29 3 -cyclopropyl - 3 - ( 2 -( ( 1- ( 2 -( (( 2 , 2 -difluorocyclopro 35 ( 1H , dt, J = 9 . 5 , 4 . 8 Hz) , 0 .33 - 0 .40 (2H , m ) , 0 .41 - 0 .52 ( 1H , pyl) methyl ) ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphe m ) , 0 .53 - 0 .67 ( 1H , m ) , 0 . 79 - 0 . 93 ( 1H , m ) , 0 . 93 - 1 . 08 ( 1H , nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic m ), 1 . 19 (3H , t , J = 7 . 2 Hz ) , 1 . 58 (4H , s ) , 1 .66 - 1 . 84 ( 3H , m ) , acid 2 .23 - 2 .37 ( 1H , m ) , 2 .55 (2H , brs ) , 2 .64 - 2 .82 ( 2H , m ) , 3 .78 (3H , s ) , 3 . 99 - 4 . 11 ( 4H , m ) , 4 . 14 ( 2H , d , J = 6 . 4 Hz ) , 6 .21 ( 1H , Step 1 ) 40 d , J = 2 . 1 Hz) , 6 .43 - 6 . 58 (1H , m ) , 6 .60 -6 .68 (2H , m ), 6 .76 N - ( ( 2 , 2 - difluorocyclopropyl) methyl ) pyridin - 2 -amine ( 1H , dd , J = 5 . 3 , 1 . 4 Hz ) , 6 . 90 ( 1H , dd , J = 6 . 6 , 4 . 8 Hz ) , 7 . 26 In the same manner as in Example 32 , step 1 , the title (1H , s ) , 7 .42 ( 1H , d , J = 8 . 5 Hz) , 8 .06 ( 1H , d , J = 5 . 3 Hz) , 8 . 36 compound ( 129 mg) was obtained as a pale -yellow oil from (1H , dd , J = 4 . 9 , 1 . 2 Hz ) . pyridin - 2 - amine (514 mg) . 4545 Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopropylm MS ( ESI + ): [M + H ] * 185 . 0 . ethyl ) ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( (( 2 , 2 -difluorocy piperidin -4 - yl)methoxy )pyridin -4 - yl) propanoic acid clopropyl )methyl ) ( pyridin - 2 - yl) carbamoyl) - 5 methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 In the same manner as in Example 1 , step 4 , the title yl) propanoic acid 50 compound (6 .00 mg ) was obtained as a white amorphous powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopropy In the samemanner as in Example 32 , step 2 and Example Imethyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi 1 , step 4 , the title compound ( 18 . 5 mg) was obtained as a din - 4 - yl) methoxy )pyridin - 4 - yl) propanoate (12 . 0 mg ) . pale -yellow oil from 2 - (4 - (( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - MS (ESI + ): [M + H ] + 585 . 3 . oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 - 55 methoxybenzoic acid ( 162 mg) and N - ( ( 2 , 2 - difluorocyclo Example 142 propyl) methyl ) pyridin - 2 - amine ( 129 mg) . 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( cyclopropylmethyl ) MS ( ESI + ) : [ M + H ] * 621 . 4 . (pyridin - 2 - yl )carbamoyl ) -5 -methoxyphenyl ) piperi Example 140 60 din - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid 3 -cyclopropyl - 3 - (2 - ( 1 -( 5 -methoxy - 2 - ( 6 -methoxy Step 1 ) 2 - ( 4 -( (( 4 -( 1 - cyclopropyl- 3 - ethoxy -3 -oxopro pyridin - 3 - yl) ( 2 -methylpropyl ) carbamoyl) phenyl) pyl )pyridin -2 -yl ) oxy ) methyl ) piperidin -1 -yl ) - 4 piperidin -4 -yl )methoxy )pyridin -4 -yl ) propanoic acid methoxybenzoic acid 65 In the samemanner as in Example 32 , step 2 and Example Racemate ( 500 mg) of 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 1 , step 4 , the title compound ( 101 mg) was obtained asa e thoxy - 3 -oxopropyl ) pyridin -2 -yl ) oxy )methyl ) piperidin - 1 US 9 ,776 , 962 B2 117 118 yl) - 4 -methoxybenzoic acid was fractionated by SFC ( col- ' H NMR (400 MHz, CDC13 ) 8 0 .10 - 0. 22 (1H , m ), 0 .25 umn: CHIRALPAK AS - H , 20 mmIDx250 mmL , 0 .35 (1H , m ), 0 .41 - 0 .52 ( 1H , m ), 0 .55 -0 .66 (1H , m ), 0 .92 manufactured by Daicel Corporation , mobile phase : CO 1 . 06 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 2 Hz) , 1 . 36 - 1 .61 ( 2H , m ) , ethanol= 740 / 260 ) to give the title compound (197 mg) 1. 64 - 1. 90 (3H , m ), 2 .25 - 2 . 36 (1H , m ), 2 .41 - 2 .63 (3H , m ), having a longer retention time. 5 2 . 48 (3H , s ) , 2 .65 - 2 .81 ( 2H , m ), 2 . 95 - 3 .59 (1H , m ), 3 . 78 ( 3H , s ), 4 .02 - 4 . 11 (2H , m ) , 4 . 16 (2H , d , J = 6 . 4 Hz ), 5 . 08 ( 2H , Step 2 ) ethyl 3 -cyclopropyl - 3 -( 2 - ( ( 1 - ( 2 - ( ( cyclopro brs ), 6 .22 ( 1H , d , J = 1 . 8 Hz ) , 6 . 33 ( 1H , brs ), 6 .53 ( 1H , dd , pylmethyl) (pyridin - 2- yl) carbamoyl ) - 5 -methoxyphe J = 8 .5 , 2 . 3 Hz ), 6 .62 (1H , s ), 6 .76 ( 1H , dd , J= 5 .4 , 1 .3 Hz ), nyl) piperidin - 4 -yl ) methoxy ) pyridin - 4 -yl ) propanoate 6 .79 ( 1H , d , J = 7 . 5 Hz ) , 7 . 16 ( 1H , s ) , 7 .38 ( 1H , d , J = 8 . 4 Hz ) , 10 8 .06 (1H , d , J = 5 .3 Hz) . In the same manner as in Example 32 , step 2 , the title compound (31 . 3 mg) was obtained as a colorless oil from Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( (6 2 -( 4 -( (( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 -oxopropyl ) pyridin -2 methylpyridin - 2 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 195 phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) pro mg) having a longer retention time and N - ( cyclopropylm 15 panoic acid ethyl )pyridin - 2 - amine ( 150 mg ). In the same manner as in Example 1 , step 4 , the title ' H NMR ( 400 MHz, CDC1z ) 8 0 . 07 - 0 . 22 ( 3H , m ) , 0 . 25 compound (81 . 6 mg) was obtained as a white amorphous 0 .33 (1H , m ), 0 . 37 ( 2H , brs ), 0 .42 -0 .53 ( 1H , m ), 0 .55 - 0 .66 powder from ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 -( 5 -methoxy - 2 ( 1H , m ) , 0 .88 - 1 . 06 ( 1H , m ) , 1. 12 - 1 . 19 ( 1H , m ) , 1 . 19 ( 3H , t , 2020 ( 6 -methylpyridin - 2 - yl ) ( 2 , 2 , 2 - trifluoroethyl ) carbamoyl) J = 7 . 2 Hz) , 1 .42 - 1 .64 (2H , m ) , 1 .67 - 1 . 90 (3H , m ) , 2 .25 - 2 .38 phenyl )piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoate (1H , m ) , 2 . 56 ( 2H , brs ) , 2 . 58 - 2 .81 (4H , m ), 3 .78 (3H , s ) , 3 .98 - 4 . 11 (4H , m ) , 4 . 14 ( 2H , d , J = 6 . 5 Hz ), 6 . 21 ( 1H , brs ) , (93 . 5 mg) . 6 .52 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz ) , 6 .58 - 6 .74 (2H , m ) , 6 . 76 ( 1H , MS (ESI + ): [ M + H ] * 627. 2 . dd , J= 5 .3 , 1. 3 Hz ), 6 .84 -6 . 97 ( 1H , m ), 7 .20 - 7 .33 ( 1H , m ), 25 Example 144 7 .42 ( 1H , d , J = 8 . 4 Hz ), 8 .06 ( 1H , d , J= 5 .3 Hz) , 8 . 36 ( 1H , d , J = 3 .6 Hz ). 3 -cyclopropyl - 3 - (2 - (( 1 -( 2- ( (( 1 - fluorocyclopropyl) methyl) (pyridin -2 - yl) carbamoyl) - 5 -methoxyphenyl ) Step 3) 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( ( cyclopropylm piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid ethyl) (pyridin -2 -yl ) carbamoyl ) -5 -methoxyphenyl ) 3030 piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoic acid Step 1 ) 1 -( ( dibenzylamino )methyl ) cyclopropanol In the same manner as in Example 1 , step 4 , the title Under a nitrogen atmosphere , a 3 . 0 M solution of ethyl compound ( 26 . 7 mg) was obtained as a white amorphous magnesium bromide in THF ( 9 .41 mL ) was added dropwise powder from ethyl 3 - cyclopropyl- 3 - (2 - (( 1 -( 2 - ( (cyclopropy - 35 to a solution of ethyl 2 -( dibenzylamino )acetate (4 .0 g ) and Imethyl ) (pyridin - 2 - yl) carbamoyl ) -5 -methoxyphenyl ) piperi - tetraisopropyl titanate (827 uL ) in THF (50 mL ) at 0° C ., and din -4 - yl) methoxy )pyridin -4 - yl) propanoate ( 31. 3 mg) . the mixture was stirred at room temperature for 16 hr. To the MS (ESI + ) : [ M + H ]* 585 .3 . reaction mixture was added saturated aqueous ammonium chloride solution , and the mixture was extracted with ethyl Example 143 40 acetate . The extract was washed with water and saturated brine , and dried over anhydrous magnesium sulfate . The 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( 6 -methyl solvent was evaporated under reduced pressure , and the pyridin - 2 -yl ) ( 2 ,2 ,2 -trifluoroethyl ) carbamoyl) phenyl ) residue was purified by silica gel column chromatography piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid ( ethyl acetate / hexane ) to give the title compound ( 2 .05 g ) as 45 a pale - yellow oil . Step 1 ) ' H NMR (400 MHz, DMSO -d ) 8 0 .26 - 0 .38 (2H , m ), 6 -methyl - N -( 2 ,2 , 2 -trifluoroethyl ) pyridin - 2 -amine 0 . 49 -0 .60 (2H , m ), 2 .53 (2H , s ), 3 .67 ( 4H , s ) , 5 .01 ( 1H , s ), 7 . 17 - 7. 25 (2H , m ), 7 .31 (4H , t, J = 7. 5 Hz ), 7. 35 - 7 .46 (4H , In the same manner as in Example 32 , step 1 , the title m ). compound ( 1 . 34 g ) was obtained as a white solid from 50 6 -methylpyridin - 2 -amine ( 1 .00 g ) and trifluoroacetic anhy Step 2 ) dride ( 1. 57 mL ). N , N - dibenzyl- 1 - ( 1 - fluorocyclopropyl) methanamine ' H NMR (400 MHz , CDC1z ) 8 2 .38 (3H , s ), 4 .07 ( 2H , qd , J = 9 .2 , 6 .9 Hz ), 4. 53 (1H , brs ), 6 .29 (1H , d, J = 8. 2 Hz ), 6 .54 In the same manner as in Example 39 , step 1 , the title ( 1H , d , J = 7 . 3 Hz) , 7 . 35 ( 1H , t, J = 7 . 8 Hz) . 55 compound (1 .05 g ) was obtained as a colorless oil from 1 - ( (dibenzylamino )methyl ) cyclopropanol ( 2 .05 g ) . Step 2) ethyl 3 -cyclopropyl - 3 - (2 - ( (1 -( 5 -methoxy - 2 'H NMR (400 MHz, CDC13 ) 8 0 .45 - 0 .59 (4H , m ), 3. 88 ( 6 -methylpyridin - 2 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbam (4H , s ) , 4 . 52 (2H , d , J = 49 .6 Hz ), 7 . 09 - 7 . 48 ( 10H , m ). oyl) phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoate 60 Step 3 ) ( 1 - fluorocyclopropyl) methanamine hydrochloride In the same manner as in Example 32 , step 2 , the title compound ( 93 . 5 mg) was obtained as a colorless oil from N , N - dibenzyl- 1 - ( 1 - fluorocyclopropyl) methanamine ( 974 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 mg) and palladium hydroxide ( 500 mg) were stirred in yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 100 65 methanol ( 30 mL ) under a hydrogen atmosphere ( 1 atm ) at mg) and 6 -methyl - N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 2 - amine room temperature for 2 hr. The reaction mixture was filtered , ( 99 .0 mg) . a 4N solution of hydrogen chloride ethyl acetate (2 .71 mL ) US 9 ,776 , 962 B2 119 120 was added to the filtrate , and the solvent was evaporated Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 under reduced pressure to give the title compound (409 mg) methylbutan - 2 - yl) (pyridin - 2 -yl ) carbamoyl) phenyl ) as a white solid . piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid ' H NMR ( 400 MHz, DMSO - d ) 8 0 . 82 - 1 . 19 ( 4H , m ), 4 . 35 - 4 . 70 ( 2H , m ), 8 . 65 ( 3H , brs ). 5 By a method similar to that in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 90 mg) was obtained Step 4 ) as a pale -yellow amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cy N - ( ( 1- fluorocyclopropyl) methyl )pyridin - 2 - amine clopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid (110 . 1 mg) and In the same manner as in Example 135 , step 1 , the title 10 N -( tert -pentyl ) pyridin - 2 -amine (52 . 2 mg) . compound (91 mg) was obtained as a white solid from MS ( ESI + ) : [ M + H ] * 601. 3 . ( 1 - fluorocyclopropyl) methanamine hydrochloride ( 204 mg) and pyridine N -oxide ( 386 mg ) . Example 146 ' H NMR ( 400 MHz, CDC1z ) 8 0 . 88 - 1 . 06 ( 4H , m ) , 4 . 33 4 .51 (2H , m ), 5 . 16 (1H , brs ), 6 .62 -6 .68 (1H , m ), 7 . 32 -7 .38 15 3 -cyclopropyl - 3 -( 2 - (( 1- (5 -methoxy - 2 -( propan - 2 -yl ( 1H , m ) , 7 . 43 - 7 .50 ( 1H , m ) , 8 .09 ( 1H , d , J = 4 . 9 Hz ). (pyridin - 2 - yl) carbamoyl) phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid Step 5 ) ethyl 3 -cyclopropyl - 3 -( 2 -( (1 -( 2 -( (( 1- fluoro cyclopropyl) methyl ) ( pyridin - 2 - yl) carbamoyl) - 5 By a method similar to that in Example 32, step 2 and methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 20 Example 1 , step 4 , the title compound ( 39 . 0 mg) was yl) propanoate obtained as a pale -yellow amorphous powder from 2 - ( 4 ( (( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) In the same manner as in Example 32 , step 2 , the title oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 111. 3 compound ( 77 mg ) was obtained as a white amorphous 25 mg ) and N - (propan - 2 - yl ) pyridin - 2 - amine (62 . 8 mg ). powder from 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopro - MS ( ESI + ) : [ M + H ] * 573 . 4 . pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 - methoxy benzoic acid ( 125 mg) and N - ( ( 1 - fluorocyclopropyl) methyl ) Example 147 pyridin - 2 -amine (91 . 0 mg) . ' H NMR (400 MHz, CDC1z ) 8 0 . 10 - 0 . 24 (1H , m ), 0 . 30 30 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - difluoropropyl) ( 4 ( 1H , dq , J = 9 . 7 , 4 . 8 Hz ) , 0 .40 - 0 . 52 ( 1H , m ), 0 .55 - 0 .67 ( 1H , methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) m ) , 0 .88 - 1 . 18 (4H , m ) , 0 .91 - 1 .04 ( 1H , m ), 1 . 19 (3H , t, J= 7 . 1 piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid Hz) , 1 .56 (4H , s ) , 1 .73 - 1 . 96 (3H , m ) , 2 . 26 - 2 .37 ( 1H , m ) , 2 .56 ( 2H , brs ), 2 .65 - 2 .80 (2H , m ), 3 .73 ( 3H , S ), 3 . 95 - 4 . 12 Step 1 ) ( 2H , m ), 4 . 17 ( 2H , d , J = 6 . 3 Hz ), 4 . 35 - 5 . 37 (2H , m ), 6 .21 35 ( 1H , d , J = 2 .3 Hz ) , 6 .47 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz ), 6 .63 ( 1H , s ) , N - (2 , 2- difluoropropyl ) - 4 -methylpyridin -2 -amine 6 .72 - 6 .81 ( 1H , m ) , 6 . 92 ( 1H , dd , J = 7 . 0 , 5 . 2 Hz) , 7 .20 - 7 .33 By a method similar to that in Example 135 , step 1, the (2H , m ), 7 .48 (1H , td, J = 7 .7 , 2 . 0 Hz) , 8 .07 (2H , d , J = 5 .1 Hz ). title compound ( 145 mg) was obtained as a pale - yellow solid Step 6 ) 3- cyclopropyl -3 - (2 -( (1 - (2 -( (( 1 - fluorocyclo 20 from 2 , 2 -difluoropropylamine hydrochloride ( 306 mg ) and propyl) methyl )( pyridin - 2 -yl ) carbamoyl) - 5 -methoxy 4 -methylpyridine 1 -oxide (202 . 8 mg ) . phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) pro MS (ESI + ). found : 186 . 92 . panoic acid Step 2 ) 3 - cyclopropyl- 3 - ( 2 - (( 1 - ( 2 - ( ( 2 , 2 - difluoropro In the same manner as in Example 1 , step 4 , the title * pyl) ( 4 -methylpyridin - 2 - yl) carbamoyl ) - 5 -methoxy compound ( 73 . 0 mg) was obtained as a white amorphous phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro powder from ethyl 3 - cyclopropyl- 3 -( 2 -( ( 1 -( 2 -( (( 1 - fluorocy panoic acid clopropyl) methyl ) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphe By a method similar to that in Example 32 , step 2 and nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoate (77 . 0 50 Example 1 , step 4 , the title compound ( 90 mg) was obtained mg ). as a pale -yellow amorphous powder from 2 - ( 4 -( (( 4 -( 1 -cy MS ( ESI + ) : [ M + H ] * 603. 3 . clopropyl- 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 - yl) - 4 - methoxybenzoic acid ( 109. 2 mg) and Example 145 N - ( 2 , 2 - difluoropropyl) - 4 -methylpyridin - 2 - amine (63 . 2 mg) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methylbu 55 MS (ESI + ) : [ M + H ] * 623 .3 . tan - 2 -yl ) (pyridin - 2 - yl) carbamoyl ) phenyl )piperidin Example 148 4 -yl )methoxy )pyridin - 4 -yl ) propanoic acid

6060 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 5 -methoxy - 2 - (( 4 -methyl Step 1 ) N - tert- pentyl )pyridin - 2- amine pyridin - 2 -yl ) ( 2 ,2 ,2 - trifluoroethyl) carbamoyl )phenyl ) piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid By a method similar to that in Example 135 , step 1 , the title compound ( 79 mg) was obtained as a pale -orange oil in the samemanner as in Example 32 , step 2 and Example from tert -amylamine ( 344 ul) and pyridine 1 - oxide ( 224. 2 65 1 , step 4 , the title compound (128 mg) was obtained as a mg) . grayish white amorphous powder from 2 -( 4 -( (( 4 -( 1 -cyclo MS (ESI + ) : [M + H ] * 165 . 1 . propyl- 3 -ethoxy - 3 -oxopropyl ) pyridin -2 - yl) oxy )methyl ) pip US 9 ,776 , 962 B2 121 122 eridin - 1 -yl ) -4 -methoxybenzoic acid ( 145 mg) and 4 -methyl Step 2 ) 3 - ( 2 - ( ( 1 - ( 2 -( cyclobutyl ( pyridin - 2 - yl) carbam N -( 2 ,2 ,2 - trifluoroethyl) pyridin -2 -amine (114 mg) . oyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyri MS (ESI + ) : [ M + H ] * 627 . 2 . din - 4 - yl) - 3 - cyclopropylpropanoic acid Example 149 5 In the samemanner as in Example 32, step 2 and Example 1 , step 4 , the title compound ( 167 mg) was obtained as a 3 - cyclopropyl - 3 - ( 2 - ( 1 - ( 2 - ( ( 2 , 2 - dimethylbutyl) (pyri white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 din - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 ethoxy - 3 - oxopropyl) pyridin - 2 - yl ) oxy )methyl ) piperidin - 1 yl) methoxy ) pyridin -4 -yl ) propanoic acid yl) - 4 -methoxybenzoic acid ( 150 mg) and N - cyclobutylpyri 10 din - 2 -amine ( 92 mg) . Step 1 ) N - ( 2 , 2 - dimethylbutyl) pyridin - 2 - amine MS (ESI + ) : [ M + H ] * 585. 3 . In the samemanner as in Example 1, step 1 , a pale -yellow Example 152 oil (540 mg) was obtained from 2, 2 -dimethylbutanoic acid ( 1. 0 g ) and pyridin - 2 -amine (737 mg) and dissolved in THF 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -methylpro ( 10 mL ) . Under a nitrogen atmosphere , the solution was pyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 -methoxy added to a suspension of lithium aluminum hydride (208 phenyl) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) pro mg) in THF ( 5 . 4 mL ) at 0° C . , and the mixture was heated panoic acid under reflux for 1 hr. To the reaction solution were added 20 water and aqueous sodium hydroxide solution , and the resulting white precipitate was removed by filtration . The Step 1) 2 -methyl - 1 - (( 6 -methylpyridin - 2 -yl ) amino ) filtrate was evaporated under reduced pressure , and the propan - 2 - ol residue was purified by silica gel column chromatography In the same manner as in Example 135 , step 1 , the title ( ethyl acetate /hexane ) to give the title compound (388 mg) 25 compound (211 mg) was obtained as a pale -yellow solid as a pale -yellow oil. from 2 -methylpyridine 1 - oxide ( 500 mg ) and 1 -amino - 2 MS (ESI + ): [ M + H ] * 179. 2 . methylpropan - 2 - ol (531 mg) . MS ( ESI + ) : [ M + H ] * 181. 1 . Step 2 ) 3 -cyclopropyl - 3 -( 2 - (( 1 - ( 2 - ( (2 ,2 -dimethylbu tyl) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) pip 30 Step 2 ) N - (3 - fluoro -3 -methylbutan - 2 -yl ) - 6 -methyl eridin - 4 -yl )methoxy )pyridin - 4 -yl )propanoic acid pyridin - 2 - amine In the samemanner as in Example 32 , step 2 and Example In the same manner as in Example 39, step 1, the title 1 , step 4 , the title compound (128 mg) was obtained as a compound (81 mg) was obtained as a pale - yellow oil from grayish white amorphous powder from 2 -[ 4 - (( (4 -( 1 -cyclo 10 - 35 412 -methyl - 1 - ( ( 6 -methylpyridin - 2 - yl) amino )propan - 2 - ol ( 211 propyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) pip mg) . eridin - 1 - yl) - 4 -methoxybenzoic acid ( 133 mg) and N - ( 2 , 2 MS (ESI + ) : [ M + H ] * 183 . 1 . dimethylbutyl) pyridin - 2 - amine ( 98 mg) . MS ( ESI + ) : [ M + H ] * 615 . 3 . Step 3 ) 3 - cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( ( 2 - fluoro - 2 -meth 40 ylpropyl ) (6 -methylpyridin - 2 - yl) carbamoyl) - 5 Example 150 methoxyphenyl) piperidin -4 - yl)methoxy ) pyridin -4 yl) propanoic acid 3 -cyclopropyl - 3 - (2 - (( 1 - (5 -methoxy - 2- ( (2 -methylpro pyl) ( 3 -methylpyridin - 2 -yl ) carbamoyl ) phenyl )piperi In the samemanner as in Example 32, step 2 and Example din -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 45 1 , step 4 , the title compound ( 85 mg) was obtained as a white In the same manner as in Example 32 , step 2 and Example amorphous powder from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy 1 , step 4 , the title compound (17 mg) was obtained as a 3 - oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 grayish white solid from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy methoxybenzoic acid (214 mg) and N - ( 3 - fluoro - 3 -meth 3 -oxopropyl ) pyridin -2 -yl ) oxy )methyl ) piperidin - 1 - yl )- 4 - 50 ylbutan - 2 - yl) - 6 -methylpyridin - 2 - amine (81 mg) . methoxybenzoic acid ( 131 mg) and 3 -methyl - N - ( 2 -methyl MS (ESI + ): [ M + H ] * 619 . 4 . propyl) pyridin - 2 - amine ( 89 mg) . MS ( ESI + ) : [ M + H ] * 601 . 3 . Example 153 Example 151 55 3 - cyclopropyl -3 - (2 - (( 1 -( 2 -( ( 2- fluoro -2 - methylpro 3 - ( 2 - ( ( 1 - ( 2 - ( cyclobutyl( pyridin - 2 -yl )carbamoyl ) - 5 pyl) ( 4 -methylpyridin - 2 -yl ) carbamoyl ) - 5 -methoxy methoxyphenyl ) piperidin - 4 - yl )methoxy ) pyridin - 4 phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) pro yl) - 3 - cyclopropylpropanoic acid panoic acid 6060 Step 1 ) N - cyclobutylpyridin - 2 - amine Step 1) 2 -methyl - 1 -( ( 4 -methylpyridin - 2 -yl ) amino ) propan - 2 -ol In the same manner as in Example 135 , step 1 , the title compound (308 mg) was obtained as a pale - yellow solid In the same manner as in Example 135 , step 1 , the title from pyridine 1 - oxide ( 250 mg) and cyclobutanamine ( 234 65 compound ( 850 mg) was obtained as a pale - yellow oil from mg) . 4 -methylpyridine 1 -oxide (600 mg) and 1 - amino - 2 -methyl MS ( ESI + ) : [ M + H ] * 149 . 1 . propan - 2 - ol ( 539 mg) . ' H NMR ( 300 MHz , CDC13 ) d 1 . 25 US 9 ,776 , 962 B2 123 124 (6H , s ), 2. 22 (3H , s ), 3. 34 (2H , d, J = 6 .0 Hz) , 4 .75 (1H , brs ), Hz) , 5 .53 (1H , s ), 6 .35 ( 1H , t, J = 5 .5 Hz) , 6 .45 (1H , ddd , 6 . 24 - 6 . 34 ( 1H , m ) , 6 .42 ( 1H , dd , J = 5 . 4 , 0 . 8 Hz) , 7 .87 (1H , J = 7 . 0 , 5 . 1 , 1 . 0 Hz) , 6 .57 ( 1H , dt, J = 8 . 5 , 0 . 9 Hz ), 7 . 34 ( 1H , d , J = 5 . 4 Hz) . ddd , J = 8 . 6 , 6 . 9 , 2 . 0 Hz) , 7 . 78 - 8 . 05 ( 1H , m ). Step 2 ) N - ( 2 - fluoro - 2 -methylpropyl ) - 4 -methylpyri - 5 Step 4 ) din - 2 -amine N -( ( 1 - fluorocyclobutyl) methyl ) pyridin -2 -amine In the same manner as in Example 39 , step 1 , the title In the same manner as in Example 39, step 1 , the title compound (313 mg) was obtained as a pale - yellow solid compound (212 mg) was obtained as a white solid from from 2- methyl - 1 - (( 4 -methylpyridin - 2 -yl ) amino )propan - 2 -ol 10 1 -( ( pyridin - 2 -ylamino )methyl ) cyclobutanol (583 mg) . (850 mg) . ' H NMR (300 MHz, CDC1z ) 8 1 .41 (6H , d , J = 21. 4 ' H NMR (300 MHz, CDC1z) 8 1 .47 - 1 .69 ( 1H , m ) , 1 . 74 Hz ), 2 .22 ( 3H , s) , 3 .54 (2H , dd, J = 21. 2 , 6 . 6 Hz ), 4. 60 (1H , 1 . 96 ( 1H , m ), 2 . 10 - 2. 45 (4H , m ), 3 .52 - 3. 78 (2H , m ), 4. 61 brs ) , 6 .25 ( 1H , s ), 6 .42 ( 1H , dd , J = 5 . 2 , 0 . 8 Hz) , 7 . 93 ( 1H , d , ( 1H , brs ) , 6 . 43 ( 1H , dt, J = 8 . 4 , 0 . 8 Hz ), 6 . 58 ( 1H , ddd , J = 7 . 1 , 5 . 1 , 0 . 8 Hz ), 7 . 33 - 7 . 47 ( 1H , m ), 7 . 98 - 8 . 14 ( 1H , m ) . J = 5 . 2 Hz ). 15 Step 3 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -meth Step 5 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -( (( 1 - fluoro ylpropyl) ( 4 -methylpyridin - 2 - yl) carbamoyl) - 5 cyclobutyl )methyl ) (pyridin - 2 -yl ) carbamoyl) - 5 methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 yl) propanoic acid yl) propanoate 20 In the same manner as in Example 32 , step 2 and Example In the same manner as in Example 32, step 2 , the title 1 , step 4 , the title compound (214 mg) was obtained as a compound (125 mg) was obtained as a colorless oil from colorless amorphous powder from N - ( 2 - fluoro - 2 -methyl - 2 - (4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 propyl) - 4 -methylpyridin - 2 -amine ( 151 mg) and 2 -( 4 - ( ( (4 - yl )oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 (1 -cyclopropyl - 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) 25 mg ) and N - (( 1 - fluorocyclobutyl)methyl ) pyridin - 2 -amine methyl) piperidin - 1- yl) - 4 -methoxybenzoic acid (200 mg) . ( 93 . 0 mg) . MS (ESI + ) : [M + H ] * 619. 3 . ' H NMR (400 MHz, CDC1z ) & 0 . 12 - 0 .22 (1H , m ) , 0 . 25 0 . 35 ( 1H , m ) , 0 . 41 - 0 .51 ( 1H , m ) , 0 .55 - 0 . 66 ( 1H , m ) , 0 . 91 Example 154 1 . 07 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 1 Hz ) , 1 .58 - 1 . 91 (6H , m ) , 30 2 . 09 - 2 .77 (6H , m ), 2 . 09 - 2 . 26 (2H , m ), 2 . 27 - 2 . 36 ( 1H , m ), 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( (( 1 - fluorocyclobutyl) 2 .66 - 2 . 80 (2H , m ), 3 . 19 - 3 .54 ( 1H , m ) , 3 . 76 ( 3H , s ) , 3 . 99 methyl) ( pyridin -2 -yl ) carbamoyl) - 5 -methoxyphenyl ) 4 . 12 ( 2H , m ) , 4 . 17 ( 2H , d , J = 6 . 7 Hz) , 4 .69 (2H , brs ) , 6 .20 piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid ( 1H , d , J = 2 . 0 Hz ) , 6 .49 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz) , 6 .59 ( 1H , brs ) , 6 .63 ( 1H , s ) , 6 . 76 ( 1H , dd , J = 5 . 3 , 1 . 3 Hz ), 6 . 88 ( 1H , dd , Step 1) 35 J = 6 . 9, 5 . 1 Hz ), 7 . 19 - 7 . 26 ( 1H , m ), 7 . 32 ( 1H , d , J = 8 . 4 Hz ), 1 - ( (trimethylsilyl ) oxy ) cyclobutanecarbonitrile 8 . 07 ( 1H , d , J = 5 . 3 Hz ) , 8 . 34 ( 1H , dd , J = 4 . 8 , 1 . 3 Hz ) . Under a nitrogen atmosphere , trimethylsilyl cyanide (6 .00 Step 6 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 -( 2 - ( ( ( 1 - fluorocy mL ) was added to a solution of cyclobutanone ( 2 . 10 g ) and clobutyl) methyl ) (pyridin - 2 - yl) carbamoyl) - 5 zinc iodide ( 479 mg ) in THF (30 mL ) at room temperature, 40 methoxyphenyl )piperidin - 4 -yl ) methoxy )pyridin - 4 and the mixture was stirred at room temperature for 4 hr . The yl) propanoic acid reaction solution was filtered through silica gel, and the solvent in the filtrate was evaporated under reduced pressure In the same manner as in Example 1 , step 4 , the title to give a crude product of the title compound as a red oil. compound (102 mg) was obtained as a white amorphous This compound was used for the next step without further 45 powder from ethyl 3 - cyclopropyl - 3 - ( 2 - ( 1 - ( 2 - ( ( ( 1 - fluorocy purification . clobutyl )methyl ) ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphe nyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoate ( 125 Step 2 ) 1 - ( aminomethyl) cyclobutanol mg ) . MS (ESI + ): [M + H ] * 617 .2 . The crude product ( entire amount) of 1 - ( ( trimethylsilyl ) 50 oxy ) cyclobutanecarbonitrile was added to a suspension of Example 155 lithium aluminum hydride ( 1 . 14 g ) in diethyl ether ( 30 mL ) at 0° C ., and the mixture was stirred at room temperature for 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 3 -methoxy 3 hr. To the reaction mixture were added water and aqueous 2 , 2 -dimethylpropyl ) (pyridin - 2 - yl) carbamoyl) phenyl) sodium hydroxide solution at 0° C ., and the resulting white 55 piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid precipitate was removed by filtration . The solvent in the filtrate was evaporated under reduced pressure to give a Step 1 ) crude product of the title compound as a white solid . 3 -methoxy -2 , 2 -dimethyl - N - (pyridin - 2 -yl ) propanamide Step 3 ) 1 -( (pyridin - 2 - ylamino )methyl ) cyclobutanol 60 Under a nitrogen atmosphere, a 1 M solution of triethyl aluminum in toluene (22 . 5 mL ) was added to a solution of In the samemanner as in Example 135 , step 1, the title 2 -aminopyridine (1 . 41 g ) and methyl 3 -methoxy -2 , 2 -dim compound (583 mg) was obtained as a pale - yellow oil from ethylpropanoate ( 2 .12 mL ) in toluene ( 30 mL ) at room a crude product ( entire amount) of 1 - ( aminomethyl) cyclobu - temperature , and the mixture was stirred at 100° C . for 2 hr tanol and pyridine N -oxide ( 1 .48 g ) . 65 and heated under reflux for 16 hr. To the reaction solution 'H NMR (300 MHz, DMSO -do ) 1 . 38 -1 . 54 (1H , m ), was added methanol and the mixture was diluted with ethyl 1 .55 -1 .71 (1H , m ), 1. 81 - 2. 06 (4H , m ), 3 . 36 ( 2H , d , J = 5 .7 acetate . The resulting precipitate was removed by filtration . US 9 ,776 ,962 B2 125 126 The solvent in the filtrate was evaporated under reduced pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy pressure, and the residue was purified by silica gel column benzoic acid (100 mg) and N - (2 , 2 -dimethylpropyl ) pyrimi chromatography (ethyl acetate /hexane ) to give the title com - din - 2 - amine ( 86 .0 mg) . pound (803 mg) as a pale -yellow oil. ' H NMR (400 MHz, CDC13 ) 8 0 . 14 - 0 .21 ( 1H , m ), 0 .25 IH NMR (400 MHz, CDC12 ) 8 1 . 27 (6H , s ) , 3 .44 (2H , s ) , 5 0 .34 ( 1H , m ) , 0 . 41 -0 .52 ( 1H , m ) , 0 .55 - 0 .66 ( 1H , m ), 0 . 86 3 .50 ( 3H , s ) , 7 . 00 ( 1H , ddd , J = 7 . 3 , 5 . 0 , 0 . 9 Hz) , 7 .62 - 7 .71 (9H , s ) , 0 . 95 - 1 .04 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 2 Hz ), 1 . 52 - 1 . 89 ( 1H , m ) , 8 . 22 (1H , d , J = 8 . 4 Hz ), 8 .26 - 8 .31 ( 1H , m ), 9 . 25 (5H , m ), 2 . 24 - 2 .35 ( 1H , m ) , 2 .36 - 2 .64 ( 3H , m ) , 2 .64 - 2 .83 ( 1H , brs ) . ( 2H , m ) , 3 . 24 ( 1H , brs ) , 3 .78 (3H , s ) , 3 . 99 - 4 . 12 (2H , m ), 4 . 15 ( 2H , d , J = 6 . 5 Hz ), 4 . 27 ( 2H , d , J = 16 . 3 Hz ), 6 . 14 ( 1H , d , Step 2 ) 10 J = 2 . 4 Hz ), 6 . 55 ( 1H , dd , J = 8 .5 , 2 . 2 Hz ) , 6 .63 ( 1H , s ), N - ( 3 -methoxy - 2 , 2 - dimethylpropyl) pyridin - 2 - amine 6 .72 -6 . 86 ( 2H , m ) , 7 . 46 ( 1H , d , J = 8 . 4 Hz ), 8 .07 ( 1H , d , J = 5 . 3 Under a nitrogen atmosphere , 3 -methoxy - 2 ,2 - dimethyl Hz ), 8 . 31 ( 2H , d , J = 4 . 8 Hz ) . N - (pyridin - 2 - yl )propanamide (803 mg) was added to a sus Step 2 ) 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( ( 2 , 2 - dimethyl pension of lithium aluminum hydride (439 mg) in THF ( 15 propyl) (pyrimidin - 2 -yl ) carbamoyl ) - 5 -methoxyphe mL ) at room temperature , and the mixture was heated under nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoic reflux for 30 min . To the reaction solution were added water acid and aqueous sodium hydroxide solution at 0° C ., and the resulting white precipitate was removed by filtration . The 20 In the same manner as in Example 1 , step 4 , the title solvent in the filtrate was evaporated under reduced pressure compound (102 mg) was obtained as a white amorphous to give the title compound ( 734 mg) as a colorless oil. powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth ' H NMR (400 MHz , CDC1z ) 8 0 .98 (6H , s) , 3 . 17 -3 .21 ylpropyl) ( pyrimidin - 2 -yl ) carbamoyl ) -5 -methoxyphenyl ) pi (2H , m ), 3 . 19 (2H , s ), 3 .33 ( 3H , s ), 5 .02 ( 1H , brs ) , 6 .40 ( 1H , peridin -4 - yl) methoxy )pyridin - 4 -yl ) propanoate ( 106 mg ) . d , J = 8 . 5 Hz ) , 6 . 46 - 6 . 56 ( 1H , m ), 7 . 38 ( 1H , ddd , J = 8 . 5 , 7 .0 , 25 MS (ESI + ) : [ M + H ] * 602. 3 . 1 . 9 Hz) , 8 .05 ( 1H , dd , J = 5 . 0 , 1 . 1 Hz) . Example 157 Step 3 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 (( 3 -methoxy - 2, 2 -dimethylpropyl ) (pyridin -2 - yl) car 3 - cyclopropyl -3 - ( 2 -( ( 1 -( 2 -( ( 2 , 2 -difluoroethyl ) ( 4 bamoyl) phenyl ) piperidin - 4 -yl ) methoxy )pyridin -4 - yl ) 30 methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) propanoate piperidin -4 -yl ) methoxy ) pyridin - 4 - yl )propanoic acid In the same manner as in Example 32 , step 2 , the title Step 1 ) compound ( 80 . 6 mg) was obtained as a colorless oil from N - ( 2 , 2 - difluoroethyl) - 4 -methylpyridin - 2 - amine 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - 35 yl) oxy )methyl ) piperidin - 1- yl ) - 4 -methoxybenzoic acid (100 In the same manner as in Example 135 , step 1 , the title mg) and N - ( 3 -methoxy - 2 , 2 - dimethylpropyl) pyridin - 2 compound (490 mg) was obtained as a colorless oil from 4 -methylpyridine 1 - oxide (420 mg) and 2 , 2 -difluoroethan amine ( 101 mg) . amine ( 343 mg) . Step 4 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 3 40 ' H NMR (300 MHz, CDC13 ) 8 2 .23 (3H , s) , 3 .77 (2H , tdd, methoxy - 2 , 2 - dimethylpropyl) (pyridin - 2 - yl) carbam J = 14 . 5 , 6 . 5 , 4 . 3 Hz) , 4 .48 ( 1H , brs) , 5 . 73 - 6 . 18 (1H , m ), 6 .28 oyl )phenyl )piperidin - 4- yl )methoxy ) pyridin -4 -yl ) (1H , d , J = 0 .7 Hz ) , 6 .48 ( 1H , dd , J = 5 .2 , 0 .7 Hz) , 7 . 96 ( 1H , d , propanoic acid J = 5 . 2 Hz) . 45 Step 2 ) 3 - cyclopropyl- 3 -( 2 - ( 1 - ( 2 - ( ( 2 , 2 -difluoro In the same manner as in Example 1 , step 4 , the title ethyl) ( 4 -methylpyridin - 2 - yl) carbamoyl ) - 5 -methoxy compound (69 . 8 mg) was obtained as a white amorphous phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) pro powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 panoic acid ( ( 3 -methoxy - 2 , 2 - dimethylpropyl) ( pyridin - 2 - yl) carbamoyl) phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) propanoate 50 In the same manner as in Example 32, step 2 and Example (80 .6 mg) . 1 , step 4 , the title compound ( 145 mg) was obtained as a MS ( ESI + ) : [ M + H ] * 631 . 3 . colorless amorphous powder from N - ( 2 , 2 - difluoroethyl) -4 methylpyridin - 2 - amine ( 128 mg) and 2 - ( 4 - ( ( (4 - ( 1 - cyclopro Example 156 pyl- 3 -ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperi 55 din -1 -yl ) - 4 -methoxybenzoic acid ( 180 mg) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( 2 , 2 -dimethylpropyl ) MS (ESI + ) : [ M + H ]* 609. 2 . (pyrimidin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) pip eridin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoic acid Example 158 Step 1 ) ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dim 3 - ( 2 - ( ( 1 -( 2 - ( ( 4 - cyanopyridin - 2 - yl) ( 2 -methylpropyl ) ethylpropyl) (pyrimidin - 2 - yl) carbamoyl) - 5 -methoxy carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) phenyl) piperidin - 4 - yl) methoxy )pyridin -4 - yl) pro methoxy )pyridin -4 -yl ) -3 -cyclopropylpropanoic acid panoate By a method similar to that in Example 32 , step 2 and In the same manner as in Example 32 , step 2 , the title 65 Example 1 , step 4 , the title compound ( 110 mg) was compound ( 106 mg) was obtained as a white amorphous obtained as a yellow solid from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 powder from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro ethoxy - 3 -oxopropyl ) pyridin - 2 - yl ) oxy )methyl ) piperidin - 1 US 9 ,776 ,962 B2 127 128 yl) - 4 -methoxybenzoic acid (126 .7 mg) and 2- ( ( 2 -methylpro solvent was evaporated under reduced pressure , and the pyl) amino )pyridine - 4 - carbonitrile (69 .0 mg) . residue was purified by silica gel column chromatography MS (ESI + ) : [ M + H ] * 612 . 3 . (NH , ethyl acetate /hexane ) to give the title compound ( 3 . 30 g ) as a colorless oil . Example 159 H NMR (400 MHz, CDC12 ) 8 1 .21 - 1 . 29 (7H , m ), 1 . 81 ( 1H , s ), 3. 65 (2H , s ), 7. 20 -7 .25 ( 1H , m ), 7 .29 - 7 .40 (4H , m ). 3 - cyclopropyl- 3 - ( 2 - (( 1 - ( 5 -methoxy - 2 - ( ( 3 -methylbu tyl) (pyridin - 2 - yl) carbamoyl) phenyl) piperidin - 4 - yl) Step 4 ) methoxy) pyridin - 4 -yl ) propanoic acid N -benzyl - 2 - isopropoxy - 2 -methylpropan - 1- amine 10 By a method similar to that in Example 32 , step 2 and Under a nitrogen atmosphere , boron trifluoride diethyl Example 1 , step 4 , the title compound ( 83 mg) was obtained ether complex ( 432 ?L ) was added to a solution of 1 -benzyl as a pale -yellow amorphous powder from 2 -[ 4 - (( (4 -( 1 -cy - 2 ,2 -dimethylaziridine (500 mg) in isopropylalcohol (20 mL ) clopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl )oxy )methyl ) at room temperature , and the mixture was heated under piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 107. 2 mg) and 15 reflux for 30 min . To the reaction solution was added N - isopentylpyridin - 2 - amine (54 . 7 mg) . saturated aqueous sodium hydrogen carbonate solution at MS ( ESI + ) : [ M + H ] * 601 . 3 . room temperature , and the mixture was extracted with ethyl acetate . The extract was washed with water, saturated aque Example 160 ous sodium hydrogen carbonate solution and saturated brine , 20 and dried over anhydrous magnesium sulfate . The solvent 3 -cyclopropyl - 3 - ( 2 - (( 1 - (2 -( ( 2 - isopropoxy -2 -methyl was evaporated under reduced pressure , and the obtained propyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) residual solid was washed with diisopropyl ether to give the piperidin - 4 -yl ) methoxy ) pyridin - 4 -yl ) propanoic acid title compound (442 mg) as a white solid . H NMR (400 MHz , CDC12 ) 8 1 . 09 (6H , d , J = 6 . 0 Hz) , Step 1) 25 1 .20 (6H , s ), 2 .53 (2H , s ), 3. 73 -3 .80 (1H , m ), 3. 81 (2H , s) , N - ( 1 - hydroxy - 2 -methylpropan - 2 - yl) benzamide 7 .19 - 7 .41 ( 5H , m ). 2 - Amino -2 -methyl - 1- propanol (4 .46 g ) and benzoyl chlo Step 5 ) 2 -isopropoxy - 2 -methylpropan - 1 -amine ride ( 8 .71 mL ) were added to a mixture of potassium carbonate ( 104 g ) , water (333 mL ) and ethyl acetate ( 100 30 N -Benzyl - 2 -isopropoxy - 2 -methylpropan - 1 - amine ( 400 mL ) at room temperature , and the mixture was stirred at mg) and palladium hydroxide (200 mg ) were stirred in room temperature for 16 hr. The reaction solution was methanol (15 mL ) at room temperature for 1 hr under a extracted with ethyl acetate . The extract was washed with hydrogen atmosphere ( 1 atm ). The reaction mixture was water and saturated brine, and dried over anhydrous mag - filtered , and the solvent in the filtrate was evaporated under nesium sulfate . The solvent was evaporated under reduced 35 reduced pressure to give a crude product of the title com pressure , and the residue was purified by silica gel column pound as a pale - yellow oil. This compound was used for the chromatography (NH , ethyl acetate /hexane ) to give the title next step without further purification . compound (6 . 08 g ) as a white solid . ' H NMR (400 MHz, DMSO -da ) 8 1 . 31 (6H , s ), 3 .50 (2H , Step 6 ) s) , 7 .38 - 7. 46 (2H , m ), 7 .47 - 7 .54 (2H , m ), 7 .78 (2H , d , J= 7. 0 40 N -( 2 -isopropoxy - 2 -methylpropyl ) pyridin - 2 -amine Hz ) . In the same manner as in Example 135 , step 1 , the title Step 2 ) 2 - (benzylamino )- 2 -methylpropan - 1 - ol compound ( 95 . 4 mg) was obtained as a pale - orange oil from a crude product (entire amount) of 2 -isopropoxy - 2 -methyl Under a nitrogen atmosphere , a solution of N - ( 1 -hydroxy - 45 propan - 1 - amine and pyridine N -oxide ( 286 mg) . 2 -methylpropan - 2- yl) benzamide (6 .08 g ) in THF (50 mL ) ' H NMR (400 MHz, CDC13 ) d 1 .14 (6H , d , J = 6 . 1 Hz ), was added to a suspension of lithium aluminum hydride in 1 . 25 (6H , s ), 3 . 27 (2H , d , J = 5 . 3 Hz ), 3 . 83 ( 1H , spt, J = 6 . 1 THF (50 mL ) at room temperature , and the mixture was Hz ), 4 . 79 ( 1H , brs ), 6 . 39 ( 1H , d , J = 8 . 3 Hz ) , 6 .49 - 6 . 56 ( 1H , heated under reflux for 1 hr. To the reaction solution were m ) , 7 .34 - 7 . 42 ( 1H , m ) , 8 .07 ( 1H , d , J = 4 . 5 Hz ) . added water and aqueous sodium hydroxide solution , and 50 the resulting white precipitate was removed by filtration . Step 7 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - iso The solvent in the filtrate was evaporated under reduced propoxy - 2 -methylpropyl ) (pyridin - 2 -yl ) carbamoyl) pressure to give the title compound ( 4 . 5 g ) as a white solid . 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 ' H NMR ( 400 MHz , DMSO -da ) 8 1 .00 (6H , s) , 3 . 18 -3 .34 yl) propanoate ( 3H , m ) , 3 .62 (2H , s ) , 4 . 55 ( 1H , brs ), 7 . 10 - 7 .40 ( 5H , m ) . 55 In the same manner as in Example 32 , step 2 , the title Step 3 ) 1 -benzyl - 2, 2 -dimethylaziridine compound (111 mg) was obtained as a colorless oil from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 Under a nitrogen atmosphere , methanesulfonyl chloride yl) oxy )methyl ) piperidin - 1- yl ) - 4 -methoxybenzoic acid ( 100 ( 3 . 24 mL ) was added dropwise to a solution of 2 - ( benzy - 60 mg) and N - ( 2 - isopropoxy - 2 -methylpropyl ) pyridin - 2 - amine lamino ) - 2 -methylpropan - 1 - ol ( 5 . 0 g ) and triethylamine (95 . 4 mg) . ( 11 . 7 mL ) in THF ( 80 mL ) at 0° C . , and the mixture was H NMR (400 MHz, CDC1 , ) & 0 . 10 - 0 .21 ( 1H , m ) , 0 . 24 stirred at 0° C . for 30 min . To the reaction solution was 0 .34 ( 1H , m ) , 0 . 41 - 0 . 52 (1H , m ), 0 .55 - 0 .65 (1H , m ), 0 .78 added water at 0° C ., and the mixture was extracted with (6H , brs ), 0 . 92 - 1 . 05 ( 2H , m ), 1 .05 - 1 . 30 (6H , m ), 1 . 19 ( 3H , ethyl acetate . The extract was washed with water, saturated 65 t, J = 7. 2 Hz ), 1 . 31- 1 . 91 (4H , m ), 2 .24 - 2 .35 (1H , m ), 2 . 36 aqueous sodium hydrogen carbonate solution and saturated 2 .70 (3H , m ), 2 .66 - 2 .79 (2H , m ), 3 .41 ( 1H , brs ) , 3 .69 ( 1H , brine , and dried over anhydrous magnesium sulfate . The spt, J = 6 . 1 Hz ) , 3 .74 ( 3H , s ) , 4 .01 - 4 . 11 (2H , m ) , 4 . 16 (2H , d , US 9 ,776 , 962 B2 129 130 J = 6 . 5 Hz) , 4 . 36 ( 2H , brs ), 6 . 19 ( 1H , brs ) , 6 . 46 ( 1H , dd , yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 J = 8 . 3 , 2 . 1 Hz) , 6 .52 -6 . 66 ( 1H , m ) , 6 .63 ( 1H , s ) , 6 .76 ( 1H , d , mg) and N - ( 2 - isopropoxy - 2 -methylpropyl ) pyridin - 2 - amine J = 5 .4 Hz) , 6 .81 -6 .88 ( 1H , m ), 7 . 20 (1H , brs ), 7. 24 - 7. 33 (1H , (55 . 6 mg) . m ) , 8 . 07 ( 1H , d , J = 5 . 3 Hz ), 8 .31 ( 1H , d , J = 3 . 3 Hz) . H NMR (400 MHz, CDC13 ) 8 0 .13 - 0 .22 (1H , m ), 0 .23 5 0 .35 ( 1H , m ) , 0 . 40 - 0 .52 ( 1H , m ), 0 . 55 - 0 .65 (1H , m ) , 0 . 92 Step 8 ) 3 - cyclopropyl -3 -( 2 - ( ( 1 - ( 2 -( ( 2 -isopropoxy -2 1 . 05 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 1 Hz ) , 1 . 26 (6H , s ) , 1 .58 - 1 . 96 methylpropyl) (pyridin - 2 -yl ) carbamoyl) - 5 -methoxy ( 3H , m ), 2 . 24 - 2 . 35 ( 1H , m ), 2 . 36 - 2 .76 (3H , m ) , 2 .66 - 2 .81 phenyl) piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) pro ( 2H , m ), 3 . 18 - 3 .63 ( 3H , m ) , 3 .75 (3H , s ) , 4 .00 - 4 . 17 (4H , m ) , panoic acid 4 . 16 (2H , d , J = 6 . 5 Hz ), 4 . 27 - 4 . 57 ( 2H , m ) , 6 . 19 ( 1H , s ) , 6 . 48 10 ( 1H , dd , J = 8 . 4 , 2 . 3 Hz ), 6 .53 ( 1H , brs ), 6 .63 ( 1H , s ) , In the same manner as in Example 1 , step 4 , the title 6 .74 - 6 .79 ( 1H , m ) , 6 .83 - 6 . 90 ( 1H , m ) , 7 . 19 ( 1H , t , J = 7 . 2 compound (99 . 1 mg) was obtained as a white amorphous Hz ), 7 .25 -7 .31 ( 1H , m ) , 8 .07 ( 1H , d , J = 5 .3 Hz) , 8 .32 ( 1H , d , powder from ethyl 3 - cyclopropyl- 3 -( 2 -( ( 1 -( 2 -( (2 - iso - J = 3 .4 Hz) . propoxy - 2 -methylpropyl ) (pyridin - 2 - yl ) carbamoyl) - 5 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) pro 1515 Step 5 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 panoate ( 111 mg) . methyl - 2 -( 2 ,2 , 2 -trifluoroethoxy )propyl ) ( pyridin - 2 MS (ESI + ) : [ M + H ] * 645 . 4 . yl) carbamoyl ) phenyl ) piperidin -4 -yl ) methoxy )pyri din -4 -yl ) propanoic acid Example 161 20 In the same manner as in Example 1 , step 4 , the title 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methyl - 2 compound (62 .8 mg) was obtained as a white amorphous ( 2 , 2 , 2 - trifluoroethoxy )propyl ) (pyridin - 2 - yl) carbam powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 oyl) phenyl ) piperidin - 4 -yl ) methoxy ) pyridin - 4 -yl ) (( 2 -methyl - 2 -( 2, 2, 2 - trifluoroethoxy )propyl ) (pyridin - 2 - yl ) propanoic acid 25 carbamoyl) phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl ) propanoate (72 mg) . Step 1 ) N - benzyl- 2 -methyl - 2 - (2 , 2, 2 - trifluoroethoxy) MS (ESI + ): [ M + H ] * 685 . 4 . propan - 1 - amine Example 162 In the same manner as in Example 160 , step 4 , the title 30 compound (446 mg) was obtained as a colorless oil from 3 -cyclopropyl -3 - (2 - ( 1 -( 2 -( ( (3 , 3 - difluorocyclobutyl) 1 - benzyl- 2 , 2 - dimethylaziridine ( 500 mg) obtained in methyl ) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) Example 160, step 3 and trifluoroethanol ( 20 mL ) . piperidin -4 -yl ) methoxy )pyridin -4 - yl) propanoic acid ' H NMR (400 MHz, CDC13 ) d 1 . 23 (6H , s ) , 2 .59 (2H , s ) , ( 5 mi 35 Step 1) 3 . 70 (2H , q , J = 8 . 7 Hz ), 3 .82 ( 2H , s ), 7 . 29 - 7 .41 ( 5H , m ) . 35 N -( ( 3 , 3 - difluorocyclobutyl) methyl ) pyridin - 2 - amine Step 2 ) 2 -methyl - 2 - ( 2 , 2 , 2 - trifluoroethoxy ) propan - 1 - amine In the samemanner as in Example 135 , step 1 , the title compound (215 mg) was obtained as a pale - yellow oil from In the same manner as in Example 160 , step 5 . a crude 40 pyridine 1 - oxide ( 150 mg) and 1 - ( 3 , 3 -difluorocyclobutyl ) product of the title compound was obtained as a pale -yellow methanamine hydrochloride ( 311 mg) . oil from N -benzyl - 2 -methyl - 2 - ( 2 , 2 , 2 - trifluoroethoxy )pro MS ( ESI + ) : [ M + H ] * 199 . 0 . pan - 1 - amine (446 mg) . This compound was used for the Step 2 ) 3 -cyclopropyl - 3 - (2 - ( (1 -( 2 -( ( (3 , 3 -difluorocy next step without further purification . 4545 clobutyl) methyl ) (pyridin - 2 -yl ) carbamoyl) - 5 Step 3 ) N - ( 2 -methyl - 2 - ( 2 , 2 , 2 - trifluoroethoxy )pro methoxyphenyl) piperidin -4 - yl)methoxy ) pyridin -4 pyl) pyridin - 2 -amine yl) propanoic acid In the same manner as in Example 32 , step 2 and Example In the same manner as in Example 135 , step 1 , the title 50 1 . step 4 . the title compound ( 73 mg) was obtained as a white compound ( 55 .6 mg) was obtained as a pale - orange oil from amorphous powder from 2 - (4 - (( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy a crude product ( entire amount) of 2 -methyl - 2 - ( 2 , 2 , 2 - trif- 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 luoroethoxy )propan - 1 - amine and pyridine N - oxide (231 methoxybenzoic acid (134 mg) and N - ( ( 3 , 3 - difluorocy mg) . clobutyl )methyl ) pyridin - 2 -amine ( 110 mg) . ' H NMR (400 MHz , CDC1z) 8 1 .28 (6H , s ), 3 . 43 ( 2H , d , 55 MS (ESI + ) : [ M + H ] * 635 . 3 . J = 5 . 6 Hz ), 3 .76 ( 2H , q , J = 8 . 5 Hz ), 4 .68 ( 1H , brs ), 6 .42 ( 1H , d , J = 8 .4 Hz ), 6 .53 - 6 .59 (1H , m ), 7 .35 - 7 .42 (1H , m ), 8. 07 Example 163 (1H , d , J = 3 . 8 Hz) . 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methyl Step 4 ) ethyl 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 - 60 pyridin - 4 -yl ) ( 2, 2 ,2 -trifluoroethyl ) carbamoyl ) phenyl ) ( ( 2 -methyl - 2 - ( 2 , 2 , 2 - trifluoroethoxy ) propyl) (pyridin piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 2 - yl) carbamoyl) phenyl) piperidin - 4 - yl) methoxy ) pyri din -4 - yl )propanoate Step 1) 2 -methyl - N -( 2 ,2 , 2 -trifluoroethyl ) pyridin -4 -amine In the same manner as in Example 32 , step 2 , the title 65 compound (72 . 0 mg) was obtained as a colorless oil from In the same manner as in Example 32 , step 1 , the title 2 -( 4 -( ( ( 4 -( 1- cyclopropyl - 3 - ethoxy -3 -oxopropyl ) pyridin -2 - compound ( 1. 43 g) was obtained as a grayish white solid US 9 ,776 ,962 B2 131 132 from 2 -methylpyridin - 4 -amine ( 1 . 00 g ) and trifluoroacetic white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 anhydride ( 1 . 57 mL ) . ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 MS ( ESI + ): [M + H ] * 191 .0 . yl) - 4 -methoxybenzoic acid ( 150 mg) and N - ( 3 , 3 - difluoro Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 -( 5 -methoxy - 2 - ( ( 2 cyclobutyl) pyridin - 2 -amine (85 mg ) . methylpyridin - 4 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) MS ( ESI + ) : [ M + H ] * 621. 3 . phenyl) piperidin -4 -yl )methoxy )pyridin -4 - yl) pro panoic acid Example 166 In the same manner as in Example 32 , step 2 and Example 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (pyrimidin - 2 1 , step 4 , the title compound (69 mg) was obtained as a yl( 2 ,2 ,2 - trifluoroethyl) carbamoyl )phenyl ) piperidin grayish white amorphous powder from 2 - [ 4 -( (( 4 -( 1 - cyclo 4 -yl )methoxy )pyridin -4 -yl ) propanoic acid propyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) pip eridin - 1 -yl ) - 4 - methoxybenzoic acid (100 mg) and 2 -methyl Step 1 ) N - ( 2 ,2 , 2 - trifluoroethyl ) pyrimidin - 2 - amine N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 4 - amine (79 mg ) . MS ( ESI + ) : [ M + H ] * 627 . 2 . 15 In the same manner as in Example 45, step 8, the title compound (513 mg ) was obtained as a pale -yellow oil from Example 164 2 , 2 , 2 -trifluoroethylamine (834 uL ) . 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methoxy ' H NMR ( 400 MHz, CDC1z ) d 4 . 18 (2H , qd , J = 9 . 0 , 6 . 9 2 -methylpropyl ) ( 4 -methylpyridin - 2 - yl) carbamoyl ) 20 Hz ), 5 .32 ( 1H , brs) , 6 .67 ( 1H , t, J= 4 .8 Hz ), 8 .33 ( 2H , d , phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro J = 4 . 8 Hz ) . panoic acid Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 Step 1) N -( 2 -methoxy -2 -methylpropyl ) -4 -methyl (pyrimidin - 2 - yl( 2 , 2 , 2 - trifluoroethyl) carbamoyl) phe pyridin - 2 -amine 25 nyl) piperidin -4 -yl ) methoxy )pyridin -4 - yl )propanoate In the same manner as in Example 135, step 1, the title In the same manner as in Example 32, step 2 , the title cocompound ( 130 mg) was obtained as a pale yellow oil from compound (75 . 5 mg ) was obtained as a white amorphous 2 -methoxy - 2 -methylpropan - 1 - amine hydrochloride ( 130 powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 -ethoxy - 3 - oxopro mg ) and 4 -methylpyridine 1 -oxide (92 mg ) . 30 pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) -4 -methoxy MS (ESI + ) : [M + H ] * 195. 2 . benzoic acid ( 112 mg) and N - ( 2 , 2 , 2 - trifluoroethyl) pyrimi din - 2 -amine ( 168 mg ) . Step 2 ) 3- cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 -( (2 ' H NMR ( 400 MHz, CDC1z ) 8 0 . 11 - 0 .20 ( 1H , m ), 0 . 26 methoxy - 2 -methylpropyl ) ( 4 -methylpyridin - 2 -yl ) 0 . 36 ( 1H , m ) , 0 .41 - 0 . 52 ( 1H , m ) , 0 . 55 - 0 .68 ( 1H , m ), 0 . 88 carbamoyl) phenyl) piperidin -4 - yl) methoxy ) pyridin 35 1 . 06 (1H , m ), 1 . 13 - 1 .42 ( 3H , m ), 1 . 19 ( 3H , t, J = 7 . 1 Hz) , 4 - yl) propanoic acid 1 .65 - 1 . 86 ( 3H , m ) , 2 . 26 - 2 . 37 ( 1H , m ) , 2 . 51 ( 2H , brs ) , 2 .63 - 2 . 82 (3H , m ) , 3 . 80 ( 3H , s ) , 4 .07 (2H , qd , J = 7 . 2 , 3 . 9 Hz) , In the same manner as in Example 32 , step 2 and Example 4 . 13 ( 2H , d , J = 6 . 5 Hz) , 4 . 90 - 5 . 17 ( 2H , m ) , 6 .21 ( 1H , d , J = 2 . 4 1 , step 4, the title compound ( 117 mg) was obtained as a Hz ), 6 . 58 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz) , 6 .63 (1H , s ) , 6 .77 ( 1H , d , grayish white amorphous powder from 2 - ( 4 - ( (( 4 - ( 1 - cyclo - 40 J = 5 . 3 Hz ), 6 . 89 ( 1H , t , J = 4 . 8 Hz ), 7 .51 ( 1H , d , J = 8 . 5 Hz ) , propyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) pip 8 .07 ( 1H , d , J = 5 . 3 Hz ) , 8 . 36 (2H , d , J = 4 . 8 Hz ) . eridin - 1 -yl ) -4 -methoxybenzoic acid ( 140 mg) and N - ( 2 methoxy - 2- methylpropyl ) -4 -methylpyridin - 2 - amine ( 113 Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (py mg) . rimidin -2 -yl ( 2 ,2 ,2 - trifluoroethyl ) carbamoyl) phenyl ) MS ( ESI + ) : [ M + H ] * 631 . 4 . 45 piperidin -4 -yl ) methoxy )pyridin -4 - yl) propanoic acid Example 165 In the same manner as in Example 1 , step 4 , the title compound (71 . 4 mg) was obtained as a white amorphous 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( ( 3 ,3 - difluorocyclobutyl) powder from ethyl 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 (pyridin - 2 -yl ) carbamoyl) -5 -methoxyphenyl ) piperi 50 (pyrimidin - 2 - yl( 2 , 2 , 2 -trifluoroethyl )carbamoyl ) phenyl) pip din - 4 -yl ) methoxy ) pyridin - 4 - yl) propanoic acid eridin -4 - yl) methoxy )pyridin -4 - yl) propanoate (75 . 5 mg) . MS (ESI + ) : [ M + H ] * 614 . 2 . Step 1 ) N - ( 3 , 3 - difluorocyclobutyl) pyridin - 2 - amine Example 167 In the same manner as in Example 135 , step 1 , the title 55 compound ( 85 mg ) was obtained as a pale - yellow solid from 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( ( 2 ,2 - difluoroethyl) (py pyridine 1 -oxide ( 66 . 2 mg) and 3 , 3 - difluorocyclobutan rimidin - 2 - yl ) carbamoyl) - 5 -methoxyphenyl ) piperi amine hydrochloride ( 100 mg) . din - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoic acid MS ( ESI + ) : [ M + H ] * 185 . 0 . 60 Step 1 ) N - ( 2 , 2 - difluoroethyl) pyrimidin - 2 - amine Step 2 ) 3 -cyclopropyl - 3 -( 2 -( (1 - (2 - (( 3 , 3 -difluorocy clobutyl) (pyridin - 2 - yl) carbamoyl) - 5 -methoxyphe In the same manner as in Example 45 , step 8 , the title nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic compound (574 mg) was obtained as a yellow solid from acid 2 , 2 - difluoroethylamine ( 849 UL ) . 65 H NMR ( 400 MHz, CDC1z ) 8 3 . 83 ( 2H , tdd , J = 14 . 4 , 6 . 5 , In the samemanner as in Example 32 , step 2 and Example 4 .3 Hz) , 5 .36 (1H , brs) , 5 .71 - 6 .18 (1H , m ), 6 .63 ( 1H , t , J = 4 . 8 1 , step 4 , the title compound ( 124 mg) was obtained as a Hz ), 8 .31 ( 2H , d , J = 4 . 8 Hz ). US 9 ,776 , 962 B2 133 134 Step 2 ) ethyl 3 - cyclopropyl - 3 -( 2 - ( 1 - ( 2 - ( ( 2 , 2 - difluo Example 169 roethyl) (pyrimidin - 2 -yl ) carbamoyl ) - 5 -methoxyphe nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoate 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 4 -methylpy rimidin - 2 - yl) ( 2 , 2 , 2 - trifluoroethyl ) carbamoyl) phenyl) In the same manner as in Example 32, step 2 , the title piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid compound (108 mg) was obtained as a white amorphous powder from 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopro Step 1 ) pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy 4 -methyl - N - ( 2 , 2 , 2 - trifluoroethyl) pyrimidin - 2 -amine benzoic acid ( 112 mg) and N -( 2 , 2 -difluoroethyl ) pyrimidin - 10 2 - amine ( 135 mg ). In the same manner as in Example 45 , step 8 , a crude ' H NMR (400 MHz, CDC13 ) 8 0 . 12 - 0 .21 ( 1H , m ), 0 .25 product of the title compound (494 mg) was obtained as a 0 .34 ( 1H , m ), 0 .41 - 0 .51 ( 1H , m ), 0 .56 - 0 .65 (1H , m ), 0 . 92 - pale -yellow solid from 2 - chloro -4 -methylpyrimidine (500 1 .06 ( 1H , m ), 1 . 15 - 1 .44 ( 2H , m ), 1 . 16 - 1 .22 (3H , m ) , 1 .62 mg) . This compound was used for the next step without 1 . 84 (3H , m ) , 2 . 26 - 2 . 36 ( 1H , m ) , 2 . 50 ( 2H , t , J = 11 . 5 Hz) , 15 further purification . 2 .61 - 3 . 18 ( 2H , m ), 2 .65 - 2 .80 ( 2H , m ), 3 . 80 ( 3H , s ) , 4 .03 MS ( ESI + ) : [ M + H ] * 192 . 0 . 4 .11 (2H , m ) , 4 .12 (2H , d , J = 6 . 5 Hz ), 4 . 38 - 4 . 93 ( 2H , m ) , 6 .09 - 6 .44 ( 1H , m ), 6 .22 (1H , d , J = 2 . 3 Hz ), 6 .59 ( 1H , dd , Step 2 ) 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 5 -methoxy - 2- (( 4 J = 8 . 5 , 2 . 3 Hz ), 6 .63 ( 1H , s ), 6 .77 ( 1H , d , J = 5 . 3 Hz) , 6 .87 methylpyrimidin - 2 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbam ( 1H , t , J= 4 .8 Hz) , 7 .54 ( 1H , d , J= 8 .5 Hz) , 8 .07 ( 1H , d , J= 5 .3 20 oyl) phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) Hz ) , 8 . 35 (2H , d , J = 4 . 8 Hz ) . propanoic acid Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - difluoro In the same manner as in Example 32 , step 2 and Example ethyl) ( pyrimidin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) 25 1 , step 4 , the title compound ( 75 . 4 mg) was obtained as a piñeridin - 4 - vlmethoyvinyridiñ á vl propanoic acid pale - yellow amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopro pyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperi In the same manner as in Example 1, step 4 , the title din - 1 - yl) -4 -methoxybenzoic acid ( 170 mg) and 4 -methyl compound ( 101 mg) was obtained as a white amorphous N - ( 2 ,2 , 2 -trifluoroethyl ) pyrimidin -2 -amine ( 135 mg ). powder from ethyl 3 - cyclopropyl cvclopropyl-- 3 - ( 2 -- ( ( 11 - ( 2 - ( (02 2 ., 2 -difluoro .- 30 MSN (ESI + ) : [ M + H ] + 628 . 3 . ethyl) (pyrimidin - 2 -yl ) carbamoyl) -5 -methoxyphenyl ) piperi din - 4 - yl) methoxy )pyridin - 4 - yl) propanoate (108 mg) . Example 170 MS (ESI +) : [M + H ] * 596 .2 . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , 3 , 3 , 3 35 pentafluoropropyl) (pyrimidin - 2 - yl) carbamoyl) phe Example 168 nyl) piperidin - 4 - yl )methoxy )pyridin - 4 -yl ) propanoic acid 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 4 , 6 - dimethylpyrimidin 2 - yl) ( 2 , 2 , 2 - trifluoroethyl ) carbamoyl) - 5 -methoxyphe 40 Step 1 ) nyl) piperidin - 4 - yl)methoxy )pyridin -4 -yl ) propanoic N - ( 2 , 2 , 3 , 3 ,3 -pentafluoropropyl ) pyrimidin - 2 - amine acid In a sealed tube , a mixture of 2 - chloropyrimidine ( 120 Step 1 ) 4 , 6 - dimethyl- N - ( 2 , 2 , 2 - trifluoroethyl )pyrimi mg ) , 2 , 2 , 3 , 3 , 3 -pentafluoropropan - 1 - amine (234 mg) and din - 2 - amine 45 diisopropylethylamine (0 . 2 mL ) was stirred at 120° C . for 4 hr. To the reaction mixture was added water at room tem perature, and the mixture was extracted with ethyl acetate . In the same manner as in Example 45 , step 8 , a crude The extract was washed with saturated brine , dried over product of the title compound ( 1 . 44 g ) was obtained as a anhydrous magnesium sulfate , and the solvent was evapo pale - yellow oil from 2 - chloro - 4 , 6 -dimethylpyrimidine ( 1 .00 50 rated under reduced pressure . The residue was purified by g ). This compound was used for the next step without further silica gel column chromatography ( ethyl acetate /hexane ) to purification . give the title compound ( 100 mg) as a mixture with 2 -chlo MS (ESI + ): [ M + H ]* 206 .1 . ropyrimidine . This compound was used for the next step without further purification . Step 2 ) 3- cyclopropyl -3 - (2 -( ( 1- (2 -( (4 ,6 -dimethylpy - 35 ' H NMR ( 300 MHz, CDC13 ) : 4 .17 -4 .32 (2H , m ) , 5 .29 rimidin - 2 -yl ) ( 2, 2 ,2 - trifluoroethyl) carbamoyl ) - 5 ( 1H , brs ), 6 .67 ( 1H , t, J = 4 . 9 Hz) , 8 . 33 (2H , d , J = 4 . 8 Hz ) . methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 yl) propanoic acid Step 2 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , 3 ,3 , 3 -pentafluoropropyl ) ( pyrimidin - 2 - yl) carbamoyl) In the samemanner as in Example 32, step 2 and Example 60 phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro 1 , step 4 , the title compound (68 mg) was obtained as a white panoic acid amorphous powder from 4 ,6 - dimethyl- N - (2 , 2 ,2 - trifluoro ethyl) pyrimidin - 2 - amine ( 145 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclo - In the samemanner as in Example 32 . step 2 and Example propyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) pip - 65 1 , step 4 , the title compound ( 10 mg) was obtained as a eridin - 1 -yl ) -4 -methoxybenzoic acid (170 mg) . colorless amorphous powder from a crude purified product MS (ESI + ) : [M + H ] * 642. 3 . (100 mg) of N -( 2 ,2 , 3, 3 ,3 -pentafluoropropyl ) pyrimidin - 2 US 9 ,776 , 962 B2 135 136 amine and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl ) Example 173 pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (130 mg ). 3 - cyclopropyl- 3 -( 2 -( ( 1 -( 2 - ( 2, 2 -dimethylpropyl ) ( 4 MS ( ESI+ ): [ M + H ] * 664 .2 . methylpyrimidin - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) 5 piperidin -4 -yl ) methoxy ) pyridin -4 - yl) propanoic acid Example 171 By a method similar to that in Example 32, step 2 and 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 -( ( 4 -methylpy Example 1 , step 4 , the title compound ( 15 .1 mg) was rimidin - 2 - yl) ( 2 , 2 , 3 , 3 , 3 - pentafluoropropyl) carbam obtained as a pale - orange amorphous powder from 2 - ( 4 oyl) phenyl) piperidin -4 - yl) methoxy )pyridin - 4 -yl ) 10 ( ( [ 4 - ( 1- cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) propanoic acid oxy )methyl ) piperidin - 1 -yl ) -4 -methoxybenzoic acid (100 mg) and N -( 2 , 2 - dimethylpropyl) - 4 -methylpyrimidin - 2 Step 1 ) 4 -methyl - N - ( 2 , 2 , 3 , 3 , 3 - pentafluoropropyl) amine (74 . 3 mg) . pyrimidin - 2 - amine 15 MS (ESI + ) : [ M + H ]* 616 .3 . In the same manner as in Example 170 , step 1, the title Example 174 compound ( 80 mg) was obtained as a mixture with 2 -chloro 4 -methylpyrimidine from 2 - chloro - 4 -methylpyrimidine 3 - cyclopropyl- 3 - ( 2 -( ( 1 -( 2 - ( ( 2 , 2 - dimethylpropyl) ( 4 ,6 ( 750 mg) and 2 , 2 , 3 , 3 , 3 - pentafluoropropan - 1 - amine ( 870 20 dimethylpyrimidin - 2 - yl) carbamoyl) - 5 -methoxyphe mg ) . This compound was used for the next step without nyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoic further purification . acid IH NMR ( 300 MHz , CDC1. ) 8 2 .36 (3H , s ) , 4 . 24 ( 2H , tdd , J = 14 . 9 , 6 .7 , 0 . 9 Hz ), 5 . 24 ( 1H , brs ) , 6 . 54 ( 1H , d , J = 5 . 0 Hz) , Step 1 ) N -( 2 , 2 - dimethylpropyl) - 4 , 6 - dimethylpyrimi 8 .18 (1H , d , J = 5 . 0 Hz) . 25 din - 2 -amine Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( (4 In the same manner as in Example 45 , step 1 , the title methylpyrimidin -2 - yl) ( 2 , 2, 3 ,3 , 3 -pentafluoropropyl ) compound (737 mg) was obtained as a yellow solid from carbamoyl) phenyl ) piperidin -4 -yl ) methoxy )pyridin 2 - chloro - 4 , 6 -dimethylpyrimidine (600 mg) and 2 , 2 -dimeth 4 - yl) propanoic acid 30 ylpropan - 1 - amine ( 990 °L ) . In the same manner as in Example 32 , step 2 and Example Step 2 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 2 -( ( 2 , 2 -dimethyl 1 , step 4 , the title compound (58 mg ) was obtained as a propyl) ( 4 ,6 - dimethylpyrimidin - 2 - yl) carbamoyl) - 5 colorless amorphous powder from a crude purified product methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 ( 80 mg) of 4 -methyl - N - ( 2 , 2 , 3 , 3 , 3 -pentafluoropropyl ) py yl) propanoic acid rimidin -2 -amine and 2 -( 4 -( (( 4 - (1 - cyclopropyl- 3 - ethoxy -3 oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 - yl) - 4 In the same manner as in Example 32 , step 2 and Example methoxybenzoic acid ( 135 mg) . 1 , step 4 , the title compound (274 mg) was obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 MS ( ESI + ) : [ M + H ] * 678 . 3 . 40 ethoxy - 3 - oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 yl) - 4 -methoxybenzoic acid (355 mg) and N - ( 2 , 2 - dimethyl Example 172 propyl) - 4 , 6 - dimethylpyrimidin - 2 - amine ( 284 mg) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - difluoroethyl) (4 MS (ESI + ) : [ M + H ] * 630 . 4 . methylpyrimidin - 2 -yl ) carbamoyl ) -5 -methoxyphenyl ) 45 piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid Example 175 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( 5 -methyl Step 1 ) pyridin - 3 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) phenyl) N -( 2, 2 - difluoroethyl) - 4 -methylpyrimidin - 2 -amine piperidin -4 -yl )methoxy )pyridin -4 -yl ) propanoic acid 50 In the same manner as in Example 45 , step 8 , the title Step 1 ) compound (227 mg) was obtained as a white solid from 5 -methyl - N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 3 - amine 2 - chloro - 4 -methylpyrimidine and 2 , 2 - difluoroethanamine . MS (ESI + ) : [M + H ] * 174 .0 . In the same manner as in Example 32 , step 1 , the title 55 compound (798 mg) was obtained as a white solid from Step 2 ) 3 -cyclopropyl - 3 -( 2 -( ( 1- (2 - (( 2 , 2 -difluoro 5 -methylpyridin - 3 - amine (500 mg) . ethyl) ( 4 -methylpyrimidin - 2 - yl )carbamoyl ) - 5 methoxyphenyl )piperidin - 4- yl) methoxy )pyridin -4 MS (ESI + ) : [ M + H ] * 191. 0 . yl) propanoic acid Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( (5 methylpyridin - 3 - yl) ( 2 , 2 , 2 -trifluoroethyl )carbamoyl ) In the samemanner as in Example 32 , step 2 and Example phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl )pro 1 , step 4 , the title compound (73 mg) was obtained as a panoic acid grayish white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclo propyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) pip - In the same manner as in Example 32, step 2 and Example eridin - 1 -yl ) -4 -methoxybenzoic acid ( 115 mg) and N -( 2, 2 - 65 1, step 4 , the title compound (59 .2 mg) was obtained as a difluoroethyl) - 4 -methylpyrimidin - 2 - amine (83 mg) . pale -yellow amorphous powder from 2 -( 4 - (( (4 - ( 1 -cyclopro MS ( ESI + ): [M + H ] * 610 .2 . pyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperi US 9 ,776 ,962 B2 137 138 din - 1 -yl ) - 4 -methoxybenzoic acid (350 mg) and 5 -methyl powder from 2 - (4 -( ( ( 4 - (1 -cyclopropyl - 3 - ethoxy - 3 -oxopro N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 3 - amine (69 mg) . pyl )pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy MS (ESI + ) : [ M + H ] * 625 . 3 . benzoic acid ( 100 mg) and 2 -methyl - N1 - (pyridin - 2 -yl ) -N2 ( 2 , 2 , 2 - trifluoroethyl) propane - 1 , 2 -diamine ( 77 mg) . Example 176 5 H NMR (400 MHz, CDC1z ) 8 0 . 13 -0 . 22 ( 1H , m ), 0 .25 0 . 35 ( 1H , m ) , 0 .42 - 0 .52 ( 1H , m ), 0 .56 - 0 .66 ( 1H , m ) , 0 . 91 3 -cyclopropyl - 3 -( 2 -( ( 1- ( 5 -methoxy -2 -( ( 2 ,2 , 2 -trifluo 1 . 15 (7H , m ), 1 . 19 (3H , t, J = 7 . 1 Hz) , 1 .23 - 1 .46 ( 2H , m ), roethyl) ( 4 - (trifluoromethyl )pyridin - 2 - yl) carbamoyl ) 1 .66 - 1 .91 ( 3H , m ) , 2 .26 - 2 . 35 ( 1H , m ) , 2 .35 - 2 .69 ( 3H , m ) , phenyl) piperidin -4 - yl) methoxy ) pyridin -4 -yl ) pro 2 .66 - 2 . 80 (2H , m ) , 2 .86 - 3 .21 ( 2H , m ) , 3 . 23 - 3 .46 ( 1H , m ) , panoic acid 10 3 . 76 ( 3H , s ) , 4 . 00 - 4 . 11 ( 2H , m ) , 4 . 16 ( 2H , d , J = 6 . 8 Hz ) , 4 . 33 ( 2H , brs ) , 6 . 17 ( 1H , d , J = 2 . 0 Hz ) , 6 . 46 - 6 . 58 ( 2H , m ) , 6 .63 By a method similar to that in Example 32 , step 2 and (1H , s ), 6 .77 (1H , d , J = 4 .4 Hz) , 6 .87 ( 1H , dd , J= 7 . 2 , 4 .9 Hz ), Example 1 , step 4 , the title compound ( 45 mg ) was obtained 7 . 20 ( 1H , t , J = 7 . 3 Hz ) , 7 . 32 ( 1H , d , J = 8 .4 Hz) , 8 .07 ( 1H , d , as a pale -yellow amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 -cy - J = 5 . 4 Hz ) , 8 . 33 ( 1H , d , J = 3 . 3 Hz ) . clopropyl -3 -ethoxy -3 -oxopropyl ) pyridin -2 -yl ) oxy )methyl ) 15 piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 100 mg ) and N - ( 2 , Step 4 ) 3 -cyclopropyl - 3 - ( 2 - (( 1 - (5 -methoxy - 2 -( (2 2 , 2 - trifluoroethyl) -4 - ( trifluoromethyl) pyridin - 2 -amine ( 101 methyl- 2 - ( ( 2 , 2 , 2 - trifluoroethyl) amino )propyl ) ( pyri mg ). din - 2 - yl) carbamoyl ) phenyl ) piperidin - 4 - yl) methoxy ) MS (ESI + ): [ M + H ] * 681. 2 . 20 pyridin -4 -yl ) propanoic acid Example 177 In the same manner as in Example 1 , step 4 , the title compound ( 24 .7 mg) was obtained as a white amorphous 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -methyl - 2 powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 ( ( 2, 2 , 2 -trifluoroethyl ) amino )propyl ) (pyridin -2 - yl) 04 ( ( 2 -methyl - 2 - ( ( 2 , 2 , 2 - trifluoroethyl) amino ) propyl) (pyridin carbamoyl) phenyl ) piperidin - 4 - yl) methoxy ) pyridin 2 -yl ) carbamoyl) phenyl ) piperidin - 4 - yl) methoxy )pyridin -4 4 - yl) propanoic acid yl) propanoate ( 30 mg) . Step 1) MS (ESI + ) : [ M + H ] * 684 .3 . 2 -methyl - N1 - (pyridin - 2 -yl ) propane - 1, 2 -diamine 30 Example 178 In the same manner as in Example 135 , step 1 , the title compound (547 mg) was obtained as a yellow oil from 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) 2 -methylpropane - 1, 2 - diamine (300 mg ) and pyridine N -ox (pyrazin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) piperi ide (417 mg ) . din -4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid H NMR (400 MHz, CDC12 ) 8 1 . 18 (6H , s ) , 3 .21 ( 2H , d . 35 J = 6 . 0 Hz) , 4 . 86 ( 1H , brs ) , 6 . 43 (1H , d , J = 8 . 4 Hz) , 6 .54 ( 1H , dd , J = 6 . 6 , 5 . 5 Hz) , 7 . 33 - 7 . 44 ( 1H , m ) , 8 .07 ( 1H , d , J = 4 . 0 Step 1 ) HZ) . 6 - chloro - N - ( 2 , 2 - dimethylpropyl )pyrazin - 2 - amine Step 2 ) 2 -methyl - N1 - ( pyridin - 2 -yl ) -N2 - ( 2 , 2 , 2 - trif 40 Under a nitrogen atmosphere , 2 , 2 - dimethylpropan - 1 luoroethyl) propane - 1 , 2 -diamine amine (869 uL ) was added to a mixture of 2 , 6 -dichloropy razine ( 1 .0 g ) , potassium carbonate ( 1 . 86 g ) and DMA ( 10 Trifluoromethanesulfonic acid 2 ,2 , 2 -trifluoroethyl ester mL ) at room temperature , and the mixture was stirred at 80° ( 196 UL ) was added to a mixture of 2 -methyl - N1 - ( pyridin - C . for 2 hr. To the reaction solution was added water at room 2 - yl) propane - 1 , 2 -diamine (500 mg) , cesium carbonate (532 45 temperature , and the mixture was extracted with ethyl mg) and DMF (3 mL) at room temperature , and the mixture acetate. The extract was washed with water and saturated was stirred at room temperature for 64 hr. To the reaction brine, and dried over anhydrous magnesium sulfate . The solution was added water at room temperature , and the solvent was evaporated under reduced pressure , and the mixture was extracted with ethyl acetate . The extract was residue was purified by silica gel column chromatography washed with water, saturated aqueous sodium hydrogen 50 ( ethyl acetate /hexane ) to give the title compound ( 845 mg) carbonate solution and saturated brine , and dried over anhy - as a white solid . drous magnesium sulfate . The solvent was evaporated under H NMR (400 MHz , CDC1 ) 8 0 . 99 (9H , s ), 3 . 16 (2H , d , reduced pressure , and the residue was purified by silica gel J = 6 . 1 Hz) , 4 .74 ( 1H , brs ) , 7 .77 (2H , s ) . column chromatography (ethyl acetate /hexane ) to give the title compound ( 225 mg) as a colorless oil . 55 ' H NMR ( 400 MHz, CDC1z ) 8 1. 17 (6H , s ), 3 . 12 ( 2H , q , Step 2 ) N - ( 2 , 2 - dimethylpropyl) pyrazin - 2 - amine J = 9 . 3 Hz ) , 3 . 24 (2H , d , J = 5 . 4 Hz ) , 4 . 87 ( 1H , brs ) , 6 .42 ( 1H , d , J = 8 . 4 Hz) , 6 .55 ( 1H , dd , J = 6 . 7 , 5 . 5 Hz ), 7 . 33 - 7 . 45 (1H , 6 - Chloro - N -( 2 ,2 - dimethylpropyl) pyrazin - 2 -amine (250 m ), 8. 08 (1H , d , J = 4. 0 Hz) . mg) , 10 % palladium carbon ( 100 mg) and triethylamine 60 (837 uL ) were stirred in methanol (15 mL ) at room tem Step 3 ) ethyl 3 - cyclopropyl- 3 -( 2 - (( 1 - ( 5 -methoxy - 2 perature for 1 hr under a hydrogen atmosphere ( 1 atm ) . The (( 2 -methyl - 2 - (( 2 ,2 , 2 -trifluoroethyl ) amino )propyl ) reaction mixture was filtered , and the solvent in the filtrate (pyridin - 2 -yl ) carbamoyl )phenyl ) piperidin - 4 - yl) was evaporated under reduced pressure to give the title methoxy )pyridin - 4 - yl) propanoate compound ( 138 mg) as a pale -yellow oil . 65 ' H NMR ( 300 MHz, CDC1z ) 8 0 .99 ( 9H , s ), 3 .18 (2H , d , In the same manner as in Example 32 , step 2 , the title J = 6 .2 Hz ), 4 .58 ( 1H , brs) , 7 .77 (1H , d , J= 2 .7 Hz) , 7 . 90 (1H , compound ( 108 mg) was obtained as a colorless amorphous d , J = 1 . 4 Hz ) , 7 . 95 ( 1H , dd , J = 2 . 7 , 1 . 5 Hz) . US 9 ,776 , 962 B2 139 140 Step 3 ) ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dim powder from 2 - (4 - (( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopro ethylpropyl )( pyrazin -2 - yl) carbamoyl) - 5 -methoxy pyl )pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy phenyl) piperidin - 4 - yl) methoxy )pyridin -4 - yl) pro benzoic acid ( 100 mg) and N - ( 2 , 2 - dimethylpropyl) panoate pyridazin - 3 -amine (51 . 4 mg) obtained in Example 179 , step In the same manner as in Example 32 , step 2 , the title 5 2 . compound (47 . 0 mg) was obtained as a white amorphous H NMR (400 MHz, CDC12 ) & 0 . 12 - 0 . 20 ( 1H , m ) , 0 . 25 powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 -ethoxy - 3 - oxopro 0. 34 ( 1H , m ), 0 . 40 -0 . 51 ( 1H , m ), 0 .55 - 0 .65 ( 1H , m ), 0 .83 pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 - yl ) - 4 -methoxy (9H , s ) , 0 . 93 - 1 . 05 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 2 Hz ) , 1 .57 - 1 . 89 benzoic acid ( 115 mg ) and N - ( 2 . 2 - dimethylpropylpyrazin - (5H , m ) , 2 . 26 - 2 . 35 ( 1H , m ) , 2 . 39 - 2 . 52 ( 2H , m ) , 2 .58 - 2 . 79 2 -amine (59 . 1 mg) . 10 (3H , m ), 3 .28 ( 1H , d , J= 12. 8 Hz ), 3. 77 (3H , s) , 3. 97 - 4 . 13 H NMR ( 400 MHz, CDC1, ) 8 0 . 13 - 0 . 21 ( 1H , m ), 0 .26 - (2H , m ), 4 . 17 ( 2H , d , J = 6 . 8 Hz ), 4 .28 -4 .59 (2H , m ), 6 . 14 0 .34 ( 1H , m ) , 0 . 41 - 0 .51 ( 1H , m ) , 0 . 56 - 0 .65 ( 1H , m ) , 0 . 83 ( 1H , s ) , 6 .53 ( 1H , dd , J = 8 . 5 , 2 . 3 Hz ), 6 .61 ( 1H , s ) , 6 .71 ( 1H , ( 9H , s ), 0 . 95 - 1 . 04 ( 1H , m ) , 1 . 15 - 1 . 35 ( 2H , m ), 1 . 19 ( 3H , t , brs ) , 6 . 74 ( 1H , d , J = 5 . 5 Hz) , 6 . 95 ( 1H , dd , J = 8 .8 , 4 . 6 Hz) , J = 7 . 1 Hz) , 1 .67 - 1 .91 (3H , m ), 2 .27 - 2 . 35 ( 1H , m ) , 2 . 35 - 2 .65 7 .39 ( 1H , d , J = 8 . 4 Hz) , 8 . 05 ( 1H , d , J = 5 . 3 Hz) , 8 . 76 (1H , d , (3H , m ) , 2 .66 - 2 .79 (2H , m ) , 3 . 30 ( 1H , d , J = 11 . 5 Hz ), 3 . 76 15 J = 4 . 3 Hz) . ( 3H , S ) , 4 . 08 ( 2H , dtt , J = 10 . 8 , 7 . 2 , 3 . 5 Hz ) , 4 . 14 - 4 . 24 ( 4H , m ) , 6 . 15 ( 1H , d , J = 2 . 0 Hz) , 6 . 56 ( 1H , dd , J = 8 . 4 , 2 . 3 Hz ) , 6 .63 ( 1H , S ) , 6 . 77 ( 1H , d , J = 5 . 4 Hz ) , 7 .42 ( 1H , d , J = 8 . 4 Hz ) , Step 4 ) 3 -cyclopropyl - 3 -( 2 -( 1- ( 2- ( ( 2 ,2 -dimethyl 7 . 83 ( 1H , brs ) , 8 . 01 - 8 . 11 ( 2H , m ), 8 .27 ( 1H , d , J = 1 . 5 Hz ) . propyl) (pyridazin -3 -yl ) carbamoyl ) - 5 -methoxyphe 20 nyl) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic Step 4 ) 3 - cyclopropyl- 3 - (2 -( ( 1- (2 - (( 2, 2 - dimethyl acid propyl) (pyrazin - 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl )methoxy )pyridin - 4 -yl ) propanoic acid In the same manner as in Example 1, step 4 , the title compound (70 .0 mg ) was obtained as a white amorphous In the same manner as in Example 1 , step 4 , the title 25 powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth compound (43 . 9 mg) was obtained as a pale - yellow amor - ylpropyl ( pyridazin - 3 - yl )carbamoyl ) - 5 -methoxyphenyl ) pip phous powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - eridin - 4 - ylmethoxylpyridin - 4 -vlorop dimethylpropyl) ( pyrazin - 2 -yl ) carbamoyl ) -5 -methoxyphe eridin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoate (74 .8 mg ) . nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) propanoate ( 47 MS (ESI + ): [M + H ]* 602. 3 . mg) . MS (ESI + ): [ M + H ]* 602. 3 . 30 Example 180 Example 179 3 - ( 2 - ( 1 - ( 2 - ( 6 - chloropyrazin - 2 - yl) ( 2 , 2 -dimethylpro 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 , 2 -dimethylpropyl ) pyl ) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) ( pyridazin - 3 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi - 35 methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpropanoic acid din -4 -yl ) methoxy )pyridin -4 -yl ) propanoic acid Step 1) Step 1) ethyl 3 -( 2 -( 1 - (2 -( ( 6 -chloropyrazin - 2- yl )( ( 2 , 6 -chloro -N -( 2 ,2 -dimethylpropyl ) pyridazin -3 -amine 2 -dimethylpropyl ) ) carbamoyl ) -5 -methoxyphenyl ) 40 piperidin - 4 -yl )methoxy )pyridin - 4 - yl) - 3 -cyclopropyl In the same manner as in Example 177, step 1 , the title propanoate compound ( 308 mg) was obtained as a pale- yellow solid from 3 ,6 - dichloropyridazine ( 1 . 0 g ) . In the same manner as in Example 32 , step 2 , the title ' H NMR ( 400 MHz, CDC1, ) 8 0 . 99 ( 9H , s ) , 3 . 18 ( 2H , d . compound ( 39 . 0 mg ) was obtained as a white amorphous J = 6 . 3 Hz ), 4 . 84 ( 1H , brs ), 6 .65 ( 1H , d . J = 9 . 3 Hz ) , 7 . 15 ( 1H . 45 powder from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro d , J = 9 . 3 Hz ). pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy benzoic acid ( 100 mg) and 6 -chloro - N - ( 2 , 2 - dimethylpropyl) Step 2 ) N - ( 2 , 2 -dimethylpropyl ) pyridazin - 3 -amine pyrazin - 2 -amine (62 . 1 mg) . ' H NMR (400 MHz, CDC1z ) 8 0. 13 -0 .21 (1H , m ), 0 .25 6 - Chloro -N -( 2 ,2 - dimethylpropyl) pyridazin - 3 -amine ( 300 50 0 .33 ( 1H , m ) , 0 . 42 -0 . 51 (1H , m ), 0 .56 - 0 .65 (1H , m ), 0 .85 mg) and 10 % palladium carbon ( 30 mg) were stirred in a (9H , s ), 0 .93 -1 .04 (1H , m ), 1. 19 (3H , t, J= 7 .2 Hz) , 1. 53 - 1. 66 mixed solvent ofmethanol ( 15 mL ) and THF ( 5 mL ) at room (2H , m ), 1 .73 - 1 . 86 (3H , m ) , 2 . 27 - 2 . 35 ( 1H , m ) , 2 . 38 - 2 . 50 temperature for 10 hr under a hydrogen atmosphere ( 1 atm ). (2H , m ) , 2 .55 - 2 .65 ( 1H , m ), 2 .66 - 2 .79 (2H , m ), 3 .26 ( 1H , d , The reaction mixture was filtered , and the solvent in the J = 12 . 4 Hz ) , 3 . 77 (3H , S ) , 4 .03 - 4 . 12 (2H , m ) , 4 . 14 - 4 . 25 ( 4H , filtrate was evaporated under reduced pressure to give the 55 m ), 6 . 17 ( 1H , d , J = 2. 1 Hz) , 6 . 59 ( 1H , dd , J = 8 . 4 , 2. 3 Hz) , title compound ( 186 mg ) as a white solid . 6 .64 ( 1H , s ) , 6 .73 -6 .79 ( 1H , m ), 7 .46 (1H , d , J = 8 . 5 Hz) , 7 .63 TH NMR (400 MHz, CDC12 ) 8 1 . 00 ( 9H , s ), 3 . 19 (2H , d . ( 1H , s ), 8 . 04 - 8 . 10 ( 2H , m ) . J = 6 . 3 Hz) , 4 .81 ( 1H , brs ) , 6 .64 ( 1H , dd , J = 9 . 1 , 1 . 2 Hz ), 7 . 14 ( 1H , dd , J = 9 . 0 , 4 . 4 Hz ), 8 . 52 ( 1H , dd , J = 4 . 5 , 1 . 2 Hz ). 60 Step 2 ) 3 - ( 2 - ( ( 1 - ( 2 - (( 6 - chloropyrazin - 2 - yl) ( 2 , 2 - dim Step 3) ethyl 3 -cyclopropyl - 3 - ( 2- ( (1 - ( 2 -( 2, 2 - dim ethylpropyl )carbamoyl ) - 5 -methoxyphenyl ) piperidin ethylpropyl) (pyridazin -3 -yl ) carbamoyl )- 5 -methoxy 4 - yl) methoxy )pyridin - 4 - yl) - 3 - cyclopropylpropanoic phenyl) piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) pro acid panoate 65 In the same manner as in Example 1 , step 4 , the title In the same manner as in Example 32 , step 2 , the title compound (31 . 1 mg) was obtained as a pale - yellow amor compound (74 .8 mg) was obtained as a white amorphous phous powder from ethyl 3 -( 2 -( (1 - ( 2 - ( 6 - chloropyrazin - 2 US 9 ,776 , 962 B2 141 142 yl) {( 2 , 2 - dimethylpropyl) ) carbamoyl) - 5 -methoxyphenyl ) pi 1 , 1 - trifluoropropan - 2 - ol ( 1 .0 g ) and iodomethane ( 1 .01 mL ) peridin - 4 -yl )methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpropano in DMF ( 5 mL) at room temperature , and the mixture was ate ( 39 . 0 mg) . stirred at room temperature for 10 min . To the reaction MS ( ESI + ) : [ M + H ] * 636 . 4 . solution was added water at room temperature , and the in mixture was extracted with ethyl acetate . The extract was Example 181 washed with water and saturated brine , and dried over anhydrous magnesium sulfate . The solvent was evaporated 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 , 2 -dimethylpropyl ) under reduced pressure to give a crude product of the title (pyridin - 2 - ylmethyl) carbamoyl ) - 5 -methoxyphenyl ) compound as a pale -yellow oil. This compound was used for piperidin - 4 - yl )methoxy ) pyridin - 4 -yl ) propanoic acid 10 the next step without further purification . By a method similar to that in Example 2 , step 5 and Example 1 , step 4 , the title compound (73 . 1 mg) was Step 3 ) 3, 3 ,3 - trifluoro - 2 -methoxypropan - 1 -amine obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - 1 hydrochloride cyclopropyl- 3 -ethoxy - 3- oxopropyl ) pyridin - 2 -yl ) oxy ) 15 methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 148 mg) In the same manner as in Example 144 , step 3 , the title and 2 , 2 - dimethyl- N - (pyridin - 2 - ylmethyl) propan - 1 - amine compound (532 mg) was obtained as a white solid from a ( 109 mg) . crude product ( entire amount) of N , N -dibenzyl - 3, 3 ,3 - trif MS (ESI + ): [ M + H ] * 615 . 3 . 20 luoro - 2 -methoxypropan - 1- amine. Example 182 ' H NMR ( 400 MHz, DMSO -do ) d 2 . 97 ( 1H , brs ) , 3 . 12 3 . 25 ( 1H , m ), 3 . 56 (3H , s ) , 4 . 26 ( 1H , ddd , J = 9 .6 , 6 .6 , 3 . 1 3 -cyclopropyl - 3 - ( 2 - (( 1 - (5 -methoxy - 2 -( (pyridin - 2 Hz ) , 8 .27 (2H , brs ) . ylmethyl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) propanoic acid 25 Step 4 ) By a method similar to that in Example 2 , step 5 and N - ( 3 , 3 , 3 - trifluoro - 2 -methoxypropyl ) pyridin - 2 - amine Example 1 , step 4 , the title compound ( 115 mg) was obtained as a pale - orange amorphous powder from 2 - ( 4 In the same manner as in Example 135 , step 1 , the title (( [4 -( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl )pyridin -2 - yl ) 30 compound ( 119 mg) was obtained as a yellow oil from oxy )methyl )piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 148 3 , 3 , 3 - trifluoro - 2 -methoxypropan - 1 - amine hydrochloride mg) and 2 , 2 ,2 - trifluoro - N - ( pyridin - 2 - ylmethyl) ethanamine (300 mg) and pyridine N - oxide ( 238 mg) . (117 mg ). ' H NMR (400 MHz, CDC1z ) 8 3 .32 - 3. 44 (1H , m ), 3. 57 MS ( ESI + ): [ M + H ] * 627 .2 . (3H , s ) , 3 .78 - 3 . 96 (2H , m ), 4 . 66 ( 1H , brs ) , 6 .44 (1H , d , J = 8 . 4 35 Hz ), 6 .62 ( 1H , dd , J= 7 . 0 , 5. 1 Hz ), 7 . 36 - 7 .52 (1H , m ) , 8. 12 Example 183 ( 1H , d , J = 3 .9 Hz ). 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (pyridin - 2 - yl Step 5 ) ethyl 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 5 -methoxy - 2 ( 3 , 3 , 3 - trifluoro - 2 -methoxypropyl ) carbamoyl) phenyl ) ( pyridin - 2 - yl( 3 , 3 , 3 -trifluoro - 2 -methoxypropyl ) car piperidin - 4- yl) methoxy ) pyridin - 4- yl) propanoic acid 40 bamoyl) phenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) Step 1 ) propanoate 3 - ( dibenzylamino ) - 1 , 1 , 1 - trifluoropropan - 2 - ol In the same manner as in Example 32 , step 2 , the title Under a nitrogen atmosphere, (trifluoromethyl )oxirane 45 compound (205 mg) was obtained as a pale - yellow oil from ( 1 . 29 mL ) was added to a mixture of dibenzylamine ( 1 . 92 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 mL ) , ytterbium trifluoromethanesulfonate hydrate (319 mg) yl) oxy )methyl ) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 192 and acetonitrile ( 4 mL ) at room temperature , and the mixture mg) and N - ( 3 , 3 , 3 - trifluoro - 2 -methoxypropyl ) pyridin - 2 was stirred at 50° C . for 20 min . To the reaction solution was amine (119 mg) . added water at room temperature , and the mixture was 50 H NMR ( 400 MHz, CDC1_ ) 8 0 . 11 - 0 .21 ( 1H , m ) , 0 . 24 extracted with ethyl acetate . The extract was washed with 0 . 34 ( 1H , m ) , 0 . 40 - 0 .51 ( 1H , m ) , 0 .55 - 0 .65 ( 1H , m ) , 0 .91 saturated aqueous sodium hydrogen carbonate solution and 1. 04 ( 1H , m ), 1. 19 (3H , t, J = 7 . 2 Hz) , 1 .64 - 1 .92 ( 4H , m ) , saturated brine , and dried over anhydrous magnesium sul- 2 . 25 - 2 .35 ( 1H , m ) , 2 .39 - 2 .70 (3H , m ), 2 .66 - 2 .79 ( 2H , m ) , fate . The solvent was evaporated under reduced pressure , 3 .41 ( 3H , brs ), 3 .78 (3H , s ) , 4 .02 - 4 .75 (5H , m ) , 4 .03 - 4 . 12 and the residue was purified by silica gel column chroma - 55 ( 2H , m ) , 4 . 14 ( 2H , d , J = 7 . 2 Hz ), 6 .21 ( 1H , brs ), 6 .54 ( 1H , dd , tography ( ethyl acetate /hexane ) to give the title compound J= 8 .4 , 2 .1 Hz ), 6 .62 (1H , s ), 6 .76 (1H , d , J= 5 .3 Hz ), 6 .92 ( 2 . 07 g ) as a white solid . ( 1H , d , J = 5 . 1 Hz ) , 7 . 18 - 7 . 33 (2H , m ), 7 . 40 ( 1H , d , J = 6 . 4 Hz ), ' H NMR (400 MHz, DMSO - d ) 8 2 .54 -2 .62 ( 1H , m ), 8 .06 (1H , d , J = 5 .4 Hz) , 8 .38 ( 1H , d , J = 3 .5 Hz ). 2 .64 - 2 .72 (1H , m ), 3 .53 - 3 .63 (2H , m ), 3 .64 - 3 .73 ( 2H , m ), 4 . 11 - 4 .27 ( 1H , m ), 6 .22 ( 1H , d , J = 6 . 1 Hz) , 7 . 19 - 7 .27 (2H , 60 Step 6 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (pyri m ) , 7 . 29 - 7 . 42 ( 8H , m ) . din - 2 -yl ( 3, 3 ,3 - trifluoro - 2 -methoxypropyl ) carbam Step 2 ) N , N - dibenzyl - 3 , 3 , 3 - trifluoro - 2 -methoxypro oyl) phenyl) piperidin -4 - yl)methoxy )pyridin - 4 -yl ) pan - 1 -amine propanoic acid 65 Under a nitrogen atmosphere, 60 % sodium hydride (oily ) In the same manner as in Example 1 , step 4 , the title ( 259 mg) was added to a solution of 3 -( dibenzylamino )- 1, compound (25 .0 mg) was obtained as a white amorphous US 9 ,776 , 962 B2 143 144 powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 Example 186 ( pyridin - 2 - yl( 3 , 3 , 3 - trifluoro - 2 -methoxypropyl ) carbamoyl) phenyl) piperidin - 4 -yl ) methoxy ) pyridin -4 -yl ) propanoate 3 - cyclopropyl- 3 -( 2 - ( ( 1 - ( 2 - ( ( ( 2R ) - 3 - fluoro - 3 -meth ( 28 . 0 mg) . ylbutan - 2 - yl) (pyridin - 2 - yl) carbamoyl ) - 5 -methoxy MS (ESI + ) : [M + H ]* 657. 4 . u phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) pro panoic acid Example 184 Step 1 ) methyl N - pyridin - 2 - yl- D - alaninate 10 3 -cyclopropyl - 3 - (2 - ( 1 -( 2 -( (2 , 2 -dimethylpropyl ) In the same manner as in Example 135, step 1, the title (pyrimidin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) pip compound ( 215 mg ) was obtained as a pale -yellow oil from eridin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid pyridine 1 -oxide (300 mg) and methyl D - alaninate hydro chloride ( 528 mg) . Step 1 ) ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dim 15 ' H NMR ( 300 MHz, CDC13 ) d 1 . 49 ( 3H , d , J = 7 . 1 Hz) , ethylpropyl) (pyrimidin - 2 - yl) carbamoyl) - 5 -methoxy 3 . 74 ( 3H , s ), 4 .61 ( 1H , quin , J = 7 . 3 Hz ), 4 . 83 ( 1H , d , J = 6 .7 phenyl) piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) pro Hz ) , 6 . 43 ( 1H , dt , J = 8 . 4 , 0 . 9 Hz) , 6 .60 ( 1H , ddd , J = 7 . 2 , 5 . 1 , panoate 0 . 9 Hz) , 7 . 34 - 7 .44 ( 1H , m ) , 8 .05 - 8 . 12 ( 1H , m ) . 20 In the same manner as in Example 32 , step 2 , the title Step 2 ) (3R )- 2 -methyl - 3 - (pyridin -2 -ylamino )butan compound ( 115 mg) was obtained as a white amorphous 2 -ol powder from 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 -oxopro pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 - yl) -4 -methoxy - To a solution of methyl N -pyridin -2 - yl - D -alaninate ( 415 benzoic acid ( 236 mg) having a longer retention time and 25 mg ) in THF ( 15 mL) was added 1M methylmagnesium N - ( 2 , 2 -dimethylpropyl ) pyrimidin - 2 - amine (202 mg) . bromide THF solution ( 8 . 06 mL ) at room temperature . The mixture was stirred at room temperature for 20 min , 1M ' H NMR ( 400 MHz, CDC13 ) 8 0 . 14 - 0 .21 ( 1H , m ), 0 . 25 methylmagnesium bromide THF solution ( 4 .00 mL ) was 0 . 34 ( 1H , m ), 0 . 42 - 0 .51 ( 1H , m ), 0 . 57 - 0 .67 ( 1H , m ) , 0 . 86 added , and the mixture was further stirred for 30 min . To the ( 9H , s ) , 0 . 94 - 1 . 04 ( 1H , m ), 1 . 08 - 1 . 36 ( 2H , m , J = 7 . 2 , 7 . 2 Hz) , 30 reaction mixture was added saturated aqueous ammonium 1 . 19 ( 3H , t , J = 7 . 2 Hz ) , 1 .61 - 1 . 88 ( 3H , m ) , 2 . 26 - 2 .35 ( 1H , chloride solution at room temperature , and the mixture was m ), 2 .34 - 2 .65 (3H , m ), 2 .65 - 2 .80 (2H , m ), 3 .13 - 3 .35 ( 1H , extracted with ethyl acetate . The extract was washed with m ) , 3 .78 (3H , s ) , 4 .02 - 4 .12 (2H , m ) , 4 . 15 ( 2H , d , J = 6 . 7 Hz) , saturated brine , dried over anhydrous magnesium sulfate , 4 . 17 - 4 . 38 ( 2H , m ), 6 . 14 ( 1H , d , J = 2 . 4 Hz) , 6 .55 ( 1H , dd , and the solventwas evaporated under reduced pressure. The J = 8 . 5 , 2 . 3 Hz ) , 6 .63 ( 1H , s ), 6 .72 - 6 .86 (2H , m ) , 7 . 46 ( 1H , d , 35 residue was purified by silica gel column chromatography J = 8 . 4 Hz ), 8 . 07 ( 1H , d , J = 5 . 3 Hz ), 8 .31 ( 2H , d , J = 4 . 8 Hz) . (ethyl acetate /hexane ) to give the title compound (130 mg) as a brown oil . Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl ' H NMR ( 300 MHz, CDC13 ) 8 1 . 14 - 1 .29 ( 10H , m ) , propyl) ( pyrimidin - 2 -yl ) carbamoyl ) - 5 -methoxyphe 3 .81 - 3 .91 ( 1H , m ), 4 . 39 ( 1H , d , J = 6 .3 Hz ), 6 .45 ( 1H , dt, nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic 40 J = 8 . 4 , 0 . 9 Hz) , 6 .55 ( 1H , ddd , J = 7 . 1 , 5 . 1 , 0 . 9 Hz ), 7 .35 - 7 . 42 acid ( 1H , m ) , 7 .99 - 8 .07 ( 1H , m ) . In the same manner as in Example 1 , step 4 , the title Step 3 ) N - ( ( 2R ) - 3 - fluoro - 3 -methylbutan - 2 - yl) pyri compound ( 83 . 2 mg) was obtained as a white amorphous 45 din - 2 - amine powder from ethyl 3 -cyclopropyl - 3 - ( 2 -( 1 -( 5 -methoxy - 2 ( ( 2 , 2 - dimethylpropyl) (pyrimidin - 2 -yl ) carbamoyl )phenyl ) In the same manner as in Example 39, step 1 , the title piperidin - 4 - yl)methoxy )pyridin - 4 - yl) propanoate ( 115 mg) . compound ( 83 mg) was obtained as a colorless solid from ( 3R ) - 2 -methyl - 3 - (pyridin - 2 - ylamino )butan - 2 - ol ( 130 mg ) . MS (ESI + ) : [ M + H ] * 602. 3 . 50 H NMR ( 300 MHz, CDC12 ) 8 1 .25 (3H , d , J = 6 . 7 Hz) , 1 . 42 (6H , d , J = 21 . 7 Hz) , 3 . 96 - 4 . 18 ( 1H , m ) , 4 .50 ( 1H , brs ) , 6 . 40 Example 185 (1H , d , J = 8 . 4 Hz ) , 6 .54 ( 1H , ddd , J = 7 . 1 , 5 . 1 , 0 . 8 Hz) , 7 . 38 ( 1H , ddd , J = 8 . 6 , 7 . 0 , 1 . 9 Hz ) , 8 . 06 ( 1H , dd , J = 5 . 1 , 1 . 1 Hz) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 - fluoro - 2 -methylpro pyl )( 4 -methylpyridin -2 - yl) carbamoyl) - 5 -methoxy 55 Step 4 ) 3 -cyclopropyl - 3 - (2 - (( 1- ( 2- (( (2R )- 3- fluoro -3 phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro methylbutan - 2 -yl ) (pyridin - 2 - yl) carbamoyl ) -5 panoic acid methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 yl) propanoic acid In the samemanner as in Example 32, step 2 and Example 60 1 , step 4 , the title compound (236 mg ) was obtained as a In the same manner as in Example 32 , step 2 and Example colorless amorphous powder from N - ( 2 - fluoro - 2 -methyl - 1 , step 4 , the title compound ( 123 mg) was obtained as a propyl) - 4 -methylpyridin - 2 - amine (199 mg ) obtained in colorless amorphous powder from N - (( 2R )- 3 - fluoro -3 Example 153 , step 2 and 2 -( 4 -( (( 4 - (1 -cyclopropyl - 3 - ethoxy methylbutan -2 -yl ) pyridin - 2 -amine ( 83 mg) and 2 - [4 - ( (( 4 -( 1 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 65 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl )oxy ) methoxybenzoic acid ( 264 mg) . methyl) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 153 mg) . MS (ESI + ) : [ M + H ] * 619 . 3 . MS (ESI + ) : [ M + H ] * 619. 3 . US 9 ,776 , 962 B2 145 146 Example 187 by silica gel column chromatography ( ethyl acetate/ hexane ) to give the title compound (5 .41 g) as a pale -yellow oil . 3- cyclopropyl- 3 -( 2 -( ( 1 -( 2 -( [( 2S )- 3 -fluoro -3 -meth TH NMR (400 MHz , CDC13) d 1 . 26 ( 3H , t, J= 7 . 1 Hz ), ylbutan - 2 - yl) (pyridin - 2 -yl ) carbamoyl) - 5 -methoxy 4 . 07 (2H , s ) , 4 .20 ( 2H , q , J = 7 . 2 Hz) , 4 .66 ( 2H , s ) , 6 .69 (2H , phenyl )piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) pro 5 d , J= 8 . 2 Hz ), 6 .75 ( 1H , t, J = 7 . 3 Hz ), 7 .20 (2H , dd , J = 8 . 7 , 7 . 4 panoic acid Hz ), 7 . 27 - 7 .44 (5H , m ) . Step 1) N -( ( 2S )- 3 - fluoro -3 -methylbutan -2 -yl ) pyri Step 3 ) 1 - (benzyl ( phenyl ) amino )- 2 -methylpropan - 2- 01 din - 2 - amine 10 In the same manner as in Example 186 , steps 1, 2 and 3, Under a nitrogen atmosphere , a 1 M solution ofmethyl the title compound (116 mg) was obtained as a colorless magnesium bromide in THF ( 9 . 28 mL ) was added to a solid from methyl L - alaninate hydrochloride ( 1409 mg) . solution of ethyl 2 - ( benzyl( phenyl) amino ) acetate ( 1 . 0 g ) in THF ( 10 mL ) at room temperature , and the mixture was H NMR (300 MHz, CDC1z) 8 1 . 24 (3H , d , J = 6 .6 Hz) , stirred at room temperature for 30 min . To the reaction 1 .42 (6H , d , J = 21 . 7 Hz ), 3 . 97 - 4 . 17 (1H , m ) , 4 . 48 ( 1H , d , solution was added saturated aqueous ammonium chloride J = 8 . 0 Hz ), 6 .39 ( 1H , d , J = 8 . 4 Hz) , 6 .54 ( 1H , ddd , J = 7 . 1 , 5 . 1 , solution at room temperature , and themixture was extracted 0 . 9 Hz) , 7 . 38 (1H , ddd , J = 8 . 6 , 7 . 0 , 1 . 9 Hz) , 8 . 06 (1H , dt, with ethyl acetate . The extract was washed with water and J = 5 . 1 , 0 . 9 Hz ). saturated brine , and dried over anhydrous magnesium sul 20 fate . The solvent was evaporated under reduced pressure , Step 2 ) 3 - cyclopropyl- 3 - ( 2 -( ( 1 -( 2 - ( (( 2S ) - 3 - fluoro -3 and the residue was purified by silica gel column chroma methylbutan - 2 - yl) (pyridin - 2 -yl ) carbamoyl) - 5 tography (ethyl acetate /hexane ) to give the title compound methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 (720 mg ) as a pale -yellow oil. yl) propanoic acid H NMR ( 400 MHz, DMSO - da ) 8 1 . 17 (6H , s ) , 3 . 41 ( 2H , 25 s ), 4 . 73 ( 2H , s ), 6 .51 ( 1H , t, J = 7 . 2 Hz ), 6 .71 ( 2H , d , J = 8 . 3 In the same manner as in Example 32 , step 2 and Example Hz) , 7 .03 (2H , dd , J = 8 .5 , 7 .3 Hz) , 7 . 12 - 7 .21 (3H , m ), 1 , step 4 , the title compound (128 mg) was obtained as a 7 .22 -7 .34 (2H , m ). colorless amorphous powder from N - ( ( 2S ) - 3 - fluoro - 3 -meth ylbutan - 2 - yl) pyridin - 2 - amine ( 116 mg) and 2 - [ 4 - ( (( 4 - ( 1 Step 4 ) cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) N -benzyl - N -( 2- methoxy - 2 -methylpropyl )aniline methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 160 mg) . MS ( ESI + ) : [ M + H ] * 619 . 3 . Under a nitrogen atmosphere , 60 % sodium hydride (oily ) ( 564 mg ) was added to a solution of 1 - ( benzyl (phenyl ) Example 188 amino ) - 2 - methylpropan - 2 -ol (720 mg) and iodomethane 35 ( 1 .76 mL ) in DMF (10 mL ) at 0° C . , and the mixture was 3 -cyclopropyl - 3 -( 2 - (( 1 -( 5 -methoxy - 2 -( (2 -methoxy stirred at room temperature for 1 hr. To the reaction solution 2 -methylpropyl ) (phenyl ) carbamoyl ) phenyl) piperi was added water at room temperature , and the mixture was din - 4 - yl )methoxy )pyridin -4 - yl) propanoic acid extracted with ethyl acetate . The extract was washed with water and saturated brine, and dried over anhydrous mag Step 1 ) ethyl 2 - (phenylamino ) acetate 40 nesium sulfate . The solvent was evaporated under reduced pressure , and the residue was purified by silica gel column Under a nitrogen atmosphere , ethyl bromoacetate ( 3. 33 chromatography ( ethyl acetate /hexane ) to give the title com mL ) was added to a solution of aniline ( 2 . 73 mL) and pound (631 mg) as a colorless oil . diisopropylethylamine ( 10 .48 mL ) in acetonitrile (25 mL ) at H NMR ( 400 MHz , CDC13 ) d 1 .24 (6H , s ), 3 .20 ( 3H , s ) , 60° C . , and the mixture was stirred at 60° C . for 3 hr. The 45 3 .49 (2H , s ) , 4 .74 (2H , s ) , 6 .64 ( 1H , t , J = 7 . 2 Hz ), 6 .76 ( 2H , solvent was evaporated under reduced pressure , and the d , J = 8 . 3 Hz ) , 7 . 06 - 7 .22 (5H , m ) , 7 . 24 - 7 . 33 ( 2H , m ) . residual solid was washed with water to give a yellow solid . The obtained solid was dissolved in toluene, and the solvent Step 5 ) N -( 2 -methoxy - 2 -methylpropyl )aniline was evaporated under reduced pressure to give a crude product of the title compound ( 5 .09 g ) as a yellow solid . This 50 N - Benzyl- N - ( 2 -methoxy - 2 -methylpropyl ) aniline (631 compound was used for the next step without further puri - mg) and 10 % palladium hydroxide (300 mg) were stirred in fication . methanol ( 30 mL ) at room temperature for 1 hr under a ' H NMR ( 400 MHz, CDC1z ) / 1 . 30 (3H , t , J= 7 . 2 Hz) , hydrogen atmosphere ( 1 atm ) . The reaction mixture was 3 . 90 ( 2H , s) , 4 .25 (2H , q, J= 7 . 1 Hz) , 6 .62 (2H , d , J = 7. 7 Hz) , filtered , and the solvent in the filtrate was evaporated under 6 . 75 (1H , t , J = 7 . 3 Hz ), 7 . 20 ( 2H , dd , J = 8 . 4 , 7 . 5 Hz) . 55 reduced pressure to give the title compound (410 mg) as a pale -orange oil . Step 2 ) ethyl 2 -( benzyl ( phenyl ) amino )acetate H NMR ( 400 MHz, CDC1z ) 8 1 . 26 (6H , s ) , 3 .07 ( 2H , d , J= 3 .5 Hz ), 3. 21 (3H , s) , 3. 96 (1H , brs ), 6 .62 (2H , d , J = 7 .7 Benzyl bromide ( 3 . 26 mL ) was added to a mixture of the Hz) , 6 .68 ( 1H , t , J = 7 . 3 Hz) , 7 .09 - 7 .22 (2H , m ) . crude product ( 4 .09 g ) of ethyl 2 - (phenylamino acetate , 60 potassium carbonate (6 .31 g ) and DMF ( 25 mL ) at room Step 6 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 temperature , and the mixture was stirred at 80° C . for 3 hr. ( ( 2 -methoxy - 2 -methylpropyl ) (phenyl ) carbamoyl ) To the reaction solution was added water at room tempera phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) pro ture, and the mixture was extracted with ethyl acetate . The panoate extract was washed with water and saturated brine , and dried 65 over anhydrous magnesium sulfate . The solvent was evapo In the same manner as in Example 32, step 2 , the title rated under reduced pressure , and the residue was purified compound (27 .3 mg ) was obtained as a white amorphous US 9 ,776 , 962 B2 147 148 powder from 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopro Step 3 ) N -( ( 1 - fluorocyclopropyl) methyl ) aniline pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy benzoic acid ( 100 mg) and N - ( 2 -methoxy - 2 -methylpropyl ) In the same manner as in Example 188 , step 5 , the title aniline (93 . 0 mg) . compound (212 mg) was obtained as a colorless oil from 1H NMR (400 MHz, CDC1, ) 8 0 .13 - 0 .21 ( 1H , m ) , 0 .25 - 5 N -benzyl - N - ( ( 1 - fluorocyclopropyl) methyl ) aniline (518 0 .34 ( 1H , m ) , 0 .43 - 0 .52 ( 1H , m ), 0 .56 - 0 .66 (1H , m ), 0 . 95 mg) . 1 .05 ( 1H , m ), 1 . 19 (3H , t, J = 7 . 2 Hz ), 1 . 18 - 1 .40 (2H , m ) , 1 . 25 H NMR (300 MHz , CDC1z ) 0 .84 - 0 .99 (4H , m ), 4 .41 (6H , s ) , 1 .45 - 1 .61 (2H , m ) , 1 . 81 - 1 . 99 ( 3H , m ) , 2 . 27 - 2 . 36 (2H , d , J= 48. 1 Hz ), 4 .39 (1H , brs ), 6 .65 -6 .79 ( 3H , m ), 7 .18 ( 1H , m ), 2 .41 - 2 .75 (2H , m ), 2 .66 - 2 .79 (2H , m ), 2 . 82 ( 3H , s ), (2H , dd , J = 8 . 4 , 7 .5 Hz ) . 3 .70 ( 3H , s ) , 3 . 97 - 4 . 20 (2H , m ) , 4 .02 - 4 . 13 (2H , m ) , 4 . 20 10 Step 4 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -( (( 1 - fluoro ( 2H , d , J = 6 . 1 Hz) , 6 . 24 ( 1H , d , J = 1 . 8 Hz ), 6 .42 ( 1H , dd , cyclopropyl) methyl )( phenyl )carbamoyl ) -5 -methoxy J = 8 . 3, 2. 1 Hz ), 6 .64 ( 1H , s ), 6 .77 (1H , dd , J= 5 .4 , 1 . 1 Hz) , phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro 6 .91 - 7 . 08 (5H , m ) , 7 . 10 ( 1H , d , J = 8 . 3 Hz) , 8 .08 ( 1H , d , J = 5 . 4 panoate Hz) . 15 In the same manner as in Example 32 , step 2 , the title Step 7 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 compound (38 . 1 mg ) was obtained as a white amorphous methoxy - 2 -methylpropyl ) (phenyl ) carbamoyl ) phe powder from 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3- oxopro nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic pyl )pyridin -2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy acid benzoic acid ( 118 mg) and N - ( ( 1 - fluorocyclopropyl) methyl ) 20 aniline ( 101 mg) . In the same manner as in Example 1 , step 4 , the title compound (21 . 3 mg) was obtained as a white amorphous 0 .37 ( 1H , m ), 0 . 40 - 0 .52 ( 1H , m ) , 0 .55 - 0 .67 (1H , m ) , 0 .72 powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 1 . 14 (5H , m ) , 1 . 19 (3H , t , J = 7 . 1 Hz) , 1 .33 - 1 . 70 (4H , m ) , ( ( 2 -methoxy - 2 -methylpropyl ) (phenyl ) carbamoyl) phenyl) pi- , 1 . 76 - 1 . 94 (3H , m ) , 2 . 24 - 2 .37 ( 1H , m ), 2 . 43 - 2 . 65 ( 2H , m ), peridin -4 -yl ) methoxy )pyridin -4 -yl ) propanoate (27 .3 mg) . 25 2 .64 - 2 . 81 ( 2H , m ), 3 .70 (3H , s ), 3 . 98 - 4 . 14 ( 2H , m ) , 4 .06 5 . 73 ( 2H , m ) , 4 . 19 ( 2H , d , J = 6 . 0 Hz ) , 6 . 22 ( 1H , d , J = 2 . 4 HZ ) . MS (ESI + ): [M + H ]* 616 .3 . 6 .45 ( 1H , dd , J = 8 . 4 , 2 . 4 Hz ) , 6 .64 ( 1H , s ) , 6 . 76 ( 1H , dd , J = 5 .4 , 1 . 4 Hz) , 6 .91 -7 .09 (5H , m ), 7 . 15 ( 1H , d , J = 8 .4 Hz ), Example 189 8 .07 ( 1H , d , J = 5 . 4 Hz ) . 30 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 1 - fluorocyclopropyl) Step 5 ) 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( (( 1 - fluorocyclo methyl) ( phenyl) carbamoyl) - 5 -methoxyphenyl ) pip propyl )methyl ) ( phenyl )carbamoyl ) - 5 -methoxyphe eridin -4 -yl )methoxy )pyridin -4 - yl) propanoic acid nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 35 Step 1 ) In the same manner as in Example 1 , step 4 , the title 1- ( ( benzyl ( phenyl ) amino )methyl ) cyclopropanol compound (34 .7 mg) was obtained as a white amorphous powder from ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( ( 1 - fluorocy Under a nitrogen atmosphere, 3 M ethylmagnesium bro - clopropyl) methyl ) (phenyl ) carbamoyl) - 5 -methoxyphenyl ) mide (7 . 43 mL) was added to a solution of ethyl 2 - (benzyl 40 piperidin -4 - yl) methoxy )pyridin -4 - yl) propanoate ( 38 . 1 mg) . ( phenyl) amino )acetate ( 2 . 0 g ) obtained in Example 188 , step MS ( ESI+ ) : [ M + H ] * 602 . 3 . 2 , and tetraisopropyl titanate (653 uL ) in THF (30 mL ) at 0° C ., and the mixture was stirred at 0° C . for 1 hr and at room Example 190 temperature for 30 min . To the reaction solution was added saturated aqueous ammonium chloride solution at 0° C ., and 45 3 - ( 2 - ( ( 1 -( 2 -( 1 -benzylpiperidin - 4 -yl ) (pyridin - 2- yl ) the mixture was extracted with ethyl acetate . The extractwas carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 - yl) washed with water and saturated brine , and dried over methoxy) pyridin - 4 -yl ) - 3 -cyclopropylpropanoic acid anhydrous magnesium sulfate . The solvent was evaporated under reduced pressure , and the residue was purified by Step 1 ) N - ( 1 -benzylpiperidin - 4 -yl ) pyridin - 2 - amine silica gel column chromatography ( ethyl acetate /hexane ) to 50 give the title compound ( 1. 54 g) as a pale -yellow solid . In the same manner as in Example 135 , step 1 , the title H NMR (300 MHz, DMSO -da ) 8 0 .46 -0 .53 (2H , m ), compound (540 mg) was obtained as a brown solid from 0 .54 - 0 .61 (2H , m ), 3 .62 (2H , s ) , 4 .66 ( 2H , s ), 5 .41 ( 1H , s) , pyridine 1 - oxide (300 mg ) and 1 -benzylpiperidin - 4 - amine 6 .53 ( 1H , t, J = 7 . 2 Hz) , 6 .72 ( 2H , dd , J = 8 . 8 , 0 . 9 Hz ), (720 mg) . 6 . 97 - 7 . 11 ( 2H . m ) . 7 . 14 - 7 .23 (3H . m ) . 7 . 24 - 7 .35 ( 2H . m ). 55 H NMR (300 MHz, CDC1z) 8 1 . 43 - 1 .62 (2H , m ) , 1 . 95 2 . 10 (2H , m ) , 2 . 19 ( 2H , td , J = 11 . 4 , 2 . 4 Hz) , 2 . 76 - 2 . 91 (2H , m ), 3 .45 - 3 . 71 ( 3H , m ), 4 . 37 ( 1H , d , J = 7 . 7 Hz) , 6 .35 (1H , d , Step 2 ) J = 8 . 4 Hz) , 6 . 53 ( 1H , ddd, J = 7 . 1 , 5 .0 , 0 . 9 Hz ), 7 . 20 - 7 .45 (6H , N -benzyl - N -( (1 - fluorocyclopropyl)methyl ) aniline m ) , 8 .02 - 8 . 10 ( 1H , m ) . 60 In the same manner as in Example 39 , step 1 , the title Step 2 ) ethyl 3 -( 2 -( 1 -( 2 -( ( 1 -benzylpiperidin - 4 -yl ) compound (518 mg) was obtained as a pale -yellow solid ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi from 1 - (( benzyl ( phenyl ) amino )methyl ) cyclopropanol (1 . 0 din - 4 - yl )methoxy )pyridin - 4 - yl) - 3 - cyclopropylpro g ) . panoate ' H NMR ( 300 MHz, CDC12 ) 8 0 . 99 - 1 . 21 ( 4H , m ), 4 . 41 - 65 4 .73 (2H , m ), 4 .77 (2H , s) , 6 .59 -6 .83 (3H , m ), 7. 06 - 7. 38 In the same manner as in Example 32 , step 2 , the title ( 7H , m ). compound (690 mg ) was obtained as a pale -yellow amor US 9 ,776 ,962 B2 149 150 phous powder from N - ( 1 -benzylpiperidin - 4 -yl ) pyridin - 2 powder from ethyl 3 -cyclopropyl -3 - ( 2 - (( 1 -( 5 -methoxy - 2 amine ( 396 mg) and 2 -( 4 - (( ( 4 -( 1 -cyclopropyl - 3 - ethoxy - 3 (pyridin - 2 -yl ( 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 - yl) carbam oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 oyl) phenyl ) piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoate methoxybenzoic acid (550 mg ) . ( 110 mg) . MS (ESI + ): [ M + H ] * 732 . 4 . 5 MS (ESI + ) : [ M + H ] * 696 . 3 . Example 192 Step 3 ) 3 - ( 2 - ( 1 - ( 2 - ( ( 1 -benzylpiperidin - 4 - yl) (pyridin 2 - yl ) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( cyclopropyl( 2 , 2 -dimeth methoxy )pyridin -4 - yl) -3 -cyclopropylpropanoic acid 10 ylpropyl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 yl )methoxy ) pyridin - 4 - yl) propanoic acid In the same manner as in Example 1, step 4 , the title compound ( 102 mg) was obtained as a colorless amorphous Step 1 ) N -( 2 ,2 -dimethylpropyl ) cyclopropanamine powder from ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( 1- benzylpiperidin - 4 - yl) 15 hydrochloride ( pyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) To a solution of pivalaldehyde ( 1 . 0 g ) , cyclopropanamine methoxy )pyridin - 4 - yl) - 3 - cyclopropylpropanoate ( 120 mg) . ( 1 .21 mL ) and acetic acid (0 .665 mL ) in THF (10 mL ) was MS (ESI + ): [ M + H ]* 704. 4 . added sodium triacetoxyborohydride ( 3 .69 g ) at room tem perature , and the mixture was stirred overnight. The reaction 20 mixture was diluted with water, and washed with ethyl Example 191 acetate . The aqueous layer was adjusted to about pH 10 with 2N aqueous sodium hydroxide solution , and extracted with 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( pyridin - 2 -yl ethyl acetate . The extract was dried over anhydrous mag ( 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 -yl ) carbamoyl ) nesium sulfate , 4N hydrogen chloride ethyl acetate solution phenyl) piperidin -4 -yl )methoxy )pyridin -4 -yl ) pro 25 ( 5 mL ) was added , and the solvent was evaporated under panoic acid reduced pressure . The residue was suspended in ethyl acetate and hexane , and the resulting precipitate was col lected by filtration . The obtained solid was dried under Step 1 ) ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 reduced pressure to give the title compound (1 . 14 g ) as a ( piperidin - 4 -yl ( pyridin - 2 -yl ) carbamoyl ) phenyl) pip 30 colorless solid . eridin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoate ' H NMR ( 300 MHz, DMSO - d . ) 8 0 .65 - 0 . 83 ( 2H , m ) , 0 . 91 - 1 .02 ( 11H , m ) , 2 .60 - 2 . 78 ( 1H , m ) , 2 . 80 - 2 . 92 (2H , m ), Under a hydrogen atmosphere , a solution of ethyl 3 - ( 2 8 . 56 (2H , brs ) . (( 1 -( 2- (( 1- benzylpiperidin - 4 -yl ) (pyridin - 2 - yl ) carbamoyl) -5 - 35 Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( cyclopropyl( 2 , 2 methoxyphenyl) piperidin -4 -yl ) methoxy ) pyridin -4 - yl) - 3 -cy dimethylpropyl) carbamoyl ) - 5 -methoxyphenyl ) pip clopropylpropanoate (570 mg) obtained in Example 190 , eridin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid step 2 , and 10 % palladium carbon (55 % water - containing , 184 mg) in ethanol ( 15 mL ) was stirred at room temperature In the same manner as in Example 32 , step 2 and Example for 5 hr. The reaction mixture was filtered through celite , and 40 1 , step 4 , the title compound ( 204 mg) was obtained as a the filtrate was concentrated under reduced pressure to give colorless amorphous powder from N - (2 ,2 -dimethylpropyl ) the title compound (475 mg) as a colorless oil . cyclopropanamine hydrochloride ( 136 mg ) and 2 - (4 - (( ( 4 -( 1 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) MS (ESI + ) : [ M + H ] * 642 . 4 . methyl) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 200 mg ). 45 MS (ESI + ): [ M + H ] * 564 . 3 . Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 (pyridin - 2 - yl( 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 -yl ) Example 193 carbamoyl) phenyl ) piperidin - 4 -yl ) methoxy ) pyridin 4 - yl) propanoate 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 1 - ( 2 , 2 , 2 50 trifluoroethyl) piperidin - 4 - yl) carbamoyl) phenyl) pip In the same manner as in Example 14 , step 1 , the title eridin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid compound (112 mg) was obtained as a colorless amorphous Step 1 ) 1 -( 2 , 2 , 2 -trifluoroethyl ) piperidin - 4 - amine powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 dihydrochloride (piperidin -4 - yl( pyridin - 2 - yl) carbamoyl ) phenyl) piperidin - 4 - 55 yl) methoxy )pyridin - 4 - yl) propanoate ( 157 mg) and 2 , 2 , 2 A solution of tert - butyl piperidin - 4 - ylcarbamate ( 1 . 0 g ) , trifluoroethyl trifluoromethanesulfonate (114 mg) . 2 , 2 , 2 - trifluoroethyl trifluoromethanesulfonate ( 1 .51 g ) and MS (ESI + ) : [ M + H ] * 724 . 4 . triethylamine (1 .39 mL ) in THF ( 10 mL ) was stirred at 70° C . for 11 hr. To the reaction mixture was added water at 60 room temperature , and the mixture was extracted with ethyl Step 3 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (pyri acetate . The extract was washed with saturated brine , dried din - 2 -yl ( 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 -yl ) car over anhydrous magnesium sulfate , and the solvent was bamoyl) phenyl ) piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) evaporated under reduced pressure . The obtained pale -yel propanoic acid low solid was dissolved in ethanol (35 mL ) and methanol 65 (15 mL ), 4N hydrogen chloride ethyl acetate solution ( 15 In the same manner as in Example 1 , step 4 , the title mL ) was added , and the mixture was stirred at room compound (78 mg) was obtained as a colorless amorphous temperature overnight. To the reaction mixture was added US 9 , 776 , 962 B2 151 152 hexane , and the resulting precipitate was collected by fil - (methyl ( 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 -yl ) carbamoyl) tration . The obtained solid was washed with hexane , and phenyl )piperidin -4 -yl ) methoxy )pyridin - 4- yl )propanoate dried under reduced pressure to give the title compound ( 964 ( 116 mg) . mg) as a colorless solid . MS (ESI + ): [ M + H ] * 633. 3 . ' H NMR ( 300 MHz, DMSO - d ) 8 1. 63 - 1 .85 (2H , m ), 5 1 .89 - 2 . 06 ( 2H , m ), 2 .59 - 2 .82 ( 2H , m ), 2 .97 - 3 .28 ( 3H , m ) , Example 195 3 .40 - 3. 72 (1H , m ) , 8 . 13 - 8. 52 (3H , m ). 3 -( 2 - (( 1 -( 2 -( ( cyclohexylmethyl ) (pyridin - 2 - yl) car bamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) Step 2 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 pyridin - 4 - yl) - 3 -cyclopropylpropanoic acid ( ( 1 - ( 2, 2 , 2 -trifluoroethyl ) piperidin -4 - yl) carbamoyl ) 10 phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro By a method similar to that in Example 32 , step 2 and panoate Example 1 , step 4 , the title compound ( 155 mg) was obtained as a white amorphous powder from 2 - ( 4 - (( ( 4 - ( 1 In the same manner as in Example 32 , step 2 , the title cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) compound (348 mg) was obtained as a colorless amorphous powder from 1 - ( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 - amine dihy and N - ( cyclohexylmethyl) pyridin - 2 - amine ( 117 mg) . drochloride (238 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 MS (ESI + ) : [ M + H ] * 627 . 2 . ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 yl) - 4 -methoxybenzoic acid (300 mg) . Example 196 MS ( ESI + ): [M + H ] * 647 .3 . 20 3 -cyclopropyl -3 -( 2 -( (1 - (5 -methoxy - 2- (pyridin - 2 -yl ( tetrahydro - 2H -pyran - 4 - ylmethyl) carbamoyl) phenyl) Step 3 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 -( ( 1 - (2 , piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid 2 , 2 - trifluoroethyl) piperidin - 4 - yl) carbamoyl ) phenyl ) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 25 By a method similar to that in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 91 mg) was obtained In the same manner as in Example 1 , step 4 , the title as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopro compound (67 mg) was obtained as a colorless amorphous pyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) piperi powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 din - 1 - yl) - 4 - methoxybenzoic acid ( 148 . 7 mg) and N - ( ( tetra ( ( 1 -( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 - yl) carbamoyl) phenyl) 30 hydroMS - 2H(ESII - pyran ) : IM - 4 -+yl 11) methyl + 629 . 4) .pyridin -2 -amine ( 118 mg) . piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) propanoate (99 mg) . MS (ESI + ) : [ M + H ] * 619 . 3 . Example 197 Example 194 3 - ( 2 - ( ( 1 - ( 2 - (benzyl ( pyridin - 2 - yl ) carbamoyl) - 5 3535 methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 yl) - 3 - cyclopropylpropanoic acid 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 5 -methoxy - 2 -( methyl ( 1 -( 2 , 2 , 2 - trifluoroethyl) piperidin - 4 -yl ) carbamoyl) phenyl ) By a method similar to that in Example 32 , step 2 and piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoic acid Example 1 , step 4 , the title compound ( 158 mg) was 40 obtained as a white amorphous powder from 2 -( 4 - (( (4 - ( 1 Step 1) ethyl 3 -cyclopropyl - 3 - ( 2 - (( 1 - (5 -methoxy - 2 cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy ) (methyl ( 1 - ( 2 , 2 , 2 - trifluoroethyl ) piperidin - 4 - yl) car methyl) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 148 . 7 mg) bamoyl) phenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) and N - benzylpyridin - 2 - amine ( 114 mg) . propanoate MS (ESI + ) : [ M + H ] * 621. 4 . 45 Example 198 In the same manner as in Example 130 , step 1 , the title compound (116 mg ) was obtained as a brown oil from ethyl 3 - ( 2 - ( ( 1 - ( 2 - ( cyclopentyl( 2 ,2 - dimethylpropyl) car 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 1 - ( 2 , 2 , 2 - trifluoro bamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl )methoxy ) ethyl) piperidin - 4 - yl) carbamoyl) phenyl) piperidin - 4 -yl ) pyridin - 4 - yl) - 3 - cyclopropylpropanoic acid methoxy )pyridin -4 -yl ) propanoate (130 mg) obtained in 50 Example 193 , step 2 . By a method similar to that in Example 32 , step 2 and ' H NMR ( 300 MHz, CDC13 ) 8 0 .09 - 0 .21 ( 1H , m ), 0 .23 23 . Example 1 , step 4 , the title compound ( 12. 9 mg) was 0 .35 ( 1H , m ), 0 .39 - 0 .53 ( 1H , m ), 0 .54 -0 .67 ( 1H , m ), 0 .91 obtained as a white amorphous powder from 2 - ( 4 - (( ( 4 -( 1 1 .04 ( 1H , m ), 1. 13 - 1 .48 (4H , m ), 1. 65 -2 .23 (7H , m ), 2 .24 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin -2 - yl) oxy ) 2 .36 (1H , m ), 2 .44 - 3 .32 ( 15H , m ), 3. 62 ( 2H , s ), 3. 78 - 3. 85 85 55> methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (118 mg) ( 3H , m ), 4 .01 - 4 .70 (4H , m ), 6 .50 - 6 .64 ( 3H , m ), 6 .72 - 6 . 80 and N -( 2, 2 -dimethylpropyl ) cyclopentanamine (379 mg) . ( 1H , m ) , 7 .07 - 7 . 20 ( 1H , m ) , 7 .98 - 8 .09 (1H , m ) . MS (ESI + ) : [ M + H ] * 592 . 3 . Example 199 Step 2 ) 3 -cyclopropyl -3 - (2 - (( 1 -( 5 -methoxy - 2 60 (methyl ( 1 - ( 2 , 2 , 2 -trifluoroethyl ) piperidin - 4 - yl) car 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( 2 , 3 -dihydro - 4H -1 ,4 -ben bamoyl) phenyl ) piperidin -4 - yl) methoxy )pyridin -4 - yl) zoxazin - 4 -ylcarbonyl ) -5 -methoxyphenyl ) piperidin propanoic acid 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid In the same manner as in Example 1 , step 4 , the title 65 By a method similar to that in Example 32 , step 2 and compound ( 70 mg) was obtained as a colorless amorphous Example 1 , step 4 , the title compound ( 146 mg) was powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 US 9 ,776 ,962 B2 153 154 cyclopropyl- 3 -ethoxy - 3- oxopropyl) pyridin - 2 - yl) oxy ) obtained as a white amorphous powder from 2 - ( 4 -( ( ( 4 - ( 1 methyl) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 148 . 7 mg) cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy) and 3 , 4 -dihydro - 2H -benzo [ b ] [ 1 , 4 ] oxazine (83 mg) . methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 114 .7 mg) MS ( ESI + ) : [ M + H ] * 572 . 2 . and 2 -phenylmorpholine hydrochloride (95 mg) . Example 200 5 MS (ESI + ): [ M + H ] * 600 . 2 . 3 -cyclopropyl - 3 - (2 - (( 1 - (5 -methoxy - 2- (3 -phenyl Example 205 morpholin - 4 -yl ) carbonyl) phenyl ) piperidin -4 -yl ) methoxy ) pyridin - 4 - yl) propanoic acid 10 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 - ( 2 -methyl By a method similar to that in Example 32 , step 2 and propyl) morpholin -4 - yl) carbonyl ) phenyl) piperidin -4 Example 1 , step 4 , the title compound ( 95 mg) was obtained yl) methoxy ) pyridin - 4 - yl) propanoic acid as a white amorphous powder from 2 - ( 4 - ( 4 - ( 1 - cyclopro pyl -3 - ethoxy - 3 -oxopropyl ) pyridin -2 -yl )oxy )methyl ) piperi - By a method similar to that in Example 32 , step 2 and din - 1 - yl) - 4 -methoxybenzoic acid ( 116 . 6 mg) and 3 -phenyl - 15 Example 1 , step 4 , the title compound (110 mg) was morpholine hydrochloride ( 96 mg) . obtained as a white amorphous powder from 2 - (4 - (( ( 4 -( 1 MS ( ESI + ) : [ M + H ] * 600 . 2 . cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy ) methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 114 . 7 mg) Example 201 and 2 -( 2 -methylpropyl ) morpholine (68 . 1 mg) . 3 -( 2 -( ( 1 -( 2 -( (3 -benzylmorpholin -4 -yl ) carbonyl ) - 5 20 MS (ESI + ): [ M + H ]* 580 . 3 . methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 yl) - 3 -cyclopropylpropanoic acid Example 206 By a method similar to that in Example 32 , step 2 and 25 Example 1 , step 4 , the title compound ( 108 mg) was 3 -cyclopropyl - 3 -( 2 - (( 1 - ( 2 - (cyclopropyl ( 2 , 2 ,3 , 3 - tetra obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 fluoropropyl) carbamoyl ) - 5 - methoxyphenyl) piperi cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy) din -4 -yl )methoxy )pyridin -4 - yl) propanoic acid methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 116 . 6 mg ) and 3 -benzylmorpholine hydrochloride ( 103 mg) . 30 In the same manner as in Example 14 , step 1 , Example 32 , MS ( ESI + ) : [ M + H ] * 614 . 3 . step 2 and Example 1 , step 4 , the title compound ( 126 mg) was obtained as a white amorphous powder from cyclopro Example 202 pylamine ( 81 mg ) and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 -ethoxy - 3 3 -cyclopropyl - 3 -( 2 - (( 1 -( 5 -methoxy - 2 -( (2 ,2 ,6 ,6 - tetra oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl ) - 4 fluoromorpholin - 4 -yl ) carbonyl ) phenyl) piperidin - 4 - 35 methoxybenzoic acid ( 200 mg ). yl) methoxy )pyridin - 4 - yl) propanoic acid MS (ESI + ) : [ M + H ] * 608 . 2 . By a method similar to that in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 114 mg) was Example 207 obtained as a white amorphous powder from 2 -( 4 - ( (( 4 -( 1- 40 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) 3 - ( 2 - ( ( 1 - ( 2 - ( cyclobutyl ( 2 , 2 , 3 , 3 -tetrafluoropropyl ) methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 116 . 6 mg ) carbamoyl) -5 -methoxyphenyl ) piperidin - 4 -yl ) and 2 , 2 , 6 , 6 - tetrafluoromorpholine (77 mg) . methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid MS (ESI + ): [ M + H ] * 596 . 1 . Example 203 45 In the samemanner as in Example 14 , step 1 , Example 32 , step 2 and Example 1, step 4 , the title compound ( 186 mg) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( (3S ) - 3 - ( 2 was obtained as a white amorphous powder from cyclobu methylpropyl) morpholin - 4 -yl ) carbonyl ) phenyl) pip tylamine ( 101 mg ) and 2 -( 4 - ( (( 4 -( 1 -cyclopropyl - 3 -ethoxy eridin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid 3 -oxopropyl ) pyridin - 2 -yl )oxy )methyl ) piperidin - 1 - yl) - 4 50 methoxybenzoic acid (200 mg) . By a method similar to that in Example 32 , step 2 and Example 1 , step 4 , the title compound (71 . 4 mg) was MS (ESI + ): [M + H ] * 622 .3 . obtained as a white amorphous powder from 2 -( 4 - ( (( 4 -( 1 cyclopropyl- 3 - ethoxy - 3 -oxopropyl )pyridin - 2 - yl ) oxy ) Example 208 methyl) piperidin -1 -yl ) -4 -methoxybenzoic acid ( 116 .6 mg) 55 and ( S )- 3 -( 2 -methylpropyl ) morpholine hydrochloride ( 261 3 -( 2 -( ( 1- ( 2 - (cyclopentyl ( 2 ,2 , 3, 3 -tetrafluoropropyl ) mg) . carbamoyl) -5 -methoxyphenyl ) piperidin -4 -yl ) MS (ESI + ) : [ M + H ] * 580 . 3 . methoxy )pyridin - 4 -yl ) - 3 - cyclopropylpropanoic acid Example 204 60 In the same manner as in Example 14 , step 1 , Example 32 , 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 -phenyl step 2 and Example 1 , step 4 , the title compound (89 mg) morpholin - 4 -yl ) carbonyl )phenyl ) piperidin -4 -yl ) was obtained as a white amorphous powder from cyclopen tylamine ( 121 mg) and 2 - [ 4 -( (( 4 -( 1 - cyclopropyl- 3 - ethoxy methoxy ) pyridin - 4 - yl) propanoic acid 65 3 -oxopropyl ) pyridin -2 -yl ) oxy )methyl ) piperidin - 1- yl ) - 4 By a method similar to that in Example 32 , step 2 and methoxybenzoic acid ( 200 mg ) . Example 1 , step 4 , the title compound (105 mg) was MS (ESI ): [M + H ] * 636 .3 . US 9 ,776 , 962 B2 155 156 Example 209 3 , 3 -pentafluoropropyl trifluoromethanesulfonate (400 mg ) and 2 - [ 4 - ( (( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyri 3 -cyclopropyl - 3 - ( 2 -( ( 1 - ( 2 - ( ethyl ( 2 , 2 , 3 , 3 , 3 -pentafluo din - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic ropropyl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 acid (200 mg) . yl) methoxy )pyridin - 4 - yl ) propanoic acid MS (ESI + ) : [ M + H ] * 640. 3 . Step 1) Example 213 N - ethyl- 2 ,2 ,3 , 3, 3 -pentafluoropropan -1 - amine 3 -cyclopropyl - 3 - ( 2- (( 1 -( 2 -( ethyl( 2 ,2 ,3 , 3 - tetrafluoro In a sealed tube, a mixture of 2M ethanamine THF 10 propyl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 -yl ) solution ( 0 .71 mL ), 2 , 2 , 3 , 3 , 3 - pentafluoropropyl trifluo methoxy ) pyridin - 4 - yl) propanoic acid romethane sulfonate (400 mg) , triethylamine ( 0 . 20 mL ) and THF (0 . 3 mL ) was stirred at 60° C . for 2 . 5 hr. This In the same manner as in Example 209 , step 1 and step 2 , compound in the form of a reaction mixture was used for the the title compound (193 mg) was obtained as a colorless next step without purification . 15 amorphous powder from 2M ethanamine THF solution ( 0 .75 mL ) , 2 , 2 ,3 , 3 - tetrafluoropropyl trifluoromethanesulfonate Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ethyl( 2 , 2 , 3 , 3 , 3 (400 mg) and 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopro pentafluoropropyl) carbamoyl) - 5 -methoxyphenyl ) pyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid 20 benzoic acid ( 200 mg) . In the samemanner as in Example 32 , step 2 and Example MS (ESI + ) : [ M + H ] * 596 .2 . 1 , step 4 , the title compound ( 183 mg) was obtained as a colorless amorphous powder from the reaction mixture Example 214 obtained in step 1 and 2 - ( 4 -( (( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) -4 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (propan - 2 -yl methoxybenzoic acid ( 200 mg ) . ( 2 , 2 , 3 , 3 - tetrafluoropropyl ) carbamoyl) phenyl ) piperi MS (ESI + ) : [ M + H ] * 614 . 3 . din -4 -yl )methoxy )pyridin -4 - yl) propanoic acid Example 210 In the same manner as in Example 209, step 1 and step 2 , 30 the title compound ( 59 mg) was obtained as a colorless 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , 3 , 3 , 3 amorphous powder from propan - 2 - amine ( 89 mg) , 2 , 2 , 3 , 3 pentafluoropropyl) ( propan - 2 -yl ) carbamoyl ) phenyl ) tetrafluoropropyl trifluoromethanesulfonate (400 mg) and piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid 2 -( 4 - ( ( (4 -( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl ) pyridin - 2 yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid (200 In the samemanner as in Example 32 , step 2 and Example 35 mg) . 1 , step 4 , the title compound ( 172 mg ) was obtained as a MS (ESI + ) : IM + H1+ 610 . 2 . colorless amorphous powder from 2 , 2, 3 ,3 ,3 -pentafluoro -N ( propan - 2 - yl) propan - 1 -amine hydrochloride ( 189 mg) and Example 215 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 yl) oxy )methyl ) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 200 40 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - (propan - 2 -yl mg) . ( 2 , 2 , 2 - trifluoroethyl) carbamoyl ) phenyl) piperidin - 4 MS (ESI + ) : [ M + H ] * 628. 2 . yl )methoxy )pyridin -4 - yl) propanoic acid Example 211 In the same manner as in Example 209, step 1 and step 2 , 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( cyclopropyl( 2 , 2 , 3 , 3 , 3 the title compound ( 114 mg) was obtained as a colorless pentafluoropropyl) carbamoyl) - 5 -methoxyphenyl ) amorphous powder from propan - 2 - amine ( 89 mg) , 2 , 2 , 2 piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid trifluoroethyl trifluoromethanesulfonate (350 mg) and 2 - ( 4 ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) In the samemanner as in Example 209 , step 1 and step 2 , 50 oxy )methyl ) piperidin - 1- yl) - 4 -methoxybenzoic acid ( 200 the title compound ( 113 mg) was obtained as a colorless mg ) . amorphous powder from cyclopropanamine (81 mg) , 2 ,2 , 3 , MS (ESI + ): [M + H ]* 578 . 2 . 3 , 3 -pentafluoropropyl trifluoromethanesulfonate ( 400 mg ) and 2 - (4 - (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopropyl) pyri Example 216 din - 2 - yl )oxy )methyl )piperidin -1 -yl ) - 4 -methoxybenzoic 55 acid (200 mg) . 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ethyl( 2 , 2 , 2 -trifluoroethyl ) MS (ESI + ) : [ M + H ] * 626 . 2 . carbamoyl) -5 -methoxyphenyl ) piperidin -4 -yl ) methoxy ) pyridin - 4 - yl) propanoic acid Example 212 60 By a method similar to that in Example 32 , step 2 and 3 - (2 -( (1 - (2 -( cyclobutyl ( 2 ,2 ,3 ,3 ,3 -pentafluoropropyl ) Example 1 , step 4 , the title compound ( 149 mg) was carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) obtained as a white amorphous powder from 2 - ( 4 - ( ( ( 4 - ( 1 methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid cyclopropyl- 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 159. 6 mg) In the samemanner as in Example 209 , step 1 and step 2 , 65 and N - ethyl- 2 , 2 , 2 - trifluoroethanamine hydrochloride ( 108 the title compound ( 138 mg) was obtained as a colorless mg ) . amorphous powder from cyclobutanamine ( 101 mg) , 2 , 2 , 3 , MS (ESI + ): [ M + H ] * 564. 3 . US 9 ,776 ,962 B2 157 158 Example 217 was obtained as a white amorphous powder from 2 , 3 dihydro - 1 -benzofuran - 3 - amine ( 266 mg) and 2 - ( 4 - ( (( 4 - ( 1 3 -( 2 -( 1 -( 2 -( bis ( 2 ,2 ,2 -trifluoroethyl ) carbamoyl ) -5 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy ) methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 methyl) piperidin - 1- yl) -4 -methoxybenzoic acid (449 mg) . yl) - 3 - cyclopropylpropanoic acid 5 MS (ESI + ) : [ M + H ]* 686 . 3 . By a method similar to that in Example 32 , step 2 and Example 222 Example 1 , step 4 , the title compound (77 mg ) was obtained as a white amorphous powder from 2 -( 4 -( ( (4 - (1 - cyclopro 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) ( 6 pyl- 3 - ethoxy - 3 -oxopropyl )pyridin - 2 - yl) oxy )methyl ) piperi ( trifluoromethyl) pyridin - 2 - yl) carbamoyl) - 5 din - 1 - yl) - 4 -methoxybenzoic acid ( 159 . 6 mg ) and bis ( 2 , 2 , 2 - methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 trifluoroethyl) amine (109 ul) . yl) propanoic acid MS ( ESI + ) : [ M + H ] * 618 . 2 . Step 1 ) N - ( 2 , 2 - dimethylpropyl) -6 - ( trifluoromethyl) Example 218 pyridin - 2 - amine 15 3 - cyclopropyl- 3 -( 2 - ( 1 - ( 2 - ( cyclopropyl( 2 , 2 , 2 - trifluo In a sealed tube , a mixture of 2 -chloro - 6 - ( trifluoromethyl) roethyl ) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) pyridine (310 mg) and 2 , 2 - dimethylpropan - 1 -amine (744 methoxy ) pyridin -4 -yl ) propanoic acid mg) was stirred at 100° C . for 18 hr. After allowing to cool to room temperature , the reaction mixture was purified by In the samemanner as in Example 209 . step 1 and step 2 . 20 silica gel column chromatography ( ethyl acetate /hexane ) to the title compound ( 161mg ) was obtained as a grayish white give the title compound (200 mg ) as a mixture with amorphous powder from cyclopropanamine (100 mg ), 2 , 2 , 2 -chloro -6 - ( trifluoromethyl) pyridine . This compound in the 2 - trifluoroethyl trifluoromethanesulfonate (407 mg) and form of a reaction mixture was used for the next step without 2 -( 4 -( (( 4 -( 1 -cyclopropyl - 3 -ethoxy -3 - oxopropyl) pyridin - 2 further purification . yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (211 25 IH NMR ( 300 MHz, CDC1z ) 8 0 . 99 (9H , s ) , 3 . 10 ( 2H , d , mg) . J = 6 . 2 Hz) , 4 .82 (1H , brs ), 6 .54 ( 1H , d , J = 8 . 5 Hz) , 6 .89 ( 1H , MS ( ESI + ): [ M + H ]* 576 . 2 . d , J = 7 . 3 Hz) , 7 .51 ( 1H , t , J = 8 . 0 Hz ) . Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - (( 2 , 2 - dimethyl Example 219 propyl) (6 - ( trifluoromethyl) pyridin - 2 - yl) carbamoyl) 30 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 3 - ( 2 - ( ( 1 - ( 2 - ( cyclobutyl( 2 , 2 , 2 -trifluoroethyl )carbam yl) propanoic acid oyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy )pyri din - 4 - yl) - 3 - cyclopropylpropanoic acid In the samemanner as in Example 32 , step 2 and Example 1, step 4 , the title compound (87 mg) was obtained as a In the same manner as in Example 209, step 1 and step 2, 35 colorless amorphous powder from a crude purified product the title compound (101 mg) was obtained as a grayish white ( 193 mg) of N - ( 2, 2 - dimethylpropyl) - 6 -( trifluoromethyl) amorphous powder from cyclobutanamine (100 mg) , 2 , 2 ,2 - pyridin - 2 - amine and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 trifluoroethyl trifluoromethanesulfonate (326 mg) and 2 -( 4 oxopropyl )pyridin -2 - yl) oxy )methyl ) piperidin -1 - yl) - 4 ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) methoxybenzoic acid ( 200 mg) . oxymethylpiperidin - 1 - yl) - 4 -methoxybenzoic acid ( 204 40 MS (ESI + ) : ( M + H ] 069. 3 . mg ) . MS (ESI + ) : [ M + H ] * 590 .3 . Example 223 Example 220 3 -cyclopropyl - 3 - ( 2 - (( 1 - (2 -( ( 2, 2 -dimethylpropyl ) ( 4 4545 ( trifluoromethyl) pyrimidin - 2 - yl) carbamoyl) - 5 3 - ( 2 - ( ( 1 - ( 2 - ( cyclopentyl( 2 , 2 , 2 - trifluoroethyl) carbam methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 oyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) pyri yl) propanoic acid din - 4 - yl) - 3 - cyclopropylpropanoic acid Step 1 ) N -( 2 , 2 -dimethylpropyl ) - 4 -( trifluoromethyl) pyrimidin - 2 -amine In the samemanner as in Example 209 , step 1 and step 2 , 50 the title compound ( 30 mg) was obtained as a pale - yellow In a sealed tube , a mixture of 2 -chloro -4 -( trifluoromethyl) amorphous powder from cyclopentanamine ( 100 mg) , 2 , 2 , pyrimidine (300 mg ) and 2 ,2 -dimethylpropan - 1 -amine (358 2 -trifluoroethyl trifluoromethanesulfonate (273 mg) and mg ) was stirred at 100° C . for 18 hr. After allowing to cool 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - to room temperature , the reaction mixture was purified by yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid (198 55 silica gel column chromatography ( ethyl acetate /hexane ) to mg ). give the title compound ( 364 mg ) as a colorless solid . MS ( ESI + ) : [ M + H ] * 604. 4 . IH NMR ( 300 MHz, CDC12 ) 8 0 .97 ( 9H , s ) , 3 . 31 ( 2H , d , J = 6 . 4 Hz) , 5 . 43 ( 1H , brs ) , 6 .78 (1H , d , J = 4 . 9 Hz) , 8 .45 ( 1H , Example 221 brs ) . 60 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( 2 , 3 -dihydro - 1- benzo Step 2 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl furan - 3 -yl ( 2 ,2 ,3 ,3 - tetrafluoropropyl) carbamoyl ) -5 propyl) (4 - (trifluoromethyl ) pyrimidin - 2 - yl) carbam methoxyphenyl) piperidin -4 -yl )methoxy )pyridin -4 oyl) - 5 -methoxyphenyl ) piperidin -4 -yl ) methoxy )pyri yl) propanoic acid din - 4 -yl ) propanoic acid 65 In the same manner as in Example 14 , step 1, Example 32 , In the same manner as in Example 32 , step 2 and Example step 2 and Example 1 , step 4 , the title compound (120 mg) 1 , step 4 , the title compound ( 161 mg) was obtained as a US 9 ,776 ,962 B2 159 160 colorless amorphous powder from N -( 2 , 2 -dimethylpropyl ) 100° C . for 20 min . The reaction mixture was purified by 4 - ( trifluoromethyl) pyrimidin - 2 -amine (193 mg) and 2 - ( 4 silica gel column chromatography ( ethyl acetate /hexane ) to ( (( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) give the title compound ( 110 mg) as a colorless amorphous oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid (200 powder. mg ). PH NMR ( 300 MHz , CDC1. ) 0 . 91 - 1 . 07 ( 18H , m , J = 2 . 5 MS (ESI + ) : [ M + H ] * 670 . 3 . Hz ), 2 .41 (3H , s ), 3. 07 (2H , d , J= 6 .0 Hz) , 3. 25 (2H , d , J = 6 .4 Example 224 Hz) , 4 .72 ( 1H , t , J = 5 . 7 Hz) , 5 . 98 - 6 . 18 ( 1H , m ) , 6 . 58 ( 2H , s ) . Step 2 ) 3 -cyclopropyl - 3 -( 2- (( 1 -( 2 -( ( 2 ,2 -dimethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 4 - cyclopropylpyrimidin - 10 propyl) ( 4 - ( ( 2 , 2 - dimethylpropyl) carbamoyl ) -6 -meth 2 -yl ) ( 2, 2 -dimethylpropyl ) carbamoyl ) -5 -methoxy ylpyridin -2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperi phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro din - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid panoic acid In the samemanner as in Example 32, step 2 and Example Step 1 ) 2 -chloro - 4 - cyclopropylpyrimidine 15 1 , step 4 , the title compound (27 mg) was obtained as a To a solution of 2, 4 -dichloropyrimidine (5 . 0 g ) and acety colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) lacetone iron ( III ) in THF ( 30 mL ) and N -methyl - 2- pyrroli 2 - ( ( 2 , 2 -dimethylpropyl ) amino ) -6 -methylisonicotinamide done (NMP ) ( 5 mL ) was added dropwise 1 M cyclopropy ( 110 mg) and 2 - ( 4 - (( ( 4 -( 1- cyclopropyl- 3 - ethoxy - 3 -oxopro Imagnesium bromide (67 mL ) under ice - cooling. The 20 pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy reaction mixture was stirred at room temperature for 1 hr. To benzoic acid ( 100 mg) . the reaction mixture was added water at room temperature , MS (ESI + ): [ M + H ]* 728 .5 . and the mixture was extracted with ethyl acetate . The extract was washed with water and saturated brine , and dried over Example 226 anhydrous magnesium sulfate . The solvent was evaporated 25 under reduced pressure , and the residue was purified by 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 -dimethylpropyl ) (6 silica gel column chromatography ( ethyl acetate /hexane ) to methyl- 4 - ( pyrrolidin - 1 - ylcarbonyl) pyridin - 2 - yl) car give the title compound ( 3 . 1 g ) as an orange oil. bamoyl) - 5 - methoxyphenyl) piperidin - 4 - yl) methoxy ) ' H NMR ( 300 MHz, CDC1z ) d 1 . 08 - 1 . 32 (4H , m ) , 1 .92 pyridin -4 -yl ) propanoic acid 2 .07 ( 1H , m ) , 7 . 08 ( 1H , d , J = 5 . 1 Hz) , 8 . 35 ( 1H , d , J = 5 . 1 Hz) . 30 Step 1 ) ( 2 -chloro -6 -methylpyridin - 4 -yl ) ( pyrrolidin Step 2 ) 4 - cyclopropyl- N - ( 2 , 2 - dimethylpropyl) py 1 -yl ) methanone rimidin - 2 -amine In the same manner as in Example 32 , step 2 , the title In the same manner as in Example 45 , step 8 , the title 35 compound (580 mg ) was obtained as a colorless solid from compound ( 1. 79 g ) was obtained as pale - yellow crystals pyrrolidine (228 mg) and 2 -chloro -6 -methylisonicotinic acid from 2 -chloro -4 - cyclopropylpyrimidine ( 1. 5 g ) . (500 mg) . MS (ESI + ) : [ M + H ] * 206 . 2 . H NMR (300 MHz, CDC1z ) & 1. 85 -2 .05 (4H , m ), 2 .57 Step 3 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( 4 -cyclopropy 40 ( 3H , s ), 3 . 37 (2H , t , J = 6 . 4 Hz) , 3 .63 (2H , t , J = 6 . 8 Hz) , 7 . 16 lpyrimidin - 2 - yl) ( 2 , 2 - dimethylpropyl) carbamoyl ) -5 (1H , d , J= 0 .6 Hz) , 7 . 19 - 7 .24 ( 1H , m ) . methoxyphenyl) piperidin -4 - yl)methoxy ) pyridin -4 Step 2 ) ( 2 - ( ( 2 , 2 - dimethylpropyl) amino ) -6 -methyl yl) propanoic acid pyridin - 4 - yl) (pyrrolidin - 1 - yl) methanone In the samemanner as in Example 32, step 2 and Example 45 1 , step 4 , the title compound (58 mg) was obtained as a In the samemanner as in Example 225 , step 1 , the title pale - vellow amorphous powder from 4 - cyclopropyl- N - ( 2 . 2 - compound ( 105 mg ) was obtained as brown solid from dimethylpropyl) pyrimidin - 2 - amine ( 145 mg) and 2 - ( 4 - ( ( ( 4 ( 2 -chloro - 6 - methylpyridin - 4 -yl ) (pyrrolidin - 1 - yl) methanone (1 -cyclopropyl - 3 -ethoxy -3 -oxopropyl ) pyridin - 2 - yl )oxy ) ( 100 mg) . methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 170 mg) . 50 " H NMR ( 300 MHz, CDC1z ) 8 0 . 98 ( 9H , s ), 1 . 80 - 2 . 02 MS (ESI + ) : [M + H ]* 642. 3 . (4H , m ) , 2 . 37 ( 3H , s ), 3 . 01 (2H , d , J = 6 . 1 Hz) , 3 . 38 (2H , t , J = 6 . 5 Hz) , 3 .61 (2H , t , J = 6 . 8 Hz ), 4 .68 ( 1H , t , J = 5 . 9 Hz ) , Example 225 6 . 25 ( 1H , s ) , 6 . 45 ( 1H , s ). 3 - cyclopropyl- 3 - ( 2 -( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) ( 4 55 Step 3 ) 3 - cyclopropyl- 3 - ( 2 -( ( 1 -( 2 - ( (2 , 2 -dimethyl (( 2 , 2 - dimethylpropyl) carbamoyl) - 6 -methylpyridin - 2 propyl) ( 6 -methyl - 4 - ( pyrrolidin - 1 - ylcarbonyl) pyri yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) din - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperidin - 4 methoxy )pyridin - 4 -yl ) propanoic acid yl) methoxy ) pyridin -4 -yl ) propanoic acid Step 1 ) N - ( 2 , 2 -dimethylpropyl ) - 2 - (( 2 ,2 -dimethyl 60 In the same manner as in Example 32 , step 2 and Example propyl) amino ) -6 -methylisonicotinamide 1 , step 4 , the title compound ( 28 mg) was obtained as a colorless amorphous powder from ( 2 - ( 2 , 2 - dimethylpropyl) In a sealed tube, a mixture of methyl 2 - chloro -6 -methyl - amino ) - 6 -methylpyridin - 4 - yl) (pyrrolidin - 1 - yl )methanone isonicotinate ( 300 mg) , 2 , 2 -dimethylpropan - 1 - amine (423 ( 105 mg) and 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopro mg) , palladium acetate (36 mg) , (9 ,9 -dimethyl - 9H -xan - 65 pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy thene - 4 , 5 - diyl ) bis ( diphenylphosphine) ( 94 mg) , sodium benzoic acid ( 100 mg) . tert- butoxide (233 mg) and toluene ( 1. 5 mL ) was stirred at MS (ESI + ): [ M + H ]+ 712 .4 . US 9 ,776 , 962 B2 161 162 Example 227 Step 4 ) 3 - cyclopropyl- 3 - ( 2 -( ( 1 -( 2 - ( ( 2 ,2 - dimethyl propyl) ( 1 -methyl - 2 -oxo - 1, 2 - dihydropyridin - 3 - yl) 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( (2 , 2 -dimethylpropyl ) ( 1 carbamoyl) -5 -methoxyphenyl ) piperidin -4 -yl ) methyl - 2 -oxo - 1 , 2 - dihydropyridin - 3 - yl) carbamoyl) methoxy )pyridin - 4 -yl ) propanoic acid 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 55 In the same manner as in Example 1 , step 4 , the title yl) propanoic acid compound (97 . 4 mg ) was obtained as a white amorphous powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 Step 1 ) 3 - ( ( 2 , 2 - dimethylpropyl ) amino ) pyridin - 2 ( ( 1 -methyl - 2 -oxo - 1 , 2 -dihydropyridin -3 - yl) (( 2 ,2 -dimethyl ( 1H ) -one 10 propyl) ) carbamoyl) phenyl ) piperidin - 4 - yl) methoxy ) pyridin 4 -yl ) propanoate ( 111 mg ). Under a nitrogen atmosphere, 2 ,2 -dimethylpropanoyl MS (ESI + ) : [ M + H ] * 631. 3 . chloride ( 1 . 29 mL ) was added to a solution of 2 -methoxy pyridin - 3 -amine ( 1 . 0 g ) in DMA ( 10 mL ) at room tempera Example 228 ture , and the mixture was stirred at room temperature for 30 15 min . To the reaction solution was added water at room temperature , and the mixture was extracted with ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( 2 , 2 - dimethylpropyl) ( 2 , 6 acetate . The extract was washed with water and saturated dimethylpyrimidin - 4 - yl) carbamoyl ) - 5 -methoxyphe brine , dried over anhydrous magnesium sulfate , and the nyl )piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic solvent was evaporated under reduced pressure . Under a 20 acid nitrogen atmosphere , the obtained residue was dissolved in THF. The solution was added to a suspension of lithium Step 1 ) N -( 2 ,2 -dimethylpropyl ) - 2 ,6 -dimethylpyrimi aluminum hydride in THF ( 20 mL ) at room temperature , and din - 4 -amine the mixture was heated under reflux for 2 hr. To the reaction solution were added water and aqueous sodium hydroxide 25 In a sealed tube , a mixture of 4 - chloro - 2 ,6 -dimethylpy solution , and the resulting precipitate was removed by rimidine ( 360 mg ) , 2 . 2 - dimethylpropan - 1 - amine ( 440 mg ) , filtration . The solvent in the filtrate was evaporated under triethylamine (511 mg) and NMP ( 0 . 3 mL ) was stirred at 70° reduced pressure , and the residue was purified by silica gel C . for 12 hr. To the reaction mixture was added water at column chromatography (ethyl acetate /hexane ) to give the room temperature, and the mixture was extracted with ethyl title compound ( 882 mg) as a pale - green solid . 30 acetate . The extract was washed with saturated brine , and ' H NMR ( 400 MHz, DMSO -do ) 8 0 . 93 ( 9H , s ), 2 .82 ( 2H , dried over anhydrous magnesium sulfate . The solvent was d , J = 6 . 1 Hz ), 5 .03 ( 1H , t , J = 5 . 8 Hz ) , 6 . 06 ( 1H , t, J = 6 . 8 Hz ), evaporated under reduced pressure , and the residue was 6 .25 ( 1H , d, J = 7. 0 Hz) , 6 .57 (1H , d , J= 6 .5 Hz) , 11 . 39 (1H , purified by silica gel column chromatography ( ethyl acetate / brs ) . hexane ) to give the title compound ( 405 mg) as a colorless 35 oil. Step 2 ) 3 -( (2 , 2 - dimethylpropyl) amino ) -1 -methyl ' H NMR (300 MHz, CDC1z ) 8 0 .98 ( 9H , s ), 2 .32 (3H , s ) , pyridin - 2 (1H ) - one 2 . 46 ( 3H , s ) , 3 .04 (2H , d , J = 6 . 1 Hz) , 4 .89 ( 1H , brs ) , 6 .02 (1H , s) . Under a nitrogen atmosphere, 1 , 1 '- ( azodicarbonyl ) dipip - 40 eridine ( 336 mg) and tributylphosphine (329 ?L ) were added Step 2 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - (( 2 , 2 - dimethyl to a solution of 3 - ( ( 2 , 2 - dimethylpropyl ) amino pyridin - 2 propyl) ( 2 ,6 -dimethylpyrimidin - 4 - yl) carbamoyl ) - 5 ( 1H ) -one ( 150 mg) and methanol ( 51 uL ) in toluene ( 10 mL ) methoxyphenyl) piperidin - 4 - yl) methoxy )pyridin - 4 at room temperature , and the mixture was stirred for 16 hr. yl) propanoic acid The reaction solution was diluted with ethyl acetate /hexane 45 ( 1 : 1 ) , and the resulting white precipitate was removed by In the samemanner as in Example 32 , step 2 and Example filtration . The solvent in the filtrate was evaporated under 1 , step 4 , the title compound ( 10 mg) was obtained as a reduced pressure , and the residue was purified by silica gel colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) column chromatography (ethyl acetate /hexane ) to give the 2 ,6 - dimethylpyrimidin - 4 - amine ( 190 mg) and 2 - [ 4 - ( ( ( 4 - ( 1 title compound ( 144 mg) as a green oil. 50 cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) pyridin -2 -yl ) oxy ) TH NMR ( 400 MHz, CDC1, ) 8 1 .00 ( 9H , s ), 2 .84 ( 2H , d , methyl) piperidin - 1 -yl ) -4 -methoxybenzoic acid (200 mg ). J = 5 . 9 Hz ), 3 .56 (3H , s ), 5 .13 (1H , brs ), 6 .07 -6 . 14 ( 1H , m ), MS (ESI + ) : [ M + H ]* 630 . 3 . 6 . 14 - 6 . 19 ( 1H , m ) , 6 .57 ( 1H , d , J = 5 . 6 Hz) . Example 229 Step 3 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 - methoxy - 2 55 ( ( 1- methyl - 2 -oxo - 1, 2 -dihydropyridin - 3 -yl ) ( ( 2, 2 3 -cyclopropyl - 3 - ( 2 - (( 1 - (2 -( ( 2, 2 -dimethylpropyl ) ( 2 dimethylpropyl) ) carbamoyl ) phenyl) piperidin -4 -yl ) methylpyrimidin -4 - yl) carbamoyl) -5 -methoxyphenyl ) methoxy )pyridin - 4 - yl) propanoate piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid In the same manner as in Example 32, step 2 , the title 60 In the samemanner as in Example 228 , step 1 and step 2 , compound (111 mg) was obtained as a white amorphous the title compound ( 8 mg) was obtained as a colorless powder from 2 - [ 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopro - amorphous powder from 4 -chloro - 2 -methylpyrimidine ( 200 pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxy mg) , 2 , 2 - dimethylpropan - 1 - amine (271 mg) and 2 - ( 4 - ( ( ( 4 benzoic acid (100 mg) and 3- (( 2, 2 -dimethylpropyl ) amino )- 65 (1 -cyclopropyl - 3 - ethoxy -3 -oxopropyl ) pyridin - 2- yl ) oxy ) 1 -methylpyridin - 2 ( 1H ) -one (55 .4 mg) . methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 200 mg) . MS ( ESI+ ) : [ M + H ] * 659. 6 . MS ( ESI + ) : [ M + H ] * 616 .3 . US 9 ,776 , 962 B2 163 164 Example 230 colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) 5 -methylpyridazin - 3 -amine (80 mg) and 2 - ( 4 - ( ( (4 - ( 1 - cyclo 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) (6 propyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) pip methylpyrimidin - 4 -yl ) carbamoyl ) - 5 -methoxyphenyl ) eridin - 1 - yl) - 4 -methoxybenzoic acid ( 200 mg) . piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 5 MS (ESI + ): [M + H ]* 616 .3 . In the same manner as in Example 228, step 1 and step 2 , Example 233 the title compound (102 mg) was obtained as a colorless amorphous powder from 4 -chloro -6 -methylpyrimidine (200 3 - cyclopropyl- 3 -( 2 -( ( 1 -( 2 -( ( 2, 2 -dimethylpropyl ) ( 1 mg) , 2 , 2 - dimethylpropan - 1 - amine ( 271 mg) and 2 - ( 4 - ( ( ( 4 - 0 ( 2 , 2 , 2 - trifluoroethyl) piperidin - 3 - yl) carbamoyl ) - 5 ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl ) oxy ) methoxyphenyl )piperidin - 4- yl )methoxy ) pyridin - 4 methyl) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 200 mg ). yl) propanoic acid MS (ESI + ) : [ M + H ] * 616 .3 . Step 1 ) benzyl 3 - oxopiperidine - 1 - carboxylate 15 Example 231 A mixture of piperidin - 3 -one hydrochloride (500 mg) , benzyl carbonochloridate ( 1. 58 mL ) , triethylamine (2 .57 3 -cyclopropyl - 3 - ( 2 - ( 1 - ( 2 -( ( 2 , 2 -dimethylpropyl ) ( 5 mL ) , THF ( 15 mL ) and pyridine ( 5 mL ) was stirred at 60° methylpyridin - 3 - yl ) carbamoyl) - 5 -methoxyphenyl ) C . for 30 min . The solvent was evaporated under reduced piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid 20 pressure , and the residue was purified by silica gel column chromatography ( ethyl acetate /hexane ) to give the title com Step 1 ) pound (770 mg ) as a mixture with benzyl alcohol. N - ( 2 , 2 - dimethylpropyl) - 5 -methylpyridin - 3 - amine IH NMR ( 300 MHz, CDC13 ) & 1 . 90 - 2 . 07 (2H , m ) , 2 . 48 (2H , t, J = 6 . 7 Hz) , 3 . 58 - 3 .72 ( 2H , m ) , 4 . 08 ( 2H , s ), 5 . 15 ( 2H , In the same manner as in Example 32 , step 1 , the title 25 s ) . 7 . 27 - 7 . 44 (5H , m ) . compound (529 mg) was obtained as a pale -yellow solid from 5 -methylpyridin - 3 - amine (500 mg ) . Step 2 ) benzyl 3 - (( tert -butoxycarbonyl )( 2 , 2 - dimeth MS (ESI + ) : [ M + H ] * 179. 1 . ylpropyl) amino ) piperidine- 1 - carboxylate Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl 30 A crude purified product (770 mg) of benzyl 3 - oxopip propyl) ( 5 -methylpyridin - 3 - yl) carbamoyl) - 5 eridine - 1 -carboxylate , 2 , 2 -dimethylpropan - 1 -amine (643 methoxyphenyl) piperidin - 4 - yl) methoxy )pyridin - 4 mg ) and acetic acid ( 0 . 5 mL ) were dissolved in THF ( 10 yl) propanoic acid mL ) , and sodium triacetoxyborohydride ( 1563 mg ) was added at room temperature . The mixture was stirred at room In the same manner as in Example 32 , step 2 and Example 35 temperature for 1 hr, to the reaction mixture was added water 1 , step 4 , the title compound (72 .3 mg ) was obtained as a at room temperature, and the mixture was extracted with ethyl acetate . The extract was washed with saturated brine , pale -yellow oil from 2 - (4 - (( ( 4 - 1 -cyclopropyl - 3 -ethoxy - 3 dried over anhydrous magnesium sulfate , and the solvent oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 -yl ) - 4 was evaporated under reduced pressure . The obtained resi methoxybenzoic acid ( 379 mg) and N - ( 2 , 2 - dimethylpropyl) 40 due was dissolved in THF ( 10 mL ) , di - tert- butyl dicarbonate 5 - methylpyridin - 3 -amine (70 mg) . ( 1610 mg) and triethylamine ( 2 .57 mL ) were added at room MS (ESI + ): [ M + H ] * 615 . 3 . temperature , and the mixture was stirred at 60° C . for 6 hr. The solvent was evaporated under reduced pressure , and the Example 232 residue was purified by silica gel column chromatography 45 ( ethyl acetate /hexane ) to give the title compound (690 mg ) 3 -cyclopropyl - 3 - (2 - ( (1 -( 2 -( ( 2 ,2 -dimethylpropyl ) (5 as a colorless oil . methylpyridazin - 3 - yl) carbamoyl) - 5 -methoxyphenyl ) IH NMR (300 MHz, CDC1 , ) 0 .89 ( 9H , brs ) , 1 . 31 - 1 .53 piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid ( 10H , m ), 1 .66 - 1 . 95 ( 2H , m ) , 2 . 10 - 3 . 82 (6H , m ), 3 . 99 - 4 . 27 ( 2H , m ) , 4 .99 - 5 . 22 (2H , m ), 7 . 28 - 7 . 41 (5H , m ) . Step 1 ) 50 N - ( 2 , 2 -dimethylpropyl ) - 5 -methylpyridazin - 3 - amine Step 3 ) N -( 2 ,2 - dimethylpropyl) - 1 -( 2 ,2 , 2 -trifluoro ethyl) piperidin - 3 - amine dihydrochloride In the same manner as in Example 225 , step 1 , the title compound ( 110 mg) was obtained as a pale - yellow solid Under a hydrogen atmosphere , a solution of benzyl from 3 -chloro -5 -methylpyridazine (200 mg) and 2 , 2 -dim - 55 3 -( ( tert -butoxycarbonyl ) ( 2 ,2 -dimethylpropyl ) amino )piperi ethylpropan - 1 -amine ( 271 mg) . dine - 1 -carboxylate (690 mg) and 10 % palladium carbon H NMR ( 300 MHz, CDC12 ) 8 1. 00 ( 9H , s ) , 2 .23 ( 3H , d , (55 % water- containing , 403 mg ) in methanol ( 10 mL ) was J = 0. 4 Hz ), 3 . 16 (2H , d , J= 6 .2 Hz) , 4 .74 ( 1H , brs ), 6 .44 ( 1H , stirred at room temperature for 2 hr. The reaction mixture d , J = 0 . 8 Hz) , 8 . 38 (1H , d , J = 1 .6 Hz ) . was filtered through celite , and the filtrate was concentrated 60 under reduced pressure . The obtained residue was dissolved Step 2 ) 3 - cyclopropyl- 3 - (2 -( ( 1- (2 - (( 2, 2 -dimethyl in THF ( 5 mL ) , 2 , 2 , 2 - trifluoroethyl trifluoromethanesul propyl) ( 5 -methylpyridazin - 3 - yl) carbamoyl) - 5 fonate (594 mg) and triethylamine ( 0 .475 mL ) were added , methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 and the mixture was stirred at 60° C . for 3 hr. To the reaction yl) propanoic acid mixture was added saturated aqueous sodium hydrogen 65 carbonate solution at room temperature , and the mixture was In the samemanner as in Example 32 , step 2 and Example extracted with ethyl acetate . The extract was washed with 1 , step 4 , the title compound (64 mg) was obtained as a saturated brine, dried over anhydrous magnesium sulfate , US 9 ,776 , 962 B2 165 166 and the solvent was evaporated under reduced pressure. The Example 235 obtained residue was dissolved in methanol ( 5 mL ) , 4N hydrogen chloride ethyl acetate solution ( 2 . 56 mL ) was 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 , 2 -dimethylpropyl ) ( 5 added , and the mixture was stirred at room temperature ( trifluoromethyl) pyridin - 3 - yl) carbamoyl) - 5 overnight. The solvent was evaporated under reduced pres - 5 methoxyphenyl )piperidin -4 - yl )methoxy ) pyridin -4 sure, the residue was suspended in methanol, ethyl acetate yl) propanoic acid and hexane , and the resulting precipitate was collected by Step 1 ) N - ( 2 , 2 - dimethylpropyl ) - 5 - ( trifluoromethyl) filtration . The obtained solid was dried under reduced pres pyridin - 3 - amine sure to give the title compound (474 mg) as a colorless solid . IH NMR ( 300 MHz, DMSO -d .) 8 1 .01 ( 9H , s) , 1 .38 - 1. 62 1010 In the same manner as in Example 45 , step 8 , the title compound ( 7 mg) was obtained as a pale -yellow solid from (2H , m ), 1. 66 -1 .84 ( 1H , m ) , 2 .01 -2 . 19 (1H , m ), 2. 31 - 2. 47 2 , 2 -dimethylpropan - 1 - amine ( 272 uL ) and 3 - chloro - 5 - ( trif ( 1H , m ), 2 .59 -2 . 96 (4H , m ), 3 .05 - 3 .25 ( 1H , m ), 3. 27 - 3. 46 luoromethyl) pyridine ( 84 mg) . (3H , m ) , 8 . 28 - 9 . 90 ( 3H , m ) . 15 MS ( ESI + ) : [ M + H ] * 233. 1 . Step 4 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl propyl) ( 1 -( 2 , 2 , 2 -trifluoroethyl ) piperidin - 3 - yl) car propyl) (5 -( trifluoromethyl ) pyridin - 3 - yl) carbamoyl) bamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl)methoxy ) 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 pyridin - 4 - yl ) propanoic acid yl) propanoic acid 20 In the samemanner as in Example 32 , step 2 and Example In the same manner as in Example 32 , step 2 and Example 1 , step 4 , the title compound ( 6 mg) was obtained as a 1 , step 4 , the title compound ( 120 mg) was obtained as a pale- yellow oil from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 colorless amorphous powder from N -( 2 , 2 - dimethylpropyl) - oxopropylpyridin - 2 -yl oxymethylpiperidin - 1 -yl ) -4 1 - ( 2 , 2 , 2 - trifluoroethyl ) piperidin - 3 - amine dihydrochloride125 25 methoxybenzoic acid ( 22 mg) and N - ( 2 , 2 - dimethylpropyl) ( 150 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro 5 -( trifluoromethyl) pyridin - 3 -amine (7 mg) . pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy MS (ESI + ) : [ M + H ] * 669 . 3 . benzoic acid (200 mg) . Example 236 MS (ESI + ): [ M + H ]* 689. 3 . 30 3 - cyclopropyl- 3 -( 2 - ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , 2 - trifluo roethyl) ( 5 - ( trifluoromethyl) pyridin - 3 - yl) carbamoyl) Example 234 phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 -yl ) pro panoic acid 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - (( 2 , 2 -dimethylpropyl ) ( 3 - 35 Step 1 ) N - ( 2 , 2 , 2 - trifluoroethyl) - 5 - ( trifluoromethyl ) fluoro -6 -methylpyridin -2 -yl ) carbamoyl )- 5 -methoxy pyridin -3 -amine phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro panoic acid In the same manner as in Example 225 , step 1 , the title compound (89 mg ) was obtained as a pale - yellow solid from 40 2 , 2 ,2 - trifluoroethanamine ( 98 uL ) and 3 - chloro - 5 - ( trifluo Step 1 ) N - ( 2 , 2 -dimethylpropyl ) - 3 - fluoro - 6 -methyl romethyl) pyridine ( 114 mg ) . pyridin - 2 -amine MS (ESI + ) : [ M + H ] * 245 . 1 . Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 2 , 2 , In a sealed tube, a mixture of 2 - chloro - 3 - fluoro -6 -meth 2 -trifluoroethyl ) ( 5 - ( trifluoromethyl) pyridin - 3 - yl) ylpyridine (225 mg) and 2, 2 -dimethylpropan - 1 -amine (0 . 5 45 carbamoyl) phenyl) piperidin - 4 - yl) methoxy )pyridin mL ) was stirred at 130° C . for 40 hr. The reaction mixture 4 -yl ) propanoic acid was allowed to cool to room temperature , and purified by silica gel column chromatography ( ethyl acetate /hexane ) to In the samemanner as in Example 32 , step 2 and Example give the title compound ( 90 mg) as a pale -yellow oil . 1 , step 4 , the title compound ( 28 mg) was obtained as a 50 pale -yellow solid from 2 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy ' H NMR ( 300 MHz, CDC13 ) 8 0 . 97 ( 9H , s ), 2 . 34 ( 3H , s ), 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl ) - 4 3 . 32 (2H , d , J = 6 . 1 Hz ), 4 .51 (1H , brs ), 6 .27 ( 1H , dd , J= 7 . 8 , methoxybenzoic acid ( 103 mg) and N - ( 2 ,2 -dimethylpropyl ) 3 . 0 Hz) , 6 . 97 ( 1H , dd , J = 11. 3 , 7 . 8 Hz ) . 5 -( trifluoromethyl) pyridin - 3 -amine (52 mg) . MS (ESI + ): [ M + H ]* 681. 2 . Step 2 ) 3 -cyclopropyl - 3 - (2 - (( 1 - ( 2 - ( 2 , 2 -dimethyl 55 propyl) ( 3 - fluoro -6 -methylpyridin - 2 - yl) carbamoyl) Example 237 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 3 - cyclopropyl - 3 - ( 2 - (( 1 - ( 2 - ( ( cyclopropylmethyl) ( 4 yl) propanoic acid (trifluoromethyl ) pyrimidin -2 -yl ) carbamoyl ) - 5 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 In the same manner as in Example 32 , step 2 and Example 60 1 , step 4 , the title compound ( 102 mg ) was obtained as a yl) propanoic acid colorless amorphous powder from N -( 2 ,2 -dimethylpropyl ) Step 1 ) N - ( cyclopropylmethyl ) - 4 - ( trifluoromethyl ) 3 - fluoro - 6 -methylpyridin - 2 - amine ( 90 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 pyrimidin - 2 - amine cyclopropyl - 3 - ethoxy - 3 -oxopropyl )pyridin - 2 - yl) oxy ) 65 methyl) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 200 mg) . To a solution of 2 -chloro - 4 - ( trifluoromethyl) pyrimidine MS (ESI + ) : [ M + H ] * 633 . 3 . ( 300 mg) in THF ( 2 mL ) was added 1- cyclopropylmethan US 9 , 776 , 962 B2 167 168 amine (351 mg) at room temperature . The mixture was H NMR ( 300 MHz , CDC1z ) 8 2 . 53 ( 3H , s ), 4 . 14 (2H , qd , stirred at room temperature for 2 days, and the reaction J = 8 . 9 , 6 . 8 Hz) , 4 . 89 ( 1H , brs ), 6 . 27 (1H , d , J = 5 . 9 Hz ), 8 . 18 mixture was purified by silica gel column chromatography ( 1H , d , J = 5 . 9 Hz ) . ( ethyl acetate / hexane) to give the title compound ( 330 mg) Step 2 ) 3 - cyclopropyl- 3 -( 2 - ( ( 1 - (5 -methoxy - 2 - ( ( 2 as a colorless oil . methylpyrimidin - 4 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbam 'H NMR (300 MHz , CDC1z ) 8 0 .22 - 0 .32 (2H , m ), 0 .49 oyl) phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) 0 .60 (2H , m ), 1. 00 - 1. 17 (1H , m ), 3 .31 (2H , dd , J = 7 .1 , 5 .5 propanoic acid Hz ), 5 .51 ( 1H , brs ), 6 . 80 ( 1H , d , J = 4 . 9 Hz ), 8 . 47 (1H , d , J = 4 .6 Hz ). In the samemanner as in Example 32, step 2 and Example 1 1 , step 4 , the title compound ( 16 mg) was obtained as a Step 2 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 2 - (( cyclopropylm colorless amorphous powder from 2 -methyl - N - ( 2 , 2 , 2 - trif ethyl) ( 4 - (trifluoromethyl ) pyrimidin - 2 - yl) carbam luoroethyl) pyrimidin - 4 - amine (40 mg) and 2 - (4 - ( ( ( 4 - ( 1 - cy oyl ) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy )pyri clopropyl- 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) din - 4 - yl) propanoic acid piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 200 mg) . 15 MS ( ESI + ) : [ M + H ]* 626 . 1 . In the samemanner as in Example 32 , step 2 and Example 1 , step 4 , the title compound (25 mg) was obtained as a Example 240 colorless amorphous powder from N - (cyclopropylmethyl ) 4 - ( trifluoromethyl) pyrimidin - 2 -amine ( 180 mg) and 2 - ( 4 3 - cyclopropyl- 3 - ( 2 - ( 1 - ( 5 -methoxy - 2 - ( 6 -methylpy ( ( ( 4 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) 20 rimidin - 4 -yl ) ( 2 ,2 ,2 - trifluoroethyl) carbamoyl )phenyl ) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 200 piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid mg) . Step 1 ) MS (ESI + ): [M + H ]* 654. 3 . 6 -methyl -N - (2 , 2, 2 -trifluoroethyl ) pyrimidin -4 - amine Example 238 25 In the same manner as in Example 225 , step 1 , the title compound ( 145 mg) was obtained as a pale - orange solid 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 ,6 - dimethylpyrimidin from 4 -chloro -6 -methylpyrimidine (200 mg ) and 2 ,2 ,2 -trif 4 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) - 5 -methoxyphe luoroethanamine (462 mg ) . nyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic ' H NMR (300 MHz, CDC1z ) 8 2 . 53 ( 3H , s ), 4 . 14 ( 2H , qd , acid 30 J = 8 . 9 , 6 . 8 Hz) , 4 . 89 ( 1H , brs ), 6 .27 (1H , d , J = 5 . 9 Hz) , 8 . 18 (1H , d , J = 5 .9 Hz ). Step 1) 2 ,6 -dimethyl - N -( 2 ,2 ,2 - trifluoroethyl) pyrimi din - 4 - amine Step 2 ) 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 -( (6 methylpyrimidin - 4 - yl) ( 2 , 2 , 2 -trifluoroethyl ) carbam In the same manner as in Example 225 , step 1 , the title 35 oyl) phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) compound ( 75 mg) was obtained as a pale -orange solid from propanoic acid 4 - chloro - 2 ,6 - dimethylpyrimidine ( 200 mg) and 2 , 2 , 2 - trif luoroethanamine (417 mg) . In the same manner as in Example 32 , step 2 and Example ' H NMR ( 300 MHz, CDC13 ) 8 2 .34 (3H , s) , 2 .51 (3H , s) , 1, step 4 , the title compound (70 mg) was obtained as a 4 . 11 (2H , qd , J= 9 .0 , 6 .9 Hz ), 4 .84 ( 1H , brs) , 6 .13 (1H , s ). 40 colorless amorphous powder from 6 -methyl - N -( 2, 2 ,2 -trif luoroethyl) pyrimidin - 4 -amine (75 mg) and 2 - ( 4 -( (( 4 -( 1 - cy Step 2 ) 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 ,6 - dimethylpy clopropyl- 3 -ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl ) rimidin - 4 -yl ) ( 2 , 2 , 2 - trifluoroethyl) carbamoyl) - 5 piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 200 mg) . methoxyphenyl )piperidin - 4- yl )methoxy ) pyridin - 4 MS ( ESI + ): [ M + H ]* 626 .1 . yl) propanoic acid 45 Example 241 In the samemanner as in Example 32, step 2 and Example 1 , step 4 , the title compound (47 mg) was obtained as a 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( 6 -methyl colorless amorphous powder from 2 ,6 - dimethyl- N - ( 2 , 2 , 2 pyridin - 2 - yl ) carbamoyl) phenyl) piperidin -4 -yl ) trifluoroethyl) pyrimidin - 4 - amine ( 75 mg) and 2 - ( 4 - ( (( 4 - ( 1 - 50 methoxy )pyridin - 4 - yl) propanoic acid cyclopropyl- 3 - ethoxy - 3 - oxopropylpyridin - 2 - yl ) oxy ) methyl) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 200 mg) . In the samemanner as in Example 32 , step 2 and Example MS ( ESI + ) : [M + H ] * 640 .3 . 1 , step 4 , the title compound ( 132 mg) was obtained as white crystals from 2 - amino -6 -methylpyridine ( 76 mg) and 2 - ( 4 Example 239 55 (( ( 4 -( 1 -cyclopropyl - 3 -ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 170 3 - cyclopropyl- 3 - (2 - (( 1 -( 5 -methoxy - 2 -( (2 -methylpy mg) . rimidin - 4 -yl ) ( 2 , 2 , 2 -trifluoroethyl ) carbamoyl) phenyl ) MS (ESI + ) : [ M + H ] * 545 .2 . piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoic acid 60 Example 242 Step 1 ) 2 -methyl - N - ( 2 , 2 , 2 - trifluoroethyl )pyrimidin - 4 - amine 3 - cyclopropyl- 3 - ( 2 -( 1 - ( 5 -methoxy - 2 - (pyridin - 2 ylcarbamoyl) phenyl) piperidin - 4 - yl) methoxy )pyridin In the same manner as in Example 225 , step 1 , the title 4 - yl) propanoic acid compound ( 40 mg) was obtained as a pale - orange solid from 65 4 -chloro - 2 -methylpyrimidine (200 mg) and 2 , 2 , 2 - trifluo In the samemanner as in Example 32 , step 2 and Example roethanamine (462 mg) . 1 , step 4 , the title compound ( 106 mg) was obtained as white US 9 ,776 , 962 B2 169 170 crystals from 2 - aminopyridine (66 mg) and 2 - ( 4 - ( ( ( 4 - ( 1 aminomethylcyclopropane ( 241 ul) and 2 , 4 - dimethylpyri cyclopropyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 -yl ) oxy ) dine 1 -oxide (273 . 7 mg) . methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 170 mg) . MS ( ESI + ) : [ M + H ] * 177 . 1 . MS ( ESI + ) : [ M + H ] * 531 . 2 . Step 2 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopropylm 5 ethyl) ( 4 ,6 - dimethylpyridin - 2 - yl) carbamoyl) - 5 Example 243 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 3 -cyclopropyl - 3- (2 - (( 1 -( 2- (( 2, 2 -dimethylpropyl ) ( 4, 6 yl) propanoic acid dimethylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphenyl ) By a method similar to that in Example 243 , step 2 and piperidin -4 -yl )methoxy )pyridin -4 - yl) propanoic acid Example 1, step 4 , the title compound (153 mg) was obtained as a white amorphous powder from 2 -( 4 - (( ( 4 -( 1 Step 1 ) cyclopropyl- 3 - ethoxy - 3 - oxopropyl )pyridin - 2 -yl ) oxy ) N - ( 2 , 2 -dimethylpropyl ) - 4 ,6 -dimethylpyridin - 2 - amine methyl) piperidin - 1 - yl) -4 -methoxybenzoic acid ( 159. 7 mg) and N - ( cyclopropylmethyl) - 4 , 6 - dimethylpyridin - 2 - amine By a method similar to that in Example 135, step 1 , the 15 (70 .0 mg) . title compound ( 160 mg) was obtained as a pale -yellow oil MS (ESI +) : [M + H ]* 613 .3 . from 2 , 2 - dimethylpropan - 1 - amine (313 ul) and 2 , 4 - dimeth ylpyridine 1 - oxide ( 262 . 4 mg) . Example 245 MS (ESI + ) : [ M + H ] * 193 . 1 . 20 ( 3S )- 3 - cyclopropyl- 3 -( 2 -( (1 -( 2 -( ( 2 ,2 -dimethylpro pyl) (6 -methylpyridin - 2 - yl) carbamoyl ) - 5 -methoxy Step 2 ) ethyl 3 - cyclopropyl- 3 - (2 - ( (1 -( 2 -( (2 , 2 -dim phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) pro ethylpropyl) ( 4 ,6 -dimethylpyridin -2 - yl) carbamoyl) -5 panoic acid methoxyphenyl )piperidin - 4- yl )methoxy ) pyridin - 4 yl) propanoate 25 Step 1 ) tert -butyl 4 - ( ( ( 4 -cyanopyridin - 2 -yl ) oxy ) 25 methyl) piperidine - 1 - carboxylate Under a nitrogen atmosphere , to a solution of 2 - ( 4 - (( ( 4 To a solution of tert - butyl 4 - (hydroxymethyl ) piperidine ( 1 - cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy ) 1 -carboxylate (4 .27 kg ) in DMF ( 14 L ) was added 60 % methyl) piperidin - 1 -yl ) - 4 -methoxybenzoic acid ( 158 . 6 mg ) sodium hydride (oily ) ( 936 g ) at 0° C ., and the mixture was in toluene (657 ul) was added 1 - chloro - N , N - 2 - trimethylpro - 30 stirred at 0° C . for 40 min . To the reaction solution was pylamine ( 47 . 8 ul) at 0° C . The mixture was stirred at room added a solution of 2 - chloroisonicotinonitrile ( 2 . 50 kg) in temperature for 3 hr, a solution of 4 , 6 - dimethyl- N - ( 2 , 2 DMF ( 6 . 0 L ) , and the mixture was stirred at 0° C . for 2 hr. dimethylpropyl) pyridin - 2 - amine ( 76 mg) in toluene (657 ul ) The reaction mixture was diluted with ethyl acetate , water and triethylamine ( 55 . 0 ul) were added at room temperature , was added , and the mixture was extracted with ethyl acetate . and the mixture was stirred at 100° C . for 2 hr. The reaction 35 The extract was washed with saturated brine , and dried over anhydrous sodium sulfate . The solvent was evaporated mixture was cooled to room temperature , the solvent was under reduced pressure , and the obtained white solid was evaporated under reduced pressure , and the residue was washed with petroleum ether, and dried to give the title purified by silica gel column chromatography (NH , ethyl compound ( 4 . 20 kg) as a white solid . acetate /hexane ) to give the title compound (184 mg) as a 40 H NMR (300 MHz , CDC1, ): 8 1 . 26 ( 2H , qd , J = 12 . 3 , 4 . 5 colorless oil . Hz) , 1 .46 ( 9H , s ) , 1 . 79 ( 2H , d , J = 12 . 6 Hz ), 1 . 85 - 2 .09 ( 1H , MS (ESI + ) : [ M + H ] * 657. 6 . m ) , 2 .74 (2H , t , J = 12 . 1 Hz) , 4 . 13 (2H , brs. ) , 4 . 19 (2H , d , J = 6 . 3 Hz ) , 6 . 98 ( 1H , t, J = 1 . 2 Hz) , 7 .06 ( 1H , dd , J = 5 . 1 , 1 . 2 Step 3 ) 3 - cyclopropyl -3 - ( 2 -( ( 1 -( 2 -( ( 2 , 2 -dimethyl Hz) , 8 .28 ( 1H , dd , J= 5 .1 , 0 . 8 Hz ). propyl) ( 4 ,6 - dimethylpyridin - 2 -yl ) carbamoyl ) -5 methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 45 Step 2 ) tert -butyl 4 - ( ( ( 4 - (cyclopropylcarbonyl ) pyri yl) propanoic acid din - 2 -yl ) oxy )methyl ) piperidine - 1 -carboxylate A solution of tert -butyl 4 - (( ( 4 -cyanopyridin - 2 -yl ) oxy ) By a method similar to that in Example 1 , step 4 , the title methyl) piperidine - 1 - carboxylate ( 4 .00 kg ) in THF ( 15 L ) compound ( 167 mg ) was obtained as a white amorphous 50 was added dropwise to a 1 M solution of cyclopropylmag powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth nesium bromide in THF ( 22. 7 L ) at room temperature , and ylpropyl) ( 4 , 6 -dimethylpyridin - 2 -yl ) carbamoyl ) - 5 -methoxy the mixture was stirred at room temperature for 2 hr. To the phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoate reaction mixture was carefully added IN hydrochloric acid ( 183 . 8 mg) . at 10° C . or lower, and the mixture was extracted with ethyl MS (ESI + ) : [ M + H ] * 629. 4 . 55 acetate . The extract was washed with water and saturated brine , and dried over anhydrous sodium sulfate . The solvent Example 244 was evaporated under reduced pressure to give a crude product ( 4 .50 kg ) of the title compound as a brown oil . This 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( cyclopropylmethyl) ( 4 , 6 compound was used for the next step without further puri dimethylpyridin - 2 -yl ) carbamoyl) - 5 -methoxyphenyl ) 60 fication . piperidin - 4 - yl )methoxy )pyridin - 4 - yl) propanoic acid Step 3 ) tert -butyl 4 -( ( ( 4 -( ( 1E ) - 1 -cyclopropyl - 3 Step 1) ethoxy - 3 -oxoprop - 1 -en - 1 - yl) pyridin - 2 -yl ) oxy ) N - (cyclopropylmethyl ) - 4 ,6 -dimethylpyridin -2 - amine methyl) piperidine - 1 - carboxylate 65 By a method similar to that in Example 135 , step 1 , the Ethyl diethylphosphonoacetate ( 4 . 95 kg ) was added to a title compound (150 mg) was obtained as a yellow oil from suspension of 60 % sodium hydride (oily ) (888 g ) in THF ( 15 US 9 ,776 ,962 B2 171 172 L ) at 0° C ., and the mixture was stirred for 30 min . To the ( 870 g ) in ethanol ( 5 .4 L ) was added dropwise a solution of reaction solution was added a solution of a crude product ( S ) - 1 - (p - tolyl) ethanamine ( 291 g ) in ethyl acetate ( 11 L ) at ( 4 . 00 kg) of tert- butyl 4 - ( ( ( 4 - cyclopropylcarbonyl )pyridin room temperature, and the mixture was stirred in dry air at 2 - yl) oxy )methyl ) piperidine - 1 - carboxylate in THF ( 15 L ), room temperature for 17 hr. The resulting white precipitate and the mixture was stirred at 80° C . for 3 hr. The reaction 5 solution was poured into saturated aqueous ammonium was collected by filtration , washed with ethyl acetate / etha chloride solution ( 15 L ), and the mixture was extracted with nol ( 2 : 1 , 2 . 4 L ) , and dried to give crude crystals (477 g ) of ethyl acetate . The extract was washed with saturated brine , the title compound . The obtained crude crystals ( 237 g ) were and dried over anhydrous sodium sulfate . The solvent was dissolved in ethanol ( 3 . 1 L ) at 70° C . , and heptane ( 4 . 7 L ) evaporated under reduced pressure to give a crude product was added dropwise at 60 -65° C . Seed crystals were added , (4 . 50 kg ) of the title compound as a brown oil . This and the mixture was stirred at 50° C . for 1 . 5 hr and at room compound was used for the next step without further puri- temperature for 12 hr. The resulting white solid was col fication . lected by filtration , washed with ethanol/heptane ( 1 : 2 ) , and dried to give the title compound as crude crystals ( 182 g ) . Step 4 ) tert -butyl 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 Crude crystals ( 372 g ) of the title compound were obtained oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidine - 1 - 15 in the same manner and dissolved in ethanol (4 . 8 L ) at 70° carboxylate C . Heptane (7 . 4 L ) was added dropwise at 60 -65° C ., seed crystals were added , and the mixture was stirred at 50° C . for Zinc powder ( 3 .97 kg ) was added in several portions to a 1 . 5 hr, at room temperature for 12 hr, and under ice - cooling solution of tert- butyl 4 - ( ( ( 4 - ( ( 1E ) - 1 - cyclopropyl - 3 - ethoxy - for 1 hr. The resulting white solid was collected by filtration , 3 -oxoprop - 1 -en - 1 - yl )pyridin - 2 -yl ) oxy )methyl ) piperidine - 1 - 20 washed with ethanol/ heptane ( 1 : 2 ), and dried to give the title carboxylate ( 4 .40 kg ) in acetic acid ( 20 L ) at room tempera compound (340 g ) . ture , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered , and the solvent was Step 7 ) (3S )- 3 -( 2 - (( 1 -( tert -butoxycarbonyl ) piperi evaporated under reduced pressure . The residue was basified din - 4 - yl) methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpro with saturated aqueous sodium hydrogen carbonate solution , 25 panoic acid and the mixture was extracted with ethyl acetate . The extract was washed with saturated aqueous sodium hydrogen car To a suspension of (1R )- 1 - (4 -methylphenyl ) ethan bonate solution and saturated brine, and dried over anhy aminium (3S ) - 3 - ( 2 - ( ( 1 - ( tert- butoxycarbonyl ) piperidin - 4 - yl) drous sodium sulfate . The solvent was evaporated under methoxy )pyridin - 4 - yl) - 3 -cyclopropylpropanoate ( 190 g ) in reduced pressure , and the residue was purified by silica gel 30 ethyl acetate ( 1 . 9 L ) was added dropwise 1N hydrochloric column chromatography ( ethyl acetate /hexane ) to give the acid ( 1 . 9 L ) at 0° C . , and the mixture was stirred at room title compound ( 2 .60 kg ) as a pale - yellow oil . temperature for 1 hr. Ethyl acetate / THF ( 1 : 1 , 1 . 0 L ), ethyl ' H NMR ( 300 MHz, CDC12 ) : 8 0 . 17 ( 1H , dt, J = 9 . 6 , 4 . 8 acetate / THF ( 1 : 1 , 1 . 0 L ) and sodium chloride (500 g ) were Hz) , 0 .28 ( 1H , dt, J = 9 .6 , 4 . 8 Hz) , 0 .39 - 0 .52 (1H , m ), added and the mixture was extracted . The extract was added 0 .54 -0 .66 (1H , m ), 0 . 94 - 1. 08 (1H , m ), 1 .15 - 1 .22 (3H , m ), 35 to saturated brine (1 . 0 L ) and sodium chloride ( 30 g ) and the 1 . 27 - 1 . 35 (2H , m ), 1 .46 ( 9H , s ) , 1 .81 ( 2H , d , J = 12 . 0 Hz) , mixture was washed with iN hydrochloric acid , and dried 1 .88 - 2 .01 ( 1H , m ) , 2 . 30 ( 1H , dt , J = 9 . 6 , 7 . 5 Hz) , 2 . 58 - 2 . 84 over anhydrous magnesium sulfate . The solvent was evapo (4H , m ) , 4 . 02 - 4 . 10 (2H , m ) , 4 . 10 - 4 . 23 (4H , m ) , 6 . 58 - 6 .62 rated under reduced pressure to give a crude product ( 162 g ) ( 1H , m ), 6 .76 (1H , dd , J = 5 . 4 , 1 . 5 Hz) , 7 . 86 - 8 . 16 (1H , m ). of the title compound as a white solid . This compound was 40 used for the next step without further purification . Step 5 ) 3 -( 2 -( ( 1 - ( tert -butoxycarbonyl ) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) - 3 -cyclopropylpropanoic acid Step 8 ) ethyl( 3S ) - 3 - cyclopropyl- 3 - ( 2 - ( piperidin - 4 ylmethoxy )pyridin - 4 -yl ) propanoate To a solution of tert- butyl 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 ethoxy - 3 - oxopropyl )pyridin - 2 - yl ) oxy )methyl ) piperidine - 1 - 45 To a solution of the crude product ( 162 g ) of ( 3S ) - 3 -( 2 carboxylate ( 2 . 50 kg ) in methanol ( 12 L ) was added 4N ( ( 1 - tert - butoxycarbonyl) piperidin - 4 - yl) methoxy )pyridin - 4 aqueous sodium hydroxide solution ( 5 . 8 L ) at room tem yl) - 3 -cyclopropylpropanoic acid in ethanol (1 . 6 L ) was perature , and the mixture was stirred at room temperature for added conc . sulfuric acid (39 . 0 mL ) at room temperature , 2 hr. The solvent was evaporated under reduced pressure and the mixture was stirred at 80° C . for 1 hr. The reaction and the residue was dissolved in water and extracted with 50 solution was neutralized with 2N aqueous sodium hydroxide diethyl ether . The aqueous layer was acidified (pH = 4 - 5 ) with solution ( 293 mL ) under ice - cooling and the solvent was IN hydrochloric acid , and the resulting solid was collected evaporated under reduced pressure . The residue was dis by filtration , washed with petroleum ether and dried to give solved in ethyl acetate / THF ( 1 : 1 , 1 .0 L ) and water ( 250 mL ), the title compound ( 2 . 10 kg ) as a white solid . and basified with 2N aqueous sodium hydroxide solution H NMR ( 300 MHz , CDC12 ) : 8 0 . 12 - 0 . 20 ( 1H , m ) , 55 ( 147 mL ) . Sodium chloride ( 300 g ) was added , the mixture 0 .30 -0 .34 ( 1H , m ), 0 .41 -0 .51 ( 1H , m ), 0 .56 -0 .65 (1H , m ), was extracted twice with ethyl acetate / THF ( 1: 1 , 1 .0 L ) , and 0 . 95 - 1 . 01 ( 1H , m ) , 1 . 18 - 1 . 32 ( 2H , m ) , 1 . 46 ( 9H , s ) , 1 . 77 - the extract was dried over anhydrous magnesium sulfate . 1 . 82 ( 2H , m ), 1 . 91 - 1 . 98 ( 1H , m ) , 2 .28 ( 1H , dd , J = 17 . 1 , 7 . 5 The solvent was evaporated under reduced pressure to give Hz) , 2 .69 - 2 .84 (4H , m ), 4 . 10 - 4 . 13 (4H , m ), 6 .61 ( 1H , 2 ) , a crude product ( 145 g ) of the title compound as a pale 6 .75 ( 1H , dd , J = 5 . 4 , 1 . 2 Hz) , 8 . 04 ( 1H , d , J = 5 . 4 Hz) . 60 yellow oil. This compound was used for the next step without further purification . Step 6 ) ( 1R ) - 1 - ( 4 -methylphenyl ) ethanaminium (3S ) - 3 - ( 2 - ( ( 1 - tert- butoxycarbonyl ) piperidin - 4 -yl ) Step 9 ) methoxy) pyridin - 4 - yl) - 3 - cyclopropylpropanoate 2 , 2 -dimethyl -N -( 6 -methylpyridin -2 -yl ) propanamide 65 To a solution of 3 -( 2 - (( 1 - tert -butoxycarbonyl ) piperidin - Under a nitrogen atmosphere , to a solution of 6 -methyl 4 -yl ) methoxy )pyridin -4 -yl ) - 3 -cyclopropylpropanoic acid pyridin - 2- amine (50 . 0 g ) in DMA (240 mL ) was added US 9 ,776 , 962 B2 173 174 dropwise 2 , 2 -dimethylpropanoyl chloride (83 . 6 g ) at 20° C . pyl) - 2 - fluoro - 4 -methoxy - N - (6 -methylpyridin - 2 -yl ) and the mixture was stirred at room temperature for 5 hr. To benzamide ( 12 . 0 g ) and cesium carbonate ( 17 . 8 g ) was the reaction solution was added saturated aqueous sodium stirred at 130° C . for 19 hr. The reaction mixture was diluted with toluene ( 330 mL ) and filtered through NH silica gel . hydrogen carbonate solution at 20° C ., and the mixture was 5 The filtrate was dissolved in ethyl acetate , and extracted with extracted with ethyl acetate . The extract was washed with 5 2N hydrochloric acid . The extract was basified with 2N saturated aqueous potassium carbonate solution and satu aqueous sodium hydroxide solution and saturated aqueous rated brine, and dried over anhydrous sodium sulfate . The sodium hydrogen carbonate solution . The mixture was solvent was evaporated under reduced pressure , and the extracted with ethyl acetate , and the extract was washed with obtained solid was washed with petroleum ether to give the saturated brine , and dried over anhydrous magnesium sul title compound (47 .0 g ) as a white solid . fate . The solvent was evaporated under reduced pressure to ' H NMR (400 MHz, DMSO ): 81. 21 (9H , s ), 2 .39 ( 3H , s ) , give the title compound ( 16 . 7 g ) as a pale -orange amorphous 6 .92 - 6 . 94 ( 1H , d , J = 7 . 6 Hz ), 7 .60 - 7 .64 ( 1H , m ) , 7 . 82 - 7 . 84 powder. ( 1H , d , J = 8 . 4 Hz) , 9 .59 ( 1H , s ). 'H NMR ( 300 MHz, CDC1z ) 8 0 . 11 -0 .22 (1H , m ), 0 .24 0 . 36 ( 1H , m ) , 0 .39 - 0 . 53 ( 1H , m ) , 0 .53 - 0 . 67 ( 1H , m ) , 0 .82 Step 10 ) 15 (9H , s ), 0 .91 - 1 .07 (1H , m ), 1 . 15 - 1 . 37 (1H , m ) , 1 . 19 (3H , t , N - ( 2, 2 -dimethylpropyl ) - 6 -methylpyridin -2 -amine J = 7 . 2 Hz ) , 1 . 44 - 1 . 89 (4H , m ) , 2 . 19 - 2 . 84 (5H , m ) , 2 .21 - 2 . 37 (1H , m ), 2 .44 ( 3H , s ) , 3 . 31 - 3 .45 (1H , m ), 3 .75 (3H , s ) , Under a nitrogen atmosphere , to a suspension of lithium 3 . 97 - 4 . 39 (6H , m ) , 6 . 19 ( 1H , d , J = 1 . 9 Hz ) , 6 . 33 ( 1H , brs) , aluminum hydride (65 . 0 g ) in THF ( 1 . 5 L ) was added a 6 .48 ( 1H , dd , J = 8 . 5 , 2 . 5 Hz ) , 6 .63 ( 1H , s ) , 6 .70 ( 1H , d , J = 7 . 6 solution of 2 , 2 - dimethyl - N - ( 6 -methylpyridin - 2 - yl) propana - 20 Hz ) , 6 . 76 ( 1H , dd , J = 5 . 5 , 1 . 3 Hz ) , 7 .08 ( 1H , t , J = 7 . 7 Hz ) , mide ( 110 g ) in THF ( 1 . 5 L ) at 0° C . , and the mixture was 7 .29 ( 1H , d , J = 8 . 3 Hz ) , 8 .07 ( 1H , d , J = 5 . 3 Hz ) . stirred at 60° C . for 2 hr. To the reaction solution were successively added water (65 mL ) , 4N aqueous sodium Step 13 ) ( 3S ) - 3 - cyclopropyl- 3 - ( 2 - ( 1 - ( 2 - ( ( 2 , 2 - dim hydroxide solution (65 mL ) and water ( 195 mL ) at 0° C . , and ethylpropyl ) (6 -methylpyridin - 2 - yl) carbamoyl ) - 5 the resulting white precipitate was removed by filtration . 25 methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 The solvent in the filtrate was evaporated under reduced yl) propanoic acid pressure to give the title compound ( 107 g ) as a colorless oil . To a solution of ethyl( 3S ) - 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , ' H NMR (400 MHz, DMSO ) : 80. 89 (9H , s ), 2 .20 ( 3H , s ) , 2 - dimethylpropyl) ( 6 -methylpyridin - 2 - yl) carbamoyl) - 5 3 .05 - 3 .07 ( 2H , d , J = 6 . 4 Hz) , 6 . 14 ( 1H , s ) , 6 .24 - 6 .26 ( 1H , d , methoxyphenyl )piperidin - 4 - yl) methoxy )pyridin - 4 - yl )pro J = 6 .8 Hz ), 6 .29 -6 .31 (1H , d , J = 8 . 4 Hz ), 7 . 16 -7 .20 (1H , m ). 30 panoate ( 16 . 7 g ) in THF ( 170 mL ) and methanol ( 85 mL ) was added 1 N aqueous sodium hydroxide solution ( 170 mL ) Step 11 ) N - ( 2 , 2 - dimethylpropyl) - 2 - fluoro - 4 at room temperature , and the mixture was stirred at 60° C . methoxy - N - (6 -methylpyridin - 2 - yl) benzamide for 30 min . To the reaction solution was added 1N hydro chloric acid ( 170 mL ) , and the mixture was extracted twice Under a nitrogen atmosphere , to a solution of 2 - fluoro - 35 with ethyl acetate ( 150 mL ) . The extract was washed with 4 -methoxybenzoic acid (76 . 0 g ) in DMF (2 .0 mL ) and THF saturated brine ( 150 mL ) , dried over anhydrous magnesium (300 mL) was added dropwise oxalyl chloride (62 . 4 g ) at 20° sulfate , and the solvent was evaporated under reduced C . over 1 hr. The solvent in the reaction solution was pressure . The residue was dissolved in isopropyl acetate evaporated under reduced pressure to give an acid chloride ( 107 mL ) at 60° C ., heptane ( 123 mL ) was added dropwise intermediate as a yellow oil. Under a nitrogen atmosphere , 40 at 60° C ., and the mixture was stirred for 30 min . Heptane to a solution of N - ( 2 , 2 - dimethylpropyl) -6 -methylpyridin - 2 (65 mL ) was further added dropwise at 60° C . , and the amine (72 . 4 g ) and triethylamine ( 123 g ) in THF (500 ml ) mixture was stirred for 30 min . The mixture was cooled to room temperature and stirred for 1 hr. The resulting crystals was added a solution of the obtained acid chloride interme were collected by filtration , and washed with isopropyl diate in THF (500 mL ) at 0° C . , and the mixture was stirred 15 acetate /heptane ( 1 : 3 ) to give the title compound as a white at 20° C . for 10 hr. To the reaction solution was added water 45 solid ( 13 . 4 g ) . (500 mL ) at 20° C ., and the mixture was extracted 3 times ' H NMR (400 MHz, DMSO - do ) 0 . 10 - 0 .22 (1H , m ), with ethyl acetate (500 mL ) . The extract was washed with 0 .23 - 0 . 39 (2H , m ) , 0 .45 - 0 .56 ( 1H , m ) , 0 . 77 ( 9H , s ), 0 . 93 water ( 500 mL ) , IN aqueous sodium hydroxide solution 1 . 05 (1H , m ) , 1 . 10 - 1 . 30 ( 1H , m ) , 1 .45 - 1 .60 ( 1H , m ), 1 .61 ( 200 mL ) and saturated brine ( 300 mL ) , and dried over 1 . 86 (3H , m ), 2 . 18 - 2 .28 ( 1H , m ) , 2 . 30 - 2 .66 ( 4H , m ) , 2 . 36 anhydrous sodium sulfate . The solvent was evaporated 50 (3H . s ) , 2 .68 (2H , d . J = 7 . 4 Hz ) , 3 .69 ( 3H , s ) , 3 . 93 - 4 . 27 ( 4H , under reduced pressure , and the residue was purified by m ) , 6 .21 ( 1H , brs ) , 6 .45 ( 1H , brs ) , 6 .52 ( 1H , d , J = 8 . 4 Hz) , silica gel column chromatography (NH , ethyl acetate / petro - 6 .71 ( 1H , s ), 6 .85 ( 1H , d , J = 7 . 5 Hz) , 6 .91 ( 1H , d , J = 5 . 1 Hz ) , leum ether ) to give the title compound (67 . 5 g ) as a white 7 . 14 ( 1H , d , J = 8 . 4 Hz) , 7 .28 ( 1H , t , J = 7 . 7 Hz) , 8 .04 ( 1H , d , solid . J = 5 . 3 Hz ), 12 .09 ( 1H , brs ) . ' H NMR (400 MHz, CDC13 ): 80. 87 (9H , s ), 2 .48 (3H , s) , 55 MS (ESI + ): [ M + H ]* 615. 3 . 3 . 74 ( 3H , s ) , 4 . 14 ( 2H , s ), 6 . 39 - 6 .41 ( 1H , d , J = 11 . 2 Hz) , 6 .53 - 6 .56 ( 1H , m ) , 6 .59 - 6 .61 ( 1H , d , J = 8 . 0 Hz ), 6 . 84 - 6 . 86 Example 246 ( 1H , d , J = 7 . 6 Hz ) , 7 . 13 - 7 . 15 ( 1H , m ) , 7 .28 - 7 . 30 ( 1H , m ) . ( 3S )- 3 - cyclopropyl- 3 -( 2 -( (1 -( 2 -( ( 2 ,2 -dimethylpro Step 12 ) ethyl( 3S ) - 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - 60 pyl) ( 4 ,6 -dimethylpyrimidin - 2 - yl) carbamoyl) - 5 dimethylpropyl) (6 -methylpyridin - 2 - yl ) carbamoyl) - 5 methoxyphenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin -4 yl) propanoic acid yl) propanoate Step 1 ) allyl 2 - fluoro - 4 -methoxybenzoate Under a nitrogen atmosphere , a mixture of a crude prod - 65 uct ( 12 . 1 g ) of ethyl( 3S ) - 3 -cyclopropyl - 3 - ( 2 - ( piperidin - 4 To a suspension of 2 - fluoro - 4 -methoxybenzoic acid ( 176 ylmethoxy )pyridin - 4 - yl) propanoate , N - ( 2 , 2 -dimethylpro - g ) and potassium carbonate ( 186 g ) in DMF ( 900 mL ) was US 9 ,776 , 962 B2 175 176 added 3 -bromoprop - 1 - ene ( 107 mL ) at room temperature , acetate (500 mL ) , and the combined organic layer was and the mixture was stirred at 50° C . for 2 hr. To the reaction washed successively with water and saturated brine , and mixture was added water at room temperature , and the dried over anhydrous sodium sulfate . The solvent was mixture was extracted with ethyl acetate . The extract was evaporated under reduced pressure , and the obtained residue washed with water and saturated brine and dried over 5 was purified by NH - silica gel column chromatography ( ethyl acetate /hexane ) to give the title compound ( 33 g ) as anhydrous magnesium sulfate . The solvent was evaporated an orange oil, and a mixture of the title compound and under reduced pressure to give a crude product (220 .7 g ) of N - ( 2 , 2 - dimethylpropyl ) - 4 , 6 -dimethylpyrimidin - 2 -amine . the title compound as a pale - yellow oil. This compound was This mixture was dissolved in ethyl acetate , and washed used for the next step without further purification . successively with 5 % aqueous citric acid solution ( 750 mL ) , MS ( ESI + ) : [ M + H ] * 211. 2 . 10 10 % aqueous citric acid solution ( 750 mL ) and saturated brine ( 750 mL ), and dried over anhydrous sodium sulfate . Step 2 ) allyl 2 - ( 4 - ( ( ( 4 - ( (1S ) - 1 - cyclopropyl- 3 The solvent was evaporated under reduced pressure to give ethoxy - 3 -oxopropyl ) pyridin - 2 -yl ) oxy )methyl )piperi the title compound ( 114 g ) as an orange oil . din - 1 - yl) -4 -methoxybenzoate 1515 MS (ESI + ) : [ M + H ] * 658. 6 . To a mixture of allyl 2 - fluoro - 4 - methoxybenzoate ( 77 g ) Step 5 ) ( 3S ) - 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth and ethyl( 3S ) -3 -cyclopropyl - 3 -( 2 -( piperidin -4 -ylmethoxy ) ylpropyl) ( 4 ,6 -dimethylpyrimidin - 2 -yl )carbamoyl ) - 5 pyridin - 4 - yl) propanoate ( 130 g ) was added cesium carbon methoxyphenyl) piperidin - 4 - yl )methoxy ) pyridin - 4 ate ( 179 g ) at room temperature , and the mixture was stirred yl) propanoic acid at 100° C . for 2 hr. To the reaction mixture was added 20 DMSO (50 ml) , and the mixture was stirred at 100° C . To a mixture of ethyl( 3S ) - 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , overnight. The reaction mixture was diluted with ethyl 2 -dimethylpropyl ) (4 ,6 -dimethylpyrimidin -2 -yl ) carbamoyl ) acetate ( 1250 mL ) , and the insoluble material was removed 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy )pyridin - 4 - yl) pro by filtration . The filtrate was washed with a mixture of panoate ( 140 g ) in THF ( 966 mL ) and MeOH (483 mL ) was saturated brine and water, dried over anhydrous sodium 25 added 1 M aqueous sodium hydroxide solution ( 966 mL ) at sulfate , and treated with NH -silica gel pad . The solvent was 30° C . or lower . The mixture was stirred at 60° C . for 1 hr, evaporated under reduced pressure , and the residue was 2 M hydrochloric acid ( 483 mL ) was added at 20° C . or treated with NH -silica gel pad . The solvent was evaporated lower , and the mixture was concentrated under reduced under reduced pressure to give the title compound (141 g ) as pressure. The residue was diluted with ethyl acetate (1000 a colorless oil . 30 mL ), and the aqueous layer was extracted with ethyl acetate MS (ESI + ) : [ M + H ] * 523 . 4 . (500 mL) . The combined organic layer was washed with saturated brine (500 mL ) , dried over anhydrous sodium Step 3 ) 2- (4 - (( ( 4 -( ( 1S ) - 1- cyclopropyl -3 - ethoxy -3 sulfate , and treated with a silica gel pad . The solvent was oxopropyl) pyridin - 2 - yl )oxy )methyl ) piperidin - 1 - yl) evaporated under reduced pressure and the residue was 4 -methoxybenzoic acid 35 crystallized from IPE to give a crude product. A suspension of the crude product in isopropyl acetate ( 900 mL ) was To a solution of allyl 2 -( 4 -( (( 4 -( (1S )- 1 -cyclopropyl - 3 - stirred at 70° C . for 1 hr, and the insoluble material was ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - removed by filtration . To the filtrate was added heptane (500 yl) - 4 -methoxybenzoate ( 146 g ) and morpholine (47 . 3 mL ) mL ) at 70° C . , and the mixture was stirred for 1 hr. The in THF ( 1500 mL ) was added tetrakis ( triphenylphosphine ) 40 mixture was cooled to room temperature , and the resulting palladium ( 0 ) ( 6 . 26 g ) at room temperature , and the mixture solid was collected by filtration , and washed with isopropyl was stirred at room temperature overnight under a nitrogen acetate /heptane (100 mL / 200 mL ) to give the title compound atmosphere . The reaction mixture was diluted with ethyl ( 108 . 3 g ) . acetate (750 mL ) , washed twice with a mixture of saturated ' H NMR (300 MHz , DMSO -do ) 8 0 . 17 ( 1H , dt, J= 8 .9 , 4 . 2 brine and water, and dried over anhydrous sodium sulfate . 45 Hz ), 0 . 22 - 0 .42 (2H , m ) , 0 . 43 - 0 . 58 ( 1H , m ), 0 .72 - 0 .84 ( 9H , The solvent was evaporated under reduced pressure, and the m ), 0 .87 - 1 . 10 ( 2H , m ) , 1 . 32 - 1 . 82 (4H , m ), 2 .02 - 2 . 13 (6H , obtained solid was washed with hexane to give the title m ) , 2 . 16 - 2 . 30 ( 1H , m ) , 2 . 31 ( 2H , brs) , 2 . 54 ( 1H , brs) , compound ( 116 g ) as a pale - yellow solid . 2 .60 - 2 .76 ( 2H , m ) , 3 . 09 ( 1H , brs ) , 3 . 64 - 3 . 74 ( 3H , m ) , MS ( ESI + ) : [ M + H ] * 483 . 3 . 3 . 94 -4 .41 (4H , m ), 6 . 15 (1H , d , J= 2 .3 Hz) , 6 .52 ( 1H , dd , 50 J = 8 . 3 , 2 . 3 Hz ), 6 .71 ( 1H , s ) , 6 .79 ( 1H , s ), 6 . 91 ( 1H , dd , Step 4 ) ethyl( 3S ) - 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 J = 5 . 5 , 1 .3 Hz ) , 7 . 17 ( 1H , d , J = 8 . 3 Hz ) , 8 .04 ( 1H , d , J = 5 . 3 dimethylpropyl) ( 4 , 6 -dimethylpyrimidin - 2 - yl) car Hz) , 12 .08 ( 1H , brs ) . bamoyl) - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) MS (ESI + ) : [ M + H ] * 630 .3 . pyridin - 4 - yl) propanoate 55 Example 247 To a solution of 2 -( 4 -( ([ 4 -( ( 1S ) -1 -cyclopropyl - 3 -ethoxy 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl ) - 4 ( 3S ) - 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpro methoxybenzoic acid (110 . 5 g ) in diethylene glycol dim pyl) (pyridin -2 - yl) carbamoyl) - 5 -methoxyphenyl ) ethyl ether (442 mL ) was added 1 - chloro - N , N , 2 piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid trimethylprop - 1 - en - 1 -amine ( 34 . 9 mL ) at room temperature , 60 and the mixture was stirred at 60° C . for 1 hr. The reaction Step 1 ) ethyl( 3S ) - 3 - cyclopropyl - 3 - ( 2 - ( ( 1 -( 2 - ( ( 2 , 2 mixture was cooled to room temperature , N - ( 2 , 2 -dimethyl dimethylpropyl) (pyridin - 2 - yl) carbamoyl ) - 5 propyl) - 4 ,6 - dimethylpyrimidin -2 - amine (51 . 0 g ) and trieth methoxyphenyl) piperidin - 4 -yl )methoxy )pyridin - 4 ylamine ( 36 . 8 mL ) were added at room temperature , and the yl) propanoate mixture was stirred at 100° C . for 3 hr. The reaction mixture 65 was diluted with ethyl acetate ( 1100 mL ) , and washed with To a solution of 2 - ( 4 - ( (( 4 - ( ( 1S ) - 1 -cyclopropyl - 3 - ethoxy water (750 mL ) . The aqueous layer was extracted with ethyl 3 - oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 4 US 9 ,776 , 962 B2 177 178 methoxybenzoic acid ( 119 g ) in THF ( 480 mL ) was added Example 248 1 - chloro - N , N , 2 - trimethylprop - 1 - en - 1 - amine (37 .6 g ) at room temperature , and the mixture was stirred at 50° C . for ( 3S ) - 3 - cyclopropyl- 3 - ( 2 -( ( 1 - ( 5 -methoxy - 2 - (( 6 -meth 1 hr. The reaction mixture was cooled to room temperature , ylpyridin - 2 -yl ) carbamoyl) phenyl) piperidin - 4 - yl) N -( 2 , 2 - dimethylpropyl) pyridin - 2 - amine ( 46 . 7 g ) and trieth - 5 methoxy )pyridin -4 -yl ) propanoic acid ylamine ( 39. 6 mL ) were added at room temperature, and the mixture was stirred at 60° C . for 3 hr. The reaction mixture In the samemanner as in Example 32, step 2 and Example was diluted with ethyl acetate (1200 mL ) , and water (800 1 , step 4 , the title compound ( 106 mg ) was obtained as white mL ) was added . The aqueous layer was extracted with ethyl crystals from 2 -amino - 6 -methylpyridine ( 76 mg) and 2 - ( 4 acetate (600 mL ), and the combined organic layer was " ( (( 4 - ( ( 1S ) - 1 - cyclopropyl - 3 - ethoxy - 3 - oxopropyl ) pyridin - 2 washed successively with a mixture of water and saturated yl) oxy )methyl ) piperidin - 1 -yl ) -4 -methoxybenzoic acid ( 170 brine , and saturated brine , and dried over anhydrous sodium mg) . sulfate . The solvent was evaporated under reduced pressure , MS ( ESI + ) : [ M + H ] * 545 . 2 . and the obtained residue was purified by NH -silica gel 15 column chromatography ( ethyl acetate /hexane ) to give the Example 249 title compound (63 . 8 g ) as a yellow oil, and a mixture of the title compound and N - (2 ,2 -dimethylpropyl ) pyridin - 2 (3S )- 3 -cyclopropyl - 3- ( 2- ( ( 1- ( 5 -methoxy -2 -( pyridin amine . This mixture was dissolved in ethyl acetate , washed 2 -ylcarbamoyl ) phenyl )piperidin - 4 -yl ) methoxy )pyri successively with 10 % aqueous citric acid solution ( 250 mL ) 20 din - 4 - yl) propanoic acid and saturated brine ( 250 mL ) , and dried over anhydrous sodium sulfate . The solvent was evaporated under reduced In the samemanner as in Example 32 , step 2 and Example pressure to give the title compound (84 . 2 g ) as a yellow oil. 1 , step 4 , the title compound ( 106 mg ) was obtained as white crystals from 2 - aminopyridine (66 mg) and 2 - ( 4 - ( ( ( 4 - ( ( 1S ) MS ( ESI+ ) : [ M + H ] * 629. 6 . 25 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl )pyridin - 2 - yl) oxy ) methyl ) piperidin - 1 - yl) - 4 -methoxybenzoic acid ( 170 mg) . Step 2 ) (3S ) - 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimeth MS ( ESI + ) : [ M + H ] * 531 . 1 . ylpropyl) (pyridin -2 -yl ) carbamoyl ) - 5 -methoxyphe nyl) piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic Example 250 acid 30 3 -cyclopropyl - 3 - (2 - ( (1 -( 2 -( ( 2 ,2 -dimethylpropyl ) (6 To a mixture of ethyl( 3S ) - 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -( ( 2 , methylpyridin - 2 - yl) carbamoyl) - 4 - fluoro - 5 -methoxy 2 -dimethylpropyl ) ( pyridin - 2 -yl ) carbamoyl ) - 5 -methoxyphe phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro nyl) piperidin - 4 -yl ) methoxy )pyridin -4 -yl ) propanoate ( 142 g ) 35 panoic acid in THF (1028 mL ) and MeOH (514 mL ) was added 1 M aqueous sodium hydroxide solution ( 1028 mL ) at 30° C . or Step 1 ) ethyl 3 -cyclopropyl - 3 - ( 2 - (piperidin - 4 - yl lower. The mixture was stirred at 60° C . for 1 hr, neutralized methoxy )pyridin -4 -yl )propanoate with 2 M hydrochloric acid at 20° C . or lower, and concen trated under reduced pressure . The residue was diluted with 40 To a solution of 3 - ( 2 - ( ( 1 - (tert -butoxycarbonyl ) piperidin ethyl acetate ( 1000 mL ) , and the aqueous layer was 4 -yl ) methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpropanoic acid extracted with ethyl acetate (500 mL ) . The combined ( 20 . 0 g ) in ethanol ( 200 mL ) was added sulfuric acid (6 .59 organic layer was washed successively with 10 % aqueous mL ) at room temperature , and the mixture was stirred at 80° sodium hydrogen carbonate solution (500 mL ) and saturated C . for 30 min . The solvent was evaporated under reduced brine (500 ml ) , dried over anhydrous sodium sulfate , and 45 pressure , and the residue was diluted with ethyl acetate ( 100 treated with a silica gel pad . The solvent was evaporated mL ) and THF ( 100 mL ) , and neutralized with 2N aqueous under reduced pressure and the residue was crystallized sodium hydroxide solution ( 99 mL ) . Sodium chloride was from IPE and TBME to give a crude product. A suspension added , and the mixture was extracted with ethyl acetate (50 of the crude product in isopropyl acetate (900 mL ) was mL ) and THF (50 mL ) . The extract was washed with stirred at 70° C . for 1 hr. and the insoluble material was 50 saturated brine ( 50 mL ) , and dried over anhydrous magne removedre by filtration . To the filtrate were added heptane sium sulfate . The solvent was evaporated under reduced ( 900 mL ) and seed crystals at 70° C . , and the mixture was pressure to give a crude product ( 17 . 1 g ) of the title stirred for 1 hr. The mixture was cooled to room tempera compound as an orange oil . This compound was used for the ture , and the resulting solid was collected by filtration , and next step without further purification . washed with isopropyl acetate /heptane ( 100 mL / 200 mL ) to » give the title compound ( 93 . 5 g ) . Step 2 ) 2 , 5 - difluoro - 4 - hydroxybenzoic acid ' H NMR ( 300 MHz, DMSO - d . ) 8 0 . 11 - 0 . 22 ( 1H , m ), 245 - Trifluorobenzoic acid (500 g ) sodium hydroxide 0 .22 - 0 . 40 (2H , m ) , 0 .45 - 0 .59 ( 1H , m ) , 0 .77 (9H , s ) , 0 .92 - (4 54 g ) and water (25 mL ) were heated at 160° C . for 10 $ (TH , m ) , 1 . 13 - 1. 39 ( TH , m ), 1. 33 ( TH , brs) , 1 .00 -1 . 8 / 60 min under microwave irradiation . To the reaction solution ( 3H , m ), 2 . 15 -2 .31 ( 1H , m ), 2 . 38 ( 1H , brs ), 2 .55 - 2 . 75 (3H , was added IN hydrochloric acid at room temperature , and m ) , 3 . 33 ( 2H , S ) , 3 .69 (3H , S ) , 3 . 94 - 4 . 25 ( 4H , m ) , 6 .21 ( 1H , the mixture was extracted with ethyl acetate . The extract was d , J = 1 . 9 Hz ) , 6 .52 ( 1H , dd , J = 8 . 5 , 2 . 5 Hz ) , 6 .63 - 6 .77 (2H , washed with water and saturated brine , and dried over m ) , 6 . 92 ( 1H , dd , J = 5 . 5 , 1 . 3 Hz ), 6 .99 ( 1H , dd , J = 7 . 0 , 5 . 1 anhydrous magnesium sulfate . The solvent was evaporated Hz) , 7 . 14 ( 1H , d , J = 8 . 3 Hz) , 7 . 34 - 7 . 46 ( 1H , m ) , 8 . 04 (1H TH , d ,, 65 under reduced pressure , and the obtained solid was washed J = 5 . 3 Hz) , 8 . 33 ( 1H , dd , J = 4 . 7 , 1. 3 Hz) , 12 . 08 ( 1H , brs ). with hexane to give the title compound ( 4 . 50 g ) as a white MS ( ESI + ): [M + H ] * 601 .3 . solid . US 9 , 776 , 962 B2 179 180 ' H NMR (400 MHz, DMSO -do ) 8 6 . 80 (1H , dd , J = 11 .8 , Step 7 ) 3 -cyclopropyl - 3 - ( 2 - ( (1 - (2 - (( 2 ,2 -dimethyl 7 .0 Hz ), 7 .58 (1H , dd , J = 11. 4 , 7 .0 Hz ), 11. 25 (1H , brs ) , 12 .99 propyl) (6 -methylpyridin - 2 -yl ) carbamoyl ) - 4 - fluoro ( 1H , brs ). 5 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) pyridin - 4 yl) propanoic acid Step 3 ) methyl 2 , 5 -difluoro - 4 -methoxybenzoate 5 In the same manner as in Example 1 , step 4 , the title Under a nitrogen atmosphere , iodomethane (4 .04 mL ) compound ( 28 . 3 mg) was obtained as a white solid from was added to a mixture of 2 , 5 - difluoro - 4 -hydroxybenzoic ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 -dimethylpropyl ) ( 6 acid ( 4 .50 g) , potassium carbonate (10 .7 g ) and DMF (25 methylpyridin -2 - yl ) carbamoyl) -4 - fluoro -5 -methoxyphenyl ) mL ) at room temperature, and the mixture was stirred at 60° 10 piperidin -4 - yl) methoxy )pyridin -4 - yl) propanoate ( 37 . 0 mg) . C . for 20 min . To the reaction solution was added water at MS (ESI + ): [ M + H ] * 633. 3 . room temperature , and the resulting precipitates were col lected by filtration , washed with water and dried to give the Example 251 title compound ( 5 . 27 g ) as a white solid . ' H NMR ( 400 MHz, CDC13 ) 8 3 . 91 (3H , s ), 3 . 93 ( 3H , s ), 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( 2 , 2 -dimethylpropyl ) ( 6 6 .71 ( 1H , dd , J = 11 .6 , 6 . 7 Hz ) , 7 .66 ( 1H , dd , J = 11 . 3 , 6 . 8 Hz) . methylpyridin - 2 - yl) carbamoyl) - 3 - fluoro - 5 - methoxy phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro Step 4 ) 2 , 5 - difluoro - 4 -methoxybenzoic acid panoic acid IN Aqueous sodium hydroxide solution (50 mL ) was 20 Step 1 ) 2, 6 - difluoro - 4 -methoxybenzoic acid added to a solution of methyl 2 , 5 - difluoro - 4 -methoxyben zoate (5 .27 g ) in THF (50 mL ) and methanol (25 mL ) at Under a nitrogen atmosphere , a 1 .6 M solution of n -bu room temperature , and the mixture was stirred at 60° C . for tyllithium in hexane ( 31 . 2 mL ) was added to a solution of 20 min . The reaction solution was neutralized with 1N 25 1, 3 - difluoro - 5 -methoxybenzene ( 5 .54 g ) in THF ( 120 mL ) at hydrochloric acid at room temperature , and extracted with 78° C . , and the mixture was stirred at - 78° C . for 30 min . ethyl acetate . The extract was washed with water and Sublimated dry ice ( 8 .46 g ) was added to the reaction saturated brine , and dried over anhydrous magnesium sul solution through a silica gel tube at - 78° C ., and the mixture fate . The solvent was evaporated under reduced pressure to was stirred at room temperature for 5 min . To the reaction give the title compound ( 3 . 53 g ) as a white solid . 30 solution was added 1N hydrochloric acid at 0° C ., and the ' H NMR ( 400 MHz, DMSO - d . ) 8 3 . 92 (3H , s ), 7 .21 (1H , mixture was extracted with ethyl acetate / THF . The extract dd , J = 12 .1 , 7 . 0 Hz) , 7 .62 ( 1H , dd , J= 11 .6 , 7 . 0 Hz) , 13 . 16 was washed with saturated brine, and dried over anhydrous ( 1H , brs ) . magnesium sulfate . The solvent was evaporated under reduced pressure and the obtained solid was washed with Step 5 ) N -( 2, 2 - dimethylpropyl) - 2, 5 -difluoro -4 35 hexane and diisopropyl ether to give the title compound methoxy -N -( 6 -methylpyridin - 2 -yl ) benzamide ( 5 .00 g ) as a white solid . ' H NMR (400 MHz , DMSO -d . ) 8 3 .83 (3H , s ), 6 .82 (2H , In the same manner as in Example 1 , step 1 , the title d , J = 11. 0 Hz) , 13 .43 ( 1H , brs ). compound (354 mg) was obtained as a white solid from 2 , 5 -difluoro - 4 -methoxybenzoic acid (300 mg ) and N - ( 2 , 2 - 40 Step 2 ) N -( 2 ,2 - dimethylpropyl) - 2 ,6 -difluoro -4 dimethylpropyl) - 6 -methylpyridin - 2 - amine ( 292 mg) . methoxy -N -( 5 -methylpyridin - 2 -yl ) benzamide H NMR ( 400 MHz , CDC13 ) 8 0 . 86 ( 9H , s ), 2 .46 ( 3H , s ) , In the same manner as in Example 1 , step 1, the title 3 . 80 ( 3H , s ) , 4 .09 (2H , s ) , 6 . 45 ( 1H , dd , J = 10 . 3 , 6 . 9 Hz ) , 6 .64 compound (682 mg) was obtained as a white solid from ( 1H , d , J = 7 . 9 Hz) , 6 .87 ( 1H , d , J = 7 .5 Hz) , 6 . 98 ( 1H , dd4 , 45 2 , 6 - difluoro - 4 -methoxybenzoic acid ( 500 mg) and N - ( 2 , 2 J = 10 . 8 , 6 . 1 Hz) , 7 . 32 ( 1H , t, J = 7 . 8 Hz ) . dimethylpropyl) - 6 -methylpyridin - 2 - amine (711 mg) . Step 6 ) ethyl 3 - cyclopropyl- 3 - ( 2 - (( 1 -( 2 -( ( 2 ,2 - dim IH NMR (400 MHz, CDC1 ) 8 0 .87 ( 9H , brs ) , 2 .44 (3H , ethylpropyl ) ( 6 -methylpyridin - 2 - yl) carbamoyl ) - 4 s ), 3. 72 (3H , s) , 4 .09 (2H , s ), 6 .26 ( 2H , d , J = 9 .4 Hz ), 6 . 76 fluoro - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) 50 ( 1H , brs ), 6 .87 ( 1H , d , J = 7 . 5 Hz) , 7 . 30 - 7 . 42 ( 1H , m ). pyridin -4 -yl ) propanoate Step 3 ) ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 -( ( 2 , 2 - dim ethylpropyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 3 In the same manner as in Example 1 , step 2 , the title fluoro - 5 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) compound (37 . 0 mg) was obtained as a white amorphous pyridin -4 -yl ) propanoate powder from N - ( 2 , 2 - dimethylpropyl) - 2 ,5 - difluoro - 4 - 55 methoxy - N - (6 -methylpyridin - 2 - yl )benzamide (69 . 7 mg) In the same manner as in Example 1 , step 2 , the title and ethyl 3 - cyclopropyl- 3 - ( 2 - ( piperidin - 4 - ylmethoxy ) pyri - compound ( 191 mg) was obtained as a white amorphous din - 4 - yl) propanoate (73 . 1 mg ) . powder from N -( 2 ,2 -dimethylpropyl ) -2 , 6 -difluoro - 4 H NMR (400 MHz, CDC13 ) d 0 . 12 -0 .22 ( 1H , m ), 0 . 25 methoxy - N -( 5 -methylpyridin - 2 -yl ) benzamide ( 150 mg) and 0 . 36 ( 1H , m ), 0 .43 - 0 .52 ( 1H , m ) , 0 .55 - 0 .67 ( 1H , m ) , 0 . 83 60 ethyl 3 - cyclopropyl- 3 - ( 2 - (piperidin - 4 - ylmethoxy )pyridin - 4 (9H , s ), 0 .93 - 1 . 06 ( 1H , m ), 1 . 19 (3H , t, J = 7 . 2 Hz) , 1 . 28 - 1 .44 yl) propanoate (143 mg) . ( 1H , m ) , 1 .49 - 1 .70 ( 1H , m ) , 1 .71 - 1 . 90 (3H , m ) , 2 .26 - 2 . 35 H NMR (400 MHz, CDC1z ) 8 0 . 10 - 0 .21 (1H , m ) , 0 . 26 ( 1H , m ) , 2 . 33 - 2 .82 (5H , m ), 2 .43 ( 3H , s ) , 3 . 37 ( 1H , brs ) , 3 .81 0 . 34 ( 1H , m ) , 0 . 42 - 0 . 53 ( 1H , m ) , 0 .56 - 0 .66 ( 1H , m ) , 0 . 86 ( 3H , s ) , 3 . 99 - 4 . 12 ( 2H , m ) , 4 . 00 - 4 .39 (2H , m ), 4 . 17 (2H , d , (9H , s ), 0 . 93 - 1 . 06 ( 1H , m ), 1. 19 ( 3H , t, J = 7 .1 Hz) , 1 . 30 - 1 .47 J = 6 . 1 Hz ) , 6 . 32 ( 1H , d , J = 6 .7 Hz) , 6 .42 ( 1H , brs ) , 6 .63 ( 1H , 65 ( 1H , m ), 1 . 49 - 1. 66 ( 1H , m ) , 1 . 73 - 1. 91 ( 3H , m ), 2 . 26 - 2 . 34 s ), 6 .73 (1H , d , J = 7 . 5 Hz ) , 6 .77 ( 1H , d , J= 5 .1 Hz) , 7 .03 - 7. 20 (1H , m ), 2 .36 -2 .55 (2H , m ), 2 .41 (3H , s ), 2 .57 -2 .82 (3H , m ), (1H , m ) , 7 . 07 ( 1H , d , J = 11 . 2 Hz) , 8 .07 ( 1H , d , J = 5 . 3 Hz) . 3 .54 (1H , d , J = 11 . 5 Hz ), 3 .71 ( 3H , s ), 4 .01 - 4 .29 (6H , m ) , US 9 ,776 , 962 B2 181 182 5 .98 ( 1H , s ) , 6 .21 (1H , d , J = 10 . 9 Hz) , 6 .53 (1H , d , J = 7 . 9 Hz) , powder from N - ( 2 , 2 -dimethylpropyl ) - 2 , 3 - difluoro - 4 6 .63 ( 1H , s ), 6 .71 - 6 .81 (2H , m ) , 7 .15 ( 1H , t , = 7 .7 Hz) , 8 .07 methoxy - N - (6 -methylpyridin - 2 -yl ) benzamide ( 150 mg) and ( 1H , d , J = 5 . 3 Hz) . ethyl 3 -cyclopropyl - 3 - ( 2 - (piperidin - 4 -ylmethoxy ) pyridin - 4 yl) propanoate ( 157 mg) . Step 4 ) 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - (2 - (( 2 ,2 -dimethyl 5 H NMR (400 MHz, CDC1z ) 8 0 . 11 - 0 .21 ( 1H , m ) , 0 .23 propyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 3 - fluoro 0 .35 ( 1H , m ) , 0 . 40 - 0 . 51 (1H , m ), 0 .53 - 0 .66 ( 1H , m ), 0 .85 5 -methoxyphenyl ) piperidin - 4 - yl )methoxy )pyridin - 4 ( 9H , brs ) , 0 .94 - 1 . 05 ( 1H , m ) , 1 . 19 (3H , t, J = 7 . 1 Hz ) , yl) propanoic acid 1 . 38 - 1 .55 (2H , m ), 1. 70 - 1. 98 (3H , m ), 2 .24 -2 . 36 ( 1H , m ), 2 . 44 ( 3H , s ) , 2 .59 - 2 . 85 ( 4H , m ), 3 . 06 - 3 .41 ( 2H , m ) , 3 . 81 In the same manner as in Example 1 , step 4 , the title 10 ( 3H , s ) , 3 . 99 - 4 . 38 (4H , m ), 4 . 15 ( 2H , d , J = 6 . 4 Hz ) , 6 .48 ( 1H , compound ( 173 mg) was obtained as a white amorphous brs ), 6 .52 - 6 .59 ( 1H , m ) , 6 .62 (1H , s ) , 6 .71 - 6 .81 (2H , m ) , powder from ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( 2 , 2 -dimeth 6 .85 (1H , d , J= 7 .3 Hz ), 7 .18 ( 1H , brs ), 8. 06 (1H , d , J = 5 .4 ylpropyl) ( 6 -methylpyridin -2 -yl ) carbamoyl ) - 3 -fluoro -5 Hz ). methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin -4 - yl) pro panoate (191 mg ). 15 Step 6 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - (6 - ( ( 2 , 2 - dimethyl MS (ESI + ) : [ M + H ] * 633 . 3 . propyl) (6 -methylpyridin - 2 - yl )carbamoyl ) - 2 -fluoro 3 -methoxyphenyl ) piperidin - 4 - yl)methoxy )pyridin -4 Example 252 yl) propanoic acid 20 3 -cyclopropyl - 3 - ( 2 - (( 1 - (6 -( (2 , 2 -dimethylpropyl ) ( 6 In the same manner as in Example 1, step 4 , the title methylpyridin -2 - yl) carbamoyl) -2 - fluoro - 3 -methoxy compound (141 mg) was obtained as a white amorphous phenyl) piperidin -4 -yl ) methoxy )pyridin -4 -yl ) pro powder from ethyl 3 - cyclopropyl- 3 -( 2 -( ( 1 -( 6 - ( (2 , 2 -dimeth panoic acid ylpropyl) (6 -methylpyridin - 2 - yl ) carbamoyl) - 2 - fluoro - 3 25 methoxyphenyl) piperidin - 4 -yl ) methoxy )pyridin -4 - yl )pro Step 1 ) 2 ,3 -difluoro -4 -hydroxybenzoic acid panoate ( 188 mg ). In the same manner as in Example 250 , step 1 , a crude MS (ESI + ): [ M + H ]* 633. 3 . product of the title compound was obtained as a white solid Example 253 from 2 , 3 , 4 - trifluorobenzoic acid ( 1 .00 g ) . This compound 30 was used for the next step without further purification . 3 -cyclopropyl - 3 - ( 2 - (( 1 - (6 -( ( 2 , 2 -dimethylpropyl ) ( 6 Step 2 ) methyl 2 , 3 - difluoro - 4 -methoxybenzoate methylpyridin - 2 - yl) carbamoyl) - 2 , 4 - difluoro - 3 methoxyphenyl )piperidin -4 -yl )methoxy )pyridin -4 In the same manner as in Example 250 , step 2 , the title yl) propanoic acid compound (422 mg) was obtained as a white solid from a 35 crude product ( entire amount) of 2 , 3 - difluoro - 4 -hydroxy Step 1 ) 2 , 3 , 5 - trifluoro - 4 - hydroxybenzoic acid benzoic acid . ' H NMR (400 MHz , CDC13 ) d 3 .89 - 3 .94 (3H , m ) , 3 . 96 In the same manner as in Example 250 , step 1 , the title ( 3H , s) , 6 .78 (1H , t, J = 7 .5 Hz ), 7 .62 -7 .86 ( 1H , m ). compound ( 4 .67 g ) was obtained as a white solid from 40 2, 3 ,4 ,5 - tetrafluorobenzoic acid ( 5 .00 g ). Step 3 ) 2 , 3 - difluoro - 4 -methoxybenzoic acid ' H NMR (400 MHz, DMSO - d ) 8 7 .47 (1H , dd , J= 10 .9 , 6 . 6 Hz ) , 11 . 79 ( 1H , brs ) , 13 . 35 ( 1H , brs ) . In the same manner as in Example 250 , step 3 , the title compound ( 387 mg) was obtained as a white solid from Step 2 ) methyl 2 ,3 ,5 -trifluoro -4 -methoxybenzoate methyl 2 , 3 -difluoro - 4 -methoxybenzoate (422 mg) . 45 'H NMR (400 MHz, DMSO - d ) 8 3 .94 (3H , s) , 7 .12 ( 1H , In the same manner as in Example 250 , step 2 , a crude t , J = 8 .0 Hz ), 7 .69 (1H , t, J = 7 . 8 Hz) , 13 .22 (1H , brs ). product of the title compound was obtained as a pale - yellow solid from 2 , 3 ,5 - trifluoro - 4 - hydroxybenzoic acid ( 4 .67 g ) . Step 4 ) N - ( 2 , 2 - dimethylpropyl ) - 2 , 3 - difluoro - 4 This compound was used for the next step without further methoxy - N - ( 6 -methylpyridin - 2 -yl ) benzamide 50 purification . In the same manner as in Example 1 , step 1 , the title Step 3 ) 2, 3 ,5 -trifluoro -4 -methoxybenzoic acid compound (455 mg) was obtained as a white solid from 2 , 3 - difluoro - 4 -methoxybenzoic acid ( 387 mg ) and N - ( 2 , 2 In the same manner as in Example 250 , step 3 , the title dimethylpropyl) -6 -methylpyridin - 2 - amine (376 mg) . 55 compound ( 3 . 66 g ) was obtained as a white solid from a ' H NMR (400 MHz, CDC13 ) 8 0 . 86 ( 9H , s ) , 2 .45 (3H , s ) , crude product ( entire amount of methyl 2 , 3 , 5 - trifluoro - 4 3 .84 (3H , s ) , 4 . 10 (2H , s ) , 6 .57 (1H , t , J = 7 . 7 Hz) , 6 .63 ( 1H , methoxybenzoate . d , J= 8 .0 Hz) , 6 . 86 ( 1H , d , J= 7 . 5 Hz) , 6 .91 ( 1H , t , J= 7. 8 Hz ), ' H NMR ( 400 MHz, DMSO -do ) 8 4 .09 ( 3H , s ), 7 . 56 ( 1H , 7 .31 ( 1H , t , J = 7 . 8 Hz ) . dd , J = 11 . 0 , 5 . 8 Hz ), 13 .65 ( 1H , brs ) . 60 Step 5 ) ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - (6 - ( ( 2 , 2 - dim Step 4 ) N - ( 2 , 2 - dimethylpropyl) - 2 , 3 , 5 - trifluoro - 4 ethylpropyl) ( 6 -methylpyridin - 2 - yl) carbamoyl) - 2 methoxy - N - (6 -methylpyridin - 2 - yl) benzamide fluoro - 3 -methoxyphenyl ) piperidin - 4 -yl ) methoxy ) pyridin - 4 - yl) propanoate In the same manner as in Example 1 , step 1 , the title 65 compound ( 317 mg) was obtained as a white solid from In the same manner as in Example 1 , step 2 , the title 2 ,3 , 5 - trifluoro - 4 -methoxybenzoic acid (300 mg) and N -( 2 , compound (188 mg) was obtained as a white amorphous 2 -dimethylpropyl ) - 6 -methylpyridin -2 -amine ( 266 mg ). US 9 ,776 , 962 B2 183 184 'H NMR (400 MHz, CDC13 ) 8 0 . 86 (9H , s ), 2 .44 (3H , s ), (3 -( piperidin -4 -ylmethoxy )phenyl ) propanoate (656 mg) and 3 . 98 ( 3H , s ), 4 .07 ( 2H , s ), 6 .70 ( 1H , d , J = 7 . 8 Hz ) , 6 .77 ( 1H , potassium carbonate (747 mg) and the mixture was stirred at dd , J = 9 . 1 , 5 . 7 Hz) , 6 . 90 ( 1H , d , J = 7 . 4 Hz ), 7 .37 ( 1H , t , J = 7 . 8 100° C . for 2. 5 hr. To the reaction mixture was added water Hz ). and the mixture was extracted with ethyl acetate . The extract Step 5 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( 1 - (6 - ( ( 2 , 2 - dim 5 was washed with saturated brine , and dried over anhydrous ethylpropyl) (6 -methylpyridin - 2 - yl) carbamoyl) - 2 , 4 magnesium sulfate. The solvent was evaporated under difluoro - 3 -methoxyphenyl ) piperidin -4 -yl ) methoxy ) reduced pressure , and the residue was purified by silica gel pyridin - 4 -yl ) propanoate column chromatography (ethyl acetate / hexane ) to give the title compound (920 mg) as a colorless oil. In the same manner as in Example 1 , step 2, the title MS (ESI + ) : [ M + H ] * 573. 3 . compound ( 24 . 0 mg) was obtained as a colorless oil from N -( 2 ,2 -dimethylpropyl ) -2 ,3 , 5 - trifluoro - 4 -methoxy - N -( 6 Step 4 ) 2 - [ 4 - ( ( 3 - ( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro methylpyridin - 2 - yl) benzamide ( 150 mg) and ethyl 3 - cyclo pyl) phenoxy) methyl ) piperidin - 1- yl ) -6 -methoxynico propyl -3 -( 2 -( piperidin -4 -ylmethoxy )pyridin -4 -yl ) propano tinic acid ate ( 136 mg) . 1515 H NMR (400 MHz, CDC12 ) d 0 . 11 - 0 . 21 ( 1H , m ) , 0 . 24 In the same manner as in Example 59 , step 4 , the title 0 . 35 ( 1H , m ), 0 . 40 - 0 .51 ( 1H , m ) , 0 . 54 - 0 .66 ( 1H , m ) , 0 . 86 compound (781 mg) was obtained as a pale -yellow oil from (9H , br. s ), 0 .94 - 1 .05 (1H , m ), 1. 19 (3H , t, J= 7 .1 Hz ), 1. 48 benzyl 2 - ( 4 - ( ( 3 - ( 1 - cyclopropyl- 3 - ethoxy - 3 -oxopropyl ) phe ( 2H , d , J = 10 . 7 Hz ) , 1 . 79 ( 2H , d , J = 11 . 5 Hz ) , 1 . 88 ( 1H , brs ) , noxy )methyl ) piperidin - 1 - yl) -6 -methoxynicotinate (920 2 .25 - 2 .35 ( 1H , m ) , 2 .43 (3H , s ), 2 . 56 (1H , brs ) , 2 .64 - 2 .87 20 ( 3H , m ) , 3 .04 - 3 .35 ( 2H , m ) , 3 . 92 ( 3H , s ), 4 . 01 - 4 . 30 (6H , m ) , 6 .58 ( 1H , d , J = 7 . 3 Hz) , 6 .62 ( 1H , s ) , 6 .67 ( 1H , d , J = 9 . 5 Hz ), MS (ESI + ): [ M + H ]* 483 . 2. 6 . 76 ( 1H , d , J= 5 .1 Hz ), 6 .81 ( 1H , d , J= 7 .3 Hz ), 7 .20 - 7 .32 Step 5 ) 3 - cyclopropyl - 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 - dimethyl ( 1H , m ), 8 .07 ( 1H , d , J = 5 . 3 Hz ) . propyl) (pyridin - 2 - yl) carbamoyl) -6 -methoxypyridin Step 6 ) 3 -cyclopropyl -3 -( 2 -( (1 - (6 -( (2 ,2 -dimethyl 25 2 -yl ) piperidin -4 -yl ) methoxy )phenyl )propanoic acid propyl) ( 6 -methylpyridin -2 - yl ) carbamoyl) - 2, 4- dif luoro - 3 -methoxyphenyl ) piperidin - 4 - yl) methoxy ) In the same manner as in Example 32 , step 2 and Example pyridin - 4 -yl ) propanoic acid 1 , step 4 , the title compound ( 140 mg ) was obtained as a pale - yellow oil from 2 -( 4 -( ( 3 -( 1 -cyclopropyl - 3 - ethoxy - 3 In the same manner as in Example 1 , step 4 , the title 30 oxopropyl) phenoxy )methyl ) piperidin - 1 -yl ) -6 -methoxynico compound ( 12 .6 mg) was obtained as a white solid from tinic acid (150 mg ) and N - (2 , 2 - dimethylpropyl) pyridin - 2 ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 6 - ( ( 2 , 2 - dimethylpropyl) (6 - amine ( 102 mg ) . methylpyridin - 2 - yl) carbamoyl) - 2 , 4 - difluoro - 3 -methoxy MS ( ESI + ) : [ M + H ] * 601. 3 . phenyl) piperidin - 4 -yl ) methoxy )pyridin -4 - yl) propanoate ( 24 . 0 mg) . 35 Example 255 MS (ESI + ) : [M + H ]* 651. 4 . 3 - cyclopropyl- 3 -( 2 - ( ( 1 - ( 5 - ( ( 2 , 2 -dimethylpropyl ) (6 Example 254 methylpyridin - 2 - yl) carbamoyl ) - 2 -methoxypyridin - 4 yl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) propanoic 3 - cyclopropyl- 3 - ( 3 - ( ( 1 - ( 3 - ( ( 2 , 2 - dimethylpropyl) 40 (pyridin - 2 - yl) carbamoyl ) - 6 -methoxypyridin - 2 -yl ) acid piperidin -4 -yl ) methoxy ) phenyl) propanoic acid Step 1 ) 4 ,6 -dichloronicotinic acid Step 1 ) 2 - chloro -6 -methoxynicotinic acid Lithium hydroxide monohydrate (665 mg) was added to To a solution (250 mL ) of 2 , 6 - dichloronicotinic acid ( 5 .004500 a solution of methyl 4 ,6 - dichloronicotinate ( 2. 97 g ) in THF g ) in methanol was added potassium tert -butoxide ( 8 .77 g ). (60 ml ) and water ( 15 ml ) at room temperature , and the and the mixture was heated under reflux for 10 hr. The mixture was stirred at room temperature for 1 hr. To the solvent in the reaction mixture was evaporated under reaction solution was added 6N hydrochloric acid at room reduced pressure , and the residue was suspended in water temperature , and the solvent was evaporated under reduced and neutralized with IN HC1. The precipitate was collected 50 pressure . The residual solid was washed with water to give by filtration to give the title compound ( 3 . 15 g ) as a white a white solid . The filtrate was extracted with ethyl acetate . solid . The extract was washed with water and saturated brine , MS (ESI + ) : [ M + H ] * 188 .0 . combined with an ethyl acetate solution of the solid obtained earlier, and dried over anhydrous magnesium sulfate . The Step 2 ) benzyl 2 -chloro -6 -methoxynicotinate 55 solvent was evaporated under reduced pressure to give the title compound (2 .60 g ) as a pale - yellow solid . In the same manner as in Example 59 , step 2 , the title ' H NMR ( 400 MHz, DMSO - do ) 8 7 . 94 ( 1H , s ) , 8 .81 (1H , compound (2 .05 g ) was obtained as a colorless oil from s ) , 13 .63 -14 . 30 (1H , m ). 2 - chloro - 6 -methoxynicotinic acid ( 1 . 5 g ) . MS (ESI + ) : [M + H ] * 278 .0 . 60 Step 2 ) benzyl 4 , 6 - dichloronicotinate Step 3) benzyl 2 - (4 - ( 3 -( 1- cyclopropyl- 3 - ethoxy - 3 Under a nitrogen atmosphere , benzyl bromide ( 1 .36 mL ) oxopropyl ) phenoxy )methyl ) piperidin - 1 -yl ) - 6 was added to a mixture of 4 ,6 - dichloronicotinic acid ( 2 . 0 g ) , methoxynicotinate potassium carbonate ( 2 .88 g ) and DMF (20 mL ) at room 65 temperature , and the mixture was stirred at 60° C . for 10 To a solution (8 mL ) of benzyl 2 -chloro -6 -methoxynico - min . To the reaction solution was added water at room timeletinate (500 solution mg) inis DMFnot awere benne added celor ethyl 3 -cyclopropyl conspice- 3 temperature, and the mixture was extracted with ethyl US 9 ,776 ,962 B2 185 186 acetate . The extract was washed with water and saturated (55 mL ) and extracted with ethyl acetate . The extract was brine, and dried over anhydrous magnesium sulfate. The washed with water and saturated brine , and dried over solvent was evaporated under reduced pressure to give a anhydrous magnesium sulfate . The solvent was evaporated crude product ( 3 . 06 g ) of the title compound as a pale under reduced pressure. Benzyl bromide (1 . 02 mL ) was added to a mixture of the obtained residue , potassium yellow oil . This compound was used for the next step 5 carbonate ( 2 . 46 g ) and DMF ( 30 ml ) at room temperature , without further purification . and the mixture was stirred at room temperature for 16 hr. ' H NMR (400 MHz, CDC13 ) 8 5. 40 (2H , s ), 7 .32 -7 .50 To the reaction solution was added water at room tempera ( 6H , m ), 8 . 87 ( 1H , s ). ture , and the mixture was extracted with ethyl acetate . The extract was washed with water and saturated brine , and dried Step 3) benzyl 6 - chloro -4 -( 4 -( hydroxymethyl )pip - 10 over anhydrous magnesium sulfate . The solvent was evapo eridin - 1- yl ) nicotinate rated under reduced pressure , and the residue was purified by silica gel column chromatography ( ethyl acetate /hexane ) A mixture of the crude product of benzyl 4 , 6 - dichloroni- to give the title compound ( 2 .70 g ) as a colorless oil . cotinate ( 3 .06 g ) , piperidin - 4 - ylmethanol ( 1 .29 g ) , potas - H NMR (400 MHz, CDC1z) / 1 . 29 - 1 .48 ( 2H , m ) , 1 .48 sium carbonate ( 2 . 11 g ) and DMF (30 mL ) was stirred at 60° 15 1. 66 ( 4H , m ), 1 .66 - 1 . 92 (5H , m ) , 2 .77 (2H , t, J = 11 . 7 Hz ), C . for 1 hr. To the reaction solution was added water at room 3 . 22 ( 1H , dd , J = 9 . 2 , 6 . 5 Hz) , 3 .43 (2H , d , J = 11 . 9 Hz) , temperature , and the mixture was extracted with ethyl 3 . 47 - 3 .56 ( 1H , m ) , 3 .56 -3 .65 ( 1H , m ) , 3 .84 ( 1H , t , J = 9 .6 acetate . The extract was washed with water and saturated Hz ) , 3 . 92 (3H , s ), 4 .57 ( 1H , brs ), 5 . 32 ( 2H , s ) , 6 . 14 ( 1H , s ) , brine , and dried over anhydrous magnesium sulfate . The 7 . 29 - 7 .40 (3H , m ) , 7 . 40 - 7 .49 ( 2H , m ) , 8 . 54 ( 1H , s ) . solvent was evaporated under reduced pressure to give a 20 crude product ( 3 . 94 g ) of the title compound as a pale Step 6 ) benzyl 4 - ( 4 - (hydroxymethyl ) piperidin - 1 - yl) yellow oil . This compound was used for the next step 6 - methoxynicotinate without further purification . 2N Hydrochloric acid (12 .3 mL ) was added to a solution Step 4 ) benzyl 6 - chloro - 4 - ( 4 - ( (( tetrahydro - 2H 25 of benzyl 6 -methoxy - 4 - ( 4 - ( ( ( tetrahydro -2H - pyran - 2 - yl) oxy ) pyran -2 -yl ) oxy )methyl ) piperidin - 1 -yl ) nicotinate methyl) piperidin -1 - yl) nicotinate (2 .70 g) in THF (30 mL ) at room temperature, and the mixture was stirred at 40° C . for p - Toluenesulfonic acid monohydrate ( 208 mg ) was added 4 hr and at 50° C . for 1 hr. To the reaction solution was added to a solution of the crude product ( 3 .94 g ) of benzyl saturated aqueous sodium hydrogen carbonate solution at 6 -chloro -4 - (4 - hydroxymethyl )piperidin - 1 -yl ) nicotinate and 30 room temperature , and the mixture was extracted with ethyl 3 , 4 - dihydro - 2H -pyran ( 2 .00 mL ) in THF ( 20 mL ) at room acetate . The extract was washed with water and saturated temperature , and the mixture was stirred at room tempera - brine, and dried over anhydrous magnesium sulfate . The ture for 16 hr. To the reaction solution was added saturated solvent was evaporated under reduced pressure , and the aqueous sodium hydrogen carbonate solution at room tem - residue was purified by silica gel column chromatography perature , and the mixture was extracted with ethyl acetate . 35 ( ethyl acetate /hexane ) to give the title compound ( 1 .67 g ) as The extract was washed with water and saturated brine , and a colorless oil . dried over anhydrous magnesium sulfate . The solvent was ' H NMR ( 400 MHz, DMSO - do) d 1 . 05 - 1 . 19 (2H , m ), evaporated under reduced pressure , and the residue was 1 .42 - 1. 57 (1H , m ), 1. 62 (2H , d, J= 12. 0 Hz ), 2 .73 (2H , t , purified by silica gel column chromatography ( ethyl acetate ! J = 11. 8 Hz) , 3. 22 (2H , t, J= 5. 6 Hz ), 3 .35 ( 2H , d , J= 12 .5 Hz) , hexane ) to give the title compound ( 3 .50 g ) as a colorless oil. 40 3 . 83 (3H , s ) , 4 .45 ( 1H , t , J = 5 . 2 Hz ), 5 . 28 (2H , s ) , 6 . 20 ( 1H , ' H NMR (400 MHz, CDC13 ) d 1 . 29 - 1. 46 ( 2H , m ), 1. 47 s) , 7. 26- 7. 52 (5H , m ), 8. 32 (1H , s) . 1 .65 (4H , m ) , 1 .66 - 1 . 90 (5H , m ), 2 .89 (2H , t , J = 12 . 0 Hz) , 3 . 22 ( 1H , dd , J = 9 . 3 , 6 . 1 Hz ), 3 .44 (2H , d , J = 12 . 5 Hz ), Step 7 ) benzyl 4 -( 4 -( ( ( 4 -( 1 -cyclopropyl - 3 - ethoxy - 3 3 .48 - 3 .55 ( 1H , m ), 3 . 56 - 3 .65 ( 1H , m ), 3 .77 - 3 .90 ( 1H , m ) , oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) 4 . 56 ( 1H , brs ), 5 .34 (2H , s ) , 6 .75 ( 1H , s ) , 7 . 31 - 7 .47 (5H , m ) , 45 6 -methoxynicotinatoyl ) oxy )methyl ) piperidin - 1 -yl ) 8 .50 ( 1H , s ). 6 -methoxynicotinate Step 5 ) benzyl 6 -methoxy - 4 - ( 4 - ( (( tetrahydro - 2H In the same manner as in Example 45 , step 6 , the title pyran - 2 -yl ) oxy )methyl )piperidin - 1 - yl ) nicotinate compound (522 mg) was obtained as a pale -orange oil from 50 benzyl 4 -( 4 - hydroxymethyl) piperidin - 1 -yl ) - 6 -methoxyni Under a nitrogen atmosphere, a solution of benzyl cotinate (576 mg) and methyl 3 -cyclopropyl - 3 -( 2 -hydroxy 6 -chloro -4 - (4 - (( ( tetrahydro - 2H -pyran - 2 - yl )oxy )methyl )pip - pyridin -4 -yl ) propanoate (329 mg) . eridin - 1 - yl) nicotinate ( 3 .37 g ) in DMF ( 10 mL ) was added ' H NMR (400 MHz , CDC1z ) 8 0 . 08 - 0 . 22 (1H , m ) , 0 .24 to a 28 % solution of sodium methoxide in methanol ( 14 . 4 0 .36 (1H , m ), 0 . 39 - 0 .53 (1H , m ), 0 . 55 - 0 .67 (1H , m ) , 0 . 91 mL ) at room temperature , and the mixture was stirred at 55 1 .07 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 1 Hz) , 1 .40 - 1 .55 ( 2H , m ) , 1 .83 room temperature for 1 hr and at 50° C . for 1 hr. The mixture ( 2H , d , J = 11. 8 Hz ), 1 . 96 ( 1H , brs ) , 2 .25 - 2 . 36 ( 1H , m ) , was diluted with ethyl acetate , IN hydrochloric acid was 2 .62 - 2 .87 ( 4H , m ) , 3 . 46 (2H , d , J = 12 . 0 Hz ) , 3 . 93 ( 3H , s ) , added to the reaction solution at 0° C ., and the mixture was 4 .01 - 4 . 19 (4H , m ) , 5 .33 ( 2H , s ) , 6 . 16 ( 1H , s ), 6 .61 ( 1H , s ) , extracted with ethyl acetate . The extract was washed with 6 .76 ( 1H , d , J = 5 . 3 Hz ), 7 . 29 - 7 .49 (5H , m ) , 8 .05 ( 1H , d , J = 5 . 1 water and saturated brine , and dried over anhydrous mag - 60 Hz ) , 8 .55 ( 1H , s ) . nesium sulfate . The solvent was evaporated under reduced pressure . The residue was dissolved in THF (30 mL ) and Step 8 ) 4 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopro methanol ( 15 mL ) , IN aqueous sodium hydroxide solution pyl) pyridin -2 - yl) oxy )methyl ) piperidin - 1- yl ) -6 ( 30 mL ) was added , and the mixture was stirred at 60° C . for methoxynicotinic acid 24 hr. The mixture was diluted with ethyl acetate , and 65 extracted with IN aqueous sodium hydroxide solution ( 25 Benzyl 4 - ( 4 - ( ( ( 4 - ( 1 - cyclopropyl- 3 - ethoxy - 3 - oxopropyl ) mL ). The extract was neutralized with 1N hydrochloric acid pyridin - 2 -yl ) oxy )methyl ) piperidin - 1 -yl ) - 6 -methoxynicoti US 9 ,776 , 962 B2 187 188 natoyl) oxy )methyl ) piperidin - 1- yl ) - 6 -methoxypyridine -3 - 1 .05 ( 1H , m ), 1 .19 ( 3H , t, J= 7 . 2 Hz) , 1. 26 - 1. 52 (2H , m ), 1. 75 carboxylate (522 mg) and 10 % palladium carbon (300 mg) (2H , d , J = 11 .7 Hz ), 1. 83 - 1. 98 ( 1H , m ) , 2. 27 - 2. 35 (1H , m ), were stirred in THF ( 15 mL ) under a hydrogen atmosphere 2 .58 - 2 .81 (4H , m ) , 3 . 17 (2H , brs ) , 3 . 90 (3H , s ) , 4 .02 - 4 .11 ( 1 atm ) at room temperature for 20 min . The reaction (2H , m ) , 4 . 14 (2H , d , J = 6 . 7 Hz) , 4 .83 - 5 . 05 ( 2H , m ) , 5 . 84 mixture was filtered , and the solvent in the filtrate was 5 ( 1H , s ) , 6 .62 ( 1H , s ) , 6 .67 ( 1H , d , J = 7 . 9 Hz ), 6 .77 ( 1H , d , evaporated under reduced pressure to give the title com - J = 5 . 3 Hz ) , 7 .02 ( 1H , dd , J = 7 . 2 , 5 . 0 Hz) , 7 . 38 ( 1H , t , J = 7 . 8 pound ( 407 mg) as a colorless amorphous powder . Hz ), 8 . 03 - 8 . 08 ( 2H , m ) , 8 .42 ( 1H , d , J = 4 . 4 Hz ) . IMMO' H NMRmg ( 400) reducandMHz, DMSO - d ) 8 0 .08 - 0 .20 ( 1H , m ) , 0 . 22 - 0 . 29 ( 1H , m ) , 0 . 31 - 0 . 40 ( 1H , m ) , 0 .44 - 0 . 56 ( 1H , m ) , Step 2 ) 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -methoxy - 5 -( pyri 0 .95 - 1 . 05 ( 1H , m ), 1 .08 ( 3H , t, J = 7 . 1 Hz) , 1 . 37 - 1 . 49 (2H , 10 din - 2 - yl( 2 , 2 , 2 - trifluoroethyl )carbamoyl ) pyridin - 4 - yl) m ) , 1 . 80 ( 2H , d , J = 11. 8 Hz) , 1 . 88 - 2 . 04 ( 1H , m ) , 2 . 16 - 2 . 30 piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid ( 1H , m ), 2 .75 (2H , d , J = 7 . 4 Hz ), 2 . 83 (2H , t , J = 12 . 1 Hz ), 3 . 45 (2H , d , J = 12 . 2 Hz) , 3 . 84 (3H , s ) , 3 .92 - 4 .02 (2H , m ) , In the same manner as in Example 1, step 4 , the title 4 . 13 (2H , d , J = 6 . 1 Hz ) , 6 . 26 ( 1H , s ) , 6 .72 ( 1H , s ) , 2876 . 91 (11 1H , 15 compound ( 18 . 6 mg) was obtained as a white amorphous d , J = 5 .3 Hz ), 8 .03 (1H , d , J = 5 . 1 Hz ), 8 . 33 ( 1H , s ), 12 .87 (1H , 15 powderC from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -methoxy - 5 brs ). (pyridin - 2 - yl( 2 , 2 , 2 - trifluoroethyl) carbamoyl) pyridin - 4 -yl ) Step 9 ) ethyl 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - (5 - ( ( 2 , 2 - dim piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) propanoate (30 . 8 mg) . ethylpropyl) (6 -methylpyridin - 2 -yl ) carbamoyl ) -2 MS (ESI + ) : [ M + H ]* 614 .2 . methoxypyridin - 4 - yl) piperidin - 4 - yl) methoxy )pyri 20 din - 4 -yl ) propanoate Example 257 In the same manner as in Example 32 , step 2, the title compound ( 14 . 5 mg ) was obtained as a colorless oil from 3 -cyclopropyl - 3 - ( 2 - ( ( 1 - ( 5 - ( ( 2 , 2 -dimethylpropyl ) ( 6 4 -( 4 - ( ( (4 -( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - 25 methylpyrimidin - 4 - yl) carbamoyl) - 2 -methoxypyri yl) oxy )methyl ) piperidin - 1 - yl) - 6 -methoxynicotinic acid ( 73 din - 4 - yl) piperidin - 4 - yl )methoxy )pyridin - 4 - yl) pro mg) and N -( 2, 2 -dimethylpropyl ) -6 -methylpyridin - 2 -amine panoic acid (67 . 3 mg) . * H NMR ( 400 MHz, CDC1z ) 8 0 . 09 - 0 .21 ( 1H , m ), 0 . 24 In the samemanner as in Example 32 , step 2 and Example 0 . 35 ( 1H , m ), 0 . 42 - 0 .53 ( 1H , m ) , 0 . 55 - 0 .67 ( 1H , m ) , 0 .82 30 1, step 4 , the title compound (21 mg) was obtained as a (9H , s ), 0 . 90 - 1 .05 ( 1H , m ), 1 . 19 (3H , t, J = 7 . 2 Hz) , 1 . 25 - 2 .01 colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) (6H , m ), 2 .30 (1H , 9 , J = 8 . 4 Hz ), 2 . 45 (3H , s ) , 2 .47 - 2 .91 (4H , 6 -methylpyrimidin - 4 -amine (68 mg) and 4 -( 4 -( (( 4 -( 1 -cyclo m ) , 3 .43 ( 1H , brs ) , 3 . 88 (3H , s ) , 4 . 00 - 4 . 29 (6H , m ) , 5 . 79 ( 1H , propyl- 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - yl) oxy )methyl ) pip s ) , 6 .43 ( 1H , brs ), 6 .62 ( 1H , s ) , 6 .76 (2H , d , J = 6 . 1 Hz) , 7 . 19 35 eridin - 1 - yl) -6 -methoxynicotinic acid ( 115 mg) obtained in ( 1H , t , J= 7 .6 Hz ), 7. 99 (1H , s ), 8. 05 (1H , d , J= 5 . 1 Hz) . 35 Example 255 , step 8 . MS (ESI + ): [ M + H ] * 617. 2 . Step 10 ) 3 - cyclopropyl- 3 - ( 2 - (( 1 - (5 - ( ( 2 , 2 - dimethyl propyl) (6 -methylpyridin - 2 - yl) carbamoyl) - 2 Example 258 methoxypyridin - 4 - yl) piperidin - 4 - yl) methoxy )pyri din - 4 - yl) propanoic acid 40 3 -cyclopropyl - 3 - ( 2 - (( 1 -( 2 -( ( 2 ,2 -dimethylpropyl ) ( 6 In the same manner as in Example 1, step 4 , the title methylpyridin - 2 -yl ) carbamoyl) - 5 -methylphenyl ) compound (13 . 5 mg) was obtained as a white amorphous piperidin - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid powder from ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 5 - ( 2 , 2 - dimeth ylpropyl) (6 -methylpyridin -2 -yl ) carbamoyl ) - 2 -methoxypyri - 45 Step 1) N -( 2 , 2 -dimethylpropyl ) - 2- fluoro -4 - methyl din -4 -yl ) piperidin -4 -yl )methoxy )pyridin -4 - yl) propanoate N - (6 -methylpyridin - 2 -yl ) benzamide ( 14 .5 mg) . MS (ESI + ) : [ M + H ] * 616 . 3 . In the same manner as in Example 1 , step 1 , the title compound (718 mg) was obtained as a white solid from Example 256 50 2 - fluoro - 4 -methylbenzoic acid ( 865 mg) and N - (2 , 2 - dimeth 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -methoxy - 5 - ( pyridin - 2 - yl ylpropyl) - 6 -methylpyridin -2 - amine (500 mg) . ( 2 ,2 ,2 - trifluoroethyl) carbamoyl ) pyridin -4 -yl ) piperi MS (ESI + ) : [ M + H ] * 315 .2 . din - 4 - yl) methoxy ) pyridin - 4 - yl) propanoic acid 55 Step 2 ) 3 -cyclopropyl -3 - (2 - ( ( 1 -( 2 -( ( 2 , 2 - dimethyl Step 1 ) ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 -methoxy - 5 propyl) (6 -methylpyridin - 2 - yl) carbamoyl) - 5 -methyl (pyridin - 2 -yl ( 2 ,2 ,2 - trifluoroethyl) carbamoyl ) pyridin phenyl) piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) pro 4 - yl) piperidin - 4 - yl )methoxy ) pyridin - 4 - yl) propanoate panoic acid In the same manner as in Example 32, step 2 , the title 60 compound (30 . 8 mg ) was obtained as a colorless oil from In the same manner as in Example 245 , step 12 and 4 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 - Example 1 , step 4 , the title compound ( 70 mg ) was obtained yl) oxy )methyl )piperidin - 1- yl) - 6 -methoxynicotinic acid as grayish white solid from ethyl 3 -cyclopropyl - 3 - ( 2 - (pip ( 58 . 7 mg) and N - ( 2 , 2 , 2 - trifluoroethyl) pyridin - 2 - amine ( 53. 5 eridin - 4 -ylmethoxy )pyridin - 4 -yl ) propanoate ( 155 mg) and mg) . 5 N -( 2 ,2 -dimethylpropyl ) - 2 - fluoro -4 -methyl -N -( 6 -methyl H NMR (400 MHz, CDC1z ) 0 . 12 -0 .22 ( 1H , m ), 0 . 26 pyridin - 2 - yl )benzamide ( 113 mg) . 0 .33 (1H , m ), 0 .41 - 0 . 52 ( 1H , m ), 0 .56 - 0 . 66 ( 1H , m ), 0 .92 MS ( ESI + ) : [ M + H ] * 599 . 3 . US 9 ,776 , 962 B2 189 190 Example 259 ' H NMR (400 MHz, CDC13 ) 8 0. 88 (9H , s ), 2 .36 (3H , s) , 4 . 06 ( 2H , s ), 6 .75 ( 1H , d , J= 7 . 4 Hz) , 6 .88 ( 1H , d , J= 7 . 5 Hz) , 3 -cyclopropyl - 3 - (2 - (( 1 -( 2 -( ( 2 , 2 -dimethylpropyl ) (6 7 . 18 ( 1H , d , J = 8 . 7 Hz) , 7 .27 - 7 .34 (2H , m ), 7 . 37 (1H , t , J = 7 . 7 methylpyridin - 2 - yl) carbamoyl) - 5 -hydroxyphenyl ) Hz ). piperidin -4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid 5 Step 2 ) ethyl 3 - ( 2 - ( ( 1 - ( 5 - cyano - 2 - ( ( 2 , 2 - dimethylpro Step 1) 4 -( benzyloxy ) - N -( 2 ,2 - dimethylpropyl) -2 pyl) ( 6 -methylpyridin - 2 - yl) carbamoyl ) phenyl) piperi fluoro - N - (6 -methylpyridin - 2 - yl )benzamide din - 4 - yl) methoxy )pyridin - 4 - yl) - 3 - cyclopropylpro panoate In the same manner as in Example 1 , step 1 , the title 10 compound ( 478 mg ) was obtained as grayish white solid In the same manner as in Example 1 , step 2 , the title from 4 - (benzyloxy ) - 2 - fluorobenzoic acid (2 . 0 g ) and N - ( 2 , compound (235 mg) was obtained as a colorless oil from 2 - dimethylpropyl) -6 -methylpyridin - 2 - amine ( 724 mg) . 4 -cyano - N - ( 2 , 2 -dimethylpropyl ) - 2 - fluoro - N - (6 -methylpyri MS ( ESI + ) : [ M + H ] * 407 . 2 . 15 din - 2 -yl ) benzamide ( 150 mg) and ethyl 3 - cyclopropyl- 3 - ( 2 (piperidin - 4 -ylmethoxy )pyridin - 4 -yl ) propanoate ( 153 mg) . Step 2 ) ethyl 3 - ( 2 - ( ( 1 - ( 5 - (benzyloxy ) - 2 - ( ( 2 , 2 - dim 'H NMR (400 MHz, CDC13 ) 8 0 . 11 -0 .22 (1H , m ), 0 .25 ethylpropyl )( 6 -methylpyridin -2 -yl ) carbamoyl) phe 0 . 34 ( 1H , m ) , 0 .41 - 0 . 51 ( 1H , m ), 0 .55 - 0 .67 ( 1H , m ) , 0 . 85 nyl) piperidin - 4 -yl )methoxy )pyridin - 4 - yl ) - 3 -cyclo ( 9H , s ) , 0 . 93 - 1 . 06 ( 1H , m ) , 1 . 19 ( 3H , t , J = 7 . 2 Hz ) , 1 . 25 - 1 . 39 propylpropanoate 20 ( 1H , m ) , 1 . 53 - 1 .68 ( 1H , m ) , 1 . 74 - 1 . 94 ( 3H , m ), 2 . 04 ( 1H , s ) , 2 .26 - 2 . 35 ( 1H , m ) , 2 .38 (3H , s ) , 2 .41 - 2 .65 (2H , m ) , 2 .66 In the same manner as in Example 245 , step 12 , the title 2 .81 (3H , m ), 3 .46 ( 1H , d , J= 10 . 9 Hz) , 4 .02 -4 . 12 ( 2H , m ), compound (200 mg) was obtained as a pale- yellow oil from 4 .12 -4 .27 (4H , m ), 6 .41 ( 1H , d , J= 7 .8 Hz) , 6 .63 (1H , s ), ethyl 3 -cyclopropyl -3 - ( 2 -( piperidin - 4 - ylmethoxy ) pyridin - 4 - 6 .72 -6 .81 ( 2H , m ), 6 .91 (1H , s) , 7 .14 ( 1H , t, J= 7 .8 Hz) , 7 .20 yl) propanoate (176 mg) and 4 -( benzyloxy ) -N -( 2 ,2 -dimeth - 25 ( 1H , d , J= 7 . 5 Hz) , 7 .41 ( 1H , d, J= 7 .9 Hz ), 8 .07 (1H , d , J = 5 . 1 ylpropyl) - 2 - fluoro - N - (6 -methylpyridin - 2 - yl ) benzamide Hz ) . (215 mg) . MS (ESI + ): [ M + H ] * 719 . 5 . Step 3 ) 3 - ( 2 - ( ( 1 - ( 5 - cyano- 2 -( ( 2 , 2 -dimethylpropyl ) (6 -methylpyridin -2 -yl ) carbamoyl )phenyl ) piperidin Step 3 ) ethyl 3 -cyclopropyl - 3 -( 2 -( ( 1 -( 2 -( (2 , 2 -dim - 30 4 - yl)methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpropanoic ethylpropyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 acid hydroxyphenyl) piperidin -4 -yl ) methoxy ) pyridin - 4 -yl ) propanoate In the same manner as in Example 1, step 4 , the title In the same manner as in Example 199, step 1, the title 355 compound (44 . 8 mg ) was obtained as a white solid from compound (155 mg) was obtained as a colorless oil from ethyl 3 -( 2 -( ( 1- ( 5 -cyano - 2- (( 2 ,2 -dimethylpropyl ) (6 -methyl ethyl 3 - ( 2 - ( ( 1 - ( 5 - (benzyloxy ) - 2 - ( ( 2 , 2 - dimethylpropyl) (6 pyridin - 2 - yl) carbamoyl ) phenyl) piperidin - 4 - yl) methoxy ) methylpyridin -2 - yl )carbamoyl ) phenyl ) piperidin -4 - yl) pyridin - 4 - yl) - 3 - cyclopropylpropanoate ( 50 . 0 mg) . methoxy ) pyridin - 4 - yl) - 3 - cyclopropylpropanoate ( 180 mg) . MS (ESI + ) : ( M + H ] ' 610 . 3 . MS ( ESI + ) : [ M + H ] * 629 .4 . 40 Example 261 Step 4 ) 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl propyl) (6 -methylpyridin - 2 - yl) carbamoyl) - 5 - hy droxyphenyl) piperidin -4 - yl) methoxy ) pyridin - 4 - yl) 3 -( 2 -( ( 1- ( 5 -carbamoyl - 2 -( (2 , 2 -dimethylpropyl ) ( 6 45 methylpyridin -2 -yl ) carbamoyl ) phenyl ) piperidin -4 propanoic acid yl) methoxy )pyridin - 4 - yl ) - 3 - cyclopropylpropanoic In the same manner as in Example 1 , step 4 , the title acid compound ( 6 . 3 mg) was obtained as a grayish white amor phous powder from ethyl 3 - cyclopropyl- 3 - (2 - ( (1 -( 2 -( (2 , 2 dimethylpropyl) (6 -methylpyridin - 2 - yl ) carbamoyl) - 5 - hy - 50 Step 1 ) N1- ( 2 ,2 -dimethylpropyl ) - 2- fluoro -N1 - ( 6 droxyphenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) methylpyridin - 2 -yl ) benzene - 1 ,4 - dicarboxamide propanoate ( 15 mg) . 30 % Hydrogen peroxide aqueous solution (235 uL ) was MS (ESI + ) : [ M + H ]* 601. 3 . added to a mixture of 4 - cyano - N - ( 2 , 2 - dimethylpropyl) - 2 fluoro - N - ( 6 -methylpyridin - 2 - yl) benzamide ( 150 mg ) , potas Example 260 sium carbonate ( 96 mg ) and DMSO ( 2 mL ) at room tem 3 -( 2 - ( 1 - (5 -cyano - 2 -( ( 2 , 2 -dimethylpropyl ) (6 -methyl perature , and the mixture was stirred at room temperature for pyridin - 2 - yl) carbamoyl ) phenyl) piperidin - 4 -yl ) 5 min . To the reaction solution was added water at room methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid temperature , and the mixture was extracted with ethyl coacetate . The extract was washed with saturated brine , and dried over anhydrous magnesium sulfate . The solvent was Step 1 ) 4 - cyano - N - ( 2 , 2 - dimethylpropyl) - 2 - fluoro - N evaporated under reduced pressure and the obtained solid (6 -methylpyridin - 2 -yl ) benzamide was washed with diisopropyl ether to give the title com In the same manner as in Example 1 , step 1 , the title pound ( 134 mg ) as a white solid . compound (503 mg) was obtained as a pale - orange solid 65 H NMR ( 400 MHz, DMSO -da ) 8 0 .81 ( 9H , s ), 2 . 27 ( 3H , from 4 -cyano -2 - fluorobenzoic acid (500 mg) and N -( 2, 2 - s ), 3 .98 (2H , s ), 6 .90 -7 .02 (2H , m ), 7 .26 ( 1H , t , J = 7 . 2 Hz ), dimethylpropyl) - 6 -methylpyridin - 2 - amine ( 360 mg) . 7 .44 - 7 .60 ( 4H , m ) , 8 . 00 ( 1H , brs ). US 9 ,776 , 962 B2 191 192 Step 2 ) ethyl 3 - ( 2 - ( ( 1 - ( 5 - carbamoyl- 2 - ( ( 2 , 2 - dimeth acetone ( 4 mL ) and water ( 4 mL ) was added sodium chlorite ylpropyl ) (6 -methylpyridin - 2 -yl ) carbamoyl ) phenyl ) ( 395 mg ) at room temperature , and the mixture was stirred piperidin - 4 -yl )methoxy )pyridin - 4 -yl ) - 3 -cyclopropyl overnight. Sodium thiosulfate was added , and the mixture propanoate was diluted with saturated brine and extracted with ethyl 5 acetate . The extract was dried over anhydrous magnesium In the same manner as in Example 1 , step 2 , the title sulfate . The solvent was evaporated under reduced pressure , compound (50 .4 mg) was obtained as a pale -yellow amor - and the residue was purified by silica gel column chroma phous powder from N1- ( 2 , 2 -dimethylpropyl ) -2 - fluoro -N1 tography ( ethyl acetate /hexane ) to give the title compound (6 -methylpyridin - 2- yl ) benzene - 1, 4 -dicarboxamide (134 (715 mg ) as a colorless oil . mg) and ethyl 3 -cyclopropyl - 3 -( 2 - (piperidin -4 - ylmethoxy ) 10 MS (ESI + ): [M + H ]+ 531 . 2 . pyridin - 4 - yl) propanoate ( 130 mg ) . ' H NMR ( 400 MHz, CDC12 ) & 0 . 11 - 0 .23 ( 1H , m ) , 0 . 25 Step 3 ) 2 - (4 - (( (4 - ( 1 - cyclopropyl- 3 - ethoxy -3 - oxopro 0 . 34 ( 1H , m ), 0 .41 - 0 .52 (1H , m ) , 0 .56 - 0 .67 ( 1H , m ) , 0 .85 pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 ( 9H , brs ), 0 . 95 - 1 . 04 ( 1H , m ) , 1 . 19 (3H , t . J = 7 . 2 Hz ) , (methylsulfanyl ) benzoic acid 1 . 24 - 1 .41 (1H , m ), 1 . 52 - 1 .70 (1H , m ), 1 .74 - 1 .93 (3H , m ), 15 2 .31 ( 1H , q , J = 8 . 0 Hz) , 2 .40 (3H , s ) , 2 .43 - 2 .87 (5H , m ), 3 . 47 Under a nitrogen atmosphere , to a solution of 4 -bromo (1H , brs ) , 3 . 97 - 4 . 31 (6H , m ) , 5 .50 (1H , brs ) , 6 . 00 ( 1H , brs ) , 2 - ( 4 - ( ( ( 4 - ( 1 -cyclopropyl - 3 - ethoxy - 3 -oxopropyl ) pyridin - 2 6 .40 ( 1H , d , J = 7 . 9 Hz) , 6 .64 ( 1H , s ) , 6 .71 ( 1H , d , J = 7 . 3 Hz ) , yl) oxy )methyl ) piperidin - 1 - yl) benzoic acid (230 mg ) in 6 .77 ( 1H , d , J = 5 . 4 Hz ) , 7 . 08 ( 1H , t, J = 7 . 6 Hz ), 7 . 21 - 7 .27 DMSO ( 2 mL ) were added copper ( I ) iodide (82 mg) and ( 2H , m ), 7 . 38 ( 1H , d , J= 7. 7 Hz ), 8 .07 ( 1H , d, J= 5 .3 Hz ). 20 zinc (II ) fluoride (36 mg ), and the mixture was stirred at 140° C . for 18 hr. The reaction mixture was allowed to cool to Step 3 ) 3 - ( 2 - (( 1 - ( 5 - carbamoyl- 2 - ( ( 2 , 2 - dimethylpro room temperature , and purified by silica gel column chro pyl) (6 -methylpyridin - 2 -yl ) carbamoyl) phenyl) piperi matography ( ethyl acetate /hexane ) to give the title com din - 4 - yl )methoxy )pyridin - 4 - yl) - 3 - cyclopropylpro pound ( 48 mg) as a brown oil. panoic acid 25 MS (ESI + ) : [ M + H ] + 499 . 3 . In the same manner as in Example 1 , step 4 , the title Step 4 ) 3 -cyclopropyl - 3 - ( 2 -( ( 1 - ( 2 -( ( 2 , 2 -dimethyl compound (20 . 9 mg) was obtained as a white amorphous propyl) (6 -methylpyridin - 2 -yl ) carbamoyl) - 5 - (methyl powder from ethyl 3 - ( 2 - ( ( 1 - ( 5 - carbamoyl- 2 - ( ( 2 , 2 -dimethyl sulfanyl) phenyl) piperidin - 4 - yl) methoxy ) pyridin - 4 propyl) ( 6 - methylpyridin - 2 - yl) carbamoyl) phenyl ) piperidin - 30 yl) propanoic acid 4 -yl ) methoxy )pyridin - 4 -yl ) - 3 -cyclopropylpropanoate (50 .4 mg) . In the samemanner as in Example 32 , step 2 and Example MS (ESI + ) : [ M + H ] * 628 . 3 . 1 , step 4 , the title compound ( 32 mg ) was obtained as a colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) Example 262 35 6 -methylpyridin -2 - amine (69 mg ) and 2- [4 - (( ( 4 -( 1 -cyclo propyl - 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) pip 3 - cyclopropyl- 3 - (2 - ( (1 -( 2 -( ( 2 ,2 -dimethylpropyl ) (6 eridin - 1 -yl ) -4 -( methylsulfanyl ) benzoic acid ( 48 mg) . methylpyridin -2 - yl )carbamoyl ) - 5 -( methylsulfanyl ) MS ( ESI + ) : [ M + H ] * 631 . 3 . phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl ) pro panoic acid 40 Example 263 Step 1 ) ethyl 3 - ( 2 - ( ( 1 - ( 5 - bromo- 2 - formylphenyl) 3 - ( 2 - ( ( 1 - ( 5 - bromo - 2 - ( ( 2 , 2 - dimethylpropyl) ( 6 -meth piperidin -4 - yl) methoxy ) pyridin -4 - yl) -3 -cyclopropyl ylpyridin - 2 - yl) carbamoyl) phenyl) piperidin - 4 -yl ) propanoate methoxy )pyridin -4 - yl) - 3 -cyclopropylpropanoic acid 45 In the same manner as in Example 1 , step 2 , the title In the samemanner as in Example 32 , step 2 and Example compound ( 960 mg) was obtained as a brown oil from ethyl 1 , step 4 , the title compound (85 mg) was obtained as a 3 -cyclopropyl - 3 - ( 2 - ( piperidin - 4 - ylmethoxy )pyridin - 4 - yl) colorless amorphous powder from N - ( 2 , 2 - dimethylpropyl) propanoate ( 730 mg ) obtained in Example 250 , step 1 , and 6 -methylpyridin - 2 - amine ( 242 mg) and 4 -bromo - 2 - ( 4 - ( ( ( 4 4 -bromo - 2 - fluorobenzaldehyde ( 580 mg ) . 50 (1 -cyclopropyl - 3 -ethoxy -3 -oxopropyl ) pyridin -2 -yl ) oxy ) ' H NMR ( 300 MHz, CDC13 ) 8 0 . 11 - 0 . 22 ( 1H , m ) , 0 . 25 - methyl ) piperidin - 1 - yl) benzoic acid ( 360 mg) obtained in 0 .35 ( 1H , m ), 0 .41 - 0 .53 (1H , m ) , 0 .54 - 0 .67 ( 1H , m ) , 0 . 93 - Example 262 , step 2 . 1 .05 ( 1H , m ), 1. 19 (3H , t, J= 7 . 2 Hz ) , 1 .56 - 1. 72 (2H , m ), MS (ESI + ): [M + H ]* 663 . 2 . 1 .89 - 2 .03 (3H , m ) , 2 . 26 - 2 .37 ( 1H , m ) , 2 .63 - 2 .82 (2H , m ) , 2 .93 ( 2H , td , J = 12 . 0 , 1 . 9 Hz ) , 3 . 28 - 3 . 39 (2H , m ), 4 . 02 - 4 . 13 55 Example 264 ( 2H , m ) , 4 . 22 (2H , d , J = 6 . 0 Hz ), 6 .62 - 6 .65 ( 1H , m ) , 6 . 77 ( 1H , dd , J = 5 . 3 , 1 . 4 Hz ) , 7 . 19 - 7 . 26 (2H , m ) , 7 .65 ( 1H , d , 3 -cyclopropyl - 3 - (2 - (( 1 - (2 - (( 2 ,2 -dimethylpropyl ) ( 6 J = 8 . 2 Hz) , 8 . 06 ( 1H , d , J = 5 . 4 Hz) , 10 .21 ( 1H , d , J = 0 . 6 Hz) . methylpyridin - 2 - yl) carbamoyl ) - 5 - (methylsulfonyl ) phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) pro Step 2 ) 4 -bromo - 2 - (4 - ( (( 4 -( 1 -cyclopropyl - 3 -ethoxy - 60 panoic acid 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) benzoic acid Step 1 ) ethyl 3 - cyclopropyl - 3 - ( 2 - ( ( 1 - ( 2 - formyl- 5 (methylsulfonyl ) phenyl) piperidin - 4 -yl )methoxy ) To a solution of ethyl 3 - ( 2 - ( ( 1 - ( 5 -bromo - 2 - formylphenyl ) pyridin - 4 - yl) propanoate piperidin -4 -yl ) methoxy )pyridin -4 -yl ) - 3 - cyclopropylpro - 65 panoate ( 750 mg) , sodium dihydrogen phosphate ( 873 mg) Under a nitrogen atmosphere , to a solution of ethyl and 2 -methylbut - 2 -ene ( 1. 55 mL ) in tert -butanol ( 12 mL ), 3 -( 2 -( ( 1- ( 5 -bromo - 2 - formylphenyl) piperidin - 4 -yl ) methoxy ) US 9 ,776 ,962 B2 193 194 pyridin -4 -yl ) - 3 -cyclopropylpropanoate (210 mg) obtained purified by silica gel column chromatography (ethyl acetate / in Example 262 , step 1 , in DMSO ( 3 mL ) were added hexane ) to give the title compound ( 285 mg) as a colorless sodium methanesulfinate (208 mg) and copper ( I) iodide (82 amorphous powder . mg) , and the mixture was stirred at 100° C . for 15 hr. The MS (ESI + ): [M + H ]* 665 . 3 . reaction mixture was allowed to cool to room temperature , 5 and purified by silica gel column chromatography ( ethyl Step 3 ) 3 - ( 2 - ( ( 1 - ( 5 -chloro - 2 - ( 2 , 2 -dimethylpropyl ) acetate /hexane ) to give the title compound ( 165 mg) as a (6 -methylpyridin - 2 - yl) carbamoyl) - 3 - fluorophenyl) pale- yellow oil . piperidin - 4 - yl) methoxy )pyridin - 4 - yl ) - 3 - cyclopropyl propanoic acid MS (ESI + ): [ M + H ]* 515 .2 . 10 Step 2 ) 2 -( 4 - ( ( [4 -( 1 - cyclopropyl - 3 - ethoxy - 3 - oxopro In the same manner as in Example 1 , step 4 , the title pyl) pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 compound ( 143 mg ) was obtained as a colorless amorphous (methylsulfonyl ) benzoic acid powder from ethyl 3 - ( 2 - ( ( 1 - ( 5 -chloro - 2 - ( ( 2 , 2 - dimethylpro pyl) (6 -methylpyridin - 2 - yl )carbamoyl ) - 3 - fluorophenyl) pip In the samemanner as in Example 2622. , step 22 , the title 15 eridin -4 -yl ) methoxy ) pyridin - 4 -yl ) -3 -cyclopropylpropanoate compound (135 mg) was obtained as a colorless oil from ( 150 mg) . ethyl 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - formyl- 5 - (methylsulfonyl ) MS (ESI + ) : [ M + H ] * 637. 3 . phenyl) piperidin - 4 -yl )methoxy )pyridin -4 -yl ) propanoate Example 266 ( 165 mg ) . 20 MS (ESI + ) : [M + H ]* 531. 2 . 3 -( 2 -( ( 1 - (5 - chloro -2 - (( 2 ,2 -dimethylpropyl ) ( 6 -meth Step 3 ) 3 - cyclopropyl- 3 - ( 2 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethyl ylpyridin - 2 - yl) carbamoyl) phenyl ) piperidin - 4 - yl) propyl) ( 6 -methylpyridin - 2 - yl) carbamoyl) -5 -( methyl methoxy )pyridin - 4 -yl ) -3 -cyclopropylpropanoic acid sulfonyl) phenyl) piperidin - 4 - yl) methoxy )pyridin - 4 - 25 Step 1) 4 -chloro -N - ( 2, 2 -dimethylpropyl ) - 2 - fluoro yl) propanoic acid N - ( 6 -methylpyridin - 2 - yl) benzamide In the samemanner as in Example 32 , step 2 and Example In the same manner as in Example 1 , step 1 , the title 1 , step 4 , the title compound (71 mg ) was obtained as a compound (258 mg) was obtained as a pale - yellow solid colorless amorphous powder from N - ( 2 , 2 -dimethylpropyl ) - 30 from 4 -chloro - 2 - fluorobenzoic acid (587 mg) and N - ( 2 , 2 6 -methylpyridin - 2 - amine (91 mg) and 2 - [ 4 - ( ( (4 -( 1 - cyclo - dimethylpropyl) - 6 -methylpyridin - 2 - amine ( 300 mg) . propyl- 3 - ethoxy - 3 - oxopropyl) pyridin - 2 - yl) oxy )methyl ) pip - MS ( ESI+ ) : [ M + H ] * 335 . 1 . eridin - 1 - yl) - 4 - (methylsulfonyl ) benzoic acid ( 153 mg) . MS ( ESI + ) : [ M + H ] * 663 . 2 . Step 2 ) 3 - ( 2 - ( ( 1 - (5 - chloro - 2 - ( ( 2 , 2 - dimethylpropyl ) 35 ( 6 -methylpyridin - 2 - yl) carbamoyl ) phenyl) piperidin Example 265 4 - yl) methoxy )pyridin - 4 - yl) - 3 - cyclopropylpropanoic acid 3 -( 2 -( ( 1 - (5 - chloro -2 -( ( 2 ,2 -dimethylpropyl ) ( 6 -meth In the same manner as in Example 245 , step 12 and ylpyridin - 2 - yl) carbamoyl) - 3 - fluorophenyl) piperidin 40 Example 1 , step 4 , the title compound (113 mg) was 4 - yl) methoxy ) pyridin - 4 - yl) - 3 - cyclopropylpropanoic obtained as a grayish white amorphous powder from ethyl acid 3 -cyclopropyl - 3 - ( 2 - (piperidin - 4 -ylmethoxy ) pyridin -4 -yl ) propanoate ( 99 mg) and 4 - chloro - N - ( 2 , 2 - dimethylpropyl) Step 1 ) 4 -chloro - N - (2 , 2 -dimethylpropyl ) - 2 ,6 -dif 2 - fluoro - N - (6 -methylpyridin - 2 -yl ) benzamide (100 mg) . luoro -N -( 6 -methylpyridin -2 -yl ) benzamide 45 MS (ESI + ): ( M + H ] + 619 . 3 . In the same manner as in Example 32 , step 2 , the title Example 267 compound ( 200 mg) was obtained as a pale -yellow amor phous powder from N - ( 2 , 2 -dimethylpropyl ) -6 -methylpyri 3 -cyclopropyl - 3 - ( 2 - ( (1 - ( 5 -( difluoromethoxy )- 2 - ( 2 , din -2 -amine (370 mg) and 4 -chloro - 2, 6 -difluorobenzoic 50 2 -dimethylpropyl ) (6 -methylpyridin - 2 -yl ) carbamoyl ) acid (200 mg) . phenyl) piperidin -4 -yl ) methoxy ) pyridin -4 -yl ) pro ' H NMR (300 MHz, CDC13 ) 8 0 . 88 (9H , s) , 2 .39 (3H , s) , panoic acid 4 .06 (2H , s) , 6 .69 -6 .86 (3H , m ), 6 . 90 ( 1H , d , J = 7. 6 Hz ), 7 .39 ( 1H , t, J = 7 . 7 Hz) . To a solution ( 2 mL ) of ethyl 3 - cyclopropyl- 3 -( 2 - ( ( 1 - ( 2 55 (( 2, 2 -dimethylpropyl ) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 Step 2 ) ethyl 3 - ( 2 - ( ( 1 - ( 5 - chloro - 2 - ( ( 2 , 2 - dimethyl hydroxyphenyl) piperidin - 4 - yl) methoxy )pyridin - 4 -yl )pro propyl) ( 6 -methylpyridin - 2 - yl) carbamoyl ) - 3 - fluoro panoate ( 100 mg) obtained in Example 259 , step 3 , and phenyl) piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) - 3 -cy methyl chloro (difluoro ) acetate ( 101 mL ) in DMA was added clopropylpropanoate cesium carbonate ( 155 mg ), and the mixture was stirred at 60 100° C . for 3 hr. To the reaction mixture was added water , Under a nitrogen atmosphere, a mixture of 4 - chloro - N - and the mixture was extracted with ethyl acetate . The extract ( 2, 2 - dimethylpropyl) - 2 ,6 - difluoro - N -( 6 -methylpyridin - 2 - was washed with water and saturated brine, and dried over yl) benzamide ( 200 mg) , ethyl 3 -cyclopropyl - 3 -( 2 - (piperi - anhydrous sodium sulfate . The solvent was evaporated din - 4 - ylmethoxy )pyridin - 4 - yl) propanoate (188 mg) under reduced pressure, and the residue was purified by obtained in Example 250 , step 1, and cesium carbonate ( 185 65 silica gel column chromatography (ethyl acetate /hexane ). mg) was stirred at 120° C . for 1 hr. The reaction mixture was The obtained residue was fractionated by HPLC (C18 , allowed to cool to 80° C ., diluted with ethyl acetate , and mobile phase : water /acetonitrile ( 0 . 1 % TFA -containing sys US 9 ,776 ,962 B2 195 196 tem ) ) . To the obtained fraction was added saturated aqueous Hz ) , 6 . 34 ( 1H , brs ) , 6 .48 ( 1H , dd , J = 8 . 4 , 2 . 4 Hz) , 6 .71 ( 1H , sodium hydrogen carbonate solution , and the mixture was d , J = 7 . 6 Hz ), 7 .09 ( 1H , t , J = 7 . 5 Hz) , 7 .28 ( 1H , d , J = 9 . 4 Hz) . extracted with ethyl acetate . The extract was dried over anhydrous magnesium sulfate, and concentrated under Step 3 ) ethyl 3 -cyclopropyl - 3 -( 2 -( 1 -( 1 -( 2 - (( 2, 2 -dim reduced pressure . In the same manner as in Example 1 , step 5 ethylpropyl) ( 6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 4 , the title compound ( 55 mg) was obtained as a grayish methoxyphenyl) piperidin -4 - yl) ethoxy )pyridin - 4 - yl) white amorphous powder from the obtained pale -yellow oil propanoate (57 mg) . In the same manner as in Example 45, step 6 , the title compound ( 95 mg) was obtained as a brown amorphous MS (ESI + ) : [ M + H ] * 651 . 3 . powder from N - ( 2 , 2 - dimethylpropyl) - 2 - ( 4 - ( 1 -hydroxyethyl ) piperidin - 1 - yl) - 4 -methoxy - N - (6 -methylpyridin - 2 - yl) benz Example 268 amide ( 164 mg) and ethyl 3 -cyclopropyl - 3 -( 2 - hydroxypyri din - 4 - yl) propanoate ( 176 mg) . MS (ESI + ) : [ M + H ] * 657 . 4 . 3 - cyclopropyl- 3 - (2 - (1 - ( 1 - (2 - (2 ,2 -dimethylpropyl ) 15 ( 6 -methylpyridin - 2 - yl) carbamoyl) - 5 -methoxyphe Step 4 ) 3 -cyclopropyl - 3 - ( 2 - (1 - (1 - (2 -( ( 2 ,2 - dimethyl nyl) piperidin - 4 - yl) ethoxy )pyridin -4 - yl) propanoic propyl) ( 6 -methylpyridin - 2 - yl) carbamoyl) - 5 acid methoxyphenyl) piperidin -4 - yl) ethoxy )pyridin - 4 - yl) propanoic acid 20 Step 1 ) N -( 2 , 2- dimethylpropyl )- 2- ( 4 - formylpiperi In the same manner as in Example 1 , step 4 , the title din -1 -yl ) - 4 -methoxy - N -( 6 -methylpyridin - 2 -yl ) benz compound (86 mg) was obtained as a colorless amorphous powder from ethyl 3 -cyclopropyl - 3 -( 2 - ( 1 -( 1 - (2 - (( 2 ,2 -dim amide ethylpropyl) (6 -methylpyridin - 2 -yl ) carbamoyl ) - 5 -methoxy To a solution of N -( 2, 2 -dimethylpropyl ) - 2 -( 4 -( hydroxym - 25 phenyl) piperidin -4 -yl ) ethoxy )pyridin -4 - yl )propanoate (95 ethyl) piperidin - 1 - yl) - 4 -methoxy - N -( 6 -methylpyridin - 2 -yl ) mgMS) . ( ESI+ ) : [ M + H ] * 629. 3 . benzamide (210 mg ) obtained in Example 110 , step 2 , and triethylamine ( 0 .69 mL ) in DMSO ( 3 mL ) was added sulfur Example 269 trioxide pyridine complex ( 314 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture 30 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) ( 6 -methylpyridin was diluted with ethyl acetate and water , sodium thiosulfate 2 - yl) carbamoyl) - 5 -methoxyphenyl ) piperidin - 4 - yl) was added , and the mixture was stirred for 30 min and methoxy )phenyl ) - 3 -methoxypropanoic acid extracted with ethyl acetate . The extract was washed with saturated brine , and dried over anhydrous magnesium sul - 35 Step 1 ) ethyl fate . The solvent was evaporated under reduced pressure to 3 - ( 3 - ( benzyloxy ) phenyl) - 3 -methoxypropanoate give the title compound ( 230 mg) as a brown oil. This A mixture of ethyl 3 - ( 3 -( benzyloxy ) phenyl) - 3 -hydroxy compound was used for the next step without further puri propanoate ( 2 . 5 g ), iodomethane (4 . 73 g ) , silver ( 1 ) oxide fication . ( 3 . 86 g ) and toluene (50 mL ) was stirred under a nitrogen ' H NMR (300 MHz, CDC13 ) 8 0 .81 ( 9H , s ), 1. 42 - 1. 96 40 atmosphere at 100° C . for 15 hr. Insoluble material was ( 4H , m ), 2 . 18 - 2 . 31 ( 1H , m ) , 2 .32 - 2 . 80 (6H , m ), 3 . 20 - 3 .49 removed , and the filtrate was concentrated . The residue was ( 1H , m ), 3 .75 ( 3H , s) , 4 .04 - 4 . 38 (2H , m ) , 6 . 18 ( 1H , d , J = 2 . 1 purified by silica gel column chromatography (ethyl acetate / Hz ), 6 . 32 ( 1H , brs ), 6 .51 ( 1H , dd , J = 8 . 5 . 2 . 4 Hz ), 6 .72 ( 1H . hexane ) to give the title compound ( 1 . 81 g ) as a colorless oil . d . J = 7 . 5 Hz ), 7 . 09 ( 11 . t . J = 7 . 9 Hz ) , 7 .28 - 7 . 33 ( 14 . m ). 9 .69 H NMR (300 MHz, CDC1z ) 01 . 18 - 1 . 27 (3H , m ), 2 . 56 ( 1H , d , J = 1 . 0 Hz ) . 45 ( 1H , dd , J = 15 . 3 , 4 . 6 Hz ) , 2 .77 ( 1H , dd , J = 15 . 3 , 9 . 2 Hz ) , 3 . 22 (3H , s ) , 4 .09 - 4 .25 ( 2H , m ) , 4 .61 ( 1H , dd , J = 9 . 2 , 4 . 6 Hz) , 5 .07 ( 2H , s ) , 6 . 86 - 6 . 95 (2H , m ), 6 .95 - 7 .01 (1H , m ) , 7 . 18 - 7 .49 Step 2 ) N - ( 2 , 2 - dimethylpropyl) - 2 - ( 4 - ( 1 - hydroxy (6H , m ). ethyl )piperidin - 1 -yl ) - 4 -methoxy -N -( 6 -methylpyri din - 2 -yl ) benzamide 50 Step 2 ) ethyl 3 - ( 3 - hydroxyphenyl) - 3 -methoxypropanoate To a solution of N - ( 2 , 2 - dimethylpropyl) - 2 - ( 4 - formylpipvlpip eridin - 1 - yl) - 4 -methoxy - N - ( 6 -methylpyridin - 2 -yl ) benz In the same manner as in Example 2 , step 4 , the title amide ( 230 mg) in THF ( 10 mL ) was added 1 M methyl- 55 compound ( 900 mg) was obtained as a colorless oil from magnesium bromide THF solution ( 1. 97 mL ) at 0° C ., and 55 ethyl 3 -( 3 -( benzyloxy )phenyl ) -3 -methoxypropanoate (1 .8 the mixture was stirred at 0° C . for 1 hr. To the reaction ' H NMR ( 300 MHz, DMSO - d . ) 81 . 10 - 1 . 17 (3H , m ) , mixture was added saturated aqueous ammonium chloride 2 . 53 - 2 .71 (2H , m ) , 3 . 09 ( 3H , s ), 3 . 98 - 4 .09 ( 2H , m ) , 4 . 46 solution at 0° C ., and the mixture was extracted with ethyl ( 11 . dd . J = 8 . 7 . 52 H2 ). 6 .63 - 6 .77 (3H . m ) . 7 . 14 ( 1H . td . acetate . The extractract was dried over anhydrousannyarous magnesium 6060 J = 757 . 5 , 080 . 8 Hz ) , 9 .40 ( 1H , s ) . sulfate and the solvent was evaporated under reduced pres sure . The residue was purified by silica gel column chro Step 3 ) 3 -( 3 -( (1 - ( 2 - (( 2 ,2 -dimethylpropyl ) (6 -methyl matography ( ethyl acetate /hexane ) to give the title com pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperi pound ( 164 mg) as a colorless solid . din - 4 - yl) methoxy )phenyl ) - 3 -methoxypropanoic acid 'H NMR (300 MHz, CDC13 ) 8 0 .81 ( 9H , s) , 1. 04 - 1. 65 65 (8H , m ), 1 . 66 - 1 . 81 (1H , m ), 2 . 29 - 2 .73 (6H , m ), 3 . 26 - 3 .70 By a method similar to that in Example 135 , step 1 and (2H , m ), 3. 75 (3H , s ), 4 .05 - 4 .41 (2H , m ), 6 .18 ( 1H , d , J = 2. 0 Example 1, step 4 , the title compound (98 mg ) was obtained US 9 ,776 , 962 B2 197 198 as a white amorphous powder from N -( 2 , 2 - dimethylpropyl) Step 2 ) tert - butyl 4 - ( ( ( 4 - ( 3 - ethoxy - 1 -hydroxy - 3 2 - ( 4 - hydroxymethyl) piperidin - 1 - yl) - 4 -methoxy - N - ( 6 oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidine - 1 methylpyridin - 2 - yl) benzamide ( 110 . 1 mg) and ethyl 3 - ( 3 carboxylate hydroxyphenyl) - 3 -methoxypropanoate (63 . 8 mg ) . 5 Under a nitrogen atmosphere , to a solution of diisopro MS ( ESI + ) : [ M + H ] * 604 .4 . pylamine ( 0 . 96 mL ) in THF ( 10 mL ) was added 1 . 6 M n -butyllithium hexane solution ( 2 . 93 mL ) at -78° C . , and the Example 270 mixture was stirred for 10 min . Ethyl acetate ( 6 . 11 mL ) was added at - 78° C . , and the mixture was stirred for 30 min . 3 -( 3- (( 1 -( 2 -( ( 2 ,2 -dimethylpropyl ) ( 6 -methylpyridin Thereto was added a solution of tert - butyl 4 - ( ( ( 4 - formylpyri 2 -yl ) carbamoyl ) - 5 -methoxyphenyl ) piperidin -4 -yl ) 10 din -2 - yl) oxy )methyl ) piperidine - 1 -carboxylate ( 1 .00 g ) in methoxy) phenyl ) - 3 - ethoxypropanoic acid THF ( 8 mL ) at - 78° C ., and the mixture was stirred at - 78° C . for 1 hr . The mixture was gradually warmed to room Step 1) ethyl temperature over 1 hr. To the reaction mixture was added 3 - (3 -hydroxyphenyl )- 3 - ethoxypropanoate saturated aqueous ammonium chloride solution at room 15 temperature , and the mixture was extracted with ethyl In the same manner as in Example 269 , step 1 and acetate . The extract was washed with saturated brine , and Example 2 , step 4 , the title compound (660 mg) was dried over anhydrous magnesium sulfate . The solvent was obtained as a colorless oil from ethyl 3 - ( 3 - ( benzyloxy ) evaporated under reduced pressure . The residue was purified phenyl) - 3 -hydroxypropanoate ( 2 . 5 g ) . by silica gel column chromatography ( ethyl acetate /hexane ) ' H NMR (300 MHz, DMSO - do) 81. 05 ( 3H , t , J = 7 . 0 Hz ) , 20 to give the title compound ( 307 mg) as a colorless oil . 1 .10 -1 .19 ( 3H , m ), 2 .53 - 2 .68 (2H , m ) , 3 . 19 -3 .34 (2H , m ), MS ( ESI + ) : [ M + H ] * 409 . 2 . 3 . 95 - 4 . 13 ( 2H , m ) , 4 . 57 ( 1H , dd , J = 8 . 5 , 5 . 5 Hz ), 6 .62 - 6 . 76 Step 3 ) tert- butyl 4 -( ( ( 4 - (3 - ethoxy - 1 -methoxy - 3 ( 3H , m ), 7 .08 - 7 . 17 ( 1H , m ) , 9 . 38 ( 1H , s ) . oxopropyl) pyridin - 2 -yl ) oxy )methyl ) piperidine - 1 25 Step 2 ) 3 - ( 3 - ( ( 1 - ( 2 - ( ( 2 , 2 - dimethylpropyl) (6 -methyl carboxylate pyridin - 2 - yl) carbamoyl ) - 5 -methoxyphenyl ) piperi To a solution of tert - butyl 4 - ( ( ( 4 - ( 3 - ethoxy - 1 - hydroxy - 3 din -4 -yl ) methoxy )phenyl )- 3 - ethoxypropanoic acid oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidine - 1 - carboxy late (307 mg) in toluene (5 mL ) were added iodomethane By a method similar to that in Example 135, step 1 and 30 (0 .231 mL ) and silver (1 ) oxide (343 mg) , and the mixture Example 1 , step 4 , the title compound (99 . 8 mg) was was stirred at 100° C . for 15 hr. Iodomethane ( 0 .462 mL ) obtained as a white amorphous powder from N - ( 2 , 2 - dim and silver ( I ) oxide ( 172 mg ) were further added , and the ethylpropyl) - 2 - ( 4 - hydroxymethyl) piperidin - 1 -yl ) - 4 mixture was stirred at 100° C . for 5 hr . The reaction mixture methoxy - N -( 6 -methylpyridin - 2 -yl ) benzamide (103 . 6 mg) was filtered through celite , and the filtrate was concentrated and ethyl 3 -ethoxy -3 - (3 -hydroxyphenyl )propanoate (63 . 8 35 under reduced pressure . The residue was purified by silica mg ) . gel column chromatography ( ethyl acetate /hexane ) to give MS (ESI + ): [M + H ] * 618 .3 . the title compound ( 128 mg) as a pale -yellow oil . Example 271 MS (ESI + ) : [ M + H ] * 423 . 2 . 40 Step 4 ) ethyl 3 - ( 2 - ( ( 1 - ( 2 - formyl - 5 -methoxyphenyl ) 3 -methoxy - 3 - ( 2 - ( ( 1 - ( 5 -methoxy - 2 - ( ( 4 -methylpyri piperidin - 4 -yl ) methoxy )pyridin - 4 - yl) - 3 -methoxypro din - 2 - yl) ( 2 , 2 , 2 -trifluoroethyl ) carbamoyl) phenyl ) panoate piperidin - 4 -yl ) methoxy )pyridin - 4 -yl ) propanoic acid To a solution of tert - butyl 4 - ( ( ( 4 - ( 3 - ethoxy - 1 -methoxy - 3 Step 1 ) tert -butyl 4 - ( ( ( 4 - formylpyridin - 2 - yl) oxy ) 45 oxopropyl) pyridin - 2 - yl) oxy )methyl ) piperidine - 1 - carboxy methyl) piperidine - 1 -carboxylate late (128 mg) in acetonitrile (2 mL ) was added trifluoro acetic acid ( 1 mL ) at 0° C . and the mixture was stirred at To a solution of tert - butyl 4 - ( ( ( 4 -cyanopyridin - 2 - yl ) oxy ) room temperature for 2 . 5 hr, and concentrated under reduced methyl) piperidine - 1 - carboxylate ( 6 . 30 g ) obtained in pressure . Toluene azeotropic distillation was performed Example 245 , step 1 , in toluene ( 25 mL ) was added a 1 . 5 M 50 twice . To the obtained residue were added DMSO ( 3 mL ) , solution ( 14 . 6 mL ) of diisobutylaluminum hydride in tolu - 2 - fluoro - 4 -methoxybenzaldehyde (92 mg ) and potassium ene at - 78° C . The mixture was stirred at room temperature carbonate ( 166 mg) , and the mixture was stirred at 100° C . for 1 hr, a 1 . 5 M solution (6 . 6 mL) of diisobutylaluminum for 3 . 5 hr. To the reaction mixture was added water at room hydride in toluene was added at 0° C ., and the mixture was temperature , and the mixture was extracted with ethyl stirred at room temperature for 1 hr. To the reaction mixture 55 acetate . The extract was washed with saturated brine , and were added saturated aqueous ammonium chloride solution dried over anhydrous magnesium sulfate . The solvent was and potassium sodium tartrate at room temperature and the evaporated under reduced pressure. The residue was purified mixture was stirred for 1 hr and extracted with ethyl acetate . by silica gel column chromatography ( ethyl acetate /hexane ) The extract was washed with saturated brine , and dried over to give the title compound (89 mg) as a colorless oil . anhydrous magnesium sulfate . The solvent was evaporated 60 MS ( ESI + ) : [ M + H ] + 457 . 2 . under reduced pressure . The residue was purified by silica gel column chromatography ( ethyl acetate /hexane ) to give Step 5 ) 2 - ( 4 - ( ( ( 4 - ( 3 - ethoxy - 1 -methoxy - 3 - oxopropyl) the title compound ( 1 .00 g ) as a pale- yellow oil . pyridin - 2 - yl) oxy )methyl ) piperidin - 1 - yl) - 4 -methoxy ' H NMR (300 MHz, CDC13 ) d 1 .20 -1 . 37 (2H , m ), 1. 47 benzoic acid ( 9H , s ), 1 .74 - 1 .88 ( 2H , m ) , 1 . 89 -2 .07 ( 1H , m ) , 2 .65 - 2 .85 65 (2H , m ) , 4 .04 - 4 .27 (4H , m ) , 7 . 13 (1H , t , J = 1 . 0 Hz) , 7 .28 (1H , In the same manner as in Example 262 , step 2 , the title dd , J = 5 . 2 , 1. 3 Hz) , 8 .34 ( 1H , d , J = 5 . 2 Hz) , 10 .01 ( 1H , s ) . compound (86 mg) was obtained as a colorless amorphous