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THAT ARALILULUKUUTUUS009776962B2 (12 ) United States Patent ( 10) Patent No 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 (Bahaloo 6 ) 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 )
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