CHA KUNA TA VE US010029986B2KATLAMAT DITUTTON (12 ) United States Patent ( 10 ) Patent No. : US 10 , 029 ,986 B2 Mita et al. (45 ) Date of Patent : Jul . 24 , 2018 (54 ) ALKYNYL PYRIDINE - SUBSTITUTED AMIDE FOREIGN PATENT DOCUMENTS COMPOUND AND PESTICIDE EP 2 218 717 AL 8 /2010 JP 2006 - 528613 A 12 /2006 @( 71 ) Applicant: NISSAN CHEMICAL INDUSTRIES, JP LTD ., Chiyoda - ku ( JP ) (Continued )

@( 72 ) Inventors : Takeshi Mita , Funabashi ( JP ) ; OTHER PUBLICATIONS Motoyoshi Iwasa , Funabashi ( JP ); Yusuke Nanjo , Funabashi ( JP ) ; Taichi International Search Report dated Apr . 28 , 2015 in PCT/ JP2015 / Shimomiya , Funabashi ( JP ); Hidehito 054439 Filed Feb . 18 , 2015 . Kuwahara , Shiraoka ( JP ); Hotaka Primary Examiner - Daniel R Carcanague Imanaka , Shiraoka ( JP ) ( 74 ) Attorney , Agent, or Firm — Oblon , McClelland , @( 73 ) Assignee : Nissan Chemical Industries , Ltd ., Maier & Neustadt, L . L . P . Chiyoda - ku ( JP ) ( 57 ) ABSTRACT @ Subject to any disclaimer, the term of this Provided is a novel pesticide, particularly a fungicide and a ( * ) Notice : nematicide . An alkynyl pyridine - substituted amide com patent is extended or adjusted under 35 pound represented by formula ( I ) , its N -oxide or a salt U . S . C . 154 ( b ) by 0 days . thereof , and a pesticide containing it . [ In the formula , Gl is a structure represented by G ? - 1a , G -3a , G²- 27a , etc . ; Xl is ( 21) Appl. No .: 15 /119 ,660 a halogen atom , difluoromethyl, trifluoromethyl , etc . ; Yl is @ a halogen atom , etc .; Y , Yº, R4 and R independently (22 ) PCT Filed : Feb . 18 , 2015 represent a hydrogen atom , etc . ; R ' is a hydrogen atom , a halogen atom ,methyl , methoxy , etc . ; R2 is a hydrogen atom , PCT / JP2015 / 054439 a halogen atom , etc . , or R and R2 together form an alkylene ( 86 ) PCT No. : chain thereby to form a cyclopropyl group together with the § 371 (c )( 1 ), carbon atom to which R and R2 are bonded , or R and R2 ( 2 ) Date : Aug . 17 , 2016 together form C , -C2 alkylidene or C , -C2 haloalkylidene ; R3 is a hydrogen atom , methyl, etc . , and Rº is C1 - C4 alkyl, (87 ) PCT Pub . No. : W02015 /125824 Cz -Co cycloalkyl, C , -C4 alkoxy (C1 - C4) alkyl, etc . ] PCT Pub . Date : Aug . 27 , 2015 Gl- la (65 ) Prior Publication Data US 2017 /0008847 A1 Jan . 12 , 2017 ( 30 ) Foreign Application Priority Data Feb . 18 , 2014 ( JP ) ...... 2014 -028087 Apr. 11, 2014 ( JP ) ...... 2014 -082159 G !- 3a (Continued ) pa (51 ) Int. CI. CO7D 213 /61 ( 2006 .01 ) CO7D 401 / 12 ( 2006 .01 ) G1- 27a ( Continued ) (52 ) U . S . CI. CPC ...... CO7D 213 /61 ( 2013 .01 ); A01N 43 / 40 (2013 .01 ) ; A01N 43 /56 (2013 .01 ) ; A01N 43760 (2013 . 01 ) ; (Continued ) ( 58 ) Field of Classification Search (1) ??? ...... CO7D 231/ 14 R6 (Continued ) O R3 R4 Y ERO ( 56 ) References Cited U . S . PATENT DOCUMENTS NXX My R1 R2 2006 /0246102 AL 11/ 2006 Mansfield et al. ogR5 2007 /0167491 A1 7 / 2007 Mansfield et al . (Continued ) 12 Claims, No Drawings US 10 ,029 , 986 B2 Page 2

( 30 ) Foreign Application Priority Data 2014 / 0088157 A1 3 / 2014 Kita et al . 2015 /0259322 AL 9 /2015 Kita et al . Apr. 22 , 2014 ( JP ) ...... 2014 - 088408 2015 / 0266853 AL 9 /2015 Kita et al . Jun . 25 , 2014 ( JP ) ...... 2014 - 130395 FOREIGN PATENT DOCUMENTS Int. CI. (51 ) 2007 -526279 A 9 /2007 CO7D 409/ 12 ( 2006 .01 ) ese 2009 - 539791 A 11 /2009 C07D 411 / 12 ( 2006 . 01 ) 2010 - 529971 A 9 /2010 CO7D 417/ 12 ( 2006 .01 ) 2013 - 528613 A 7 / 2013 AOIN 43 /40 ( 2006 . 01 ) 2017039722 * 2 / 2017 AOIN 43 / 56 WO 2004 /016088 A2 2 / 2004 ( 2006 .01 ) WO 2004 /074280 All 9 / 2004 A01N 43 /60 ( 2006 . 01) WO 2005 / 014545 A2 2 / 2005 AOIN 43 / 78 ( 2006 .01 ) WO 2005 /016876 A2 2 / 2005 A61K 45 / 06 ( 2006 . 01 ) WO 2005 /058828 A1 6 / 2005 C07D 401/ 06 ( 2006 .01 ) wo 2005 /058833 A1 6 / 2005 WO 2005 /085238 Al 9 / 2005 AOIN 43 / 84 ( 2006 . 01 ) WO WO 2006 / 122952 AL 11 / 2006 A01N 55 / 00 ( 2006 .01 ) WO WO 2006 / 122955 AL 11 / 2006 ( 52 ) U . S . CI. WO 2007 / 108483 AL 9 / 2007 ??? ...... AOIN 43 / 78 ( 2013 .01 ) ; AOIN 43 / 84 WO 2007 / 141009 A1 12 / 2007 WO WO 2007 / 141473 Al 12 / 2007 ( 2013. 01 ) ; A01N 55 / 00 ( 2013 .01 ) ; A61K 45/ 06 WO WO 2008 /093065 AL 8 / 2008 (2013 .01 ) ; C07D 401 / 06 ( 2013 .01 ) ; C07D WO 2008 / 151828 A2 12 / 2008 401/ 12 (2013 .01 ) ; C07D 409 / 12 (2013 .01 ) ; wo 2011 / 151369 Al 12 / 2011 C07D 411/ 12 ( 2013 .01 ) ; C07D 417 / 12 WO WO 2011 / 151370 AL 12 / 2011 WO 2012 / 028676 A1 3 /2012 (2013 .01 ) WO WO 2012 /052489 A1 4 /2012 (58 ) Field of Classification Search WO WO 2012 /052491 A2 4 /2012 USPC ...... 546 /275 .4 WO WO 2012 / 118139 A1 9 / 2012 See application file for complete search history . WO WO 2013 /064460 Al 5 / 2013 WO WO 2013 / 064461 A2 5 / 2013 ( 56 ) References Cited Wo WO 2013 / 120940 A2 8 /2013 WO 2014 /010737 A1 1 /2014 U . S . PATENT DOCUMENTS WO WO 2014 /034750 A13 /2014 WO WO 2014 / 034751 A13 / 2014 2010 / 0222389 AL 9 /2010 Walter et al . WO 2014 / 173921 A1 10 / 2014 2011/ 0136831 A1 6 / 2011 Oda et al . WO W O 2018003924 * 1 /2018 2011/ 0207771 AL 8 /2011 Stierli et al. 2013/ 0131119 Al 5 / 2013 Benting et al. * cited by examiner US 10 ,029 , 986 B2

ALKYNYL PYRIDINE - SUBSTITUTED AMIDE Patent Document 6 : WO2005 /014545 COMPOUND AND PESTICIDE Patent Document 7 : WO2005 /058828 Patent Document 8 : WO2005 /058833 TECHNICAL FIELD Patent Document 9 : WO2005 /085238 5 Patent Document 10 : WO2007/ 108483 The present invention relates to a novel alkynyl pyridine Patent Document 11 : EP2218717 substituted amide compound, its N - oxide or a salt thereof, Patent Document 12 : WO2011/ 151369 and a pesticide containing it as an active ingredient. DISCLOSURE OF INVENTION BACKGROUND ART 10 Technical Problem Heretofore, with respect to alkynyl pyridine -substituted amide compounds, for example , N -[ [ 1- [ 3 -chloro - 5 -( 3 ,3 , 3 Infection or parasitism of pests such as pathogens and trifluoro - 1 -propynyl ) pyridin - 2 - yl] cyclopropyl] methyl ] - 3 - parasites causes, in a case where the hosts are plants such as fluoropyridine- 2 -carboxamide , N - [[ 1 -[ 3 -chloro -5 - (3 , 3 ,3 - tri- 15 grain , fruits , vegetables or ornamental plants , a decrease in fluoro - 1 -propynyl ) pyridin - 2 - yl] cyclopropyl ]methyl ] - 3 the quality of agricultural crops and a remarkable decrease chloropyridine - 2 - carboxamide , N - [ [ 1 - [ 3 - chloro - 5 - ( 3 , 3 , 3 - in the yield , and in some cases , serious damages such as trifluoro - 1 -propynyl ) pyridin - 2 - yl] cyclopropyl] methyl ] - 3 - death of the plants , and inflicts heavy economic losses not methylpyridine - 2 - carboxamide and N - [ [ 1 - [3 - chloro - 5 - ( 3 , 3 , only on the producers but also on the consumers . Thus, to 3 - trifluoro - 1 -propynyl ) pyridin - 2 -yl ] cyclopropyl ] methyl ]- 3 - 20 effectively control such pests is a very important object to ( trifluoromethyl) pyridine - 2 - carboxamide are known to achieve efficient and stable production of agricultural crops . show nematicidal activities (see Patent Document 1 ) ; N - [ 2 - Further , in a case where the hosts are animals such as [ 5 - (4 - ethoxyphenylethynyl) pyridin - 2 - yl] ethyl ] acetamide is companion creatures /pets or livestock /poultry , to effectively known to have an acetyl COA carboxylase inhibitory activity control such pests is an important object also for the purpose ( see Patent Document 2 ) ; and as an intermediate for pro - 25 ofmaintaining health of the target animals and further , in a ducing BACE - 1 inhibitors , N - [ 1 - ( S ) - [ ( 3 , 5 - difluorophenyl) case where the target animals are livestock or poultry , for the methyl] - 2 - [ 5 - ( 3 - fluorophenylethynyl) pyridin - 2 -yl ) - 2 - (hy - purpose of stably producing safe food or high quality droxylethyl) - 3 - ( N , N - di ( normal propyl) carbamoyl) - 5 - general merchandise such as wool, feathers or leathers . methylbenzamide is known (see Patent Document 3 ). From such a viewpoint, heretofore , development of pesti Further with respect to pyridine - substituted amide com - 30 cides targeted at pathogens or parasites has advanced , and pounds, for example , N - [ 2 - [3 - chloro - 5 - ( trifluoromethyl) various effective pesticides have been put into practical use . pyridin - 2 - yllethyl) - 2 - ( trifluoromethyl) benzamide ( see Pat- However, recently, control of pests with conventional ent Document 4 ), N - [ 2 - [3 -chloro - 5 - ( trifluoromethyl) pesticides has become difficult in more and more cases, as pyridin - 2 - yl] ethyl] - 3 - difluoromethyl - 1 -methyl - 1H pathogens or parasites acquire resistance to them over many pyrazole - 4 - carboxamide ( see Patent Document 5 ) , N - [ 2 - ( 3 , 35 years of their use . Problems of the high toxicity of some 5 - dichloropyridin - 2 - yl) ethyl) - 2 - ( trifluoromethyl) benzamide conventional pesticides and of the disturbance of the eco (see Patent Document 6 ) , N - [ 2 - [ 3 -chloro - 5 - ( trifluorom system by some conventional pesticides which remain in the ethyl) pyridin - 2 -yl ] - 1 -methylethyl ] - 2 - ( trifluoromethyl ) benz - environment for a long period are becoming apparent. Under amide ( see Patent Document 7 ) , N - [ 2 - 13 - chloro - 6 - ( trifluo - these circumstances , development of novel pesticides not romethyl) pyridin -2 -yl ] butyl ]- 3 -difluoromethyl - 1 -methyl - 40 only having excellent pesticidal activity on pathogens and 1H -pyrazole - 4 -carboxamide (see PatentDocument 8 ) , N -[ 2 - parasites but also having high pesticidal properties such as (5 - chloropyridin - 2 -yl ) butyl ] -3 - difluoromethyl- 1- methyl low toxicity and low persistence and of an effective con 1H -pyrazole - 4 - carboxamide (see Patent Document 9 ) , N - [ 2 trolling method is always expected . [ 3 -chloro -5 -( trifluoromethyl ) pyridin - 2 -yl ] ethyl] - 3 It is an object of the present invention to provide a trifluoromethyl) pyrazine - 2 - carboxamide (see Patent 45 development of a new pesticide and controlling method , Document 10 ), N - [ 2 - [ 3 - chloro - 5 - ( trifluoromethyl) pyridin - which not only have excellent controlling activities against 2 -yl ] - 1 -methylethyl ] - N - cyclopropyl- 3 - difluoromethyl- 1 - pathogenic bacteria and parasites, but also have a high level methyl- 1H -pyrazole -4 -carboxathioamide ( see Patent Docu - of controlling characteristics such as low toxicity , low ment 11) , N - [2 - [ 3 -chloro -5 -( trifluoromethyl) pyridin - 2 -yl ) - residual effects , etc . 1 -methylethyl ] - N -cyclopropyl - 3 -difluoromethyl - 5 - fluoro - 50 1 -methyl - 1H -pyrazole -4 -carboxamide ( see Patent Solution to Problem Document 12 ) , etc . are known to show bactericidal activi ties . The present inventors have conducted extensive studies to However , there has been no patent literature having a achieve the above object and as a result, found that a novel disclosure with respect to the alkynyl pyridine -substituted 55 alkynyl pyridine - substituted amide compound represented amide compounds of the present invention , and their use by the following formula ( l) is a very useful compound fulness as pesticides is not known . which is excellent in pesticidal activities , especially in antifungal and nematicidal activities, and has little harmful PRIOR ART DOCUMENTS effect on non - target organisms such as plants , mammals , 60 fishes , useful insects and natural enemies, and accomplished Patent Documents the present invention . That is , the present invention relates to an alkynyl pyri Patent Document 1 : WO2014 / 173921 dine- substituted amide compound of the formula (I ) (here Patent Document 2 : WO2012 /028676 inafter referred to also as the compound of the present Patent Document 3 : WO2005 /016876 65 invention ), its N - oxide or a salt thereof, all stereoisomers Patent Document 4 : WO2004 /016088 thereof, production intermediates thereof, and to a pesticide Patent Document 5 : WO2004 /074280 containing one or more of them as an active ingredient. US 10 , 029 , 986 B2

- continued Base 2016) G1 - 8 - R6 0 R3 R4 N * NYy3 ? ? R R ' R2 Gl. 9

wherein G ' is a structure represented by G - 1 to GF - 51 ,

GL1 G -10

0 x G - 11

Gl - 12 N 30 G- 3 sm335 GI - 13 G - 4

40 GI - 14

Gl , 45 G - 15 R ? ??? 50 G - 6 G - 16 S5

?

G -7 60 G - 17

R7 - N ???????? 65 US 10, 029, 986 B2

-continued -continued G - 18 GI- 28

N R7 G1- 19 GI- 29 ? 10

G -20 15 G - 30

20 G1 - 21 GI - 31

25 XX?

GI - 22

30 . GH - 32

G - 23 35

. Gl - 33

G - 24 40 XX?

45 . G - 34 G- 25

50

????????? Gl . 26 GI - 35

55 P ? . GH -27 60 GI - 36

N ? P ? US 10 ,029 , 986 B2

-continued -continued G²- 37 G1- 47

is

G1- 38 G1-48 10

Nel G1- 39 15 G1- 49

o 20 G1- 40 G1- 50

25 N = G1- 41 ( O ) r G²- 51 30

G1- 42 35 X ! is a halogen atom , nitro , C7 -C4 alkyl or CZ -C4 haloalkyl, X² is a hydrogen atom or a halogen atom , provided that when G is a structure represented by G²- 27 , and Xl is G1-43 40 dihalomethyl, X² is a hydrogen atom , X3 is a hydrogen atom or CZ - C4 alkyl , Yl is a hydrogen atom , a halogen atom , nitro , C , - C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy, C1- C4 haloalkoxy or 45 C1- C4 alkylthio , Y ? and Y² are each independently a hydrogen atom , a G²- 44 halogen atom or methyl, R and R2 are each independently a hydrogen atom , a V halogen atom , cyano , C , -C4 alkyl, C , -C4 haloalkyl, 50 Cz- Co cycloalkyl , phenylmethyl, phenylmethyl substi N tuted by ( Z )m , C , -C4 alkoxy, C .- C4 haloalkoxy, cyano ( C , - C4 )alkoxy , Cz -Co alkenyloxy, Cz- Co haloalkeny loxy, Cz- C . alkynyloxy, Cz - C haloalkynyloxy, phenyl ( C , -C4 )alkoxy , CZ - C4 alkylthio , C1- C4 alkoxyamino , G1-45 55 CZ - C4 alkoxycarbonyl, C (O )NH , or — C ( S )NH2 , alternatively , R ' and R together form a C2- C , alkylene chain thereby to form a 3 -6 membered ring together with the carbon atom to which R and R are bonded , wherein the alkylene chain may contain one or two oxygen atoms, sulfur atoms or nitrogen atoms and may G1- 46 60 optionally be substituted by a C , - CZ alkyl group , a C , -Cz haloalkyl group or an oxo group , or R and R ? together form CZ - C6 alkylidene , C . - C . haloalkylidene or C , -C4 alkoxy (C , -C2 ) alkylidene , R² and R + are each independently a hydrogen atom , C , -C4 65 alkyl, C .- C4 haloalkyl, C . -C4 alkoxymethyl, C3- C6 cycloalkyl or phenyl, US 10 , 029 , 986 B2 10 alternatively , R3 and R4 together form an ethylene chain -continued thereby to form a cyclopropyl ring together with the D - 10 carbon atom to which Rand R * are bonded , further alternatively , R or R ? , and R3 or R4, together form aC , -C4 alkylene chain thereby to form a 3 - 6 membered 5 ring together with the carbon atoms to which Ri or R2 and R3 or R4 , are bonded , wherein the alkylene chain D - 11 may contain one oxygen atom or sulfur atom , Dn R is a hydrogen atom , C , - C4 alkyl, C , - C4 haloalkyl, (C -C2 ) alkyl substituted by R?, Cz- Co cycloalkyl , C2- C4 alkenyl, C3- C4 alkynyl , — OH , CZ -C4 alkoxy , C2 - C4 haloalkoxy, C . -C4 haloalkylthio , C ( O ) R ' or D - 12 C1- C4 alkoxycarbonyl, Ró is a hydrogen atom , a halogen atom , C , - C4 alkyl, 15 ND (2 ) C2 - C4 haloalkyl, (C ,- C4) alkyl optionally substituted by R10, C3 -C6 cycloalkyl, C3 - C6 halocycloalkyl, hydroxy (C3 -C .) cycloalkyl, E - 9, C5 -C6 cycloalkenyl, D - 22 tri (CZ -C4 alkyl) silyl , C (R ') ) = NOR12 , phenyl, phe nyl substituted by ( Z ) m , D - 1 to D - 4 , D - 7 , D - 8 , D - 10 to 20 II D - 12 , D - 22 , D - 28 , D - 29 or D -32 , provided that when G ' is a structure represented by GP- 1 to GP- 7 , and R ! and R ’ together form an ethylene chain thereby to form D - 28 a cyclopropyl ring together with the carbon atom to which Rl and R2 are bonded , R is a hydrogen atom , 25 CZ - C4 alkyl, (C , -C4 ) alkyl optionally substituted by Rº, Cz- Co cycloalkyl, C3 -C , halocycloalkyl, hydroxy (C3 - C . ) cycloalkyl, E - 9 , C5 -Co cycloalkenyl, tri ( C1 -C4 D - 29 alkyl) silyl , C (R ) = NOR12 , phenyl , phenyl substi (Z ) n tuted by ( Z ) . , D - 1 to D - 4 , D - 7 , D - 8 , D - 10 to D - 12 , 30 D - 22 , D - 28 , D - 29 or D - 32 , D - 1 to D - 4 , D - 7 , D - 8 , D - 10 to D - 12 , D - 22 , D - 28 , D - 29 and D - 32 are respectively aromatic heterocyclic rings D - 32 represented by the following structural formulae , 35

7- D - 1

; 40 Z is a halogen atom , cyano , nitro , C . - C . alkyl, trifluo DD - 2 romethyl, methoxy , difluoromethoxy, trifluoromethoxy , V (Z 2 )n methylthio , methylsulfinyl, methylsulfonyl, trifluorom ethylthio , trifluoromethylsulfinyl, trifluoromethylsulfo nyl or phenyl; when m or n is 2 ormore , the respective D -3 45 Z ' s may be identical with or different from one another; and when there are two Z ' s , the two neighboring Z ' s : may form — CH = CH CH = CH — to form a 6 -mem g bered ring together with the carbon atoms attached to the two Z ' s , D - 4 50 R7 is CZ -C4 alkyl or CZ -C4 haloalkyl, R® is cyano, OR14 , C , -C4 alkylthio , C , -C4 alkoxycar ( Z ). bonyl, C ( O )NH , or C (S )NH2 , Rºis CZ -C4 alkyl, C . - C4 alkoxymethyl , C3- C4 cycloalkyl 55 or C2- C4 alkenyl, D - 77 R10P10 is: cyano , OH , OR15 , C . -C4 alkylcarbonyloxy , C2- C4 alkylsulfonyloxy, C , -C4 alkylthio , C . -C4 : haloalkylthio , D -3 , D - 7, D - 11, D - 22 , D - 28 or D -29 , Rll is a hydrogen atom or C . -C4 alkyl, 60 R12 is C , -C4 alkyl, D - 8 R13 is CZ -C4 alkyl, R13 R14 is C - C4 alkyl, C2- C4 haloalkyl, C . -C4 alkylcarbonyl, Cz- C , cycloalkylcarbonyl or C - C4 alkoxycarbonyl, N - N (Z ) R $ 15 is C , - C4 alkyl, C , -C4 haloalkyl , C .- C4 alkoxy (C1 a C2) alkyl , E -5 , E -14 , C3 -C4 alkenyl, C3 -C4 haloalkenyl, ? C3- C4 alkynyl , C3- C4 haloalkynyl, phenyl or phenyl substituted by ( Z )m , US 10 , 029 , 986 B2 12 E - 5 , E - 9 and E - 14 are respectively saturated heterocyclic group , a n - propyl group , an i -propyl group , a n -butyl group , rings represented by the following structural formulae , an i -butyl group , a s -butyl group , a tert- butyl group , a pentyl group , a 1 -ethylpropyl group , a 2 , 2 - dimethylpropyl group or a hexyl group , and it is selected in the range of the specified E - 5 5 numbern of carbon atoms. R16 The expression “ Co -Ch haloalkyl” represents a linear or branched hydrocarbon group containing from a to b carbon atoms in which hydrogen atom ( s ) on carbon atom ( s ) are optionally substituted with halogen atom ( s ) which may be E -9 10 identical with or different from one another if two or more halogen atoms are substituted . For example , a fluoromethyl group , a chloromethyl group , a bromomethyl group , an 794 iodomethyl group , a difluoromethyl group , a dichloromethyl E - 14 group , a trifluoromethyl group , a chlorodifluoromethyl (R16 ) 15 group , a trichloromethyl group , a bromodifluoromethyl group , a 1 - fluoroethyl group , a 2 - fluoroethyl group , a 2 - chloroethyl group , a 2 -bromoethyl group , a 2 , 2 - difluoro ethyl group , a 2 , 2 , 2 - trifluoroethyl group , a 2 - chloro - 2 , 2 difluoroethyl group , a 2 , 2 , 2 - trichloroethyl group , a 2 - bromo 20 2 ,2 -difluoroethyl group , a 1, 1, 2 ,2 - tetrafluoroethyl group , a R16 is C -C4 alkyl, and when p is 2 , the respective R16 s 2 - chloro - 1 , 1 , 2 -trifluoroethyl group , a pentafluoroethyl may be identical with or different from one another, group , a 2 , 2 - difluoropropyl group , a 3 , 3 , 3 - trifluoropropyl m is 1 , 2 , 3 , 4 or 5 , group , a 3 -bromo - 3 , 3 -difluoropropyl group , a 2 , 2 , 3 , 3 - tetra n is 0 , 1 , 2 , 3 or 4 , fluoropropyl group , a 2 ,2 ,3 ,3 , 3 -pentafluoropropyl group , a p is 0 , 1 or 2 , 25 1 , 1 , 2 , 3 , 3 , 3 -hexafluoropropyl group , a heptafluoropropyl r is 0 , 1 or 2 . group , a 2 , 2 , 2 - trifluoro - 1 - (methyl )ethyl group , a 2 , 2 , 2 - trif luoro - 1 - ( trifluoromethyl) ethyl group , a 1 ,2 , 2 , 2 - tetrafluoro Advantageous Effects of Invention 1 -( trifluoromethyl ) ethyl group , a 2 , 2 ,3 ,4 , 4 ,4 -hexafluorobu tyl group , a 2 , 2 , 3 , 3 , 4 , 4 , 4 -heptafluorobutyl group or a The compound of the present invention represented by the 30 nonafluorobutyl group , etc . may be mentioned as specific formula ( I ) and a pesticide containing the compound as an examples, and it is selected within the range of the specified active ingredient, exhibit excellent controlling effects number of carbon atoms. against pests in agricultural and horticultural fields or live - The expression “ Ca- C , cycloalkyl ” represents a cyclic stock and sanitation fields, especially against fungi and hydrocarbon group containing from a to b carbon atoms in nematodes , and also exhibit sufficient controlling effects 35 the form of a 3 - to 10 -membered monocyclic or polycyclic against such pests that have acquired resistance to existing ring . Further , each ring may optionally be substituted by an drugs. Further , they bring about little adverse effect against alkyl group within the range of the specified number of non - target organisms such as plants and mammals , fish , carbon atoms. For example, a cyclopropyl group , a cyclobu useful insects , natural enemies , etc ., and the load on the tyl group , a 1- methylcyclopropyl group , a 2 -methylcyclo environment is light with low residual effects. Thus, the 40 propyl group , a cyclopentyl group , a 2 , 2- dimethylcyclopro present invention can provide a useful novel pesticide . pyl group , a 1 -methylcyclobutyl group , a cyclohexyl group , etc . may be mentioned as specific examples, and it is DESCRIPTION OF EMBODIMENTS selected within the range of the specified number of carbon atoms. In the alkynyl pyridine - substituted amide compounds 45 The expression “ C - C . halocycloalkyl ” represents a represented by the formula ( 1 ) covered by the present cyclic hydrocarbon group containing from a to b carbon invention , there may sometimes be optically active isomers atoms in which hydrogen atom ( s ) on carbon atom ( s ) are due to the presence of one or more asymmetric carbon atoms optionally substituted with halogen atom ( s ) and which may depending upon their substituents , and , the present invention be in the form of a 3 - to 10 -membered monocyclic or covers all of such optically active isomers or racemates . In 50 polycyclic ring . Further, each ring may optionally be sub the compounds covered by the present invention , there may stituted by an alkyl group within the range of the specified sometimes be geometric isomers such as E - isomers and number of carbon atoms; the substitution by halogen atom ( s ) Z -isomers depending upon their substituents, and the present may be in a ring moiety and / or in a side chain ; and when invention covers such E - isomers , Z - isomers and mixtures substituted by two or more halogen atoms, such halogen containing E - isomers and Z - isomers in optional proportions. 55 atoms may be identical with or different from one another . In this specification , the following terms or expressions For example , a 1 - fluorocyclopropyl group , a 2 , 2 - difluoro are, respectively , used in the following meanings or usage . cyclopropyl group , a 2 ,2 - dichlorocyclopropyl group , a 2 ,2 As the halogen atom , a fluorine atom , a chlorine atom , a dibromocyclopropyl group , a 2 , 2 - difluoro - 1 -methylcyclo bromine atom and an iodine atom may be mentioned . In this propyl group , a 2 ,2 - dichloro - 1 -methylcyclopropyl group , a specification , the expression " halo ” also represents these 60 2 , 2 -dibromo - 1 -methylcyclopropyl group , a 2 , 2 , 3 , 3 - tetra halogen atoms. fluorocyclobutyl group , etc . may be mentioned as specific In the specific description of the substituents , the expres examples, and it is selected within the range of the specified sion “ n - ” means “ normal” , “ i -” means “ iso ” , “ s ” means number of carbon atoms. “ secondary ” , and “ tert - ” means “ tertiary ” . The expression “ Ca- Cp alkenyl” represents a linear or The expression “ Ca- C ) alkyl” represents a linear or 65 branched unsaturated hydrocarbon group containing from a branched hydrocarbon group containing from a to b carbon to b carbon atoms and having one or more double bond ( s ) in atoms, and may , for example , be a methyl group , an ethyl the molecule , and for example , a vinyl group , a 1 -propenyl US 10 ,029 , 986 B2 13 14 group , a 2 -propenyl group , a 1- methylethenyl group , a group , etc .may be mentioned as specific examples, and it is 1 -butenyl group , a 2 -butenyl group , a 1 -methyl - 1 -propenyl selected within the range of the specified number of carbon group , a 2 -methyl - 1 - propenyl group, a 2 -methyl - 2 - propenyl atoms. group , a 3 -methyl - 3 - butenyl group , etc . may be mentioned The expression “ C - C , alkoxy ” represents an alkyl- 0 as specific examples , and it is selected within the range of 5 group in which the alkyl is a previously mentioned alkyl the specified number of carbon atoms. group containing from a to b carbon atoms. For example , a The expression “ Ca- C ) haloalkenyl” represents a linear or methoxy group , an ethoxy group , a n -propyloxy group , an branched unsaturated hydrocarbon group containing from a i- propyloxy group , a n - butyloxy group , an i -butyloxy group , to b carbon atoms and having one or more double bond ( s ) in a s -butyloxy group , a tert- butyloxy group , a pentyloxy the molecule , in which hydrogen atom (s ) on carbon atom ( s ) group , a hexyloxy group , etc . may be mentioned as specific are optionally substituted by halogen atom ( s ). Here , when examples, and it is selected within the range of the specified substituted by two or more halogen atoms, such halogen number of carbon atoms. atoms may be identical with or different from one another. The expression “ Ce -Ch haloalkoxy ” represents a For example , a 2 - fluorovinyl group , a 2 - chlorovinyl group , 15 haloalkyl- O group in which the haloalkyl is a previously a 1 , 2 -dichlorovinyl group , a 2 , 2 - dichlorovinyl group , a mentioned haloalkyl group containing from a to b carbon 2 ,2 -dibromovinyl group , a 2 - fluoro - 2 -propenyl group , a atoms; for example , a difluoromethoxy group , a trifluo 2 - chloro - 2 -propenyl group , a 3 -chloro - 2 - propenyl group , a romethoxy group , a chlorodifluoromethoxy group , a bro 3 , 3 -difluoro - 2 - propenyl group , a 2 , 3 -dichloro - 2 -propenyl modifluoromethoxy group , a 2 - fluoroethoxy group , a group , a 3, 3 -dichloro - 2 -propenyl group , a 2, 3, 3 -trifluoro - 2 - 20 2 -chloroethoxy group , a 2, 2 ,2 - trifluoroethoxy group , a 1, 1, propenyl group , a 2 ,3 , 3 - trichloro - 2 -propenyl group , a 1 - (tri 2 , 2 -tetrafluoroethoxy group , a 2 - chloro - 1 , 1 , 2 - trifluoroeth fluoromethyl) ethenyl group , a 4 ,4 - difluoro - 3 -butenyl group , oxy group , a 1, 1 ,2 , 3, 3, 3 -hexafluoropropyloxy group , etc . a 3 , 4 , 4 - trifluoro - 3 -butenyl group , a 2 , 4 , 4 , 4 - tetrafluoro - 2 may be mentioned as specific examples , and it is selected butenyl group , a 3 -chloro - 4 , 4 , 4 - trifluoro - 2 -butenyl group , within the range of the specified number of carbon atoms. etc . may be mentioned as specific examples , and it is 25 The expression “ Ca- Ch alkenyloxy ” represents an alk selected within the range of the specified number of carbon enyl- O group in which the alkenyl is a previously men atoms. tioned alkenyl group containing from a to b carbon atoms; The expression “ Ce -C , cycloalkenyl” represents a cyclic for example , a 2 -propenyloxy group , a 2 - butenyloxy group , unsaturated hydrocarbon group containing from a to b a l - methyl- 2 -propenyloxy group , a 2 -methyl - 2 -propenyloxy carbon atoms and containing one or more double bond ( s ) in 30 group , a 3 -methyl - 2 - butenyloxy group , a 1 , 1 -dimethyl - 2 propenyloxy group , etc . may be mentioned as specific the form of a 3 - to 10 -membered monocyclic or polycyclic examples , and it is selected within the range of the specified ring . Further, each ring may optionally be substituted by an number of carbon atoms. alkyl group within the range of the specified number of The expression “ Ca- Ch haloalkenyloxy ” represents a carbon atoms, and further , the double bond may be either ,35 haloalkenyl- 0 group in which the haloalkenyl is a previ endo - form or exo - form . For example , a 1 - cyclopentenyl ously mentioned haloalkenyl group containing from a to b group , a 2 - cyclopentenyl group , a 1 - cyclohexenyl group , a carbon atoms; for example , a 2 - fluoro - 2 - propenyloxy group , 2 - cyclohexenyl group , a bicyclo [ 2 . 2 . 1 ] - 5 -hepten - 2 - yl group , a 2 -chloro - 2 -propenyloxy group , a 3 - chloro - 2 - propenyloxy etc . may be mentioned as specific examples , and it is group , a 3 , 3 -difluoro - 2 -propenyloxy group , a 2, 3 - dichloro selected within the range of the specified number of carbon 40 2 -propenyloxy group , a 3 , 3 - dichloro - 2 - propenyloxy group , atoms. a 2 , 3 , 3 - trifluoro - 2 - propenyloxy group , etc . may be men The expression “ Ca- Ch alkynyl” represents a linear or t ioned as specific examples , and it is selected within the branched unsaturated hydrocarbon group containing from a range of the specified number of carbon atoms. to b carbon atoms and having one or more triple bond ( s ) in The expression “ Ca- C , alkynyloxy ” represents an alky the molecule . For example , an ethynyl group , a 1 -propynyl 45 nyl- O group in which the alkynyl is a previously men group , a 2 - propynyl group , a 1 -butynyl group , a 2 -butynyl tioned alkynyl group containing from a to b carbon atoms; group , a 3 -butynyl group , a 1 -methyl - 2 -propynyl group , a for example , a 2 -propynyloxy group , a 2 - butynyloxy group , 1 -pentynyl group , a 2 - pentynyl group , a 1 -hexynyl group , a a 1 -methyl - 2 - propynyloxy group , a 1 , 1 -dimethyl - 2 - propy 3 -hexynyl group , a 3 - methyl- 1 - petynyl group , a 4 -methyl nyloxy group , etc . may be mentioned as specific examples , 1 - pentynyl group , a 3 , 3 - dimethyl- 1 - butynyl group , etc . may 50 and it is selected within the range of the specified number of be mentioned as specific examples, and it is selected within carbon atoms. the range of the specified number of carbon atoms. The expression “ Ca- Ch haloalkynyloxy ” represents a The expression “ C . - C , haloalkynyl” represents a linear or haloalkynyl - O - group in which the haloalkynyl is a pre branched unsaturated hydrocarbon group containing from a viously mentioned haloalkynyl group containing from a to b to b carbon atoms and having one or more triple bond ( s ) in 55 carbon atoms; for example , a 3 - chloro - 2 - propynyloxy the molecule , in which hydrogen atom ( s ) on carbon atom ( s ) group , a 3 -bromo - 2 -propynyloxy group , a 3 - iodo - 2 -propy are optionally substituted by halogen atom ( s ). Here , when nyloxy group , etc . may be mentioned as specific examples , substituted by two or more halogen atoms, such halogen and it is selected within the range of the specified number of atoms may be identical with or different from one another. carbon atoms. For example , a 2 -chloroethynyl group , a 2 -bromoethynyl 60 The expression “ C . - C , alkylthio ” represents an alkyl- S — group , a 2 - iodoethynyl group , a 3 - fluoro - 1 - propynyl group , group in which the alkyl is a previously mentioned alkyl a 3 - chloro - 1 -propynyl group , a 3 -chloro - 2 - propynyl group , group containing from a to b carbon atoms; for example , a a 3 -bromo - 1 - propynyl group , a 3 - bromo- 2 - propynyl group , methylthio group , an ethylthio group , a n -propylthio group , a 3 - iodo - 2 -propynyl group , a 3 , 3 -difluoro - 1 - propynyl group , an i- propylthio group , a n -butylthio group , an i -butylthio a 3 ,3 , 3 - trifluoro - 1 -propynyl group , a 3 -bromo - 1 -butynyl 65 group , a s -butylthio group , a tert - butylthio group , etc . may group , a 3 - fluoro - 3 -methyl - 1 - butynyl group , a 3 - chloro - 3 - be mentioned as specific examples , and it is selected within methyl- 1 - butynyl group , a 3 - bromo- 3 -methyl - 1 - butynyl the range of the specified number of carbon atoms. US 10 ,029 , 986 B2 15 16 The expression “ C2- Cb haloalkylthio ” represents a The expression “ Ce- Ch alkoxymethyl” or “ Ca- C , alkoxy haloalkyl- s — group in which the haloalkyl is a previously (Co -Ce ) alkyl” , respectively , represents a methyl group or a mentioned haloalkyl group containing from a to b carbon previously mentioned alkyl group containing from d to e atoms; for example , a difluoromethylthio group , a trifluo carbon atoms in which hydrogen atom (s ) on carbon atom ( s ) romethylthio group , a chlorodifluoromethylthio group , a 5 are optionally substituted by previously mentioned optional trichloromethylthio group , a bromodifluoromethylthio Ca -Chalkoxy group , and it is selected within the range of the specified number of carbon atoms. group , a 2 , 2, 2 -trifluoroethylthio group , a 1 , 1, 2 ,2 - tetrafluo The expression “ (Ca -Cb ) alkyl substituted by RIO ” repre roethylthio group , a 2 - chloro - 1 , 1 , 2 - trifluoroethylthio group , sents a previously mentioned alkyl group containing from a a pentafluoroethylthio group , a 1, 1 ,2 , 3 ,3 ,3 -hexafluoropro 10 to b carbon atoms in which hydrogen atom ( s) on carbon pylthio group , a heptafluoropropylthio group , a 1 , 2 , 2 , 2 atom ( s ) are substituted by optional RS , and it is selected tetrafluoro - 1 - trifluoromethyl) ethylthio group , a nonafluo within the range of the specified number of carbon atoms. robutylthio group , etc . may be mentioned as specific The expression “ ( C . - C ) alkyl optionally substituted by examples, and it is selected within the range of the specified R10 » represents a previously mentioned alkyl group con number of carbon atoms. 15 taining from a to b carbon atoms in which hydrogen atom ( s ) The expression “ tri (C2 - C , alkyl) silyl” represents a silyl on carbon atom ( s ) are optionally substituted by optional R10, group replaced by previously mentioned alkyl groups con and it is selected within the range of the specified number of taining from a to b carbon atoms which may be identical carbon atoms. Here , when two or more substituents R10 are with or different from one another, for example , a trimeth present on the Ca -C alkyl group , the respective Rlº' s may ylsilyl group , a triethylsilyl group , a tri( n -propyl ) silyl group , 20 be identical with or different from one another. an ethyldimethylsilyl group , a n -propyldimethylsilyl group , The expression “ hydroxy ( C / -C .) cycloalkyl” represents a a n - butyldimethylsilyl group , an i -butyldimethylsilyl group , previously mentioned cycloalkyl group containing from d to a tert- butyldimethylsilyl group , etc . may be mentioned as e carbon atoms in which hydrogen atom ( s ) on carbon specific examples , and it is selected within the range of the atom ( s ) are substituted by hydroxy group ( s ), and it is specified number of carbon atoms. selected within the range of the specified number of carbon The expression “ C . - C . alkylcarbonyl ” represents an atoms. alkyl- C ( O ) - group in which the alkyl is a previously The expression “ C . - C . alkylidene ” represents a linear or mentioned alkyl group containing from a to b carbon atoms; branched hydrocarbon group containing from a to b carbon for example , an acetyl group , a propionyl group , a butyryl atoms, bonded by a double bond ; for example , a methyl group , an isobutyryl group , a valeryl group , an isovaleryl 30 idene group , an ethylidene group , a propylidene group , a group , a 2 -methylbutanoyl group , a pivaloyl group , etc .may 1 -methylethylidene group , a butylidene group , a 1 -methyl be mentioned as specific examples, and it is selected within propylidene group , a pentylidene group , a 1- methylbutyl the range of the specified number of carbon atoms. idene group , a 1 - ethylethylidene group , a hexylidene group , The expression “ Co -Ch cycloalkylcarbonyl” represents a etc . may be mentioned as specific examples, and it is cycloalkyl- C ( O ) - group in which the cycloalkyl is a pre - 35 selected within the range of the specified number of carbon viously mentioned cycloalkyl group containing from a to b atoms . carbon atoms; for example , a cyclopropylcarbonyl group, a The expression “ Ca- C , haloalkylidene ” represents a linear cyclobutylcarbonyl group , a 1 -methylcyclopropylcarbonyl or branched hydrocarbon group containing from a to b group , a 2 -methylcyclopropylcarbonyl group , a cyclopen carbon atoms, bonded by a double bond , in which hydrogen tylcarbonyl group , a 2 , 2 -dimethylcyclopropylcarbonyl 40 atom ( s ) on carbon atoms are optionally substituted by halo group , a cyclohexylcarbonyl group , etc . may be mentioned gen atom ( s ) . Here , when substituted by two or more halogen as specific examples , and it is selected within the range of atoms, such halogen atomsmay be identical with or different the specified number of carbon atoms. from one another. For example, a fluoromethylidene group , The expression “ Ca- Ch alkoxycarbonyl” represents an a chloromethylidene group , a difluoromethylidene group , a alkyl- 0 - C ( O ) - group in which the alkyl is a previously 45 dichloromethylidene group , a 2 , 2 , 2 - trifluoroethylidene mentioned alkyl group containing from a to b carbon atoms; group , etc . may be mentioned as specific examples, and it is for example , a methoxycarbonyl group , an ethoxycarbonyl selected within the range of the specified number of carbon group , a n -propyloxycarbonyl group , an i- propyloxycarbo - atoms. nyl group , a n -butoxycarbonyl group , an i- butoxycarbonyl The expression “ Ce- Cb alkoxy (Cr - C . )alkylidene ” repre group , a tert- butoxycarbonyl group , etc . may be mentioned 50 sents a previously mentioned alkylidene group containing as specific examples, and it is selected within the range of from d to e carbon atoms in which hydrogen atom ( s ) on the specified number of carbon atoms. carbon atom (s ) are substituted by previously mentioned The expression “ Ca -C7 alkylcarbonyloxy ” represents an optional C2- C alkoxy group , and it is selected within the alkyl- C ( 0 )40 group in which the alkyl is a previously range of the specified number of carbon atoms. mentioned alkyl group containing from a to b carbon atoms; 55 A specific example of the expression “ R ? and R² together for example , an acetyloxy group , a propionyloxy group , a form a C2- C , alkylene chain thereby to form a 3 - 6 mem butyryloxy group , an isobutyryloxy group , etc . may be bered ring together with the carbon atom to which R and R ? mentioned as specific examples, and it is selected within the are bonded , wherein the alkylene chain may contain one or range of the specified number of carbon atoms. two oxygen atoms, sulfur atoms or nitrogen atoms ” ,may , for The expression “ C . - C , alkylsulfonyloxy ” represents an 60 example , be a ring such as cyclopropane , oxirane , thiirane, alkylsulfonyl - 0 — group in which the alkylsulfonyl is a aziridine , cyclobutane, oxetane, thietane, azetidine, cyclo previously mentioned alkylsulfonyl group containing from a pentane , oxolane , thiolane, pyrrolidine, dioxolane, dithi to b carbon atoms; for example , a methylsulfonyloxy group , olane , cyclohexane, tetrahydropyran , tetrahydrothiopyran , an ethylsulfonyloxy group , a n - propylsulfonyloxy group , an piperidine , 1 , 3 -dioxane or 1 , 3 - dithiane , and it is selected i - propylsulfonyloxy group , etc . may be mentioned as spe- 65 within the range of the specified number of carbon atoms. cific examples , and it is selected within the range of the A specific example of the expression “ R ? or R2 , and R or specified number of carbon atoms. R4, together form a C , -C4 alkylene chain thereby to form a US 10 ,029 , 986 B2 17 18 3 -6 membered ring together with the carbon atoms to which Y - I: Y is a halogen atom , and Y2 and Y3 are simultane R1 or R ? , and R3 or R4, are bonded , wherein the alkylene ously hydrogen atoms. chain may contain one oxygen atom or sulfur atom ” , may , Y - II : Yl is methyl, and Y2 and Y3 are simultaneously for example , be a ring such as cyclopropane , oxirane , hydrogen atoms. thiirane, cyclobutane, oxetane , thietane , cyclopentane , oxo - 5 Y - III: Y ' is a halogen atom or methyl, Y - is methyl, and lane , thiolane , cyclohexane , tetrahydropyran or tetrahydro Y ? is a hydrogen atom . Among these , the combination of substituents represented thiopyran , and it is selected within the range of the specified by Y ' , Y2 and Y >, is more preferably Y - I or Y - II, particularly number of carbon atoms. preferably Y - I . In the present invention , a preferred range of the substitu 10 preferred range of the combination of substituents ent represented by G? includes , for example , the following represented by R ', R2, R3 and R4, includes, for example , the groups G - I to G ? - XXV. following groups R - I to R -XVIII . That is , G - I: GP- 1 [ wherein , Xl is a halogen atom or R - I : R ' , R² , R3 and R + are hydrogen atoms. trifluoromethyl, and X2 is a hydrogen atom ] . R -II : R1 is methyl or methoxy, and R2 , R3 and R4 are G - II : G™- 2 [ wherein X ! is a halogen atom or trifluorom - 15 hydrogen atoms. ethyl] . R - III : R is cyano , C . - C , haloalkyl, cyclopropyl, phenyl G - III: G - 3 [wherein X is a halogen atom , difluorom methyl substituted by (Z ). [wherein Z is a halogen atom , ethyl or trifluoromethyl , and X² is a hydrogen atom ] . and m is 1 or 2 , when m is 2 , the respective Z ’s may be GP- IV : G - 7 [wherein Xl is trifluoromethyl] . identical with or different from one another ] , C , - C , alkylthio Gl- V : GP- 11 [ wherein X ! is methyl or trifluoromethyl ] . 20 or C , - C , alkoxycarbonyl, and R2, R3 and R4 are hydrogen GP- VI: G ? - 12 [wherein Xl is a halogen atom , and X² is a atoms. hydrogen atom ]. R - IV : R1 and R2 are simultaneously fluorine atoms, cyano , GP- VII : G - 27 [ wherein Xl is difluoromethyl or trifluo - methyl or C . - C2 alkoxycarbonyl, and R3 and R4 are hydro romethyl, X² is a hydrogen atom , and R ' is methyl] . gen atoms. GP- VIII : GP- 33 [wherein X ! is difluoromethyl or trifluo - 25 R - V : R and R2 together form an ethylene chain thereby romethyl , and X ’ is methyl] . to form a cyclopropyl ring together with the carbon atom to GP- IX : G - 50 [wherein X1 is trifluoromethyl , and r is 0 ]. which R and R2 are bonded , and R3 and R4 are hydrogen G - X : Gº- 1 [ wherein Xl is nitro , methyl or difluorom atoms. ethyl, and X2 is a hydrogen atom ] . R - VI: R ! and R² together formC H ,0 — thereby to GP- XI: GP- 1 [ wherein X and X represent each indepen - 30 form an oxirane ring together with the carbon atom to which dently a fluorine atom or a chlorine atom ]. R and R? are bonded , and R3 and R + are hydrogen atoms. G + -XII : GP- 2 [wherein Xl is difluoromethyl] . R - VII: R ' and R² together form C ,- C2 alkylidene or C , -C2 GP- XIII : G™- 3 [wherein Xl is methyl, and X2 is a hydro - haloalkylidene , and R3 and R + are hydrogen atoms. gen atom ]. R - VIII: R ' is methoxy, ethoxy, C . - C2 haloalkoxy , cyano G - XIV : GP- 7 [wherein Xl is a halogen atom , methyl or 35 ( C , -C2 ) alkoxy , C3 -C4 alkenyloxy, C3- C4 alkynyloxy, benzy difluoromethyl ]. loxy or C . - C haloalkylthio , R2 is a hydrogen atom , R * is GP- XV : GP- 8 [wherein X is trifluoromethyl, and X is a methyl, and R is a hydrogen atom . hydrogen atom or methyl] . R - IX : R and R ’ are hydrogen atoms, R? is methyl, and R + G ? -XVI : G - 9 [wherein Xl is difluoromethyl or trifluo - is a hydrogen atom . romethyl, X2 is a hydrogen atom , and X3 is a hydrogen atom 40 R - X : R and R2 are hydrogen atoms, and R3 and R4 or methyl] . together form an ethylene chain thereby to form a cyclo GP-XVII : G ? - 11 [wherein X is a halogen atom or dif propyl ring together with the carbon atom to which R3 and luoromethyl] . R4 are bonded . GP- XVIII : G1- 12 [wherein Xl is difluoromethyl or trif R - XI: R ' is a halogen atom , C7 - C4 alkyl , CZ -C4 haloalkyl , luoromethyl, and X2 is a hydrogen atom ) . 45 CZ -C4 alkoxy, C , -C4 haloalkoxy, CZ -C4 alkylthio , C ,- C4 GP- XIX : GP- 13 [ wherein Xl is a halogen atom , difluo - haloalkylthio , C , -C4 alkoxyamino , C , -C4 alkoxycarbonyl , romethyl or trifluoromethyl, and X2 is a hydrogen atom ) . C ( O )NH , or - C ( S )NH ,, and R , R and R4 are hydrogen G - XX : GP- 16 [ wherein Xl is difluoromethyl or trifluo - atoms. romethyl, X² is a hydrogen atom , and R ' is methyl] . R -XII : R ' is a halogen atom , cyano, C , -C4 alkyl, - C ( O ) GP- XXI: G²- 27 [wherein X ! is methyl , ethyl or trifluo - 50 NH , or - C ( S ) NH2, R2 is a halogen atom , cyano or methyl , romethyl, X² is a halogen atom , and R ’ is methyl] . and R3 and R * are hydrogen atoms. G1- XXII : G1- 32 [wherein Xl is difluoromethyl or trifluo R - XIII : R7 and R2 together form a C . - C , alkylene chain romethyl, and X² is a hydrogen atom or methyl] . thereby to form a 3 - 6 membered ring together with the GP- XXIII : GP- 33 [wherein X is difluoromethyl or trif carbon atom to which R and R2 are bonded , wherein the luoromethyl, and X² is a hydrogen atom ) . 55 alkylene chain may contain one oxygen atom or sulfur atom , G ? - XXIV : G²- 44 [wherein X ! is difluoromethyl or trif - and R3 and R + are hydrogen atoms. luoromethyl, and R ' is methyl ] . R -XIV : R and R2 together form C .- C . alkylidene, C . - C . GP- XXV: GP - 50 [wherein Xl is methyl or trifluoromethyl , haloalkylidene or CZ -C4 alkoxy (C7 -C2 ) alkylidene , and R3 and r is 0 , 1 or 2 ) . and R + are hydrogen atoms . Among these, as the substituent represented by G ', more 60 R - XV : R ' is C , -C4 alkyl, C . -C4 alkoxy , C -C4 haloalkoxy , preferred is GP- I to G -- IX , G ? - XI, G?- XII, GP- XIV , cyano (C2 -C2 ) alkoxy , Cz- Co alkenyloxy , C3 -C6 alkynyloxy , GP- XVII, GP- XVIII or GP- XX to GP- XXII , and particularly phenyl (C7 - C _ ) alkoxy or CZ -C4 alkoxyamino , R² is a hydro preferred is G ' -I to G - V , G ? - VII, G ' -VIII , GP- XII , GP -XIV , gen atom , R3 is methyl, and R4 is a hydrogen atom . G - XVII or GP- XVIII . R - XVI: R and R2 are hydrogen atoms, R² is C , -C4 alkyl A preferred range of the combination of substituents 65 or CZ- C4 haloalkyl, and R + is a hydrogen atom . represented by Y ', Y2 and Y3 includes, for example , the R -XVII : R1 and R2 are hydrogen atoms, and R3 and R4 are following groups Y - I to Y - III . methyl. US 10 ,029 , 986 B2 19 20 R -XVIII : R and R3 together form a C2- C4 alkylene chain TABLE 1 -continued thereby to form a 4 - 6 membered ring together with the carbon atoms to which R ' and R3 are bonded , wherein the G1 R ! - R4 RO alkylene chain may contain one oxygen atom , and R2 and R + GU- I R - III R - II are hydrogen atoms. 5 G1- 1 R - IV R6- I GU- I R - IV R - II Among these , the combination of substituents represented GP- I R - IV R - III by R1, R2, R3 and R *, is more preferably R - I to R - V , R - VII G - I R - IV R - IV to R - IX , R - XI, R -XII , R -XV or R -XVI , particularly prefer G1- I R - IV R - V G - I R - IV R - VII ably R - I , R - II, R - IV , R - V or R - VII to R - IX . GP - I R - V RO- I A preferred range of the substituent represented by RS . 10 Gº- I R - V R - II includes , for example , the following groups R - I to R - IV . GP- I R - V R - III RS - I: a hydrogen atom . GU- I R - V R - IV G4- 1 R - V R - VI RS- II: cyclopropyl. GU- I R - V RO- VII R ” - III : C , -C4 alkoxycarbonyl. 15 G - I R - V R - VIII RS- IV : methoxy . G - I R - VI R - 1 Among these , the substituent represented by R is more G1- 1 R - VI R - II G1- 1 R - VII R - I preferably RS - I or RS- II , particularly preferably R - I. G - I R - VII R - II The preferred range of the substituent represented by R ', Gl- I R - VII RO- III includes, for example , the following groups R -I to Rº- IX . G1- 1 R - VII RO- IV GU- I R - VII R - V RO- 1: CZ - C4 alkyl. R - VII R - VII R?- II: C3- Co cycloalkyl . G - - I R - VIII R - 1 RO - III : (C2 - C4 ) alkyl optionally substituted by R10 R - VIII R - II [wherein R10 is OH or — ORS, RlS is C , -C4 alkyl or GU- I R - VIII R -III C1 - C4 haloalkyl] . G1- 1 R - VIII RO- IV 25 G - I R - VIII R - V RÓ - IV : trimethylsilyl. G1- 1 R - VIII R -VI RÓ- V : a halogen atom or C , -C4 haloalkyl. G1- 1 R - VIII R -VII RÓ - VI: ( CZ- C4) alkyl substituted by R10 [wherein Riº is G1- 1 R - VIII RO- VIII OR15, and R15 is C , -C4 alkoxymethyl] . G1- 1 R - VIII R - IX G1- 1 R - IX R - 1 RO -VII : Cz -Co halocycloalkyl or tri (CZ -C4 alkyl) silyl. G1- 1 R - IX RO- II RO - VIII : _ C ( R ) NOR12 [wherein Ri is a hydrogen 30 GU- I R - IX RO - III atom or methyl , and Rl2 is methyl or ethyl] . GU- I R - IX R - IV Rº -IX : a hydrogen atom . G1- 1 R - IX R - V Among these, the substituent represented by Rº , is more G4- 1 R - IX R6 -VI GU- I R - IX RO- VII preferably R $ -I to RO- IV or R?- VII, particularly preferably Gl- I R - IX R - VIII RO - I, RO - II or RO- III . G1- 1 R - IX R - IX In the present invention , the respective groups represent GP- 1 R - X R - I ing a preferred range of the respective substituents may Gl- I R - X R - II G1- 1 R - XI R - 1 optionally be combined and represent a preferred range of G1- 1 R - XI R - II the present compounds . G1- 1 R - XII R - I For example , the combinations as shown in the following 40 GU- I R - XII R - II Table 1 may be mentioned as examples of combinations of GP - I R - XIII R - I GU- I R - XIII R6- II preferred range with respect to Gº, RP- R + ( expressed by R - I G - I R - XIV R - I to R - XVIII ) of the compound of formula (I ) . However, the G -I R - XIV R - II combinations in Table 1 are for the purpose of exemplifi G - I R - XV R - I cation , and the compound of the present invention repre - 43 GU- I R - XV R - II GU- I R - XVI R - 1 sented by the formula (I ) is by no means limited thereto . GP- I R -XVI RO- II G1- I R -XVII R - I TABLE 1 G1- 1 R -XVII R - II GP- 1 R -XVIII R - I R ?~ R4 RO 50 GU- I R - XVIII R - II G1 G - - II R - I R - I G1- 1 R - I R - I Gl-II R - I R - II Gl- I R - I RO- II G - II R - II R -I G1- 1 R - I RO - III GP- II R - II RO - II G1- 1 R - I R - IV Gl- II R - IV R - I Gl- I R - I R - V 55 G - II R - IV R - II G1- 1 R - I R - VI GP- II R - V R - I G1- 1 R - I RO- VII GP- II R - V RO- II G1- 1 R - I R - VIII G - II R - VII R - I G1- 1 R - I R - IX G - II R - VII R - II GU- I R - II R - I G - II R - VIII R - I GU- I R - II RO- II G - II R - VIII RO - II G1- 1 R - II R - III 60 GP- II R - IX R6- I GU- I R - II R - IV G1- II R - IX R - II G - I R - II R - V GP- II R - XI R - 1 G1- 1 R - II R -VI G - II R - XI R - II GP- 1 R - II R - VII G - II R -XV R - 1 G1- 1 R - II R6- VIII G -II R - XV R - II G1- 1 R - II R - IX 65 G - - III R - I R -1 G1- I R - III R - I GP- III R - I RO- II US 10 ,029 , 986 B2 21 22 TABLE 1 -continued TABLE 1 - continued G1 R ?~ R4 RO G R ?~ R4 RO Gl- III R - I RO- III G1- IV R - I RO - III GU- III R - I R - IV 5 GP- IV R - I R - IV Gl- III R - I R - V G1- IV R - I R - V GP- III R - I RO - VI GP- IV R - I RO- VI G1- III R - I RO- VII G - IV R - I R - VII G1- III R - I R - VIII GL- IV R - I R - VIII GP- III R - I R - IX GP- IV R - I R - IX G - III R - II R - I 10 GP- IV R - II RO- I G - III R - II R - II GP- IV R - II R - II Gl- III R - II R - III GP- IV R - II R - III GP- III R - II R - IV GP- IV R - II R - IV GU- III R - II R - V Gl- IV R - II R - V G1- III R - II RO- VI Gl- IV R - II RO- VI Gl- III R - II R - VII G - IV R - II R - VII Gl- III R - II R - VIII GP- IV R - II R - VIII Gl- III R - II RO- IX Gl- IV R - II R - IX Gl- III R - III R - I G - IV R - III R - I G1- III R - III R6- II G - IV R - III R - II G - III R - IV R6- I GP- IV R - IV R - I GP- III R - IV R - II GP- IV R - IV R - II GU- III R - IV R - III 20 G1- IV R - IV R - III G - III R - IV R6 - IV GP- IV R - IV R - IV GP- III R - IV R - V GP- IV R - IV R - V GU- III R - IV R - VII G - IV R - IV R - VII GU- III R - V R - 1 G1- IV R - V R - I G - III R - V R - II G1- IV R - V R - II G - III R - V R - III 25 GP- IV R - V R - III Gl- III R - V R - IV G1- IV R - V R - IV Gl- III R - V R - VI G1- IV R - V R -VI GU- III R - V R - VII GP- IV R - V R - VII GU- III R - V R - VIII G - IV R - V R - VIII Gº- III R - V R - IX G - IV R - V R - IX G1- III R - VI R - 1 30 G - IV R - VI R - I GP- III R - VI R - II GP- IV R - VI RO- II G - III R - VII R - I GP- IV R - VII R - I G - III R - VII R - II GP- IV R - VII R - II Gl- III R - VII R - III GP- IV R - VII RO- III Gl- III R - VII RO- IV GT- IV R - VII R - IV GP- III R - VII R - V 35 GP- IV R - VII RO- V Gl- III R - VII RO- VII GP- IV R - VII R - VII G - III R - VIII R - I Gl- IV R - VIII R - I G - III R - VIII R - II GP- IV R - VIII R - II GP- III R - VIII R - III GP- IV R - VIII R - III G1- III R - VIII R - IV GP- IV R - VIII R - IV Gl- III R - VIII R - V G1- IV R - VIII R - V GP- III R - VIII R - VI 40 GP- IV R - VIII R - VI G - III R - VIII R - VII GP- IV R - VIII RO- VII Gl- III R - VIII R6- VIII GP- IV R - VIII R - VIII Gl- III R - VIII R - IX G1- IV R - VIII R - IX GP- III R - IX R - I GP- IV R - IX R - I G1- III R - IX R - II GP- IV R - IX R - II G - III R - IX R - III 45 Gl- IV R - IX R - III Gl- III R - IX R - IV G1- IV R - IX R - IV GP- III R - IX R - V GP- IV R - IX R - V Gl- III R - IX RO- VI GP- IV R - IX RO- VI Gº- III R - IX R - VII G - IV R - IX R - VII GP- III R - IX R - VIII G -IV R - IX RO - VIII G - III R - IX R - IX 50 Gl- IV R - IX RO- IX GP- III R - X R - I G1- IV R - X R - I Gl- III R - X R - II GP- IV R - X R - II G - III R - XI R - I GP- IV R - XI R - I Gl- III R - XI R - II GP- IV R - XI RO - II GP- III R - XII R - I GP- IV R - XII R - I G1- III R - XII RO - II 55 GP- IV R - XII R - II GP- III R - XIII R - I GP- IV R - XIII R - I G - III R - XIII RO- II GP- IV R - XIII RO- II GU- III R - XIV R - I GP- IV R - XIV R - I Gl- III R - XIV R - II G - IV R - XIV R - II G1- III R -XV R - I GP- IV R - XV R - I GP- III R - XV RO - II GP- IV R - XV RO- II G1- III R - XVI R - I 60 GP- IV R -XVI R6- I Gl- III R - XVI RO - II GP- IV R - XVI 2003ze.R - II G - III R -XVII R - I GP- IV R -XVII R - 1 GU- III R - XVII R - II G1- IV R - XVII R - II GP- III R - XVIII R - I G1- IV R - XVIII R - 1 Gl- III R -XVIII R - II G -- IV R - XVIII R - II G - IV R - I R - I 65 G - V R - I R -1 Gl- IV R - I R - II Gl - y R - I RO- II US 10 ,029 , 986 B2 23 24 TABLE 1 - continued TABLE 1 -continued G R ?~ R4 R6 G RI- R4 RO Gl- V R - II R - I G1 - VII R - VIII R - II G1- V R - II R - II 5 G - VII R - VIII R - III Gl- v R - IV R - I G1 - VII R - VIII R - IV Gl- V R - IV R - II G - VII R - VIII R - V Gl- V R - V R - 1 G1- VII R - VIII R - VI Gl- V R - V R - II G - VII R - VIII R - VII Gl- V R - VII R -I G1- VII R - VIII R - VIII Gl- V R - VII R - II 10 G -VII R - VIII RO- IX Gl- V R - VIII R - 1 G1- VII R - IX R - I G1- V R - VIII R - II Gi - VII R - IX R - II G ?- V R - IX R - I G²- VII R - IX R - III GP- V R - IX R - II GP - VII R - IX R - IV Gl- V R - XI R - I Gl- VII R - IX R - V Gl- V R - XI RO - II G1- VII R - IX R - VI Gl- V R -XV R - I GP- VII R - IX R - VII Gl- v R - XV RO- II Gl-VII R - IX RO- VIII G1- VI R - I R - I G - VII R - IX R - IX G1- VI R - I R - II G1- VII R - X R - 1 G - VI R - II R6- I G1- VII R - X R - II G - VI R - II R - II GP - VII R - XI RO- I Gl- VI R - IV R6- 1 20 G1- VII R - XI R - II G - VI R - IV R - II G1- VII R - XII R - I G -VI R - V RO- I GP- VII R - XII R - II Gl- VI R - V R - II G1- VII R - XIII R - 1 G1- VI R - VII R - I G1 - VII R - XIII R6- II G1- VI R - VII R - II GU- VII R - XIV R6- 1 Gl- VI R - VIII R - I 25 GP- VII R - XIV R - II Gl- VI R - VIII R - II G1 - VII R - XV R - I G - VI R - IX R - 1 G1- VII R - XV R - II Gl- VI R - IX RO- II G1- VII R - XVI R - I G - VI R - XI R - 1 G - VII R -XVI R - II Gl- VI R - XI R - II G1- VII R - XVII R - I G1- VI R - XV R - 1 30 G1- VII R -XVII RO- II G - VI R - XV R - II GP - VII R - XVIII R - I G ! - VII R - I R - I GP- VII R - XVIII R - II Gl- VII R - I R - II G - VIII R - I R -I G1- VII R - I R - III G1- VIII R - I R - II GP- VII R - I R - IV G1- VIII R - I R - III G - VII R - I R - V 35 GP - VIII R - I RO - IV Gl- VII R - I RO - VI G1- VIII R - I R - V Gl- VII R - I R6 - VII G1- VIII R - I R - VI GU- VII R - I R - VIII G - VIII R - I R - VII G1- VII R - I RO- IX G - VIII R - I R - VIII Gl- VII R - II RO- I G " - VIII R - I R - IX G1- VII R - II RO- II G1 - VIII R - II R - I G1- VII R - II R - III 40 GP- VIII R - II R - II G - VII R - II R - IV G -VIII R - II R - III G1- VII R - II R - V Gi - VIII R - II RO- IV G1- VII R - II R - VI GU- VIII R - II R - V G ! - VII R - II R - VII G ' - VIII R - II R -VI G1- VII R - II R - VIII G1 - VIII R - II R - VII Gl- VII R - II R - IX 45 G1- VIII R - II R6 - VIII Gl- VII R - III R - 1 G1- VIII R - II R - IX G1- VII R - III R - II GP - VIII R - III R - 1 G - VII R - IV R - 1 G " - VIII R - III R - II G - VII R - IV R - II G1 - VIII R - IV R - I G - VII R - IV R - III G -VIII R - IV RO - II G - VII R - IV R - IV 50 G - VIII R - IV R - III G1- VII R - IV R - V G1 - VIII R - IV R - IV Gl- VII R - IV RO- VII Gº- VIII R - IV R - V G ! - VII R - V R - I GP- VIII R - IV RO- VII GP- VII R - V R - II G1- VIII R - V R - I G1- VII R - V R - III G - VIII R - V R - II G1- VII R - V R - IV 55 G1- VIII R - V R - III G?- VII R - V R - V G - VIII R - V RO- IV G - VII R - V RO- VI G - VIII R - V RO- V G1- VII R - V R - VII Gi - VIII R - V R - VI G1- VII R - V R - VIII G " - VIII R - V RO- VII G - VII R - V R - IX G1- VIII R - V R - VIII GP- VII R - VI R - I G -VIII R - V R - IX Gl- VII R - VI R - II 60 G " - VIII R - VI R - 1 G1- VII R - VII R - I G1- VIII R - VI R - II G1- VII R - VII R - II G -VIII R - VII R6- I G1- VII R - VII R - III G1- VIII R - VII R - II G1- VII R - VII RO- IV G1- VIII R - VII R - III G1- VII R - VII R - V G1- VIII R - VII R - IV GI- VII R - VII R - VII 65 G - VIII R - VII R - V Gl- VII R - VIII R - 1 G1- VIII R - VII R - VII US 10 ,029 , 986 B2 25 26 TABLE 1 -continued TABLE 1 -continued G1 R1- R4 R6 G RI- R4 R6 G1- VIII R - VIII R - I G -XI R - XV R - II G?- VIII R - VIII R - II 5 G -XII R - I R6- I G1- VIII R - VIII R - III G1- XII R - I RO - II G1- VIII R - VIII R - IV G - XII R - II R -I G - VIII R - VIII R6- V G1- XII R - II R - II G1- VIII R - VIII RO - VI G1- XII R - IV R - I G1- VIII R - VIII RO- VII G1- XII R - IV R - II GU-VIII R - VIII R - VIII 10 GP- XII R - V RO- I G1- VIII R - VIII R - IX G1- XII R - V RO- II G - VIII R - IX R - 1 Gº- XII R - VIII R - I GI- VIII R - IX R - II G ' -XII R - VIII RO- II G1- VIII R - IX R - III G -XII R - IX R - I Gl- VIII R - IX RO- IV G²- XII R - IX R - II Gl- VIII R - IX R - V G1- XIII R - I R - I RO- VI R - I G1- VIII R - IX G1- XIII R aaa,- II G1- VIII R - IX R - VII G1- XIII R - II R - II G1- VIII R - IX RO - VIII G - XIII R - IV R - II G1- VIII R - IX R - IX G1- XIII R - V R6- 1 GI- VIII R - X RO- I G -XIII R - V R - II G1- VIII R - X RO - II G - - XIII R - VIII RO- I Gl- VIII R - XI R - I 20 GP- XIII R - VIII R - II G1- VIII R - XI R - II GP- XIII R - IX R - 1 GP- VIII R - XII R - I G ' - XIII R - IX R - II G?- VIII R - XII R - II Gº- XIV R - I R -1 Gl- VIII R - XIII R - I G1- XIV R - I R6- II G1- VIII R - XIII R - II G -XIV R - II R6- 1 G - VIII R - XIV R - I 25 GP- XIV R - II R - II G1- VIII R -XIV R - II G1- XIV R - IV R - I GI- VIII R - XV R - 1 G1- XIV R - IV R - II G1- VIII R - XV RO- II GU- XIV R - V R - I G - VIII R - XVI R - 1 G1- XIV R - V R - II GI- VIII R -XVI R - II G1- XIV R - VII R - I G1- VIII R - XVII R - 1 30 G1- XIV R - VII RO- II G1- VIII R - XVII R - II G1- XIV R - VIII R - I GP- VIII R - XVIII R - I G1- XIV R - VIII R - II G?- VIII R - XVIII R - II GU- XIV R - IX R - I G - IX R - I R - I GP- XIV R - IX R - II GP- IX R - I RO - II GP- XV R - I R - I G - IX R - II R - I 35 Gº- XV R - I R - II Gl- IX R - II RO - II Gº- XV R - II R6- I Gl- IX R - IV R - I Gº- XV R - II R - II G -- IX R - IV R - II G - XV R - IV R - I Gl- IX R - V R - I G ' -XV R - IV R - II G1- IX R - V R - II Gº -XV R - V R - I Gº- X R - VII R - I G1- XV R - V R - II G -- IX R - VII R - II 40 GU-XV R - VIII R - 1 G -- IX R - VIII R - I G ' -XV R - VIII R - II G -- IX R - VIII R - II G +- XV R - IX R - 1 G - IX R - IX R6 - 1 GP- XV R - IX R - II G - IX R - IX R - II GP- XVI R - I R - I G - X R - I R - 1 Gº- XVI R - I R - II G1- X R - I R - II 45 G1- XVI R - II R6- I G1- X R - II R - II G -XVI R - II RO - II G '- X R - IV R - II Gº- XVI R - IV R -I G1- X R - V R - 1 Gº -XVI R - IV R - II GU- X R - V R - II Gº- XVI R - V R - I G - X R - VII R - II G - XVI R - V R - II GP- X R - VIII R -I 50 G -XVI R - VIII RO- I GU- X R - VIII RO - II Gº- XVI R - VIII RO- II GU- X R - IX R - I G -XVI R - IX R - I G - X R - IX R - II G -XVI R - IX R - II G1- XI R - I R - 1 GP- XVII R - I R - 1 G - XI R - I RO- II Gº- XVII R - I R - II G1- XI R - II R - I 55 Gº- XVII R - II R - I G1- XI R - II R - II GP-XVII R - II R - II G1-XI R - IV R - I G ' -XVII R - IV R - I GU- XI R - IV R - II Gº- XVII R - IV R - II G1- XI R - V R6- I Gº- XVII R - V R - I G - XI R - V R - II GP- XVII R - V R - II G - XI R - VII R - I G - XVII R - VIII R - I G - XI R - VII R6- II 60 G1- XVII R - VIII R - II GU- XI R - VIII R - I G1- XVII R - IX R6- I G - XI R - VIII RO - II G -XVII R - IX R - II G - XI R - IX R - I G1- XVIII R - I R6- 1 G1- XI R - IX RO - II Gº- XVIII R - I R - II Gº- XI R - XI R - I G1- XVIII R - II R - I GU- XI R - XI R6- II 65 G ' -XVIII R - II RO- II GU- XI R - XV R -I GP- XVIII R - IV R - I US 10 ,029 , 986 B2 27 28 TABLE 1 - continued TABLE 1 -continued G1 R ?~ R4 RO G R ! - R4 R6 Gº-XVIII R - IV R - II Gº- XXIII R - IX R - II G -XVIII R - V R - I 5 Gº- XXIV R - I R6- I G1- XVIII R - V RO- II Gº- XXIV R - I RO - II G1- XVIII R - VII R - 1 GP- XXIV R - II R -I Gº- XVIII R - VII R - II G - XXIV R - II R - II G1- XVIII R - VIII R - 1 Gº- XXIV R - IV R - I G + - XVIII R - VIII R - II G1- XXIV R - IV R - II G1-XVIII R - IX R -1 10 GP- XXIV R - V RO- I Gº- XVIII R - IX R - II Gº- XXIV R - V RO- II G -- XVIII R - XI R - I Gº- XXIV R - VIII R - I G1- XVIII R - XI R - II GP- XXIV R - VIII R - II G1- XVIII R - XV R - I GP- XXIV R - IX R - 1 G - XVIII R - XV R - II G1- XXIV R - IX R - II G1- XIX R - I R - I 15 Gº- XXV R - I R - I G1- XIX R - I RO - II G - XXV R - I R - II G?-XIX R - II R - I GP- XXV R - II R - I Gl- XIX R - II RO - II Gº- XXV R - II R - II G1- XIX R - IV R6- I G -XXV R - IV R - I G?-XIX R - IV R - II GP- XXV R - IV R - II G + - XIX R - V R - I G - XXV R - V R - 1 GU- XIX R - V R - II 20 Gº- XXV R - V R - II G1- XIX R - VIII R - 1 G1-XXV R - VIII R - I G ? -XIX R - VIII R - II G - - XXV R - VIII RO - II G1- XIX R - IX R6- 1 G1- XXV R - IX R -I G1- XIX R - IX R - II Gº- XXV R - IX R - II G -XX R - I R - 1 G1- XX R - I RO- II 25 Gº-XX R - II R - 1 Among the compounds represented by the formula (I ), the GP- XX R - II R - II acid addition salts may, for example , be salts of hydrohalic G ? - XX R - IV R - I GP-XX R - IV R - II acids such as hydrofluoric acid , hydrochloric acid , hydro G - XX R - V R - I bromic acid , hydriodic acid , etc . , salts of inorganic acids G1- XX R - V RO- II 30 such as nitric acid , sulfuric acid , phosphoric acid , chloric G - XX R - VII R - 1 acid , perchloric acid , etc . , salts of sulfonic acids such as G -XX R - VII R - II Gº-XX R - VIII R - I methanesulfonic acid , ethanesulfonic acid , trifluorometh G1- XX R - VIII R - II anesulfonic acid , benzenesulfonic acid , p -toluenesulfonic G - XX R - IX R - I acid , etc ., salts of carboxylic acids such as formic acid , GP-XX R - IX R - II GU- XXI R - I R - I acetic acid , propionic acid , trifluoroacetic acid , fumaric acid , Gº-XXI R - I R - II tartaric acid , oxalic acid , maleic acid , malic acid , succinic G1- XXI R - II R - I acid, benzoic acid , mandelic acid , ascorbic acid , lactic acid , G1- XXI R - II R - II gluconic acid , citric acid , etc . , salts of amino acids such as G + - XXI R - IV R - I GU- XXI R - IV R - II glutamic acid , aspartic acid , etc . GP- XXI R - V R6 - 1 40 Among the compounds represented by the formula (I ) , the GP-XXI R - V R - II metal salts may, for example , be salts of alkali metals such G1- XXI R - VIII R - I as lithium , sodium , potassium , etc . , salts of alkaline earth GU-XXI R - VIII R - II G - XXI R - IX RO- I metals such as calcium , barium , magnesium , etc . an alumi Gº-XXI R - IX R - II num salt, etc . G -XXII R - I R - I 45 In this specification , “ pesticides ” means fungicides and Gº-XXII R - I RO- II parasiticides for controlling harmful pathogens and parasites G1- XXII R - II R - 1 GU-XXII R - II R - II which infect /parasitize plants or animals , and more specifi G1- XXII R - IV R - 1 cally means fungicides and nematicides in agricultural/ G + - XXII R - IV R - II horticultural fields, or antifungal agents and endoparasite G1-XXII R - V R - I 50 controlling agents for animals . G²- XXII R - V R - II G -- XXII R - VII R - I In this specification , " pathogens ” means microorganisms G1- XXII R - VII R - II which cause plant diseases and animal infectious diseases . G + - XXII R - VIII R - 1 As specific examples, the following microorganisms may be GU-XXII R - VIII R - II mentioned , but the pathogens are not limited thereto . GU- XXII R - IX R - I Fungi of the phylum Ascomycota , such as Taphrina spp . G + - XXIII R - X R - II G1- XXIII R - I R - I ( e . g . Taphrina deformans, T. pruni, etc . ), Pneumocystis spp . , GU- XXIII R - I R - II Geotrichum spp ., Candida spp . ( e . g . Candida albicans, C . G1- XXIII R - II R6- I sorbosa , etc . ) , Pichia spp . ( e . g . Pichia kluyveri, etc . ) , Cap G1- XXIII R - II RO- II G + - XXIII R - II RO - II nodium spp ., Fumao spp ., Hypocapnodium spp . , Cercospora Gº-XXIII R - IV R - I 60 spp . ( e. g . Cercospora apii, C . asparagi, C . beticola , C . GU- XXIII R - IV RO - II capsici, C . carotae, C . kaki , C . kikuchii , C . zonata , etc . ) , Gº-XXIII R - V R - I Cercosporidium spp ., Cladosporium spp . ( e . g . Cladospo G -XXIII R - V R - II G1- XXIII R - VIII R - I rium colocasiae , C . cucumerinum , C . variabile , etc . ) , Davi G - XXIII R - VIII R - I diella spp ., Didymosporium spp ., Heterosporium spp . ( e . g . G -XXIII R - VIII RO- II 65 Heterosporium allii, etc . ), Mycosphaerella spp . (e .g . Gº- XXIII R - IX R -I Mycosphaerella arachidis , M . berkeleyi, M . cerasella , M . fijiensis , M . fragariae, M . graminicola , M . nawae, M . US 10 , 029 , 986 B2 29 30 pinodes, M . pomi, M . zingiberis , etc .) , Mycovellosiella spp . fabae, B . squamosa , etc .) , Ciborinia spp . , Grovesinia spp ., ( e . g . Mycovellosiella fulva , M . nattrassii , etc . ), Paracer Monilia mumecola , Monilinia spp . ( e. g . Monilinia fructi cospora spp . ( e . g . Paracercospora egenula , etc . ) , Phaeoisa cola , M . fructigena, M . laxa , M . mali, M . vaccinii -corym riopsis spp . , Phaeoramularia spp . , Pseudocercospora spp . bosi , etc .) , Sclerotinia spp . ( e. g . Sclerotinia borealis , S. ( e. g . Pseudocercospora abelmoschi, P. fuligena , P . vitis , 5 homoeocarpa , S . minor, S . sclerotiorum , etc . ), Valdensia etc . ) , Pseudocercosporella spp . ( e . g . Pseudocercosporella spp . ( e . g . Valdensia heterodoxa , etc . ) , Claviceps spp . ( e . g . capsellae, etc .) , Ramichloridium spp . , Ramularia spp ., Sep Claviceps sorghi, C . sorghicola , etc . ) , Epichloe spp . , Ephelis toaloeum spp . , Septoria spp . ( e . g . Septoria albopunctata , S . japonica , Villosiclava virens, Hyypomyces spp . ( e . g . Hypo apiicola , S . chrysanthemella , S . helianthi, S . obesa , etc . ) , myces solani f. sp . mori , H . s . f . sp . pisi, etc .) , Trichoderma Sphaerulina spp . , Aureobasidium spp ., Kabatiella spp . , 10 spp . ( e . g . Trichoderma viride , etc . ) , Calonectria spp . ( e . g . Plowrightia spp ., Stigmina spp ., Elsinoe spp . (e . g. Elsinoe Calonectria ilicicola, etc .) , Candelospora spp ., Cylindro ampelina, E . araliae, E . fawcettii , etc . ) , Sphaceloma spp . carpon spp ., Cylindrocladium spp ., Fusarium spp . (e . g . ( e . g . Sphaceloma caricae , etc . ), Ascochyta spp . ( e . g . Asco Fusarium arthrosporioides , F . crookwellense, F . culmorum , chyta pisi , etc . ), Corynespora spp . ( e . g . Corynespora cassii F . cuneirostrum , F . oxysporum , F . o . f . sp . adzukicola , F . o . cola , etc .) , Leptosphaeria spp . ( e. g . Leptosphaeria conio - 15 f. sp . allii , F . o . f . sp . asparagi, F . o . f . sp . batatas, F. o . f. thyrium , L . maculans, etc . ), Saccharicola spp . , sp. cepae, F . o . f. sp . colocasiae , F. o . f. sp . conglutinans, F . Phaeosphaeria spp ., Ophiosphaerella spp ., Setophoma spp ., 0 . f. sp . cubense, F. o . f. sp . cucumerinum , F . o . f . sp . fabae , Helminthosporium spp ., Alternaria spp . ( e .g . Altemaria F. o . f. sp . fragariae , F . o . f . sp . lactucae , F. o . f. sp . altemata , A . brassicae, A . brassicicola , A . citr, A . dauci, A . lagenariae , F. o . f. sp . lycopersici, F. o . f. sp . melongenae , helianthi, A . japonica , A . kikuchiana , A . mali, A . panax , A . 20 F. o . f. sp . melonis , F. o . f. sp . nelumbinicola , F . o . f. sp . porri, A . radicina , A . solani, etc . ), Bipolaris spp . ( e . g . niveum , F . o . f . sp . radicis -lycopersici , F . o . f . sp . raphani, Bipolaris sorghicola , etc . ) , Cochliobolus spp . ( e . g . Coch - F . o . f . sp . spinaciae, F . sporotrichioides, F . solani, F . s . f . sp . liobolus heterostrophus, C . lunatus , C . miyabeanus, etc . ), cucurbitae , F . s . f . sp . eumartii, F. s. f. sp . i, F. s. f. sp . Curvularia spp . ( e . g . Curvularia geniculata , C . verruculosa , radicicola , etc . ), Gibberella spp . ( e . g . Gibberella avenacea , etc . ), Drechslera spp ., Pleospora spp . (e . g. Pleospora her - 25 G . baccata, Q . fuiikuroi, Q . zeae, etc . ), Haematonectria spp ., barum , etc . ) , Pyrenophora spp . ( e . g . Pyrenophora Nectria spp ., Ophionectria spp ., Caldariomyces spp ., graminea , P. teres, etc .) , Setosphaeria spp . ( e. g . Setospha - Myrothecium spp ., Trichothecium spp ., Verticillium spp . eria turcica , etc .) , Stemphylium spp . ( e .g . Stemphylium (e .g . Verticillium albo -atrum , V. dahliae , V . longisporum , botryosum , S . lycopersici, S . solani, S. vesicarium , etc . ), etc . ), Ceratocystis spp . (e . g . Ceratocystis ficicola , C . fim Fusicladium spp ., Venturia spp . ( e . g . Venturia carpophila , V . 30 briata , etc . ), Thielaviopsis spp . ( e . g . Thielaviopsis basicola , Inaequalis, V . nashicola , V . Dirina, etc .) , Didymella spp . etc . ), Adisciso spp ., Monochaetia spp ., Pestalotia spp . ( e . g . ( e. g . Didymella bryoniae , D . fabae , etc .) , Hendersonia spp ., Pestalotia eriobotrifolia , etc . ), Pestalotiopsis spp . (e . g . Phoma spp . ( e . g . Phoma erratica var . mikan , P . exigua var. Pestalotiopsis funerea , P . lonaiseta , P . neplecta , P . theae , exigua , P . wasabiae , etc . ), Pyrenochaeta spp . ( e . g . Pyreno etc . ), Physalospora spp . , Nemania spp . , Nodulisporium spp ., chaeta lycopersici, etc . ) , Stagonospora spp . ( e . g . Stagono - 35 Rosellinia spp . ( e . g . Rosellinia necatrix , etc . ) , spora sacchari , etc . ), Botryosphaeria spp . ( e .g . Botryospha - Monographella spp . (e . g. Monographella nivalis , etc . ), eria berengeriana f . sp . piricola , B . dothidea , etc . ) , Ophiostoma spp ., Cryphonectria spp . ( e . g . Cryphonectria Dothiorella spp ., Fusicoccum spp ., Guignardia spp . , Lasio - parasitica , etc . ), Diaporthe spp . (e . g . Diaporthe citri , D . diplodia spp . ( e . g . Lasiodiplodia theobromae , etc . ), Macro - kyushuensis , D . nomurai, D . tanakae , etc . ) , Diaporthopsis phoma spp ., Macrophomina spp ., Neofusicoccum spp ., Phyl - 40 spp ., Phomopsis spp . (e .g . Phomopsis asparai, P . fukushii, P. losticta spp . ( e .g . Phyllosticta zingiberis , etc . ), obscurans, P . vexans, etc .) , Cryptosporella spp ., Discula Schizothyrium spp . ( e .g . Schizothyrium pomi, etc . ), spp . ( e .g . Discula theae - sinensis , etc .) , Gnomonia spp ., Acrospermum spp ., Leptosphaerulina spp ., Asperillus spp ., Coniella spp ., Coryneum spp ., Greeneria spp ., Melanconis Penicillium spp . ( e. g . Penicillium digitatum , P. italicum , P. spp ., Cytospora spp ., Leucostoma spp ., Valsa spp . (e . g . sclerotigenum , etc .) , Microsporum spp ., Trichophyton spp . 45 Valsa ceratosperma, etc . ), Tubakia spp . , Monosporascus ( e . g . Trichophton mentagrophytes, T . rubrum , etc . ), Histo spp ., Clasterosporium spp . , Gaeumannomyces spp . ( e . g . plasma spp ., Blumeria spp . ( e . g . Blumeria graminis f. sp . Gaeumannomyces graminis , etc . ), Magnaporthe spp . (e . g . hordei , B . g . f. sp . tritici , etc . ) , Erysiphe spp . ( e . g . Erysiphe Magnaporthe grisea , etc . ), Pyricularia spp . ( e . g . Pyricu betae, E . cichoracearum , E . c . var. cichoracearum , E . hera laria zingiberis , etc .) , Monilochaetes infuscans, Colletotri clei, E . pisi , etc .) , Golovinomyces spp . ( e . g . Golovinomyces 50 chum spp . ( e . g . Colletotrichum acutatum , C . capsici , C . cichoracearum var. latisporus , etc . ) , Leveillula spp . ( e . g . cereale , C . destructivum , C . fragariae, C . lindemuthianum , Leveillula taurica , etc .) , Microsphaera spp ., Oidium spp . C . niarum , C . orbiculare , C . spinaciae , etc. ), Glomerella ( e. g . Oidium neolycopersici, etc .) , Phyllactinia spp . (e . g . spp . (e . g. Glomerella cingulata , etc .) , Khuskia oryzae , Phyl Phyllactinia kakicola , P . mali , P . moricola , etc . ), Podospha - lachora spp . ( e . g . Phyllachora pomigena , etc . ), Ellisembia era spp . ( e . g . Podosphaera fusca , P . leucotricha, P . pannosa , 55 spp ., Briosia spp ., Cephalosporium spp . ( e . g . Cephalospo P . tridactyla var. tridactyla , P . xanthii , etc .) , Sphaerotheca rium gramineum , etc .) , Epicoccum spp ., Gloeocercospora spp . ( e. g . Sphaerotheca aphanis var . aphanis , S. fuliginea , sorghi, Mycocentrospora spp ., Peltaster spp . (e .g . Peltaster etc . ), Uncinula spp . ( e . g . Uncinula necator , U . n . var. fructicola , etc . ) , Phaeocytostroma spp . , Phialophora spp . necator, etc . ), Uncinuliella spp . ( e . g . Uncinuliella simulans ( e . g . Phialophora gregata , etc . ) , Pseudophloeosporella var . simulans, U . s . var . tandae , etc . ) , Blumeriella spp . ( e . g . 60 dioscoreae, Pseudoseptoria spp . , Rhynchosporium spp . ( e . g . Blumeriella jaapii , etc .) , Cylindrosporium spp ., Diplocar - Rhynchosporium secalis , etc. ), Sarocladium spp ., Coleop pon spp . ( e . g . Diplocarpon mali, D . mespili , D . rosae , etc .) , homa spp ., Helicoceras orzae , etc . Gloeosporium spp . (e . g . Gloeosporium minus, etc . ), Fungi of the phylum Basidiomycota , such as Septoba Marssonina spp ., Tapesia spp . ( e. g . Tapesia acuformis , T. sidium spp . ( e .g . Septobasidium boaoriense , S . tanakae , yallundae , etc . ) , Lachnum spp ., Scleromitrula spp . , Botryo - 65 etc . ), Helicobasidium spp . ( e . g . Helicobasidium longispo tinia spp . ( e. g . Botryotinia fuckeliana , etc .) , Botrytis spp . rum , etc .) , Coleosporium spp . (e .g . Coleosporium plectran ( e . g . Botrytis allii , B . byssoidea , B . cinerea , B . elliptica, B . thi , etc . ), Cronartium spp . , Phakopsora spp . ( e . g . Phakop US 10 ,029 , 986 B2 31 32 sora artemisiae, P . nishidana , P . pachyrhizi, etc . ) , paroecandrum , P . periplocum , P . spinosum , P . sulcatum , P . Physopella spp . ( e . g . Physopella ampelopsidis , etc . ), Kue - sylvaticum , P . ultimum var. ultimum , P . vanterpoolii , P . hneola spp . ( e .g . Kuehneola japonica , etc . ), Phragmidium vexans, P . volutum , etc .) , etc . spp . ( e . g . Phragmidium fusiforme , P . mucronatum , P . rosae Gram -positive bacteria of the phylum Actinobacteria such multiflorae , etc . ) , Gymnosporangium spp . ( e . g . Gymnospo - 5 as Clavibacter spp . ( e . g . Clavibacter michiganensis subsp . rangium asiaticum , G . yamadae , etc . ), Puccinia spp . ( e . g . michiganensis , etc . ) , Curtobacterium spp ., Leifsonia spp . Puccinia allii , P . brachypodii var. pode -nemoralis , P. coro - ( e . g . Leifsonia xyli subsp . xyli , etc .) , Streptomyces spp . ( e . g . nata , P . c . var. coronata , P . cynodontis , P . graminis , P . g . Streptomyces ipomoeae , etc . ) , etc . subsp . graminicola , P . hordei , P . horiana , P . kuehnii, P . Gram -positive bacteria of the phylum Firmicutes such as melanocephala , P. recondita , P. striiformis var. striiformis , 10 Clostridium sp ., etc . P . tanaceti var. tanaceti , P. tokvensis , P. zovsiae , etc . ) , Gram - positive bacteria of the phylum Tenericutes such as Uromyces spp . (e .g . Uromyces phaseoli var. azukicola, U . Q . Phytoplasma , etc . var. phaseoli , Uromyces viciae - fabae var . viciae -fabae , etc . ) , Gram - negative bacteria of the phylum Proteobacteria Naohidemyces vaccinii, Nyssopsora spp ., Leucotelium spp ., such as Rhizobium spp . ( e. g . Rhizobium radiobacter, etc . ), Tranzschelia spp . ( e .g . Tranzschelia discolor, etc .) , 15 Acetobacter spp . , Burkholderia spp . (e . g. Burkholderia Aecidium spp ., Blastospora spp . ( e . g . Blastospora smilacis , andropogonis , B . cepacia , B . gladioli , B . glumae , B . plan etc . ), Uredo spp ., Sphacelotheca spp ., Urocystis spp . , Spor tarii , etc .) , Acidovorax spp . ( e .g . Acidovorax avenae subsp . isorium spp . ( e. g . Sporisorium scitamineum , etc .) , Ustilago avenae, A . a . subsp . citrulli , A . konjaci, etc .) , Herbaspirillum spp . ( e . g . Ustilago maydis , U . nuda , etc . ) , Entyloma spp ., spp ., Ralstonia spp . ( e . g . Ralstonia solanacearum , etc . ) , Exobasidium spp . ( e . g . Exobasidium reticulatum , E . vexans, 20 Xanthomonas spp . ( e . g . Xanthomonas albilineans, X . arbo etc . ) , Microstroma spp . , Tilletia spp . ( e . g . Tilletia caries, T . ricola gp . Druni, X . axonopodis pv . vitians, X . campestris pv . controversa , T . laevis , etc . ) , Itersonilia spp . ( e . g . Itersonilia campestris, X . c . pv. cucurbitae , X . c . V . glycines , X . C . V . perplexans , etc . ), Cryptococcus spp. , Bovista spp . ( e . g . mangiferaeindicae , X . c . pv . nigromaculans, X . c . pv . vesi Bovista dermoxantha , etc .) , Lycoperdon spp . ( e. g . Lycoper catoria , X . citri subsp . citri , X . oryzae pv. oryzae , etc .) , don curtisii , L . perlatum , etc .) , Conocybe spp . (e .g . Cono - 25 Pseudomonas spp . (e . g. Pseudomonas cichorii, P. fluore cybe apala , etc . ) , Marasmius spp . ( e . g . Marasmius oreades , scens, P . marginalis , P . m . pv. marginalis , P . savastanoi pv . etc . ) , Armillaria spp . , Helotium spp ., Lepista spp . ( e . g . alvcinea , P . syrinage, P. s . pv . actinidiae, P. s . pv. eriobot Lepista subnuda , etc . ), Sclerotium spp . ( e. g . Sclerotium ryae, P . s. pv . helianthi, P . s. pv. lachrymans, P . s. pv . cepiyorum , etc . ), Typhula spp . (e . g . Typhula incarnata , T . maculicola , P . s . pv . mori, P . s . pv . morsprunorum , P . s . pv . ishikariensis var. ishikariensis , etc . ) , Athelia spp . ( e . g . Athe - 30 spinaciae , P . s . pv . syrinage, P . s . Pv . theae , P . viridiflava , lia rolfsii , etc . ) , Ceratobasidium spp . (e . g . Ceratobasidium etc . ) , Rhizobacter spp . , Brenneria spp . ( e . g . Brenneria nig cornigerum , etc. ), Ceratorhiza spp ., Rhizoctonia spp . (e . g . rifluens, etc .) , Dickeya spp . (e .g . Dickeya dianthicola , D . Rhizoctonia solani, etc . ), Thanatephorus spp. ( e . g . Thanate - zeae , etc .) , Erwinia spp . ( e . g . Erwinia amylovora , E . rha phorus cucumeris , etc . ) , Laetisaria spp ., Waitea spp ., Fomi pontici , etc . ), Pantoea spp ., Pectobacterium spp . ( e . g . Pec tiporia spp . , Ganoderma spp . , Chondrostereum purpureum , 35 tobacterium atrosepticum , P . carotovorum , P . wasabiae , Phanerochaete spp . , etc . etc . ), etc . Fungi of the phylum Chitridiomycota such as Olidium As specific examples the plant diseases and animal infec spp ., etc . tious diseases caused by infection /proliferation of such Fungi of the phylum Blastocladiomycota such as Physo pathogens , the following plant diseases and animal infec derma spp ., etc . 40 tious diseases may, for example , be mentioned , but the Fungi of the phylum Mucoromycotina such as Choane - present invention is not restricted thereto . phora spp ., Choanephoroidea cucurbitae, Mucor spp . ( e . g . Plant Diseases : Mucor fragilis , etc . ) , Rhizopus spp . ( e . g . Rhizopus arrhizus, Leaf curl ( Taphrina deformans ), Plum pockets ( Taphrina R . chinensis, R . oryzae , R . stolonifer var. stolonifer , etc . ) , pruni) , Leaf spot (Cercospora asparagi) , Cercospora leaf etc . 45 spot (Cercospora beticola ) , Frogeye leaf spot ( Cercospora Protista of the phylum Cercozoa such as Plasmodiophora capsici) , Angular leaf spot ( Cercospora kaki ) , Purple stain spp . ( e . g . Plasmodiophora brassicae , etc . ) , Spongospora (Cercospora kikuchii ), Brown Leaf spot (Mycosphaerella subterranea f. sp . subterranea , etc . arachidis ) , Cylindrosporium leaf spot (Mycosphaerella Microorganisms of the phylum Heterokontophyta class cerasella , Blumeriella jaapii ), Speckled leaf blotch (My Oomycetes such as Aphanomyces spp . ( e . g . Aphanomyces 50 cosphaerella graminicola ) , Circular leaf spot (Mycosphaer cochlioides, A . raphani, etc .) , Albugo spp . (e . g . Albugo ella nawae ), Mycosphaerella blight (Mycosphaerella macrospora, A . wasabiae, etc .) , Bremia spp . (e . g. Bremia pinodes ), Leaf spot (Mycosphaerella zingiberis ), Leaf mold lactucae , etc .) , Hyaloperonospora spp ., Peronosclerospora (Mycovellosiella fulva ) , Leaf mold (Mycovellosiella nat spp ., Peronospora spp . ( e .g . Peronospora alliariae -wasabi , trassii ), Cercospora leafmold ( Pseudocercospora fuligena ) , P . chrysanthemi- coronarii , P . destructor, P . farinosa f. sp . 55 Isariopsis leaf spot (Pseudocercospora vitis ), Leaf spot spinaciae, P . manshurica , P . parasitica , P . soarsa , etc . ) , ( Pseudocercosporella capsellae ) , Leaf spot (Septoria chry Plasmopara spp . (e .g . Plasmopara halstedii , P . nivea , P. santhemella ), Leaf blight (Septoria obesa ) , Anthracnose viticola , etc . ) , Pseudoperonospora spp . ( e . g . Pseudoperono (Elsinoe ampelina ) , Spot anthracnose ( Elsinoe araliae ) , spora cubensis , etc . ), Sclerophthora spp ., Phytophthora spp . Scab ( Elsinoe fawcettii ) , Leaf spot ( Ascochyta pisi) , Coryne ( e . g . Phytophthora cactorum , P . capsici , P . citricola , P . 60 spora leaf spot ( Corynespora cassiicola ), Stem canker ( Lep citrophthora, P . cryotoaea , P . fragariae , P. infestans, P . tosphaeria coniothyrium ) , Leaf spot (Altemaria alternata ) , melonis , P . nicotianae, P . palmivora , P . porni, P . soiae, P . Leaf blight ( Altemaria dauci) , Black spot ( Altemaria kiku syrinage , P . vignae f. sp . adzukicola , etc . ), Pythium spp . ( e .g . chiana ), Altemaria blotch ( Altemaria mali) , Altemaria leaf Pythium afertile , P . aphanidermatum , P . apleroticum , P . spot (Altemaria porri ), Target spot (Bipolaris sorghicola ), aristosporum , P. arrhenomanes, P . buismaniae , P. debarya - 65 Southem leaf blight ( Cochliobolus heterostrophus ), Brown num , P . graminicola , P . horinouchiense , P . irregulare , P . spot (Cochliobolus miyabeanus ) , Tip blight (Pleospora her iwavamai, P . myriotylum , P . okanoganense , P . paddicum , P . barum ), Stripe (Pyrenophora graminea ) , Net blotch US 10 , 029 , 986 B2 33 34 (Pyrenophora teres) , Leaf blight (Setosphaeria turcica ), lata ), Anthracnose ( Colletotrichum acutatum ), Ripe rot Northern leaf blight (Setosphaeria turcica ), Leaf spot ( Stem - (Colletotrichum acutatum , Glomerella cingulata ) , Anthra phylium botryosum ) , Scab ( Venturia carpophila ), Scab ( Ven cnose (Colletotrichum acutatum ) , Anthracnose (Colletotri turia Inaequalis ), Scab (Venturia nashicola ), Gummy stem chum lindemuthianum ) , Anthracnose ( Colletotrichum blight (Didymella bryoniae ) , Leaf spot ( Phoma exigua var. 5 orbiculare ), Anthracnose on Dioscorea japonica (Glom exigua ), Streak ( Phoma wasabiae ), Ring rot ( Botryospha - erella cingulata ), Anthracnose on Castanea crenata (Glom eria berengeriana f. sp . piricola ), Soft rot ( Botryosphaeria erella cingulata ), Anthracnose on Diospyros kaki (Glom dothidea , Lasiodiplodia theobromae , Diaporthe sp . ), Com - erella cingulata ) , Brown stem rot (Phialophora gregata ) , mon green mold ( Penicillium digitatum ) , Blue mold (Peni - Leaf spot ( Pseudophloeosporella dioscoreae ) , Scald (Rhyn cillium italicum ), Powdery mildew (Blumeria graminis f . sp . 10 chosporium secalis ) , hordei) , Powdery mildew ( Blumeria graminis f . sp . tritici) , Rust ( Phakopsora nishidana ), Rust (Phakopsora pachy Powdery mildew ( Erysiphe betae, Leveillula taurica , rhizi ), Rust (Kuehneola japonica , Phragmidium fusiforme , Oidium sp ., Podosphaera xanthii ), Powdery mildew ( Ery - P . mucronatum , P . rosae -multiflorae ), Rust (Gymnosporan siphe cichoracearum , Leveillula taurica , Sphaerotheca gium asiaticum ), Rust (Gymnosporangium yamadae ) , Rust fuliginea ), Powdery mildew (Erysiphe heraclei) , Powdery 15 (Puccinia allii) , Rust (Puccinia horiana ), Brown rust (Puc mildew ( Erysiphe pisi) , Powdery mildew (Leveillula tau cinia recondita ) , Rust (Puccinia tanaceti var. tanaceti ), Rust rica, Oidium neolycopersici , Oidium sp .) , Powdery mildew (Uromyces viciae- fabae var. viciae - fabae ), Smut (Sporiso (Leveillula taurica ) , Powdery mildew (Oidium sp ., rium scitamineum ) , Smut (Ustilago maydis ) , Loose smut Podosphaera xanthii ) , Powdery mildew (Oidium sp . ) , Pow - ( Ustilago nuda ), Net blister blight ( Exobasidium reticula dery mildew ( Phyllactinia kakicola ) , Powdery mildew (Po - 20 tum ) , Blister blight ( Exobasidium vexans ), Stem rot, dosphaera fusca ) , Powdery mildew ( Podosphaera leucotri - Southem blight ( Athelia rolfsii) , Root and stem rot (Cera cha ), Powdery mildew ( Podosphaera pannosa , Uncinuliella tobasidium cornigerum , Rhizoctonia solani) , Damping - off simulans var. simulans, U . s . var . tandae) , Powdery mildew on Zingiber officinale (Rhizoctonia solani) , Damping -off on (Podosphaera xanthii ), Powdery mildew ( Sphaerotheca Brassica oleracea capitata (Rhizoctonia solani) , Damping aphanis var. aphanis ) , Powdery mildew (Sphaerotheca 25 off on Cryptotaenia japonica (Rhizoctonia solani) , Bottom fuliginea ) , Powdery mildew (Uncinula necator, U . n . var . rot ( Rhizoctonia solani) , Brown patch , Large patch ( Rhizoc necator ) , Blotch (Diplocarpon mali ) , Black spot (Diplocar - tonia solani) , Sheath blight ( Thanatephorus cucumeris ) , pon rosae ) , Gray mold neck rot (Botrytis allii ), Gray mold , Root rot/ Leaf blight ( Thanatephorus cucumeris ) , Rhizopus Botrytis blight ( Botrytis cinerea ) , Leaf blight (Botrytis rot (Rhizopus stolonifer var. stolonifer ) , Clubroot ( Plasmo cinerea , B . byssoidea, B . squamosa ), Chocolate spot (Botry - 30 diophora brassicae ), Aphanomyces root rot ( Aphanomyces tis cinerea , B . elliptical, B . fabae ), Brown rot (Monilinia cochlioides ) , White rust ( Albuo macrospora ) , Downy mil fructicola , M . fructigena , M . laxa ), Blossom blight (Mo - dew (Bremia lactucae ) , Downy mildew (Peronospora chry nilinia mali ) , Dollar spot ( Sclerotinia homoeocarpa ) , Cot - santhemi- coronarii ) , Downy mildew (Peronospora destruc tony rot, Sclerotinia rot, Stem rot ( Sclerotinia sclerotiorum ) , tor ) , Downy mildew ( Peronospora farinosa f. sp . False smut (Villosiclava virens) , Root necrosis (Calonectria 35 spinaciae ), Downy mildew (Peronospora manshurica ), ilicicola ) , Fusarium blight (Fusarium crookwellense , F . cul- Downy mildew (Peronospora parasitica ) , Downy mildew morum , Gibberella avenacea , G . zeae, Monographella niva - (Peronospora sparsa ), Downy mildew ( Plasmopara halste lis ) , Fusarium blight ( Fusarium culmorum , Gibberella ave - dii ) , Downy mildew ( Plasmopara nivea ), Downy mildew nacea , G . zeae ), Dry rot (Fusarium oxysporum , F . solani f . (Plasmopara viticola ), Downy mildew (Pseudoperonospora sp . radicicola ) , Brown rot ( Fusarium oxysporum , F . solani 40 cubensis ) , Phytophthora root rot ( Phytophthora cactorum ) , f . sp . pisi, F. s . f. sp . radicicola ) , Fusarium wilt (Fusarium Brown rot (Phytophthora capsici ), Phytophthora rot ( Phy oxysporum f. sp . adzukicola ) , Fusarium basal rot (Fusarium tophthora capsici) , Phytophthora blight (Phytophthora oxysporum f . sp . allii , F . solani f. sp . radicicola ) , Stem rot capsici) , Phytophthora rot ( Phytophthora cryotogea ) , Late (Fusarium oxysporum f . sp . batatas , F . solani) , Dry rot b light (Phytophthora infestans) , White powdery rot ( Phy (Fusarium oxysporum f. sp . colocasiae ), Yellows ( Fusarium 45 tophthora palmivora ), Leaf blight ( Phytophthora porri ) , oxysporum f . sp . conglutinans ) , Panama disease ( Fusarium Phytophthora root and stem rot ( Phytophthora sojae ) , Phy oxysporum f . sp . cubense ), Fusarium wilt ( Fusarium tophthora stem rot ( Phytophthora vignae f . sp . adzukicola ) , oxysporum f. sp . fragariae ) , Root rot ( Fusarium oxysporum Damping -off (Pythium aphanidermatum , P . myriotylum , P . f . sp . lactucae ) , Fusarium wilt ( Fusarium oxysporum f. sp . paroecandrum , P . ultimum var. ultimum ) , Root rot ( Pythium lagenariae, F. o . f. sp . niveum ), Fusarium wilt (Fusarium 50 aristosporum ), Browning root rot ( Pythium arrhenomanes, oxysporum f. sp . lycopersici ) , Fusarium wilt ( Fusarium P . graminicola ) , Damping -off ( Pythium buismaniae , P . oxysporum f. sp . melonis ) , Yellows (Fusarium oxysporum f . myriotylum ), Root rot (Pythium myriotylum ) , Root rot (Py sp . raphani) , Fusarium wilt (Fusarium oxysporum f . sp . thium myriotylum , P . ultimum var. ultimum ) , Brown blotted spinaciae ) , root rot ( Pythium sulcatum ) , Bacterial canker (Clavibacter “ Bakanae ” disease (Gibberella fujikuroi) , Verticillium black 55 michiganensis subsp . michiganensis ), Scab (Streptomyces spot ( Verticillium albo -atrum , V . dahliae ) , Verticillium wilt spp .) , ( Verticillium dahliae ), Ceratocystis canker (Ceratocystis Crown gall ( Rhizobium radiobacter ) , Bacterial stripe ( Bur ficicola ) , Black rot ( Ceratocystis fimbriata ) , Gray blight kholderia andropogonis ) , Soft rot ( Burkholderia cepacia , (Pestalotiopsis longiseta , P . theae ) , Endothia canker ( Cry - Pseudomonas marginalis pv . marginalis , Erwinia rhapon phonectria parasitica ) , Melanose ( Diaporthe citri ) , Stem 60 tici) , Bacterial grain rot ( Burkholderia gladioli, B . glumae ) , blight ( Phomopsis asparagi) , Phomopsis canker ( Phomopsis Bacterial fruit blotch (Acidovorax avenae subsp . citrulli) , fukushii ) , Brown spot ( Phomopsis vexans ), Anthracnose Bacterial leaf blight (Acidovorax konjaci) , Bacterial wilt (Discula theae -sinensis ), Valsa canker ( Valsa cera (Ralstonia solanacearum ), Bacterial shot hole ( Xanthomo tosperma ), Blast (Magnaporthe grisea ), Crown rot ( Col nas arboricola pv . pruni, Pseudomonas syrinage gv . syri letotrichum acutatum , C . fragariae, Glomerella cingulata ), 65 nage , Brenneria nigarifluens ), Bacterial leaf spot Bitter rot (Colletotrichum acutatum , Glomerella cingulata ) , (Xanthomonas arboricola pv . pruni ) , Bacterial spot Anthracnose (Colletotrichum acutatum , Glomerella cingu ( Xanthomonas axonopodis pv . vitians) , Black rot US 10 ,029 , 986 B2 35 36 (Xanthomonas campestris pv. campestris ), Bacterial pustule dus) , Stomach hair worm ( Trichostrongylus axei ), Tricho ( Xanthomonas campestris pv. glycines) , Bacterial spot strongylus colubriformis , Oriental trichostrongylus ( Xanthomonas campestris pv . nigromaculans ) , Bacterial (Trichostronylus orientalis ) , Red stomach worm (Haemon spot ( Xanthomonas campestris pv . vesicatoria ) , Citrus can chus contortus) , Cattle stomach worm (Mecistocirrus digi ker ( Xanthomonas citri subsp . citri) , (Pseudomonas cichorii, 5 tatus ), Brown stomach worm (Ostertagia ostertagi) , Com P . marginalis pv . marginalis , Erwinia sp . ) , Bacterial rot mon lungworm (Dictyocaulus filaria ), Bovine lungworm ( Pseudomonas cichorii, P . marginalis pv. marginalis, P . (Dictyocaulus viviparus) , Thin - necked intestinal worm viridiflava ), Bacterial blossom blight (Pseudomonas mar ginalis pv. marginalis, P . syrinage pv . syrinage, P. viridi (Nematodirus filicollis ) , Swine lungworm (Metastronagylus flava ) , Bacterial canker (Pseudomonas syrinage V . 10 elongatus) , Lungworm (Filaroides hirthi) , Lungworm actinidiae ), Canker ( Pseudomonas syrinage pv . eriobot ( Crenosoma aerophila ) , Fox lungworm (Crenosoma vulpis ) , ryae ), Bacterial spot (Pseudomonas syrinage pv. lachry Rat lung worm (Angiostrongylus cantonensis ), French heart mans ), Bacterial black spot (Pseudomonas syrinage pv . worm (Angiostronagylus vasorum ), Protostrongylus spp ., maculicola ), Bacterial canker ( Pseudomonas syrinage pv. etc . morsprunorum , Erwinia sp . ), Bacterial shoot blight 15 Nematodes of the order Aphelenchida such as Rice white ( Pseudomonas syrinage py , theae ) , Bacterial soft rot (Dick - tip nematode (Aphelenchoides besseyi) , Strawberry foliar eya sp ., Pectobacterium carotovorum ), Fire blight ( Erwinia nematode ( Aphelenchoides fragariae ), Chrysanthemum amylovora ) , Soft rot (Pectobacterium carotovorum ), Bacte foliar nematode (Aphelenchoides ritzemabosi) , Pine wood rial soft rot (Pectobacterium carotovorum ). nematode (Bursaphelenchus xylophilus) , etc . Animal Infectious Diseases : 20 Nematodes of the order Tylenchida such as White potato Pneumocystis pneumonia (Pneumocystis jirovecii) , Candidi - cyst nematode (Globodera pallida ) , Potato cyst nematode asis (Candida albicans ) , Aspergillosis (Asperaillus fumiga (Globodera rostochiensis ) , Cereal cyst nematode (Het tus) , Trichophytosis (Microsporum canis, M . gypseum , erodera avenae ), Soybean cyst nematode (Heterodera gly Trichophyton mentagrophytes , T . rubrum , T . tonsurans, T . cines ), Sugarbeet cyst nematode (Heterodera schachtii ) , verrucosum ) , Histoplasmosis ( Histoplasma capsulatum ) , 25 Clover cyst nematode (Heterodera trifolii) , Peanut root -knot Cryptococcosis (Cryptococcus neoformans ) . nematode (Meloidogyne arenaria ) , Northern root -knot In this specification , “ parasites ” means Nematoda which nematode (Meloidogyne hapla ) , Southern root- knot nema includes plant- parasitic nematodes and animal- parasitic tode (Meloidogyne incognita ), Javanese root- knot nematode nematodes , Acanthocephala , Platyhelminthes, Protozoa and (Meloidogyne javanica ) , Apple root- knot nematode (Melo the like, and specifically , the following parasites may , for 30 idogyne mali ), Coffee root - lesion nematode ( Pratylenchus example , be mentioned , but the parasites are not limited coffeae ) , Pratylenchus crenatus Loof (Pratylenchus drena thereto . tus ), Tea root - lesion nematode ( Pratylenchus loosi ), Cali Nematodes of the order Enoplida such as Giant kidney fornia root- lesion nematode (Pratylenchus neglectus ) , worm (Dioctophyma renale ) , Thread worms ( Capillaria Cobb ' s root- lesion nematode (Pratylenchus penetrans) , annulata ) , Cropworm (Capillaria contorta ) , Capillary liver 35 Walnut root - lesion nematode ( Pratylenchus vulnus ) , Citrus worm (Capillaria hepatica ) , Capillaria perforans, Capil - burrowing nematode (Radopholus citrophilus ), Banana bur laria philippinensis , Capillaria suis , Whipworm ( Trichuris rowing nematode (Radopholus similis ) , etc . discolor) , Whipworm ( Trichuris ovis ), Pig whipworm ( Tri - Nematodes of the order Oxyurida such as Pinworm ( En churis suis ) , Human whipworm ( Trichuris trichiura ) , Dog terobius vermicularis ) , Equine pinworm ( Oxyuris equi) , whipworm ( Trichuris vulpis ), Pork worm ( Trichinella spi- 40 Rabbit pinworm ( Passalurus ambiguus) , etc . ralis ) , etc . Nematodes of the order Ascaridida such as Pig round Nematodes of the order Rhabditida such as Intestinal worm ( Ascaris suum ), Horse roundworm ( Parascaris equo threadworm ( Strongyloides papillosus) , Strongyloides plani rum ) , Dog roundworm ( Toxascaris leonina ) , Dog intestinal ceps, Pig threadworm ( Strongyloides ransomi) , Threadworm roundworm ( Toxocara canis ) , Feline roundworm ( Toxocara ( Strongyloides stercoralis ) , Micronema spp . , etc . 45 cati) , Large cattle roundworm ( Toxocara vitulorum ) , Anisa Nematodes of the order Strongylida such as Hookworm kis spp ., Pseudoterranova spp ., Caecal worm (Heterakis (Ancylostoma braziliense ) , Dog hookworm (Ancylostoma gallinarum ) , Chicken roundworm (Ascaridia galli ), etc . caninum ), Old World hookworm ( Ancylostoma duodenale ), Nematodes of the order Spirurida such as Guinea worm Cat hookworm ( Ancylostoma tubaeforme ) , The Northern (Dracunculus medinensis ) , Gnathostoma doloresi, Gna hookworm of dogs (Uncinaria stenocephala ), Cattle hook - 50 thostoma hispidum , Gnathostoma nipponicum , Reddish - co worm ( Bunostomum phlebotomum ) , Small ruminant hook - loured worm (Gnathostoma spinigerum ) , Dog stomach worm (Bunostomum trigonocephalum ), New World hook - worm ( Physaloptera canis ) , Cat stomach worm (Physalop worm (Necator americanus ) , Cyathostomum spp . , tera felidis , P . praeputialis ), Feline /canine stomach worm Cylicocyclus spp ., Cylicodontophorus spp . , Cylicostephanus ( Physaloptera rara ), Eye worm ( Thelazia callipaeda ) , spp ., Strongylus asini, Strongylus edentatus, Blood worm 55 Bovine eyeworm ( Thelazia rhodesi) , Large mouth stomach ( Strongylus equinus ) , Blood worm ( Strongylus vulgaris ) , worm ( Draschia megastoma ) , Equine stomach worm (Ha Large -mouthed bowel worm (Chabertia ovina ) , Nodular bronema microstoma ), Stomach worm (Habronema mus worm (Oesophagostomum brevicaudatum ), Nodule worm cae ) , Gullet worm (Gonaylonema pulchrum ) , Thick stom ( Oesophagostomum columbianum ) , Nodule worm (Oesoph - ach worm ( Ascarops strongylina ) , Parafilaria ( Parafilaria agostomum dentatum ), Nodular worm (Oesophagostomum 60 bovicola ) , Parafilaria multipapillosa , Stephanofilaria oki georgianum ), Nodular worm (Oesophagostomum maplesto - nawaensis , Bancroft filaria (Wuchereria bancrofti ), Brugia nei ), Nodular worm (Oesophagostomum quadrispinulatum ), malayi , Neck threadworm (Onchocerca cervicalis ) , Nodular worm (Oesophagostomum radiatum ), Nodular Onchocerca gibsoni, Cattle filarial worm (Onchocerca gut worm ( Oesophaostomum venulosum ), Synagmus skrjabino - turosa ), Onchocerca volvulus , Bovine filarial worm ( Setaria morpha , Gapeworm ( Syngamus trachea ) , Swine kidney 65 digitata ), Peritoneal worm ( Setaria equina ) , Setaria labi worm ( Stephanurus dentatus ) , Cattle bankrupt worm (Coo - atopapillosa , Setaria marshalli , Dog heartworm (Dirofilaria peria oncophora ) , Red stomach worm (Hyostrongylus rubi- immitis ) , African eye worm ( Loa loa ), etc . US 10 ,029 , 986 B2 37 38 Microorganisms of the phylum Acanthocephala such as cystis cruzi , Sarcocystis felis, Sarcocystis hominis , Sarco Moniliformis moniliformis , Giant thomy - headed worm cystis miescheriana , Sarcocystis neurona, Sarcocystis (Macracanthorhynchus hirudinaceus) , etc . tenella , Sarcocystis ovalis , Toxoplasma ondii , Hepatozoon Cestodes of the order Pseudophyllidea such as Fish tape - canis , Hepatozoon felis , etc . worm (Diphyllobothrium latum ), Diphyllobothrium 5 Vestibuliferida ciliata such as Balantidium coli , etc . nihonkaiense , Manson tapeworm (Spirometra erinaceieuro - Trichomonadida flagellata such as Histomanas melea paei) , Diploaonoporus grandis, etc . gridis, Pentatrichomonas hominis , Trichomonas tenax , etc . Cestodes of the order Cyclophyllidea such as Mesoces - Diplomonadida flagellata such as Giardia intestinalis , toides lineatus (Mesocestoides lineatus ) , Chicken tapeworm Giardia muris, Hexamita meleagridis , Hexamita parva , etc . ( Raillietina cesticillus ), Fowl tapeworm ( Raillietina echino - 10 Kinetoplastida flagellata such as Leishmania donovani, bothrida ), Chicken tapeworm ( Raillietina tetragona ) , Leishmania infantum , Leishmania major Leishmania Canine tapeworm ( Taenia hydatigena ), Canine tapeworm tropica , Trypanosoma brucei gambiense , Trypanosoma bru ( Taenia multiceps ) , Sheep measles ( Taenia ovis ) , Dog tape - cei rhodesiense , Tryanosoma cruzi, Trypanosoma eauiper worm ( Taenia pisiformis ) , Beef tapeworm ( Taenia sagi- dum , Trypanosoma evansi, etc . nata ), Tapeworm ( Taenia serialis ), Pork tapeworm ( Taenia 15 In this specification “ plants ” means grain , fruits and solium ) , Feline tapeworm ( Taenia taeniaeformis ) , Hydatid vegetables cultivated as food for human , feed crop for tapeworm (Echinococcus granulosus) , Small fox tapeworm livestock and poultry, ornamental plants of which appear ( Echincooccus multilocularis ), Echinococcus oligarthrus, ances are enjoyed , or Tracheophyta such as planting of Echinococcus vogeli , Rattapeworm ( Hymenolepis parks , streets and the like , and specifically , the following diminuta ), Dwarf tapeworm (Hymenolepis nana ), Double - 20 plants may, for example , be mentioned , but the plants are not pored dog tapeworm (Dipylidium caninum ) , Amoebotaenia limited thereto . sphenoides , Choanotaenia infundibulum , Metroliasthes Plants of the order Pinales belonging to the family cotumix , Equine tapeworm (Anoplocephala magna ), Cecal Pinaceae such as Japanese Red Pine (Pinus densiflora ), tapeworm ( Anoplocephala perfoliata ), Dwarf equine tape - Scots Pine ( Pinus sylvestris ) , Japanese Black Pine (Pinus worm (Paranoplocephala mamillana ), Common tapeworm 25 thunbergii ) , etc . (Moniezia benedeni) , Sheep tapeworm (Moniezia expansa ), Plants of the group magnoliids belonging to the family Stilesia spp ., etc . Piperaceae such as pepper ( Piper nigrum ), etc . , the family Trematodes of the order Strigeidida such as Pharyngos - Lauraceae such as Avocado ( Persea americana ) , etc . tomum cordatum , Blood fluke ( Schistosoma haematobium ) , Plants of the group monocots belonging to the family Blood fluke (Schistosoma japonicum ) , Blood fluke (Schis - 30 Araceae such as Konjac ( Amorphophallus konjac ) , Eddoe tosoma mansoni) , etc . ( Colocasia esculenta ) , etc ., the family Dioscoreaceae such Trematodes of the order Echinostomida such as Echinos - as Chinese yam (Dioscorea batatas) , Japanese yam (Di toma cinetorchis , Echinostoma hortense , Giant liver fluke oscorea japonica ), etc . , the family Alliaceae such as Leek ( Fasciola gigantica ) , Common liver fluke (Fasciola (Allium ampeloprasum var . porrum ) , Onion ( Allium cepa ) , hepatica ) , Fasciolopsis buski , Homalogaster paloniae, etc . 35 Rakkyo ( Allium chinense ) , Welsh onion ( Allium fistulosum ) , Trematodes of the order Plagiorchiida such as Dicrocoe Garlic ( Allium sativum ) , Chives ( Allium schoenoprasum ) , lium chinensis , Lancet liver fluke (Dicrocoelium dendriti - Chive ( Allium schoenoprasum var . foliosum ) , Oriental garlic cum ) , African lancet fluke (Dicrocoelium hospes ) , Eury - ( Allium tuberosum ) , Scallion ( Alliumxwakegi ), etc ., the fam trema coelomaticum , Pancreatic fluke (Eurytrema ily Asparagaceae such as Asparagus (Asparagus officinalis ), pancreaticum ) , Paragonimus miyazakii, Paragonimus ohi- 40 etc . , the family Arecaceae subfamily Arecoideae such as rai, Lung fluke (Paragonimus westermani) , etc . Coconut palm (Cocos nucifera ) , Oil palm (Elaeis guineen Trematodes of the order Opisthorchiida such as Amphime- sis ) , etc . , the family Arecaceae the subfamily Coryphoideae rus spp ., Chinese liver fluke ( Clonorchis sinensis ) , Cat liver such as Date palm (Phoenix dactylifera ) , etc ., the family fluke (Opisthorchis felineus ), Southeast Aasian liver fluke Bromeliaceae such as Pineapple ( Ananas comosus ), etc . , the (Opisthorchis viverrini) , Pseudamphistomum spp . , 45 family Poaceae subfamily Ehrhartoideae such as Rice (Oryz Metorchis spp ., Parametorchis spp . , Intestinal fluke (Het - sativa ) , etc ., the family Poaceae subfamily Pooideae such as erophyes heterophyes ) , Metagonimus yokokawai, Pvaidiop Bent grass (Aarostis spp .) , Blue grass ( Poa spp .) , Barley sis summa , etc . (Hordeum vulgare ) , Wheat ( Triticum aestivum , T . durum ) , Amebas such as Entamoeba histolytica , E . invadens, etc . Rye (Secale cereale ), etc ., the family Poaceae subfamily Piroplasmida sporozoans such as Babesia bigemina , 50 Chloridoideae such as Bermuda grass (Cynodon dactylon ), Babesia bovis , Babesia caballi, Babesia canis , Babesia felis , Grass ( Zoysia spp. ) , etc . , the family Poaceae subfamily Babesia aibsoni, Babesia ovata , Cytauxzoon felis , Theileria Panicoideae such as Sugarcane ( Saccharum officinarum ) , annulata , Theileria mutans, Theileria orientalis , Theileria Sorgum (Sorghum bicolor) , Corn (Zea mays ), etc ., the garva , etc . family Musaceae such as Banana (Musa spp . ) , etc . , the Haemosporida sporozoans such as Haemoproteus man - 55 family Zingiberaceae such as Myoga ( Zingiber mioga ) , soni , Leucocytozoon caullervi , Plasmodium falciparum , Ginger (Zingiber officinale ) , etc . Plasmodium malariae , Plasmodium ovale , Plasmodium Plants of the group eudicots belonging to the family vivax , etc . Nelumbonaceae such as Lotus root (Nelumbo nucifera ), etc ., Eucoccidiorida sporozoans such as Caryospora spp ., the family Fabaceae such as Peanut ( Arachis hypogaea ) , Eimeria acervulina , Eimeria bovis , Eimeria brunetti , Eime - 60 Chickpea (Cicer arietinum ) , Lentil (Lens culinaris ) , Pea ria maxima, Eimeria necatrix, Eimeria ovinoidalis , Eimeria (Pisum sativum ), Broad bean ( Vicia faba ) , Soybean (Glycine stiedae , Eimeria tenella , Isospora canis , Isospora felis , max ), Common bean (Phaseolus vulgaris ), Adzuki bean Isospora suis, Tyzzeria alleni, Tyzzeria anseris, Tyzzeria ( Vigna anaularis ), Cowpea ( Vigna unguiculata ), etc ., the pemiciosa , Wenyonella anatis , Wenyonella gagari, Cryp - family Cannabaceae such as Hop (Humulus lupulus ) , etc ., tosporidium canis , Cryptosporidium felis , Cryptosporidium 65 the family Moraceae such as Fig Tree (Ficus carica ), hominis , Cryptosporidium meleagridis , Cryptosporidium Mulberry (Morus spp . ) , etc . , the family Rhamnaceae such as muris, Cryptosporidium Darvum , Sarcocystis canis, Sarco Common jujube (Ziziphus jujuba ) , etc ., the family Rosaceae US 10 , 029 , 986 B2 39 40 subfamily Rosoideae such as Strawberry (Fragaria ) , Rose Oleaceae such as Olive ( Olea europaea ) , etc . the family ( Rosa spp .) , etc ., the family Rosaceae subfamily Maloideae Convolvulaceae such as Sweet potato (Ipomoea batatas) , such as Japanese loquat ( Eriobotrya japonica ) , Apple etc ., (Malus pumila ), European Pear (Pyrus communis) , Nashi the family Solanaceae such as Tomato (Solanum lycopersi Pear (Pyrus pyrifolia var. culta ), etc ., the family Rosaceae 5 cum ) , Eggplant ( Solanum melongena ) , Potato ( Solanum subfamily Prunoideae such as Peach (Amyydalus persica ), tuberosum ), Chili pepper ( Capsicum annuum ), Bell pepper ( Capsicum annuum var. " grossum ' ) , Tobacco (Nicotiana Apricot (Prunus armeniaca ), Cherry ( Prunus avium ), Prune tabacum ), etc . , the family Apiaceae such as Celery (Apium (Prunus domestica ), Almond (Prunus dulcis ), Japanese graveolens var . dulce ), Coriander (Coriandrum sativum ), Apricot (Prunus mume) , Japanese Plum ( Prunus salicinano ), 10 Japanese honeywort (Cryptotaenia Canadensis subsp . Cerasus speciosa , Cerasusxyedoensis 'Somei - yoshino ' , japonica ) , Carrot (Daucus carota subsp . sativus ) , Parsley etc . , the family Cucurbitaceae such as Winter melon ( Beni ( Petroselium crispum ) , Italian parsley (Petroselinum nea ncasa hispida ) , Watermelon ( Citrullus lanatus ) , Bottle politanum ) , etc . , the family Araliaceae such as Udo ( Aralia gourd (Lagenaria siceraria var. hispida ) , Luffa ( Luffa cylin cordata ) , Aralia elata , etc . , the family Asteraceae subfamily drica ), Pumpkin ( Cucurbita spp . ) , Zucchini ( Cucurbita 15 . Carduoideae such as Artichoke ( Cynara scolymus ) , etc ., the pepo ) , Bitter melon (Momordica charantia var . pavel) , family Asteraceae subfamily Asteraceae such as Chicory Muskmelon ( Cucumis melo ), Oriental pickling melon (Cu - (Cichorium intybus ), Lettuce ( Lactuca sativa ), etc . , the cumis melo var. conomon ), Oriental melon ( Cucumis melo family Asteraceae subfamily Asteraceae such as Florists ' var. makuwa ) , Cucumber (Cucumis sativus) , etc . , the family daisy ( Dendranthema grandiflorum ) , Crown daisy (Glebio Fagaceae such as Japanese Chestnut (Castanea crenata ), 20 nis coronaria ) , Sunflower (Helianthus annuus ), Fuki (Peta etc . , the family Juglandaceae such as Walnut ( Juglans spp .) , sites japonicus ), Burdock ( Arctium lappa ), etc . etc ., the family Anacardiaceae such as Cashew (Anacardium In this specification animals ” means human , companion occidentale ) , Mango (Mangifera indica ), Pistachio (Pistacia creatures /pets , livestock /poultry , and vertebrate such as vera ) , etc . , the family Rutaceae subfamily Rutoideae such as experimental/ laboratory animals , and specifically, the fol Japanese pepper ( Zanthoxylum piperitum ), etc . , the family 25 lowing animals may, for example , be mentioned , but the Rutaceae subfamily Aurantioideae such as Bitter orange animals are not limited thereto . Animals of the class Mammalia belonging to the family (Citrus aurantium ), Lime (Citrus aurantifolia ) , Hassaku Cebidae such as Tufted capuchin (Cebus apella ) , etc . , the orange ( Citrus hassaku ) , Yuzu (Citrus junos ), Lemon ( Cit family Cercopithecidae such as Crab -eating macaque rus limon ) , Natsumikan (Citrus natsudaidai ) , Grapefruittrus 30 (Macaca fascicularis ) , Rhesus macaque (Macaca mulatta ) , ( Citrusxparadisi ) , Orange (Citrus sinensis ), Kabosu ( Citrus etc ., the family Hominidae such as Chimpanzee (Pan trog sphaerocarpa ), Sudachi ( Citrus sudachi ), Mandarin Orange lodytes ), Human (Homo sapiens ) , etc ., the family Leporidae (Citrus tangerina ) , Satsuma (Citrus unshiu ), Kumquat ( For such as European rabbit (Oryctolagus cuniculus ) , etc ., the tunella spp . ), etc . , the family Brassicaceae such as Horse family Chinchillidae such as Long -tailed chinchilla (Chin radish (Armoracia rusticana ), Mustard ( Brassica luncea ) ;, 35 chilla lanigera ), etc ., the family Caviidae such as Guinea pig Takana ( Brassica juncea var. integrifolia ) , Rapeseed (Bras (Cavia porcellus) , etc ., the family Cricetidae such as Golden sica napus ), Cauliflower (Brassica oleracea var. botrytis ), hamster (Mesocricetus auratus ) , Djungarian hamster Cabbage (Brassica oleracea var. capitata ), Brussels sprout (Phodopus sungorus ), Chinese hamster (Cricetulus griseus ) , ( Brassica oleracea var. gemmifera ), Broccoli (Brassica etc ., the family Muridae such as Mongolian gerbil (Meriones oleracea var . italica ), Green pak choi ( Brassica rapa var. 40 unguiculatus) , House mouse (Mus musculus ) , Black rat chinensis ) , Nozawana ( Brassica rapa var. hakabura ), Napa (Rattus rattus ) , etc ., the family Sciuridae such as Chipmunk cabbage ( Brassica rapa var. nippo -oleifera ) , Potherb Mus- ( Tamias sibiricus) , etc ., the family Camelidae such as Drom tard ( Brassica rapa var. nipposinica ) , Napa cabbage ( Bras - edary ( Camelus dromedarius ) , Bactrian camel (Camelus sica rapa var. pekinensis ), Turnip leaf (Brassica rapa var. bactrianus) , Alpaca ( Vicugna pacos) , Llama (Lama glama) , perviridis ) , Tumip ( Brassica rapa var. rapa ) , Garden rocket 45 etc . , the family Suidae such as Pig ( Susscrofa domesticus ) , (Eruca vesicaria ) , Daikon (Raphanus sativus var. longipin - etc . , the family Cervidae such as Reindeer (Rangifer taran natus) , Wasabi (Wasabia japonica ), etc . , the family Carica - dus ), Red deer (Cervus elaphus ), etc . , the family Bovidae ceae such as Papaya (Carca papaya ) , etc ., the family such as Yak ( Bos grunniens ), Cattle (Bos taurus) , Water Malvaceae such as Okra ( Abelmoschus esculentus ) , Cotton buffalo (Bubalus amee ), Goat (Capra hircus ) , Sheep (Ovis plant (Gossypium spp . ) , Cacao ( Theobroma cacao ) , etc . , the 50 aries ) , etc . , the family Felidae such as Cat ( Felis silvestris family Vitaceae such as Grape ( Vitis spp. ), etc ., the family catus ) , etc ., the family Canidae such as Dog (Canis lupus Amaranthaceae such as Sugar beet ( Beta vulgaris ssp . familiaris ) , Red fox ( Vulpes vulpes ), etc . , the family Mus vulgaris var . altissima ) , Table beet (Beta vulgaris ssp . vul- telidae such as European mink (Mustela lutreola ) , American garis var . vulgaris ), Spinach (Spinacia oleracea ) , etc . , the mink (Mustela vison ) , Ferret (Mustela putorius furo ) , etc ., family Polygonaceae such as Buckweat ( Fagopyrum escu - 55 the family Equidae such as Donkey ( Equus asinus) , Horse lentum ), etc . , the family Ebenaceae such as KakiPersimmon (Equus caballus ) , etc ., the family Macropodidae such as Red ( Diospyros kaki) , etc ., the family Theaceae scuh as Tea plant kangaroo (Macropus rufus) , etc . ( Camellia sinensis) , etc . , the family Actinidiaceae such as Animals of the class Aves belonging to the family Stru Kiwifruit (Actinidia deliciosa , A . chinensis ), etc ., the family thionidae such as Ostrich (Struthio camelus) , etc ., the family Ericaceae such as Blueberry ( Vaccinium spp . ) , Cranberry 60 Rheidae such as American rhea (Rhea americana ), etc . , the ( Vaccinium spp . ) , etc . , the family Rubiaceae such as Coffee family Dromaiidae such as Emu (Dromaius novaehollan plants ( Coffea spp. ), etc . , the family Lamiaceae such as diae ) , etc . , the family Phasianidae such as Ptarmigan ( Lago Lemon balm (Melissa officinalis ) , Mint (Mentha spp . ) , Basil pus muta ), Wild turkey (Meleagris gallopavo ) , Japanese (Ocimum basilicum ), Shiso (Perilla frutescens var . crispa ) , quail (Coturnix japonica ) , Chicken (Gallus gallus domesti Perilla frutescens var . frutescens , Common Sage (Salvia 65 cus ) , Common pheasant ( Phasianus colchicus) , Golden officinalis ), Thyme ( Thymus spp . ) , etc . , the family Pedali - pheasant ( Chrysolophus pictus) , Indian peafowl ( Pavo cris aceae such as Sesame ( Sesamum indicum ), etc ., the family tatus ), etc ., the family Numididae such as Helmeted guinea US 10 , 029 , 986 B2 42 fowl ( Numida meleagris ), etc ., the family Anatidae such as the family Scombridae such as Pacific bluefin tuna ( Thunnus Mallard ( Anas platyrhynchos ), Domesticated duck (Anas orientalis ), etc ., the family Tetraodontidae such as Japanese platyrhynchos var. domesticus) , Spot- billed duck (Anas pufferfish ( Takifugu rubripes) , etc . poecilorhyncha ) , Greylag goose ( Anser anser ), Swan goose In this specification , " useful insects” means insects useful ( Anser cyanoides ) , Whooper swan ( Cyanus cyagnus ), Mute 5 for human life by utilizing their products , or useful to make swan (Cygnus olor ), etc ., the family Columbidae such as agricultural work efficient e .g . by using them for pollination Rock dove (Columba livia ), Oriental turtle dove ( Streptope lia orientalis) , European turtle dove ( Streptopelia turtur ) , of orchards/ vegetables , and specifically , Japanese honeybee etc . , the family Cacatuidae such as Sulphur -crested cockatoo (Apis cerana japonica ), Western honey bee ( Apis mellifera ), ( Cacatua galerita ), Galah ( Eolophus roseicapilla ) , Cocka - 10 Bumblebee (Bombus consobrinus wittenburgi, B . diversus tiel (Nymphicus hollandicus) , etc . , the family Psittacidae diversus, B . hypocrita hypocrita , B . initus , B . terrestris ) , such as Rosy - faced lovebird (Agapomis roseicollis ) , Blue Homfaced bee (Osmia comifrons) , Silkworm (Bombyx mori) and - yellow macaw ( Ara ararauna ), Scarlet Macaw ( Ara may, for example , be mentioned , but the useful insects are macao ), Budgerigar (Melopsittacus undulatus ), African grey not limited thereto . parrot (Psittacus erithacus ), etc . , the family Stumidae such 155 In this specification , “ natural enemies ” means organisms as Common hill myna (Gracula religiosa ), etc . , the family which kill specific organisms particularly specific organisms Estrildidae such as Red avadavat ( Amandava amandava ) , damaging agricultural crops by predation or parasitism or Zebra finch ( Taeniopygia guttata ) , Bengalese finch ( Lon which inhibit propagation of such organisms, and specifi chura striata var. domestica ), Java sparrow ( Padda cally, the following organisms may, for example , be men oryzivora ), etc ., the family Fringillidae such as Domestic 20 tioned , but the natural enemies are not limited thereto . canary (Serinus canaria domestica ), European goldfinch Parasitic wasps belonging to the family Braconidae such (Carduelis carduelis ), etc . as Dacnusa sasakawai, Dacnusa sibirica , Aphidius cole Animals of the class Reptilia belonging to the family mani, Apanteles glomeratus, etc . , the family Aphelinidae Chamaeleonidae such as Veiled chameleon ( Chamaeleo such as Aphelinus albipodus, Aphelinus asychis , Aphelinus calyptratus ) , etc ., the family Iguanidae such as Green iguana 25 gossypii , Aphelinus maculatus, Aphelinus varipes, Encarsia (Iguana iguana ) , Carolina anole ( Anolis carolinensis ) , etc ., formosa , Eretmocerus eremicus, Eretmocerus mundus, etc . , the family Varanidae such as Nile monitor (Varanus niloti and the family Eulophidae such as Chrysocharis pentheus, cus) , Water monitor (Varanus salvator ) , etc . , the family Neochrysocharis formosa , Diglyphus isaea , Hemiptarsenus Scincidae such as Solomon islands skink (Corucia zebrata ) , varicornis , etc . ; Aphidophagous gall midge ( Aphidoletes etc ., the family Colubridae such as Beauty rat snake (Elaphe 30 aphidimyza ); Seven -spot ladybird ( Coccinella septempunc taeniura ) , etc ., the family Boidae such as Boa constrictor (Boa constrictor ) , etc . , the family Pythonidae such as Indian tata ); Asian lady beetle (Harmonia axyridis ); Predatory python (Python molurus ) , Reticulated python (Python beetle ( Proylea japonica ); Anthocorid predatory bugs reticulatus ), etc . , the family Chelydridae such as Common belonging to the family Anthocoridae such as Oriusminutus , snapping turtle (Chelvdra serpentina ) , etc . , the family Emy - 35 Orius nagaii , Orius sauteri, Minute pirate bug ( Orius strigi didae such as Diamondback terrapin (Malaclemys terrapin ), collis ) , etc . , Predatory mirids belonging to the family Miri Pond slider ( Trachemys scripta ), etc. , the family Geoemy dae such as Pilophorus tyicus, Nesidiocoris tenuis , etc . ; didae such as Japanese pond turtle (Mauremys japonica ), Predatory thrips belonging to the family Aeolothripidae such etc ., the family Testudinidae such as Central Asian tortoise as Franklinothrips vespiformis , etc .; Green lacewing ( Agrionemys horsfieldii) , etc . , the family Trionychidae such 402in belonging to the family Chrysopidae such as Dichochrysa as Soft - shelled turtle (Pelodiscus sinensis ) , etc. , the family formosanus , Chrysoperla nipponensis , etc . ; Predatory mites Alligatoridae such as American alligator (Alligator missis belonging to the family Phytoseiidae such as Neoseiulus sippiensis ), Black caiman (Melanosuchus niger ), etc . , the californicus , Amblyseius cucumeris , Amblyseius depener family Crocodylidae such as Siamese crocodile ( Crocodylus ans, Amblyseius swirskii , Phytoseiulus persimilis, etc .; Wolf siamensis ) , etc . 45 spider (Pardosa pseudoannulata ) ; Crab spider (Misumenops Animals of the classclass Actinopterygii belonging to thethe tricuspidatus ) . family Cyprinidae such as Carp (Cyprinus carpio ) ,Goldfish The compounds of the present invention represented by (Carassius auratus auratus ), Zebrafish (Danio rerio ), etc . , the formula (1 ) can be produced , for example , by the the family Cobitidae such as Kuhli loach (Pangio kuhlii ), following methods. etc . , the family Characidae such as Red piranha (Pygocen - 50 Production Method A trus nattereri ), Neon tetra ( Paracheirodon innesi) , etc ., the family Salmonidae such as Maraena whitefish (Coregonus lavaretus maraena ) , Coho salmon (Oncorhynchus kisutsh ) , Rainbow trout (Oncorhynchus mykiss ) , Chinook salmon + ( Oncorhynchus tshawytscha ) , Atlantic salmon (Salmo 55 ( G salar ) , Brown trout ( Salmo trutta ) , etc. , the family Percich thyidae such as Spotted sea bass ( Lateolabrax maculatus ) , ( III) etc . , the family Serranidae such as Sea goldie (Pseudanthias squamipinnis ), Longtooth grouper ( Epinephelus bruneus ) , Convict grouper ( Epinephelus septemfasciatus ) , etc . , the 60 SRO family Centrarchidae such as Bluegill ( Lepomis macrochi R3 R4 rus ), etc ., the family Carangidae such as White trevally base ( Pseudocaranx dentex ) , Greater amberjack (Seriola HN y ' N y3 dumerili ), Japanese amberjack ( Seriola quinqueradiata ) , etc ., the family Sparidae such as Red sea bream ( Pagrus 65 R5 R1 R2 major ) , etc . , the family Cichlidae such as Nile tilapia ( Ore (II ) ochromis niloticus) , Angelfish (Pterophyllum scalare ), etc . , US 10 , 029 , 986 B2 43 44 -continued -continued RO Y ! = R3 R4 Y ERO O=

0 N y3 R5 R R2 R5 R R2 ( I) 10 (1 ) ( In the formula (I ) and formula (II ), Y ! , Y ?, Y3, R1, R2, R3, R4, R and R are as defined above . In the formula (I ) and formula ( III ) , G ' is as defined above . In the formula ( III ) , J ! is a chlorine atom , a bromine atom , a C , -C4 alkylcarbony loxy group ( e . g . a pivaloyloxy group ) , a C , -C4 alkoxycar - 15 bonyloxy group ( for example , an isobutyloxycarbonyloxy group ) or an azolyl group ( e . g . an imidazol- 1 - yl group ) , etc . ) ( InIn the formula ( la ) andand formula ( 1I ) , 6°G ', Y ', Y ? , Y , R " , R ?, It is possible to obtain a compound of the present com - R9, R1 and R? are as defined above. In the formula (IV ) , RSav pound represented by the formula ( I) by reacting a com is as defined above but excluding a hydrogen atom , - OH , pound represented by the formula ( II ) or its salt ( e . g . , hydrochloride , hydrobromide, trifluoroacetate , p - toluenesul* 20 CZ -C4 alkoxy and C ,- C4 haloalkoxy, and J2 represents a fonate , etc . ) and a compound represented by the formula good leaving group such as a chlorine atom , a bromine atom , ( III ) , in a temperature range of from 0° C . to the reflux an iodine atom , a C1 -C4 alkylcarbonyloxy group ( e . g . a temperature of the reaction mixture , for from 30 minutes to pivaloyloxy group, etc . ), a C1- C4 alkyl sulfonate group ( e . g . 24 hours , if necessary in the presence of a base such as a methanesulfonyloxy group , etc . ) , a C . - C . haloalkyl sul sodium carbonate, potassium carbonate , sodium bicarbon - 25 ate , sodium acetate , triethylamine, ethyldiisopropylamine , fonate group (e . g . a trifluoromethanesulfonyloxy group , N -methylmorpholine , pyridine or 4 - ( dimethylamino )pyri - etc .) , an aryl sulfonate group ( e . g . a benzenesulfonyloxy dine in an amount of from 1 to 3 equivalents per 1 equivalent Šgroup , a p - toluenesulfonyloxy group , etc . ) or an azolyl of the compound of the formula ( II ) , if necessary by using , group ( e . g . an imidazol- 1 -yl group , etc .) . In the formula (I ) , as a solvent, benzene , toluene , dichloromethane , chloro - 30 R5 is as defined above ) form , 1 , 2 - dichloroethane , diethyl ether , tert -butyl methyl ether , tetrahydrofuran , 1 , 4 - dioxane , ethyl acetate , N , N - dim It is possible to obtain a compound of the present com ethylformamide , N ,N -dimethylacetamide , acetonitrile , pound represented by the formula (I ) by reacting 1 equiva water or a mixture of two or more of them in optional proportions . lent of a compound of the present invention represented by Some of the compounds represented by the formula (III ) the formula ( la ) in which R is a hydrogen atom and from 1 to be used here are known compounds, and some of them are to 10 equivalents of a compound represented by the formula commercially available . The rest of them can be synthesized in accordance with known methods disclosed in literatures , ( IV ), in a temperature range of from 0 to 90° C . for from 10 for example , by a method in accordance with the method minutes to 24 hours , if necessary in the presence of a base disclosed in Journal of Medicinal Chemistry [ J . Med . 40 such as sodium hydride , potassium tert - butoxide , potassium Chem . ] , 1991, vol. 34 , pp . 1630 , etc . ( in which a corre sponding known carboxylic acid is reacted with a haloge hydroxide, potassium carbonate , triethylamine or pyridine in nating agent such as thionyl chloride, phosphorus pentachlo an amount of from 1 to 3 equivalents per 1 equivalent of the ride or oxalyl chloride ), a method in accordance with the compound represented by the formula ( la ), if necessary by method disclosed in Tetrahedron Letters [ Tetrahedron Lett. ], 45 using a polar solvent such as tert - butyl methyl ether, tetra 2003 , vol . 44 , pp . 4819, Journal of Medicinal Chemistry [ J . Med . Chem . ], 1991, vol. 34 , pp . 222 , etc . ( in which a hydrofuran , 1, 4 - dioxane, acetonitrile or N ,N -dimethylfor corresponding known carboxylic acid is reacted with an mamide . organic acid halide such as pivaloyl chloride or isobutyl Some of the compounds represented by the formula (IV ) chloroformate in the presence of a base if necessary ) , or a 50 method disclosed in The Journal of Organic Chemistry [ J . to be used here are known compounds, and some of them are Org . Chem . ], 1989 , vol . 54 , pp . 5620 , etc . ( in which a commercially available . The rest of them can be synthesized corresponding known carboxylic acid is reacted with car in accordance with known methods disclosed in literatures , bonyl diimidazole , sulfonyl diimidazole or the like ) . 55 for example , by methods disclosed in Chemical and Phar Production Method B maceutical Bulletin (Chem . Pharm . Bull. ], 1986 , vol . 34 , pp . 540 and 2001 , vol. 49, pp . 1102 , Journal of the American Ro Chemical Society [J . Am . Chem . Soc. ], 1964 , vol. 86 , pp . Y ! J2 — R5 4383, The Journal of Organic Chemistry [ J . Org . Chem . ], O R3 R4 (IV ) 1983 , vol. 48 , pp . 5280, Organic Synthesis [Org . Synth . ], OSO 1988 , collective volume 6 , pp . 101, Synlett , 2005, pp . 2847 , N ' N y3 Synthesis , 1990 , pp . 1159 , Japanese Unexamined patent R1 R2 65 application publication ( JP - A 05 / 125017 ), European Patent (la ) Publication ( EP 0, 051 , 273 ) , British Patent Publication (GB 2 , 161 , 802) , etc . US 10 , 029 ,986 B2 4545 46 Production Methodod C tion , whereby it is possible to obtain the desired alkynyl pyridine - substituted amide compound . Further, in a case where need for purification arises, separation and purifica RO tion can be made by an optional purification method , such as 5 recrystallization , column chromatography , thin - layer chro - matography or liquid chromatography . W The compound represented by the formula (II ) to be used in the production method A can be synthesized , for example , or as shown by Reaction Schemes 1 to 9 .

Reaction Scheme 1 Y 13 M HSRO( VII ) ? R3 R4 b=0 Pd 15 NX . R901 V OR " R5 R1 R2 ( IX ) base ( V ) N Y V2 RO06 201420 (VIII VIII ) ole S R3 R4 - N p5 25 R5 R R2 RO ' N y3 (I ) OR ( In the formula (I ) and formula (V ), G , Y , Y , Y ), R ' , R ?, 30 R ”, R4 andolish Rare as defined above. In the formula (V ) , J3 represents a good leaving group such as a chlorine atom , a bromine atom , an iodine atom or a C , - C4 haloalkyl sulfonate 7 group ( e. g. a trifluoromethanesulfonyloxy group , etc .) . In 35 RºOO = O- the formula ( I ) , formula (VI ) and formula (VII ), Rº is as y3 defined above . In the formula ( VII ) , M is a — ZnCl group , ' N a — ZnBr group or a — Znl group . ) - OR It is possible to obtain a compound of the present inven tion represented by the formula ( 1 ) by reacting a compound 40 represented by the formula ( V ) , with a substituted acetylene ( XII ) represented by the formula (VI ) , for example , under com mon Sonogashira coupling reaction conditions disclosed e . g . in International Patent Application Publication (WO 2008 / or 093065 ) , or with an alkynyl zinc represented by the formula 45 HERO (VII ) , for example , under common Negishi coupling reac (VI ) tion conditions described in e . g . Heterocycles, 1997 , vol. 46 , RO pp . 209 . Some of the compounds represented by the formula ( V ) to be used here are known compounds as described in , for 50 example, International Patent Application Publication (WO (VII ) 2005 /014545 ) , International Patent Application Publication y3PdPd (WO 2013/ 064461 ) , International Patent Application Publi cation (WO 2013 /064521 ) , etc . , and the rest of them can also be synthesized in the same manner as known compounds . 55 Further, some of the compounds represented by the for (XIII ) mula (VI ) and formula (VII ) are known compounds , and some of them are commercially available . The rest of them can also be readily synthesized according to general syn ERO thetic methods described in literatures relating to known 60 H2NNH2 compounds . In each of the production methods A to C , the reaction mixture after completion of the reaction , may be subjected to usual post treatment, such as direct concentration , or dissolution in an organic solvent and washing with water , 65 followed by concentration , or pouring into ice water and ( XIV ) extraction with an organic solvent, followed by concentra ht US 10 ,029 , 986 B2 47 48 - continued V2 Reaction Scheme 2 ERO R6 13 H HN (VI ) (IIa ) y3 Pd lo ( In the formula (VIII ) and formula (XIII ) , Y ! , Y2, Y and 33J3 are as defined above . In the formula ( VIII) , J4 is a halogen (XV ) atom . In the formula ( IX ) , Rº is a C1- C4 alkyl group . In the Ro formula (X ) and formula (XII ) , Y !, Y ? , YS, J and R are as defined above . In the formula (XI ) , P is a chlorine atom , a 15 = O2N bromine atom , an iodine atom or a C , -C4 alkylcarbonyloxy (XVII ) base group (e .g . an acetoxy group, etc .) . In the formula (VI ) , RO N

is as defined above. In the formula (VII ) , R and M are as = defined above. In the formula (XIV ) and formula (IIa ) , Y ', 20 DEÓO Y ? , Y and Ró are as defined above. ) VI ) A compound represented by the formula (VIII ) and a V2 RO known malonic acid ester represented by the formula (IX ) = are reacted by a method disclosed , for example , in Synthetic 25 po Communications [ Synth . Commun . ], 1990 , vol. 20 , pp . 2965 to obtain a compound represented by the formula ( X ) , which is then reacted with a known phthalimide derivative repre (XVIII ) sented by the formula (XI ) in accordance with a method disclosed , for example , in Journal of Medicinal Chemistry 30 RO [ J . Med . Chem . ] , 2001, vol. 44 , pp . 1217 , whereby it is = possible to synthesize a compound represented by the for mula ( XII ) . Then , the compound of the formula (XII ) is subjected to as HN ' N Y3 decarboxylation by heating in accordance with a method ( IIb ) disclosed , for example , in Tetrahedron Letters [ Tetrahedron Lett . ], 2012 , vol. 53 , pp . 3853 , to obtain a compound ( In the formula (XV ) , Y ! , Y ? , Y3 and 13 are as defined above. represented by the formula (XIII ) , which is then reacted with In the formula (VI ) , R is as defined above . In the formula a substituted acetylene represented by the formula ( VI) or an 40 (XVI ) . Yl. Y2. Y3 and Ró are as defined above . In the alkynyl zinc represented by the formula ( VII ) under the formula (XVII ), R3 is as defined above . In the formula same conditions as in the production method C , whereby it (XVIII ) and formula ( IIb ), Y ' , Y ? , Y , R3 and Ró are as is possible to synthesize a compound represented by the defined above. ) formula (XIV ) . A compound represented by the formula (XV ) and a The compound represented by the formula (XIV ) thus * compound represented by the formula (VI ) are reacted under obtained , is reacted with an aqueous methylamine , an aque - common Sonogashira coupling reaction conditions dis ous hydrazine solution or hydrazine monohydrate in an closed , for example , in The Journal of Organic Chemistry [ J . amount of from 1 to 4 equivalents per 1 equivalent of the Org . Chem . ], 2003 , vol. 68 , pp . 9907 , to obtain a compound compound of the formula (XIV ) in a temperature range of 50 represented by the formula (XVI ) , which is then reacted with a known nitro alkane derivative represented by the formula from room temperature to the reflux temperature of the (XVII ) in accordance with a method disclosed , for example , reaction mixture , for from 1 to 24 hours , if necessary , by in Journal of the Chemical Society , Perkin Transactions 1 [ J . using , as a solvent, toluene , dichloromethane , chloroform , Chem . Soc . Perkin Trans . 1 ] , 1979, pp . 643 , whereby it is methanol, ethanol, tetrahydrofuran , 1 , 4 -dioxane , water, or a 55 possible to synthesize a compound represented by the for mixture of two or more of them at optional concentrations, mula (XVIII ) . if necessary under an inert gas atmosphere such as nitrogen , The compound of the formula (XVIII ) thus obtained , is argon , etc . , whereby it is possible to obtain a compound reduced by using a reducing agent such as lithium aluminum represented by the formula ( IIa ) which corresponds to the hydride in accordance with a method disclosed , for example , gen 60 in Journal of Medicinal Chemistry [ J . Med . Chem . ], 2005 , formula ( II ) wherein R1, R², R3, R4 and RS are hydrogen 60 volin Journal . 48 , pp . 2407 , whereby it is possible to obtain a com atoms. pound represented by the formula ( IIb ) which corresponds to Some of the compounds of the formula (VIII ) to be used the formula ( II ) wherein R ', R ?, R4 and Rs are hydrogen here are known compounds , and some of them are commer - atoms. cially available . The rest of them can also be readily syn - 65 Some of the compounds of the formula (XV ) to be used thesized according to general synthetic methods described in here are known compounds, and some of them are commer the literatures relating to known compounds . cially available . The rest of them can also be readily syn US 10 , 029 , 986 B2 49 50 thesized according to general synthetic methods described in & Medicinal Chemistry Letters [ Bioorganic & Med . Chem . literatures relating to known compounds. Lett . ] , 2009 , vol . 19 , pp . 6331 , whereby it is possible to synthesize a compound represented by the formula (XXI ) . The compound of the formula (XXI ) thus obtained and a Reaction Scheme 3 5 substituted acetylene of the formula (VI ) are reacted under common Sonogashira coupling reaction conditions as dis closed , for example , in Tetrahedron Letters [ Tetrahedron Lett. ] , 2012 , vol. 53 , pp . 4117 , to obtain a compound R3 OR represented by the formula (XXII ) , which is then reacted 13 (XIX ) with a known amine represented by the formula (XXIII ) or base its salt ( e . g . hydrochloride , acetate , etc . ) in the presence of a reducing agent such as sodium cyanoborohydride , in 14NY accordance with a method disclosed , for example , in Euro (VIII ) 15 pean Journal of Medicinal Chemistry [ European J . Med . Chem . ] , 2009 , vol. 44 , pp . 4862 , whereby it is possible to obtain a compound represented by the formula ( IIc ) which R3 Y corresponds to the formula (II ) wherein R , R2 and R4 are hydrogen atoms. OSÓ ' N y3 20 C Reaction Scheme 4 O= OR

RO 25 OR M E- (XXIV ) base ( VI) 23 PdPd (VIII ) OSO 13 ( XXI) Bar H2N - R5 35 (XXIII ) NC NaBH3CN en y } OC OR ( XXII ) RO 80 ( XXV ) y2 13 — R ! S 13 (XXVII ) base 45 HN NC RS ( XXVI) ( IIC ) Y2 50 H ( In the formula (VIII ), Y !, Y ?, Y ), J3 and J4 are as defined Boco above . In the formula ( XIX ) , R3 is as defined above, and Ra NC is a C , -C4 alkyl group . In the formula ( XX ) and formula N 73 (XXI ) , Y ! , Y ? , Y , R3 and are as defined above . In the 55 formula (XX ) , R is as defined above . In the formula in (VI ) , R is as defined above. In the formula (XXII ), Y ! , Y ? , Y , R3 (XXVIII ) and Rare as defined above . In the formula (XXIII ) , R5 is as RO defined above. In the formula ( IIc ) , Y ! , Y ? , Y , R3, RS and Rºare as defined above. ) YM - S O ( VI) A compound represented by the formula (VIII ) and a — known B -keto ester represented by the formula (XIX ) are Pd reacted in accordance with a method disclosed , for example , " N y3 in Tetrahedron Letters [ Tetrahedron Lett . ], 2011 , vol. 52, pp . N 5292 , to obtain a compound represented by the formula 65 (XX ), which is then subjected to decarboxylation in accor (XXIX ) dance with a method disclosed , for example , in Bioorganic US 10 , 029 , 986 B2 51 52 -continued ( IId ) which corresponds to the formula ( II ) wherein R2, RS , poR6 R * and Rare hydrogen atoms, or its salt ( e . g . hydrochloride , hydrobromide, trifluoroacetate , etc . ) . [H ] 5 Reaction Scheme 5 R3 ( XXX ) - M RO 10 XXXII ) = NC N (XXXI ) HN yny 15 ( 1 ) halogenation (IId ) 20 ( In the formula ( VIII ), Y !, Y ?, Y , J3 and J4 are as defined NK above . In the formula (XXIV ) , R is a CZ -C4 alkyl group . In the formula ( XXV ), Y ' , Y ? , Y , j3 and Ra are as defined XXXIII ) above. In the formula (XXVI ) , Y ', Y ? , Y and J3 are as RO defined above . In the formula ( XXVII ) , J3 is as defined 25 = above , and R is a C1 - C4 alkyl group or a C1 -C4 haloalkyl p group . In the formula (XVIII ) and formula (XXIX ) , Y ! , Y ? , 3 Y , R1 and J3 are as defined above . In the formula ( VI) , RO is as defined above . In the formula (XXX ) and formula ( IId ) , - Pd Y ? , Y ? , Y } , R and Roare as defined above. ) 30 A compound represented by the formula (VIII ) and a known cyanoacetic acid ester represented by the formula (XXIV ) are reacted in accordance with a method as dis (XXXIV ) closed , for example , in The Journal of Organic Chemistry [ J . y2 Org . Chem . ], 2008 , vol. 73 , pp . 1643 , Bioorganic & Medici - 35 nal Chemistry Letters [Bioorganic & Med . Chem . Lett. ), (1 ) [H ] 2009, vol. 19 , pp . 4484 , to obtain a compound represented R3 ( 2 ) Rb - 13 by the formula ( XXV ) , which is then subjected to decar boxylation by heating in accordance with a method dis y3 (XXXVI ) closed , for example, in Journal of Medicinal Chemistry [ J . 40 Med . Chem . ], 2005 , vol. 48 , pp . 2167 , Synthesis , 2010 , pp . RO 3332 , etc . , whereby it is possible to synthesize a compound of formula (XXVI ) . (XXXV ) Then , the compound of the formula (XXVI ) is reacted with a known compound of the formula (XXVII ) in accor - 45 dance with a method disclosed , for example , in Journal of ER Heterocyclic Chemistry [ J. Heterocyclic Chem . ], 1987 , vol. R3 24 , pp . 1061, to obtain a compound of the formula (XXVIII ) , H2NNH2 BottesN y3 which is then reduced in the coexistence of di -tert -butyl dicarbonate , in accordance with a method disclosed , for 50 example , in Bioorganic & Medicinal Chemistry Letters Rb [ Bioorganic & Med . Chem . Lett . ] , 2012 , vol. 22 , pp . 6108 , whereby it is possible to synthesize a compound represented (XXXVII ) by the formula ( XXIX ) . RO The compound of the formula (XXIX ) thus obtained , and 55 a substituted acetylene represented by the formula ( VI) , are reacted under common Sonogashira coupling reaction con R3 ditions as disclosed , for example , in International Patent Application Publication (WO 2008 /093065 ) , to obtain a H?N compound represented by the formula (XXX ) , which is then 60 reacted with hydrochloric acid , hydrobromic acid , trifluo roacetic acid , etc . for deprotection , in accordance with a method disclosed , for example, in European Patent Publi (Ile ) cation ( EP 1 , 574 ,511 ) , International Patent Application Pub lication (WO 2008 /021927 ) , International Patent Applica - 65 ( In the formula (XXXI ) , Y !, Y ? , Y and J are as defined tion Publication (WO 2010 /075200 ), etc ., whereby it is above. In the formula (XXXII ), R3 and M are as defined possible to obtain a compound represented by the formula above. In the formula (XXXIII ) and formula (XXXIV ) , Y ! , US 10 ,029 , 986 B2 53 54 Y ? , Y , R3 and J3 are as defined above. In the formula (VI ) , -continued R is as defined above. In the formula (XXXV ) , Y ! , Y ? , R3 and R? are as defined above. In the formula (XXXVI ) , JP is y2 as defined above , and R is a C , -C4 alkyl group or a C ,- C4 haloalkyl group . In the formula (XXXVII ) and formula ( Ile ), 5 I HERO Y ' , Y ? , Y , R3, R and R ' are as defined above. ) A compound represented by the formula (XXXI ) is Ez reacted with a known Grignard reagent of formula ( XXXII ) in accordance with a method disclosed , for example, in The R ! R2 Journal of Organic Chemistry [ J . Org . Chem .] , 2009 . vol. 74 , 10 (XL ) pp . 4547 , Journal of Medicinal Chemistry [ J . Med . Chem . ], RO 2006 , vol . 49 , pp . 6343 , whereby it is possible to synthesize a compound represented by the formula (XXXIII ). O [H ], Then , the compound of the formula (XXXIII ) is haloge - 15 = nated and then reacted with potassium phthalimide in accor O dance with a method disclosed , for example , in International IZ v3 Patent Application Publication (WO 2014 /010737 ) , etc ., to R ! R2 obtain a compound of the formula (XXXIV ) , which is then reacted with a substituted acetylene represented by the 20 (XLI ) formula (VI ) under common Sonogashira coupling reaction conditions , as disclosed , for example , in Dalton Transactions [ Dalton Trans. ] , 2011, vol. 40 , pp . 7534 , etc ., whereby it is po possible to synthesize a compound represented by the for mula ( XXXV ) . 25 The compound of the formula (XXXV ) thus obtained , is reduced by using hydrogen or a reducing agent such as sodium borohydride in accordance with a method disclosed , HON for example , in Bioorganic & Medicinal Chemistry Letters R1 R2 [Bioorganic & Med . Chem . Lett . ], 2010 , vol. 20 , pp . 903 , 30 ( IIS ) Tetrahedron Letters [ Tetrahedron Lett . ], 2012 , vol. 53 , pp . 6761, etc ., and then reacted with a known compound rep resented by the formula (XXXVI ) to obtain a compound (In the formula (XXVIII ) and formula (XXXIX ), Y , Y ? , Y , represented by the formula (XXXVII ) , which is then reacted J3 and Rl are as defined above . In the formula (XXXVIII ) , with an aqueous methylamine solution , an aqueous hydra - 35 J3 is as defined above , and R2 is a C , -C4 alkyl group or a zine solution or hydrazinemonohydrate , in the same manner C . - C . haloalkyl group . In the formula (XXXIX ) , R2 is as as in Reaction Scheme 1 , whereby it is possible to obtain a defined above. In the formula (IIf ) , Y !, Y ? , Y , R1, R2 and compound represented by the formula ( Ile ) which corre Rº are as defined above .) sponds to the formula (II ) wherein Rl is — OR ' , and R2 , R4 and Rare hydrogen atoms. 40 A compound represented by the formula (XXVIII ) being Some of the compounds of the formula (XXXI ) to be used a synthetic intermediate in Reaction Scheme 4 , is reacted here are known compounds , and some of them are commer - with a known compound of the formula (XXXVIII ) in cially available . The rest of them can also be readily syn accordance with a method disclosed , for example, in Euro thesized according to general synthetic methods described in pean Journal ofMedicinal Chemistry ( Eur. J . Med . Chem .) , literatures relating to known compounds . 45 2004 , vol . 39, pp . 993 , etc ., whereby it is possible to synthesize a compound represented by the formula (XXXIX ) . Reaction Scheme 6 The compound of the formula (XXXIX ) thus obtained , is reacted in the same manner as in Reaction Scheme 4 , 50 whereby it is possible to obtain a compound represented by 13 — R ? the formula ( IIf ) which corresponds to the formula ( II ) (XXXVIII ) wherein R , R4 and R are hydrogen atoms, or its salt (e . g. NC base hydrochloride, hydrobromide , trifluoroacetate , etc . ) . 55 Reaction Scheme 7 ( XXVIII ) Y2 Y / 60 13 Bry H -] (XLII ) " Boc20 NC Ny3 NC Ny3 R1 R2 65 ( XXXIX ) + (XXVI ) US 10 ,029 , 986 B2 55 56 -continued Reaction Scheme 8 0 0 0 0

NC Boc20 Z -

1

t - BuLi XLIII) 10 NC N RO (XXVI ) H E 15 H7 ( VI) (VI ) Boco Pd NC Ny3 NH 20 R1 R2 ( XLIV ) (XLVI )

Ro 25 ERO ( VI ) Pd Ny}

P3 30 R ! R NH ( XLVII ) ( XLV ) ERO [ H ] 3s. ???V2 6 ?? – – N y3 R ! R2 ( XLVIII ) 40 HON RO = ( IIS ) 45 HNY ( In the formula (XXVI ) and formula (XLIII ), YT, Y ? , Y and R ! R2 J3 are as defined above . In the formula (XLII ), J4 is as ( IIh ) defined above . In the formula (IIg ) , Y , Y2, Y and Rºare as defined above .) A compound represented by the formula (XXVI ) being a 50 (In the formula (XXVI 1 ) and formula (XLVI ) , Y ', Y , Y and synthetic intermediate in Reaction Scheme 4 , and a known J3 are as defined above . In the formula ( IIh ), Y ! , Y ? , Y3 and compound represented by the formula (XLII ) are reacted in Rare as defined .) accordance with a method disclosed , for example , in Journal A compound represented by the formula (XXVI ) being a ofMedicinal Chemistry [ J . Med . Chem . ] , 2010 , vol. 53 , onpp . 55 syntheticsya intermediate in Reaction Scheme 4 , is reacted with 6003 , etc . , whereby it is possible to synthesize a compound a fluorinating agent such as N -Fluorobenzenesulfonimide , in accordance with a method disclosed , for example, in The of the formula (XLIII ) . Journal of Organic Chemistry [ J . Org . Chem . ] , 1998 , vol . 63 , The compound of the formula (XLIII ) thus obtained , is pp . 8052 , etc ., whereby it is possible to synthesize a com reacted in the same manner as in Reaction Scheme 4# , 60 pound represented by the formula (XLVI ) . whereby it is possible to obtain a compound represented by The compound of the formula ( XLVI) thus obtained , is the formula ( Ilg ) which corresponds to the formula (II ) reacted in the same manner as in Reaction Scheme 4 , wherein Rand R together form - CH2CH2 - thereby to whereby it is possible to obtain a compound represented by form a cyclopropyl ring together with the carbon atom to the formula ( Illh ) which corresponds to the formula ( II ) which R1 and R2 are bonded , and R3, R4 andRare hydrogen 65 wherein Rl and R2 are fluorine atoms, and R3, R4 andRare atoms, or its salt ( e. g. hydrochloride , hydrobromide, trifluo - hydrogen atoms, or its salt (e .g . hydrochloride , hydrobro roacetate , etc . ). mide, trifluoroacetate , etc .) . US 10 , 029 ,986 B2 57 58 synthesized according to general synthetic methods Reaction Scheme 9 described in literatures relating to known compounds. In each of Reaction Schemes as described above , after the RO RC completion of the reactions , by performing ordinary post Y ! P3 Ph3P - CH2« Je 5 treatment, it is possible to obtain each of the production ( XLIV ) intermediates to be the starting compound in Production Method A to Production Method C . base The production intermediates respectively produced by O these methods, may, respectively , be used for the reaction of 10 the subsequent step as they are , without isolation or purifi cation . (XXXV ) As alkynyl pyridine- substituted amide compounds of the RO formula ( I ) in the present invention that can be produced = using these methods, specifically compounds represented by Rif 15 the following formulae [ I] - 1 to [ I] - 42 , may , for example , be H2NNH2 mentioned . However , it should be understood that the com ' N y3 pounds represented by the following formulae [ I ] - 1 to [ I ] - 42 are for the purpose of exemplification , and alkynyl pyridine substituted amide compounds encompassed by the present WRC 20 invention are not limited thereto . (XLV ) RO = LR []] - 1 O pill 25 F R3 R4 ) HN ' N y3 TO=O 30 R5 R8 R2 11-2 RO ( In the formula (XXXV ) , Y ! , Y ? , Y3, R3 and R? are as Y ! defined above . In the formula (XLIV ) , Rº is a hydrogen 35 0 R3 R4 atom , a halogen atom , C -Cz alkyl, C1- C5 haloalkyl or C1- C4 O= alkoxy , etc ., and Jº is a chlorine atom , a bromine atom or an iodine atom . In the formula (XLV ) and formula ( Ili ) , Y ! , Y , Z N y } - Y ? , R3, R and Rº are as defined above . ) R R2 Acompound represented by the formula ( XXXV ) being a 40 R5 10- synthetic intermediate in Reaction Scheme 5 , and a com R? pound represented by the formula (XLIV ) , are reacted in the - presence of a strong base such as potassium tert- butoxide , Y sodium hexamethyldisilazide , lithium diisopropylamide or Br 0 R3 R4 an alkyl lithium , in accordance with a method disclosed , for 45 example, in Angewandte Chemie International Edition [An Ny? gew . Chemie , Int. Ed . ] , 2011 , vol. 50 , pp . 2593 , Organic Z- Letters [ Organic Lett. ] , 2007 , vol. 9 , pp . 5219, The Journal R5 R1 R2 of Organic Chemistry [ J . Org . Chem . ], 1993 , vol. 58 , pp . 6509 , Tetrahedron , 2010 , vol. 66 , pp . 3499 , European Jour- 50 [I ] - 4 nal of Medicinal Chemistry ( European J . Org . Chem . ] , 2007 , pp . 266 , etc ., whereby it is possible to synthesize a com ERO 0 R3 R4 pound represented by the formula (XLV ) . O=0 Then , the compound of the formula ( XLV ) is reacted in the samemanner as in Reaction Scheme 1 , with an aqueous 55 N X methylamine solution , an aqueous hydrazine solution or hydrazine monohydrate , in a temperature range of from R5 R1 R2 room temperature to the reflux temperature of the reaction 11- 5 mixture , for from 1 to 24 hours , whereby it is possible to R obtain a compound represented by the formula ( Ili ) which 60 E corresponds to the formula ( II) wherein R and R2 together Y ! form C , -Co alkylidene , C . -Co haloalkylidene or C , - C4 CH3 0 R3 R4 alkoxy (CZ -C2 ) alkylidene , and R4 and RS are hydrogen atoms. Some of the compounds of the formula (XLIV ) to be used 65 R5 R1 R2 here, are known compounds, and some of them are com mercially available . The rest of them can also be readily US 10 , 029 , 986 B2 59 60 - continued -continued 17. Y2 - R6 [ l] - 13 - F F 0 R3 R4 F F Yl ERO R3 R4 Ny3 y3 R5 R R2 ' N 10 R5 R R2 [1I) ] .- 7 F > [ I ] -14 F 0 R3 R4 F 15 F . F Y ERO O R3 R // R5 R R2 [ I ] - 8 20 R1 R2 RO R5 Y [ I] - 15 0 R3 R4 RO Sistemas25 ' N N 73 ?? =o R3 R4 Y N R5 R8 R2 Ny3 [1] - 9 R^ 30 R1 R2 de= R5 la Br o=0 R3 R4 [ I ] - 16 35 R5 R1 R2 FF [I ] - 10 r 0 R3 R4 ERO

Ro 40 N FF = 0 R3 R4 R5 R1 R2

45 R5 R1 R2 [ I ]- 17 Ro [I ] - 11 F RO FLF = F 50 O R3 R4 Y FF Y ! O=0 O = R3 R4 N -? 0 R5 R ! R2 -? 55dojn EN R5 R1 R2 [I ]- 12 [ I ] -18 -ROpo RO 60 F F ORR* F O= R3 R4 N X N Y3 O -Z -Z R5 R1 R2 65 R5 R1 R2 US 10 , 029 , 986 B2 61 62 -continued o US 193. 986 822 -continued [ I ]- 19 [ I] - 26 RO 5 Y ERO O 0 R3 R4 R3 R4 =

NX N y3 R5 R R2 10 R5 R1 R2 [I ] - 20 [I ] - 27 Ro F Y ERO 15 = R3 R4 O R3 R4 Ny3 Ny3

R5 R1 R2 20 R5 R1 R2 [10 -2 , II[I ] - 28 V2 RO = > Y O R3 R4 25 R3 R4 = De

O N X ' N -Z R5 R1 R2 R5 R1 R2 II- 22 30 _ R6 Y ! [I ] - 29 CH3 0 R3 R4 RO 35 F YL = O= R3 R4

R5 R1 R2 0 [I ] - 23 40 R5 R1 R2

F Y R3 R4 ERO [I ] - 30 45 NAN- N y3 RO R5 R1 R2 T Y ! = O

= R3 R4 [I ]- 24 O R6 50 SRO R5 R1 R2 F o R3 R4

y3 55 N N ' N R5 R1 R2 [I ] - 31 RO (LU -23 = – R Y ! – 60 O R3 R4 Y ! O=

O= I 0 R3 R4 2

- 0 R5 R1 R2 R5 R1 R2 65 CH3B US 10 ,029 , 986 B2 63 US10 ,.029 ,B 986986 B2 64 -continued - continued [I ] - 32 [ I ] - 37

FI a Y IF F R3 R4 ERO =o R3 R4

N y3 RS R1 R2 10 R5 R RP CH3 CH3 [ 1] - 38

[11- 33 15 F RO R3 R4 SRO = OSO Ny CH3 R3 R 20 R5 R R ? N N 73 R5 R R2 CH3 mas [I ] -39 25 CH3 Ro F F F O = R3 R4 [ I] - 34 0 RO 30 = Y R5 R1 R2

O

= R3 R4 Y CH3 O CHL 35 [ I ] -40 -Z 39 R5 R1 R2 RO

O= R3 R4 de 40 per y Y 0i [I ] - 35 - Ñ R5 R1 R2 Ý RS 45 F yl 45 ch 0 R3 R4 [I ] -41 O=0 X ' N y3 -Z F F Yl Spo R5 R R2 50 F V 0 R3 R4 =0 ' N Y3 N R5 R1 R2 55 or [l ] - 36 [I ] - 42 Y ! ERO O 60 FF YI ERO R3 R4 0 R3 R4

R R2 N R5 R1 R2 65 R5 CH3 Mix US 10 ,029 , 986 B2 65 66 Here , as examples of specific combinations of substitu -continued ents represented by Y !, Y ? , Y , R ' , R ?, R , R4, R $ and Ró in T - 2 the formulae [ l ] - 1 to [ I ] - 42 , combinations as shown in Table 2 may , for example , be mentioned . However , the combina tions shown in Table 2 are merely for the purpose of 5 exemplification , and specific combinations of substituents represented by Y ! , Y ? , Y , R1, R2, R3, R4, R and R in the alkynyl pyridine - substituted amide compounds included in the present invention , are not limited thereto . In the Table , symbol Et represents an ethyl group , and likewise n - Pr represents a normalpropyl group , i - Pr and Pr- i represent an isopropyl group , C - Pr represents a cyclopropyl group , Bu - s represents a secondary butyl group , t -Bu and Bu - t represent a tertiary butyl group , C -Pen represents a In the Table , symbol ( S ) in the column for substituent R3 cyclopentyl group , and Ph represents a phenyl group . In the Table , T- 1 and T- 2 respectively represent the 15 represents that ( S ) - isomer is 90 % or more , in the mixing following structures: ratio of optical isomers with respect to the carbon atom to which R3 is bonded . T - 1 In the Table , symbol ( E ) or ( Z ) in the columns for I- 1 20 SUsubstituents R1 and R² represents that ( E ) isomer or ( Z ) isomer is, respectively , 90 % or more , in the mixing ratio of CH3 geometrical isomers of the alkylidene group , which substitu ents Rl and R form together. TABLE 2 1 R3 R4 R R2 y Y2 RO y3 ? ? HCl ? ? H H HCl Br I CH3 CH3 CH3 Et CH3 i - Pr CH3 C - Pr CHZ C - Bu CH3 CH CHF2 CH3 CHOCHZ CH3 CHOEt CH3 CHOC ( O ) CHZ CH3 CH ,OC ( O )OCHz H CH3 CH SCHZ CHZ CH- CN . CH3 CH C ( O )OCHZ CH3??? CHÚC( O ) NH , CH3??? CH _ C ( S ) NH2 CH3??? CH2CH = CH2 ??? CHÚC = CH ??? OCH ??? OEt CH ; SCC13 CH3 C (O )CH : CH3 C ( O )OCHZ CH3 Et n - Pr i - Pr C - Pr C - Pr H C -Pr OCHZ C - Pr t - Bu C -Pr t - Bu OCH3 t - Bu H T - 1 C - Pen CH , F CHF2 CF3 T - 2 CH OCHZ C - Pr CH OCH OCHZ CHOCHZ CHOE 0000000000000000000000002220999999999999999999 CHAOBurt US 10 ,029 , 986 B2 67 89 TABLE 2 - continued R3 R4 R R2 y y2 R6 CHOCH CF3 CHOCHOCHZ C ( CH3)2OCHZ C (CH3 )2OCH CF3 CH( OCH3) 2 Si( CH3 ) 3 C ( CH ) = NOCH , Ph ?? * ?? * o - Id ?? * 1 - ng ?? * ?? “ HO0 * Br CH3 222222222222Br C - Pr Br t - Bu Br CHOCHZ CH3 CH3 ?? C - Pr ?? t -Bu CH3??? H H O H { CH3 CH3 CH3 CHZ CHz C - Pr H CH3??? t - Bu ??? HO CHOCHZ ??3??? CH3 CF3??? c - Pr H CF3CF??? , H t-- BuBu

CF3???? CHOCHZ HOO H CH3 HOO H C - Pr HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-? ??? * ? t - Bu HO H CHOCHZ OCHF , H CHZ OCHF2 H u - Id OCHF2 H 7 - ng OCHF2 H HOO??? * SCHZ ? ??* SCH ; ? o - Id SCHZ ? t - Bu SCH ? CHOCHZ ID ?? * C - Pr t - Bu CHOCHZ CH3 C - Pr CH3 H c - Pr C -Pr C - Pr t -Bu C - Pr t - Bu ? CH F C - Pr CHF ? CHOCHZ C - Pr CHOCHZ =*6$3B8H CHOEt C - Pr ???? CHOEt CHAOBurt C - Pr CHAOBurt CH OCH _ CF3 C - Pr CHOCH CF3 H SHOÀIS( C - Pr Si( CH3 ) 3 H Ph c - Pr Ph H { u - Id HHH t - Bu CHOCHZ H? { CH3 Id CH3 7 - ng CHZ SHOOCH3 OCHZ ?? * OCHZ o - Id OCH3 t - Bu OCH ; CHOCHZ H CH3 I CH3 c - Pr CHZ 1 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH US 10. 029 , 986 B2 69 70 TABLE 2 -continued RS R3 R4 R ! Ryly R6 OCHg CH3 H CH3CH? H CH3 Hcc -- PrPr c - Pr CH Hcc -- PrPr OCH ; CH3 Hcc - PrPr H CH3 t - Bu c - Pr t - Bu CH3111mm*3 OCH ; CH3 t - Bu CH3 CHOF c - Pr CH3 CHF OCH , CH, CHAF H CH3 CHOCH3 c - Pr CH3 CH -OCH , OCH CH3 CHOCH3 H CH3 CHOEt c - Pr CH3 CHOEt OCH CH3 CH , Et H CHOBu- t c - Pr |3333 CHAOBul- t OCH ?HHHHHHHHHHHHHHHH CHOBurt CHOCH . CF3 c - Pr CH3 CHOCH. CF3 OCH CH CHAOCH . CF , CH, Si (CH3 ) 3 c - Pr CH Si ( CH3) 3 OCH3 CH3 Si( CH3 ) 3 gnWuW=wuwuwmwwmwwmWan?????????wuwuwuwun???H EEEEEEEESCH3 Ph c - Pr CH3 Ph OCH , CH Ph CH3 CH ; CH3 c - Pr HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-? t - Bu HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-A CH3 CH3 CHOCH3 HHHHHHHHHHHHFFFFCC?HHHHHHHHHHHHHHHHCCHHHHCH3C CH ; CH , CH 3333? CHCl c - Pr CH3 CHCl3 t - Bu CH , CHOCH3 CH; c - Pr t - Bu CHOCH3 CHCl CH , ( CH3Cl c - Pr t - Bu uuuuuuuEt CH3 CHOCH3 n - Pr CH3 c - Pr n -Pr CH3 HHHHHHHHHHHHHHHHOCH3 n- Pr CH3 n - Pr c - Pr c - Pr n - Pr c - Pr OCH3 n - Pr c -Pr n - Pr t - Bu c - Pr n - Pr t - Bu OCH3 n - Pr t - Bu H n - Pr CHOCH c - Pr n -Pr CHOCH3 OCH: n - Pr CHOCH3 H i -Pr CH3 i -Pr c - Pr i - Pr t - Bu HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH i- Pr CHOCH : c - Pr CH, c- Pr c - Pr c - Pr t - Bu c - Pr CHAOCH , CHSCF3??? CH3 ??? c - Pr ??? t - Bu HH CHOCH : 5 CH, CH , HHHHHHHHHHHHHHHHHHHHH c - Pr CH) t - Bu CH , CHOCH mmmmmu???????mmmmm??????? CH) Si (CH3 ) 3 CH2 Ph CHz CH3 CH ) - c - Pr CH2 t - Bu HHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHH CH aaaaaadddddddddddddaaaaaaaaddddddddddddddddddddddddddaaaaaaaddddddddddddddumww HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CHAOCH3 US 10. 029 , 986 B2 71 TABLE 2 -continued RS R3 R4 RI Ryly R6 CH( F ) | CIH CH3 CH (F ) ( E ) CH3 CH ( F ) ( Z ) CH , CH( F ) c -Pr CH( F ) ( E ) c - Pr CH( F ) ( Z ) c - Pr CH( F ) t - Bu CH( F ) ( E ) t - Bu ?HHHHHHHHHHHHHH CH( F ) ( Z ) t - Bu CH( F ) CHOCH : CH( F ) ( E ) CHOCH3 CH( F ) ( Z ) CHOCH3 CH ( F ) Si( CH3) 3 CH( F ) ( E ) Si (CH3 ) 3 CH ( F ) ( Z ) Si( CH3 ) CH( F ) Ph CH ( F ) ( E ) Ph H ?HHHHHHHHHHHHHHH CH (F ) ( Z ) Ph CHCl ) CH3 CH( Cl ) ( E ) CH3 CH( Cl ) ( Z ) CH3 CH( Cl ) c - Pr CH ( Cl ) ( E ) c - Pr CH( Cl ) ( Z ) c- Pr CH ( Cl ) – t - Bu CHICI) ( E ) t - Bu CHCl) { Z ) t - Bu CH( Cl ) CHAOCH3 CH( Cl ) ( E ) CHOCH : HHHHHHHHHH CH( Cl) ( Z ) CHOCH3 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-? CHICI ) SiCH3) 3 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-A CH ( Cl ) ( E ) Si (CH3 ) 3 CH( Cl ) ( Z ) Si( CH3 ) : CH( Cl ) Ph CHICI) ( E ) Ph CH ( Cl) ( Z ) Ph CH ( CH3) CH3 CHICHA ) ( E ) CH3 CHICH3 ) ( Z ) CH3 CHICH3 ) c - Pr CH( CH3 ) ( E ) c - Pr HHHHHHHHHH CH (CH3 ) ( Z ) c - Pr CHICH3) t - Bu CH ( CH3 ) = ( E ) . t - Bu CHICHA ) ( Z ) C1 t - Bu CHICH3 ) CHOCH3 ACH( CH3 ) ( E ) CHAOCH , CHICH ) ( Z ) CHOCH CHICH3 ) Si( CH3 ) 3 CHICH3) ( E ) Si( CH3 ) 3 CH( CH3 ) ( Z ) Si( CH3 ) 3 CHICH3 ) Ph CHICH3 ) ( E ) Ph CH ( CH3 ) ( Z ) Ph HHHHHHHHHH CH3CH2 – CHOCH) CH3 CH2CH2 – CHOCH ) n - Pr = CH - CH2 i - Pr HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CH2CH2 – c- Pr - CH - CH t - Buu - CH - CH T- 1 CH2CH2 c - Pen CHOCH ) T - 2 CHACH CHOCH , EH CHOCH ) CHAOEL

HHHHHHHHH - CH - CH22. CHAOBu -t ACH, CH ) CHOCH, CF ,

HHHHHHHHHHHHH 2 HCH2CH2 CHOCHOCH3 = CH - CH C ( CH3 )20CH3 CHOCH ) C (CH3 )20CH -CF3 CHOCH , CH ( OCH3) 2 HOHO ( Si( CH3 ) 3 HOHO ( C (CH3 ) -NOCH3 CHOCHO Ph CHOCH ) CH3 CH2CH2 – c - Pr HHHHHHHH HHHHHHHHHHHH CH2CH2 – ddddddddddddddaaaaaaaadddddddddddddddddddddddddddddddddddddddddddddddddddddmww HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH t - Bu US 10 ,029 , 986 B2 73 74 TABLE 2 -continued R3 R4 R R2 yi Y2 RO CH2CH2 – Br H CH OCH , - CH2CH2 CH3 CH3 - CH CH2 CH3 C - Pr CH2CH2 CH3 t - Bu - CH - CH2 CH3 CHOCHZ CH2CH2 OCHZ CH3 - CH2CH2 OCHZ C - Pr CH2CH2 OCHZ t -Bu CHÚCH , — OCHZ CHOCH3 CH - CH - CH , — CH3 CH , CH CH2 C - Pr CH2CH2CH2 t - Bu CH2CH2CH2 CHF = CH - CH - CH , CHOCHZ CH2CH2CH2 CHOET - CH2CH . CH CHAOBu - t - CHÚCH , CH , CHOCH _CF3 CH CH - CH , Si( CH3 ) 3 CH ,CH CH2 Ph CHOCH2– CH3 CHOCH2 C - Pr t -Bu CH209CHOCH , CHOCHZ CH SCH2 CH3 CH SCH C - Pr CH SCH , t - Bu CH SCH2 CHOCHZ CH2S (O ) CH2– CHZ CH2S ( O ) CH2 C - Pr CH S ( O ) CH2 t - Bu HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-? - CH2S ( O )CH2 ??!????????????????CHOCHZ - CH2SO2CH2 – CH3 - CH2SO2CH2 C - Pr _ CH _ SO CH2 – t -Bu - CH2SO2CH2 CHOCHZ CHACHACH - CHU CH3 CH2CH2CH2CH2 C - Pr - CH2CH2CH2CH2 t -Bu - CH2CH2CH2CH2– CHOCHZ OCHZ CHZ OCH c - Pr C - Pr OCHZ?? C - Pr OCHZ?? t - Bu H OCHZ??? CHF OCH ; CHOCHZ OCH3 CHOET OCHZ CHOBu - t OCHZ ?CHOCH2CF3 OCH Si( CH3 ) 3 OCH3 Ph OET CH3 OET C - Pr OE t - Bu OET CHZF OET CHOCHZ OET CH2OEt OEt CHAOBu- t OET CHOCH CF3 OET Si( CH3 ) 3 OEt Ph OPr - n CH3 OPr- n C - Pr OPr- n t - Bu OPr- n CH OCH OPr- i CH3 OPr - i C -Pr OPr- i t - Bu OPr- i CHOCHZ OCH ,CF3 ??? CH3 OCH CF3??? C - Pr OCH CF3??? t - Bu OCH , CF3??? CH OCHZ OCH , CH| = CH H CH3 OCH CH = CH H C - Pr OCH ,CH = CH , H t - Bu OCH CH = CH2 H CHOCHZ OCH C = CH H CH3 | OCH - C = CH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 00000000000000000000000000000000000000000000000000000000000000000000 C - Pr US 10. 029 , 986 B2 75 16 TABLE 2 -continued R3 R4 RI | R ' y y R6 FH00 > = HD t - Bu OHO0 = HO H CHOCH3 CH00 CH , H00 ( c - Pr CH00 t - Blu OCH , CHOCH , OCHOCH ) CH3 OCH, CH ) c - Pr OCHOCH t - Bu OCHICH) CHOCH : SCH CH, SCH3 c -Pr SCH HHHHHH| t - Bu SCH, CHOCH. NHOCH , CH , NHOCH , c - Pr NHOCH???, t - Bu NHOCH??? , CHOCH : NHOEt CH3 NHOEt c - Pr NHOEt t - Bu NHOEt CHOCH, ooHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-? NHOPr?i CH3 R-HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH NHOPr?i c - Pr NHOPr - i t - Bu NH0P - CHOCH , NHOBu- S CH, NHOBu - S c - Pr NHOBu- S t - Bul NHOBul- s CHOCH3 NHOBu - t CH3 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-A NHOBu - t c - Pr NHOBu - t t - Bu NHOBu - t CHOCH CN CH3 CN c - Pr CN t - Bu NO CHOCH NO CH , CH3 CN CH3 c - Pr CN t - Bul CN HHHHHHHHHHHHHHHHHHHHHH CHOCH3 CN )( CH3 ?HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CN CN c - Pr CN CN t- Bu CN CN CHOCH3 C ( O ) 0CH H CH3 C700CH, c - Pr C ( O )0CH : t -Bu C700CH , CHOCH C ( O ) NH) CH3 C ( O ) NH ) c - Pr C ( O ) NH t - Bu C ( O ) NH , CHOCH , C (SNH CH3 C ( S ) NH) c - Pr C ( S ) NH) t - Bu C (SNH CHOCH H H Cl CH3 Br CH3 HO * CH3 HO ) S ( H c - Pr CH3??? |33 OCH CH3 CH3 OEt CH3 CH3HHHH H CH3??? Et CH , n - Pr CH3?? HHHHHHHHHHHHHHHHHHH i - Pr H CH3 c - Pr ???????am9w=????mmanyH CH ( S ) H c - Pr c - Pr CH3??? c - Pr OCH ; CHCH3H??? c - Pr OEt c -Pr CH3??? HHHHHHHHHHHHHHHHHHH CH3 t - Bu H CH ( S ) H t - Bu c - Pr CH , H HHHHHHHHHHHH aaaaaadddddddddddddaaaaaaaaddddddddddddddddddddddddddaaaaaaadddddddddddddddddd HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH t - Bu US 10 ,029 , 986 B2 77 78 TABLE 2 -continued RS R3 R4 R1 R2 y y2 R6 OCHZ CH3CH , H H H H tt -- BuBu OET CH , H H t - Bu CH3 CHF ? . CH3( S ) CHF C - Pr CH3??? CH F OCHZ CH ???, CH F H CH3??? CHF2 ? CH3 CHOCHZ ? CH3( S ) CHOCHZ C - Pr CH3??? CHOCHZ OCHZ CH3??? CHOCHZ OEt CHZ??? CH ,OCH H CH3??? CHOET C - Pr CHZ??? CHLOE ???3 CH3 CH ,OET H CH3 CHAOBu - t C - Pr ??? CHOBurt ??? , ??? CHAOBurt ? ??? CHOCH2CF3 C - Pr ??? CHOCH _CF3 OCH3 CH3??? CH OCH _ CF3 ? . CHE??? Si( CH3 ) 3 C - Pr CH3??? Si( CH3 ) 3 OCHZ CCH3 ??? Si( CH3 ) 3 CH3??? C ( CH3) = NOCH , CH3??? Ph C - Pr CHZ??? H PhPh |k8z1115???22z:21115???3 CH3 H PhPh CH3 CH3 CH3 ??? CHz C - Pr ??? t - Bu ??? Cl CH3 CHOCHZ ??? Br CHZ Br C - Pr CH3 Br t -Bu ??? Br CH OCH CH3??? CH3 CH3 CH3??? JJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJCH3 C - Pr CH3??? CH3 t - Bu CH3 CH3 CHOCHZ CH3??? CHZ ??? C - Pr CH3 t - Bu CH3 CHOCHZ CH3??? CHZ CH3 C - Pr CH3??? CH3 CH3 ??? CH3 c - Pr C -Pr LH ??? CH3 C - Pr CH3 CH3 t -Bu C - Pr CH3 ? CH3 t - Bu H CH3 CH ; CHOCHZ C - Pr CH3 CH3 CHOCHZ H CH CH2 – CH CH , ( S ) H CHZ H CH, H CH , C - Pr CH ,( S) H CH2NN C - Pr CH ; CH2 t - Bu CH3( S ) CH2 t - Bu CHZ CH2 CHOCHZ CH , ( S ) H - CH2 CHOCHZ CH H CH2 Si( CH3 ) 3 CH ( S ) H CH , — Si( CH3 ) 3 CH ; H CH2 Ph CHZ( S ) H - CH , Ph CH3??? CH2CH2 CH3 CH3??? LI CH2CH2 c - Pr CH3 CH2CH2 – t -Bu CH ??? CH , CH2 – CHOCHZ CH3??? OCH CH3??? OCHZ cl CH3??? OCHZ Br CHZ??? OCH CH3??? OCHZ CH3 c - Pr CH3??? OCHZ CH3 OCH3 CH3??? OCHZ CH3 CH3??? OCHZ Et CH3 OCHZ n - Pr CH3 OCHZ 000000000000000000000000000000000000 i - Pr US 10 ,029 , 986 B2 79 08 TABLE 2 - continued RS R3 R4 R R2 yi Y2 RO H CH3 OCHZ H CIH CC - Pr C - Pr CH3 OCH HCC - Pr OCHZ ??? OCHZ HcC - Pr H ??? OCHZ H tt - Bu C - Pr ??? OCH3 t - Bu OCH ??? OCHZ t - Bu H ??? OCHZ CHF C - Pr CH3??? OCH CH F OCHZ ??? OCHZ CH F ? CH ???, OCHZ CHF2 H ??? OCHZ CHOCHZ C - Pr CH3 OCHZ CHOCHZ OCHZ CH3 OCHZ CHOCHZ ? CHZ??? OCHZ CH ,OET C - Pr ?? * OCHZ CHOET |21-5825325.=58253238587+OCHZ CH3??? OCHZ??? CHOE ? ??? CH3??? OCH ? CHOBurt C - Pr ??? OCH3??? CHÀOBurt OCHZ ??? OCHZ??? CHAOBurt ??? OCH3??? CH OCH CF3 C - Pr CH3??? OCH ; CH OCH CF3 OCH3 CHZ??? OCHZ CH ,OCH , CF ? CH3??? OCHZ Si( CH3 ) 3 C - Pr CH3C ??? OCHZ Si( CH3 ) 3 ??? , CH3??? OCHZ Si( CH3 ) 3 ? CH3??? OCH3 C ( CH3) = NOCH , ? CH3 OCHZ Ph C - Pr CH3??? OCH Ph OCH3 CH3??? OCHZ??? Ph ??? OCHZ??? Br CH3 ??? OCHZ??? Br C - Pr ??? OCHZ??? Br t - Bu CH3??? OCHZ??? Br CH , OCHZ CH3 OCHZ CH3 CH3 CH ???; OCH CH3 C - Pr ??? OCH CH3 t - Bu ??? OCHZ CHE CHOCHZ CH3??? OCH3 OCHZ CH3 CH3??? OCHZ OCHZ C - Pr CH3 OCHZ OCHZ t - Bu CH3??? OCHZ OCHZ CH ,OCHZ CH3??? OE CH3 CH3??? OET C - Pr CH3??? OET t - Bu ?? ???* OET CHF CH3??? OET CHOCHZ ??? OET CH ,OET CH3 OET CHAOBu- t CH3 OEt CHOCH CF3 CH3 OEt Si( CH3 ) 3 CH3 OET Ph CHZ??? OET 22222222 CH3 ??? OET Br C - Pr ??? OET Br t - Bu ??? OET Br CHOCHZ ??? OET CH3 CH3 ??? OET CH3 C - Pr ??? OET CH3 t -Bu ??? OET CH3 CHOCHZ ??? OET OCH CH ??? OET OCH C - Pr ??? OEt ???3 t - Bu CH3 OET OCHZ CHOCHZ CHZ OPr - n CH ??? OPr- n C - Pr CH3??? OPr- n t - Bu CH3??? OPr- n CH , F ??? OPr- n CHOCHZ CH3??? OPr - n CHOEt CH3??? OPr- n CHAOBurt CH3??? OPr- n CH OCH _ CF3 CH3??? OPr - n Si( CH3 ) 3 CH3??? OPr- n Ph CH3??? OPr- i CHZ CH3??? OPr- i C - Pr CH3??? OPr- i t - Bu CH3 OPr- i CHF HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CH3 OPr- i 0000000000000 CHOCHZ US 10. 029 , 986 B2 81 TABLE 2 -continued RS R3 R4 R Ryly R6 CH; OPr -i CHAOEL CH3 OP - 1 CHOOBurt ??? OPri | CHAOCH ? CF , ??? OPr - 1 Si( CH3 ) 3 ??? OPr - i Ph ??? OCH, CF, ??? CH3 ??? OCH CFS??? c - Pr CH3??? OCH . CFs??? t - Bu ??? OCHOCFs???- CHOCH ??? OCH. CN CH, ??? OCH .CN c - Pr CH, OCH . CN t - Bu ??? OCH. CN HHHHHHH CHOCH3 CH???, OCH CH - CH , CH3 CH3 OCH- CH -CH , c- Pr CH3 OCH -CH CH , t -Bu CH ; OCH CH - CH , CHOCH3 ??? OCH . CACH CH3 ??? OCH. CACH c - Pr ??? OCH . CACH t - Bu CH??? ; OCH . CACH CHOCH CH ???, OCH Ph CH3 ??? OCH- Ph c - Pr CH3??? OCH, Ph t - Bu CH3??? OCH Ph CHOCH , ??? SCHOCF3 CH3 CH3??? SCH. CF3 c - Pr CH3??? SCH, CF3 t - Bu CH3??? SCH. CF3 CHOCH, CH??? , NHOCH??? , CH3 R-HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ??? NHOCH??? , c - Pr HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH-A ??? NHOCH??? , t - Bu CH??? , NHOCH??? , CHAOCH , NHOEt CH3 ??? NHOE c - Pr ??? NHOEt HH t - Bu CH3??? NHOEt CHOCH , CH??? NHOPr - i CH3 CH??? , ?HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHCC NH0P - c - Pr CH3 NH0P - t - Bu CH, NHOPr - i CHOCH, CH3 NHOBul- s CH3 CH3 NHOBu - S c - Pr CH3 NHOBu - S t - Bu CH3??? NHOBu - S CHOCH3 ??? NHOBu -t CH3 CH??? NHOBu - t c- Pr CH??? NHOBu - t t - Bul NHOBu - t ?HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CHOCH , CH3 CH3 CH ; H CH3 CH3 CH , H c - Pr CH3 CH3 t - Bu CH; CH CHOCH : CH , c - Pr Et t - Bul HHHHHHH CHOCH, OCH CH, HHH OCH c - Pr Et OCH : t - Bu Et OCH CHAOCH n -Pr HHH CH3 n - Pr c - Pr n - Pr t - Bu n - Pr CHOCH i - Pr CH3 i - Pr H c - Pr i- Pr HHHHHHHHHHHHH t - Buu i- Pr H CHAOCH CHÚCH CH3 CH. CH - H HH c - Pr CH . CH - H t - Bu CH , CH , CHOCH3 CH c - Pr HHHHHHHHHHHH CHOCH ) CH3 CH - CH2 – c - Pr CHOCH ) t - Bu HHHHH CH - CH2 – HHHHHHHHHHHH aaaaaaddddddddddddaaaaaaaadddddddddddddddddddddddddddddddddddddddddddaaaaaaaaa HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CHOCH , US 10 ,029 , 986 B2 83 84 TABLE 2 -continued R3 R4 R R2 y y2 R6 - CH20CH , O H H CH3CH , _ CH20 HCC - Pr R-HHHHHHHHHH CH , 0 t - Bu CH , 0 % CHOCHZ CH2CH2CH2 CH3 CH2CH2CH2 C - Pr - CH2CH2CH2 t - Bu CH2CH2CH2– CHOCHZ CH2CH2CH2CH2 – CH3 CH2CH2CH2CH2 C - Pr CH2CH2CH2CH2 t - Bu CH ,CH2CH2CH2 CHOCHZ CH , F H CH3 C - Pr CH , F H CH3 ??? , CH , F H CH3 H CH , F H C - Pr C - Pr CH , F H C - Pr ??? , CH F H c - Pr CH F H t - Bu C - Pr CHFH t - Bu OCH3 CH , F H t - Bu H CH , F H CHOCHZ C - Pr CH F H CHOCHZ OCH CH F H HHHHHHHHHHHH H CHLOCHZ 25 The compounds of the present invention are capable000000000000000000000000 of control internal parasites parasitizing animals of the class controlling pathogens causing plant diseases in Trache - Mammalia belonging to the family Cebidae , the family ophyta such as plants of the order Pinales , the group Cercopithecidae , the family Hominidae, the family Lepori magnoliids, the group monocots and the group eudicots , and dae, the family Chinchillidae , the family Caviidae , the pathogens causing infections of Vertebrata such as animals 30 family Cricetidae , the family Muridae, the family Sciuridae , of the class Mammalia , the class Aves, the class Reptilia and the family Camelidae, the family Suidae, the family Cervi the class Actinopterygii , and pests such as plant- parasitic or dae , the family Bovidae , the family Felidae, the family animal- parasitic nematodes , Acanthocephala , Platyhelmin Canidae , the family Mustelidae , the family Equidae , the thes and Protozoa . family Macropodidae and the like , especially animal- para Pests against plants may , for example , be fungi of the 35 sitic nematodes belonging to the order Enoplida , the order phylum Ascomycota , fungi of the phylum Basidiomycota , Rhabditida, the order Strongylida , the order Aphelenchida , fungi of the phylum Chitridiomycota , fungi of the phylum the order Tylenchida , the order Ascaridida and the order Blastocladiomycota , fungi of the phylum Mucoromycotina , Spirurida, parasitizing mammals of the family Suidae , the protists of the phylum Cercozoa , microorganisms of the family Bovidae , the family Felidae , the family Canidae and phylum Heterokontophyta class Oomycetes , gram -positive 40 the family Equidae. bacteria of the phylum Actinobacteria , gram -positive bacte The compounds of the present invention are also effective ria of the phylum Tenericutes , gram -negative bacteria of the on pests which have acquired resistance to conventional phylum Proteobacteria , nematodes of the order Aph - fungicides or nematicides, and the compounds of the present elenchida and nematodes of the order Tylenchida . The invention have very useful characteristics such that they compounds of the present invention have excellent control - 45 have little harmful effect on non - target animals such as ling effect particularly on plant pathogenic fungi belonging mammals , fishes , crustaceans , natural enemies and useful to the phylum Ascomycota and the phylum Basidiomycota , insects . and plant - parasitic nematodes belonging to the order Aph - The compounds of the present invention may be used in elenchida and the order Tylenchida at low doses . any dosage form such as a soluble concentrate , an emulsi Pests against animals may , for example , be fungi of the 50 fiable concentrate , a wettable powder , a water soluble pow phylum Ascomycota , fungi of the phylum Basidiomycota , der, a water dispersible granule , a water soluble granule , a gram - positive bacteria of the phylum Actinobacteria , gram - suspension concentrate , a concentrated emulsion , a suspoe positive bacteria of the phylum Firmicutes , gram - positive mulsion , a microemulsion , a dustable powder , a granule , a bacteria of the phylum Tenericutes, gram - negative bacteria tablet or an emulsifiable gel usually after mixed with an of the phylum Proteobacteria , nematodes of the order 55 appropriate solid carrier or a liquid carrier, and if necessary , Enoplida, nematodes of the order Rhabditida, nematodes of with a surfactant, a penetrant, a spreader, a thickener , an the order Strongylida , nematodes of the order Ascaridida , anti - freezing agent, a binder, an anti -caking agent, a disin nematodes of the order Spirurida , microorganisms of the tegrant, an antifoaming agent, a preservative , a stabilizer or phylum Acanthocephala , cestodes of the order Pseudophyl- the like . A formulation in an arbitrary dosage form may be lidea , cestodes of the order Cyclophyllidea , trematodes of 60 sealed in water- soluble packaging such as a water - soluble the order Strigeidida , trematodes of the order Echinosto - capsule or a water- soluble film , for labor saving or improved mida , trematodes of the order Plagiorchiida , trematodes of safety . the order Opisthorchiida, amebas, Piroplasmida sporozoa , As solid carriers , natural minerals such as quartz , calcite , Haemosporida sporozoa , Eucoccidiorida sporozoa , Vestibu - meerschaum , dolomite , chalk , kaolinite , pyrophyllite , seric liferida ciliata , Trichomonadida flagellata , Diplomonadida 65 ite , halloysite , methahalloysite , kibushi clay , gairome clay, flagellata and Kinetoplastida flagellata . Particularly , the pottery stone , zeeklite , allophone, Shirasu , mica , talc , ben compounds of the present invention have excellent effect to tonite , activated clay , acid clay , pumice , attapulgite , zeolite US 10 ,029 , 986 B2 85 86 and diatomaceous earth , calcined natural minerals such as present invention , though there is no particular restrictions. calcined clay , pearlite , Shirasu -balloons , vermiculite , atta These surfactants may be used alone or in combination of pulgus clay and calcined diatomaceous earth , inorganic salts two or more . such as magnesium carbonate , calcium carbonate , sodium The suitable application dose of the compounds of the carbonate , sodium hydrogen carbonate , ammonium sulfate , 5 present invention is usually from 0. 005 to 50 kg per hectare sodium sulfate , magnesium sulfate , diammonium hydrogen (ha ) in terms of the active ingredient, though it varies phosphate , ammonium dihydrogen phosphate and potassium depending on the application situation , the application sea chloride, saccharides such as glucose , fructose , sucrose and son , the application method and the cultivated crop . lactose , polysaccharides such as starch , cellulose powder When the compounds of the present invention are used to and dextrin , organic substances such as urea , urea deriva - control internal parasites in mammals and birds as farm tives , benzoic acid and benzoic acid salts , plants such as animals /poultry and companion animals , the compounds of wood flour, powdered cork , corncob , walnut shell and the present invention may be administered in an effective tobacco stems, fly ash , white carbon (such as hydrated amount together with pharmaceutically acceptable additives synthetic silica , anhydrous synthetic silica and hydrous 15 orally, parenterally by injection ( intramuscular, subcutane synthetic silicate ) , fertilizers and the like may be mentioned . ously , intravenously or intraperitoneally ) ; percutaneously by As liquid carriers , aromatic hydrocarbons such as xylene , dipping, spraying , bathing, washing , pouring -on and spot alkyl ( C , or C10 etc . ) benzene, phenylxylylethane and alkyl ting -on and dusting , or intranasally . The compounds of the (C? or Cz etc . )naphthalene , aliphatic hydrocarbons such as present invention may be administered through molded machine oil, normalparaffin , isoparaffin and naphthene, mix - 20 articles such as chips, plates, bands, collars , ear marks , limb tures of aromatic hydrocarbons and aliphatic hydrocarbons bands and ID tags. The compounds of the present invention such as kerosene, alcohols such as ethanol , isopropanol, are administered in an arbitrary dosage form suitable for the cyclohexanol, phenoxyethanol and benzyl alcohol, polyhy - administration route . dric alcohols such as ethylene glycol, propylene glycol, The dosage form may be a solid preparation such as a diethylene glycol, hexylene glycol, polyethylene glycol and 25 dust , a granule , a wettable powder, a pellet, a tablet , a ball , polypropylene glycol, ethers such as propyl cellosolve , butyl a capsule and an molded article containing an active ingre cellosolve, phenyl cellosolve, propylene glycolmonomethyl dient, a liquid preparation such as an injection fluid , an oral ether , propylene glycol monoethyl ether, propylene glycol liquid , a liquid preparation applied to the skin or coelom , a monopropyl ether, propylene glycol monobutyl ether and pour- on preparation , a spot- on preparation , a flowable , an propylene glycol monophenyl ether, ketones such as aceto - 30 emulsion , and a semisolid preparation such as an ointment phenone, cyclohexanone and y -butyrolactone , esters such as and a gel. fatty acid methyl esters , dialkyl succinates , dialkyl gluta A solid preparation may generally be used by oral admin mate , dialkyl adipates and dialkyl phthalates , acid amides istration or by percutaneous or by environmental application such as N - alkyl (C1 , Cg or C12 etc . ) pyrrolidone , fats and oils after dilution with water or the like . A solid preparation can such as soybean oil , linseed oil, rapeseed oil, coconut oil , 35 be prepared by mixing an active ingredient with an appro cottonseed oil and castor oil , dimethyl sulfoxide , water and priate vehicle , and with an adjuvant if necessary , and for the like may be mentioned . mulating the mixture into a desired dosage form . These solid and liquid carriers may be used alone or in As the vehicle , an inorganic vehicle such as a carbonate , combinations of two or more . a hydrogen carbonate , a phosphate, aluminum oxide , silica As surfactants , nonionic surfactants such as polyoxyeth - 40 or clay or an organic vehicle such as a saccharide , cellulose , ylene alkyl ether, polyoxyethylene alkyl( mono or di) phenyl cereal flour or starch may , for example , be mentioned . ether, polyoxyethylene( mono , di or tri ) styrylphenyl ether , An injection fluid may be administered intravenously , polyoxyethylenepolyoxypropylene block copolymers , poly intramuscularly or subcutaneously . An injection fluid can be oxyethylene fatty acid (mono or di) ester , sorbitan fatty acid prepared by dissolving an active ingredient in an appropriate ester , polyoxyethylene sorbitan fatty acid ester , ethylene 45 solvent and , if necessary , adding additives such as a solu oxide adducts of castor oil , acetylene glycol, acetylene b ilizer, an acid , a base , a buffering salt , an antioxidant and alcohol, ethylene oxide adducts of acetylene glycol, ethylene a protectant . oxide adducts of acetylene alcohol and alkyl glycosides , As solvents , water, ethanol, butanol, benzyl alcohol, glyc anionic surfactants such as alkyl sulfate salts , alkylbenze - erin , propylene glycol, polyethylene glycol, N -methylpyr nesulfonic acid salts , lignin sulfonate , alkylsulfosuccinic 50 rolidone and mixtures thereof, physiologically acceptable acid salts, naphthalenesulfonic acid salts , alkylnaphthalene - vegetable oils and synthetic oils suitable for injection may sulfonic acid salts , salts of naphthalenesulfonic acid - forma - be mentioned . lin condensates , salts of alkylnaphthalenesulfonic acid - for- As solubilizers, polyvinylpyrrolidone , polyoxyethylated malin condensates, polyoxyethylene alkyl ether sulfate or castor oil, polyoxyethylated sorbitan ester , etc . may be phosphate salts , polyoxyethylene (mono or di) alkylphenyl 55 mentioned . ether sulfate or phosphate salts , polyoxyethylene (mono , di As protectants , benzyl alcohol, trichlorobutanol, p - hy or tri )styrylphenyl ether sulfate or phosphate salts , polycar - droxybenzoic acid esters , n -butanol , etc . may be mentioned . boxylic acid salts (such as polyacrylates , polymaleates and An oral liquid may be administered directly or after copolymers of maleic acid and an olefin ) and polystyrene - dilution . Or, it can be prepared in the same manner as an sulfonic acid salts, cationic surfactants such as alkylamine 60 injection fluid . salts and alkyl quaternary ammonium salts , amphoteric A flowable , an emulsion or the like may be administered surfactants such as amino acid types and betaine types, directly or after dilution percutaneously or by environmental silicone surfactants and fluorine surfactants may be men application . tioned . A liquid preparation to be applied to the skin is admin The amount of these surfactants is usually preferably from 65 istered by dripping, spreading, rubbing , spraying , sprinkling 0 .05 to 30 parts by weight, more preferably from 0 . 5 to 20 or dipping ( soaking, bathing or washing) and can be pre parts by weight, per 100 parts by weight of the agent of the pared in the same manner as an injection fluid . US 10 , 029 , 986 B2 87 88 A pour- on preparation and a spot - on preparation are Formulation examples of preparations using the com dripped or sprayed to a limited area of the skin so that they pounds of the present invention are given below . However, permeate through the skin and act systemically . A pour -on formulations of the present invention are by no means preparation and a spot -on preparation can be prepared by restricted thereto . In the following formulation examples, dissolving , suspending or emulsifying an active ingredient 5 “ parts ” means parts by weight. in an appropriate skin - friendly solvent or solvent mixture. If [Wettable Powder ] necessary, additives such as a surfactant, a colorant, an absorbefacient, an antioxidant, a light stabilizer and an adhesive may be added . Compound of the present invention 0 . 1 to 80 parts As appropriate solvents , water, alkanol, glycol, polyeth Solid carrier 5 to 98 . 9 parts ylene glycol, polypropylene glycol, glycerin , benzyl alco Surfactant 1 to 10 parts hol , phenylethanol, phenoxyethanol, ethyl acetate , butyl Others 0 to 5 parts acetate , benzyl benzoate , dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, acetone , methyl 15 As the others , an anti - caking agent, a stabilizer and the ethyl ketone , aromatic and / or aliphatic hydrocarbons, veg - like may etable or synthetic oils , DMF, liquid paraffin , lightS ;liquid. veo like may be mentioned . paraffin , silicone , dimethylacetamide , N -methylpyrrolidone [Emulsifiable Concentrate ] or 2 , 2 - dimethyl- 4 -oxy -methylene - 1 , 3 -dioxolane may be mentioned 20 Compound of the present invention 0 . 1 to 30 parts As absorbefacients , DMSO , isopropyl myristate , pelar Organic solvent 45 to 95 parts Surfactant 4 . 9 to 30 parts gonic acid dipropylene glycol, silicone oil, fatty acid esters , Water 0 to 50 parts triglycerides and aliphatic alcohols may be mentioned . Others 0 to 10 parts As antioxidants , sulfites , metabisulfites, ascorbic acid , butylhydroxytoluene , butylhydroxyanisole and tocopherol 25 may be mentioned . As the others , a spreader, a stabilizer and the like may be An emulsion may be administered orally , percutaneously mentioned . or by injection . An emulsion can be prepared by dissolving an active ingredient in a hydrophobic phase or a hydrophilic [Suspension Concentrate ] phase and homogenizing the resulting solution with another 30 liquid phase together with an appropriate emulsifier, and Compound of the present invention 0 . 1 to 70 parts further if necessary with additives such as a colorant, an Liquid carrier 15 to 98 . 89 parts absorbefacient, a protectant , an antioxidant, a light screen Surfactant 1 to 12 parts and a thickener. Others 0 .01 to 30 parts As hydrophobic phases ( oils ) , paraffin oil, silicone oil, 35 sesame oil, almond oil, castor oil , synthetic triglycerides, ethyl stearate , di- n -butyryl adipate , hexyl laurate , pelargonic As the others, an anti - freezing agent, a thickener and the acid dipropylene glycol, esters of branched short - chain fatty like may be mentioned . acids with C16 - C18 saturated fatty acids, isopropyl myristate, [Water Dispersible Granule ] isopropyl palmitate , esters of C12 - C18 saturated alcohols 40 with caprylic / capric acid , isopropyl stearate , oleyl oleate , decyl Oleate , ethyl oleate , ethyl lactate , fatty acid ester Compound of the present invention 0 . 1 to 90 parts Solid carrier 0 to 98 . 9 parts waxes, dibutyl phthalate , diisopropyl adipate , isotridecyl Surfactant 1 to 20 parts alcohol, 2 -octyldodecanol , cetylstearyl alcohol, oleyl alco Others 0 to 10 parts hol, etc . may be mentioned . 45 - As hydrophilic phases , water, propylene glycol, glycerin , sorbitol, etc . may be mentioned . As the others , a binder , a stabilizer and the like may be As emulsifiers , nonionic surfactants such as polyoxyeth mentioned . ylated castor oil , polyoxyethylated sorbitan monoolefinic oncen acid , sorbitan monostearate , glycerin monostearate , poly - 50 oxyethyl stearate and alkyl phenol polyglycol ether, ampho teric surfactants such as disodium N - lauryl- B - iminodipropi Compound of the present invention 0 .01 to 70 parts onate and lecithin ; anionic surfactants such as sodium lauryl Liquid carrier 20 to 99 .99 parts sulfate , aliphatic alcohol sulfate ether, mono / dialkylpolygly Others 0 to 10 parts col orthophosphate monoethanolamine salt ; and cationic 55 surfactants such as cetyltrimethylammonium chloride may , for example , be mentioned . As the others , an anti- freezing agent , a spreader and the As other additives , carboxymethylcellulose, methylcellu like may be mentioned . lose , polyacrylate , alginate , gelatin , gum arabic , polyvi- [Granule ] nylpyrrolidone , polyvinyl alcohol, methyl vinyl ether , 60 maleic anhydride copolymers, polyethylene glycol, waxes , Compound of the present invention 0 .01 to 80 parts colloidal silica , etc . may be mentioned . Solid carrier 10 to 99. 99 parts A semisolid preparation is administered by applying or Others 0 to 10 parts spreading onto the skin or introducing into the coelom . A gel can be prepared by adding a thickener to a solution 65 prepared in the samemanner as an injection fluid sufficiently As the others , a binder , a stabilizer and the like may be to give a transparent viscous substance like an ointment. mentioned . US 10 ,029 , 986 B2 89 90 [Dustable Powder] [Formulation Example 4 ] Emulsifiable Concentrate

Compound of the present invention 0 . 01 to 30 parts Solid carrier 65 to 99 . 99 parts 55 Compound No. 3 -016 of the present invention 4 parts Others 0 to 5 parts DBE 11 parts ( tradename for a mixture of dimethyl adipate, dimethyl glutarate and dimethyl succinate : manufactured by INVISTA ) As the others, an anti -drift agent, a stabilizer and the like Diisobutyl adipate 30 parts may be mentioned . N -methylpyrrolidone 5 parts Next, more specific examples of preparations containing Soprofol BSU 14 parts ( tradename for a nonionic surfactant: manufactured compounds of the present invention as an active ingredient by Rhodia Nicca . Ltd . ) are given below . However, the present invention is by no Rhodacal 70BC 6 parts ( tradename for an anionic surfactant: manufactured means restricted thereto . by Rhodia Nicca . Ltd . ) In the following Formulation Examples , “ parts ” means 15 Propylene glycol 10 parts parts by weight. Water 20 parts [Formulation Example 1 ] Wettable Powder The above ingredients are mixed homogenously to obtain an emulsifiable concentrate . [Formulation Example 5 ] Suspension Concentrate Compound No. 1 -002 of the present invention 20 parts Pyrophyllite 74 parts Sorpol 5039 4 parts ( tradename for a mixture of a nonionic surfactant and an anionic 25 Compound No. 3 -016 of the present invention 25 parts surfactant: AGRISOL S -710 10 parts manufactured by TOHO Chemical Industry Co. , Ltd .) ( tradename for a nonionic surfactant: manufactured CARPLEX # 80D 2 parts by Kao Corporation ) (hydrous synthetic silicic acid : tradenamemanufactured by Lunox 1000C 0 .5 part Shionogi & Co ., Ltd . ) ( tradename for an anionic surfactant : manufactured 30 by TOHO Chemical Industry Co ., Ltd . ) Xanthan gum 0 . 2 part The above ingredients are mixed and pulverized homog Water 64 . 3 parts enously to obtain a wettable powder . The above ingredients are mixed homogenously and [ Formulation Example 2 ] Emulsifiable Concentrate 35 wet- pulverized to obtain a suspension concentration . [Formulation Example 6 ] Water Soluble Granule Compound No. 1 -017 of the present invention 5 parts Xylene 75 parts N -methylpyrrolidone 15 parts 40 Sorpol 2680 5 parts Compound No. 3- 016 of the present invention 75 parts ( tradename for a mixture of a nonionic surfactant and HITENOL NE - 15 5 parts an anionic surfactant: manufactured by TOHO ( tradename for an anionic surfactant: manufactured Chemical Industry Co ., Ltd . ) by Dai- ichi Kogyo Seiyaku Co ., Ltd .) VANILLEX N . 10 parts 45 ( tradename for an anionic surfactant: manufactured by Nippon Paper Industries Co . , Ltd . ) The above ingredients are mixed homogenously to obtain CARPLEX # 80D 10 parts an emulsifiable concentrate . ( tradename for hydrous synthetic silicic acid : manufactured by Shionogi & Co ., Ltd . ) [Formulation Example 3 ] Emulsifiable Concentratencentrate 50 The above ingredients are mixed and pulverized homog enously , then kneaded with a small amount of water , granu lated through an extrusion granulator and dried to obtain a Compound No. 3 -001 of the present invention 4 parts DBE 36 parts water soluble granule. ( tradename for a mixture of dimethyl adipate , dimethyl 55 glutarate and dimethyl succinate : manufactured [ Formulation Example 7 ] Granule by INVISTA ) Diisobutyl adipate 30 parts N -methylpyrrolidone 10 parts Soprofol BSU 14 parts ( tradename for a nonionic surfactant : manufactured by 60 Compound No. 8 -001 of the present invention 5 parts Rhodia Nicca . Ltd . ) Bentonite 50 parts Rhodacal 70BC 6 parts Talc 45 parts ( tradename for an anionic surfactant: manufactured by Rhodia Nicca The above ingredients are mixed and pulverized homog 65 enously , then kneaded with a small amount of water , granu The above ingredients are mixed homogenously to obtain lated through an extrusion granulator and dried to obtain a an emulsifiable concentrate . granule . US 10 ,029 , 986 B2 91 [Formulation Example 8 ] Dustable Powder [Formulation Example 13 ] Liquid Preparation for Percutaneous Administration

Compound No . 9 -006b of the present invention 3 parts Compound No . 3 -021 of the present invention 5 parts CARPLEX # 80D 0 .5 part Propylene glycol monomethyl ether 50 parts ( tradename for a hydrous synthetic silicic acid : Dipropylene glycol 45 parts manufactured by Shionogi & Co ., Ltd .) Kaolinite 95 parts 10 Diisopropyl phosphate 1. 5 parts [ Formulation Example 14 ] Liquid Preparation for Percutaneous Administration (by Dripping ) The above ingredients are mixed and pulverized homo geneously to obtain a dustable powder . 1515 - Compound No . 1 - 002 of the present invention 2 parts It is applied after diluted with water by a factor of from Light liquid paraffin 98 parts 1 to 20000 so as to achieve an active ingredient concentra tion of from 0 .005 to 50 kg /ha . 20 [Formulation Example 15 ] Liquid Preparation for [Formulation Example 9 ] Wettable Powder Percutaneous Administration (by Dripping ) Preparation

25 Compound No . 1 -017 of the present invention 2 parts Compound No . 1 -002 of the present invention 25 parts Light liquid paraffin 58 parts Sodium diisobutylnaphthalenesulfonate 1 part Olive oil 30 parts Calcium n - dodecylbenzenesulfonate 10 parts ODO - H 9 parts Alkyl aryl polyglycol ether 12 parts Shin - etsu silicone 1 part Naphthalenesulfonic acid - formalin condensate sodium salt 3 parts ( tradename for silicone : manufactured by Shin - etsu Chemical Silicone emulsion 1 part Co ., Ltd . ) Silicon dioxide 3 parts Kaolin 45 parts For use as agricultural fungicides or nematicides, the compounds of the present invention in effective amounts may be used alone as active ingredients , or if necessary , the [ Formulation Example 10 ] Water - Soluble 35 compounds of the present invention may be mixed with Concentrate Preparation other fungicides, other nematicides , insecticides, miticides, plant growth regulators, herbicides, synergists , fertilizers, soil conditioners and the like at the time of formulation or application . Compound No . 1 -017 of the present invention 20 parts 40 Further, for use as endoparasite , the compounds of the Polyoxyethylenelauryl ether 3 parts Sodium dioctylsulfosuccinate 3 .5 parts present invention in effective amounts may be applied alone Dimethyl sulfoxide 37 parts as active ingredients , or if necessary , they may be mixed 2 - Propanol 36 . 5 parts with other antibiotics , other anthelmintic and the like at the time of formulation or application . Particularly , the combined use with other fungicides , other nematicides , other antibiotics, other anthelmintic or [ Formulation Example 11 ] Liquid Preparation for the like is expected to broaden the pesticidal spectrum by the Spraying additive or synergistic effect of the other agrochemicals , to 50 improve the pesticidal effect, to reduce the application cost by enabling control at lower doses , and further , to prolong Compound No . 3 -001 of the present invention 2 parts the pesticidal effect for a long period of time. Particularly , Dimethyl sulfoxide 10 parts the combined use with other fungicides, nematicides , anti 2 - Propanol 35 parts biotics or anthelmintic differing in the mechanism of action Acetone 53 parts 55 is a very useful controlling method with a view to preventing the pests from acquiring resistance to pesticides. In such cases , they may be combined with a plurality of known fungicides, known nematicides, known insecticides, known [Formulation Example 12 ] Liquid Preparation for miticides, known antibiotics or known anthelmintic simul Percutaneous Administration 60 taneously . The fungicides, nematicides , insecticides , miticides , anthelmintic and antibiotics to be used in combination with Compound No. 3 -016 of the present invention 5 parts the compounds of the present invention include, for Hexylene glycol 50 parts example , the compounds disclosed in e . g . The Pesticidal Isopropanol 45 parts 65 Manual , 16th edition , 2012 . Specifically , their common names will be exemplified below , but useful agents are not limited thereto . US 10 , 029 ,986 B2 93 94 Fungicides: I : Melanin Synthesis Inhibitors A : Nucleic Acid Biosynthesis Inhibitors phthalide, pyroquilon , tricyclazole , benalaxyl, benalaxyl- M , furalaxyl, metalaxyl, metalaxyl carpropamid , diclocymet , fenoxanil , M , ofurace , oxadixyl, P : Resistance of Plants Inducing Agents bupirimate, ethirimol, 5 acibenzolar - S -methyl , hymexazol, probenazole, B : Mitosis and Cell Division Inhibitors isotianil, tiadinil, benomyl, carbendazim , fuberidazole , thiabendazole , thio laminarin , phanate- methyl, M : Drugs of Multi -Point of Action diethofencarb , 10 bordeaux mixture , cheshunt mixture , copper carbonate ethaboxam , zoxamide , basic , copper hydroxide, copper naphthenate , copper pencycuron , oleate , copper oxychloride , copper sulfate , copper sul fluopicolide , fate basic , oxine copper , calcium polysulfide , sulfur, C : Respiration Inhibitors 15 amobam , ferbam , mancozeb , maneb , metiram , polycar diflumetorim , bamate , propineb , thiram , ziram , captan , folpet, chlo benodanil, benzovindiflupyr, bixafen , boscalid , carboxin , rothalonil , dichlofluanid , tolylfluanid , guazatine , imi fenfuram , fluopyram , flutolanil , fluxapyroxad , furam noctadine - albesilate , iminoctadine - triacetate , anilazine , etpyr , isofetamid , isopyrazam , mepronil, oxycarboxin , dithianon , chinomethionat, fluoroimide , penflufen , penthiopyrad , pyraziflumid , sedaxane, thi- 20 and fluzamide , U : Mechanism of Action Unknown and Other Agents azoxystrobin , coumoxystrobin , dimoxystrobin , enes cyflufenamid , cymoxanil, diclomezine , dipymetitrone , trobin , enoxastrobin , famoxadone, fenamidone , dodine , ferimzone , flusulfamide , flutianil , fosetyl- alu fenaminstrobin , flufenoxystrobin , fluoxastrobin , kre minium , metrafenone , oxathiapiprolin , picarbutrazox , soxim -methyl , mandestrobin , metominostrobin , 25 pyriofenone , tebufloquin , tolprocarb , triazoxide , potas orysastrobin , picoxystrobin , pyraclostrobin , pyrameto sium hydrogen carbonate , sodium hydrogen carbonate , strobin , pyraoxystrobin , pyribencarb -methyl , pyrimi shiitake mushroom mycelium extract, shiitake mush nostrobin , triclopyricab , trifloxystrobin , amisulbrom , cyazofamid , room fruiting body extract , BCF -082 ( test name) , dinocap , fluazinam , meptyldinocap , ZF - 9646 (test name) , etc . fentin , tributyltin oxide , Insecticides , Acaricides: silthiofam , 1 : Acetylcholinesterase (AChE ) Inhibitors ametoctradin , alanycarb , aldicarb , bendiocarb , benfuracarb , butocar D : Amino Acid and Protein Biosynthesis Inhibitors boxim , carbaryl, carbofuran , carbosulfan , ethiofencarb , cyprodinil, mepanipyrim , pyrimethanil , 35 fenobucarb , formetanate , furathiocarb , isoprocarb , blasticidin - S , methiocarb , methomyl, pirimicarb , thiodicarb , thio kasugamycin , fanox , triazamate , E : Drugs acting on the signaling system acephate , azamethiphos , azinphos- ethyl, azinphos proquinazid , quinoxyfen , methyl, chlorethoxyfos , chlorfenvinphos, chlorme fenpiclonil , fludioxonil , 40 phos, chlorpyrifos, chlorpyrifos- methyl , cyanophos , chlozolinate , iprodione , procymidone , vinclozolin , diazinon , dichlorvos, dimethoate , dimethylvinphos, F : Lipid Synthesis and Cell Membrane Formation Inhibitors disulfoton , EPN , fenitrothion , fenthion , isoxathion , edifenphos , iprobenfos, isoprothiolane, pyrazophos, malathion , methamidophos , methidathion , omethoate , biphenyl, chloroneb , dicloran , etridiazole, quintozene , oxydemeton -methyl , parathion -methyl , phenthoate , tecnazene, tolclofos- methyl , 45 phorate , phosalone , phosmet, phoxim , pirimiphos propamocarb hydrochloride , methyl , profenofos , prothiofos, pyraclofos, sulfotep , Bacillus subtilis , Strain : D747, FZB24 , GBO3 , HA10404 , terbufos , tetrachlorvinphos, thiometon , trichlorfon , MB1600 , QST713, Y1336 , etc ., 2 : GABA -Gated Chloride Channel Antagonists G : Sterol Biosynthesis Inhibitors endosulfan , alpha - endosulfan , azaconazole , bitertanol, bromuconazole , cyproconazole , 50 ethiprole , fipronil, flufiprole , pyriprole , difenoconazole, diniconazole , diniconazole - M , epoxi conazole , etaconazole , fenarimol, fenbuconazole , afoxolaner, fluralaner, lotilaner , sarolaner, fluquinconazole , flusilazole , flutriafol, hexaconazole , 3 : Sodium Channel Modulators imazalil , imibenconazole , ipconazole , metconazole , acrinathrin , allethrin , benfluthrin , bifenthrin , kappa- bifen myclobutanil, nuarimol, oxpoconazole fumarate , 55 thrin , bioallethrin , bioresmethrin , cycloprothrin , cyflu pefurazoate , penconazole , prochloraz , propiconazole , thrin , beta - cyfluthrin , cyhalothrin , gamma- cyhalothrin , prothioconazole , pyrifenox , pyrisoxazole , simecon lambda - cyhalothrin , cypermethrin , alpha - cyper azole , tebuconazole , tetraconazole , triadimefon , triadi methrin , beta -cypermethrin , zeta - cypermethrin , cyphe menol, triflumizole , triforine , triticonazole , nothrin , deltamethrin , empenthrin , esfenvalerate , aldimorph , dodemorph -acetate , fenpropidin , fenpropi- 60 etofenprox , fenpropathrin , fenvalerate , flucythrinate , morph , piperalin , spiroxamine, tridemorph , flumethrin , fluvalinate , tau - fluvalinate , halfenprox , fenhexamid , fenpyrazamine , heptafluthrin , imiprothrin , meperfluthrin , metofluthrin , H : Cell Wall Synthesis Inhibitors permethrin , phenothrin , pyrethrins, resmethrin , silaflu validamycin , ofen , tefluthrin , kappa -tefluthrin , tetramethrin , d - te polyoxins, polyoxorim , 65 tramethrin , tetramethylfluthrin , tralomethrin , transflu benthiavalicarb -isopropyl , dimethomorph , flumorph , thrin , iprovalicarb , mandipropamid , pyrimorph , valifenalate , methoxychlor, US 10 ,029 , 986 B2 95 96 4 : Nicotinic Acetylcholine Receptor (NACHR ) Agonists 28 : Ryanodine Receptor Modulators acetamiprid , clothianidin , dinotefuran , imidacloprid , chlorantraniliprole , cyantraniliprole , cyclaniliprole , nitenpyram , thiacloprid , thiamethoxam , flubendiamide , tetraniliprole , and sulfoxaflor, 5. UN : Mechanism of Action Unknown and Other Drugs flupyradifurone , azadirachtin , benzoximate , bifenazate , bromopropylate , 5 : Nicotinic Acetylcholine Receptor (nACHR ) Allosteric dicofol, pyridalyl, pyrifluquinazon , Modulators afidopyropen , broflanilide, dicloromezotiaz , flometoquin , spinetoram , spinosad , fluhexafon , pyflubumide , triflumezopyrim , ME5382 6 : Chloride Ion Channel Activators ( test name) , NA - 89 ( test name ) , NC -515 (test name) , abamectin , emamectin -benzoate , lepimectin , milbemec ZD12501 (test name) , etc . tin , Nematicides: cadusafos, dichlofenthion , ethoprophos, 7 : Juvenile Hormone Similar Agents fenamiphos, fluensulfone , fosthiazate, fosthietan , imicyafos, methoprene, isamidofos, isazofos , methyl bromide , methyl isothiocya fenoxycarb , nate , oxamyl, sodium azide , tioxazafen , BY1 - 1921 (test 15 nname ) , MAI- 08015 ( test name) , etc . pyriproxyfen , Anthelmintics : acriflavine , albendazole , atovaguone , 9 : Hemiptera Selective Feeding Inhibitors azithromycin , bithionol, bromofenofos , cambendazole , pymetrozine , camidazole , chloroquine, clazuril, clindamycin hydrochlo flonicamid , ride, clorsulon , closantel , coumaphos , cymiazol, dichloro 10 : Mite Growth Inhibitors 20 phen , diethylcarbamazine , diminazene , disophenol, dithi clofentezine , hexythiazox , azanine iodide , doxycycline hydrochloride , doramectin , etoxazole , emodepside , eprinomectin , febantel , fenbendazole, fluben 11 : Microorganism -Derived Insect Intestinal Membrane dazole , furazolidone , glycalpyramide, imidocarb , ivermec Disrupting Agents tin , levamisole , mebendazole , mefloquine , melarsamine izowni 25 hydrochloride , metronidazole , metyridine , milbemycin bacillus thuringiensis, subsp . israelensis , subsp . aizawai, 25 oxime , monepantel, morantel tartrate , moxidectin , nicarba subsp . kurstaki, subsp . tenebrionis , etc. , zin , niclosamide, nitroscanate, nitroxynil, omphalotin , oxan 12 : Mitochondrial ATP Synthase Inhibitors tel pamoate , oxantel tartrate , oxfendazolee , oxibendazole , diafenthiuron , oxyclozanide , pamaquine , phenothiazine, piperazine adi azocyclotin , fenbutatin oxide, pate , piperazine citrate , piperazine phosphate , PNU - 97333 propargite , ( paraherquamide A ) , PNU - 141962 ( 2 - deoxyparaherqu 13 : Oxidative Phosphorylation Uncouplers amide ) , praziquantel, primaquine , propetamphos , propoxur, chlorfenapyr, pyrantel pamoate , pyrimethamine , santonin , selamectin , sul fadimethoxine , sulfadoxine , sulfamerazine , sulfa 14 : Nicotinic Acetylcholine Receptor (nACHR ) Channel monomethoxine, sulfamoildapsone , thiabendazole , tinida Blockers 35 zole , toltrazuril , tribromsalan , triclabendazole , etc . bensultap , cartap , thiocyclam , Antifungal agents : climbazole , ketoconazole , miconazole 15 : Chitin Biosynthesis Inhibitors ( Type 0 ) nitrate , etc . bistrifluron , chlorfluazuron , diflubenzuron , flucycloxuron , Antimicrobials : amoxicillin , ampicillin , bethoxazin , bithi flufenoxuron , hexaflumuron , lufenuron , novaluron , onol, bronopol, cefapirin , cefazolin , cefquinome, ceftiofur, noviflumuron , teflubenzuron , triflumuron , 40 chlortetracycline, clavulanic acid , danofloxacin , difloxacin , 16 : Chitin Biosynthesis Inhibitors ( Type 1 ) dinitolmide , enrofloxacin , florfenicol, lincomycin , lom buprofezin , efloxacin , marbofloxacin , miloxacin , mirosamycin , nitrapy 17 : Molting Inhibitors (Diptera Insect ) rin , norfloxacin , octhilinone , ofloxacin , orbifloxacin , oxo cyromazine , linic acid , oxytetracycline, penicillin , streptomycin , 18 : Molting Hormone ( Ecdysone ) Receptor Agonists 4545 thiamphenicothiamphenicol , tiamulin fumarate , tilmicosin phosphate , chromafenozide, halofenozide, methoxyfenozide, tebufe acetylisovaleryltylosin , tylosin phosphate , tulathromycin , nozide , valnemulin , calcined shell calcium (calcium oxide ) , Talaro 19 : Octopamine Receptor Agonists myces genus, Trichoderma, Koniochiriumu spp ., etc . amitraz , EXAMPLES 20 : Mitochondrial Electron Transport Chain Complex III 50 Inhibitors In the following , the present invention will be described hydramethylnon , in further detail by specifically describing Synthesis acequinocyl, Examples and Test Examples of the compounds of the fluacrypyrim , present invention as Examples, but the present invention is 21: Mitochondrial Electron Transport Chain Complex I 55 by no means limited thereto . Inhibitors Synthesis Example 1 fenazaquin , fenpyroximate , pyrimidifen , pyridaben , tebufenpyrad, tolfenpyrad , N -[ 2 - [3 -chloro -5 -( 3 ,3 -dimethyl - 1 -butynyl ) pyridin -2 rotenone , yllethyl ] -2 - ( trifluoromethyl) benzamide ( Compound 22 : Voltage - Dependent Sodium Channel Blockers No . 1 - 003 of the present invention ) indoxacarb , indoxacarb -MP , metaflumizone, Step 1: Production of 2 - (5 -bromo -3 - chloropyridin 23 : Acetyl CoA Carboxylase Inhibitors 2 -yl ) - 2 -[ [ 2 -( trifluoromethyl ) benzamide ]methyl ] ma spirodiclofen , spiromesifen , spirotetramat , lonic acid diethyl ester 25 : Mitochondrial Electron Transport System Complex II 65 Inhibitors To a 30 ml solution of 3 . 00 g of 2 - ( 5 -bromo - 3 - chloro cyenopyrafen , cyflumetofen , pyridin - 2 - yl) malonic acid diethyl ester in N ,N - dimethylfor US 10 ,029 , 986 B2 97 98 mamide, 1 .92 g of potassium tert- butoxide was added under it was eluted with ethyl acetate -hexane ( gradient of from 1 :9 ice -cooling and stirring , followed by stirring for 30 minutes to 4 : 6 ) , to obtain 36 mg of the desired product as white at 0° C . Then , to this reaction mixture , 2 . 44 g of N - chlo - crystals . romethyl- 2 - (trifluoromethyl ) benzamide was added , and stir Melting point: 90 . 0 to 92. 0° C . ring was continued at room temperature for further 30 5 H NMR (CDC1z , Me Si , 300 MHz ) 88 . 33 (d , J = 1 . 8 Hz, minutes . After completion of the reaction , 100 ml of water 1H ), 7 .65 (d , J = 1 .8 Hz, 1H ), 7 .45 - 7 .65 (m , 4H ), 6 . 76 (bs , was added to the reaction mixture , followed by extraction 1H ), 3 . 94 ( q , J = 6 .0 Hz, 2H ) , 3 . 20 ( t, J = 6 . 0 Hz, 2H ) , 1 .32 (s , with ethyl acetate (50 mlx2 ), and organic layers were 9H ). combined and washed with water ( 50 mlx1 ) , whereupon it was dehydrated and dried in the order of with a saturated 10 Synthesis Example 2 sodium chloride solution and then with anhydrous sodium N - [ 2 - [ 3 - chloro - 5 - ( 1 - propynyl) pyridin - 2 - yl] ethyl] - 2 sulfate , and then , the solvent was evaporated under reduced ( trifluoromethyl) benzamide ( compound No. 1 -001 pressure . The residue was purified by silica gel column of the present invention ) chromatography wherein it was eluted with ethyl acetate - 1615 hexane ( gradient of from 5 : 95 to 30 :70 ( volume ratio , the To a 20 ml suspension of 467 mg of zinc ( II ) bromide in same applies hereinafter ) ) , to obtain 1 .11 g of the desired tetrahydrofuran under a nitrogen atmosphere , 3 . 76 ml of a product as a colorless oily substance . 0 .5M tetrahydrofuran solution of 1 - propynylmagnesium ' H NMR (CDC1z , Me. Si, 300 MHz ) 88 .47 ( d , J = 1 . 8 Hz, bromide was added dropwisely under ice- cooling and stir 1H ) , 7 . 91 ( d , J = 1 . 8 Hz, 1H ) , 7 . 15 - 7 .65 ( m , 4H ) , 6 . 93 (bs , 20 ring , followed by stirring at room temperature for 30 min 1H ) , 4 . 56 ( d , J = 6 . 6 Hz, 2H ) , 4 .2 - 4 . 35 ( m , 4H ), 1 . 2 - 1 . 35 ( m , utes . Then , to this reaction mixture , 192 mg of N - [ 2 - ( 5 6H ) . bromo - 3 - chloropyridin - 2 - yl) ethyl] - 2 - ( trifluoromethyl ) benzamide produced in Step 2 of Synthesis Example 1 and Step 2 : Production of N - [ 2 - (5 -bromo - 3 -chloropyri 20 mg of dichloro [ 1 , 1' - bis (diphenylphosphino ) ferrocene ] din -2 -yl ) ethyl ] - 2 -( trifluoromethyl) benzamide 25 palladium ( II ) were added , and stirring was continued at room temperature for 12 hours . After completion of the To a 10 ml solution of 1 .11 g of 2 -( 5 -bromo - 3 - chloro reaction , 30 ml of water was added to the reaction mixture , pyridin - 2 - yl) - 2 - [ [ 2 - ( trifluoromethyl) benzamide ]methyl ]ma - followed by extraction with ethyl acetate ( 25 mlx2) , and lonic acid diethyl ester in N -methyl - 2 - pyrrolidone, 50 mg of organic layers were combined and washed with water ( 20 potassium chloride , 10 ml of water and 274 mg of concen - 30 mlx1 ) , followed by dehydration and drying in the order of trated hydrochloric acid were added and stirred at 180° C . with saturated brine and then with anhydrous sodium sul for 12 hours. After completion of the reaction , the reaction fate , and the solvent was evaporated under reduced pressure . mixture was left to cool to room temperature , and after The residue was purified by silica gel column chromatog addition of water 30 ml, the mixture was extracted with ethyl raphy wherein it was eluded with ethyl acetate -hexane acetate (50 mlx1) . Organic layers were combined and »35 (gradient of from 1 : 4 to 2 : 3) , to obtain 22 mg of the desired washed with water (20 mlx1 ), whereupon it was dehydrated product as white crystals. and dried in the order of with a saturated sodium chloride Melting point: 100 . 0 to 103. 0° C . solution and then with anhydrous sodium sulfate , and the ' H NMR (CDC1z , Me Si, 300 MHz ) 88. 35 (d , J= 1 .8 Hz , solvent was distilled off under reduced pressure . The residue 40 (1H )1 ,= 63 7 .45 62 - 7 . 7 21( m ), 5H2 . 06) , 6( . s70 . 3H( bs). , 1H ), 3 . 9 - 4 . 0 ( m , 2H ), 3 . 20 was purified by silica gel column chromatography wherein it was eluted with ethyl acetate - hexane ( gradient of from 2 : 8 Synthesis Example 3 to 4 : 6 ) , to obtain 0 .40 g of the desired product as a colorless oily substance . N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl] ' H NMR (CDC1z , Me. Si , 300 MHz ) 88 .44 (d , J= 2 . 1 Hz, 45 ethyl] - 2 - ( difluoromethyl) nicotinamide ( compound 1H ) , 7 .85 ( d , J = 2 . 1 Hz, 1H ) , 7 . 5 - 7 . 7 ( m , 4H ) , 6 .65 (bs , 1H ) , No. 3 - 001 of the present invention ) 3 . 95 ( q, J = 6 .0 Hz , 2H ), 3 .19 ( t, J = 6 .0 Hz, 2H ) . Step 1 : Production of tert - butyl N - [ 2 - ( 5 -bromo - 3 Step 3 : Production of N - [2 - [3 -chloro -5 -( 3, 3 -dim chloropyridin -2 -yl ) ethyl ] carbamate ethyl- 1 - butynyl) pyridin - 2 - yl] ethyl] - 2 - ( trifluorom 50 ethyl) benzamide To a 10 ml solution of 1 . 00 g of 2 - ( 5 - bromo- 3 - chloro pyridin - 2 - yl) acetonitrile in dichloromethane under a nitro To a 10 ml solution of 150 mg of N - [ 2 - ( 5 - bromo - 3 gen atmosphere, 12 ml of a 1 . 0M hexane solution of chloropyridin - 2 - yl) ethyl] - 2 - (trifluoromethyl ) benzamide , 45 diisobutylaluminum hydride was added dropwisely under mg of 3 , 3 - dimethyl- 1 - butyne and 186 mg of triethylamine in 55 stirring at - 40° C . over 30 minutes , and after completion of N , N - dimethylformamide , 25 mg of copper ( I ) iodide and 86 the dropwise addition , the mixture was stirred for 1 hour at mg of dichlorobis ( triphenylphosphine )palladium ( II ) were the same temperature . Then , the reaction mixture was added and stirred at 40° C . for 6 hours under a nitrogen warmed to room temperature and dropped into 50 ml of a atmosphere . After completion of the reaction , the reaction saturated aqueous solution of sodium potassium tartrate mixture was left to cool to room temperature , and after 60 (Rochelle salt ) under ice - cooling and stirring . After the addition of 30 ml of water, the mixture was extracted with completion of the dropping , stirring was further continued ethyl acetate (25 mlx2 ) . Organic layers were combined and for one hour at room temperature . After completion of the washed with water (20 mlx1) , whereupon it was dehydrated reaction , the mixture was extracted with dichloromethane and dried in the order of with a saturated sodium chloride (50 mlx2 ) , and organic layers were combined , and dehy solution and then with anhydrous sodium sulfate , and the 65 drated and dried in the order of with saturated brine and then solvent was distilled off under reduced pressure . The residue with anhydrous sodium sulfate , and the solvent was distilled was purified by silica gel column chromatography wherein off under reduced pressure . US 10 ,029 , 986 B2 99 100 The residue was dissolved in 20 ml of dichloromethane, N , N -dimethylformamide ( 1 :1 (volume ratio ) ) mixed sol and 1 .41 g of di -tert - butyl dicarbonate and 0 . 66 g of trieth vent, and 75 mg of 2 - ( difluoromethyl )nicotinic acid and 104 ylamine were added , followed by stirring at room tempera mg of 1 - ( 3 - dimethylaminopropyl ) - 3 - ethylcarbodiimide ture for 1 hour . After completion of the reaction , 20 ml of hydrochloride were added , followed by stirring at room water was added to the reaction mixture , followed by 5 temperature for 12 hours . After completion of the reaction . extraction with chloroform (20 mlx1) . The organic layer was washed with water ( 10 mlxl) , and then dehydrated and dried 10 ml of water was added to the reaction mixture , followed in the order of with saturated brine and then with anhydrous by extraction with ethyl acetate ( 10 mlx2 ) . Organic layers sodium sulfate , and the solvent was distilled off under were combined and washed with water ( 5 mlxl ) , and reduced pressure . The residue was purified by silica gel dehydrated and dried in the order of with a saturated sodium column chromatography wherein it was eluted with ethylthui 10 chloride solution and then anhydrous sodium sulfate , and the acetate -hexane ( gradient of from 1 : 9 to 5 : 5 ) , to obtain 615 solventwas distilled off under reduced pressure . The residue mg of the desired product as a pale yellow oily substance . was purified by silica gel column chromatography wherein ' H NMR (CDC1 , , Me Si, 300 MHz ) 88 .49 ( d , J = 1 . 8 Hz, it was eluted with ethyl acetate - hexane ( gradient of from 1 : 9 1H ), 7 .82 ( d , J = 1. 8 Hz, 1H ) , 5 .08 (bs , 1H ) , 3 . 5 - 3 .65 ( m , 2H ) , to 4 : 6 ), to obtain 70 mg of the desired product as white 3 . 06 ( t, J = 6 . 0 Hz, 2H ) , 1 .42 (s , 9H ) . 15 crystals . Step 2 : Production of tert -butyl N -[ 2 - [3 -chloro -5 Melting point: 114 . 0 to 117. 0° C . (cyclopropylethynyl ) pyridin - 2 -yl ] ethyl] carbamate " H NMR (CDC1z , Me_ Si, 300 MHz) 88 .71 (dd , = 4 . 5 , 1 . 8 Hz , 1H ), 8 .34 (d , J= 1. 8 Hz , 1H ) , 7 .86 (d , J = 7 . 8 Hz , 1H ), 7 .63 To a 6 ml solution of615 mg of tert -butyl N - [ 2 - 05 -bromo ( d , J = 1 . 8 Hz, 1H ), 7 .43 (dd , J = 7 . 8 , 1 . 8 Hz, 1H ) , 7 . 05 (bs , 3 - chloropyridin - 2 - yl )ethyllcarbamate , in N . N - dimethylfor- 20 1H ) , 6 .94 ( t, J = 54. 3 Hz, 1H ), 3 . 9 - 4 . 0 ( m , 2H ), 3 . 19 ( t , J = 6 . 3 mamide , 742 mg of triethylamine, 45 mg of cyclopropy . Hz, 2H ) , 1 .35 - 1 . 5 ( m , 1H ) , 0 .75 - 0 . 95 ( m , 4H ) . lacetylene, 105 mg of copper( I ) iodide and 128 mg of dichlorobis ( triphenylphosphine ) palladium ( II ) were added Synthesis Example 4 and stirred at room temperature for 18 hours under a nitrogen atmosphere . After completion of the reaction , 20 ml 25 N - [ 2 - [ 3 - chloro - 5 - (cyclopropylethynyl ) pyridin - 2 -yl ] of a saturated aqueous ammonium chloride solution was propyl ) - 2 - ( trifluoromethyl) benzamide (compound added to the reaction mixture , followed by extraction with No . 1 - 007 of the present invention ) ethyl acetate (15 mlx2 ). Organic layers were combined and washed with 20 ml of a saturated aqueous ammonium Step 1: Production of chloride solution and then with 20 ml of water , and then 30 2 - ( 5 -bromo - 3 - chloropyridin - 2 -yl )propanenitrile dehydrated and dried in the order of with saturated brine and then with anhydrous sodium sulfate , and the solvent was To a 20 ml solution of 1 .50 g of 2 - ( 5 -bromo - 3 - chloro distilled off under reduced pressure. The residue was puri fied by silica gel column chromatography wherein it was pyridin - 2 - yl ) acetonitrile in tetrahydrofuran , 7 ml of a 1 .0M eluted with ethyl acetate -hexane ( gradient of from 1 : 9 to 35 tetrahydrofuran solution of potassium tert- butoxide was 2 : 8 ) , to obtain 233 mg of the desired product as a pale yellow10 35 added under stirring at - 5° C ., followed by stirring at room oily substance. temperature for 2 hours . Then , 0 .97 g of iodomethane was ' H NMR (CDC1z ,Me Si, 300 MHz) 88 .36 (d , J= 1 . 8 Hz, added to this reaction mixture , and stirring was further 1H ), 7 .58 (d , J = 1 .8 Hz, 1H ), 5 .08 (bs , 1H ) , 3. 45 - 3 .6 ( m , 2H ), continued for 1 hour at room temperature . After completion 3 .05 (t , J= 6 .0 Hz, 2H ) , 1 .4 - 1. 5 ( m , 1H ), 1 .39 ( s, 9H ), of the reaction , 30 ml of water was added to the reaction 0 .75 -0 . 95 ( m , 4H ). 40 mixture , followed by extraction with ethyl acetate ( 25 mlx2 ). Organic layers were combined and washed with Step 3 : Production of 2 - [ 3 - chloro - 5 - ( cyclopropyl water ( 20 mlx1 ) , and then dehydrated and dried in the order ethynyl) pyridin -2 -yllethylamine of with a saturated sodium chloride solution and then with To a 5 ml solution of 233 mg of tert - butyl N - [ 2 - [ 3 - chloro anhydrous sodium sulfate , and the solvent was distilled off 5 - ( cyclopropylethynyl) pyridin - 2 - yl] ethyl ] carbamate in 45 under reduced pressure . The residue was purified by silica dichloromethane, 2 ml of trifluoroacetic acid was added , gel column chromatography wherein it was eluted with ethyl followed by stirring at room temperature for 2 hours . acetate -hexane ( gradient of from 5 :95 to 15 :85 ) , to obtain After completion of the reaction , the solvent was distilled 1 . 38 g of the desired product as a colorless oily substance . off under reduced pressure, and to the residue , 10 ml of a 10 ' H NMR (CDC12 , Me Si, 300 MHz) 88 .58 ( d , J = 2 . 1 Hz, wt % potassium carbonate solution was added , followed by 50 1H ), 7. 88 (d , J = 2. 1 Hz , 1H ) , 4 .43 (q , J = 7 .2 Hz, 1H ), 1. 67 (d , extraction with ethyl acetate ( 10 mlx1) . The organic layer J= 7. 2 Hz, 3H ). was dehydrated and dried in the order of with saturated brine and then with anhydrous sodium sulfate , and the solvent was Step 2 : Production of distilled off under reduced pressure to obtain 160 mg of the 2 - ( 5 - bromo - 3 - chloropyridin - 2 - yl ) - 1 - propanamine crude desired product as a brown oily substance . This To a 20 ml solution of 1 .38 g of 2 -( 5 - bromo- 3 -chloro compound was used directly in the next step without further pyridin - 2 - yl) propanenitrile in dichloromethane under a purification . nitrogen atmosphere, 16 ml of a 1 .OM hexane solution of ' H NMR (CDC1z , Me Si, 300 MHz) 88. 40 ( d , J = 1 . 8 Hz, diisobutylaluminum hydride was added dropwisely over 20 1H ), 7 .62 ( d , J= 1. 8 Hz , 1H ), 3. 0 - 3 . 2 ( m , 4H ), 1. 4 - 1. 5 (m This , 60 minutes under stirring at - 40° C . After completion of the 1H ), 0 .75 -0 .9 (m , 4H ). dropwise addition , the mixture was stirred for 1 hour at the Step 4 : Production of N - [ 2 - [ 3 - chloro - 5 - ( cyclopro same temperature . Then , the reaction mixture was warmed pylethynyl) pyridin - 2 -yllethyl )- 2 -( difluoromethyl ) to room temperature and added dropwisely to 50 ml of a nicotinamide saturated aqueous solution of sodium potassium tartrate 65 (Rochelle salt ) under ice -cooling and stirring . After comple 80 mg of 2 - [3 -chloro - 5- (cyclopropylethynyl ) pyridin - 2- tion of the dropwise addition , stirring was further continued yl] ethylamine was dissolved in 2 ml of a dichloromethane for one hour at room temperature. After completion of the US 10 , 029 , 986 B2 101 102 reaction , the reaction mixture was extracted with dichlo dichloromethane, 3 ml of trifluoroacetic acid was added , romethane ( 50 mlx2 ) , and organic layers were combined and followed by stirring at room temperature for 1 hour. After washed with water (20 mlx1) , and then , the solvent was distilled off under reduced pressure . The residue was dis completion of the reaction , the solvent was distilled off solved in 10 ml of ethyl acetate and extracted with 10 ml of 5 under reduced pressure, and to the residue , 10 ml of a a IN aqueous hydrochloric acid solution , whereupon to the saturated aqueous potassium carbonate solution was added , aqueous layer , a 10 wt % sodium hydroxide aqueous solu followed by extraction with ethyl acetate ( 10 mlx2 ) . Organic tion was added until the pH became 14 , followed by back layers were combined and washed with 10 ml of a saturated extraction with 30 ml of ethyl acetate . The organic layer was aqueous potassium carbonate solution , and then dehydrated dehydrated and dried in the order of with a saturated sodium and dried in the order of with a saturated sodium chloride chloride solution and then with anhydrous sodium sulfate , 10 solution and then with anhydrous sodium sulfate , and the and the solvent was distilled off under reduced pressure to solvent was distilled off under reduced pressure to obtain obtain 1 .04 g of the crude desired product as a reddish brown 414 mg of the crude desired product as a brown oily oily substance . This product was used directly in the next substance. This product was used directly in the next step step without further purification . without further purification . H NMR (CDC12 , Me Si, 300 MHz ) 88 . 50 ( d , J = 2 . 1 Hz, 15 H NMR (CDC12 , Me Si, 300 MHz ) 88 . 42 ( d , J = 1 . 8 Hz, 1H ), 7 . 80 ( d , J = 2 . 1 Hz, 1H ), 3 . 35 - 3 .45 ( m , 1H ), 3 .05 - 3 . 15 1H ) , 7. 60 (d , J = 1 . 8 Hz , 1H ), 3 .35 - 3 .5 (m , 1H ), 3 .05 -3 .2 (m , ( m , 1H ) , 2 . 85 - 2 . 95 ( m , 1H ) , 1 . 20 (d , J = 6 .6 Hz, 3H ). 1H ) , 2 . 8 -2 .95 (m , 1H ), 1. 35 - 1. 5 ( m , 1H ), 1. 19 (d , J= 6 .6 Hz , 3H ) , 0 .75 - 0 .95 ( m , 4H ) . Step 3 : Production of tert -butyl N - [2 - (5 -bromo -3 chloropyridin - 2 -yl ) propyl] carbamate 20 Step 6 : Production of N - [ 2 - [3 - chloro - 5 - ( cyclopro pylethynyl) pyridin - 2 - yl ] propyl ) - 2 - ( trifluoromethyl) To a 10 ml solution of 1 . 04 g of 2 - ( 5 - bromo- 3 - chloro benzamide pyridin - 2 - yl) - 1 -propanamine and 0 .63 g of triethylamine in dichloromethane , 1 .08 g of di - tert- butyl dicarbonate was To a 3 ml solution of 104 mg of 2 - [ 3 -chloro - 5 - ( cyclopro added , followed by stirring at room temperature for 1 hour . 25 pylethynyl) pyridin - 2 -yl ] - 1 - propanamine and 54 mg of tri After completion of the reaction , the solvent was distilled off ethylamine in dichloromethane , 92 mg of 2 - ( trifluorom under reduced pressure , and the residue was purified by ethyl) benzoyl chloride was added under ice - cooling and silica gel column chromatography wherein it was eluted stirring , followed by stirring at room temperature for 1 hour. with ethyl acetate - hexane ( gradient of from 5 : 95 to 15 :85 ) to After completion of the reaction , the solvent was distilled off obtain 1 .05 g of the desired product as a colorless oily 30 under reduced pressure , and the residue was purified by substance . silica gel column chromatography wherein it was eluted ' H NMR (CDC13 , Me Si, 300 MHz) 8. 51 ( d , J= 1 .8 Hz , with ethyl acetate -hexane ( gradient of from 1 :4 to 2: 3 ), to 1H ), 7 .82 (d , J = 1 . 8 Hz, 1H ), 4 . 86 (bs , 1H ) , 3 .55 - 3 . 7 ( m , 1H ) , obtain 67 mg of the desired product as a colorless resinous 3 . 4 - 3 . 5 ( m , 2H ) , 1 .41 ( s , 9H ) , 1 . 21 ( d , J = 7 . 2 Hz, 3H ) . substance . 35 H NMR ( CDC12 , Me_ Si, 300 MHz ) 88 . 32 ( d , J = 1 . 8 Hz, Step 4 : Production of tert - butyl N - [ 2 - [ 3 - chloro - 5 1H ) , 7 . 4 - 7 .65 ( m , 5H ), 6 .49 (bs , 1H ) , 3 . 8 - 3 .85 ( m , 2H ) , ( cyclopropylethynyl) pyridin - 2 - yl] propyl ] carbamate 3 . 7 - 3 . 8 ( m , 1H ) , 1 . 35 - 1 . 45 ( m , 1H ), 1 . 26 ( d , J = 6 .6 Hz, 3H ) , 0 .75 -0 . 95 (m , 4H ). To a 5 ml solution of 1 . 05 g tert - butyl N - [ 2 - ( 5 - bromo - 3 chloropyridin - 2 - yl) propyl] carbamate in N , N - dimethylfor- 40 Synthesis Example 5 mamide , 1 . 22 g of triethylamine , 238 mg of cyclopropy lacetylene , 171 mg of copper( I ) iodide and 211 mg of N - [[ 1 - [ 3 - chloro - 5 - ( cyclopropylethynyl ) pyridin - 2 -yl ] dichlorobis ( triphenylphosphine )palladium (II ) were added , cyclopropyl] methyl ] - 3 -difluoromethyl - 1 methyl- - 1H followed by stirring at room temperature for 12 hours under pyrazole -4 -carboxamide (compound No. 8 -018 of a nitrogen atmosphere . After completion of the reaction , 30 45 the present invention ) ml of a saturated aqueous ammonium chloride solution was added to the reaction mixture , followed by extraction with Step 1: Production of tert -butyl N - [[ 1 - (5 -bromo - 3 ethyl acetate ( 20 mlx2 ) . Organic layers were combined and chloropyridin - 2 - yl) cyclopropyl ]methyl ] carbamate washed with 20 ml of a saturated aqueous ammonium chloride solution and then with 20 ml of water, and then 50 To a 5 ml solution of 462 mg of [ 1 - ( 5 -bromo - 3 - chloro dehydrated and dried in the order of with a saturated sodium pyridin - 2 - yl) cyclopropyl] methylamine and 269 mg of tri chloride solution and then with anhydrous sodium sulfate , ethylamine in dichloromethane , 578 mg of di- tert -butyl and the solvent was distilled off under reduced pressure. The dicarbonate was added , followed by stirring at room tem residue was purified by silica gel column chromatography perature for 1 hour. After completion of the reaction , 10 ml wherein it was eluted with ethyl acetate -hexane ( gradient of 55 of water was added to the reaction mixture , followed by from 1 : 9 to 2 : 8 ) , to obtain 871 mg of the desired product as extraction with dichloromethane ( 10 mlx2 ) . Organic layers a brown oily substance . were combined , and dehydrated and dried in the order of ' H NMR (CDC1z , Me Si, 300 MHz ) 8 .41 ( d , J = 1 . 8 Hz , with a saturated sodium chloride solution and then with 1H ) , 7 .61 ( d , J = 1 . 8 Hz, 1H ) , 4 .89 (bs , 1H ), 3 .55 - 3 . 7 ( m , 1H ) , anhydrous sodium sulfate , and the solvent was distilled off 3 . 45 ( t, J = 6 . 3 Hz, 2H ), 1 . 35 - 1 . 5 ( m , 10H ), 1 .21 ( d , J = 6 . 9 Hz, 60 under reduced pressure . The residue was purified by silica 3H ) , 0 . 75 - 0 . 95 ( m , 4H ) . gel column chromatography wherein it was eluted with ethyl acetate -hexane ( gradient of from 1 : 9 to 3 : 7 ) , to obtain 498 Step 5 : Production of 2 - [ 3 - chloro - 5 - (cyclopropyl mg of the desired product as white crystals . ethynyl) pyridin - 2 -yl ] - 1 -propanamine Melting point: 81 . 0 to 82 . 0° C . 65 H NMR (CDC12 , Me . Si, 300 MHz ) 88 .47 ( d , J = 2 . 1 Hz, To a 5 ml solution of 871 mg of tert -butyl N - [2 - [3 -chloro - 1H ) , 7 .83 (d , J= 2 . 1 Hz, 1H ), 4 .78 (bs , 1H ), 3 .38 (d , J = 6 .0 Hz, 5 -( cyclopropylethynyl ) pyridin - 2 -yl ) propyl ] carbamate in 2H ), 1 .33 (s , 9H ), 0 .9 - 1. 05 ( m , 4H ). US 10 ,029 , 986 B2 103 104 Step 2 : Production of tert- butyl N - [ [ 1 - [ 3 - chloro - 5 gel column chromatography wherein it was eluted with ethyl (cyclopropylethynyl ) pyridin - 2 -yl ] cyclopropyl ] acetate -hexane ( gradient of from 1 : 9 to 3 : 7 ) , to obtain 23 mg methyl] carbamate of the desired product as a colorless resinous substance . ' H NMR (CDC1z , Me Si, 300 MHz) 88 . 35 ( d , J = 1 . 8 Hz, To a 3 ml solution of 498 mg of tert- butyl N - [[ 1 - ( 5 - 5 1H ), 7 . 76 ( s , 1H ) , 7 .61 ( d , J = 1 . 8 Hz, 1H ), 6 . 86 (t , J = 54 . 3 Hz, bromo - 3 - chloropyridin - 2 - yl ) cyclopropyl ]methyl ] carbamate 1H ) , 6 . 46 ( bs , 1H ) , 3 .89 (s , 3H ) , 3 .63 ( d , J = 5 . 4 Hz, 2H ) , in N ,N - dimethylformamide, 557 mg of triethylamine , 110 1 .35 -1 .5 (m , 1H ), 1. 0 - 1 .1 (m , 4H ), 0 .75 -0 .95 ( m , 4H ). mg of cyclopropylacetylene, 79 mg of copper( I ) iodide and 97 mg of dichlorobis ( triphenylphosphine )palladium ( II ) Synthesis Example 6 were added , followed by stirring at room temperature for 12 10 hours under a nitrogen atmosphere . After completion of the N - [ 2 - [ 3 - chloro - 5 -( 1 -propynyl ) pyridin - 2 - yl] - 2 - prope reaction , 15 ml of a saturated aqueous ammonium chloride nyl] - 2 - (trifluoromethyl ) benzamide ( compound No. solution was added to the reaction mixture , followed by 1 -012 of the present invention ) extraction with ethyl acetate ( 15 mlx2 ) . Organic layers were combined and washed with 10 ml of water, and then 15 Step 1 : Production of dehydrated and dried in the order of with a saturated sodium 1 - ( 5 - bromo- 3 - chloropyridin - 2 - yl) ethanone chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure . The To a 15 ml solution of 3 . 0 g of 5 -bromo - 3 - chloropyridine residue was purified by silica gel column chromatography 2 -carbonitrile in toluene, 4 . 8 ml of a 3M diethyl ether wherein it was eluted with ethyl acetate- hexane ( gradient of 20 solution of methylmagnesium bromide was added drop from 1: 9 to 2 : 8 ), to obtain 334 mg of the desired product as wisely under ice - cooling and stirring , followed by stirring a pale yellow oily substance. for 0 . 5 hours at the same temperature . After completion of H NMR (CDC1z , Me Si, 300 MHz ) 88 . 36 ( d , J = 1 . 8 Hz , the reaction , the reaction mixture was poured into 20 ml of 1H ) , 7 .60 ( d , J = 1 . 8 Hz, 1H ) , 4 . 75 (bs , 1H ), 3 . 36 ( d , J = 5 . 4 Hz, 4N hydrochloric acid under ice - cooling and stirring , fol 1H ), 1 .4 -1 . 5 ( m , 1H ), 1. 32 (s , 9H ), 0 .75 - 1. 05 ( m , 8H ). 25 lowed by extraction with toluene ( 30 mlx2 ). Organic layers were combined , and then dehydrated and dried in the order Step 3 : Production of [ 1 - [ 3 -chloro - 5 - ( cyclopropyl of with a saturated sodium chloride solution and then with ethynyl) pyridin - 2 - yl] cyclopropyl ]methylamine anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure to obtain 2 . 7 g of the crude desired To a 5 ml solution of 334 mg of tert -butyl N - [ [ 1 - [ 3 - 30 product as brown crystals . This product was used directly in chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl] cyclopropyl] the next step without further purification . methyl] carbamate in dichloromethane , 2 ml of trifluoro - Melting point: 78 . 0 to 79 .0° C . acetic acid was added , followed by stirring for 2 hours at H NMR (CDC12 , Me Si, 300 MHz ) 88 .58 ( d , J = 1 . 8 Hz, room temperature . After completion of the reaction , the 1H ) , 7 . 97 ( d , J = 1 . 8 Hz, 1H ) , 2 .67 ( s , 3H ) . solvent was distilled off under reduced pressure , and to the 35 residue , 10 ml of a saturated aqueous potassium carbonate Step 2 : Production of solution was added , followed by extraction with ethyl 2 -bromo - 1 - ( 5 -bromo - 3 - chloropyridin -2 -yl ) ethanone acetate ( 10 mlx1 ) . The organic layer was washed with a saturated aqueous potassium carbonate solution ( 10 mlx2 ), To a 8 ml solution of 1 . 60 g of 1 - ( 5 - bromo- 3 - chloropyri and then dehydrated and dried in the order of with a 40 din - 2 - yl) ethanone in toluene , 5 . 5 ml of a 30 % hydrogen saturated sodium chloride solution and then with anhydrous bromide acetic acid solution was added , and 1 . 28 g of sodium sulfate , and the solvent was distilled off under bromine was added dropwisely under ice -cooling and stir reduced pressure , to obtain 230 mg of the crude desired ring . After stirring 18 hours at room temperature , 0 . 62 g of product as a pale yellow oily substance . This product was bromine was added , and further 2 .5 hours later, 0 . 31 g of used directly in the next step without further purification . 45 bromine was added again , followed by continuously stirring ' H NMR ( CDC1z , Me. Si, 300 MHz ) 88 .41 ( d , J= 1. 8 Hz, for 3 hours . After completion of the reaction , 50 ml ofwater 1H ) , 7 .63 ( d , J = 1 . 8 Hz , 1H ) , 2 . 93 (bs , 2H ) , 1 . 3 - 1 . 5 ( m , 1H ), was added to the reaction mixture , followed by extraction 1 . 33 (bs , 2H ) , 0 . 75 - 1 . 0 ( m , 8H ) . with toluene (50 mlx2 ) . Organic layers were combined and washed with 100 ml of water and then with 100 ml of a Step 4 : Production of N - [ [ 1 - [ 3 -chloro - 5 - ( cyclopro 50 saturated aqueous sodium bisulfite solution , and then dehy pylethynyl ) pyridin - 2 - yl] cyclopropyl) methyl ) - 3 - dif drated and dried in the order of with a saturated sodium luoromethyl - 1 -methyl - 1H -pyrazole - 4 -carboxamide chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure . To 115 mg of [ 1 - [ 3 -chloro - 5 - (cyclopropylethynyl ) pyridin - 2 - the residue , 20 ml ofheptane was added , followed by stirring yl] cyclopropyl] methylamine was dissolved in 3 ml of a 55 for 30 minutes under ice - cooling , whereupon the precipi dichloromethane - N , N - dimethylformamide ( 2 : 1 ) mixed sol- tated solid was filtered to obtain 1. 7 g of the desired product vent, and 99 mg of 3 - difluoromethyl - 1 -methyl - 1H -pyrazole - as white crystals . 4 -carboxylic acid and 135 mg of 1 - ( 3 - dimethylaminopro Melting point: 58. 0 to 62 . 0° C . pyl) - 3 -ethylcarbodiimide hydrochloride were added , 'H NMR (CDC1z , Me, Si, 300 MHz) 88 .60 (d , J= 2. 1 Hz , followed by stirring at room temperature for 12 hours . After 60 1H ) , 8 .02 ( d , J = 2 . 1 Hz, 1H ), 4 .76 ( s , 2H ) . completion of the reaction , 10 ml of water was added to the reaction mixture , followed by extraction with ethyl acetate Step 3 : Production of N - [ 2 - ( 5 -bromo - 3 - chloropyri ( 10 mlx2 ) . Organic layers were combined and washed with din - 2 -yl )- 2 -oxoethyl ] phthalimide water ( 10 mlxl ), and then dehydrated and dried in the order of with a saturated sodium chloride solution and then with 65 To a 30 ml solution of 3 . 0 g of potassium phthalimide in anhydrous sodium sulfate , and the solvent was distilled off dimethyl sulfoxide , a 20 ml solution of 5 . 1 g of 2 -bromo under reduced pressure. The residue was purified by silica 1 -( 5 -bromo - 3 - chloropyridin - 2 -yl ) ethanone in dimethyl sul US 10 , 029 , 986 B2 105 106 foxide was added dropwisely . After completion of the reac in dichloromethane, 283 mg of 2 - ( trifluoromethyl) benzoyl tion , 50 ml of water was added to the reaction mixture , chloride was added dropwisely under ice -cooling and stir followed by extraction with ethyl acetate ( 100 mlx2 ) . ring. After completion of the dropwise addition , stirring was Organic layers were combined and washed with water ( 100 mlx1) , and then dehydrated and dried in the order of with a 5 continued at room temperature for additional 1 . 5 hours . saturated sodium chloride solution and then with anhydrous 5 After completion of the reaction , 15 ml of water was added sodium sulfate , and the solvent was distilled off under to the reaction mixture, followed by extraction with dichlo reduced pressure , to obtain 4 .5 g of the crude desired product romethane ( 20 mlx1 ) . Thereafter, the organic layer was as yellow crystals . This product was used directly in the next dehydrated and dried in the order of with a saturated aqueous step without further purification . sodium chloride solution and then with anhydrous sodium Melting point: 62 . 0 to 68 . 0° C . sulfate , and the solvent was distilled off under reduced ' H NMR (CDC12 , Me Si, 300 MHz ) 88 .67 ( d, J= 1. 8 Hz , pressure . The residue was purified by silica gel column 1H ), 8 .03 (d , J = 1 .8 Hz, 1H ) , 7. 7 - 7 .95 ( m , 4H ), 5 .28 (s , 2H ). chromatography wherein it was eluted with ethyl acetate hexane ( 1 : 9 ) , to obtain 240 mg of the desired product as pale Step 4 : Production of N - [ 2 - ( 5 -bromo - 3 - chloropyri yellow crystals . din -2 - yl) - 2 -propenyl ] phthalimide 15 Melting point: 49 .0 to 53 . 0° C . ' H NMR (CDC1z , Me Si, 300 MHz ) 88 .50 (d , J= 2 . 1 Hz, To a 100 ml solution of 2 . 20 g of N - [ 2 - ( 5 - bromo - 3 1H ) , 7 . 93 ( d , J = 2 . 1 Hz, 1H ), 7 .45 - 7 . 7 ( m , 4H ), 6 . 43 ( bs, 1H ) , chloropyridin - 2 - yl) -2 -oxoethyl ]phthalimide , 2 .34 g ofmeth - 5 .90 ( s, 1H ), 5 .83 ( s, 1H ), 4 .49 ( d , J = 5 .7 Hz , 2H ) . yltriphenylphosphonium iodide and 0 .01 g of crown ether ( 18 - Crown - 6 ) in toluene , 0 .65 g of potassium tert - butoxide 20 Step 7 : Production of N - [ 2 - [ 3 - chloro - 5 - ( 1 - propynyl) was added , followed by stirring under heating and refluxing . pyridin - 2 - yl) - 2 - propenyl ] - 2 - ( trifluoromethyl ) benz After 4 hours , 2 . 34 g ofmethyltriphenylphosphonium iodide and 0 .65 g of potassium tert -butoxide were added to the amide reaction mixture , and stirring was further continued under heating and refluxing for one hour. After completion of the To a 23 ml solution of 543 mg of zinc ( II ) bromide in reaction , the solvent was distilled off under reduced presde 25 tetrahydrofuran under a nitrogen atmosphere, 4 . 4 ml of a sure , and 200 ml of water and 200 ml of ethyl acetate were 0 . 5M tetrahydrofuran solution of 1 - propynylmagnesium added to the residue , whereupon the organic layer was bromide was added dropwisely under ice- cooling and stir separated . The organic layer was washed with water (50 ring, followed by stirring for 10 minutes at the same mlxl) , and then dehydrated and dried in the order of with a temperature . Then , to this reaction mixture, a 5 ml solution saturated sodium chloride solution and thenen with anhydrous 30 of 230 mg of N -[ 2 -( 5 -bromo - 3 -chloropyridin -2 -yl ) - 2 -prope sodium sulfate, and the solvent was distilled off " under nyl] - 2 - (trifluoromethyl ) benzamide in tetrahydrofuran and reduced pressure . The residue was purified by silica gel 45 mg of dichloro [ 1 , 1' - bis (diphenylphosphino )ferrocene ] column chromatography wherein it was eluted with ethyl palladium ( II) were added , and stirring was continued at acetate- hexane (gradient of from 1: 9 to 2 : 8 ) , to obtain 0 .83 room temperature for 2 . 5 hours . After completion of the g of the desired product as yellow crystals . 35 reaction , the reaction mixture was poured into 40 ml of a IN Melting point: 63 . 0 to 67 .0° C . aqueous hydrochloric acid solution under ice - cooling and ' H NMR (CDC1z , Me. Si, 300 MHz ) 8 .50 ( d , J = 2 . 1 Hz , stirring , followed by extraction with ethyl acetate (50 mlx2 ) . 1H ), 7 .87 (d , J = 2 . 1 Hz, 1H ) , 7 .65 - 7 .9 (m , 4H ), 5 .66 (s , 1H ), Organic layers were combined , and dehydrated and dried in 5 . 63 ( s , 1H ) , 4 .73 (s , 2H ) . the order of with a saturated sodium chloride solution and 40 then with anhydrous sodium sulfate , and the solvent was Step 5 : Production of distilled off under reduced pressure . The residue was puri 2 -( 5 -bromo -3 - chloropyridin - 2 -yl ) -2 -propenylamine fied by silica gel column chromatography wherein it was To a 8 ml toluene / 0 . 5 ml ethanol solution of 830 mg of eluted with ethyl acetate -hexane ( gradient of from 1 : 9 to N - [ 2 -( 5 - bromo- 3 - chloropyridin - 2 - yl) - 2 - propenyl] phthalim 2 : 8 ), to obtain 180 mg of the desired product as a brown ide, 1 .70 g of a 40 wt % aqueous methylamine solution was 45 solid . added under ice -cooling and stirring, followed by stirring at Melting point : 85 . 0 to 90 .0° C . room temperature for 8 hours. After completion of the ' H NMR (CDC12 , Me Si, 300 MHz ) 88 .41 ( d , J = 2 . 1 Hz, reaction , 10 ml of water was added to the reaction mixture , 1H ), 7 .72 ( d , J = 2 . 1 Hz, 1H ) , 7 .4 - 7 .7 (m , 4H ), 6 .53 (bs , 1H ), and concentrated hydrochloric acid was added dropwisely 5. 88 (s , 1H ), 5 .84 (s , 1H ), 4 .49 (d , J= 5 .7 Hz, 2H ), 2 .08 (s , under ice - cooling and stirring until the pH became 1 . Then , 30 3H ) . the aqueous layer was separated , and after addition of sodium carbonate until the pH became from 13 to 14 , the Synthesis Example 7 mixture was extracted with ethyl acetate ( 50 mlx2 ) . Organic layers were combined , and dehydrated and dried in the order N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl] of with a saturated sodium chloride solution and then with 55 2 -propenyl ] - 3 - difluoromethyl - 1 -methyl - 1H -pyra anhydrous sodium sulfate , and the solvent was distilled off zole - 4 -carboxamide (compound No . 8 - 011 of the under reduced pressure to obtain 280 mg of the crude desired present invention ) product as a yellow oily substance . This product was used directly in the next step without further purification . Step 1 : Production of N - [ 2 - [ 3 - chloro - 5 - (cyclopro H NMR (CDC12 , Me Si, 300 MHz ) 88 . 5 - 8 . 6 ( m , 1H ) , 60 pylethynyl) pyridin - 2 - yl] - 2 - oxoethyl] phthalimide 7. 85 -7 .95 (m , 1H ), 5. 65 ( s, 1H ) , 5 .49 (s , 1H ), 3 .71 (s , 2H ). To a 5 ml solution of 300 mg of N - [ 2 - ( 3 , 5 - dichloropyri Step 6 : Production of N - [ 2 - ( 5 - bromo - 3 - chloropyri din - 2 - yl ) - 2 -oxoethyl ] phthalimide in N , N -dimethylforma din - 2 - yl) - 2 -propenyl ] - 2 - ( trifluoromethyl) benzamide mide , 181 mg of triethylamine , 70 mg of cyclopropylacety 65 lene , 25 mg of copper( I) iodide and 31 mg of dichlorobis To a 3 ml solution of 280 mg of 2 - ( 5 -bromo - 3 -chloro - ( triphenylphosphine) palladium ( II ) were added , followed by pyridin - 2 -yl ) - 2 -propenylamine and 228 mg of triethylamine stirring at 50° C . for 8 hours under a nitrogen atmosphere. US 10 ,029 , 986 B2 107 108 After completion of the reaction , the reaction mixture was Step 4 : Production of N - [ 2 - [3 - chloro - 5 - ( cyclopro left to cool to room temperature , and 30 ml of water and 30 pylethynyl) pyridin - 2 -yl ] - 2 -propenyl ] - 3 -difluorom ml of ethyl acetate were added , followed by filtration ethyl- 1 -methyl - 1H - pyrazole -4 - carboxamide through Celite , whereupon the organic layer was separated , and the aqueous layer was extracted with ethyl acetate ( 50 5 To a 2 ml solution of 88 mg of 3 - difluoromethyl - 1 mlx2 ) . Organic layers were combined and washed with methyl- 1H -pyrazole - 4 - carboxylic acid in dichloromethane , water ( 30 mlx1 ) , and then dehydrated and dried in the order 10 mg of N , N -dimethylformamide and 76 mg of oxalyl of with a saturated sodium chloride solution and then with chloride were added , followed by stirring at room tempera anhydrous sodium sulfate , and the solvent was distilled off ture for 30 minutes . After completion of the reaction , the under reduced pressure . The residue was purified by silica 10 solvent was distilled off under reduced pressure , and the gel column chromatography wherein it was eluted with ethyl residue was dissolved in 1 ml of dichloromethane, and added acetate -hexane ( gradient of from 0 : 10 to 2 : 8 ) , to obtain 260 dropwisely to a 2 ml solution of 90 mg of 2 - [ 3 - chloro - 5 mg of the desired product as pale yellow crystals . (cyclopropylethynyl ) pyridin - 2 - yl ) - 2 - propenylamine and 117 mg of triethylamine in dichloromethane under ice Melting point: 156 .0 to 160 .0° C . 15 cooling and stirring . After stirring at the same temperature 'H NMR (CDC1z , Me Si, 300 MHz) 88. 53 (d , J= 1 .7 Hz , for 30 minutes , 10 ml of water was added to the reaction 1H ), 7 .85 -7 .95 (m , 2H ), 7 .7 -7 . 8 (m , 3H ), 5. 32 (s , 2H ), mixture , followed by extraction with dichloromethane ( 20 1 .45 - 1 .6 ( m , 1H ) , 0 . 85 - 1 . 05 ( m , 4H ). mlx1) . The organic layer was dehydrated and dried in the order of with a saturated sodium chloride solution and then Step 2: Production of N - [2 - [ 3 -chloro - 5 -( cyclopro 20 with anhydrous sodium sulfate , and the solvent was distilled pylethynyl) pyridin - 2 - yl) - 2 -propenyl ] phthalimide off under reduced pressure . The residue was purified by silica gel column chromatography wherein it was eluted To a 60 ml solution of 1 .03 g of N -[ 2 -[ 3 - chloro -5 with ethyl acetate -hexane ( gradient of from 1 : 9 to 4 : 6 ) , to ( cyclopropylethynyl) pyridin - 2 -yl ] - 2 -oxoethyl ] phthalimide , obtain 81 mg of the desired product as white crystals . 2 . 17 g of methyltriphenylphosphonium iodide and 0 . 071 g 25 Melting point: 66 . 0 to 70 .0° C . of crown ether ( 18 - Crown - 6 ) in toluene , 0 .60 g of potassium lH NMR (CDC1 , Me Si, 300 MHz ) 88 .43 ( d , J = 1 . 8 Hz, tert- butoxide was added , followed by stirring for 2 . 5 hours 1H ) , 7 . 87 (s , 1H ), 7 .68 ( d , J = 1 . 8 Hz, 1H ) , 6 . 93 (bs , 1H ) , 6 . 80 under heating and refluxing . After completion of the reac - (t , J= 54 .6 Hz, 1H ), 5 .79 (s , 1H ), 5. 76 (s , 1H ), 4. 45 (d , J= 6 . 0 tion , the solvent was distilled off under reduced pressure , Hz, 2H ) , 3 . 91 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 75 - 0 . 95 ( m , 4H ) . and to the residue , 100 ml of water and 100 ml of ethyl 30 acetate were added , whereupon the organic layer was sepa Synthesis Example 8 rated , and the aqueous layer was extracted with ethyl acetate ( 100 mlx2 ) . Organic layers were combined , and dehydrated N - [ 2 - [ 3 - chloro - 5 - (cyclopropylethynyl ) pyridin - 2 -yl ) and dried in the order of with a saturated sodium chloride 2 -methylpropyl ] - 2 - ( difluoromethyl) nicotinamide solution and then with anhydrous sodium sulfate , and the 35 (compound No. 3 - 007 of the present invention ) solvent was distilled off under reduced pressure . The residue was purified by silica gel column chromatography wherein Step 1 : Production of 2 - ( 5 - bromo- 3 -chloropyridin it was eluted with ethyl acetate -hexane ( gradient of from 1 : 9 2 - yl) - 2 -methylpropanenitrile to 4 :6 ) , to obtain 0 . 30 g of the desired product as a brown resinous substance . 40 To a 20 ml solution of 1. 50 g of 2 - (5 -bromo -3 -chloro ' H NMR (CDC1z , Me_ Si, 300 MHz) 88 . 40 ( d , J = 1 . 5 Hz , pyridin - 2 - yl) acetonitrile in tetrahydrofuran , 13 . 6 ml of a 1H ) , 7 . 5 - 7 . 9 ( m , 5H ) , 5 .62 ( s , 1H ) , 5 .60 ( s , 1H ) , 4 .74 ( s , 2H ) , 1 .0M tetrahydrofuran solution of potassium tert -butoxide 1 . 35 - 1 .55 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . was added under stirring at - 5° C . , followed by stirring for 10 minutes at the same temperature . Then , 1 . 94 g of Step 3 : Production of 2 - [ 3 - chloro - 5 - ( cyclopropyl- 45 iodomethane was added to the reaction mixture, and stirring ethynyl) pyridin -2 - yl) - 2 -propenylamine was continued at room temperature for 1 hour. After comple tion of the reaction , 30 mlof water was added to the reaction To a 3 ml solution of 300 mg N - [ 2 - [ 3 -chloro - 5 - cyclo - mixture , followed by extraction with ethyl acetate ( 25 propylethynyl) pyridin - 2 -yl ) - 2 - propenyl] phthalimide in mlx2 ) . Organic layers were combined and washed with toluene , 615 mg of a 40 wt % aqueous methylamine solution 50 water (20 mlx1) , and then dehydrated and dried in the order was added under ice - cooling and stirring , followed by of with a saturated sodium chloride solution and then with stirring at room temperature for 19 hours. After completion anhydrous sodium sulfate , and the solvent was distilled off of the reaction , 10 ml of water was added to the reaction under reduced pressure. The residue was purified by silica mixture , and concentrated hydrochloric acid was added gel column chromatography wherein it was eluted with ethyl dropwisely until the pH became 1 under ice -cooling and 55 acetate -hexane ( gradient of from 0 : 10 to 1 : 9 ), to obtain 1. 61 stirring . The aqueous layer was separated , and after addition g of the desired product as a colorless oily substance . of sodium carbonate until the pH became from 13 to 14 , it ? H NMR (CDC12 , Me Si, 300 MHz ) 88 .45 ( d , J = 2 . 0 Hz, was extracted with ethyl acetate (40 mlx2 ). Organic layers 1H ), 7 .84 (d , J= 2 .0 Hz , 1H ) , 1 .76 ( s, 6H ) . were combined , and dehydrated and dried in the order of with a saturated sodium chloride solution and then with 60 Step 2 : Production of 2 - ( 5 -bromo - 3 - chloropyridin anhydrous sodium sulfate , and the solvent was distilled off 2 - yl) - 2 -methyl - 1 - propanamine under reduced pressure to obtain 90 mg of the crude desired product as a brown oily substance . This product was used To a 15 ml solution of 1 .61 g of 2 - ( 5 -bromo - 3 - chloro directly in the next step without further purification . pyridin - 2 - yl) - 2 -methylpropanenitrile in dichloromethane ' H NMR (CDC1z , Me_ Si, 300 MHz) 88 .43 ( d , J = 1 . 5 Hz , 65 under a nitrogen atmosphere , 18 . 5 ml of a 1 .0M hexane 1H ), 7 .68 ( d , J = 1 . 5 Hz, 1H ) , 5 .61 ( s , 1H ) , 5 .47 ( s , 1H ) , 3 .70 solution of diisobutylaluminum hydride was added drop ( bs , 2H ) , 1 . 4 - 1 .6 ( m , 1H ) , 0 .75 - 1 . 0 ( m , 4H ) . wisely under stirring at - 40° C . over 20 minutes, and after US 10 ,029 , 986 B2 109 110 completion of the dropwise addition , stirring was continued Step 5 : Production of 2 - [ 3 - chloro - 5 - (cyclopropyl at the same temperature for 15 minutes . After completion of ethynyl) pyridin - 2 -yl ) - 1- propanamine the reaction , to the reaction mixture , 30 ml of water was added dropwisely , followed by stirring at the same tempera To a 1 ml solution of 770 mg of tert -butyl N - [ 2 - [ 3 - chloro ture for 30 minutes, and then , the temperature was raised to 5 5 - ( cyclopropylethynyl) pyridin - 2 - yl] - 2 -methylpropyl ] car roomro temperature , whereupon 15 ml of dichloromethane bamate in chloroform , 1 ml of trifluoroacetic acid was and 6 .70 g of sodium potassium tartrate (Rochelle salt ) were added , followed by stirring at 40° C . for 2 hours. After added , and stirring was further continued at room tempera completion of the reaction , the solvent was distilled off ture for 3 hours . The organic layer was separated , and the under reduced pressure , and to the residue , 10 ml of a aqueous layer was extracted with dichloromethane (50 10 saturated aqueous potassium carbonate solution was added , mlx2 ) . Organic layers were combined and washed with followed by extraction with ethyl acetate ( 10 mlx2 ). Organic water ( 20 mlxl ), and then dehydrated and dried in the order layers were combined and washed with 10 ml of a saturated of with a saturated sodium chloride solution and then with aqueous potassium carbonate solution , and then dehydrated anhydrous sodium sulfate , and the solvent was distilled off and dried in the order of with a saturated sodium chloride under reduced pressure , to obtain 1. 54 g of the crude desired 15 solution and then with anhydrous sodium sulfate , and the product as a brown oily substance . This product was used solvent was distilled off under reduced pressure to obtain directly in the next step without further purification . 593 mg of the crude desired product as a brown oily H NMR (CDC1z , Me . Si, 300 MHz) 88 . 44 (d , J = 2 .1 Hz, substance . This product was used directly in the next step 1H ), 7 .74 (d , J = 2 . 1 Hz, 1H ), 3. 90 (bs , 2H ) , 3 . 10 ( s , 2H ), 1 .44 without further purification . ( s , 6H ) . 20 H NMR ( CDC12 , Me. Si, 300 MHz) 88 . 37 ( d , J = 1 . 8 Hz, Step 3 : Production of tert- butyl N - [ 2 - ( 5 - bromo - 3 1H ) , 7 .61 ( d , J = 1 . 8 Hz, 1H ), 3 .32 (bs , 2H ) , 3 . 13 (bs , 2H ) , chloropyridin - 2 -yl ) -2 -methylpropyl ] carbamate 1 .35 - 1 .5 (m , 1H ) , 1 . 47 (s , 6H ) , 0 .75 - 1 .0 ( m , 4H ) . To a 15 ml solution of 1 .54 g of 2 - ( 5 -bromo - 3 - chloro Step 6 : Production of N - [ 2 - [ 3 - chloro - 5 - ( cyclopro pyridyn - 2 - yl) - 2 -methyl - 1 - propanamine and 1 .60 ml of tri - > > pylethynyl) pyridin - 2 - yl] - 2 -methylpropyl ) -2 - (difluo ethylamine in dichloromethane , 1 . 50 g of di -tert - butyl dicar romethyl) nicotinamide bonate was added , followed by stirring at room temperature for 1 hour. After completion of the reaction , 10 ml of water To a 4 ml solution of 200 mg of 2 - [ 3 - chloro - 5 - ( cyclopro was added to the reaction mixture , followed by extraction pylethynyl) pyridin - 2 - yl) - 1 - propanamine and 163 mg of tri with ethyl acetate (20 mlx2 ) . Organic layers were combined , 30 ethylamine in dichloromethane, 185 mg of 2 -( difluorom and dehydrated and dried in the order of with a saturated ethyl) nicotinyl chloride was added under ice - cooling and sodium chloride solution and then with anhydrous sodium stirring , followed by stirring at room temperature for 1 hour. sulfate , and the solvent was distilled off under reduced After the completion of the reaction , 10 ml of water was pressure . The residue was purified by silica gel column added to the reaction mixture , followed by extraction with chromatography wherein it was eluted with ethyl acetate 35 ethyl acetate ( 10 mlx2 ) . Organic layers were combined , and hexane ( gradient of from 0 : 10 to 3 : 7 ) , to obtain 911 mg of then dehydrated and dried in the order of with a saturated sodium chloride solution and then with anhydrous sodium the desired product as a yellow oily substance . sulfate , and the solvent was distilled off under reduced ' H NMR (CDC1z , Me Si, 300 MHz) 88 .45 (d , J= 2 . 0 Hz, pressure . The residue was purified by silica gel column 1H ), 7 .80 ( d, J= 2. 0 Hz, 1H ), 5. 41 (bs , 1H ), 3 .54 ( d, J= 6 . 5 Hz ', 40 chromatography wherein it was eluted with ethyl acetate 2H ), 1 .47 ( s , 6H ) , 1 . 42 ( s , 9H ) . hexane (gradient of from 1: 9 to 4 : 6 ), to obtain 238 mg of the Step 4 : Production of tert -butyl N -[ 2 - [3 -chloro -5 desired product as a colorless resinous substance . ( cyclopropylethynyl) pyridin - 2 -yl ] - 2 -methylpropyl ] H NMR (CDC12 , Me Si, 300 MHz ) 88 .71 ( d , J = 4 . 4 Hz , carbamate 1H ) , 8 .31 ( d , J = 2 . 0 Hz, 1H ) , 7 . 86 ( d , J = 8 . 2 Hz, 1H ) , 7 .63 ( d , 45 J = 2 . 0 Hz, 1H ) , 7 . 43 ( dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 7 . 35 ( bs , 1H ) , To a 2 . 5 ml solution of 911 mg of tert -butyl N - [ 2 - (5 - 6 .99 ( t , J = 58 . 2 Hz, 1H ) , 3 . 86 ( d , J = 6 . 5 Hz, 2H ), 1 .55 ( s , 6H ) , bromo - 3 -chloropyridin - 2 - yl) - 2 -methylpropyl ] carbamate in 1 . 35 - 1 . 55 ( m , 1H ), 0 .75 - 1. 0 ( m , 4H ). N , N -dimethylformamide , 1 . 7 ml of triethylamine, 248 mg of cyclopropylacetylene, 143 mg of copper ( I ) iodide and 175 Synthesis Example 9 mg of dichlorobis ( triphenylphosphine )palladium ( II ) were 50 added , followed by stirring at 50° C . for 1 hour under a N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl ] nitrogen atmosphere. After completion of the reaction , 30 ml 2 , 2 - difluoroethyl )- 2 - (difluoromethyl ) nicotinamide of a saturated aqueous ammonium chloride solution was ( compound No. 3 -003 of the present invention ) added to the reaction mixture , followed by extraction with ethyl acetate (20 mlx2 ) . Organic layers were combined and 55 Step 1 : Production of 2 - ( 5 -bromo - 3 -chloropyridin washed with 20 ml of water, and then dehydrated and dried 2 - yl) - 2 , 2 - difluoroacetonitrile in the order of with a saturated sodium chloride solution and then with anhydrous sodium sulfate , and the solvent was To a 40 ml solution of 2 .00 g of 2 - ( 5 -bromo - 3 - chloro distilled off under reduced pressure . The residue was puri- pyridin - 2 - yl ) acetonitrile in tetrahydrofuran , 16 ml of a 1 . 3M fied by silica gel column chromatography wherein it was 60 tetrahydrofuran solution of lithium bis ( trimethylsilyl) amide eluted with ethyl acetate -hexane ( gradient of from 0 : 10 to was added dropwisely under stirring at - 78° C . , and after the 1 : 9 ) , to obtain 770 mg of the desired product as a brown oily completion of the addition , stirring was continued for 30 substance . minutes at the same temperature . Then , to this reaction ' H NMR (CDC13 , Me Si, 300 MHz) 88 . 36 ( d , J = 1 . 8 Hz, mixture, a 25 ml solution of 6 . 00 g of N - fluorobenzenesul 1H ) , 7 .60 ( d , J = 1 . 8 Hz, 1H ) , 5 . 45 (bs , 1H ) , 3 . 53 ( d , J = 6 . 7 Hz, 65 fonimide in tetrahydrofuran was added dropwisely , and after 2H ) , 1 . 35 - 1 . 5 ( m , 1H ) , 1 .45 ( s , 6H ) , 1 .42 ( s , 9H ) , 0 .75 - 1 . 0 completion of the addition , stirring was further continued at ( m , 4H ) . the same temperature for 3 hours. After completion of the US 10 , 029 , 986 B2 111 112 reaction , 50 ml of water was added to the reaction mixture , ethyl acetate ( 15 mlx2 ) . Organic layers were combined and followed by extraction with hexane (50 mlx3 ) . Organic washed with water ( 10 mlx2 ) , and then dehydrated and dried layers were combined and washed with water ( 50 mlxl ) , and in the order of with a saturated sodium chloride solution and then dehydrated and dried in the order of with a saturated then with anhydrous sodium sulfate , and the solvent was sodium chloride solution and then with anhydrous sodium 5 distilled off under reduced pressure . The residue was puri sulfate , and the solvent was distilled off under reduced fied by silica gel column chromatography wherein it was pressure. The residue was purified by silica gel column eluted with ethyl acetate -hexane ( gradient of from 3 : 97 to chromatography wherein it was eluted with ethyl acetate 10 : 90 ) , to obtain 340 mg of the desired product as a pale hexane ( gradient of from 0 : 100 to 5 : 95 ) , to obtain 0 . 81 g of yellow oily substance . the desired product as a pale yellow oily substance . 1 H NMR (CDC13 , Me Si, 300 MHz) 88. 40 (d , J= 1. 8 Hz , ' H NMR ( CDC12 , Me_ Si, 300 MHz ) 88 .66 ( d , J = 2 . 1 Hz, 1H ), 7 .74 (d , J = 1. 8 Hz, 1H ), 5 .08 (bs , 1H ), 3 . 95 - 4 .15 (m , 1H ) , 8 .08 ( d , J = 2 . 1 Hz, 1H ). 2H ) , 1 . 4 - 1 . 5 ( m , 1H ), 1 . 40 ( s , 9H ) , 0 . 9 - 1 . 0 ( m , 2H ) , 0 . 8 - 0 . 9 Step 2 : Production of 2 - ( 5 -bromo - 3 - chloropyridin ( m , 2H ) . 2 - yl ) - 2 , 2 - difluoroethanamine 15 Step 5 : Production of 2 -[ 3 -chloro -5 -( cyclopropyl To a 20 ml solution of 810 mg of 2 - ( 5 - bromo - 3 - chloro pyridin - 2 -yl ) - 2 ,2 -difluoro acetonitrile in dichloromethane ethynyl )pyridin - 2 - yl) - 2 , 2 -difluoroethanamine under a nitrogen atmosphere, 9 ml of a 1 . 0M hexane solution of diisobutvlaluminum hydride was added dropwisely under 20 To a 2 ml solution of 340 mg of tert -butyl N - [ 2 - [ 3 - chloro stirring at - 78° C . , and after completion of the dropwise 5 - ( cyclopropylethynyl) pyridin - 2 -yl ) - 2 , 2 - difluoroethyl?car addition , stirring was continued for 2 hours at the same bamate in dichloromethane , 1 ml of trifluoroacetic acid was temperature. Then , to the reaction mixture , 20 ml of a added , followed by stirring at room temperature for 1 hour. saturated aqueous solution of sodium potassium tartrate After completion of the reaction , the solvent was distilled off (Rochelle salt ) and 20 ml of dichloromethane were added , 25 under reduced pressure , and to the residue , 10 ml of a 10 wt followed by further stirring at room temperature for 2 hours. % aqueous potassium carbonate solution was added , fol After completion of the reaction , 30 ml of water was added lowed by extraction with ethyl acetate ( 10 mlx2 ). Organic to the reaction mixture , and the organic layer was separated layers were combined and washed with water ( 10 mlx1 ), and and washed in the order of with a saturated Rochelle salt then dehydrated and dried in the order of with a saturated solution (20 mlx1 ) and then with water ( 20 mlx2 ) , where - 30 sodium chloride solution and then with anhydrous sodium upon the solvent was distilled off under reduced pressure , to sulfate , and the solvent was distilled off under reduced obtain 607 mg of the crude desired product as a brown oily pressure , to obtain 235 mg of the crude desired product as substance . This product was used directly in the next step a pale yellow oily substance . This product was used directly without further purification . in the next step without further purification . H NMR (CDC13 , Me_ Si, 300 MHz ) 88. 56 ( d , J = 2 . 1 Hz, 35 ' HH NMNMR ( CDC12 , Me Si, 300 MHz) 88. 42 (d , J = 1 . 5 Hz, 1H ) , 8 .00 ( d , J = 2 . 1 Hz, 1H ) , 3 .49 ( t , J = 13 . 8 Hz, 2H ) . 1H ) , 7 .74 ( d , J = 1 . 5 Hz, 1H ) , 3 . 48 ( t , J = 14 . 1 Hz, 2H ) , 1 . 4 - 1 . 5 Step 3 : Production of tert -butyl N - [ 2 - ( 5 - bromo - 3 ( m , 1H ) , 0 . 9 - 1 . 0 ( m , 2H ) , 0 . 8 - 0 . 9 ( m , 2H ) . chloropyridin -2 -yl ) - 2 , 2 -difluoroethyl ] carbamate 4040 Step 6 : Production of N - [ 2 - [3 - chloro - 5 - ( cyclopro To a 5 ml solution of 607 mg of 2 - ( 5 -bromo - 3 -chloro pylethynyl) pyridin -2 - yl] - 2, 2- difluoroethyl )- 2 -( dif pyridin - 2 - yl) - 2 , 2 - difluoroethanamine and 271 mg of trieth luoromethyl) nicotinamide ylamine in dichloromethane , 584 mg of di- tert - butyl dicar bonate was added , followed by stirring at room temperature 78 mg of 2 - [3 -chloro - 5 -( cyclopropylethynyl) pyridin -2 for 2 hours. After completion of the reaction , the solvent was 45 v11 - 2 . 2 - difluoroethanamine was dissolved in 2 ml of a distilled off under reduced pressure, and the residue was dichloromethane- N , N - dimethylformamide ( 1 : 1 ) mixed sol purified by silica gel column chromatography wherein it was vent , and 64 mg of 2 - ( difluoromethyl) nicotinic acid and 72 eluted with ethyl acetate - hexane ( gradient of from 0 : 10 to mg of 1 - ( 3 - dimethylaminopropyl) - 3 -ethylcarbodiimide 1 : 9 ), to obtain 430 mg of the desired product as a pale yellow hydrochloride were added , followed by stirring at room oily substance . 50s temperature for 12 hours . After completion of the reaction , H NMR (CDC12 , Me Si, 300 MHz ) 8 .55 (d , J = 2 .1 Hz, 10 ml of water was added to the reaction mixture, followed 1H ) , 8 . 00 ( d , J = 2 . 1 Hz, 1H ), 5 . 05 (bs , 1H ) , 4 .0 - 4 . 2 (m , 2H ) , by extraction with ethyl acetate (8 mlx2 ) . Organic layers 1 .40 ( s , 9H ) . were combined and washed with water ( 10 mlx1) , and then dehydrated and dried in the order of with a saturated sodium Step 4 : Production of tert- butyl N -[ 2 - [ 3 - chloro - 5 - 55 chloride solution and then with anhydrous sodium sulfate , ( cyclopropylethynyl) pyridin - 2 - yl) - 2 , 2 - difluoroethyl] and the solvent was distilled off under reduced pressure . The carbamate residue was purified by silica gel column chromatography To a 3 ml solution of 430 mg of tert -butyl N - [ 2 - ( 5 -bromo wherein it was eluted with ethyl acetate - hexane ( gradient of 3 - chloropyridin - 2 -yl ) - 2 , 2 - difluoroethyl] carbamate in N , N - 60 from 1 : 9 to 3 : 7 ) , to obtain 81 mg of the desired product as dimethylformamide, 468 mg of triethylamine , 153 mg of white crystals . cyclopropylacetylene , 66 mg of copper ( I ) iodide and 81 mg Melting point: 116 .0 to 118 .0° C . of dichlorobis (triphenylphosphine )palladium ( II ) were ' H NMR (CDC13 , Me Si, 300 MHz) 88. 74 (dd , J= 4 . 8, 1. 5 added, followed by stirring at 50° C . for 2 hours under a Hz, 1H ), 8 . 38 (d , J = 1 . 8 Hz, 1H ) , 7 . 91 (dd , J = 7 . 8 , 1 . 5 Hz, nitrogen atmosphere . After completion of the reaction , 20 ml 65 1H ) , 7 .78 ( d , J = 1 . 8 Hz, 1H ) , 7 . 46 ( dd , J = 7 . 8 , 4 . 8 Hz , 1H ) , of a saturated aqueous ammonium chloride solution was 6 .89 ( t , J = 54 . 9 Hz, 1H ) , 6 .81 (bs , 1H ), 4 . 35 - 4 . 5 ( m , 2H ) , added to the reaction mixture , followed by extraction with 1 .4 - 1 . 55 ( m , 1H ) , 0 . 9 - 1 . 0 ( m , 2H ) , 0 . 8 - 0 . 9 ( m , 2H ) . US 10 , 029 , 986 B2 113 114 Synthesis Example 10 bamate in dichloromethane , 1 ml of trifluoroacetic acid was added , followed by stirring at room temperature for 1 hour. N - [ 2 - [ 3 - chloro -5 - ( 3 - fluoro - 1 -propynyl )pyridin - 2 - yl ) After completion of the reaction , 5 ml of water and 10 mlof 2 ,2 -difluoroethyl ] - 3 -difluoromethyl - 1 -methyl - 1H a saturated aqueous sodium bicarbonate solution were added pyrazole - 4 - carboxamide ( compound No. 8 - 005 of 5 to the reaction mixture to adjust the pH to be from 10 to 11, the present invention ) followed by extraction with dichloromethane ( 15 mlx2 ) . Organic layers were combined and washed with water ( 10 Step 1 : Production of tert -butyl N - [ 2 - [ 3 -chloro - 5 mlx1) , and then dehydrated and dried in the order of with a ( 3 -hydroxy -1 -propynyl ) pyridin -2 - yl] - 2 ,2 -difluoro saturated sodium chloride solution and then with anhydrous ethyl] carbamate 10 sodium sulfate , and the solvent was distilled off under reduced pressure , to obtain 90 mg of the crude desired To a 1 ml solution of 370 mg of tert -butyl N - [2 - (5 -bromo - product as a yellow oily substance . This product was used 3 - chloropyridin - 2 - yl) - 2 , 2 - difluoroethyl] carbamate produced directly in the next step without further purification . in Step 3 of Synthesis Example 9 in N , N - dimethylforma- H NMR (CDC1z , Me Si , 300 MHz ) 88 . 54 ( d , J = 1 . 5 Hz, mide, 313 mg of triethylamine, 60 mg of propargyl alcohol, 15 1H ) , 7 . 87 ( d , J = 1 . 5 Hz , 1H ) , 5 . 19 ( d , J = 47 . 4 Hz, 2H ) , 3 . 51 41 mg of copper ( I ) iodide and 43 mg of dichlorobis ( triph - ( t , J = 14 . 4 Hz, 2H ) . enylphosphine )palladium ( II ) were added , followed by stir ring under a nitrogen atmosphere at 50° C . for 30 minutes. Step 4 : Production of N - [ 2 - [ 3 -chloro - 5 - ( 3 - fluoro - 1 After completion of the reaction , 10 ml of a saturated propynyl) pyridin - 2 - yl )- 2 , 2 - difluoroethyl ] - 3 - difluo aqueous ammonium chloride solution was added to the 20 romethyl- 1 -methyl - 1H -pyrazole - 4 -carboxamide reaction mixture , followed by extraction with ethyl acetate ( 15 mlx2 ). Organic layers were combined and washed with To a 2 ml solution of 39 mg of 3 -difluoromethyl - 1 a saturated aqueous ammonium chloride solution ( 10 mlx1) methyl- 1H - pyrazole - 4 - carboxylic acid in dichloromethane , and then with water ( 10 mlxl ) , and then dehydrated and 10 mg of N , N - dimethylformamide and 34 mg of oxaly1 dried in the order of with a saturated sodium chloride 25 chloride were added , followed by stirring at room tempera solution and then with anhydrous sodium sulfate , and the ture for 20 minutes . After completion of the reaction , the solvent was distilled off under reduced pressure . The residue solvent was distilled off under reduced pressure , and the was purified by silica gel column chromatography wherein residue was dissolved in 1 ml ethyl acetate and added it was eluted with ethyl acetate -hexane ( gradient of from dropwisely to a mixture of a 1 ml ethyl acetate solution of 0 : 10 to 4 : 6 ) , to obtain 350 mg of the desired product as pale 30 45 mg of 2 - [ 3 -chloro - 5 - ( 3 - fluoro - 1 -propynyl ) pyridin - 2 - yl ] yellow crystals . 2 , 2 - difluoroethanamine and a 1 ml ethyl acetate solution of Melting point: 45 . 0 to 47. 0° C . 50 mg of potassium carbonate under ice - cooling and stir ' H NMR (CDC1z , Me Si, 300 MHz) 88 .48 ( d , J = 1 . 5 Hz, ring. Then , stirring was continued for 10 minutes at the same 1H ), 7 . 80 ( d , J = 1 . 5 Hz, 1H ) , 5 . 05 ( bs , 1H ) , 4 .45 - 4 .55 ( m , temperature , and then 10 ml of water was added to the 2H ) , 3 . 9 - 4 . 15 ( m , 2H ) , 1. 38 ( s , 9H ) . 35 reaction mixture , followed by extraction with ethyl acetate ( 10 mlx1 ) . The organic layer was dehydrated and dried in Step 2 : Production of tert -butyl N - [ 2 - [ 3 -chloro - 5 the order with a saturated sodium chloride solution and then ( 3 - fluoro - 1 - propynyl) pyridin - 2 - yl] - 2 , 2 - difluoro with anhydrous sodium sulfate , and the solvent was distilled ethyl] carbamate off under reduced pressure . The residue was purified by 40 silica gel column chromatography wherein it was eluted To a 2 ml solution of 230 mg of tert -butyl N - [ 2 - [3 - chloro - with ethyl acetate -hexane ( gradient of from 0 :10 to 5 :5 ) to 5 - ( 3 -hydroxy - 1 - propynyl) pyridin - 2 - yl) - 2 , 2 - difluoroethyl] obtain 60 mg of the desired product as white crystals . carbamate in dichloromethane , 128 mg of ( N , N -diethyl Melting point: 110 .0 to 111. 0° C . amino ) sulfur trifluoride was added under ice -cooling and H NMR (CDC13 , Me_ Si, 300 MHz) 88 . 53 ( d , J = 1 . 5 Hz, stirring , followed by stirring at room temperature for 45 45 1H ) , 7 . 93 ( s , 1H ) , 7 .89 ( d , J = 1 . 5 Hz, 1H ) , 7 .06 ( bs, 1H ) , 6 . 75 minutes . After completion of the reaction , 10 ml of a (t , J = 54 .0 Hz , 1H ) , 5 .20 (d , J = 47 . 1 Hz , 2H ) , 4 .3 - 4 .5 (m , 2H ), saturated aqueous sodium bicarbonate solution was added to 3 .91 ( s , 3H ). the reaction mixture under ice - cooling and stirring , followed by extraction with dichloromethane ( 10 mlx2 ) . Organic Synthesis Example 11 layers were combined and washed with water ( 10 mlxl) , and 50 then dehydrated and dried in the order of with a saturated N -[ 2- [3 -chloro -5 -( cyclopropylethynyl) pyridin - 2 - yl] sodium chloride solution and then with anhydrous sodium 2 - (methylthio ) ethyl] - 3 - difluoromethyl- 1 -methyl - 1H sulfate , and the solvent was distilled off under reduced pyrazole -4 -carboxamide (compound No . 8 -020 of pressure . The residue was purified by silica gel column the present invention ) chromatography wherein it was eluted with ethyl acetate - 55 hexane ( gradient of from 0 : 5 to 1 : 4 ) , to obtain 115 mg of the Step 1 : Production of 2 - ( 5 -bromo - 3 - chloropyridin desired product as white crystals . 2 -yl ) ] - 2 -( methylthio )acetonitrile Melting point : 84 . 0 to 86 . 0° C . H NMR (CDC12 , Me Si, 300 MHz) 88 .52 (d , J= 1. 5 Hz, To a 30 ml solution of 574 mg of 2 - methylthio Jacetoni 1H ) , 7 . 87 ( d , J = 1 . 5 Hz, 1H ) , 5 .20 (d , J = 47 . 4 Hz, 2H ) , 5 .06 60 trile in tetrahydrofuran , 9 . 7 ml of a 1 .03M tetrahydrofuran ( bs , 1H ) , 3 . 95 - 4 . 15 ( m , 2H ) , 1 .40 ( s , 9H ) . n -hexane solution of lithium diisopropylamide was added dropwisely with stirring at - 78° C ., followed by stirring for Step 3 : Production of 2 -f3 -chloro - 5 - ( 3 - fluoro - 1 10 minutes at the same temperature . Then , to this reaction propynyl) pyridin - 2 -yl )- 2 , 2 - difluoroethanamine mixture , a 10 ml solution of 1 . 0 g of 5 -bromo - 2 , 3 - dichlo 65 ropyridine in tetrahydrofuran was added dropwisely under To a 1 ml solution of 145 mg of tert -butyl N - [2 - [3 -chloro stirring at the same temperature. After completion of the 5 - ( 3 - fluoro - 1 - propynyl) pyridin - 2 - yl ) - 2 , 2 - difluoroethyl] car dropwise addition , while raising the temperature to room US 10 ,029 , 986 B2 115 116 temperature, stirring was further continued for 18 hours . N , N -dimethylformamide , 490 mg of triethylamine, 128 mg After completion of the reaction , 50 ml of water was added of cyclopropylacetylene , 65 mg of copper( I ) iodide and 68 to the reaction mixture , followed by extraction with ethyl mg of dichlorobis ( triphenylphosphine) palladium ( II) were acetate (50 mlx2 ) . Organic layers were combined and added , followed by stirring under a nitrogen atmosphere at washed with water ( 20 mlx1 ) , and then dehydrated and dried 5 in the order of with a saturated sodium chloride solution and 65° C . for 3 hours . After completion of the reaction , the then with anhydrous sodium sulfate , and the solvent was reaction mixture was left to cool to room temperature , 10 ml distilled off under reduced pressure . The residue was puri of a saturated aqueous solution of ammonium chloride was fied by silica gel column chromatography wherein it was added , and the mixture was extracted with ethyl acetate ( 25 eluted with ethyl acetate -hexane (3 : 97 ) , to obtain 430 mg of . mlx2 ). Organic layers were combined and washed with the desired product as brown crystals . water (50 mlx1) , and then dehydrated and dried in the order Melting point : 46 . 0 to 51 . 0° C . of with a saturated sodium chloride solution and then with H NMR (CDC1 , Me Si, 300 MHz ) 88 . 58 ( d , J = 1 . 8 Hz, anhydrous sodium sulfate , and the solvent was distilled off 1H ) , 7 .93 ( d , J = 1 . 8 Hz , 1H ), 5 . 16 ( s , 1H ), 2 . 32 ( s , 3H ) . under reduced pressure . The residue was purified by silica 15 gel column chromatography wherein it was eluted with ethyl Step 2: Production of 2 -( 5 -bromo - 3 - chloropyridin - 158acetate -hexane (gradient of from 0 : 10 to 1 :9 ), to obtain 283 2 - yl ) - 2 - (methylthio ) ethanamine mg of the desired product as a brown oily substance . To a 5 ml solution of 430 mg of 2 -( 5 -bromo -3 -chloro H NMR (CDC12 , Me. Si, 300 MHz ) 8 . 41 (d , J = 1 . 8 Hz , pyridin -2 - yl) ] -2 -( methylthio )acetonitrile in dichlorometh 1H ) , 7 .65 ( d , J = 1 . 8 Hz, 1H ) , 4 . 95 (bs , 1H ) , 4 . 43 ( t, J = 7 . 2 Hz, ane under a nitrogen atmosphere . 4 . 6 ml of a 1 . 0M hexane 20 1H ), 3 .65 - 3 . 8 ( m , 2H ) , 2 .07 ( s , 3H ) , 1 . 4 - 1 . 5 m , 1H ) , 1 . 42 ( S , solutionion of diisobutylaluminum hydridehydride was addedadded dropdron - 9H ), 0 . 75 - 0 . 95 ( m , 4H ) . wisely under stirring at - 78° C ., and after completion of the dropwise addition , the mixture was stirred for 2 hours at the Step 5 : Production of 2 - [ 3 - chloro - 5 - ( cyclopropyl same temperature . Then , the reaction mixture was warmed ethynyl) pyridin - 2 -yl ] - 2 -( methylthio ) ethanamine to room temperature and added dropwisely to 10 ml of a 25 saturated aqueous solution of sodium potassium tartrate To a 1 . 5 ml solution of 283 mg of tert - butyl N - [ 2 - 13 (Rochelle salt ) under ice - cooling and stirring . After comple chloro - 5 - ( cyclopropylethynyl) pyridin - 2 -yl ) - 2 - (methythio ) tion of the dropwise addition , stirring was further continued ethyl ] carbamate in dichloromethane , 1 . 5 ml of trifluoro at room temperature for one hour. After completion of the acetic acid was added , followed by stirring for 2 hours at reaction , the reaction mixture was extracted with dichlo - 30 room temperature . After completion of the reaction , 10 mlof romethane ( 30 mlx1 ) , and organic layers were combined and water and 5 ml of a 6M aqueous sodium hydroxide solution washed with water (20 mlx1) , and the solvent was distilled were added to the reaction mixture , followed by extraction off under reduced pressure to obtain 310 mg of the crude with dichloromethane ( 15 mlx2 ) . Organic layers were com desired product as a brown oily substance . This product was bined and washed with water ( 10 mlx1) , and then dehy used directly in the next step without further purification . 35 drated and dried in the order of with a saturated sodium 'H NMR (CDC1z , Me, Si, 300 MHz) 88. 53 (d , J = 1. 8 Hz , chloride solution and then with anhydrous sodium sulfate , 1H ), 7 .93 ( d , J = 1 . 8 Hz , 1H ), 4 . 23 ( t , J = 7 . 2 Hz, 1H ), 3 . 2 - 3 . 4 and the solvent was distilled off under reduced pressure, to ( m , 2H ) , 2 . 02 ( s , 3H ) . obtain 196 mg of the crude desired product as a brown oily substance . This product was used directly in the next step Step 3 : Production of tert -butyl N - [ 2 - ( 5 -bromo - 3 40 without further purification . chloropyridin -2 -yl ) - 2 - (methylthio ) ethyl] carbamate ' H NMR (CDC1z , Me Si, 300 MHz ) 88 . 35 - 8 .45 ( m , 1H ), 7 .6 - 7 . 7 ( m , 1H ), 4 . 15 - 4 . 35 ( m , 1H ) , 3 . 1 - 3 . 4 ( m , 2H ), 2 . 04 ( s , To a 2 ml solution of 303 mg of 2 - ( 5 -bromo -3 - chloro - 3H ), 1 .4 - 1. 5 (m , 1H ), 0 .75 - 0 .9 (m , 4H ). pyridin - 2 - yl) - 2 - (methylthio ) ethanamine and 126 mg of pyri dine in dichloromethane, 277 mg of di- tert- butyl dicarbonate 45 Step 6 : Production of N - [ 2 - [ 3 - chloro - 5 - ( cyclopro was added , followed by stirring at room temperature for 1 pylethynyl) pyridin - 2 - yl) - 2 - (methylthio ) ethyl ]- 3 hour . After completion of the reaction , to the reaction difluoromethyl- 1 -methyl - 1H -pyrazole - 4 -carboxam mixture , 10 ml of water was added , followed by extraction ide with dichloromethane ( 10 mlx2 ) . Organic layers were com bined and washed with water ( 10 mlx1 ) , and then dehy - 50 To a 2 ml solution of 47 mg of 3 - difluoromethyl - 1 drated and dried in the order of with a saturated sodium methyl- 1H - pyrazole - 4 - carboxylic acid in dichloromethane , chloride solution and then with anhydrous sodium sulfate , 10 mg of N , N - dimethylformamide and 44 mg of oxaly1 and the solvent was distilled off under reduced pressure. The chloride were added , followed by stirring at room tempera residue was purified by silica gel column chromatography ture for 20 minutes. After completion of the reaction , the wherein it was eluted with ethyl acetate -hexane ( gradient of 55 solvent was distilled off under reduced pressure , and the from 0 : 10 to 1 : 9 ) , to obtain 380 mg of the desired product residue was dissolved in 1 mlof dichloromethane , and added as a yellow oily substance . dropwisely to a 2 ml solution of 60 mg of 2 - 13 -chloro - 5 ' H NMR ( CDC12 , Me_ Si , 300 MHz ) 88 .51 ( d , J = 1 . 8 Hz, ( cyclopropylethynyl) pyridin - 2 - yl] - 2 - (methylthio ) ethan 1H ) , 7 .87 ( d , J = 1 . 8 Hz, 1H ), 4 . 93 (bs , 1H ), 4 .41 ( t, J = 7 . 2 Hz , amine and 45mg of triethylamine in dichloromethane under 1H ) , 3 .6 - 3 .85 ( m , 2H ) , 2 .09 (s , 3H ) , 1 . 42 ( s , 9H ) . 60 ice - cooling and stirring . After stirring at the same tempera ture for 20 minutes , 10 ml of water was added to the reaction Step 4 : Production of tert - butyl N - [ 2 - [ 3 - chloro -5 mixture , followed by extraction with dichloromethane ( 10 (cyclopropylethynyl ) pyridin - 2 -yl ) - 2 -( methylthio ) mlx1) . The organic layer was dehydrated and dried in the ethyl] carbamate order of with a saturated sodium chloride solution and then 65 with anhydrous sodium sulfate , and the solvent was distilled To a 1 ml solution of 370 mg of tert -butyl N - [2 - (5 -bromo off under reduced pressure . The residue was purified by 3 -chloropyridin - 2 -yl ) - 2 -( methylthio ) ethyl] carbamate in silica gel column chromatography wherein it was eluted US 10 ,029 , 986 B2 117 118 with ethyl acetate -hexane ( gradient of from 0 : 10 to 4 : 6 ) , to acetate -hexane ( gradient of from 0 : 10 to 4 :6 ) , to obtain 125 obtain 60 mg of the desired product as a yellow resinous mg of thethe desired product as brownbro crystals. substance . Melting point: 43 . 0 to 46 .0° C . IH NMR (CDCI . . Me. Si. 300 MHz ) 88 . 42 ( d . J = 1 . 8 Hz. H NMR (CDC1z , Me. Si, 300 MHZ ) 08 .47 (d , J = 1. 5 Hz. 1H ), 7 .86 (s , 1H ), 7 .65 (d , J= 1. 8 Hz , 1H ), 6 . 86 (bs , 1H ), 6 .74 5 1H ) , 7 . 91 ( s , 1H ), 7 .69 ( d , J = 1 . 5 Hz, 1H ) , 6 .93 (bs , 1H ) , 6 .75 (t , J = 53 . 7 Hz, 1H ) , 4 . 57 (dd , J = 8 . 4 , 6 . 0 Hz, 1H ) , 4 . 0 - 4 . 2 ( m , (t , J = 54 .6 Hz, 1H ), 4 .78 (t , J = 6 . 9 Hz, 1H ), 3 . 9 - 4 . 2 ( m , 2H ), 2H ) , 3 . 90 (s , 3H ) , 2 .09 ( s , 3H ), 1. 4 - 1 .55 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 3 .91 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 4H ) . Synthesis Example 13 Synthesis Example 12 10 N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl) 2 , 2 -dicyanoethyl ) - 2 - ( trifluoromethyl )benzamide N - [ 2 - [ 3 - chchloro - 5 -( cyclopropylethynyl) pyridin - 2 ( compound No. 1 -023 of the present invention ) yl] - 2 -cyanoethyl ] -3 - difluoromethyl- 1 -methyl - 1H pyrazole - 4 -carboxamide ( compound No. 8 -021 of Step 1: Production of the present invention ) 1515 2 - ( 5 - bromo - 3 - chloropyridin - 2 - yl )malononitrile To a 30 ml solution of 2 . 0 g of 5 -bromo - 2 , 3 - dichloro Step 1 : Production of N - [ 2 - ( 5 -bromo - 3 - chloropyri pyridine and 1 . 2 g of malononitrile in dimethyl sulfoxide , din - 2 -yl ) - 2 - cyanoethyl] - 3 - difluoromethyl- 1 -methyl 5 . 7 g of cesium carbonate was added , and the mixture was 1HTH -Pyaz pyrazole - 4 - carboxamide 20 stirred for 5 hours at 100° C . After completion of the reaction , the reaction mixture was left to cool to room To a 2 ml solution of 240 mg of 2 - ( 5 -bromo - 3 - chloro temperature , and 30 ml of a saturated aqueous ammonium pyridin -2 -yl ) acetonitrile in tetrahydrofuran , 1 . 1 ml of a chloride solution was added , followed by washing with ethyl 1. 0M tetrahydrofuran solution of potassium tert- butoxide acetate (30 mlx1 ). To the aqueous layer, 5 ml of a IN was added under ice- cooling and stirring , followed by 25 pHaqueous to 4 ,hydrochloric followed by acid extraction solution with was addedethyl toacetate adjust ( 100 the stirring at room temperature for 1 hour . Then , to this reaction mlx2 ) . Organic layers were combined and washed with mixture, 276 mg of [ 3 - difluoromethyl- 1 -methyl - 1H - pyra water (50 mlx1 ) , and then dehydrated and dried in the order zole - 4 - carboxamide ]methyl acetate was added , and stirring of with a saturated sodium chloride solution and then with was further continued at room temperature for 1 hour. After anhydrous sodium sulfate , and the solvent was distilled off completion of the reaction , 10 ml of a saturated aqueous 30 under reduced pressure to obtain 1 . 1 g of the desired product solution of ammonium chloride was added to the reaction as brown crystals . mixture , followed by extraction with ethyl acetate ( 20 Melting point: 157 . 0 to 159. 0° C . mlx1 ) . The organic layer was dehydrated and dried in the IH NMR (CDC12 , Me Si, 300 MHz ) 88 . 01 ( d , J = 1 . 8 Hz, order of with a saturated sodium chloride solution and then 1H ) , 7 .61 ( d , J = 1 . 8 Hz, 1H ) , 4 . 43 ( s , 1H ) . with anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure . The residue was purified by Step 2 : Production of N - [2 - (5 -bromo - 3 -chloropyri silica gel column chromatography wherein it was eluted din - 2 - yl) - 2 , 2 - dicyanoethyl) - 2 - (trifluoromethyl )benz with ethyl acetate -hexane (gradient of from 0 :10 to 5 : 5 ), to amide obtain 150 mg of the desired product as brown crystals . 40 To a 4 ml solution of 150 mg of 2 - 05 - bromo - 3 - chloro Melting point: 65 . 0 to 69. 0° C . pyridin - 2 - yl) malononitrile in tetrahydrofuran , 75 mg of ' H NMR (CDC13 , Me_ Si, 300 MHz ) 88. 60 ( d , J = 2 . 1 Hz , potassium tert - butoxide was added under ice - cooling and 1H ), 7 . 93 (d , J = 2 . 1 Hz, 1H ), 7 .92 (s , 1H ), 6 .83 (bs , 1H ), 6 .74 stirring , followed by stirring at 0° C . for 30 minutes. Then , ( t , J = 54 .6 Hz, 1H ) , 4 .79 ( t , J = 6 .6 Hz, 1H ) , 4 . 0 - 4 . 2 ( m , 2H ) , to this reaction mixture, 150 mg of N - chloromethyl- 2 3 .92 (s , 3H ). 45 ( trifluoromethyl) benzamide was added , followed by further stirring at room temperature for 1 hour. After completion of Step 2 : Production of N -[ 2 - [ 3 - chloro - 5 - ( cyclopro the reaction , to the reaction mixture , 10 ml of a saturated pylethynyl) pyridin - 2 -yl ] - 2 -cyanoethyl ] - 3 -difluorom aqueous ammonium chloride solution was added , followed ethyl- 1- methyl - 1H -pyrazole - 4 -carboxamide by extraction with ethyl acetate (10 mlx2 ) . Organic layers 50 were combined and washed with water (50 mlx1) , and then To a 1 ml solution of 135 mg of N - [ 2 - ( 5 -bromo - 3 - dehydrated and dried in the order of with a saturated sodium chloropyridin - 2 -yl ) - 2 -cyanoethyl ] - 3 -difluoromethyl - 1 - chloride solution and then with anhydrous sodium sulfate , methyl- 1H -pyrazole - 4 -carboxamide , 32 mg of cyclopropy - and the solvent was distilled off under reduced pressure . The lacetylene and 163 mg of triethylamine in N , N residue was purified by silica gel column chromatography dimethylformamide , 21mg of copper (I ) iodide and 23 mg of 55 wherein it was eluted with ethyl acetate -hexane (gradient of dichlorobis ( triphenylphosphine palladium ( II ) were added , from 0 : 100 to 5 : 95 ) , to obtain 170 mg of the desired product followed by stirring at 50° C . for 45 min under a nitrogen as a colorless resinous substance . atmosphere . After completion of the reaction , the reaction ' H NMR (CDC12 , Me Si, 300 MHz) 88 .59 ( d , J = 2 . 1 Hz, mixture was left to cool to room temperature, and 10 mlof 1H ), 8 . 11 ( d , J = 2 . 1 Hz, 1H ) , 7 . 5 - 7 .65 ( m , 4H ), 6 .66 ( t, J = 6 . 9 water was added , followed by extraction with ethyl acetate 60 Hz, 1H ) , 4 .71 ( d , J = 6 . 9 Hz, 2H ) . ( 20 mlx1) . The organic layer was washed with a saturated aqueous ammonium chloride solution ( 10 ml) and then with Step 3 : Production of N - [ 2 - [ 3 -chloro -5 - ( cyclopro water ( 10 ml) , and then dehydrated and dried in the order of pylethynyl) pyridin - 2 -yl ) - 2 ,2 -dicyanoethyl ] - 2 -( trif with a saturated sodium chloride solution and then with luoromethyl) benzamide anhydrous sodium sulfate , and the solvent was distilled off 65 under reduced pressure . The residue was purified by silica To a 1 ml solution of 150 mg of N - [ 2 -( 5 - bromo- 3 gel column chromatography wherein it was eluted with ethyl chloropyridin - 2 -yl ) - 2, 2 -dicyanoethyl ] - 2 -( trifluoromethyl ) US 10 ,029 , 986 B2 119 120 benzamide, 33 mg of cyclopropylacetylene and 167 mg of combined and washed with water ( 10 mlx2 ) , and then triethylamine in N , N -dimethylformamide , 22 mg of copper dehydrated and dried in the order of with a saturated sodium ( I) iodide and 23 mg of dichlorobis ( triphenylphosphine ) chloride solution and then with anhydrous sodium sulfate , palladium ( II ) were added , followed by stirring at 50° C . for and the solvent was distilled off under reduced pressure . The 30 minutes under a nitrogen atmosphere . After completion 5 residue was purified by silica gel column chromatography of the reaction , the reaction mixture was left to cool to room wherein it was eluted with ethyl acetate - hexane ( gradient of temperature , and 10 ml of water was added , followed by from 1 : 9 to 6 : 4 ), to obtain 2 .50 g of the desired product as extraction with ethyl acetate ( 10 mlx2 ) . Organic layers were a colorless oily substance . combined and washed with a saturated aqueous ammonium H NMR ( CDC1z , Me Si, 300 MHz) 88 .44 ( d , J = 1 . 8 Hz, chloride solution ( 10 mlx1 ) and then with water ( 10 mlx1 ) , 10 1H ) , 7 .67 ( d , J = 1 . 8 Hz, 1H ) , 5 . 18 ( s, 1H ) , 4 .31 ( q , J = 7 . 2 Hz, and then dehydrated and dried in the order of with a 4H ) , 1 . 4 - 1 . 55 ( m , 1H ), 1 .29 (t , J = 7 . 2 Hz, 6H ) , 0 . 8 - 1 . 0 ( m , saturated sodium chloride solution and then with anhydrous 4H ) . sodium sulfate , and the solvent was distilled off under reduced pressure . The residue was purified by silica gel Step 3 : Production of 2 - [ 3 - chloro - 5 - ( cyclopropyl column chromatography wherein it was eluted with ethyl 15 ethynyl) pyridin - 2 - yl] - 2 - [ ( 3 - difluoromethyl- 1 acetate -hexane (gradient of from 0 : 10 to 4 : 6 ), to obtain 12 . 1 methyl- 1H - pyrazole - 4 -carboxamide )methyl ] malonic mg of the desired product as brown crystals . acid diethyl ester Melting point: 42 . 0 to 44 . 0° C . ' H NMR ( CDC12 , Me Si, 300 MHz) 88 .42 (d , J= 1. 5 Hz, To a 15 ml solution of 2 .48 g of 2 -[ 3 -chloro -5 - (cyclopro 1H ), 7 .84 (d , J = 1 . 5 Hz, 1H ), 7 . 5 -7 .75 (m , 4H ), 6 .66 ( t, J = 6 .9 20 pylethynyl) pyridin -2 -yl ] malonic acid diethyl ester in N ,N Hz, 1H ) , 4 .71 ( d , J = 6 . 9 Hz, 2H ) , 1 . 4 - 1 .55 ( m , 1H ) , 0 . 8 - 1 . 0 dimethylacetamide , 2 .02 g of [3 - difluoromethyl- 1 -methyl ( m , 4H ) . 1H -pyrazole -4 - carboxamide ]methyl acetate and 0 .67 g of sodium acetate were added under stirring at room tempera Synthesis Example 14 ture , followed by stirring at 80° C . for 9 hours. Then , after 25 the completion of the reaction , the reaction mixture was 2 - [ 3 - chloro - 5 - (cyclopropylethynyl ) pyridin - 2 - yl] - 2 cooled to 10° C . , and 50 ml of water was added , followed by [ ( 3 -difluoromethyl - 1 -methyl - 1H -pyrazole - 4 - carbox extraction with dichloromethane (30 mlx2 ) . Organic layers amide )methyl ] malonic acid diethyl ester (compound were combined and washed with a saturated aqueous solu No. 8 -023 of the present invention ) tion of ammonium chloride ( 30 mlx1) and then with water 30 ( 30 mlx1) . Then , dehydration and drying were carried out in Step 1 : Production of the order of with a saturated sodium chloride solution and 2 , 3 - dichloro - 5 - ( cyclopropylethynyl) pyridine then with anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure. The residue was puri To a 50 ml solution of 19. 3 mg of dichlorobis( triphenyl- fied by silica gel column chromatography wherein it was phosphine )palladium ( II ) and 52 .5 mg of copper (I ) iodide in 35 eluted with ethyl acetate -hexane (gradient of from 1 : 9 to dimethyl sulfoxide , 72 . 3 mg of triphenylphosphine was 5 : 5 ) , to obtain 3 .51 g of the desired product as white crystals . added , and the mixture was stirred at room temperature for Melting point : 87 .0 to 88 .0° C . 15 minutes . Then , to this reaction mixture , 5 .00 g of ' H NMR (CDC12 , Me, Si, 300 MHz ) 88 . 33 ( d , J = 1 . 8 Hz, 5 -bromo -2 , 3 - dichloropyridine , 9. 50 g of cyclopropylacety - 1H ) , 7 .72 (s , 1H ), 7 .65 (d , J= 1 .8 Hz, 1H ), 7 .28 (bs , 1H ), 6 .81 lene and 22 .30 g of triethylamine were added , followed by 40 (t , J = 54 . 3 Hz, 1H ) , 4 .50 ( d , J = 6 . 3 Hz, 2H ) , 4 . 2 - 4 .35 (m , 4H ) , stirring under a nitrogen atmosphere at 100° C . for 6 hours . 3 . 90 (s , 3H ), 1 . 4 - 1 . 55 (m , 1H ) , 1 . 25 ( t, J = 7 . 2 Hz, 6H ) , After completion of the reaction , the reaction mixture was 0 . 8 - 1 . 0 ( m , 4H ) . left to cool to room temperature , and 50 ml of a saturated aqueous solution of ammonium chloride was added , fol Synthesis Example 15 lowed by extraction with ethyl acetate ( 100 mlx2 ) . Organic 45 layers were combined and washed with water ( 100 mlx1 ) , 2 - [3 -chloro - 5 - (cyclopropylethynyl ) pyridin - 2 - yl] - 3 and then dehydrated and dried in the order of with a ( 3 -difluoromethyl - 1 -methyl - 1H -pyrazole - 4 -carbox saturated sodium chloride solution and then with anhydrous amide) propionic acid methyl ester ( compound No. sodium sulfate , and the solvent was distilled off under 8 -022 of the present invention ) reduced pressure . The residue was purified by silica gel 50 column chromatography wherein it was eluted with ethyl To a 5 ml solution of 440 mg of 2 - 13 -chloro - 5 - ( cyclopro acetate -hexane (gradient of from 0 : 10 to 1 :9 ), to obtain pylethynyl) pyridin - 2- yl ) -2 -[ (3 -difluoromethyl - 1 -methyl 18 . 96 g of the desired product as a brown oily substance . 1H -pyrazole - 4 - carboxamide )methyl ] malonic acid diethyl ' H NMR ( CDC12 , Me Si, 300 MHz) 88 .25 (d , J= 1 . 8 Hz, ester in tetrahydrofuran , a 5 . 5 ml solution of 100 mg of 1H ), 7 .72 ( d , J = 1 . 8 Hz, 1H ) , 1 . 35 - 1 . 6 ( m , 1H ) , 0 .75 - 1 . 1 ( m , 55 sodium hydroxide in water was added , followed by stirring 4H ) . for 10 hours under heating and refluxing . After completion of the reaction , the reaction mixture was left to cool to room Step 2 : Production of 2 -[ 3 - chloro -5 -( cyclopropyl temperature , and 15 ml of water and Iml of acetic acid were ethynyl) pyridin - 2 - yl] malonic acid diethyl ester added , followed by extraction with dichloromethane ( 10 60 mlx2 ) . Organic layers were combined and washed with To a 10 ml solution of 2 .00 g of 2 ,3 -dichloro -5 - ( cyclo - water ( 10 mlx1) , and then dehydrated and dried in the order propylethynyl) pyridine and 3 .32 g of diethyl malonate in of with a saturated sodium chloride solution and then with dimethyl sulfoxide , 6 . 74 g of cesium carbonate was added , anhydrous sodium sulfate , and the solvent was distilled off followed by stirring at 90° C . for 5 hours. After completion under reduced pressure . The residue was dissolved in 4 ml of the reaction , the reaction mixture was left to cool to room 65 of N , N - dimethylformamide , and 174 mg of potassium car temperature , and 30 ml of water was added , followed by bonate and 127 mg of dimethyl sulfate were added under extraction with ethyl acetate (20 mlx2 ). Organic layers were stirring at room temperature, followed by stirring for 30 US 10 , 029 , 986 B2 121 122 minutes at the same temperature . After completion of the ' H NMR (CDC1z , Me Si, 300 MHz ) 88 .67 and 8 .64 (d , reaction , 5 ml of water was added to the reaction mixture , J = 2 .1 Hz, 1H ) , 7 .95 and 7 .91 (d , J= 2 . 1 Hz , 1H ), 5. 35 and followed by extraction with ethyl acetate ( 3 mlx2 ) . Then , 5 . 30 ( d , J = 6 . 3 and 9 . 6 Hz, 1H ) , 5 . 1 - 5 .25 ( m , 1H ) and 5 .04 organic layers were combined and washed with water (5 (qui , J = 6 .6 Hz , 1H ), 3. 36 and 3 .27 (s , 3H ), 1. 69 and 1 .29 (d , mlx1 ) , and then dehydrated and dried in the order ofwith a 5 J = 6 . 9 Hz , 3H ) . saturated aqueous sodium chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off Step 3 : Production of 2 - ( 5 - bromo - 3 -chloropyridin under reduced pressure . The residue was purified by silica 2 - yl ) - 2 -methoxy - 1 -methylethylamine gel column chromatography wherein it was eluted with ethyl acetate -hexane ( gradient of from 1 : 9 to 7 : 3 ) , to obtain 152 10 340 mg of 5 - bromo - 3 - chloro - 2 - ( 1 -methoxy - 2 -nitropro mg of the desired product as a colorless resinous substance . pyl) pyridine was dissolved in 4 mlof a methanol - water ( 1 : 1 ) ' H NMR (CDC1z , Me Si, 300 MHz) 88 .40 (d , J = 1 .8 Hz, mixed solvent, and 350 mg of ammonium chloride and 182 1H ), 7 .83 ( s , 1H ) , 7 .66 ( d , J = 1 . 8 Hz, 1H ) , 7 .03 (bs , 1H ) , 6 .82 mg of reduced iron were added , followed by stirring for 30 ( t , J = 54 . 0 Hz, 1H ) , 4 . 57 ( t, J = 6 . 3 Hz, 1H ) , 4 . 05 - 4 . 2 ( m , 1H ) , minutes at room temperature and then for 1 . 5 hours at 65° 3 .95 - 4 .05 ( m , 1H ) , 3 . 91 ( s , 3H ) , 3 .71 ( s , 3H ) , 1 . 4 - 1 .55 ( m , 15 C . After completion of the reaction , the reaction mixture was 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . left to cool to room temperature , and after removing the insoluble matter by filtration by Celite , the solvent was Synthesis Example 16 distilled off under reduced pressure . The residue was dis solved in 30 ml of diethyl ether , and then extracted with 20 N - [ 2 - [ 3 - chloro - 5 - (cyclopropylethynyl ) pyridin - 2 -yl ) 20 ml of a 1 wt % aqueous hydrochloric acid solution , where 2 -methoxy - 1 -methylethyl ] - 3 -difluoromethyl - 1 upon 20 ml of a saturated aqueous sodium bicarbonate methyl - 1H -pyrazole - 4 - carboxamide ( compound No. solution was added to the water layer so that the water layer 8 - 028 of the present invention ) was made basic , followed by back extraction with 100 mlof ethyl acetate . The organic layer was dehydrated and dried in Step 1 : Production of 25 the order of with a saturated sodium chloride solution and 5 -bromo - 3- chloro - 2 -( 2 -nitro - 1- propenyl ) pyridine then with anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure to obtain 200 mg of the A 10 ml solution of 2 . 06 g of 5 -bromo - 3 -chloropicolyl crude desired product as a brown oily substance. This aldehyde and 1 .00 g of 1 - butylamine in toluene, was heated product was used directly in the next step without further and refluxed for 2 hours while azeotropically dried using a 30 purification . Dean - Stark tube . Then , the solvent was distilled off under ? H NMR (CDC12 , Me Si, 300 MHz ) 88 .66 and 8 .65 ( d , reduced pressure , and to the residue, 10 ml of acetic acid and J= 2 . 1 Hz , 1H ) , 7 .88 and 7. 87 ( d , J= 2 . 1 Hz , 1H ) , 4 . 58 and 1 .05 g of nitroethane were added , followed by stirring at 4 .46 ( d , J = 5 . 7 and 7 . 5 Hz, 1H ) , 3 . 30 and 3 .27 ( s , 3H ) , 100° C . for 40 minutes . After completion of the reaction , the 3 .25 - 3 .45 ( m , 1H ) , 1 . 12 and 0 . 93 ( d , J = 6 .6 Hz, 3H ). reaction mixture was left to cool to room temperature , and 35 after addition of 30 mlof water , the mixture was extracted Step 4 : Production of tert -butyl N - [ 2 -( 5 -bromo -3 with ethyl acetate (50 mlx2 ) . Organic layers were combined , chloropyridin -2 -yl ) -2 -methoxy - 1 -methylethyl ] car and dehydrated and dried in the order of with a saturated bamate sodium chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off under reduced 40 To a 2 ml solution of 190 mg of 2 - C5 - bromo- 3 - chloro pressure . The residue was purified by silica gel column pyridin - 2 - yl ) - 2 -methoxy - 1 -methylethylamine and 80 mg of chromatography wherein it was eluted with ethyl acetate - pyridine in dichloromethane , 178 mg of di- tert -butyl dicar hexane ( 3 :97 ) , to obtain 0 . 76 g of the desired product as bonate was added , followed by stirring at room temperature brown crystals . for 30 minutes . After completion of the reaction , 10 ml of Melting point: 44 .0 to 50 .0° C . 45 water was added to the reaction mixture , followed by ' H NMR (CDC1z , Me Si, 300 MHz ) 88 .65 (d , J= 1 .8 Hz, extraction with dichloromethane ( 10 mlx2 ). Organic layers 1H ), 8 . 25 ( s , 1H ) , 7 . 96 ( d , J = 1 . 8 Hz, 1H ) , 2 .67 and 2 .66 ( s , were combined , and then dehydrated and dried in the order 3H ) . of with a saturated sodium chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off Step 2 : Production of 5 -bromo - 3 - chloro - 2 - ( 1 - 50 under reduced pressure . The residue was purified by silica methoxy - 2- nitropropyl ) pyridine gel column chromatography wherein it was eluted with ethyl acetate -hexane ( gradient of from 2 : 98 to 20 :80 ) , to obtain To a 10 ml solution of 760 mg of 5 - bromo - 3 - chloro - 2 - 200 mg of the desired product as a colorless oily substance . ( 2 -nitro - 1 -propenyl )pyridine in toluene, 2 . 1 g of a 28 % ' H NMR ( CDC13, Me. Si, 300 MHz ) 88 .65 and 8 . 59 ( d , sodium methoxide methanol solution diluted by 3 ml of 55 J = 1 . 8 Hz, 1H ) , 7 .87 and 7 . 85 ( d , J = 1 . 8 Hz, 1H ) , 5 .31 and methanol, was added dropwisely with stirring under ice - 4 .85 ( d , J = 8 . 1 Hz , 1H ) , 4 .75 and 4 .67 ( d , J = 4 . 2 and 2 . 4 Hz, cooling . After stirring for 30 minutes at the same tempera - 1H ) , 4 . 0 - 4 . 3 ( m , 1H ) , 3 . 53 ( s , 3H ) , 1 . 42 and 1 . 26 ( s , 9H ) , ture , 1 . 5 ml of acetic acid and 10 ml of water were added to 1 . 32 and 1 .05 ( d , J = 6 . 6 Hz, 3H ) . the reaction mixture , followed by extraction with dichlo romethane (30 mlx1) . Then , organic layers were combined , 60 Step 5 : Production of tert -butyl N - [ 2 - [ 3 -chloro - 5 and dehydrated and dried in the order of with a saturated ( cyclopropylethynyl) pyridin - 2 - yl) - 2 -methoxy - 1 sodium chloride solution and then with anhydrous sodium methylethyl?carbamate sulfate , and the solvent was distilled off under reduced pressure . The residue was purified by silica gel column To a 1 ml solution of 200 mg of tert -butyl N - [ 2 - ( 5 -bromo chromatography wherein it was eluted with ethyl acetate - 65 3 -chloropyridin -2 -yl ) - 2 -methoxy - 1 -methylethyl ] carbamate hexane ( 3 :97 ) , to obtain 683 mg of the desired product as a in N ,N -dimethylformamide , 267 mg of triethylamine, 52 mg red oily substance. of cyclopropylacetylene , 35 mg of copper ( I ) iodide and 37 US 10 ,029 , 986 B2 123 124 mg of dichlorobis ( triphenylphosphine )palladium ( II ) were in the order of with a saturated sodium chloride solution and added , followed by stirring under a nitrogen for 1 . 5 hours at then with anhydrous sodium sulfate , and the solvent was room temperature, then for 1 . 5 hours at 45° C . and further distilled off under reduced pressure. The residue was puri at 60° C . for 3 . 5 hours. After completion of the reaction , the fied by silica gel column chromatography wherein it was reaction mixture was left to cool to room temperature , and 5 eluted with ethyl acetate- hexane ( gradient of from 1 : 9 to 10 ml of water was added , and after removing the insoluble 7 : 3 ) , to obtain 140 mg of the desired product as a yellow materials by filtration by Celite , the mixture was extracted resinous substance . with ethyl acetate ( 10 mlx2 ) . Organic layers were combined ' H NMR (CDC12 , Me Si, 300 MHz ) 88 .55 and 8 . 42 ( d , and washed with 20 ml of water , and then dehydrated and J = 1 . 8 Hz, 1H ) , 7 . 86 and 7 . 76 ( s , 1H ) , 7 .68 and 7 . 64 ( d , J = 1 . 8 dried in the order of with a saturated sodium chloride 10 Hz, 1H ) , 6 . 96 and 6 . 94 ( t, J = 54 . 3 Hz, 1H ) , 6 .53 and 6 .50 ( bs , solution and then with anhydrous sodium sulfate , and the 1H ) , 4 . 86 and 4 .79 ( d , J = 3 . 9 and 3 . 3 Hz, 1H ) , 4 .4 - 4 .6 ( m , solvent was distilled off under reduced pressure . The residue 1H ) , 3 . 93 and 3 . 92 ( s , 3H ) , 3 . 37 and 3 . 35 ( s , 3H ) , 1 . 35 - 1 . 55 was purified by silica gel column chromatography wherein ( m , 1H ) , 1 . 38 and 1 .07 ( d , J = 6 . 9 Hz , 3H ) , 0 .75 - 1 . 0 ( m , 4H ) . it was eluted with ethyl acetate -hexane ( gradient of from 1 : 19 to 2 : 18 ), to obtain 140 mg of the desired product as a 15 Synthesis Example 17 yellow oily substance . ' H NMR (CDC12 , Me. Si, 300 MHz ) 88 . 45 - 8 . 6 m , 1H ) , N - [ 2 -benzyloxy - 2 - [ 3 - chloro - 5 - (cyclopropylethynyl ) 7 .6 -7 . 7 ( m , 1H ), 5. 46 and 4 .89 (d , J = 7 .5 Hz , 1H ) , 4 .78 and pyridin - 2 -yl ] - 1 -methylethyl ] - 2 - ( trifluoromethyl) 4 .68 (d , J = 4 . 5 and 3 . 0 Hz, 1H ) , 4 . 0 - 4 . 3 ( m , 1H ) , 3 . 35 and benzamide ( compound No . 1 -031 of the present 3 . 33 ( s , 3H ) , 1 .43 and 1 .28 ( s , 9H ) , 1 . 4 - 1 . 6 ( m , 1H ), 1 . 29 and 20 invention ) 1 .02 ( d , J = 9 . 3 and 6 . 9 Hz, 3H ) , 0 . 75 - 1 . 1 ( m , 4H ) . Step 1 : Production of tert -butyl N -[ 2 -[ 3 -chloro -5 Step 6 : Production of 2 -[ 3 -chloro - 5 -( cyclopropyl ( cyclopropylethynyl) pyridin - 2 - yl] - 2 -oxo - 1 -methyl ethynyl) pyridin - 2 - yl] - 2 -methoxy - 1 -methylethylam ethyl] carbamate ine 25 To a 34 ml solution of 927 mg of dichlorobis (triphenyl To a 1 .5 ml solution of 140 mg of tert- butyl N -[ 2- [ 3 phosphine )palladium ( II) and 754 mg of copper (I ) iodide in chloro - 5 -( cyclopropylethynyl) pyridin - 2 - yl) - 2 -methoxy - 1 - dimethyl sulfoxide , 1 . 5 g of triphenylphosphine was added , methylethyl ]carbamate in dichloromethane , 1 ml of trifluo - followed by stirring at room temperature for 15 minutes . roacetic acid was added with stirring under ice - cooling , 30 Then , to this reaction mixture , 4 .21 g of tert - butyl N - [ 2 - ( 5 followed by stirring at room temperature for 1. 5 hours . After bromo -3 -chloropyridin -2 - yl) -2 -oxo - 1- methylethyl ] carbam completion of the reaction , to the reaction mixture , 5 ml of ate , 9 . 2 ml of triethylamine and 1 . 1 g of cyclopropylacety water was added , and then , a 4M aqueous sodium hydroxide lene were added , followed by stirring under a nitrogen solution was added to adjust the pH to 13 , followed by atmosphere at 110° C . for 5 hours. After completion of the extraction with dichloromethane ( 10 mlx2 ) . The organic 35 reaction , the reaction mixture was left to cool to room layer was dehydrated and dried in the order of with a temperature , and 30 ml of a saturated aqueous solution of saturated sodium chloride solution and then with anhydrous ammonium chloride was added , followed by extraction with sodium sulfate , and the solvent was distilled off under ethyl acetate (50 mlx2 ) . Organic layers were combined and reduced pressure to obtain 90 mg of the crude desired washed with water ( 50 mlx1 ) , and then dehydrated and dried product as a brown oily substance. This product was used 40 in the order of with a saturated sodium chloride solution and directly in the next step without further purification . then with anhydrous sodium sulfate , and the solvent was ' H NMR (CDC1z , Me Si, 300 MHz) 88 . 45 - 8 .6 ( m , 1H ) , distilled off under reduced pressure . The residue was puri 7 .65 and 7 .6 - 7 . 7 ( d and m , J = 1 . 2 Hz, 1H ) , 4 .55 - 4 .65 and 4 .46 fied by silica gel column chromatography wherein it was ( m and d , J = 7 .8 Hz, 1H ) , 3 . 26 ( s , 3H ) , 3 . 2 - 3 .35 ( m , 1H ) , eluted with ethyl acetate - hexane ( gradient of from 1: 10 to 1 . 4 - 1 . 6 ( m , 1H ) , 1 .05 - 1 . 2 and 0 . 9 - 1. 0 (m , 3H ) , 0 . 8 - 1 .0 ( m , 45 3 : 7 ) , to obtain 3 .04 g of the desired product as a yellow 4H ) . resinous substance . 1H NMR (CDC1z , Me Si, 300 MHz ) 88 .47 ( d , J = 1 . 8 Hz , Step 7 : Production of N - [ 2 - [3 - chloro -5 - (cyclopro 1H ) , 7 .73 ( d , J= 1. 8 Hz, 1H ), 7. 32 (bs , 1H ) , 5 . 35 -5 .55 (m , pylethynyl) pyridin - 2 -yl ) - 2 -methoxy - 1 -methylethyl ] 1H ), 1 .45 - 1 . 55 ( m , 1H ) , 1 .44 (s , 9H ), 1 . 35 ( d , J = 7 . 4 Hz, 3H ) , 3 -difluoromethyl - 1 -methyl - 1H -pyrazole - 4 -carbox - 50 0 .8 - 1 . 05 ( m , 4H ). amide Step 2 : Production of tert -butyl N - [ 2 - [ 3 - chloro - 5 To a 2 ml solution of 72 mg of 3 - difluoromethyl- 1 ( cyclopropylethynyl) pyridin - 2 - yl] - 2 -hydroxy - 1 methyl- 1H -pyrazole - 4 -carboxylic acid in dichloromethane , methylethyl] carbamate 65 mg of oxalyl chloride and 10 mg of N , N -dimethylfor - 55 mamide were added , followed by stirring at room tempera 1 .80 g of tert -butyl N - [ 2 - [ 3 -chloro - 5 - (cyclopropylethy ture for 20 minutes . Then , the solvent was distilled off under nyl ) pyridin - 2 - yl ] - 2 - oxo - 1 -methylethyl ] carbamate is dis reduced pressure, and the residue was dissolved in 1 ml of solved in 20 ml of a tetrahydrofuran -methanol ( 1 : 1 ) mixed dichloromethane , and added dropwisely to a 2 ml dichlo - solvent, and 0 .74 g of sodium borohydride was added under romethane solution of 90 mg of 2 - f3 -chloro - 5 - cyclopropy - 60 stirring at - 5° C . , followed by stirring at the same tempera lethynyl) pyridin - 2 - yl) - 2 -methoxy - 1 -methylethylamine and ture for 30 minutes. After completion of the reaction , 10 ml 101 mg of triethylamine with stirring under ice - cooling of a saturated aqueous ammonium chloride solution was After completion of the dropwise addition , the mixture was added to the reaction mixture , followed by extraction with stirred for 20 minutes at the same temperature . After ethyl acetate ( 20 mlx2 ) . Organic layers were combined , and completion of the reaction , 10 ml of water was added to the 65 then dehydrated and dried in the order of with a saturated reaction mixture , followed by extraction with dichlorometh - sodium chloride solution and then with anhydrous sodium ane ( 10 mlx1 ) . The organic layer was dehydrated and dried sulfate , and the solvent was distilled off under reduced US 10 ,029 , 986 B2 125 126 pressure to obtain 1 . 85 g of the crude desired product as a ( m , 1H ) , 4 .65 ( d , J = 11 . 9 Hz, 1H ) and 4 . 60 ( d , J = 11 .6 Hz, yellow resinous substance . This product was used directly in 1H ), 4 .47 ( d , J = 11. 6 Hz, 1H ) and 4 .39 ( d , J = 11 . 9 Hz, 1H ) , the next step without further purification . 1 . 35 - 1 .55 ( m , 1H ) , 1 .40 ( d , J = 6 . 5 Hz, 3H ) and 1 . 12 ( d , J = 6 . 8 ' H NMR (CDC12 , Me . Si, 300 MHz ) 88 . 45 and 8 .42 (d . Hz , 3H ), 0 . 75 - 1 . 0 (m , 4H ) . J = 1 . 7 Hz, 1H ) , 7 .66 and 7 .64 ( d , J = 1 . 7 Hz, 1H ) , 4 . 8 - 5 . 3 ( m , 5 2H ) , 4 . 4 - 4 . 8 ( m , 1H ) , 4 . 15 - 4 . 4 ( m , 1H ) , 1 . 4 - 1 .55 ( m , 10H ) , Synthesis Example 18 1 . 35 and 0 .79 ( d , J = 6 . 8 Hz, 3H ) , 0 . 75 - 1 . 0 ( m , 4H ) . N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl] Step 3: Production of tert- butyl N -[ 2 -benzyloxy - 2 1 -methylethyl ] - 3 -difluoromethyl - 1- methyl - 1H -pyra [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 -yl ) - 1 - 10 zole - 4 - carboxamide ( compound No. 8 -024 of the methylethyl] carbamate present invention ) Step 1 : Production of 3 -difluoromethyl - 1 -methyl - N To a 1 ml solution of 100 mg of tert - butyl N - [ 2 - [ 3 - chloro [ 1 - ( 4 -methylphenylsulfonyl ) ethyl] - 1H -pyrazole - 4 5 -( cyclopropylethynyl ) pyridin - 2 -yl ] -2 -hydroxy - 1- methyl carboxamide ethyl] carbamate in tetrahydrofuran , 25 mg of 60 % oily 15 sodium hydride was added under stirring at - 5° C ., followed To a 15 ml solution of 500 mg of 3 - difluoromethyl- 1 by stirring for 1 hour at the same temperature . Then , 102 mg methyl- 1H -pyrazole - 4 -carboxamide in formic acid - water of benzyl bromide was added to this reaction mixture , and ( 1 : 4 ) , 151 mg of paraldehyde and 609 mg of sodium stirring was further continued at room temperature for 18 p - toluenesulfinate were added , followed by stirring for 2 hours . After completion of the reaction , 1 ml of water was 20 hours at 90° C . After completion of the reaction , the reaction added to the reaction mixture , followed by extraction with mixture was left to cool to room temperature and extracted ethyl acetate ( 10 mlx2 ) . Organic layers were combined , and with ethyl acetate (30 mlx1 ) . The organic layer was washed then dehydrated and dried in the order of with a saturated with water ( 20 mlx1) , and then dehydrated and dried in the sodium chloride solution and then with anhydrous sodium order of with a saturated sodium chloride solution and then sulfate , and the solvent was distilled off under reduced 25 with anhydrous sodium sulfate , and the solvent was distilled pressure . The residue was purified by silica gel column off under reduced pressure . The residue was purified by chromatography wherein it was eluted with ethyl acetate silica gel column chromatography wherein it was eluted hexane (gradient of from 1 : 10 to 3 : 7 ) , to obtain 63 mg of the with ethyl acetate -hexane ( gradient of from 1 : 9 to 5 : 5 ) , to desired product as a yellow resinous substance . obtain 573 mg of the desired product as white crystals . ' H NMR (CDC1 , Me Si, 300 MHz ) 88 . 5 - 8 .55 and 8 . 4 - 30 Melting point: 116 . 0 to 118 . 0° C . 8 .45 (m , 1H ) , 7 .63 and 7 .61 ( d , J= 1 . 8 Hz, 1H ), 7 .25 - 7 . 35 ( m , TH NMR (CDC1z , Me Si, 300 MHz ) 57 . 83 ( s , 1H ) , 7 . 76 5H ) , 5 .64 ( d , J = 9 . 5 Hz, 1H ) and 5 .50 ( d , J = 8 . 9 Hz , 1H ) , 4 . 90 ( d . J = 8 . 1 Hz, 2H ), 7 . 28 ( d , J = 8 . 1 Hz, 2H ) , 6 .82 ( bs, 1H ) , 6 . 78 ( d , J = 4 . 9 Hz, 1H ) and 4 . 82 ( d , J = 3 . 4 Hz, 1H ) , 4 .68 ( d , J = 12 . 3 ( t , J = 54 .6 Hz, 1H ) , 5 . 4 - 5 .55 (m , 1H ), 3 . 90 ( s , 3H ) , 2 .41 ( s , Hz, 1H ) and 4 .60 ( d , J = 11 . 6 Hz, 1H ) , 4 .49 ( d , J = 12 . 3 Hz, 3H ) , 1 .66 ( d , J = 6 . 9 Hz, 3H ) . 1H ) and 4 . 39 ( d , J = 11. 6 Hz, 1H ) , 4 . 2 - 4 .35 ( m , 1H ) , 1 . 35 - 35 1 .55 ( m , 10H ) , 1 . 24 ( d , J = 6 . 7 Hz, 3H ) and 1 .07 ( d , J = 7 . 0 Hz, Step 2 : Production of 2 - ( 5 -bromo - 3 -chloropyridin 3H ), 0 .75 - 1. 0 (m , 4H ) . 2 - yl) - 3 - ( 3 -difluoromethyl - 1 -methyl - 1H -pyrazole - 4 carboxamide ) butyric acid methyl ester Step 4 : Production of N - [ 2 -benzyloxy - 2 - [ 3 - chloro 5 -( cyclopropylethynyl ) pyridin -2 -yl ] - 1 -methylethyl ] - 40 To a 3 ml solution of 200 mg of 3 -difluoromethyl - 1 2 - ( trifluoromethyl) benzamide methyl - N - [ 1 -( 4 -methylphenylsulfonyl ) ethyl] - 1H -pyrazole 4 - carboxamide and 148 mg of 2 - ( 5 - bromo - 3 - chloropyridin To a 1 ml solution of63 mg of tert -butyl N -[ 2 -benzyloxy 2 -yl ) acetic acid methyl ester in N , N -dimethylformamide , 2 -[ 3 - chloro -5 - ( cyclopropylethynyl) pyridin -2 - yl] - 1 -methyl - 365 mg of cesium carbonate was added , followed by stirring ethyl] carbamate in dichloromethane, 1 ml of trifluoroacetic 45 at room temperature for 12 hours . After completion of the acid was added with stirring under ice - cooling , followed by reaction , 15 ml of water was added to the reaction mixture , stirring at room temperature for 1 hour. After completion of followed by extraction with ethyl acetate ( 10 mlx2 ). Organic the reaction , 2 ml of toluene was added to the reaction layers were combined and washed with water (10 mlx2 ) , and mixture , and then , the solvent was distilled off under reduced then dehydrated and dried in the order of with a saturated pressure . The residue was dissolved in 1 ml of dichlorometh - 50 sodium chloride solution and then with anhydrous sodium ane , and 0 . 2 ml of water, 59 mg of potassium carbonate and sulfate , and the solvent was distilled off under reduced 36 mg of 2 - ( trifluoromethyl) benzoyl chloride were added pressure . The residue was purified by silica gel column with stirring under ice -cooling , followed by stirring at room chromatography wherein it was eluted with ethyl acetate temperature for 1 hour. After completion of the reaction , 1 hexane ( gradient of from 2 : 8 to 4 : 6 ) , to obtain 98 mg of the ml of the water was added to the reaction mixture , followed 55 desired product as a colorless resinous substance . by extraction with ethyl acetate (10 mlx2 ) . Then , organic ' H NMR (CDC1z , Me Si, 300 MHz) 88 .36 ( d , J = 2 . 1 Hz, layers were combined , and then dehydrated and dried in the 1H ) , 7 . 86 ( d , J = 2 . 1 Hz, 1H ) , 7 .72 ( s , 1H ) , 7 .21 ( d , J = 7 . 2 Hz, order of with a saturated sodium chloride solution and then iH ) , 6 .90 ( t, J = 54 . 6 Hz , 1H ) , 4 .75 - 4 .85 ( m , 1H ), 4 .49 (d , with anhydrous sodium sulfate , and the solvent was distilled J = 3 . 3 Hz, 1H ) , 3 .91 ( s , 3H ) , 3 .74 ( s , 3H ) , 1 .45 ( d , J = 7 . 2 Hz, off under reduced pressure . The residue was purified by 60 3H ) . silica gel column chromatography wherein it was eluted with ethyl acetate -hexane ( gradient of from 1 : 9 to 4 : 6 ) , to Step 3 : Production of N - [ 2 -( 5 -bromo - 3 -chloropyri obtain 58 mg of the desired product as a colorless resinous din - 2 -yl ) - 1 -methylethyl ]- 3 - difluoromethyl - 1 -methyl substance . 1H -pyrazole - 4 - carboxamide ' H NMR (CDC1z , Me. Si, 300 MHz ) 88 . 51 and 8 .45 ( d , 65 J = 1 . 7 Hz , 1H ), 7 . 2 - 7 . 7 ( m , 10H ) , 6 .47 ( d , J = 8 . 2 Hz, 1H ) , To a 10 ml solution of 2 . 50 g of 2 - ( 5 -bromo - 3 -chloro 5 . 05 ( d , J = 4 . 1 Hz, 1H ) and 4 . 95 ( d , J = 2 .7 Hz, 1H ) , 4 .75 - 4 . 95 pyridin - 2 - yl) - 3 - ( 3 - difluoromethyl- 1 -methyl - 1H -pyrazole - 4 US 10 ,029 , 986 B2 127 128 carboxamide )butyric acid methyl ester in methanol, a 5 ml reaction mixture , followed by extraction with diethyl ether solution of 0 .43 g of sodium hydroxide in water was added , ( 25 mlx2 ) . Organic layers were combined and washed with followed by stirring at room temperature for 4 hours . Then , water (20 mlx1) , and then dehydrated and dried in the order to the reaction mixture, 1N aqueous hydrochloric acid was of with a saturated sodium chloride solution and then with added until the pH became 2 or less , and stirring was 5 anhydrous sodium sulfate , and the solvent was distilled off continued at 90° C . for 2 hours . After completion of the under reduced pressure , to obtain 300 mg of the crude reaction , the reaction mixture was left to cool to room desired product as a pale yellow oily substance . This product temperature , and 40 ml of water was added , followed by was used directly in the next step without further purifica extraction with ethyl acetate (50 mlx2 ) . Organic layers were tion . combined and washed with water ( 20 mlx1) , and then 10 dehydrated and dried in the order of with a saturated sodium ' H NMR ( CDC12 , Me_ Si, 300 MHz) 88. 45 (d , J = 1 . 8 Hz, chloride solution and then with anhydrous sodium sulfate , 1H ), 7. 68 (d , J= 1 .8 Hz, 1H ), 5 .2 -5 .35 (m , 1H ), 4 .5 -4 . 6 ( m , and the solvent was distilled off under reduced pressure . The 1H ) , 3 .78 (dd , J= 10 . 8 , 3. 6 Hz , 1H ), 3 .69 (dd , J= 10 . 8 , 5 .7 Hz, residue was crystallized by adding diisopropyl ether to 1H ) , 1. 4 - 1 .55 ( m , 1H ) , 0 . 8 - 1 . 0 (m , 4H ). obtain 2 . 2 g of the desired product as white crystals . 15 Melting point: 136 . 0 to 138 .0° C . Step 2 : Production of 1 - [ 3 - chloro - 5 - ( cyclopropyl ' H NMR ( CDC1z , Me Si, 300 MHz ) 88 .47 ( d, J= 2 .1 Hz , ethynyl) pyridin - 2 - yl) - 2 - ( cyclopropylamino ) ethanol 1H ) , 7 .83 (d , J = 2 .1 Hz , 1H ), 7 .82 (s , 1H ), 6 .89 (bs , 1H ), 6 .87 ( t , J = 54 . 3 Hz, 1H ), 4 .6 - 4 .75 ( m , 1H ) , 3 . 91 ( s , 3H ) , 3 .05 - 3 . 25 20 To a 10 ml solution of 300 mg of 2 -bromo - 1 -[ 3 - chloro ( m , 2H ), 1. 28 ( d , J = 6 .6 Hz , 3H ). 5 - ( cyclopropylethynyl) pyridin - 2 - yljethanol in acetonitrile , Step 4 : Production of N - [ 2 - [ 3 -chloro - 5 - ( cyclopro 285 mg of cyclopropylamine and 431 mg of potassium pylethynyl) pyridin - 2 -yl ) - 1- methylethyl ] - 3 -difluo carbonate were added , followed by stirring for 3 hours at 60° romethyl- 1 -methyl - 1H -pyrazole - 4 -carboxamide C . After completion of the reaction , the reaction mixture was 25 left to cool to room temperature , and 20 ml of water was To a 2 ml solution of 200 mg of N - [ 2 - ( 5 -bromo - 3 - added , followed by extraction with diethyl ether ( 15 mlx2 ) . chloropyridin - 2 - yl) - 1 -methylethyl ] -3 - difluoromethyl- 1 - Organic layers were combined and washed with water ( 20 methyl- 1H -pyrazole - 4 - carboxamide in N , N -dimethylforma - mlx1 ), and then dehydrated and dried in the order of with a mide , 200 mg of triethylamine , 65 mg of saturated sodium chloride solution and then with anhydrous cyclopropylacetylene, 28 mg of copper ( I) iodide and 35 mg 30 sodiumsodi sulfate , and the solvent was distilled off under of dichlorobis (triphenylphosphine )palladium (II ) were added , followed by stirring under a nitrogen atmospherewere at reduced pressure . The residue was purified by silica gel 50° C . for 2 hours . After completion of the reaction , the column chromatography wherein it was eluted with ethyl reaction mixture was left to cool to room temperature , and acetate - hexane ( gradient of from 1 : 9 to 5 : 5 ) , to obtain 70 mg 10 mlof a saturated aqueous solution of ammonium chloride 3525 of the desired product as a colorless oily substance. was added , followed by extraction with ethyl acetate ( 10 H NMR (CDC1z , Me Si, 300 MHz ) 88 .43 ( d , J = 1 . 8 Hz, mlx2 ) . Organic layers were combined and washed with 1H ) , 7 .65 ( d , J = 1 . 8 Hz, 1H ) , 5 . 1 - 5 . 2 ( m , 1H ) , 4 . 0 - 4 . 2 ( m , water ( 10 mlx1 ), and then dehydrated and dried in the order 1H ) , 3 .05 - 3 .15 ( m , 1H ), 2 . 7 - 2 . 8 ( m , 1H ) , 2 .15 - 2 .25 ( m , 1H ) , of with a saturated sodium chloride solution and then with 1 .55 - 1 . 9 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) , 0 . 3 - 0 .45 anhydrous sodium sulfate , and the solvent was distilled off 40 (m , 4H ). under reduced pressure . The residue was purified by silica gel column chromatography wherein it was eluted with ethyl acetate -hexane ( gradient of 2 : 8 to 5 : 5 ) , to obtain 47 mg of Step 3 : Production of N - [ 2 - [ 3 - chloro - 5 - ( cyclopro the desired product as white crystals . pylethynyl) pyridin - 2 - yl) - 2 - hydroxyethyl ]- N - cyclo Melting point: 127 . 0 to 130 .0° C . 45 propyl- 2 -( trifluoromethyl) benzamide ' H NMR ( CDC1z , Me_ Si, 300 MHz ) 88. 38 ( d, J= 1. 8 Hz , 1H ) , 7 .79 ( s , 1H ) , 7 .62 ( d , J = 1 . 8 Hz, 1H ), 7 .00 ( bs , 1H ) , 6 . 90 To a mixture of a 5 ml solution of 70 mg of 1- [3 - chloro ( t, J = 54 . 6 Hz , 1H ), 4 .55 - 4 . 7 ( m , 1H ) , 3 .92 ( s , 3H ) , 3 . 05 - 3 .25 5 - ( cyclopropylethynyl) pyridin - 2 -yl ) - 2 - (cyclopropylamino ) ( m , 2H ), 1. 4 - 1. 5 (m , 1H ) , 1 . 26 (d , J= 6 .3 Hz, 3H ) , 0 . 8 - 0 .95 ethanol in ethyl acetate and a 5 ml solution of 105 mg of ( m , 2H ) , 0 . 75 - 0 . 85 ( m , 2H ) . 50 potassium carbonate in water , 57 mg of 2 - (trifluoromethyl ) benzoyl chloride was added dropwisely with stirring under Synthesis Example 19 ice - cooling . After completion of the dropwise addition , the N -[ 2- [3 -chloro - 5 -( cyclopropylethynyl ) pyridin - 2 -yl ) mixture was stirred for 1 hour at the same temperature . After 2 - methoxyethyl] - N -cyclopropyl - 2 - ( trifluoromethyl ) completion of the reaction , 10 ml of water and 10 ml of ethyl acetate were added to the reaction mixture , and then , the benzamide ( compound No. 12 - 001 of the present organic layer was separated and washed with water ( 10 invention ) mlx1) . Then , dehydration and drying were carried out in the Step 1 : Production of 2 -bromo - 1 - [3 -chloro - 5 -( cy order of with a saturated sodium chloride solution and then clopropylethynyl ) pyridin - 2 - yl] ethanol 60 with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure . The residue was purified by To a 5 ml solution of 310 mg of 2 - bromo - 1 - [ 3 - chloro - 5 silica gel column chromatography wherein it was eluted ( cyclopropylethynyl) pyridin - 2 - yllethanone in methanol. 39 with ethyl acetate -hexane (gradient of from 1 : 9 to 3 : 7 ), to mg of sodium borohydride was added with stirring under obtain 101 mg of the desired product as a colorless resinous ice -cooling , followed by stirring at the same temperature for 65 substance . 1 hour .After completion of the reaction , 20 ml of a saturated ' H NMR (CDC1z , Me Si, 300 MHz) 88 .47 ( d , J = 1. 5 Hz , aqueous ammonium chloride solution was added to the 1H ), 7 .67 (d , J = 1. 5 Hz, 1H ), 7 . 4 -7 .65 ( m , 4H ), 5. 35 - 5 .6 ( m , US 10 , 029 , 986 B2 129 130 1H ), 4 .2 -4 .45 (m , 2H ), 3 .2 - 3 .65 (m , 1H ) , 2 .7 - 3 .0 (m , 1H ), solution of hydrochloric acid was added to the reaction 1 . 4 - 1 . 55 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) , 0 . 3 - 0 . 7 ( m , 4H ) . mixture until themixture became acidic , followed by extrac tion with ethyl acetate ( 15 mlx2 ) . Organic layers were Step 4 : Production of N - [ 2 - [3 -chloro -5 - (cyclopro combined , and then dehydrated and dried in the order of pylethynyl) pyridin - 2 -yl ] - 2 -methoxyethyl ] -N -cyclo 5 with a saturated sodium chloride solution and then with propyl- 2 -( trifluoromethyl) benzamide anhydrous sodium sulfate , and the solvent was distilled off under reduced pressure to obtain 754 mg of the crude desired To 12 mg of 55 % oily sodium hydride in 15 ml of product as white crystals . This product was used directly in tetrahydrofuran , a 3 ml solution of 101 mg of N - [ 2 - [ 3 the next step without further purification . chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl) - 2 - hydroxy - 10 Melting point: 170 .0 to 172 .0° C . ethyl] - N -cyclopropyl - 2 - ( trifluoromethyl) benzamide in tetra - TH NMR (CDCI . . Me . Si. 300 MHz ) 88 . 38 ( d , J = 1 . 8 Hz, hydrofuran was added dropwisely with stirring under ice cooling . After completion of the dropwise addition , the 1H ), 7 . 80 ( d , J = 1 . 8 Hz, 1H ) , 3 . 05 - 3 . 15 ( m , 1H ), 2 . 2 - 2 . 3 ( m , mixture was stirred for 30 minutes at the same temperature. 1H ) , 1 . 6 - 1 .75 ( m , 2H ) . Then , 49 mg of methyl iodide was added, and stirring was 15 continued at room temperature for 2 hours . After completion Step 3 : Production of tert -butyl N - [ 2 - [ 5 - bromo - 3 of the reaction , 20 ml of water was added to the reaction chloropyridin - 2 - yl] cyclopropyl] carbamate mixture , followed by extraction with ethyl acetate ( 15 mlx2 ) . Organic layers were combined and washed with To a 10 ml suspension of 754 mg of 2 - [ 5 - bromo - 3 water ( 20 mlx1 ) . and then dehydrated and dried in the order 20 chloropyridin - 2 -yllcyclopropane carboxylic acid in tert- bu of with a saturated sodium chloride solution and then with tanol, 304 mg of triethylamine and 902 mg of diphenyl anhydrous sodium sulfate , and the solvent was distilled off phosphate azide were added , and the mixture was stirred for under reduced pressure . The residue was purified by silica 2 hours at 80° C . After completion of the reaction , the gel column chromatography wherein it was eluted with ethyl reaction mixture was left to cool to room temperature , and acetate -hexane ( gradient of from 5 : 95 to 20 :80 ) , to obtain 55 25 after addition of 20 ml of a saturated aqueous sodium mg of the desired product as a colorless resinous substance . bicarbonate solution , the mixture was extracted with ethyl ' H NMR (CDC13 , Me Si, 300 MHz) 88 . 56 ( d , J = 1 .5 Hz, acetate ( 15 mlx2 ). Organic layers were combined and 1H ), 7 .67 ( d , J = 1 .5 Hz, 1H ) , 7 .4 - 7 .65 ( m , 4H ) , 5 . 3 - 5 . 45 ( m , washed with water ( 20 mlx1) , and then dehydrated and dried 1H ) , 3 .75 - 4 . 3 ( m , 1H ) , 3 . 2 - 3 .65 ( m , 1H ), 3 .35 ( s , 3H ) , in the order of with a saturated sodium chloride solution and 2 . 5 - 2 . 8 ( m , 1H ), 1 . 4 - 1 . 55 ( m , 1H ) , 0 .8 - 1 . 0 ( m , 4H ) , 0 . 3 - 0 . 7 30 then with anhydrous sodium sulfate , and the solvent was ( m , 4H ) . distilled off under reduced pressure. The residue was puri fied by silica gel column chromatography wherein it was Synthesis Example 20 eluted with ethyl acetate -hexane ( gradient of from 5 : 95 to 15 : 85 ) , to obtain 410 mg of the desired product as white tert- butyl N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) 35 crystals. pyridin -2 - yl] cyclopropyl ] -N -[ 3 - difluoromethyl- 1 Melting point: 132 . 0 to 134 . 0° C . methyl- 1H - pyrazole -4 -carbonyl ] carbamate (com H NMR (CDC1z , Me Si , 300 MHz ) 88 .34 ( d , J = 2 . 1 Hz, pound No . 12 - 002 of the present invention ) 1H ) , 7 .75 ( d , J = 2 . 1 Hz , 1H ), 4 .80 (bs , 1H ), 3 . 0 - 3 . 15 (m , 1H ), Step 1 : Production of ethyl= 2 - [ 5 - bromo- 3 - chloro - 40 24 .: 5 - 2 .6 ( m , 1H ), 1 . 5 - 1 .6 ( m , 1H ) , 1 .43 ( s , 9H ), 1 . 2 - 1 . 35 ( m , pyridin -2 - yl ]cyclopropanecarboxylate 1H ). To a 5 ml solution of 1 . 56 g of 5 - bromo - 3 - chloro - 2 Step 4 : Production of tert -butyl N - [ 2 - [ 3 -chloro - 5 vinylpyridine in toluene, 5 .43 g of a 15 % toluene solution of (cyclopropylethynyl ) pyridin - 2 -yl ] cyclopropyl ] car ethyl diazoacetate was added dropwisely with stirring under 45 bamate heating at 110° C . , and after completion of the dropwise addition , stirring was continued for one hour at the same To a 3 ml solution of 573 mg of tert -butyl N - [2 - [ 5 -bromo temperature . After completion of the reaction , the reaction 3 -chloropyridin - 2 - yl| cyclopropyl?carbamate in N , N - dim mixture was left to cool to room temperature , and the solvent ethylformamide, 667 mg of triethylamine, 218 mg of cyclo was evaporated under reduced pressure. The residue was 50 propylacetylene , 94 mg of copper( I ) iodide and 116 mg of purified by silica gel column chromatography wherein it was dichlorobis ( triphenylphosphine )palladium ( II ) were added , eluted with ethyl acetate -hexane ( gradient of from 0 : 100 to followed by stirring under a nitrogen atmosphere at 50° C . 15 : 85 ), to obtain 0 .85 g of the desired product as a colorless for 2 hours . After completion of the reaction , the reaction oily substance . mixture was left to cool to room temperature , and after ' H NMR (CDC12 , Me. Si, 300 MHz ) 88 .37 ( d , J = 2 . 1 Hz, 55 addition of 10 ml of a saturated aqueous solution of ammo 1H ) , 7 .79 ( d . J = 2 . 1 Hz, 1H ) , 4 . 18 ( g . J = 7 . 2 Hz, 2H ) , nium chloride , the mixture was extracted with ethyl acetate 2 . 95 - 3 .05 ( m , 1H ) , 2 . 2 - 2 . 3 ( m , 1H ) , 1 . 55 - 1 . 7 ( m , 2H ) , 1 . 28 ( 10 mlx2 ) . Organic layers were combined and washed with ( t , J = 7 . 2 Hz , 3H ) . water ( 10 mlx1) , then dehydrated and dried in the order of with a saturated sodium chloride solution and then with Step 2 : Production of 2 -15 -bromo - 3 - chloropyridin - 60 anhydrous sodium sulfate , and the solvent was distilled off 2 - yl] cyclopropanecarboxylic acid under reduced pressure . The residue was purified by silica gel column chromatography wherein it was eluted with ethyl To a 5 ml solution of 850 mg of ethyl= 2 - [ 5 - bromo- 3 acetate hexane ( gradient of from 5 :95 to 15 : 85 ) , to obtain chloropyridin - 2 - yl] cyclopropane carboxylate in ethanol, 5 438 mg of the desired product as white crystals. ml of a 10 wt % sodium hydroxide aqueous solution was 65 Melting point: 137 .0 to 139. 0° C . added , and the mixture was stirred at room temperature for ' H NMR ( CDC13 , Me_ Si, 300 MHz ) 88 . 26 (d , J = 1 . 8 Hz, 3 hours. After completion of the reaction , a 10 wt % aqueous 1H ) , 7 . 57 ( d , J = 1 . 8 Hz, 1H ) , 4 .81 ( bs, 1H ) , 3 . 0 - 3 . 15 ( m , 1H ) , US 10 , 029 , 986 B2 131 132 2 . 5 - 2 . 6 ( m , 1H ) , 1 . 5 - 1 . 6 ( m , 1H ) , 1 . 4 - 1 . 5 m , 1H ) , 1 .44 ( s , Synthesis Example 22 9H ) , 1 . 2 - 1 . 3 ( m , 1H ) , 0 . 85 - 0 . 95 ( m , 2H ) , 0 . 75 - 0 . 85 ( m , 2H ) . N - [ 2 - [ 3 - chloro - 5 - ( cyclopropylethynyl) pyridin - 2 - yl] Step 5 : Production of tert -butyl N - [ 2 - [ 3 - chloro - 5 1 -methylethyl ] - 4 - difluoromethyl - 2 -methylthiazole ( cyclopropylethynyl )pyridin - 2 - yl ]cyclopropyl ] - N - 13 - 5 5 -carboxamide ( compound No . 9 -007 of the present difluoromethyl- 1 -methyl - 1H -pyrazole - 4 -carbonyl ] invention ) carbamate Step 1 : Production of To a 3 ml solution of 256 mg of 3 - difluoromethyl - 1 5 - bromo- 3 - chloro - 2 - ( 2 - nitropropyl) pyridine methyl - 1H -pyrazole - 4 -carboxylic acid in dichloromethane , 10 To a 1 . 5 ml solution of 156 mg of 5 -bromo - 3 - chloro - 2 335 mg of oxalyl chloride and 5 mg of N ,N -dimethylfor - ( 2 -nitro -1 -propenyl ) pyridine produced in Step 1 of Synthe mamide were added , followed by stirring at room tempera sis Example 16 in methanol, 85 mg of sodium borohydride ture for 2 hours . Then , the solvent was distilled off under was added with stirring under ice -cooling , and the mixture reduced pressure , and the residue was dissolved in 3 ml of was stirred for 6 hours at room temperature . After comple tetrahydrofuran . 15 tion of the reaction , to the reaction mixture , 5 ml of water was added , followed by extraction with ethyl acetate ( 10 To a 10 ml solution of 438 mg of tert - butyl N - [ 2 - [ 3 mlx2 ) . Organic layers were combined , and then dehydrated chloro -5 -( cyclopropylethynyl) pyridin - 2 - yl] cyclopropyl] car and dried in the order of with a saturated sodium chloride bamate in tetrahydrofuran , 0 .73 ml of a n - butyl lithium solution and then with anhydrous sodium sulfate , and the hexane solution ( 2 .65M ) was added dropwisely with stirring 20 solvent was distilled off under reduced pressure , to obtain at - 78° C . After completion of the dropwise addition , 120 mg of the crude desired product as a yellow resinous stirring was further continued at the same temperature for 1 substance. This product was used directly in the next step hour, and then , the above tetrahydrofuran solution of 3 - di- without further purification . fluoromethyl- 1- methyl - 1H -pyrazole -4 -carbonyl chloride H NMR (CDC13 , Me4Si, 300 MHz) 88. 38 (d , J= 2 . 1 Hz, was added dropwisely , and while raising the temperature to 25 1H ) , 7 . 76 ( d , J = 2 . 1 Hz, 1H ) , 5 . 1 - 5 . 25 ( m , 1H ), 3 .62 ( dd , room temperature , stirring was continued for 2 hours . After J= 16 . 5 , 8 .6 Hz , 1H ), 3 . 11 (dd , J = 16 . 5 , 5 .2 Hz, 1H ) , 1 .599 (d , completion of the reaction , 20 ml of a saturated aqueous J= 7 .0 Hz, 3H ) . ammonium chloride solution was added to the reaction Step 2: Production of 2 - (5 -bromo - 3 -chloropyridin mixture , followed by extraction with ethyl acetate ( 20 2 - yl) - 1 -methylethylamine mlx2 ) . Organic layers were combined and washed with 30 120 mg of 5 -bromo -3 - chloro - 2 -( 2 -nitropropyl )pyridine water ( 20 mlx1) , and then dehydrated and dried in the order was dissolved in 3 ml of a methanol- water ( 2 : 1 ) mixed of with a saturated sodium chloride solution and then with solvent , and 138 mg of ammonium chloride and 72 mg of anhydrous sodium sulfate , and the solvent was distilled off reduced iron were added , followed by stirring at room 75° under reduced pressure . The residue was purified by silica C . for 16 hours. After completion of the reaction , the gel column chromatography wherein it was eluted with ethyl reaction mixture was left to cool to room temperature , and after removing insoluble matters through Celite filtration , acetate -hexane ( gradient of from 5 : 95 to 50 : 50 ), to obtain the solvent was distilled off under reduced pressure . The 167 mg of the desired product as white crystals . residue was dissolved in 10 ml of diethyl ether, and extracted Melting point: 110 . 0 to 112 .0° C . with 10 ml of a IN aqueous hydrochloric acid solution , and ' H NMR (CDC13 , Me Si, 300 MHz) 88. 31 ( d, J = 2 .1 Hz, 40 after addition of a 1N aqueous sodium hydroxide solution to 1H ), 7 .74 ( s , 1H ) , 7 .59 ( d , J = 2 . 1 Hz, 1H ) , 6 . 86 ( t , J = 55 . 2 Hz, the aqueous layer until the pH became 14 , followed by back extraction with ethyl acetate ( 30 mlx2 ). Organic layers were 1H ) , 3 . 93 ( s, 3H ) , 3 . 3 - 3 .4 (m , 1H ), 2 .7 -2 .8 ( m , 1H ), 1. 7 - 1 .8 combined , and then dehydrated and dried in the order of ( m , 1H ), 1. 35 - 1. 45 (m , 2H ), 1. 34 (s , 9H ), 0 .8 -0 .95 ( m , 4H ). with a saturated sodium chloride solution and then with anhydrous sodium sulfate , and the solvent was distilled off Synthesis Example 21 45 under reduced pressure , to obtain 86 mg of the crude desired product as a yellow resinous substance . This product was N - [ 2 - [3 - chloro - 5 -( cyclopropylethynyl ) pyridin - 2 -yl ] used directly in the next step without further purification . cyclopropyl ]- 3 -difluoromethyl - 1 -methyl - 1H - pyra ' H NMR (CDC12 , Me Si, 300 MHz ) 88 .50 ( d , J = 2 . 1 Hz, zole -4 -carboxamide ( compound No . 8 -033 of the 1H ), 7 . 82 ( d , J = 2 . 1 Hz, 1H ) , 3 . 4 - 3 . 55 ( m , 1H ) , 2 . 98 (dd , present invention ) 50J= 14 . 4 , 4 . 9 Hz, 1H ) , 2 . 85 ( dd , J = 14 . 2 , 8 . 1 Hz , 1H ) , 1 . 76 (bs , 2H ) , 1 . 18 (d , J = 6 . 4 Hz, 3H ). To a 9 ml solution of 167 mg of tert -butyl N - [2 - [3 - chloro Step 3 : Production of tert -butyl N - [ 2 - ( 5 -bromo - 3 5 -( cyclopropylethynyl) pyridin - 2 - yl] cyclopropyl ] - N -[ 3 -dif chloropyridin - 2 - yl) - 1 -methylethyl ]carbamate luoromethyl- 1 -methyl - 1H -pyrazole - 4 -carbonyl ]carbamate in dichloromethane , 1 ml of trifluoroacetic acid was added , 55 To a 1 ml solution of 86 mg of 2 - ( 5 - bromo - 3 -chloropyri followed by stirring at room temperature for 12 hours . After din - 2 - yl) - 1 -methylethylamine and 42 mg of triethylamine in completion of the reaction , the solvent was distilled off dichloromethane , 91 mg of di- tert -butyl dicarbonate was under reduced pressure , and the residue was purified by added , followed by stirring at room temperature for 1 hour. silica gel column chromatography wherein it was eluted After completion of the reaction , the solvent was distilled off with ethyl acetate - hexane ( gradient of from 1 : 4 to 2 : 3 ) , to 60 under reduced pressure , and the residue was purified by obtain 81 mg of the desired compound as white crystals . silica gel column chromatography wherein it was eluted Melting point: 176 . 0 to 178 . 0° C . with ethyl acetate -hexane ( gradient of from 2 : 8 to 4 : 6 ) , to H NMR (CDC12 , Me, Si, 300 MHz ) 88 . 29 ( d , J = 2 . 1 Hz, obtain 74 mg of the desired product as a yellow resinous 1H ) , 7 .91 (s , 1H ), 7 .57 (d , J= 2 . 1 Hz , 1H ), 6 .81 ( t, J = 54 .9 Hz , substance . 1H ), 6 .55 (bs , 1H ) , 3 . 91 ( s , 3H ) , 3 . 35 - 3 . 45 ( m , 1H ) , 2 . 6 - 2 . 7 65 H NMR (CDC12 , Me, Si, 300 MHz ) 88 .48 ( d , J = 2 . 0 Hz, ( m , 1H ) , 1 .65 - 1 .75 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 3 - 1 . 4 ( m , 1H ), 7 .81 ( d , J = 1 . 7 Hz, 1H ) , 4 . 92 (bs , 1H ) , 4 . 0 - 4 . 3 ( m , 1H ) , 1H ) , 0 .75 - 0 .95 ( m , 4H ) . 2 .9 -3 . 2 ( m , 2H ), 1. 36 (s , 9H ), 1. 21 (d , J = 6 .5 Hz, 3H ). US 10 ,029 , 986 B2 133 134 Step 4 : Production of tert -butyl N - [ 2 - [ 3 - chloro - 5 wherein it was eluted with ethyl acetate - hexane ( gradient of ( cyclopropylethynyl) pyridin - 2 - yl) - 1 -methylethyl ] from 3 : 7 to 6 : 4 ) , to obtain 55 mg of the desired product as carbamate a colorless resinous substance . ' H NMR (CDC12 , Me. Si, 300 MHz ) 88 .41 ( d , J = 1 . 5 Hz , To a 3 ml solution of 74 mg of tert -butyl N - 12 - ( 5 -bromo - 5 1H ) , 7 . 66 ( d , J = 1 . 5 Hz, 1H ) , 7 .51 ( d , J = 7 . 4 Hz, 1H ) , 7 . 26 ( t , 3 -chloropyridin - 2 -yl ) - 1 -methylethyl ] carbamate in dimethyl J = 54 . 1 Hz, 1H ) , 4 .45 - 4 . 7 ( m , 1H ) , 3 .21 ( dd , J = 14 . 7 , 6 . 4 Hz, sulfoxide , 107 mg of triethylamine , 28 mg of cyclopropy . 1H ) , 3 . 13 (dd , J = 14 . 5 , 4 . 7 Hz, 1H ) , 2 .75 ( s , 3H ) , 1 . 4 - 1 .55 ( m , lacetylene , 12 mg of copper ( I ) iodide and 15 mg of dichlo - 1H ) , 1 . 28 ( d , J = 6 . 7 Hz, 3H ) , 0 . 75 - 1 .0 ( m , 4H ) . robis ( triphenylphosphine )palladium ( II ) were added , fol lowed by stirring under a nitrogen atmosphere at 50° C . for 10 Synthesis Example 23 1 hour. After completion of the reaction , the reaction mixture was left to cool to room temperature , and 10 ml of a N - [ 2 - [ 3 -chloro - 5 -( cyclopropylethynyl ) pyridin - 2 -yl ) saturated aqueous solution of ammonium chloride was 2 - fluoropropyl) - 2 - (difluoromethyl ) nicotinamide added to the reaction mixture , followed by extraction with ethyl acetate (30 mlx2 ) . Organic layers were combined and ( compound No. 3 -038 of the present invention ) washed with water ( 20 mlxl ), and then dehydrated and dried 15 in the order of with a saturated sodium chloride solution and Step 1 : Production of 2 - C5 -bromo - 3 - chloropyridin then with anhydrous sodium sulfate , and the solvent was 2 - yl) - 2 - fluoropropanenitrile distilled off under reduced pressure. The residue was puri fied by silica gel column chromatography wherein it was To a 20 ml solution of 1 .40 g of 2 - ( 5 -bromo - 3 - chloro eluted with ethyl acetate -hexane ( gradient of from 15 : 85 to 20 pyridin - 2 - yl) propanenitrile produced in Step 1 of Synthesis 35 :65 ) , to obtain 60 mg of the desired product as a brown Example 4 in tetrahydrofuran , 5 . 5 ml of a 1 . 3M tetrahydro resinous substance . furan solution of lithium bis (trimethylsilyl ) amide was added ' H NMR (CDC1z , Me Si, 300 MHz) 88 . 38 ( d , J = 1 . 7 Hz, dropwisely with stirring at - 78° C . After completion of the 1H ), 7 .60 (d , J = 2 .0 Hz, 1H ), 4 .98 (bs , 1H ) , 4. 05 - 4. 2 ( m , 1H ), dropwise addition , stirring was continued at the same tem 3 .04 ( d , J = 6 . 5 Hz, 2H ) , 1 . 4 - 1 .55 ( m , 1H ), 1. 37 (s , 9H ), 1 . 18 3525 perature for 30 minutes. Then , a 10 ml solution of 2 .00 g of ( d , J = 6 . 5 Hz, 3H ), 0 .75 - 1 . 0 ( m , 4H ) . N - fluorobenzenesulfonimide in tetrahydrofuran was added dropwisely to this reaction mixture . After completion of the Step 5 : Production of 2 - [3 -chloro -5 - (cyclopropyl dropwise addition , stirring was continued for an additional ethynyl )pyridin - 2 -yl ) - 1- methylethylamine 2 hours at the same temperature . After completion of the To a 5 ml solution of 335 mg tert -butyl N - [ 2 - [3 - chloro 30 reaction , 30 ml of water was added to the reaction mixture , 5 -( cyclopropylethynyl )pyridin - 2 -yl ) - 1 -methylethyl ] carbam followed by extraction with ethyl acetate ( 25 mlx2 ) . Organic ate in dichloromethane, 5 ml of trifluoroacetic acid was layers were combined and washed with water (30 mlx1 ) , and added with stirring under ice -cooling , followed by stirring at then dehydrated and dried in the order of with a saturated room temperature for 1 hour. After completion of the reac sodium chloride solution and then with anhydrous sodium tion , 10 ml of toluene was added to the reaction mixture , and 35 sulfate , and the solvent was distilled off under reduced the solvent was distilled off under reduced pressure . The pressure . The residue was purified by silica gel column residue was dissolved in 20 mlof ethyl acetate and washed chromatography wherein it was eluted with ethyl acetate with 10 ml of a saturated aqueous sodium bicarbonate hexane ( gradient of from 0 : 10 to 1 : 9 ) , to obtain 1. 33 g of the solution and then with 10 ml of water. The organic layer was desired product as a colorless oily substance. dehydrated and dried in the order of with a saturated sodium an H NMR (CDC12 , Me Si, 300 MHz ) 88 .59 ( d , J = 2 . 4 Hz, chloride solution and then with anhydrous sodium sulfate , 1H ) , 8 .02 ( d , J = 2 . 4 Hz, 1H ) , 2 .23 ( d , J = 22 . 2 Hz, 3H ) . and the solvent was distilled off under reduced pressure to obtain 266 mg of the crude desired product as a yellow Step 2 : Production of tert - butyl N - [ 2 - ( 5 - bromo - 3 resinous substance . This product was used directly in the chloropyridin - 2 -yl ) - 2 - fluoropropyl ] carbamate next step without further purification . ' H NMR (CDC12 , Me Si, 300 MHZ ) 08 .36 ( s, 1H ) , 7 .65 % To a 20 ml solution of 1. 33 g of 2 - (5 - bromo- 3 - chloro ( d , J = 1 . 5 Hz, 1H ) , 5 .25 ( bs, 2H ) , 3 . 5 - 3 .75 ( m , 1H ) , 2 . 95 - 3 . 2 pyridin - 2 - yl) - 2 - fluoropropanenitrile in dichloromethane ( m , 2H ), 1 .4 - 1 .55 ( m , 1H ), 1 . 37 ( d , J= 6 .4 Hz, 3H ) , 0 . 75 - 1. 0 under a nitrogen atmosphere , 11 ml of a 1 . 0M hexane ( m , 4H ). solution of diisobutylaluminum hydride was added drop wisely with stirring at - 78° C . After completion of the Step 6 : Production of N - [ 2 -[ 3 - chloro - 5 - (cyclopro 50 dropwise addition , stirring was continued at the same tem pylethynyl) pyridin - 2 - yl) - 1 -methylethyl ) - 4 - difluo perature for 1 hour. Then , 30 ml of dichloromethane was romethyl- 2 -methylthiazole - 5 - carboxamide added to the reaction mixture , and the temperature was raised to room temperature , and 30 mlof a saturated aqueous 53 mg of 2 - [ 3 -chloro - 5 - ( cyclopropylethynyl) pyridin - 2 solution of sodium potassium tartrate (Rochelle salt ) was yl ] - 1 -methylethylamine was dissolved in 2 ml of a dichlo - 55 added . After continuing stirring for further 2 hours at the romethane - N , N -dimethylformamide ( 1 : 1 ) mixed solvent, same temperature, 30 ml of water was added to the reaction and 52 mg of 4 - difluoromethyl- 2 -methylthiazole - 5 -carbox - mixture, and the organic layer was separated . The separated ylic acid , 2 mg of N , N - dimethyl- 4 -aminopyridine and 65 mg organic layer was washed with a saturated Rochelle salt of 1 - ( 3 -dimethylaminopropyl ) - 3 - ethylcarbodiimide hydro - solution ( 20 mlx1) and then with water ( 20 mlx2 ) , and chloride were added , followed by stirring at room tempera - dehydrated and dried in the order of with a saturated sodium ture for 16 hours. After completion of the reaction , 10 ml of ou chloride solution and then with anhydrous sodium sulfate , water was added to the reaction mixture , followed by and the solvent was distilled off under reduced pressure . The extraction with ethyl acetate ( 10 mlx2 ) . Organic layers were residue was dissolved in 10 mlof dichloromethane , and 0 .57 combined and washed with water ( 10 mlx1 ), and then g of triethylamine and 1 .21 g of di- tert -butyl dicarbonate dehydrated and dried in the order of with a saturated sodium were added , followed by stirring at room temperature for 2 chloride solution and then with anhydrous sodium sulfate , 65 hours . After completion of the reaction , the solvent was and the solvent was distilled off under reduced pressure. The distilled off under reduced pressure , and the residue was residue was purified by silica gel column chromatography purified by silica gel column chromatography wherein it was US 10 , 029 , 986 B2 135 136 eluted with ethyl acetate -hexane ( gradient of from 0 : 100 to layers were combined and washed with 10 ml of water , and 5 : 95 ) , to obtain 375 mg of the desired product as a colorless then dehydrated and dried in the order of with a saturated oily substance . sodium chloride solution and then with anhydrous sodium IH NMR (CDC12 , Me Si, 300 MHz) 88 . 51 ( d , J = 2 . 1 Hz, sulfate , and the solvent was distilled off under reduced 1H ), 7 .90 ( d , J = 2 . 1 Hz , 1H ) , 5 .03 (bs , 1H ) , 3 .87 ( d , J = 6 .0 Hz , pressure to obtain 230 mg of the crude desired product as a 1H ), 3 .81 ( d , J = 6 . 0 Hz, 1H ) , 1 .78 ( d , J = 21. 9 Hz, 3H ) , 1. 41 brown oily substance . This product was used directly in the (s , 9H ). next step without further purification . ' H NMR (CDC1z , Me Si, 300 MHz ) 88 .41 (d , J= 1. 5 Hz , Step 3 : Production of tert -butyl N -[ 2 -[ 3 -chloro -5 1H ) , 7 .68 ( d , J = 1 . 5 Hz, 1H ) , 3 .45 - 3 . 6 ( m , 1H ) , 3 .05 - 3 . 15 ( m , (cyclopropylethynyl ) pyridin - 2 - yl) - 2 - fluoropropyl] 1H ) , 1 .72 ( d , J = 21. 6 Hz, 3H ) , 1 .4 - 1. 55 (m , 1H ), 0. 8 -1 .0 ( m , carbamate 10 4H ). To a 3 ml solution of 375 mg of tert -butyl N - [ 2 - ( 5 - bromo Step 5 : Production of N - [ 2 - [ 3 - chloro - 5 - (cyclopro 3 -chloropyridin - 2 -yl ) - 2 - fluoropropyl ]carbamate in N , N -di pylethynyl )pyridin - 2 -yl ] - 2 - fluoropropyl) - 2 -( difluo methylformamide , 413 mg of triethylamine , 135 mg of romethyl) nicotinamide cyclopropylacetylene , 58 mg of copper (I ) iodide and 70 mg 15 of dichlorobis (triphenylphosphine ) palladium (II ) were To a 2 ml solution of 58 mg of 2 - [ 3 -chloro - 5 - ( cyclopro added , followed by stirring under a nitrogen atmosphere at pylethynyl) pyridin - 2 - yl] - 2 -fluoro - 1 -propanamine in dichlo 50° C . for 2 hours . After completion of the reaction , the romethane, 5 mg of N , N - dimethyl - 4 - aminopyridine , 44 mg reaction mixture was left to cool to room temperature, and of 2 - (difluoromethyl ) nicotinic acid and 66 mg of 1 - ( 3 20 ml of a saturated aqueous ammonium chloride solution dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride was added , followed by extraction with ethyl acetate ( 15 were added , followed by stirring at room temperature for 2 mlx2 ) . Organic layers were combined and washed with hours. After completion of the reaction , 3 ml of water was added to the reaction mixture , followed by extraction with water ( 10 mlx2 ) , and then dehydrated and dried in the order dichloromethane ( 2 mlxl) , and the organic layer was of with a saturated sodium chloride solution and then with washed with water ( 10 mlx1) and then passed through a anhydrous sodium sulfate , and the solvent was distilled off silica gel short path column eluting with ethyl acetate , under reduced pressure . The residue was purified by silica whereupon the solvent was distilled off under reduced gel column chromatography wherein it was eluted with ethyl pressure . The residue was washed with hexane , to obtain 43 acetate - hexane ( gradient of from 5 : 95 to 15 : 85 ) , to obtain mg of the desired product as white crystals . 310 mg of the desired product as a colorless resinous Melting point: 113 . 0 to 115 . 0° C . substance . ' H NMR (CDC1z , Me Si, 300 MHz) 88 .73 (dd , J = 4 . 8 , 1 . 8 H NMR (CDC1z , Me. Si, 300 MHz ) 88 . 38 ( d , J= 1. 8 Hz, Hz, 1H ) , 8 .36 ( d , J = 1 . 8 Hz , 1H ), 7 . 87 (d , J = 8 . 1 Hz, 1H ) , 7 .71 1H ), 7 .68 (d , J = 1 . 8 Hz, 1H ) , 5 .08 (bs , 1H ) , 3 . 85 - 3 . 9 m , 1H ) , ( d , J = 1. 8 Hz, 1H ) , 7 .45 ( dd , J = 8 . 1 , 4 . 8 Hz, 1H ) , 6 . 90 ( t , 3 .75 - 3 .85 ( m , 1H ) , 1 .77 ( d , J = 21 .6 Hz, 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , J = 54 . 9 Hz, 1H ), 6 .74 (bs , 1H ) , 4 . 15 - 4 . 3 ( m , 2H ) , 1 .86 ( d , 1 .41 ( s, 9H ), 0 .8 - 1. 0 ( m , 4H ). J = 21. 3 Hz, 3H ) , 1 . 4 - 1 . 5 ( m , 1H ), 0 . 8 - 1 . 0 ( m , 4H ) . The compounds of the present invention can be produced Step 4 : Production of 2 -[ 3 - chloro -5 - ( cyclopropyl- 35 according to the above- described production methods and ethynyl) pyridin - 2 - yl] - 2 -fluoro - 1 -propanamine Examples . Examples of alkynyl pyridine- substituted amide compounds which are encompassed by the present invention To a 2 mlsolution of 310 mg of tert -butyl N - [ 2 - 13 -chloro - which were prepared in the same manner as in Synthesis 5 -( cyclopropylethynyl )pyridin -2 - yl )- 2- fluoropropyl] car Examples 1 to 23 , are shown in Tables 3 to 14 , but the bamate in dichloromethane , 2 ml of trifluoroacetic acid was 40 alkynyl pyridine -substituted amide compounds encom added , followed by stirring for 2 hours at room temperature . passed by the present invention and their production inter After completion of the reaction , the solvent was distilled off mediates are not limited thereto . under reduced pressure , and 10 ml of a 10 % aqueous In the Tables , the symbol “ * 1 ” in the column for melting potassium carbonate solution was added to the residue , point means that the properties of the compounds are oily or followed by extraction with ethyl acetate ( 10 mlx2 ) . Organic resinous . TABLE 3 RO = x 0 R3 R4

R1 R2

No. x1 R3 R4 R R2 y1 RO m .p . (°C . )

T) 1 - 001 ??? ?? CH3 100 .0 - 103 .0 1 - 002 CF3??? ? ? C1 C - Pr 105 . 0 - 108 . 0 T 1 -003 ??? CI t - Bu 90 . 0 - 92 . 0

T 1 -004 CF3??? HHHHFF Cl CHOCHZ 82 . 0 - 83 . 0 1 -005 CF3??? F C C - Pr 137 . 0 - 139 . 0 1 - 006 T HHHHFFH CF ??? F CL CHOCH , CFz 105. 0 - 106 . 0 1 - 007 T??? CHZ H CI C - Pr 1 - 008 T??? CH3 CH , Cl C - Pr T 1 - 009 ??? C -Pr ? CI C - Pr

T 1 - 010 CFz??? CH2CF3 H C1 C - Pr US 10 ,029 , 986 B2 137 138 TABLE 3 -continued

R3 R4

R ! R2

No . X R3 R4 R1 R2 y RO m . p . ( ° C .)

1 - 011 ??? H CH2( Ph -3 ,4 - F2) H C - Pr * 1 1 -012 ( ??? CH2 – CH3 85 . 0 - 90 . 0 1 -013 CFz17 CH2 – C - Pr 50 . 0 - 55 . 0 1 -014 Cl CH - CH2 C - Pr * 1 1 -015 I CH2CH2 – C - Pr 125. 0 - 126 . 0 1 - 016 CH CH2CH2 c - Pr 96 . 0 - 97 . 0 1 -017 CF3 CH2CH2 C - Pr * 1 1 -018 NO , CH2CH2 C - Pr 98 . 0 - 99 . 0 1 -019 CF3??? CH2CH2– CH , OCH , CFz 75 . 0 -76 . 0 1 -020 CF??? - OCH2 CH3 * 1 1 - 021 ??? SCHZ ? C - Pr * 1 1 - 022 CF3??? CN H C - Pr 132 . 0 - 134 . 0 1 -023 CF3??? H CN CN c - Pr 42 . 0 - 44 . 0 1 -024 ??? CH3 OCHZ C - Pr * 1 1 - 025 ??? CH3 OCHZ ? t -Bu 36 . 0 - 38 . 0 1 - 026 CFz??? CH3 OET C - Pr 1 -027 CF3??? ??3 OCH CF3 C - Pr 1 -028 CF3??? CH3 OCH CN C - Pr 1 -029 CF??? CH3 OCH , CH = CH , C - Pr 1 -030 CF??? CH ? H OCH2C = CH H C -Pr 1 - 031 ??3??? CH3 ? OCH Ph ? C - Pr 1 -032 CF3??? CHZ H SCH CF3 C - Pr 1 -033 1 -033 CF3??? CH CH - ? c - Pr 115 . 0 22- 120 . 0 1 - 034 CF??? , CH , H C - Pr 116 . 0 - 117. 0 1 -035 CF3TTTTTTTTTTTTTTTTT??? EEEEEEEEH H CH3 C - Pr 129 . 0 131. 0 TABLE 4 0000000000000000000000000 RO Y o R3 R4 B

R ! R2

# No. x1 R3 R4 R : R2 y R6 m .p . (°C . ) 2 - 001 CF3 H H F F Clc -Pr 157 . 0 - 158 . 0 2 - 002 CFz H H CH Cic - Pr 107 . 0 - 109 . 0 2 - 003 Cl H H CHÚCH, — Cl cher * 1 2 - 004 CF3 H H CH CH2 – Cic-Pr 1 * 50

TABLE 5

Y ! o= R3 R4 EZ R1 R2 No . x1 R3 R4 R R2 y? R6 m .p . (°C . ) 33 --001 CHF , H H H CI C - Pr 114 . 0 - 117 . 0 3 - 002 CHF, H H H H C t - Bu 144 . 0 - 146 . 0 US 10 ,029 , 986 B2 139 140 TABLE 5 - continued

R3 R4 SRO

R RP

No . X R3 R4 RI R2 Y RO m . p . (° C . )

3 - 003 CHF , ? ? IJI C C - Pr 116 . 0 - 118 . 0 3 - 004 CI ? ? C CH ,OCH CFz 108 .0 - 109. 0 3 -005 ? CH3CH2H C1 C - Pr 3 - 006 CHF ? CHZ c - Pr = 3 -007 CHF ) FFHH = H CH3 3 C -Pr 3 - 008 CHF2 C -Pr C - Pr = 3 -009 CHF2 H CH2( Ph -3 , 4- F2) C - Pr = 3 -010 CI CH , — C - Pr 120 . 0 - 123. 0 3 - 011 CHF, H CH c - Pr 114 . 0 - 116 . 0 3 -012 CFZ H CH C - Pr 125 . 0 - 129 . 0 3 - 013 CHF , H CH( Cl ) = ( E C - Pr * 3 - 014 CHF , H CH ( Cl) - ( Z C - Pr * 3 -015 CI H - CH2CH2 C - Pr *22 3 -016 CHF, ? CH2CH2 C - Pr 94 .0 -95 .0 3 -017 CF H H CH2CH2 C - Pr 140 . 0 - 140 . 5 3 -018 CH H - CH2CH2 CI CHOCH CF3 * 1 3 -019 CF CH2CH2 – CH OCH CF2 107 . 0 - 108 . 5 3 -020 CHF H H SCH ; C - Pr * = 3 -021 CHF, CH2 H OCHZ C - Pr * = 3 -022 CHF, CH , H OET C - Pr * = 3 -023 C1 CH? H . OCH CFz C - Pr * = 3 - 024 CHF, CH? H . OCH CF3 C - Pr * = 3 - 025 CHF , CH , H C - Pr * = 3 - 026 CH3 H OCH CH = CH 48 . 0 - 50 . 0 3 - 027 CH CHZ H OCH CH = CH , 3 -028 CICI CH3 H OCH , C = CH * 1 3 - 029 CHF , CH , H OCH _ C = CH * 1 3 -030 ?? OCH Ph 50 . 0 -52 . 0 3 - 031 CI ?? OCH , Ph *1 3 -032 CI ??? ? SCH CF2??? C - Pr * 1 3 -033a SCH , CFz??? C -Pr 72 . 0 - 74 . 0 33 -- 034034 CF , CH? H SCH , CF3??? C - Pr * 1 3 - 034a 13 CH , H SCH , CF3??? C - Pr 65 . 0 -66 . 0 3 - 035 CI CHE H H C - Pr 146 . 0 - 147 . 0 33 -036 CHF , CH H ? c - Pr 149 . 0 - 150 . 0 3 - 037 C? ? ? CH3 C - Pr 83 . 0 - 85 . 0 3 -038 CHF H H CHZ C - Pr 113 . 0 - 115 . 0

HHHHHHHHHHHHHHHHHHFF 45 TABLE 6 000000000000000000000000000000000020 TABLE 7 YA 0 R3 R4 50 R3 R4 N R ! R2 R1 R2 55 No. X R3 R4 R1 R2 y ! RO m .p . (°C . ) No . X R3 R4 R1 R2 y R6 m . p . (°C . )

4 -001 CF??? ; H H F F cic-Pr 161. 0 - 163 . 5 -001 CH2 H H F F c c -Pr 71. 0 -73 . 0 4 - 002 CF3??? H H CH – C1 C -Pr 101. 0 - 103. 0 5 -002 CF3 H H CH CH – Cic - Pr * 1 4- 003 CF???, H H = CH - CH2 - c1 c- Pr 125. 0- 126. 5 4- 004 CF??? ; CH3 H OCH ; H CI C- Pr * 1 US 10 , 029, 986 B2 141 142 TABLE 8 TABLE 9 Rº E ERO 0 R3 R4 R3 R4 NH R1 R2 R1 R2 10 y CH3CH No. X ' R3 R4 R R2 R6 m .p . (* C .) No. X R3 R4 R R2 y R6 m . p. (° C .) 6 -001 1 H H CH2CH2 – Cic- Pr 64. 0 -65 . 0 15 7- 001 CF3 H H F F Cic -Pr 68. 0 - 69 . 0

TABLE 10 - R6 - 0 R3 R4 IZ R R2 CH3 No . X R3 R4 R2 y R6 m .p . (°C . ) 8 -001 CHF H H H H C - Pr Pr 9696 . 0 - 98 . 0 8 -002 CHF, H I H t - Bu * 1 8 -003 CHF , H TIJ C - Pr 100 . 0 - 101. 0 8 - 004 CF3 H H IJMIJF C - Pr 105 . 0 - 106 . 0 8 -005 CHF2?' H CH F 110 . 0 - 111 . 0 IJ 8 -006 CHF? , H CHOCHZ 135 .0 - 138 . 0 8 -007 CHF? , H CH C - Pr

8 - 008 CHF? H H CHz CH3 c - Pr

8 -009 CHFN H c - Pr H C - Pr

8 -010 CHFN, H H CH ( Ph- 3 , 4- F2) H c - Pr

8 -011 CHFN H - CH2– C - Pr 66 . 0 -70 . 0

8 -012 CHFN , H - CH ( Cl ) = ( E ) C - Pr

8 -013 CHF2N H CH ( Cl ) ( Z ) C- Pr

= 8 -014 CHFN , H CH (CH3 ) – ( E ) C - Pr * 1

8 -015 CHF2N H - CH ( CH3) - ( Z ) C - Pr

8 -016 CHFN , H CH ( CH3) – ( E ) t - Bu 8 -017 CHF H H CH( CH3) =( Z ) t - Bu 103 .0 - 105 . 0 8 -018 CHF , H CH2CH2 – C - Pr * 1 8 -019 CHF , H OCHZ H C -Pr 110 .0 - 111 . 0 8 -020 8 -020 CHFN , H SCHZ H C - Pr * 1

8 - 021 CHFN , H H CN C -Pr 1-243 . 0 -46 . 0 8 - 022 * 1 8 -022 CHFN , H C ( O )OCHZ C -Pr

8 -023 CHFN H H C ( O )OEt C ( O )OE C - Pr 87 . 0 - 88 . 0 H 127 . 0 - 130 . 0 8 - 024 CHFN , CH, H H C - Pr

8 - 025 CHFN, CH , H H CH OH * 1

8 -026 CHFN , CHE H H Si( CH3 ) 3 125 .0 - 126 .0

8- 027 CHFN , CH , H ? Ph

8 -028 CHF2N CH2 H OCHZ c - Pr

8 -029 CHF2N CH3H OEt ? C - Pr

8 -030 CHF2N CH3 H OCH CF3 C - Pr

8 -031 CHF2N CH3 H OCH2CH = CH2 C - Pr 8 -032 CHF2 CH3 H OCH Ph C - Pr 8 -033 CHF , H - CH2- (trans ) c - Pr 176 . 0 - 178 . 0 8 - 034 CF, CH, H H C - Pr * 1 8 -035 CHF2 H H CH3 F 00000000000000000000000000000000000cic -Pr88 . 0 - 91 . 0 US 10 , 029 , 986 B2 143 144 TABLE 11 TABLE 12 - RO ERO Y x 0 R3 R4 O= R3 R4 Y

0 N R R2 R ! R2 10

CH3 No. X R3 R4 R : R2 y R6 m .p . (° C. ) 10 -001 CF3 H H CH CH – Cic-Pr 117. 0 - 120 .0

No. X R3 R4 R1 R2 y ! R6 m. p . (°C . ) 15 9 -001 CF3 H H F F C1 C -Pr 129 .0 - 131. 0 TABLE 13 9 - 002 CHF2 H H CH3 HCl c- Pr * 1 9 -003 CHF2 H H CH – Cic-Pr * 1 9 - 004 CHF H H CH ,CH2 – Cic-Pr * 1 20 x 0 R3 R4 9 - 005 CF3 H H CH CH2 – Cic- Pr 120 . 0 -122 . 0 9 - 006a CHF2 CH3 ? ??? , ? CI c - Pr 9 - 006b CHF2 CH3 H OCH ; H CI C- Pr R ! R2 9 - 007 CHF , CH , H H H c1 c- Pr 25 9 -008 CF3 CH2 H H H CLC - Pr 122. 0 - 123. 0 No. x ' x2 R3 R4 R R y R6 m .p . (° C .) 11 - 001 F F H H CH CH — -Pr 140 .0 - 140. 5

TABLE 14

? R3 R4

R5 R1 R2 In the Table , symbols Gl- la and G4- 27a in the column for substituent G ', respectively, represent the following structural formulae. G1- la

G1- 27a

No . G x1 R3 R3 R4 R R2 R5 m .p . (°C . ) 12 -001 Gl- la CF3 C- PrH H OCHZ H C- Pr * 1 12 -002 Gº- 27a CHF , COOBu - t H CH - ( trans) H C -Pr 110 .0 - 112. 0 US 10 ,029 , 986 B2 145 146 TABLE 15 TABLE 15 -continued Ro RO Y R3 R4 R3 R4 HN HN R5 R R2 R5 R R2 10 No. R5 R3 R4 R1 R2 y R6 m .p . (° C . ) y 13 -014 H CH H H H cic -Pr * 1 No. R3 R3 R4 R ! R2 R6 m .p . (°C . ) 13 -015 H H H CH F C1 C -Pr ** 1 13- 001 H H H IH H cic-Pr 1* 15 13 - 002 H H H F F Cic - Pr TABLE 16 13 - 003 H H H F F CICH F * 1 1313 - 004004 H H H F F C1 CH2OCH ; * 1 Ro 13 - 005 H H H CH, H C c - Pr 10* 20 Y 1313- - 006 H H H CH3CH , CH ,3 C1 cC- - Pr 0 R3 R4 13- 007 H H H C - PrH cic - Pr 13- 008 H H H CH – C1 C - Pr 13- 009 C - Pr H H H CH( Cl) – cl 25 RR2 1313 - 010 H H H CH CH – Cic C - Pr Pr 13 - - 011 C - Pr H H OCH H C1 C -Pr 13- 012 H H H SCH , H Cl C - Pr * 1 No. R3 R4 R R2 yi R6 m .p . (° C .) 13 - 013 ? ?? , ? ??? , ? CI C -Pr 30 14 -001 H H CH – Cic - Pr * 1

TABLE 17 EROR6 0 R3 R4

R5 R1 R2 No . RS R3 R4 R R2 y R6 m .p . (° C. ) 15 - 001 H H H H H C -Pr 15 - 002 002 H H H C - Pr . 2 1515 - 003 H H H F F CHZF 84 . 0 - 86 . 0 15 -004 H H H F IIIF CH OH 45 . 0 - 47 . 0 1515 - 005 005 H H H F F CHOCHZ 15 - 006 006 H H H CH3CH H C - Pr | 15- 007 H H H CH , CH , C - Pr 15 -008 H H H C -PrH C- Pr 15 - 009 H H H CH - C - Pr 15- 010 H H H CH ( Cl ) – C - Pr 1515 -011 011 H H H CH2CH2 – JoJoJoJoo C - Pr 15 -012 012 H H H CH2CH2 CH OCH CF 15 -013 H H H SCH7 H C - Pr 15 -011 H CH2 H OCHZ HH C - Pr 15 -015 H CH3 H OCH Ph H C -Pr 15 - 016 H CH3 H SCH2CF3 H C -Pr 15 - 017 H H CH2- ( trans ) HH C - Pr 137 . 0 - 139 . 0 15- 018 H CH , H H . H C - Pr 15- 019 H H H CH , F C - Pr : US 10 ,029 , 986 B2 147 148 Among the compounds in Table 3 to Table 17 , with respect to those , of which no melting points are indicated , ' H NMR data will be shown in Table 18 . TABLE 18 No. ' H NMR (CDC13 , Me Si , 300 MHz ) 1 - 008 d 8 . 28 ( d , J = 1 . 8 Hz, 1H ) , 7 .45 - 7 . 8 ( m , 6H ) , 3 . 86 ( d , J = 3 . 2 Hz , 2H ) , 1 .55 ( s , 6H ) , 1 . 35 - 1. 5 ( m , 1H ) , 0 .75 - 1 .05 ( m , 4H ) . 1 -009 S 8 .39 ( d , J = 1 . 8 Hz , 1H ), 7 . 65 ( d , J = 1 . 8 Hz, 1H ) , 7 . 45 - 7 .65 ( m , 4H ) , 6 .41 (bs , 1H ) , 3 . 85 - 4 .05 ( m , 2H ) , 3 . 05 - 3 . 15 ( m , 1H ) , 1 . 4 - 1 . 5 (m , 1H ) , 1 . 0 - 1 . 2 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) , 0 . 3 - 0 . 65 ( m , 4H ) . 1 -010 S 8 .39 ( d , J = 1 . 8 Hz , 1H ), 7 .67 ( d , J = 1 . 8 Hz , 1H ), 7 . 65 - 7 . 7 (m , 1H ) , 7 . 4 - 7 . 6 ( m , 3H ) , 6 .33 (bs , 1H ) , 4 . 0 - 4 . 2 ( m , 1H ) , 3 .85 - 3 .95 ( m , 1H ) , 3 . 7 - 3 . 85 ( m , 1H ) , 2 . 75 - 2 . 9 ( m , 1H ) , 2 . 4 - 2 . 6 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 1 - 011 8 8 . 39 ( d , J = 1 . 8 Hz, 1H ) , 7 .65 ( dd , J = 7 . 8 , 1 . 5 Hz , 1H ) , 7 .59 ( d , J = 1 . 8 Hz , 1H ) , 7 . 4 - 7 .6 ( m , 3H ) , 6 . 75 - 7 .05 ( m , 3H ) , 6 .50 ( bs , 1H ) , 3 .75 - 4 . 0 ( m , 3H ) , 2 .85 - 3 . 05 ( m , 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) . 1 -014 à 8 . 36 ( d , J = 2 . 0 Hz , 1H ) , 7 .64 ( d , J = 2 . 0 Hz , 1H ) , 7 . 5 - 7 .55 ( m , 1H ) , 7 . 2 - 7 . 4 ( m , 3H ), 6 .51 (bs , 1H ), 3 .71 ( d , J = 5 . 1 Hz, 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 .05 - 1 .15 ( m , 4H ) , 0 .85 - 0 . 95 ( m , 2H ) , 0 . 75 - 0 .85 ( m , 2H ) . 1 -017 d 8 .32 ( d , J = 1 . 8 Hz , 1H ) , 7 .63 ( d , J = 1 . 8 Hz , 1H ) , 7 . 35 - 7 .65 ( m , 4H ) , 6 .14 (bs , 1H ) , 3 .67 ( d , J = 5 . 1 Hz , 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 0 - 1 . 1 ( m , 4H ) , 0 .75 - 0 . 95 ( m , 4H ) . 1 -020 S 8 . 48 ( d , J = 1 . 8 Hz , 1H ), 7 . 70 ( d , J = 1 . 8 Hz, 1H ), 7 . 45 - 7 .75 ( m , 4H ) , 6 .21 ( d , J = 6 . 6 Hz, 1H ) , 4 . 17 (dd , J = 14 . 7 , 6 . 0 Hz , 1H ) , 3 . 97 (dd , J = 14 . 7 , 6 . 0 Hz, 1H ) , 3 .26 ( d , J = 4 . 5 Hz, 1H ) , 3 .09 ( d , J = 4 . 5 Hz , 1H ) , 2 .08 ( s , 3H ) . 1 -021 S 8 . 36 ( d , J = 1 . 8 Hz , 1H ), 7 .68 ( d , J = 1 . 8 Hz, 1H ) , 7 . 45 - 7 .65 ( m , 4H ) , 6 .42 (bs , 1H ) , 4 . 56 (dd , J = 7 . 8 , 6 .0 Hz , 1H ), 4 .05 - 4 . 2 ( m , 2H ) , 2 . 11 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 1 - 024 8 8 .50 and 8 .47 (d , J = 2 . 1 Hz, 1H ) , 7 .70 and 7 .68 ( d , J = 2 . 1 Hz, 1H ) , 7 . 4 - 7 . 7 ( m , 3H ) , 7 . 25 - 7 . 35 ( m , 1H ) , 6 . 39 and 6 . 36 ( bs, 1H ) , 4 . 92 and 4 .79 ( d , J = 4 . 2 and 2 .4 Hz, 1H ), 4 . 5 - 4 .65 ( m , 1H ) , 3 . 38 and 3 . 35 ( s , 3H ) , 1 . 46 and 1 . 16 ( d , J = 7 . 2 Hz, 3H ) , 1 . 45 - 1 .55 ( m , 1H ) , 0 . 8 - 1 .0 ( m , 4H ) . 1 - 026 S 8 .47 ( d , J = 2 . 0 Hz , 1H ) and 8 .43 ( d , J = 1 . 7 Hz, 1H ) , 7 . 3 - 7 . 7 ( m , 5H ) , 6 . 46 ( d , J = 8 . 5 Hz , 1H ) , 5 .00 ( d , J = 4 . 1 Hz, 1H ) and 4 . 90 ( d , J = 2 . 7 Hz , 1H ) , 4 . 7 - 4 . 9 and 4 . 4 - 4 . 6 ( m , 1H ) , 3 .45 - 3 .65 and 3 . 3 - 3 . 45 ( m , 2H ) , 1 . 4 - 1 . 55 ( m , 1H ) , 1 . 45 and 1 . 11 ( d , J = 6 . 8 Hz, 3H ) , 1 . 20 and 1 . 19 ( t , J = 7 . 0 Hz, 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 1 -027 S 8 .47 ( d , J = 1 . 5 Hz , 1H ) and 8 . 46 ( d , J = 1 . 8 Hz , 1H ), 7 .45 - 7 . 75 ( m , 4H ) , 7 .33 ( d , J = 6 . 7 Hz , 1H ) and 7 .22 ( d , J = 8 . 3 Hz , 1H ) , 6 .31 ( d , J = 8 . 9 Hz , 1H ), 5 . 20 ( d , J = 4 . 0 Hz, 1H ) and 5 . 14 ( d , J = 2 . 8 Hz , 1H ) , 4 .75 - 4 . 95 and 4 . 55 - 4 . 8 ( m , 1H ) , 3 . 5 - 4 . 2 ( m , 2H ) , 1 .46 ( d , J = 6 . 7 Hz , 3H ) and 1 .14 ( d , J = 7 . 0 Hz , 3H ), 1 . 4 - 1 . 55 ( m , 1H ) , 0 . 75 - 1 . 0 ( m , 4H ) . 1 -028 d 8 .47 ( d , J = 1 . 5 Hz , 1H ) and 8 .45 (d , J = 1 .8 Hz, 1H ) , 7 .45 -7 . 8 ( m , 4H ) , 7 . 32 ( d , J = 7 . 0 Hz , 1H ) and 7 .22 ( d , J = 8 . 9 Hz, 1H ) , 6 .20 ( d , J = 8 .9 Hz, 1H ) , 5 . 26 ( d , J = 4. 0 Hz, 1H ) and 5 . 16 ( d , J = 3 . 1 Hz, 1H ) , 4 . 8 - 5 .0 and 4 .45 - 4 . 7 ( m , 1H ) , 4 .45 and 4 .44 ( d , J = 16 . 2 Hz , 1H ) , 4 .21 and 4 . 10 ( d , J = 16 . 2 Hz , 1H ) , 1 . 4 - 1 .55 ( m , 1H ), 1 . 14 ( d , J = 6 . 7 Hz, 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 1 -029 8 8 .48 ( d , J = 1 . 7 Hz , 1H ) and 8 .44 (d , J = 2 .0 Hz, 1H ), 7 .25 - 7 .75 (m , 5H ) , 6 . 44 ( d , J = 8 . 5 Hz , 1H ) , 5 .75 - 6 . 0 ( m , 1H ) , 5 . 1 - 5 . 3 ( m , 2H ) , 5 .06 ( d , J = 4 . 1 Hz , 1H ) and 4 .97 ( d , J = 2 . 4 Hz, 1H ) , 4 . 7 - 4 . 9 and 4 .45 - 4 . 6 m , 1H ) , 3 . 7 - 4 . 2 ( m , 2H ) , 1 . 35 - 1 . 55 ( m , 1H ) , 1 .46 and 1 . 11 ( d , J = 6 . 8 Hz , 3H ) , 0 .75 - 1 . 0 ( m , 4H ) . 1 -030 8 8 .47 ( d , J = 2 . 0 Hz , 1H ) and 8 .45 ( d , J = 1 .7 Hz , 1H ) , 7 .71 - 7 .44 (m , 4H ) , 7 . 32 ( d , J = 6 . 5 Hz, 1H ) and 7 . 23 ( d , J = 8 . 5 Hz, 1H ) , 6 .34 ( d , J = 8 . 9 Hz , 1H ) , 5 .34 ( d , J = 4 . 1 Hz, 1H ) and 5 .23 ( d , J = 2 . 4 Hz, 1H ) , 4 .75 - 4 . 9 and 4 .55 - 4 .65 ( m , 1H ) , 4 .34 and 4 . 33 (dd , J = 16 . 2 , 2 . 6 Hz , 1H ) , 4 .07 and 3 . 97 (dd , J = 16 . 0 , 2 .4 Hz, 1H ) , 2 .42 (t , J = 2 .4 Hz , 1H ) , 1 . 4 - 1 .55 ( m , 1H ) , 1 . 47 ( d , J = 5 . 1 Hz , 3H ) and 1 . 12 (d , J = 6 .8 Hz, 3H ), 0 . 8 - 1 . 0 ( m , 4H ) . 1 -032 8 8 .45 ( d , J = 2 . 1 Hz, 1H ) and 8 . 33 ( d , J = 1 . 7 Hz , 1H ) , 8 .02 ( d , J = 8 . 4 Hz, 1H ) and 5 .98 ( d , J = 8 . 7 Hz, 1H ) , 7 . 5 - 7 . 75 ( m , 5H ) , 4 . 6 - 4 .95 ( m , 2H ) , 3 . 0 - 3 .45 ( m , 2H ) , 1 . 4 - 1 .55 ( m , 1H ) , 1 .28 ( d , J = 6 . 9 Hz, 3H ) and 1 . 18 ( d , J = 6 . 3 Hz, 3H ), 0 . 8 - 1 . 0 ( m , 4H ). 2 - 003 d 8 .43 (dd , J = 4 . 5 , 1 . 5 Hz, 1H ) , 8 . 37 ( d , J = 1 . 8 Hz , 1H ) , 7 .98 (bs , 1H ) , 7 . 76 ( dd , J = 8 . 0 , 1 . 5 Hz, 1H ) , 7 .63 ( d , J = 1 . 8 Hz, 1H ) , 7 .31 (dd , J = 8 . 0 , 4 . 5 Hz , 1H ) , 3 . 72 ( d , J = 5 . 7 Hz , 2H ) , 1. 4 - 1 . 5 ( m , 1H ) , 1 .05 - 1 . 15 m , 4H ) , 0 .85 - 0 . 95 ( m , 2H ) , 0 . 75 - 0 . 85 ( m , 2H ) . US 10 ,029 , 986 B2 149 150 TABLE 18 - continued No . ' H NMR (CDC13 , Me Si, 300 MHz ) 2 - 004 8 8 . 70 ( d , J = 4 . 2 Hz, 1H ) , 8 . 37 ( d , J = 1 . 8 Hz, 1H ) , 8 . 11 ( d , J = 8 . 1 Hz , 1H ) , 7 .89 (bs , 1H ) , 7 .64 ( d , J = 1 . 8 Hz, 1H ) , 7 . 51 (dd , J = 8 . 1 , 4 . 2 Hz , 1H ) , 3. 73 (d , J = 5. 7 Hz , 2H ), 1 .4 - 1. 5 (m , 1H ), 0 .85 -0 . 95 ( m , 4H ), 0 .75 - 0 .85 (m , 4H ). 3 -005 8 8 .42 (dd , J = 4 . 5 , 1 . 8 Hz , 1H ) , 8 .40 ( d , J = 1 . 8 Hz, 1H ) , 8 .06 ( dd , J = 7 . 5 , 1 . 8 Hz, 1H ) , 7 .64 ( d , J = 1 . 8 Hz, 1H ) , 7 .31 (dd , J = 7 . 5 , 4 . 5 Hz , 1H ) , 7 .25 - 7 . 3 m , 1H ) , 3 . 7 - 4 . 0 ( m , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 31 ( d , J = 6 . 9 Hz, 3H ) , 0 . 75 - 0 . 95 ( m , 4H ) . 3 - 006 d 8 .72 (dd , J = 5 . 1 , 1 . 8 Hz , 1H ) , 8 . 37 ( d , J = 1 . 8 Hz , 1H ) , 7 .86 (dd , J = 7 . 8 , 1 . 8 Hz , 1H ) , 7 .64 ( d , J = 1 . 8 Hz , 1H ) , 7 .44 (dd , J = 7 . 8 , 5 . 1 Hz , 1H ) , 6 .91 (bs , 1H ) , 6 . 91 ( t , J = 54 .6 Hz, 1H ) , 3 . 7 - 4 . 0 ( m , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 30 ( d , J = 6 . 9 Hz, 3H ) , 0 .75 - 0 .95 (m , 4H ). 3 - 008 8 8 . 73 ( dd , J = 5 . 1 , 1 . 5 Hz , 1H ) , 8 . 41 ( d , J = 1 . 8 Hz , 1H ) , 7 .84 (dd , J = 7 .5 , 1 . 5 Hz , 1H ), 7 .66 (d , J = 1 . 8 Hz , 1H ) , 7 .45 (dd , J = 7 . 5 , 5 . 1 Hz , 1H ) , 6 . 93 (t , J = 54 .6 Hz, 1H ) , 6 . 83 (bs , 1H ) , 3 .95 - 4 . 05 ( m , 1H ) , 3 . 8 - 3 . 9 ( m , 1H ) , 3 . 0 - 3 .15 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 0 - 1 . 2 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) , 0 . 3 - 0 . 7 ( m , 4H ) . 3 - 009 8 8 .72 (dd , J = 4 . 8 , 1 . 5 Hz , 1H ) , 7 . 41 ( d , J = 1 . 8 Hz , 1H ) , 7 .84 (dd , J = 8 . 1 , 1 . 5 Hz , 1H ) , 7 .59 ( d , J = 1 . 8 Hz , 1H ) , 7 .45 (dd , J = 8 . 1 , 4 . 8 Hz, 1H ) , 6 .89 (t , J = 54 . 3 Hz , 1H ) , 6 .75 - 7 . 1 ( m , 4H ) , 3 . 6 - 4 . 0 ( m , 3H ) , 2 . 85 - 3 . 05 ( m , 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) . 3 - 013 S 8 .70 (dd , J = 4 . 8 , 1 . 8 Hz , 1H ) , 8 . 37 ( d , J = 1 . 8 Hz, 1H ) , 7 .74 ( d , J = 1 . 8 Hz , 1H ) , 7 .66 (dd , J = 7 . 8 , 1 . 8 Hz, 1H ) , 7 . 44 (dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 6 . 89 (bs , 1H ) , 6 . 74 ( t , J = 54 . 6 Hz , 1H ) , 6 .71 ( s , 1H ), 4 .71 ( d , J = 6 .6 Hz, 2H ) , 1 . 4 - 1 .55 (m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) . 3 - 014 8 8 . 75 ( dd , J = 4 . 8 , 1 . 8 Hz , 1H ) , 8 . 47 ( d , J = 1 . 8 Hz , 1H ) , 7 . 8 - 7 . 9 ( m , 1H ) , 7 .74 ( d , J = 1 . 8 Hz , 1H ) , 7 .44 (dd , J = 7 . 8 , 4 . 8 Hz , 1H ) , 6 . 95 ( t , J = 54 . 6 Hz, 1H ) , 6 .65 ( s , 1H ) , 6 .62 (bs , 1H ) , 4 .42 ( d , J = 6 . 6 Hz, 2H ) , 1 . 4 - 1 . 55 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) . 3 - 015 8 8 .41 (dd , J = 4 . 8 , 2 . 1 Hz, 1H ) , 8 . 36 ( d , J = 2 . 1 Hz , 1H ) , 7 . 94 ( dd , J = 7 . 5 , 2 . 1 Hz, 1H ) , 7 .64 ( d , J = 2 . 1 Hz, 1H ) , 7 . 28 ( dd , J = 7 . 5 , 4 . 8 Hz , 1H ) , 6 . 85 (bs , 1H ) , 3 .71 ( d , J = 4 . 8 Hz , 2H ) , 1 . 4 - 1 .5 ( m , 1H ) , 1 . 0 - 1 . 15 ( m , 4H ) , 0 . 75- 0 . 95 ( m , 4H ) . 3 -018 d 8 . 46 ( d , J = 1 . 5 Hz , 1H ), 8 .43 (dd , J = 4 . 8 , 2 . 1 Hz, 1H ) , 7 .98 ( dd , J = 7 . 8 , 2 . 1 Hz , 1H ) , 7 . 75 ( d , J = 1 . 5 Hz , 1H ) , 7 . 30 (dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 6 . 81 (bs , 1H ) , 4 .54 ( s , 2H ) , 3 .97 ( q , J = 8 . 7 Hz, 2H ), 3 . 74 ( d , J = 5 . 1 Hz , 2H ) , 1 . 05 - 1 . 2 ( m , 4H ) . 3 - 020 8 8 . 73 (dd , J = 5 . 1 , 1 . 8 Hz, 1H ) , 8 .37 ( d , J = 1 . 8 Hz , 1H ) , 7 .91 (dd , J = 7 . 8 , 1 . 8 Hz , 1H ) , 7 .68 ( d , J = 1 . 8 Hz , 1H ) , 7 .45 (dd , J = 7 . 8 , 5 . 1 Hz, 1H ) , 6 .92 (t , J = 54 . 3 Hz , 1H , 6 .87 (bs , 1H ) , 4 .57 (dd , J = 7 . 2 , 5 . 7 Hz, 1H ) , 4 .05 - 4 .25 ( m , 2H ), 2 . 13 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) . 3 - 021 8 8 .76 and 8 .73 (dd , J = 7 . 8 , 1 . 8 Hz , 1H ) , 8 . 47 ( d , J = 1 . 8 Hz , 1H ) , 7 . 95 - 8 .05 ( m , 1H ) , 7 . 79 and 6 . 57 ( d , J = 8 . 1 Hz, 1H ) , 7 .71 ( d , J = 1 . 8 Hz , 1H ) , 7 . 49 and 7 .43 (dd , J = 7 . 8 , 4 . 8 Hz , 1H ) , 7 .05 and 6 .92 ( t, J = 54 . 6 Hz , 1H ) , 4 . 92 ( d , J = 4 . 2 Hz , 1H ) and 4 .80 ( d , J = 2 . 4 Hz , 1H ) , 4 . 8 - 4 . 9 and 4 . 5 - 4 . 6 ( m , 1H ) , 3 . 38 and 3 . 35 ( s , 3H ) , 1 .47 and 1 . 11 ( d , J = 6 . 9 Hz , 3H ) , 1 . 4 - 1 .55 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 3 - 022 8 8 .76 (dd , J = 4 . 8 , 1 . 7 Hz , 1H ) and 8 .74 ( dd , J = 3 . 4 , 1 . 7 Hz , 1H ) , 8 .47 and 8 . 44 ( d , J = 1 . 7 Hz, 1H ) , 7 .97 ( d , J = 7 . 8 Hz , 1H ) and 7 .92 ( d , J = 8 . 9 Hz, 1H ) , 7 . 83 and 6 . 64 ( d , J = 8 . 2 Hz, 1H ) , 7 .69 and 7 .66 ( d , J = 1 . 7 Hz, 1H ) , 7 .47 (dd , J = 7 . 7 , 4 . 6 Hz , 1H ) and 7 .43 (dd , J = 3 . 1 , 1 . 5 Hz , 1H ) , 7 .09 and 6 . 98 (t , J = 54 . 3 Hz, 1H ) , 5 .00 ( d , J = 4 . 1 Hz, 1H ) and 4 .91 ( d , J = 2 . 4 Hz , 1H ) , 4 .75 - 4 . 9 and 4 . 4 - 4 . 6 (m , 1H ) , 3 . 3 - 3 . 7 ( m , 2H ), 1 . 4 - 1 .55 ( m , 1H ) , 1 . 47 ( d , J = 6 . 5 Hz, 3H ) and 1 . 11 ( d , J = 6 . 8 Hz, 3H ) , 1 . 21 and 1 . 20 ( t , J = 7 . 0 Hz, 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 3 -023 S 8 . 4 - 8 .55 ( m , 2H ) , 8 .07 and 7 . 80 (dd , J = 7 . 5 , 2 . 0 Hz, 1H ) , 7 . 88 ( d , J = 8 . 2 Hz , 1H ) and 6 .75 ( d , J = 8 . 9 Hz , 1H ) , 7 .72 ( d , J = 2 . 0 Hz , 1H ) and 7 .68 ( d , J = 1 . 7 Hz, 1H ) , 7 . 33 and 7 .27 (dd , J = 7 . 8 , 4 . 8 Hz , 1H ) , 5 . 22 ( d , J = 4 . 4 Hz , 1H ) and 5 . 15 ( d , J = 3 . 1 Hz , 1H ) , 4 .75 - 4 . 95 and 4 .6 - 4 . 8 (m , 1H ) , 3 . 5 - 4 . 2 ( m , 2H ) , 1 .51 and 1 . 18 ( d , J = 6 . 8 Hz , 3H ) , 1 . 4 - 1 .55 ( m , 1H ) , 0 .75 - 1 . 0 ( m , 4H ) . 20013 -024 8876S 8 . 76 ( dd , JI = 313 . 1 , 151 . 5 HzHZ , 1H ) and 8 .74 ( dd dd ., J = 48. 1 . 4 H7 11 ). 8 .47 ( d , J = 2 .0 Hz , 1H ) and 8 .43 ( d , J = 1 . 7 Hz , 1H ) , 7 .94 and 7 . 81 ( d , J = 7 . 8 Hz, 1H ) , 7 .72 and 7 .68 ( d , J = 1 . 7 Hz , 1H ) , 7 .65 and 6 . 51 ( d , J = 8 . 9 Hz, 1H ) , 7 . 4 - 7 .55 ( m , 1H ) , 7 .03 ( t , J = 54 . 3 Hz, 1H ) and 6 . 94 ( t , J = 54 . 5 Hz, 1H ) , 5 .20 ( d , J = 4 . 1 Hz , 1H ) and 5 . 14 ( d , J = 2 . 4 Hz, 1H ) , 4 . 8 4 . 95 and 4 . 6 4 . 7 ( m , 1H ), 3 . 5 - 4 . 15 ( m , 2H ) , 1 .50 and 1 . 14 ( d , J = 6 . 8 Hz, 3H ) , 1 . 4 - 1 . 5 m , 1H ) , 0 .75 - 1 .05 ( m , 4H ) . US 10 ,029 , 986 B2 151 152 TABLE 18 - continued No . ' H NMR (CDC13 , Me Si, 300 MHz ) 3 -025 S 8 . 75 ( dd , J = 4 . 8 , 1 . 4 Hz, 1H ) , 8 .47 ( d , J = 1 . 7 Hz, 1H ) , 7 . 98 ( dt, J = 7 . 8 , 0 . 7 Hz , 1H ) , 7 . 74 ( d , J = 1 . 7 Hz , 1H ) , 7 .60 ( d , J = 8 . 5 Hz , 1H ) , 7 .49 (dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 7 .01 ( t , J = 54 . 5 Hz, 1H ) , 5 . 27 ( d , J = 4 . 1 Hz, 1H ) , 4 . 8 - 5 . 0 ( m , 1H ) , 4 .44 ( d , J = 16 . 3 Hz , 1H ) , 4 . 19 ( d , J = 16 . 3 Hz, 1H ) , 1 . 4 1 .55 ( m , 1H ) , 1 . 15 ( d , J = 6 . 8 Hz , 3H ) , 0 . 8 - 1 . 05 ( m , 4H ) . 3 -027 S 8 .76 (dd , J = 4 . 9 , 1 . 5 Hz , 1H ) and 8 .73 ( dd , J = 3 . 1 , 1 . 5 Hz , 1H ) , 8 .45 ( d , J = 1 . 7 Hz, 1H ) , 7 .96 ( d , J = 7 . 8 Hz, 1H ) and 7 . 90 (d , J = 8. 2 Hz, 1H ) , 7 . 81 ( d , J = 8 . 5 Hz, 1H ) and 6 .64 ( d , J = 7 . 8 Hz, 1H ) , 7 .69 and 7 .66 ( d , J = 2 . 0 Hz, 1H ) , 7 . 47 and 7 . 43 (dd , J = 7 . 7 , 4 . 6 Hz, 1H ) , 7 .07 ( t , J = 54 . 8 Hz , 1H ) and 6 . 95 ( t, J = 54 . 5 Hz, 1H ) , 5 . 75 - 6 .0 ( m , 1H ) , 5 .15 - 5 . 3 ( m , 2H ) , 5 . 06 ( d , J = 4 . 1 Hz , 1H ) and 4 . 98 ( d , J = 2 . 7 Hz , 1H ) , 4 .75 - 4 . 9 and 4 . 5 - 4 .6 ( m , 1H ) , 3 .75 - 4 . 2 ( m , 2H ) , 1 . 4 - 1. 55 ( m , 1H ) , 1 .48 and 1 . 11 ( d , J = 6 . 8 Hz, 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 3 -028 8 8 .53 ( d , J = 2 . 0 Hz , 1H ) and 8 .51 ( d , J = 1 . 7 Hz , 1H ) , 8 . 45 (dd , J = 4 . 8 , 1 . 0 Hz, 1H ) and 8 .41 (dd , J = 4 . 8 , 2 . 0 Hz, 1H ) , 8 .09 (dd , J = 9. 5 , 4 .8 Hz, 1H ) and 7. 77 (dd , J = 7 .7 , 1. 9 Hz , 1H ), 7 .90 and 6 .72 ( d , J = 8 . 5 Hz , 1H ) , 7 . 70 ( d , J = 2 . 0 Hz , 1H ) and 7 .67 ( d , J = 1 . 7 Hz , 1H ), 7 . 33 and 7 . 26 (dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 5 .36 ( d , J = 4 . 1 Hz , 1H ) and 5 .25 ( d , J = 2 . 7 Hz , 1H ) , 4 .75 - 4 . 9 and 4 .55 - 4 . 7 ( m , 1H ) , 4 . 36 ( dd , J = 16 . 0 , 2 . 4 Hz , 1H ) and 4 . 33 (dd , J = 16 . 2 , 2 . 6 Hz , 1H ) , 4 .06 (dd , J = 16 . 0 , 2 . 4 Hz , 1H ) and 3 .97 (dd , J = 16 . 2 , 2 . 4 Hz , 1H ) , 2 .44 and 2 . 43 ( t , J = 2 . 4 Hz , 1H ) , 1 . 4 - 1 . 55 ( m , 1H ) , 1 . 50 and 1 . 16 ( d , J = 6 . 8 Hz , 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 3 -029 S 8 .75 (dd , J = 4 . 8 , 1 . 7 Hz , 1H ) and 8 .72 (dd , J = 4 . 8 , 1 . 4 Hz , 1H ) , 8 .47 and 8 .44 ( d , J = 1 . 7 Hz, 1H ) , 7 . 97 ( d , J = 8 . 5 Hz, 1H ) and 7 . 81 ( d , J = 7 . 2 Hz, 1H ) , 7 .71 ( d , J = 2 . 0 Hz , 1H ) and 7 .68 ( d , J = 1 . 7 Hz, 1H ) , 7 .47 ( dd , J = 7 . 8 , 4 . 8 Hz, 1H ) and 7 .43 ( dd , J = 8 . 2 , 5 . 1 Hz, 1H ) , 7 .08 and 6 . 93 ( t , J = 54 . 3 Hz , 1H ) , 6 .61 ( d , J = 8 . 5 Hz , 1H ) , 5 .34 ( d , J = 4 . 1 Hz, 1H ) and 5 . 24 ( d , J = 2 . 7 Hz , 1H ), 4 .75 - 4 . 9 and 4 . 55 - 4 . 7 m , 1H ) , 4 .34 (dd , J = 16 . 2 , 2 . 5 Hz , 1H ) and 4 .32 (dd , J = 16 . 0 , 2 . 4 Hz , 1H ) , 4 .07 (dd , J = 16 . 0 , 2 . 4 Hz , 1H ) and 3 .97 (dd , J = 16 . 0 , 2 . 5 Hz , 1H ) , 2 . 4 - 2 .5 ( m , 1H ) , 1 .48 ( d , J = 6 . 5 Hz , 3H ) and 1 . 13 ( d , J = 6 . 8 Hz , 3H ) , 1 . 4 - 1 .55 ( m , 1H ) , 0 . 75 - 1 . 0 ( m , 4H ) . 3 -031 S 8 . 75 ( dd , J = 4 . 6 , 1 . 5 Hz , 1H ) and 8 .73 (dd , J = 6 . 1 , 1 . 4 Hz, 1H ) , 8 . 48 and 8 .47 ( d , J = 1 . 7 Hz , 1H ) , 7 . 85 and 7 .82 ( d , J = 7 . 8 Hz , 1H ) , 7 .69 ( d , J = 2 . 0 Hz, 1H ) and 7 . 66 ( d , J = 1 . 7 Hz, 1H ) , 7 . 4 - 7 . 5 ( m , 1H ) , 7 . 25 - 7 .35 ( m , 5H ) , 7 .05 (t , J = 54. 3 Hz, 1H ) and 6 .96 (t , J = 54 .5 Hz , 1H ) , 6 .68 ( d , J = 8 . 5 Hz, 1H ), 5 . 06 ( d , J = 4 . 4 Hz, 1H ) and 4 .96 (d , J = 2 . 4 Hz , 1H ) , 4 . 75 - 4 . 95 m , 1H ) , 4 .65 ( d , J = 11. 9 Hz, 1H ) and 4 . 59 ( d , J = 11 . 6 Hz , 1H ) , 4 .48 ( d , J = 11 . 6 Hz, 1H ) and 4 .25 (d , J = 11 . 9 Hz, 1H ), 1 . 4 - 1 .55 ( m , 1H ), 1 .42 and 1 . 12 ( d , J = 6 . 8 Hz , 3H ) , 0 . 8 - 1 . 0 (m , 4H ) . 3 -032 8 8 .62 ( d , J = 7 . 8 Hz , 1H ) and 6 .60 ( d , J = 8 . 4 Hz , 1H ) , 8 .4 - 8 . 5 ( m , 2H ) , 8 . 13 and 8 .07 (dd , J = 7 . 5 , 2 . 1 Hz , 1H ) , 7 .71 ( d , J = 2 . 1 Hz , 1H ) and 7 .68 ( d , J = 1 . 8 Hz, 1H ) , 7 .34 (dd , J = 7 . 5 , 4 . 8 Hz, 1H ) , 4 . 7 - 4 . 95 (m , 2H ) , 3 . 0 - 3 . 4 ( m , 2H ) , 1 . 4 - 1 .55 ( m , 1H ) , 1 . 34 and 1 .21 (d , J = 6 .6 Hz, 3H ) , 0 . 8 - 1 . 0 (m , 4H ) . 3 - 034 8 8 . 7 - 8 . 8 m , 1H ) , 8 .45 ( d , J = 1 . 7 Hz , 1H ) and 8 . 32 ( d , J = 1 . 8 Hz, 1H ) , 8 .21 ( d , J = 8 . 1 Hz , 1H ) and 6 .04 ( d , J = 8 . 7 Hz , 1H ) , 8 . 0 - 8 .05 and 7 . 9 - 8 . 0 ( m , 1H ) , 7 .71 ( d , J = 1 . 8 Hz , 1H ) and 7 .69 ( d , J = 1 . 7 Hz, 1H ) , 7 .57 (dd , J = 7 . 8 , 4 . 8 Hz, 1H ) , 4 . 6 - 4 . 95 (m , 2H ) , 3 . 0 - 3 . 4 ( m , 2H ) , 1 . 4 - 1. 55 ( m , 1H ) , 1 . 30 and 1 . 18 ( d , J = 6 . 6 Hz , 3H ) , 0 . 8 - 1 . 0 (m , 4H ) . 4 - 004 S 8 . 7 - 8 . 8 ( m , 2H ) , 8 .54 and 8 .40 ( d , J = 1 . 8 Hz , 1H ) , 7 . 75 ( d , J = 8 . 4 Hz, 1H ) and 7 . 2 - 7 . 3 m , 1H ) , 7 .70 and 7 .65 ( d , J = 1 . 8 Hz , 1H ) , 4 . 93 ( d , J = 4 . 2 Hz , 1H ) and 4 .84 ( d , J = 2 . 4 Hz , 1H ) , 4 .7 - 4 . 8 and 4 . 5 - 4 . 6 ( m , 1H ) , 3 . 39 and 3 . 38 ( s , 3H ) , 1 .49 ( d , J = 6 .6 Hz, 3H ) and 1 . 14 ( d , J = 7 . 2 Hz, 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 5 - 002 S 8 .37 ( d , J = 2 . 1 Hz , 1H ) , 7 .63 ( d , J = 2 . 1 Hz , 1H ) , 7 . 38 ( d , J = 5 . 1 Hz, 1H ) , 7 .20 ( d , J = 5 . 1 Hz, 1H ), 6 .57 (bs , 1H ) , 3 .66 (d , J = 5 . 1 Hz , 2H ) , 1 . 4 - 1 . 5 m 1H ) , 1 . 0 - 1 . 15 ( m , 4H ) , 0 . 75 - 0 . 95 (m . 4H ) . 8 - 002 S 8 .41 ( d , J = 2 . 1 Hz, 1H ) , 7 .84 ( s, 1H ) , 7 .64 ( d , J = 2 . 1 Hz , 1H ), 7 . 13 (bs , 1H ) , 6 .83 (t , J = 54 . 6 Hz , 1H ) , 3 .91 ( s , 3H ) , 3 .85 - 3 . 9 ( m , 2H ) , 3 . 17 ( t , J = 6 . 3 Hz , 2H ) , 1 . 32 ( s , 9H ) . 8 -007 S 8 .42 ( d , J = 1 . 8 Hz , 1H ) , 7 . 85 ( s , 1H ) , 7 .61 ( d , J = 1 . 8 Hz, 1H ) , 6. 96 (bs , 1H ), 6 .74 (t , J = 54 .0 Hz, 1H ), 3. 90 ( s, 3H ) , 3 .75 -3 .85 ( m , 2H ) , 3 . 5 - 3 . 75 ( m , 1H ) , 1 . 4 - 1 . 55 ( m , 1H ) , 1 .26 ( d , J = 6 . 9 Hz , 3H ) , 0 . 8 - 0 .95 ( m , 4H ) . US 10 ,029 , 986 B2 153 154 TABLE 18 - continued No . ' H NMR (CDC13 , Me Si, 300 MHz ) 8 - 008 8 8 . 38 ( d , J = 1 . 7 Hz, 1H ) , 7 . 87 ( s , 1H ) , 7 .62 ( d , J = 2 . 4 Hz, 1H ) . 7 .50 (bs , 1H ) , 6 .74 ( t , J = 54 . 1 Hz, 1H ) , 3 . 89 ( s , 3H ) , 3 .82 ( d , J = 6 . 5 Hz, 2H ) , 1 . 50 ( s , 6H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 8 - 009 S 8 .46 ( d , J = 1 . 8 Hz, 1H ), 7 . 83 ( s , 1H ) , 7 .62 ( d , J = 1 . 8 Hz , 1H ) , 6 . 78 (bs , 1H ) , 6 . 74 ( t, J = 54 . 0 Hz , 1H ), 3 .91 ( s , 3H ) , 3 . 8 - 3 . 95 ( m , 2H ) , 3 . 0 - 3 . 1 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 0 - 1 . 2 ( m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) , 0 . 3 - 0 . 7 m , 4H ) . 8 -010 S 8 .46 ( d , J = 1 . 8 Hz, 1H ) , 7 .85 ( s , 1H ) , 7 . 56 ( d , J = 1 . 8 Hz , 1H ) , 6 . 7 - 7 . 0 ( m , 4H ) , 6 .72 (t , J = 54 . 6 Hz , 1H ) , 3 . 90 ( s , 3H ) , 3 .85 - 4 .0 (m , 1H ) , 3 . 7 - 3 . 8 ( m , 2H ), 2 .85 - 3 .05 ( m , 2H ) , 1 .4 - 1 . 5 ( m , 1H ), 0 . 8 - 0 . 95 ( m , 4H ) . 8 -012 S 8 .42 ( d , J = 1 . 8 Hz, 1H ) , 7 .83 ( s , 1H ) , 7 .67 ( d , J = 1 . 8 Hz , 1H ) , 6 . 80 (bs , 1H ) , 6 .74 ( s , 1H ) , 6 .74 ( t , J = 54 . 9 Hz, 1H ) , 4 .67 ( d , J = 6 . 0 Hz , 2H ) , 3 . 90 ( s , 3H ) , 1 . 4 - 1 .55 ( m , 1H ) , 0 . 8 0 . 95 ( m , 4H ) . 8 -013 S 8 . 48 ( d , J = 1 . 8 Hz , 1H ), 7 . 85 ( s , 1H ), 7 .71 ( d , J = 1. 8 Hz, 1H ) , 6 .81 ( t, J = 54 . 9 Hz , 1H ) , 6 .66 ( bs, 1H ) , 6 .57 ( s , 1H ) , 4 . 37 ( d , J = 5 . 4 Hz, 2H ) , 3 .91 ( s , 3H ) , 1 . 4 - 1 . 55 (m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) . 8 -014 S 8 .40 ( d , J = 1 . 8 Hz , 1H ) , 7 . 83 ( s , 1H ) , 7 .66 ( d , J = 1 . 8 Hz, 1H ) , 6 .93 (bs , 1H ) , 6 . 80 ( t , J = 54 . 6 Hz, 1H ) , 6 .24 ( 9 , J = 7 . 2 Hz , 1H ) , 4 . 45 ( d , J = 5 . 1 Hz , 2H ) , 3 . 90 ( s , 3H ) , 1 . 98 ( d , J = 7 . 2 Hz, 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) . 8 -015 8 8 .48 ( d , J = 1 . 8 Hz , 1H ) , 7 . 81 ( s , 1H ) , 7 .69 ( d , J = 1 . 8 Hz, 1H ) , 6 .84 ( t, J = 54 . 3 Hz , 1H ) , 6 . 59 ( bs, 1H ) , 6 .01 ( q , J = 7 . 2 Hz, 1H ) , 4 .29 ( d , J = 5 . 1 Hz, 2H ) , 3 . 91 ( s , 3H ) , 1 .52 ( d , J = 7 . 2 Hz, 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 0 .95 ( m , 4H ) . 8 -016 S 8 .41 ( d , J = 2 . 1 Hz , 1H ), 7 .82 ( s , 1H ) , 7 .68 (d , J = 2 . 1 Hz , 1H ) , 6 .95 (bs , 1H ) , 6 . 81 ( t , J = 54 . 6 Hz, 1H ) , 6 .23 ( q , J = 7 . 2 Hz , 1H ) , 4 .45 ( d , J = 5 . 4 Hz, 2H ) , 3 .90 ( s , 3H ) , 1 . 98 ( d , J = 7 . 2 Hz , 3H ) , 1 . 31 ( s , 9H ) . 8 -025 S 8 . 46 ( d , J = 1 . 8 Hz , 1H ), 7 .81 ( s , 1H ) , 7 .68 ( d , J = 1. 8 Hz , 1H ) , 6 .93 (bs , 1H ) , 6 . 87 ( t, J = 54 . 0 Hz , 1H ), 4 . 6 - 4 .7 ( m , 1H ) , 4 . 50 ( s , 2H ) , 3 . 91 ( s , 3H ) , 3 .23 ( dd , J = 14 . 4 , 6 . 9 Hz , 1H ) , 3 . 14 ( dd , J = 14 . 4 , 5 . 4 Hz , 1H ) , 1 . 28 ( d , J = 6 . 6 Hz, 3H ) . 8 - 027 8 8 .55 ( d , J = 1 . 8 Hz, 1H ) , 7 .81 ( s , 1H ) , 7 . 78 ( d , J = 1 . 8 Hz , 1H ) , 7 . 45 - 7 .6 ( m , 2H ) , 7 . 3 - 7 . 4 ( m , 3H ) , 7 .01 ( d , J = 7 . 8 Hz , 1H ) , 6 .90 ( t , J = 54 . 6 Hz , 1H ), 4 . 6 - 4 .75 ( m , 1H ), 3 .92 ( s , 3H ) , 3 .26 (dd , J = 14 . 4 , 6 . 9 Hz, 1H ) , 3 .16 (dd , J = 14 . 4 , 5 . 4 Hz , 1H ) , 1 . 30 ( d , J = 6 .6 Hz, 3H ) . 8 -029 8 8 . 5 - 8 .55 and 8 . 4 - 8 .45 ( m , 1H ) , 7 . 87 and 7 .78 ( s , 1H ) , 7 .65 - 7 . 7 and 7 .6 - 7 .65 ( m , 1H ) , 7 .51 and 6 .65 ( d , J = 7 . 7 Hz , 1H ) , 7 .00 and 6 . 96 ( t , J = 54 . 2 Hz, 1H ) , 4 . 96 ( d , J = 4 . 3 Hz, 1H ) and 4 .90 ( d , J = 3 . 4 Hz, 1H ), 4 .65 - 4 . 8 and 4 . 4 - 4 .55 (m , 1H ) , 3 . 93 and 3 . 92 ( s , 3H ) , 3 . 3 - 3 . 6 ( m , 2H ), 1 . 4 - 1 . 55 ( m , 1H ) , 1 . 38 ( d , J = 6 . 7 Hz , 3H ) and 1 . 10 ( d , J = 6 . 4 Hz , 3H ) , 1 .22 ( t , J = 6 . 9 Hz, 3H ) and 1 . 20 ( t , J = 7 . 0 Hz, 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 8 - 030 8 8 .53 and 8 . 38 (d , J = 1 . 7 Hz, 1H ) , 7 . 86 and 7 . 76 ( s , 1H ) , 7 .68 ( d , J = 1 . 4 Hz, 1H ) and 7 .64 ( d , J = 1 . 7 Hz, 1H ) , 7 .30 and 6 .61 (bs , 1H ) , 6 .94 and 6 .93 ( t , J = 54 . 1 Hz , 1H ) , 5 .16 ( d , J = 4 . 1 Hz , 1H ) and 5 . 12 ( d , J = 3 . 1 Hz , 1H ) , 4 . 7 - 4 . 9 and 4 .55 - 4 .7 ( m , 1H ) , 3 . 5 - 4 . 1 ( m , 2H ) , 3 . 93 and 3 .91 ( s , 3H ) , 1 . 4 - 1 .55 ( m , 1H ) , 3 .41 and 1 . 13 ( d , J = 6 . 8 Hz, 3H ) , 0 . 75 - 1 . 0 ( m , 4H ) . 8 -031 ' 8 .53 and 8 .41 ( d , J = 1 . 7 Hz , 1H ) , 7 .84 and 7 . 75 ( s , 1H ) , 7 . 66 and 7 .61 ( d , J = 1 . 7 Hz, 1H ) , 7 .48 and 6 .58 ( d , J = 8 . 9 Hz , 1H ) , 6. 97 and 6. 94 (t , J = 54. 1 Hz , 1H ), 5 .75 -6 .0 (m , 1H ), 5. 1- 5 .3 (m , 2H ), 5 .02 ( d , J = 4 . 1 Hz , 1H ) and 4 .96 ( d , J = 3 . 1 Hz , 1H ) , 4 .65 - 4 . 8 and 4 . 4 - 4 .55 (m , 1H ) , 3 .75 4 . 2 ( m , 2H ) , 3 .93 and 3 .92 ( s , 3H ). 1 . 4 - 1 .55 (m , 1H ) , 1 . 39 ( d , J = 6 . 5 Hz, 3H ) and 1 .09 ( d , J = 6 . 8 Hz, 3H ) , 0 . 8 - 1 . 0 (m , 4H ) . 8 -032 8 8 .54 ( d , J = 1 . 7 Hz, 1H ) and 8. 43 (d , J = 2 .0 Hz, 1H ), 7 .75 and 7 .72 (s , 1H ), 7 .66 ( d , J = 1 . 7 Hz , 1H ) and 7 .62 ( d , J = 2 . 0 Hz , 1H ) , 7 .49 ( d , J = 8 . 2 Hz, 1H ) and 6 .63 ( d , J = 7 . 8 Hz, 1H ) , 7 .25 - 7 .35 ( m , 5H ) , 6 . 99 and 6 .97 ( t, J = 54 . 1 Hz , 1H ) , 5 .02 ( d , J = 4 . 4 Hz , 1H ) and 4 .95 ( d , J = 3 . 1 Hz , 1H ) , 4 . 7 - 4 . 9 ( m , 1H ) , 4 .64 and 4 .58 ( d , J = 11. 7 Hz , 1H ) , 4 . 45 and 4 . 28 ( d , J = 11 . 7 Hz , 1H ) , 3 .92 and 3 .91 ( s , 3H ) , 1 . 4 - 1. 55 ( m , 1H ) , 1 . 36 and 1 . 10 ( d . J = 6 . 8 Hz . 3H ) , 0 . 8 - 1 . 0 ( m . 4H ) . 8 -034 S 8 .37 ( d , J = 1 . 7 Hz , 1H ), 7 .84 ( s , 1H ) , 7 .62 ( d , J = 1. 7 Hz, 1H ) , 7 .12 ( d , J = 7 .2 Hz, 1H ) , 4 .55 -4 .75 ( m , 1H ) , 3 .25 (s , 3H ) , 3 . 22 ( dd , J = 14 .6 , 6 . 8 Hz , 1H ) , 3 .09 (dd , J = 14 . 6 , 4 . 8 Hz , 1H ) , 1 . 4 - 1 . 55 ( m , 1H ) , 1 . 25 ( d , J = 6 . 8 Hz, 3H ) , 0 .75 - 1 . 0 ( m , 4H ) . 9 -002 8 8 .42 ( d , J = 1 . 8 Hz , 1H ), 7 . 64 ( d , J = 1. 8 Hz , 1H ), 7 . 25 - 7 . 3 ( m , 1H ) , 7 .16 ( t, J = 54 . 3 Hz, 1H ), 3 . 8 - 3 .95 ( m , 1H ) , 3 .65 - 3 .75 ( m , 2H ) , 2 .73 ( s , 3H ), 1 . 4 - 1 .55 ( m , 1H ) , 1 . 27 ( d , J = 6 . 9 Hz , 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . US 10 ,029 , 986 B2 155 156 TABLE 18 - continued No . ' H NMR (CDC13 , Me Si, 300 MHz ) 9 -003 S 8 . 43 ( d , J = 1 . 5 Hz, 1H ) , 7 . 71 ( d , J = 1 . 5 Hz, 1H ) , 7 . 19 (bs , 1H ) , 7 . 18 ( t , J = 54 . 3 Hz, 1H ) , 5 .85 ( s , 1H ) , 5 . 84 ( s , 1H ) , 4 .41 ( d , J = 5 . 4 Hz , 2H ) , 2 .73 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 (m , 4H ) . 9 -004 8 8 . 38 ( d , J = 1 . 8 Hz , 1H ), 7 .64 ( d , J = 1 . 8 Hz, 1H ), 7 . 16 ( t, J = 54 . 6 Hz, 1H ) , 6 .53 (bs , 1H ) , 3 .61 ( d , J = 4 . 8 Hz , 2H ) , 2 .73 ( s , 3H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 . 0 - 1 . 15 ( m , 4H ) , 0 . 75 - 0 . 95 ( m , 4H ) . 9 -006a 8 8 .55 (d , J = 1. 8 Hz, 1H ) , 8 . 06 (d , J = 7. 5 Hz, 1H ) , 7 .72 ( d , J = 1 .8 Hz, 1H ) , 7 . 30 ( t , J = 54 . 0 Hz , 1H ) , 4 . 87 ( d , J = 3 . 9 Hz , 1H ) , 4 . 7 - 4 . 8 ( m , 1H ) , 3 .36 ( s, 3H ), 2 .76 ( s , 3H ), 1 .45 - 1 .55 ( m , 1H ) , 1 .07 ( d , J = 6 . 6 Hz , 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 9 - 0065 8 8 .43 ( d , J = 1 . 8 Hz, 1H ) , 7 .65 ( d , J = 1. 8 Hz, 1H ) , 7 . 15 ( t , J = 54 . 0 Hz, 1H ) , 6 .55 ( d , J = 7 . 8 Hz , 1H ) , 4 .79 ( d , J = 2 . 4 Hz , 1H ) , 4 . 35 - 4 . 5 ( m , 1H ) , 3 . 34 ( s , 3H ) , 2 .74 ( s , 3H ) , 1 . 4 1 . 55 ( m , 1H ) , 1 .44 ( d , J = 6 . 6 Hz , 3H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 13 -004 8 8 .52 ( d , J = 1 . 8 Hz , 1H ), 7 .84 ( d , J = 1 . 8 Hz, 1H ) , 4 .41 ( s , 2H ) , 3 . 35 - 3 .55 ( m , 2H ) , 3 . 46 ( s , 3H ) . 13 - 007 S 8 . 4 - 8 . 5 ( m , 1H ) , 7 .63 ( d , J = 1 . 8 Hz , 1H ) , 3 . 0 - 3 . 3 ( m , 2H ) , 2 . 6 - 2 . 8 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 .05 - 1 . 2 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) , 0 . 15 0 . 7 ( m , 4H ) . 13 - 009 8 8 .50 and 8 .44 ( d , J = 1 . 8 Hz , 1H ) , 7 . 74 and 7 .72 ( d , J = 1 . 8 Hz , 1H ) , 6 . 4 - 6 . 5 ( m , 1H ) , 3 .65 ( s , 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 0 . 8 - 1 . 0 ( m , 4H ). 15 - 005 8 8 .50 ( d , J = 1 . 8 Hz, 1H ) , 7 . 84 ( d , J = 1 . 8 Hz , 1H ) , 5 . 07 (bs , 1H ) , 4 .34 ( s , 2H ) , 3 . 95 - 4 . 15 ( m , 2H ), 3 . 46 ( s , 3H ) , 1 . 40 ( s , 9H ) . 15 - 008 S 8 . 45 ( d , J = 1 . 8 Hz , 1H ) , 7 .62 ( d , J = 1 . 8 Hz, 1H ) , 4 . 74 (bs , 1H ) , 3 . 4 - 3 . 7 ( m , 2H ) , 2 . 85 - 3 . 05 ( m , 1H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 .39 ( s , 9H ) , 1 . 0 - 1 . 15 ( m , 1H ) , 0 . 8 - 0 . 95 ( m , 4H ) , 0 . 2 - 0 . 6 m , 4H ) . 15 - 009 d 8 .42 ( d , J = 2 . 1 Hz, 1H ) , 7 .67 ( d , J = 2 . 1 Hz , 1H ) , 5 .67 ( s , 1H ) , 5 .62 ( s , 1H ) , 4 . 94 (bs , 1H ) , 4 . 1 - 4 . 2 ( m , 2H ) , 1 . 4 - 1 . 5 ( m , 1H ) , 1 .42 ( s , 9H ) , 0 . 8 0 . 95 ( m , 4H ) . 15 - 010 S 8 .45 - 8 .55 and 8 . 35 - 8 .45 ( m , 1H ), 7 .55 - 7 . 75 ( m , 1H ) , 6 .58 and 6 .47 ( s , 1H ) , 4 . 82 ( bs , 1H ) , 4 . 0 - 4 . 2 ( m , 2H ) , 1 . 4 - 1 . 5 m , 1H ) , 1 .39 and 1 . 38 ( s , 9H ) , 0 . 8 - 1 . 0 ( m , 4H ) . 15 - 012 8 8 . 47 ( d , J = 1 . 5 Hz , 1H ) , 7 .72 ( d , J = 1 . 5 Hz, 1H ) , 4 . 80 (bs , 1H ) , 4 .54 ( s , 2H ) , 3 . 97 ( q , J = 8 . 4 Hz , 2H ) , 3 .40 ( d , J = 5 . 7 Hz, 2H ) , 1 . 33 ( s , 9H ) , 0 . 95 - 1 . 1 ( m , 4H ) . 15 -016 d 8 .44 ( d , J = 1 . 8 Hz , 1H ) , 7 .65 ( d , J = 1 . 8 Hz, 1H ) , 4 .55 - 4 . 7 (m , 2H ) , 4 .25 - 4 . 4 ( m , 1H ) , 3 .05 - 3 .35 ( m , 2H ) , 1 .45 - 1 .55 ( m , 1H ) , 1 . 44 ( s , 9H ) , 1 .16 ( d , J = 6 . 9 Hz , 3H ), 0 . 8 - 1 . 0 ( m , 4H ) .

TEST EXAMPLES was sprayed . After drying in air, the pot was placed in an air - conditioned greenhouse (20° C . ) , and a suspension of Usefulness of the compounds of the present invention as conidium of Erysiphe polygoni ( synonym : Erysiphe betae ) pesticides will be described in detail by referring to the 40 was sprayed . After the pot were replaced at the same following the Test Examples , but the present invention is not temperature for 9 days , the proportion of the formed lesion limited thereto . in the inoculated leaves were counted to calculate the control Preparation of the Test Solution A : value in accordance with the following formula . The test Compounds of the present invention were dissolved in a - - was carried out in duplicate . solvent for emulsion ( a mixture of Sorpol ( registered trade mark ) 3005XL (manufactured by Toho Chemical Industry Control value = [ 1 - ( lesion area ratio in treated plot/ Co ., Ltd . ): N -methylpyrrolidone : Solvesso (registered trade lesion are a ratio in non -treated plot ) ]x100 mark ) 200 (manufactured by ExxonMobil Chemical) in a As results of the compounds were tested , the following ratio of 1 : 5 : 2 ) to prepare 20 wt % emulsifiable concentrates . 50 compounds showed a control value of at least 70 % . Then , distilled water was added to dilute the emulsifiable The compounds of the present invention : No. 1 -001 , 1 - 002 , concentrates to the prescribed concentration (500 ppm ) , and 1 -003 . 1 - 004 . 1 - 005 . 1 - 007 . 1 - 008 . 1 - 009 . 1 -010 , 1 - 011 . the obtained solutions were used in the following the Test 1 -012 , 1 - 013 , 1 -016 , 1 -017 , 1 - 018 , 1 -020 , 1 -021 , 1 -024 , Examples 1 to 8 . 1 -025 , 1 - 026 , 1 -027 , 1 - 028 , 1 -029 , 1 -030 , 1 - 031, 1 - 032 , Preparation of the Test Solution B : 55 Compounds of the present invention were dissolved in 2 -004 * , 3 - 001, 3 -002 , 3 - 003, 3 - 005 , 3 -006 , 3 - 007, 3 - 008 , dimethyl sulfoxide to prepare 1 wt % solutions . Then , 3 - 009 , 3 -010 , 3 -011 , 3 -012 * , 3 -013 , 3 -014 , 3 -015 , 3 -016 , distilled water was added to dilute the solutions to the 3 -020 , 3 -021 , 3 - 022 * , 3 -025 , 3 - 026 , 3 -027 , 3 -028 , 3 - 029 , prescribed concentration ( 100 ppm ) , and the obtained solu - 3 -030 , 3 -031 , 3 -032 , 3 - 033a , 3 -034 , 4 -003 , 4 - 004 , 5 - 002 , tions were used in the following the Test Examples 9 to 12 . 60 6 -001 , 8 - 001 , 8 - 002 , 8 - 003 , 8 -007 , 8 -008 , 8 -009 , 8 - 010 , 8 -011 , 8 - 012 , 8 -013 , 8 - 014 , 8 -015 , 8 -016 , 8 - 017 , 8 - 018 , Test Example 1 : Test on the Preventive Effect 8 -019 , 8 -020 , 8 -022 , 8 - 023 , 8 - 024 , 8 -026 , 8 -027 , 8 - 028 , Against Cucumber Powdery Mildew 8 -031 , 8 - 032 , 9 - 002 , 9 -003 , 9 - 004, 9 -005 , 9 - 006a, 9 - 006b , Cucumber (varieties : Sagami Hanjiro ) was seeded in 90 65 10 -001 * . cm plastic pot, and at the cotyledon stage, 5 ml per pot of The symbol * means that the test was carried out using a test solution A of the compounds of the present invention 100 ppm solution . US 10 ,029 , 986 B2 157 158 Test Example 2 : Test on the Preventive Effect The symbol * means that the test was carried out using a Against Cucumber Gray Mold (Spore Inoculation ) 100 ppm solution . Cucumber ( varieties: Sagami Hanjiro ) was seeded in 90 Test Example 4 : Test on the Preventive Effect cm plastic pot, and at the cotyledon stage, 5 ml per pot of 5 Against Cucumber Stem Rot test solution A of the compounds of the present invention was applied . After drying in air, the treated leaves were cut Cucumber ( varieties : Sagami Hanjiro ) was seeded in 90 and transferred in plastic containers . 30 ul of a mixture of a cm plastic pot , and at the cotyledon stage , 5 mlper pot of suspension of conidium of Botrytis cinerea and a dissolved test solution A of the compounds of the present invention PDA medium in a ratio of 1 : 1 was dropped on each treated 10 was applied . After drying in air , the pot was transferred in a leaf and inoculated . After the inoculation , the plastic con plastic container , and an agar blocks (diameter : 5 mm ) tainers were placed in 20° C . with humid conditions for 3 containing Sclerotinia sclerotiorum which was preliminarily days , and the proportion of the formed lesion in the inocu cultivated in a PDA medium was inoculated to the seed lated leaves were counted to calculate the control value in 15 leaves of the cucumber treated with the solution . After the accordance with the same formula as in the Test Example 1 . 15 inoculation , the plastic container was covered with a plastic The test was carried out in duplicate . sheet, and placed at 20° C . and humidified for 2 days , thus As results of the compounds were tested , the following the proportion of the formed lesion in the inoculated leaves compounds showed a control value of at least 70 % . were measured to calculate the control value in accordance The compounds of the present invention : No . 1 -001 , 1 - 002 , 20 withcarried the outsame in formuladuplicate as in the Test Example 1 . The test was 1 - 003 , 1 - 004 , 1 - 005 , 1 -007 , 1 -008 , 1 - 009 , 1 -010 , 1 - 011 , As results of the compounds were tested , the following 1 -012 , 1 - 013 , 1 -016 , 1 -017 , 1 -018 , 1 -020 , 1 -021 , 1 -024 , compounds showed a control value of at least 70 % . 1 -025 , 1 -026 , 1 - 027 , 1 -028 , 1 -029 , 1 - 030 , 1 -031 , 1 - 033 , The compounds of the present invention : No. 1 - 001, 1 -002 , 2 -004 * , 3 -001 , 3 - 002, 3 -003 , 3 -005 , 3 -006 , 3 -007 , 3 - 008 , 1 -003 , 1 -004 , 1 - 005 , 1 -007 , 1 -008 , 1 - 009, 1 -010 , 1 -012 , 3 -009 , 3 - 010 , 3 -011 , 3 - 012 * , 3 -013 , 3 - 014 , 3 - 015 , 3 -016 , 25 1 - 013 , 1 - 016 , 1 - 017 , 1 - 018 , 1 - 020 , 1 - 021 , 1 - 024 , 1 -025 , 3 -020 , 3 -021 , 3 -022 * , 3 -025 , 3 -026 , 3 -027 , 3 - 028 , 3 -029 , 1 -026 , 1 -027 , 1 - 028 , 1 - 029 , 1 - 030 , 1 -031 , 1 -033 , 2 - 004 * , 3 - 030 , 3 - 031, 3 - 032 , 3 - 033a , 3 - 034 , 4 - 003 , 4 -004 , 5 -002 , 3 -001 , 3 - 002 , 3 - 003 , 3 - 005 , 3 -006 , 3 - 007 , 3 - 008 , 3 - 009 , 6 - 001, 8 - 001 , 8 -002 , 8 - 003 , 8 - 007 , 8 - 008 , 8 -009 , 8 -010 , 3 -010 , 3 -011 , 3 -012 * , 3 -013 , 3 - 014 , 3 -015 , 3 -016 , 3 - 020 , 8 -011 , 8 - 012 , 8 -013 , 8 -014 , 8 - 015 , 8 -016 , 8 - 017 , 8 -018 , 3 -021 , 3 -022 * , 3 - 025 , 3 - 026 , 3 - 027 , 3 - 028 , 3 - 029 , 3 - 030 , 8 - 019 , 8 - 020 , 8 -022 , 8 - 023 , 8 - 024 , 8 - 026 , 8 -027 , 8 -028 , 30 3 -031 , 3 - 032 , 3 - 034 , 4 - 003 , 4 -004 , 5 - 002 , 6 - 001 , 8 - 001 , 8 -031 , 8 - 032 , 8 - 033 , 9 -002 , 9 - 003 , 9 - 004 , 9 -005 , 9 -006a , 8 -002 , 8 -003 , 8 -007 , 8 -008 , 8 - 009 , 8 - 010 , 8 - 011 , 8 - 012 , 9 -006b , 10 -001 * , 12 - 002 . 8 - 013 , 8 - 014 , 8 -015 , 8 -016 , 8 -017 , 8 -018 , 8 -019 , 8 -020 , The symbol * means that the test was carried out using a 8 -022 , 8 - 024 , 8 -026 , 8 -027 , 8 -028 , 8 - 031, 8 -032 , 8 - 033 , 100 ppm solution . 9 - 002 , 9 -003 , 9 -004 , 9 -005 , 9 -006a , 9 -006b , 10 - 001 * . 35 The symbol * means that the test was carried out using a Test Example 3 : Test on the Preventive Effect Against Cucumber Gray Mold (Mycelium 100 ppm solution . Inoculation ) Test Example 5 : Test on the Preventive Effect Against Cucumber Anthracnose Cucumber (varieties : Sagami Hanjiro ) was seeded in 90 40 cm plastic pot, and at the cotyledon stage, 5 ml per pot of Cucumber ( varieties : Sagami Hanjiro ) was seeded in 90 test solution A of the compounds of the present invention cm plastic pot, and at the cotyledon stage , 5 ml per pot of was applied . On the next day, the pot was transferred in a test solution A of the compounds of the present invention plastic container, and an agar blocks (diameter : 5 mm ) was sprayed . One day later, a suspension of conidium of containing Botrytis cinerea which was preliminarily culti - 45 Colletotrichum lagenarium (Synonym : Colletotrichum vated in a PDA medium was inoculated on the cotyledon of orbiculare ) was sprayed , and the pot was left for 2 days in the cucumber treated with the solution . After the inoculation , the inoculation chamber at 25° C . under humidity of 100 % the plastic container was covered with a plastic sheet , then RH . Thereafter, the pot was placed in an air - conditioned placed at 20° C . and humidified for 2 days . Thus the greenhouse ( 23° C . ) and left at the same temperature for 7 proportion of the formed lesion in the inoculated leaves were 50 days . Thereafter, the proportion of the formed lesion in the measured to calculate the control value in accordance with inoculated leaves were measured to calculate the control the same formula as in the Test Example 1 . The test was value in accordance with the same formula as in Test carried out in duplicate . Example 1 . The test was carried out in duplicate . As results of the compounds were tested , the following As results of the compounds were tested , the following compounds showed a control value of at least 70 % . 55 compounds showed a control value of at least 70 % . The compounds of the present invention : No . 1 - 001, 1 - 002 , The compounds of the present invention : No . 1 -001 , 1 - 002 , 1 - 003 , 1 - 004, 1 -005 , 1 - 007 , 1 - 008 , 1 - 012 , 1 -013 , 1 -016 , 1 -005 , 1 -013 , 1 - 020 , 3 - 002 , 3 -003 , 3 - 006 , 3 - 008 , 3 -016 , 1 -017 , 1 -018 , 1 - 020 , 1 -021 , 1 -024 , 1 - 025 , 1 -026 , 1 - 027 , 3 - 020 , 3 -033a , 6 -001 , 8 -003 , 8 - 009, 8 -010 , 8 -016 , 8 -017 , 1 -028 , 1 -029 , 1- 030 , 1 -031 , 1- 033 , 2 -004 * , 3 -001 , 3 -002 , 8 -020 , 8 -024 , 8 -025 * , 8 -026 , 8- 027 , 8 -032 , 9 -002 . 3 - 003 , 3 - 005 , 3 - 006 , 3 -007 , 3 -008 , 3 - 009 , 3 -010 , 3 -011 , 60 The symbol * means that the test was carried out using a 3 -012 * , 3 -013 , 3 -014 , 3 -015 , 3 -016 , 3 - 020 , 3 - 021, 3 - 022 * , 100 ppm solution . 3 -025 , 3 - 026 , 3 -027 , 3 -028 , 3 - 029 , 3 - 030 , 3 -031 , 3 - 034 , 4 -003 , 4 - 004 , 5 - 002 , 6 - 001, 8 - 001, 8 - 002 , 8 - 003 , 8 - 007 , Test Example 6 : Test on the Preventive Effect 8 -008 , 8 -009 , 8 - 011, 8 -012 , 8 - 013 , 8 - 014 , 8 -015 , 8 -016 , Against Wheat Powdery Mildew 8 -017 , 8 - 018 , 8 -019 , 8 - 020 , 8 - 022 , 8 - 024 , 8 - 026 , 8 - 027 , 65 8 - 028 , 8 - 031, 8 -032 , 8 -033 , 9 - 002 , 9 - 003 , 9 - 004 , 9 - 005 , Wheat ( varieties: Norin 61 ) was seeded in 90 cm plastic 9 - 006a , 9 - 006b . pot, and at the 1 . 3 - leaf stage , 5 ml per pot of test solution A US 10 ,029 , 986 B2 159 160 of the compounds of the present invention were applied . One of the formed lesion in the inoculated leaves were counted day after treatment, the pot was placed in an air- conditioned to calculate the control value in accordance with the same greenhouse ( 20° C . ) , and conidium of Blumeria graminis f . formula as in the Test Example 1 . The test was carried out sp . tritici was inoculated to the wheat. 7 days after, the inin duplicate . 5 As results of the compounds were tested , the following proportion of the formed lesion in the inoculated leaves were 5 compounds showed a control value of at least 70 % . measured to calculate the control value in accordance with The compounds of the present invention : No. 1 -016 , 1 -024 , the same formula as in the Test Example 1 . The test was 1 -025 , 1 - 031 , 3 - 001 , 3 - 002 , 3 -003 , 3 -008 , 3 -009 , 3 -011 , carried out in duplicate . 3 -013 , 3 -014 , 3 -016 , 3 - 020 , 3 -021 , 3 - 029 , 4 - 004 , 6 -001 . As results of the compounds were tested , the following 8 - 001 , 8 - 002 , 8 -007 , 8 -009 , 8 - 011 , 8 -012 , 8 - 014 , 8 - 015 , compounds showed a control value of at least 70 % . 10 8 - 016 , 8 -017 , 8 -022 , 8 - 024 , 8 -026 , 8 - 027 , 8 -033 , 9 - 003 , The compounds of the present invention : No . 1 - 001, 1 - 002 , 9 -006b . 1 -003 , 1 - 004 , 1 - 005 , 1 -007 , 1 -008 , 1 - 009 , 1 - 011 , 1 - 012 , 1 -013 , 1 - 016 , 1 -017 , 1 -018 , 1 -020 , 1 - 021 , 1 - 024 , 1 - 025 , Test Example 9: Test on the Antifungal Activity 1 -026 , 1 -027 , 1 -028 , 1- 029 , 1 - 030 , 1 -031 , 2 -004 * , 3 -001 , Against Asperaillus niger 3 - 002 , 3 - 003 , 3 -005 , 3 -006 , 3 -007 , 3 - 008 , 3 -010 , 3 - 011 , 15 3 -012 * , 3 -013 , 3 - 014 , 3 -015 , 3 -016 , 3 - 020 , 3 -021 , 3 - 022 * , 60 ul of a potato dextrose 1 % agar medium was added to 3 -025 , 3 - 026 , 3 -027 , 3 - 028 , 3 -029 , 3 -030 , 3 - 031, 4 -003 , each well of a 96 well plate , and 30 ul of sterilized water 4 - 004 , 5 - 002 , 6 -001 , 8 -001 , 8 -002 , 8 - 003 , 8 -007 , 8 - 008 , containing spores of Asperaillus niger ( 10 spores /3 ul) was 8 - 009 , 8 -011 , 8 - 012 , 8 - 013 , 8 - 014 , 8 -015 , 8 -016 , 8 -017 , added to each well. Further , 10 ul per well of test solution B 8 - 018 . 8 - 019 , 8 - 020 . 8 - 022 , 8 - 023 . 8 -024 . 8 - 026 . 8 - 027 . 20 of the compounds of the present invention was added , and 8 - 028 , 8 - 031 , 8 -032 , 9 - 002 , 9 - 003 , 9 - 004 . 9 - 006a . 9 - 006b . the plate was left at rest at 25° C . under dark conditions . 2 days after treatment , the flora area ratio ( % ) was determined The symbol * means that the test was carried out using a to calculate the efficacy ( % ) relative to the non - treated well 100 ppm solution . in accordance with the following formula . Test Example 7 : Test on the Preventive Effect 25 Efficacy ( % ) = [ 1 - ( flora area ratio in treated plot / flora Against Wheat Glume Blotch area ratio in non -treated well) ]x100 As results of the compounds were tested , the following Wheat ( varieties: Haruyutaka ) was seeded in 90 cm3 compounds showed an efficacy of at least 50 % . plastic pot, and at 1 . 3 - leaf stage , 5 ml per pot of test solution The compounds of the present invention : No . 1 -002 , 1 - 003 , A of the compounds of the present invention was applied . 30 1 -004 , 1 -005 , 1 - 007 , 1 -008 , 1 - 009 , 1 -011 , 1 -012 , 1 -013 , One day after treatment, a suspension of conidium of 1 -017 , 1 - 021 , 1 - 024 , 1 - 025 , 1 -033 , 3 - 001 , 3 - 002 , 3 - 003 , Phaeosphaeria nodorum (Synonym : Septoria nodorum ) was 3 - 005 , 3 - 006 , 3 -007 , 3 - 008 , 3 - 009 , 3 - 015 , 3 -016 , 3 -020 , sprayed to the wheat, and the pot was left in the inoculation 3 -021 , 8 - 001, 8 - 002 , 8 -003 , 8 -007 , 8 - 008 , 8 -009 , 8 -010 , chamber at 20° C . under humidity of 100 % RH for 2 days . 8 -011 , 8 -019 , 8 -020 , 8 -028 , 8 -033 , 9- 002, 9 -004 , 9 -006a . Then , the pot was placed in an air - conditioned greenhouse 35 ( 20° C . ) for 6 days . The proportion of the formed lesion in Test Example 10 : Insecticidal Test Against the inoculated leaves were measured to calculate the control Southern Root- Knot Nematode value in accordance with the same formula as in the Test Example 1 . The test was carried out in duplicate . 60 ul of a potato dextrose 1 % agar medium was added to As results of the compounds were tested , the following 40 each well of a 96 well plate , and 30 ul of sterilized water compounds showed a control value of at least 70 % . containing eggs of Southern root- knot nematode (Meloid The compounds of the present invention : No . 1 - 001, 1 - 002 , ogyne incognita ) (10 eggs/ 3 ul) was added to each well . 1 -003 , 1 - 004 , 1 -005 , 1 - 007 , 1 -008 , 1 -009 , 1 -010 , 1 -012 , Further, 10 ul per well of test solution B of the compounds 1 -013 , 1 - 017 , 1 -018 , 1 -020 , 1 -021 , 1 -023 , 1 -024 , 1 -025 , of the present invention was added , and the plate was left at 1 -026 , 1 -027 , 1 - 029 , 1 - 030 , 1 -031 , 1 - 032 , 1 -033 , 3 - 001, 45 rest at 25° C . under dark conditions . 4 days after treatment, 3 -002 , 3 - 003 , 3 - 005 , 3 - 006 , 3 - 007 , 3 - 008 , 3 - 009 , 3 -010 , unhatched eggs and inactive larvae were counted , and cal 3 - 011 , 3 - 012 * , 3 -013 , 3 - 015 , 3 - 016 , 3 -020 , 3 - 021, 3 -022 * . culated the efficacy ( % ) relative to the non - treated plot in 3 -026 , 3 - 027 , 3 -028 , 3 - 029 , 3 - 030 , 3 - 031, 3 -032 , 3 - 033a , aceaccordance with the following formula . 3 - 034 , 3 - 034a , 4 - 003 , 4 - 004 , 5 - 002 , 6 - 001 , 8 -001 , 8 - 002 , Efficacy ( % ) = [ ( number of unhatched eggs + inactive 8 -003 , 8 - 007 , 8 - 008 , 8 -009 , 8 -010 , 8 - 011 , 8 -012 , 8 -013 , 50 larvae in treated well )/ number of active larvae 8 -014 , 8 -015 , 8 -016 , 8 -017 , 8 -018 , 8 -019 , 8 -022 , 8 -023 , in non - treated well ]x100 8 - 024 , 8 - 026 , 8 -027 , 8 -028 , 8 - 031 , 8 - 032 , 9 -002 , 9 -003 , As results of the compounds were tested , the following 9 - 004 , 9 - 005 , 9 -006a , 9 - 006b , 10 - 001 , 11 - 001. compounds showed an efficacy of at least 50 % . The symbol * means that the test was carried out using a The compounds of the present invention : No. 1 - 001 , 1 - 002 , 100 ppm solution . 55 1 - 003 , 1 - 004 , 1 -005 , 1 -007 , 1 - 008 , 1 - 009 , 1 - 010 , 1 - 011 , 1 -012 , 1 - 013 , 1 -014 , 1 - 015 , 1 -016 , 1 -017 , 1 -018 , 1 - 021 , Test Example 8 : Test on the Preventive Effect 1 -024 , 1 - 025 , 1 - 031 , 1 - 033 , 2 -003 , 2 - 004 , 3 - 001 , 3 - 002 , Against Wheat Leaf Rust 3 -003 , 3 - 005 , 3 - 006 , 3 - 007 , 3 -008 , 3 -009 , 3 -010 , 3 -011 , 3 -015 , 3 - 016 , 3 -017 , 3 - 020 , 3 -021 , 5 -002 , 6 -001 , 8 -001 , Wheat ( varieties : Norin 61 ) was seeded in 90 cm plastic 60 8 -003 , 8 -007 , 8 - 008, 8 - 010 , 8 - 011, 8 -018 , 8 - 019 , 8 - 028 , pot, and at 1 . 3 -leaf stage , 5 ml per pot of test solution A of 9 -006a , 10 - 001. the compounds of the present invention was applied . One day after treatment, a suspension of spores of Puccinia Test Example 11 : Test on the Preventive Effect recondita was sprayed to the wheat, and the pot was left in Against Southern Root- Knot Nematode the inoculation chamber at 20° C . under humidity of 100 % 65 RH for 1 day . Thereafter, the pot was placed in an air - 1 ml per seedling of test solution B of the compounds of conditioned greenhouse (20° C .) for 8 days . The proportion the present invention was treated to the bases of garden US 10 , 029 , 986 B2 161 162 balsam seedlings ( about 2 weeks after budding ) planted in a Patent Application No. 2014 -088408 filed on Apr. 22 , 2014 cell tray of which each cell was filled with 10 g of soil. 1 and Japanese Patent Application No. 2014 - 130395 filed on hour after the application , 1 ml per cell of water containing Jun . 25, 2014 including specifications, claims and summa Southern root- knot nematode (Meloidogyne incognita ) 2 L ries are incorporated herein by reference in their entireties . larvae ( 100 larvae of 2 L / 1 ml) was applied to the base . The 5 tray was placed in a greenhouse for 3 weeks, and the degree The invention claimed is : of root knot on the root was determined in accordance with 1 . An alkynyl pyridine - substituted amide compound of the following damage index and the damage degree to the formula ( I) , its N - oxide or a salt thereof: calculate the efficacy ( % ) relative to the non - treated plot in accordance with the following formula . 10 po < Damage Index > 0 : No knot formation was observed . 1 : Knot formations were observed on parts of the root 0 R3 R4 system . 2 : Knot formations were observed on the entire root 15 system . Z 3 : Large knot formations were observed . R5 R R2 4 : Large knot formations were observed on the entire root system . [Damage degree] = [ % ( damage indexxnumber of each 20 damaged indexed seedling) /( 4xnumber of seed wherein : lings investigated ) ]x100 xl is difluoromethyl, X2 is a hydrogen atom , Efficacy (% ) = [ 1 - (damage degree in treated plot/ R ’ is methyl, damage degree in non - treated plot) ]x100 25 Yl is a hydrogen atom , a halogen atom , nitro , C1- C4 alkyl, As results of the compounds were tested , the following C1- C4 haloalkyl , C1- C4 alkoxy, C1- C4 haloalkoxy or compounds showed an efficacy of at least 50 % . C , -C4 alkylthio , The compounds of the present invention : No . 1 - 003 , 1 - 005 , Y and Yare each independently a hydrogen atom , a 1 - 007 , 1 - 009 , 1 -011 , 1 - 012 , 1 -013 , 1 -017 , 1 -024 , 1 -025 , halogen atom or methyl, 3 - 001, 3 - 002 , 3 -003 . 3 - 005 . 3 - 006 . 3 - 008 . 3 -009 . 3 -016 . 30 R and R ? are each independently a hydrogen atom , a 3 -020 , 3 -021 , 8 - 001, 8 - 002 , 8 -007 , 8 - 009, 8 -019 , 8 -028 , halogen atom , cyano, C , -C4 alkyl , C , -C4 haloalkyl , 9 -006a . Cz- Co cycloalkyl , phenylmethyl, phenylmethyl substi tuted by ( Z ) m , C , -C4 alkoxy, C .- C4 haloalkoxy, cyano Test Example 12 : Insecticidal Test Against Barber (CZ -C4 ) alkoxy , Cz -Co alkenyloxy, Cz- C6 haloalkeny Pole Worm 3535 loxy, C3 -C , alkynyloxy, C3- C , haloalkynyloxy, phenyl (C1 - C4) alkoxy, C2- C4 alkylthio , C -C4 alkoxyamino , 60 ul of a potato dextrose 1 % agar medium was added to CZ - C4 alkoxycarbonyl, C (O )NH2 , or — C (S )NH2 , each well of a 96 well plate , and 30 ul of sterilized water alternatively , R and R ’ together form a C2- C , alkylene containing eggs of Barber pole worm ( Haemonchus contor chain thereby to form a 3 -6 membered ring together tus ) (10 eggs / 3 ul) was added to each well. Further, 10 ul per 40 with the carbon atom to which R and R2 are bonded , well of test solution B of the compounds of the present wherein the alkylene chain optionally contains one or invention was added , and the plate was left at rest at 25° C . two oxygen atoms, sulfur atoms or nitrogen atoms and under dark conditions . 4 days after treatment, unhatched is optionally substituted by a C2 -Cz alkyl group , a eggs and inactive larvae were counted to calculate the C1- Cz haloalkyl group or an oxo group , or R and R ? efficacy ( % ) relative to the non - treated plot in accordance 45 together form C1- C6 alkylidene, C . - C . haloalkylidene with the same formula as in the Test Example 9 . or CZ -C4 alkoxy ( C , - C2) alkylidene, As results of the compounds were tested , the following R3 and R + are each independently a hydrogen atom , C . - C4 compounds showed an efficacy of at least 50 % . alkyl, C , -C4 haloalkyl, C1- C4 alkoxymethyl, Cz - C . The compounds of the present invention : No . 1 -001 , 1 - 002 , cycloalkyl or phenyl, 1- 003 , 1- 004 , 1 -005 , 1 -007 , 1- 008 , 1- 009 , 1 -010 , 1 -011 , 50 alternatively , R3 and R * together form an ethylene chain 1 -012 , 1 - 013 , 1 - 017 , 1 - 021 , 1 -024 , 1 - 025 , 1 - 033 , 3 -001 , thereby to form a cyclopropyl ring together with the 3 -002 , 3 - 003 , 3 -005 , 3 - 006 , 3 - 007 , 3 -008 , 3 - 009, 3 - 015 , carbon atom to which R3 and R4 are bonded , 3 -016 , 3 - 020 , 3 -021 , 4 - 004 , 8 - 001 , 8 - 002 , 8 -003 , 8 -007 , further alternatively , R or R , and R3 orR4 , together form 8 -008 , 8 -009 , 8 - 010 , 8 -011 , 8 -012 , 8 -013 , 8 -018 , 8 -019 , a CZ -C4 alkylene chain thereby to form a 3 - 6 membered 8 -020 , 8 -028 , 9 -002 , 9 - 004 , 9 - 005 , 9 - 006a. 55 ring together with the carbon atoms to which R ' or R², and R3 or R4 , are bonded , wherein the alkylene chain INDUSTRIAL APPLICABILITY optionally contains one oxygen atom or sulfur atom , R is a hydrogen atom , C1- C4 alkyl, C1- C4 haloalkyl, The alkynyl pyridine - substituted amide compounds of the (C2 - C2) alkyl substituted by R8, C3 -C6 cycloalkyl, present invention are very useful compounds which are 60 C2- C4 alkenyl, C3- C4 alkynyl, OH , CZ -C4 alkoxy, excellent in pesticidal activities, especially in fungicidal and C1- C4 haloalkoxy, C . -C4 haloalkylthio , C (O ) Rº or nematocidal activities , and have little harmful effect on CZ - C4 alkoxycarbonyl, non - target organisms such as mammals , fishes and useful Róis phenyl or phenyl substituted by ( Z ), insects . Z is halogen , The entire disclosures of Japanese Patent Application No. 65 m is an integer of 1 to 5 , 2014 -028087 filed on Feb . 18 , 2014 , Japanese Patent Appli R® is cyano, OR14 , CZ -C4 alkylthio , C , - C4 alkoxycar cation No. 2014 -082159 filed on Apr. 11 , 2014 , Japanese bonyl, C ( O ) NH2, or C ( S )NH2 , US 10 , 029 , 986 B2 163 164 Rºis C1- C4 alkyl, C , - C4 alkoxymethyl, C3- C4 cycloalkyl 7 . A method comprising applying the agricultural fungi or C2- C4 alkenyl , and cidal or nematicidal composition of claim 5 to soil in which R14 is C , -C4 alkyl, C2 -C4 haloalkyl, C . -C4 alkylcarbonyl, Cz- Co cycloalkylcarbonyl or C , -C4 alkoxycarbonyl. one or more plants grow . 2 . The compound of claim 1 , wherein : 8 . A method comprising applying the agricultural fungi Rl and R2 are H , cidal or nematicidal composition of claim 5 to a seed , a R3 is CH3, tuberous root or a rhizome of a plant. R4 is H , 9 . An antifungal or endoparasiticidal composition suitable R $ is H , Yl is Cl, and for mammals or birds, comprising the alkynyl pyridine Y2 and Y3 are H . 10 substituted amide compound , its N - oxide or a salt thereof of 3 . The compound of claim 2 , wherein R is phenyl . claim 1 , as an active ingredient. 4 . A pesticidal composition comprising the alkynyl pyri - 10 . A method , comprising orally administering the anti dine -substituted amide compound , its N -oxide or a salt fungal or endoparasiticidal composition of claim 9 a mam thereof according to claim 1 , as an active ingredient. mal or a bird . 5 . An agricultural fungicidal or nematicidal composition 15 11 . A method , comprising parenterally administering the comprising the alkynyl pyridine -substituted amide com antifungal or endoparasiticidal composition of claim 9 to a pound, its N -oxide or a salt thereof of claim 1 , as an active mammal or a bird ingredient. 6 . A method omprising applying the agricultural fungi 12 . The method of claim 11 , wherein the parenteral cidal or nematicidal composition of claim 5 to a plant byV 20 administration is transdermal administration . foliar treatment. * * * * *