DIPEPTIDYL PEPTIDASE IV INHIBITOR

Title:

DIPEPTIDYL PEPTIDASE IV INHIBITOR

Document Type and Number:

WIPO Patent Application WO/2005/025554

Kind Code:

Abstract:

A compound of the formula [I] wherein each symbol is as defined in the specification, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof show a DPP-IV inhibitory activity and are novel compounds effective for the treatment of type II diabetes, obesity and the like.

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Inventors:

TSUTSUMI KAZUHIRO (JP)
SHINKAI HISASHI (JP)
KITAO YUKI (JP)
YAMASHITA MASAKI (JP)
KOBAYASHI SATORU (JP)
MATSUI KENICHI (JP)
ODA TOMOHIRO (JP)
TANIGUCHI TOSHIO (JP)
ASAHINA KOTA (JP)

Application Number:

PCT/JP2004/013480

Publication Date:

March 24, 2005

Filing Date:

September 09, 2004

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Assignee:

JAPAN TOBACCO INC (JP)
TSUTSUMI KAZUHIRO (JP)
SHINKAI HISASHI (JP)
KITAO YUKI (JP)
YAMASHITA MASAKI (JP)
KOBAYASHI SATORU (JP)
MATSUI KENICHI (JP)
ODA TOMOHIRO (JP)
TANIGUCHI TOSHIO (JP)
ASAHINA KOTA (JP)

International Classes:

A61K31/16; A61K31/18; C07C237/14; C07C237/22; C07C237/24; C07C309/46; C07C311/20; C07C311/29; C07C311/46; C07C311/47; (IPC1-7): A61K31/00

Domestic Patent References:

WO2003045977A2	2003-06-05
WO1998045330A1	1998-10-15
WO1996006074A1	1996-02-29
WO2000034241A1	2000-06-15
WO2003029200A2	2003-04-10

Other References:

CHAKRABATTI J. ET AL: "Synthesis of N-(2-Chloroethyl) amides of Amino Acids as Potential Cytotoxic Agents" J. MED. CHEM., vol. 10, March 1967 (1967-03), pages 285-287, XP002324628
SENTEN, K. ET AL.: "Rapid Parallel Synthesis of Dipeptide Diphenyl Phosphonate Esters as Inhibitors of Dipeptidyl Peptidases" J. COMB. CHEM., vol. 5, no. 3, 2 April 2003 (2003-04-02), pages 336-344, XP002324626
HOEL A.M.L ET AL.: "Microwave-Assisted Solid-Phase Ugi four-component Condensations" TERAHEDRON LETTERS, vol. 40, 1999, pages 3941-3944, XP002324627
RICH, D.H. ET AL: "Synthesis of Analogues of Pepstatin" J. MED. CHEM., vol. 26, 1983, pages 904-910, XP002324629

Attorney, Agent or Firm:

Takashima, Hajime (1-1 Fushimimachi 4-chome, Chuo-k, Osaka-shi Osaka, JP)

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Claims:

Claims

A DPPIV inhibitor comprising a compound represented by the formula [I] wherein Ru ils selected from the following [A] [E] : [A] hydrogen atom, [B] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1><B14>), <B1> halogen atom, #<B2> C312 cycloalkyl, #<B3> hydroxyl, #<B4> C16 alkoxy, #<B5> C16 alkylthio, <B6> aryloxy, #<B7> aralkyloxy, <B8> heterocyclyloxy, #<B9> heterocyclylC16 alkoxy, #<B10> nitro, #<B11> amino, #<B12> cyano, #<B13> carboxyl and #<B14> X1R11 (R11 is selected from the following (Bal) and (Ba2) and X1 is selected from the following (Bb1)(Bb23)), '' (Bal) aryl and ##(Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Baal><Baal7>), ###<Baa1> halogen atom, ###<Baa2> C16 alkyl, ###<Baa3> haloC16 alkyl, ###<Baa4> C312 cycloalkyl, ###<Baa5> aralkyl, <Baa6> heterocyclylCi6 alkyl, ###<Baa7> hydroxyl, ###<Baa8> C16 alkoxy, ###<Baa9> C16 alkylthio, ###<Baa10> aryloxy, ###<Baa11> aralkyloxy, ###<Baa12> heterocyclyloxy, ###<Baa13> heterocyclylC16 alkoxy, ###<Baa14> nitro, Baal5> amino, ###<Baa16> cyano and ###<Baa17> carboxyl; ##(Bb1) single bond, (Bb2)0, ## (Bb3) S, ## (Bb4) NH, ## (Bb5) CO, ## (Bb6) CO2, ## (Bb7) OCO, ## (Bb8) OCO2, ## (Bb9) SO, ## (Bb10) SO2, ## (Bb11) OSO2, ## (Bb12) SO3, (Bbl3)CONH, ## (Bb14) NHCO, ## (Bb15) CSNH, .. (Bbl6)NHCS, ## (Bb17) NHSO2, ## (Bb18) SO2NH, ## (Bb19) NHCO2, ## (Bb20) OCONH, ## (Bb21) NHCONH, .. (Bb22)NHCSNHand ## (Bb23) NHSO2NH; [C] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1><C17>), #<C1> halogen atom, #<C2> C16 alkyl, #<C3> haloC16 alkyl, #<C4> aralkyl, '<C5> heterocyclylCi6 alkyi, #<C6> hydroxyl, . <C7> Cl6 alkoxy, #<C8> C16 alkylthio, #<C9> aryloxy, #<C10> aralkyloxy, #<C11> heterocyclyloxy, #<C12> heterocyclylC16 alkoxy, '<C13> nitro, #<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> X1X11 (R11 and X1 are as defined above) ; [D] X1R11 (R1l and X1 are as defined above); or [E] wherein R12 and R13 are each independently selected from the following (El) (E3), j and k are each independently an integer of 0 to 3, which is formed by R and R4 in combination, (E1) hydrogen atom, (E2) X12R14 (R14 is selected from the following (Eal) and (Ea2), X12 is selected from the following (Eb1)(Eb24)), ##(Eal) aryl and ##(Ea2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Eaal><Eaal7>), ###<Eaa1> halogen atom, ###<Eaa2> C16 alkyl, ###<Eaa3> haloC16 alkyl, ... <Eaa4> C312 cycloalkyl, ###<Eaa5> aralkyl, ###<Eaa6> heterocyclylC16 alkyl, ###<Eaa7> hydroxyl, ###<Eaa8> C16 alkoxy, ###<Eaa9> C16 alkylthio, ###<Eaa10> aryloxy, ###<Eaa11> aralkyloxy, ###<Eaa12> heterocyclyloxy, ###<Eaa13> heterocyclylC16 alkoxy, <Eaal4> nitro, ###<Eaa15> amino, ###<Eaa16> cyano and ###<Eaa17> carboxyl; ##(Eb1) single bond, ## (Eb2) O, .. (Eb3)S, ## (Eb4) NH, " (Eb5)CO, ## (Eb6) CO2, ## (Eb7) OCO, ## (Eb8) OCO2, . (Eb9)SO, (EblO)SO2, ## (Eb11) OSO2, ## (Eb12) SO3, ## (Eb13) CONH, ## (Eb14) NHCO, ## (Eb15) CSNH, .. (Ebl6)NHCS, ## (Eb17) NHSO2, ## (Eb18) SO2NH, ## (Eb19) NHCO2, ## (Eb20) OCONH, ## (Eb21) NHCONH, ## (Eb22) NHCSNH, ## (Eb23) NHSO2NH and ##(Eb24) 4 to 7membered divalent saturated heterocycle; or (E3) benzene ring formed by R 12 and R13 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ecl><Ecl7>), ##<Ec1> halogen atom, ##<Ec2> C16 alkyl, ##<Ec3> haloC16 alkyl, ##<Ec4> C312 cycloalkyl, ##<Ec5> aralkyl, ##<Ec6> heterocyclylC16 alkyl, ##<Ec7> hydroxyl, ##<Ec8> C16 alkoxy, ##<Ec9> C16 alkylthio, ##<Ec10> aryloxy, ##<Ec11> aralkyloxy, "<Ecl2> heterocyclyloxy, "<Ecl3> heterocyclylC16 alkoxy, "<Ecl4> nitro, ##<Ec15> amino, ##<Ec16> cyano and ##<Ec17> carboxyl; R2 is selected from the following [F] [H] : [F] hydrogen atom, [G] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1><G18>), #<G1> halogen atom, #<G2> C312 cycloalkyl, #<G3> hydroxyl, #<G4> C16 alkoxy, #<G5> C16 alkylthio, *. <G6> aryloxy, #<G7> aralkyloxy, #<G8> heterocyclyloxy, #<G9> heterocyclylC16 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, #<G14> =O, #<G15> carboxyl, #<G16> PO (OH) 2, #<G17> PO(OC16 alkyl)2 and <G18>PO (Oaryl) 2 ; and [H] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1><H21>), #<H1> halogen atom, #<H2> C16 alkyl, <H3> haloCl6 alkyl, #<H4> aralkyl, #<H5> heterocyclylC16 alkyl, #<H6> hydroxyl, #<H7> C16 alkoxy, #<H8> C16 alkylthio, #<H9> aryloxy, #<H10> aralkyloxy, #<H11> heterocyclyloxy, #<H12> heterocyclylC16 alkoxy, <H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, #<H17> =O, #<H18> carboxyl, #<H19> PO (OH) 2, #<H20> PO(OC16 alkyl) 2 and <H21>PO (0aryl) 2 ; R3 is selected from the following [I] and [J] [I] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <I1><I18>), #<I1> halogen atom, #<I2> C112 cycloalkyl, #<I3> hydroxyl, #<I4> C16 alkoxy, #<I5> C16 alkylthio, *<16> aryloxy, #<I7> aralkyloxy, #<I8> heterocyclyloxy, #<I9> heterocyclylCl6 alkoxy, #<I10> nitro, <I11> amino, <112> cyano, #<I13> amido, #<I14> =0, #<I15> carboxyl, #<I16> PO (OH) 2, #<I17> PO(OC16 alkyl)2 and <I18>PO (Oaryl) 2 ; and [J] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1><J21>), #<J1> halogen atom, #<J2> C16 alkyl, #<J3> haloC16 alkyl, #<J4> aralkyl, #<J5> heterocyclylC16 alkyl, #<J6> hydroxyl, #<J7> C16 alkoxy, #<J8> C16 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heterocyclyloxy, #<J12> heterocyclylC16 alkoxy, . <J13> nitro, #<J14> amino, '<J15> cyano, #<J16> amido, #<J17> =0, #<J18> carboxyl, <J19>PO (OH) 2, #<J20> PO(OC16 alkyl)2 and #<J21> PO(Oaryl)2 ; R4 is selected from the following [K] [S] : [K] hydrogen atom, [L] Cl_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Ll><L14>), #<L1> halogen atom, #<L2> C312 cycloalkyl, #<L3> hydroxyl, #<L4> C16 alkoxy, #<L5> C16 alkylthio, #<L6> aryloxy, #<L7> aralkyloxy, #<L8> heterocyclyloxy, #<L9> heterocyclylC16 alkoxy, #<L10> nitro, . <L11> amino, . <L12> cyano, #<L13> carboxyl and #<L14> Y41R41 (R41 is selected from the following (Lal) (La8), and y41 is selected from the following (Lbl) and (Lb2)), ##(La1) hydrogen atom, ##(La2) C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal><Laa24>), ###<Laa1> halogen atom, ... <Laa2> C312 cycloalkyl, ###<Laa3> hydroxyl, ###<Laa4> aralkyloxy, ###<Laa5> heterocyclyloxy, ###<Laa6> heterocyclylC1_6 alkoxy, ###<Laa7> nitro, ###<Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> OR413, ###<Laa11> COR414, ... <Laal2>C02 R413, ###<Laa13> OCOR413, ###<Laa14> CONR415R416, ... <Laal5>OCONR R ###<Laa16> NR415R416, ###<Laa17> NR417COR413, ###<Laa18> NR417CO2R413, ###<Laa19> SR413, ###<Laa20> SOR413, ###<Laa21> SO2R413, ... <Laa22>S02NR R ###<Laa23> NR417SO2R413 and ###<Laa24> NR417CONR415R416 (R413 is C16 alkyl, C312 cycloalkyl or aryl, R414, R415 and R416 are the same or different and each is hydrogen atom, C16 alkyl, C312 cycloalkyl or aryl, R417 is hydrogen atom or C1_6 alkyl, or R417 in combination with R413 form 14 alkylene); (La3) C3_12 cycloalkyl ; ##(La4) C312 cycloalkylC16 alkyl ; ##(La5) aryl; ##(La6) aralkyl ; ##(La7) heterocyclyl and (La8) heterocyclylC1_6 alkyl (said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl><Lab33>), ###<Lab1> halogen atom, ###<Lab2> C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C1_6 alkoxy, SO2C16 alkyl, SO2aryl, NHSO2C16 alkyl and NHSO2haloC16 alkyl), ... <Lab3> halOCI6 alkyl, ###<Lab4> aralkyl, ###<Lab5> heterocyclylC16 alkyl, ###<Lab6> C312 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C16 alkoxy, '"<Lab9> aralkyloxy, ###<Lab10> heterocyclyloxy, ###<Lab11> heterocyclylC16 alkoxy, "<Labl2> nitro, ###<Lab13> amino, ###<Lab14> cyano, ###<Lab15> carboxyl, ###<Lab16> (C16 alkoxy) carbonyl, ###<Lab17> C16 alkylsulfonyl, ###<Lab18> CH2CO2H, ###<Lab19> OR413, ###<Lab20> COR414, ###<Lab21> CO2R413, ###<Lab22> OCOR413, ... <Lab23>CONR415R416, ###<Lab24> OCONR415R416, ###<Lab25> NR415R416, ... <Lab26>NR COR ###<Lab27> NR417CO2R413, ###<Lab28> SR413, ... <Lab29> _SOR413, ... <Lab3D>S02 R413 ###<Lab31> SO2NR415R416, ###<Lab32> NR417SO2R413 and ###<Lab33> NR417CONR415R416 (R413, R414, R415, R416 and R417 are as defined above); ## (Lb1) single bond and ## (Lb2) X41 (X41 is (CHR418)cX41a(CHR419)d, X41a is selected from the following (Lba1)(Lba23), R418 and R419 are the same or different and each is hydrogen atom or C1_6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4), ### (Lba1) O, (Lba2)S, ### (Lba3) CO, ... (Lba4)CO2, ### (Lba5) OCO, ### (Lba6) OCO2, g (Lba7) SO, ### (Lba8) SO2, ### (Lba9) OSO2, ### (Lba10) SO3, ### (Lba11) NR411, ### (Lba12) CONR411, ### (Lba13) NR411CO, ### (Lba14) CSNR411, ### (Lba15) NR411CS, ### (Lba16) SO2NR411, ### (Lba17) NR411SO2, ### (Lba18) OCONR411, ### (Lba19) NR411CO2, ... (Lba2 0)NR"'CONR"', ### (Lba21) NR411CSNR412, ###(Lba22) NR411SO2NR412 (R411 and R412 are the same or different and each is selected from the following (Lbaa1)(Lbaa3)), ####(Lbaa1) hydrogen atom, ####(Lbaa2) C16 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal><Lbaaal4>), #####<Lbaaa1> halogen atom, #####<Lbaaa2> C312 cycloalkyl, #####<Lbaaa3> hydroxyl, "."<Lbaaa4> Cig alkoxy, #####<Lbaaa5> C16 alkylthio, #####<Lbaaa6> aryloxy, #####<Lbaaa7> aralkyloxy, #####<Lbaaa8> heterocyclyloxy, #####<Lbaaa9> heterocyclylC16 alkoxy, #####<Lbaaa10> nitro, #####<Lbaaa11> amino, #####<Lbaaa12> cyano, #####<Lbaaa13> carboxyl, '""<Lbaaal4> oxo; and #####(Lbaa3) (CH2)p (p is an integer of 1 to 3) formed by R 411 and R412 in combination; and ###(Lba23) 4 to 7membered divalent saturated heterocycle; [M] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1><M18>), #<M1> halogen atom, #<M2> C16 alkyl, #<M3> haloC16 alkyl, <M4> aralkyl, #<M5> heterocyclylC16 alkyl, #<M6> hydroxyl, #<M7> C16 alkoxy, #<M8> C16 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heterocyclyloxy, #<M12> heterocyclylC16 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, #<M17> carboxyl and #<M18> Y42R41 (R41 is as defined above, and y42 is selected'from the following (Ma1)(Ma12)), ##(Ma1) single bond, ## (Ma2) X41, ## (Ma3) Z41, ## (Ma4) Z41Z42, ##(Ma5) X41Z41, ## (Ma6) Z41X41, ## (Ma7) X41Z41X42, ## (Ma8) X41Z41Z42, ## (Ma9) Z41X41Z42, ## (Ma10) Z41Z42X41, (Mall) and (Mal2) (X41 is as defined above, X42 and X43 are each independently (CHR420)eX42a(CHR421)f, X42a is selected from the following (Maal) (Maa23), R420 and R421 are the same or different and each is hydrogen atom or C1_6 alkyl, e and f are each independently an integer of 0 to 2, Z42 and Z42 are the same or different and each is selected from the following (Mab1)(Mab6), and Z43 is selected from the following (Mac1)(Mac5)), ###(Maa1) single bond, ### (Maa2) O, (Maa3)S, ### (Maa4) CO, . (Maa5)C02, ### (Maa6) OCO, ### (Maa7) OCO2, ### (Maa8) SO, ### (Maa9) SO2, ### (Maa10) OSO2, (Maall)S03, (Maal2)NR, ### (Maa13) CONR411, ### (Maa14) NR411CO, ### (Maa15) NR411CO2, ### (Maa16) OCONR411,' ### (Maa17) CSNR411, ### (Maa18) NR411CS, ### (Maa19) SO2NR411, ### (Maa20) NR411SO2, ### (Maa21) NR411CONR412, ... (Maa22)NR41lCSNR4l2and ###(Maa23) NR411SO2NR412 (R411 and R412 are as defined above); ###(Mab1) C16 alkylene, ###(Mab2) C26 alkenylene, ###(Mab3) C26 alkynylene (said alkylene, alkenylene and alkynylene are optionally substituted by 1 to 3 substituents selected from the following <Mabal><Mabal3>), ####<Maba1> halogen atom, ####<Maba2> C312 cycloalkyl, ####<Maba3> hydroxyl, ####<Maba4> C16 alkoxy, ####<Maba5> C16 alkylthio, ***<Maba6> aryloxy,. ####<Maba7> aralkyloxy, ####<Maba8> heterocyclyloxy, <Maba9> heterocyclylC1_6 alkoxy, ####<Maba10> nitro, ####<Maba11> amino, ####<Maba12> cyano and ""<Mabal3> carboxyl; ###(Mab4) C312 cycloalkylene, ###(Mab5) arylene and ###(Mab6) divalent heterocycle (said cycloalkylene, arylene and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Mabbl><Mabbl8>), ####<Mabb1> halogen atom, ####<Mabb2> C16 alkyl, ####<Mabb3> haloC16 alkyl, .... <Mabb4> aralkyl, ####<Mabb5> heterocyclylC16 alkyl, ####<Mabb6> C312 cycloalkyl, ####<Mabb7> hydroxyl, ####<Mabb8> C16 alkoxy, ####<Mabb9> C16 alkylthio, ""<MabblO> aryloxy, ####<Mabb11> aralkyloxy, ####<Mabb12> heterocyclyloxy, ####<Mabb13> heterocyclylC16 alkoxy, ####<Mabb14> nitro, ####<Mabb15> amino, "<Mabbl6> cyano, ####<Mabb17> carboxyl and ####<Mabb18> X4cR4c (R4c is selected from the following (Mabbal) (Mabba4), and X4c is selected from the following (Mabbbl)(Mabbb9)), #####(Mabba1) hydrogen atom, #### (Mabba2) C16 alkyl, #### (Mabba3) aryl and ##### (Mabba4) aralkyl (alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Mabbaal><Mabbaa4>) ...... <Mabbaal> halogen atom, ...... <Mabbaa2> carboxyl, ######<Mabbaa3> (C16 alkoxy) carbonyl and ######<Mabbaa4> C16 alkylsulfonyl ; ##### (Mabbb1) single bond, ##### (Mabbb2) CO, ##### (Mabbb3) CO2, ..... (Mabbb4)OCO, ..... (Mabbb5)CoNR41c, #### (Mabbb6) NR41cCO, #### (Mabbb7) SO2, ..... (Mabbb8)S02NR41cand ##### (Mabbb9) NR41cSO2 (R41c is hydrogen atom or C1_6 alkyl) ; ### (Mac1) C16 alkanetriyl, ### (Mac2) C26 alkenetriyl (said alkanetriyl and alkenetriyl are optionally substituted by 1 to 3 substituents selected from the following <Macal><Macal3>) ""<Macal> halogen atom, ###<Maca2> C312 cycloalkyl, ####<Maca3> hydroxyl, ####<Maca4> C16 alkoxy, ####<Maca5> C16 alkylthio, ####<Maca6> aryloxy, ####<Maca7> aralkyloxy, ####<Maca8> heterocyclyloxy, ####<Maca9> heterocyclylC16 alkoxy, ####<Maca10> nitro, ####<Maca11> amino, ####<Maca12> cyano and '"'<Macal3> carboxyl; ### (Mac3) C312 cycloalkanetriyl, ### (Mac4) arenetriyl and ... (Mac5) trivalent heterocycle (said cycloalkanetriyl, arenetriyl and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Macbl><Macbl8>), ####<Macb1> halogen atom, ####<Macb2> C16 alkyl, ####<Macb3> haloC16 alkyl, ####<Macb4> aralkyl, ""<Macb5> heterocyclylCie alkyi, ####<Macb6> C312 cycloalkyl, ####<Macb7> hydroxyl, ####<Macb8> C16 alkoxy, ####<Macb9> C16 alkylthio, ####<Macb10> aryloxy, ####<Macb11> aralkyloxy, ####<Macb12> heterocyclyloxy, ####<Macb13> heterocyclylC16 alkoxy, ""<Macbl4> nitro, ####<Macb15> amino, ####<Macb16> cyano, ####<Macb17> carboxyl and .... <Macbl8>CH2C02H ; [N] aryl, [0] aralkyl, [P] heterocyclyl, [Q] heterocyclylC16 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclylC16 alkyl are optionally ; substituted by 1 to 3 substituents selected from the following <N1><N19>), #<N1> halogen atom, #<N2> C16 alkyl, #<N3> C312 cycloalkyl, #<N4> haloC16 alkyl, <N5> aralkyl, #<N6> heterocyclylC16 alkyl, #<N7> hydroxyl, <N8> Cl6 alkoxy, #<N9> C16 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heterocyclyloxy, <N13> heterocyclylC1_6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano, #<N17> =0, #<N18> carboxyl and #<N19> Y42R41 (R41 and Y42 are as defined above); [R] Y41R41 (R41 and Y41 are as defined above), or [S] (R42 and R43 are each independently selected from the following (S1)(S3), and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination, (S1) hydrogen atom, #(S2) Y41R44 (R44 is selected from the following (Sal) and (Sa2) and Y41 are as defined above), ## (Sal) aryl and ## (Sa2) heterocyclyl (aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Saal><Saal7>), ###<Saa1> halogen atom, ###<Saa2> C16 alkyl, ###<Saa3> haloC16 alkyl, "<Saa4> aralkyi, ###<Saa5> heterocyclylC16 alkyl, ###<Saa6> C312 cycloalkyl, '"<Saa7> hydroxyl, <Saa8> CI6 alkoxy, <Saa9> C1_6 alkylthio, ###<Saa10> aryloxy, ###<Saa11> aralkyloxy, ###<Saa12> heterocyclyloxy, ###<Saa13> heterocyclylC16 alkoxy, ###<Saa14> nitro, ###<Saa15> amino, ###<Saa16> cyano and ###<Saa17> carboxyl; or #(S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl><Scl7>), ##<Sc1> halogen atom, ##<Sc2> C16 alkyl, ##<Sc3> haloC16 alkyl, ##<Sc4> aralkyl, ##<Sc5> heterocyclylC16 alkyl, "<Sc6> 312 cycloalkyi, ##<Sc7> hydroxyl, ##<Sc8> C16 alkoxy, ##<Sc9> C16 alkylthio, ##<Sc10> aryloxy, ##<Sc11> aralkyloxy, ##<Sc12> heterocyclyloxy, "<Scl3> heterocyclylCie alkoxy, ##<Sc14> nitro, ##<Sc15> amino, ##<Sc16> cyano and ##<Sc17> carboxyl ; R5 is selected from the following [T][BB], [T] hydrogen atom, [U] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1><U14>), #<U1> halogen atom, #<U2> C312 cycloalkyl, <U3> hydroxyl,, <U4> Cl6 alkoxy, #<U5> C16 alkylthio, #<U6> aryloxy, <U7> aralkyloxy, #<U8> heterocyclyloxy, <U9> heterocyclylCi_6 alkoxy, #<U10> nitro, #<U11> amino, #<U12> cyano, #<U13> carboxyl and #<U14> X44R45 (R45 is selected from the following (Ual) and (Ua2), and X44 is selected from the following (Ub1)(Ub23)), ##(Ua1) aryl and ##(Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Uaal><Uaal7>) ###<Uaa1> halogen atom, ###<Uaa2> C16 alkyl, ###<Uaa3> haloC16 alkyl, ###<Uaa4> C312 cycloalkyl, ###<Uaa5> aralkyl, ###<Uaa6> heterocyclylC16 alkyl, ###<Uaa7> hydroxyl, ###<Uaa8> C16 alkoxy, ###<Uaa9> C16 alkylthio, ###<Uaa10> aryloxy, ###<Uaa11> aralkyloxy, ###<Uaa12> heterocyclyloxy, ###<Uaa13> heterocyclylC16 alkoxy, ... <Uaal4> nitro, ###<Uaa15> amino, ###<Uaa16> cyano and ###<Uaa17> carboxyl ; ## (Ub1) single bond, ## (Ub2) O, (Ub3) S, ## (Ub4) NH, (Ub5) CO, .. (Ub6)C02, ## (Ub7)OCO, ## (Ub8) OCO2, ## (Ub9) SO, ## (Ub10) SO2, ## (Ub11) OSO2, (Ubl2)S03, ## (Ubl3) CONH, ## (Ubl4) NHCO, ## (Ub15) CSNH, ## (Ub16) NHCS, ## (Ub17) NHSO2, ## (Ub18) SO2NH, ## (Ub19) NHCO2, ## (Ub20) OCONH, ## (Ub21)NHCONH, (Ub22)NHCSNHand ## (Ub23) NHSO2NH; [V] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1><V17>), #<V1> halogen atom, . <V2> Cl_6 alkyl, #<V3> haloC16 alkyl, #<V4> aralkyl, #<V5> heterocyclylC16 alkyl, <V6> hydroxyl, <V7> C16 alkoxy, #<V8> C16 alkylthio, <V9> aryloxy, #<V10> aralkyloxy, . <Vll> heterocyclyloxy, #<V12> heterocyclylC16 alkoxy, #<V13> nitro, <V14> amino, #<V15> cyano, #<V16> carboxyl and #<V17> XX44R45 (R45 and X44 are as defined above) ; [W] 3 to 7membered saturated heterocycle, [X] aryl, [Y] heterocyclyl, [Z] aralkyl, [AA] heterocyclylC16 alkyl (said saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclylC16 alkyl are optionally substituted by 1 to 3 substituents selected from the following <W1><w16>), #<W1> halogen atom, #<W2> C16 alkyl, #<W3> C312 cycloalkyl, #<W4> aralkyl, #<W5> heterocyclylC16 alkyl, #<W6> hydroxyl, #<W7> C16 alkoxy, #<W8> C16 alkylthio, #<W9> aryloxy, #<W10> aralkyloxy, #<W11> heterocyclyloxy, #<W12> heterocyclylC16 alkoxy, <W13> nitro, #<W14> amino, #<W15> cyano and #<W16> carboxyl ; and [BB] X44R45 (R45 and X44 are as defined above), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A compound represented by the formula [II] wherein R1 is selected from the following [A][E] : [A] hydrogen atom, [B] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1><B14>), #<B1> halogen atom, <B2> C312 cycloalkyl, #<B3> hydroxyl, #<B4> C16 alkoxy, <B5> C16 alkylthio, <B6> aryloxy, #<B7> aralkyloxy, #<B8> heterocyclyloxy, #<B9> heterocyclylC1_6 alkoxy, #<B10> nitro, #<B11> amino, #<B12> cyano, #<B13> carboxyl and #<B14> X1R11 (R11 and X1 are defined in claim 1) ; [C] 312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1><C17^), #<C1> halogen atom, #<C2> C16 alkyl, #<C3> haloC16 alkyl, #<C4> aralkyl, #<C5> heterocyclylC16 alkyl, #<C6> hydroxyl, #<C7> C16 alkoxy, #<C8> C16 alkylthio, <C9> aryloxy, #<C10> aralkyloxy, #<C11> heterocyclyloxy, #<C12> heterocyclylC16 alkoxy, <C13> nitro, #<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> X1R11 (R11 and X1 are as defined in claim 1) ; [D] X1R11 (Rll and Xl are as defined in claim 1) ; or [E] wherein R12, R13, j and k are as defined in claim 1, which is formed by R1 and R4 in combination; R2 is selected from the following [F] [H], [F] hydrogen atom, [G] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1><G18>), <G1> halogen atom, <G2> C312 cycloalkyl, #<G3> hydroxyl, #<G4> C16 alkoxy, #<G5> C16 alkylthio, #<G6> aryloxy, #<G7> aralkyloxy, #<G8> heterocyclyloxy, #<G9> heterocyclylC16 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, #<G14> =O, #<G15> carboxyl, <G16>PO (OH) 2, #<G17> PO (OC16 alkyl) Z and #<G18> PO (Oaryl)2; [H] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1><H16> and <H18><H21>), #<H1> halogen atom, #<H2> C16 alkyl, #<H3> haloC16 alkyl, <H4> aralkyl, #<H5> heterocyclylC16 alkyl, #<H6> hydroxyl, #<H7> C16 alkoxy, #<H8> C16 alkylthio, <H9> aryloxy, #<H10> aralkyloxy, #<H11> heterocyclyloxy, #<H12> heterocyclylC16 alkoxy, #<H13> nitro, <H14> amino, #<H15> cyano, #<H16> amido, #<H18> carboxyl, #<H19> PO (OH) 2, #<H20> PO(OC16 alkyl) 2 and <H21>PO (0aryl) 2 ; R3' is the following [J] [J] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1><J16> and <J18><J21>), #<J1> halogen atom, #<J2> C16 alkyl, #<J3> haloC16 alkyl, #<J4> aralkyl, #<J5> heterocyclylC16 alkyl, <J6> hydroxyl, #<J7> C16 alkoxy, #<J8> C16 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heterocyclyloxy, #<J12> heterocyclylC16 alkoxy, #<J13> nitro, #<J14> amino, #<J15> cyano, #<J16> amido, #<J18> carboxyl, #<J19> PO (OH) 2, #<J20> PO(OC16 alkyl)2 and <J21>PO (0aryl) 2 ; R4 is selected from the following [K] [M], [P], [R] and [S], [K] hydrogen atom, [L] Ci6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1><L14>) <L1> halogen atom, #<L2> C312 cycloalkyl, <L3> hydroxyl, #<L4> C16 alkoxy, #<L5> C16 alkylthio, #<L6> aryloxy, #<L7> aralkyloxy, <L8> heterocyclyloxy, #<L9> heterocyclylC16 alkoxy, #<L10> nitro, #<L11> amino, #<L12> cyano, . <L13> carboxyl and #<L14> Y41R41' (R41' is selected from the following (Lal), (La2), (La5) and (La7), and Y41 is as defined in claim 1), (las) hydrogen atom, ## (La2) C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal><Laa24>), ###<Laa1> halogen atom, ###<Laa2> C312 cycloaLkyl, ###<Laa3> hydroxyl, ###<Laa4> aralkyloxy, ###<Laa5> heterocyclyloxy, ###<Laa6> heterocyclylC16 alkoxy, ###<Laa7> nitro, "<Laa8> cyano, ###<Laa9> carboxyl, ... <LaalO>OR413, ###<Laa11> COR414, ... <Laal2>CO2 R413 ###<Laa13> OCOR413, ###<Laa14> CONR415R416, ###<Laa15> OCONR415R416, ###<Laa16> NR415R416, ###<Laa17> NR417COR413, ###<Laa18> NR417CO2R413, ###<Laa19> SR413, ###<Laa20> SOR413, ###<Laa21> SO2R413, ###<Laa22> SO2NR415R416, ###<Laa23> NR417SO2R413 and ###<Laa24> NR417CONR415R416 (R413, R414, R415, R416 and R417 is as defined in claim 1); ### (La5) aryl and ## (La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl><Lab33>), ###<Lab1> halogen atom, <Lab2> C6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C16 alkoxy,SO2C16 alkyl, SO2aryl,NHSO2C1_6 alkyl andNHSO2haloC1_6 alkyl), ###<Lab3> haloC16 alkyl, ###<Lab4> aralkyl, ###<Lab5> heterocyclylC16 alkyl, ###<Lab6> C312 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C16 alkoxy, ###<Lab9> aralkyloxy, ###<Lab10> heterocyclyloxy, <Labll> heterocyclylC16 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, '"<Labl4> cyano, '"<Labl5> carboxyl, ###<Lab16> (C16 alkoxy) carbonyl, ###<Lab17> C16 alkylsulfonyl, ###<Lab18> CH2CO2H, ###<Lab19> OR413, ... <Lab20>COR ###<Lab21> CO2R413, ###<Lab22> OCOR413, ###<Lab23> CONR415R416, ###<Lab24> OCONR415R416, ###<Lab25> NR415R416, ###<Lab26> NR417COR413, ###<Lab27> NR417CO2R413, ###<Lab28> SR413, ###<Lab29> SOR413, ###<Lab30> SO2R413, ###<Lab31> SO2NR415R416, ###<Lab32> NR417SO2R413 and ###<Lab33> NR417CONR415R416 (R413, R414, R415, R416 and R417 are as defined in claim 1); [s12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1><M18>), <M1> halogen atom, #<M2> C16 alkyl, #<M3> haloC16 alkyl, <M4> aralkyl, #<M5> heterocyclylC16 alkyl, <M6> hydroxyl, <M7> C1_6 alkoxy, #<M8> C16 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heterocyclyloxy, #<M2> heterocyclylC16 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, <M17> carboxyl and #<M18> Y42R41' (R41' is as defined above and Y42 is as defined in the claim 1); [P] 3 to 7membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1><N16> and <N18>), #<N1> halogen atom, #<N2> C16 alkyl, #<N3> C3_12 cycloalkyl, #<N4> haloCl6 alkyl, #<N5> aralkyl, <N6> heterocyclylCl_6 alkyl, #<N7> hydroxyl, #<N8> C16 alkoxy, #<N9> C16 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heterocyclyloxy, #<N13> heterocyclylC16 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano and <N18> carboxyl; [R] Y41R41' (R41' and Y41 are as defined above), or [S] (R42 and R43 are each as defined in claim 1, m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination, R5 is selected from the following [Tl[Wl and [BB], [T] hydrogen atom, [U] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1><U14>), #<U1> halogen atom, #<U2> C3_12 cycloalkyl, <U3> hydroxyl, <U4> Cl6 alkoxy, #<U5> C16 alkylthio, #<U6> aryloxy, #<U7> aralkyloxy, #<U8> heterocyclyloxy, #<U9> heterocyclylC16 alkoxy, #<U10> nitro, #<U11> amino, #<U12> cyano, #<U13> carboxyl and <U14>X44R45 (R45 and X44 are as defined in claim 1); [V] C3_12 cycloalkyl (cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1><V17>), #<V1> halogen atom, #<V2> C16 alkyl, #<V3> haloC16 alkyl, #<V4> aralkyl, #<V5> heterocyclylC16 alkyl, #<V6> hydroxyl, <V7> CI6 alkoxy, <V8> Ci6 alkylthio, #<V9> aryloxy, #<V10> aralkyloxy, #<V11> heterocyclyloxy, #<V12> heterocyclylC16 alkoxy, #<V13> nitro, #<V14> amino, #<V15> cyano, #<V16> carboxyl and <V17>X44R45 (R45 and X44 are as defined in claim 1); [W] 3 to 7membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <W1><W16>), #<W1> halogen atom, <W2> C1_6 alkyl, #<W3> C312 cycloalkyl, #<W4> aralkyl, #<W5> heterocyclylC16 alkyl, #<W6> hydroxyl, #<W7> C1_6 alkoxy, #<W8> C16 alkylthio, #<W9> aryloxy, #<W10> aralkyloxy, aralkyloxy, #<W11> heterocyclyloxy, <W12> heterocyclylC16 alkoxy, #<W13> nitro, #<W14> amino, #<W15> cyano and <W16> carboxyl; [BB]X44R45 (R45 and X44 are as defined in claim 1), provided that, when R1 and R2 are hydrogen atoms and R3 is cyclopropyl, then the combination of one of R4 and R5 being isopropyl or tertbutyl, and the other being hydrogen atom does not occur, and when R1 and R2 are hydrogen atoms and R3' is cyclobutyl, then the combination of one of R4 and R5 being tert butyl, and the other being hydrogen atom does not occur, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

The compound of claim 2, wherein R41 is selected from the following (Lal), (La2), (La5) and (La7), X41a is selected from the following (Lba1) (Lba23), and other symbols are as defined in claim 2, ## (La1) hydrogen atom, ## (La2) C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal><Laa24>), ###<Laa1> halogen atom, ###<Laa2> C312 cycloAlkyl, ###<Laa3> hydroxyl, '"<Laa4> aralkyloxy, ###<Laa5> heterocyclyloxy, ###<Laa6> heterocyclylC16 alkoxy, *"<Laa7> nitro, ###<Laa8> cyano, "<Laa9> carboxyl, ###<Laa10> OR413, ###<LAA11> COR414, ###<Laa12> CO2R413, ###<Laa13> OCOR413, ###<Laa14> CONR415R416, ###<Laa15> OCONR415R416, ###<Laa16> NR415R416, ###<Laa17> NR417COR413, ###<Laa18> NR417CO2R413, ###<Laa19> SR413, <Laa20>SoR413, ###<Laa21> SO2R413, ... <Laa22>S02NR R ###<Laa23> NR417SO2R413 and ###<Laa24> NR417CONR415R416 (R413 is C1_6 alkyl, C3_12 cycloalkyl or aryl, R414, R415 and R416 are the same or different and each is hydrogen atom, C16 alkyl, C312 cycloalkyl or aryl, R417 is hydrogen atom or C1_6 alkyl) ; ## (La5) aryl and ## (La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl><Lab33>), ###<Lab1> halogen atom, ###<Lab2> C16 alkyl, ###<Lab3> haloC16 alkyl, <Lab4> aralkyl, ###<Lab5> heterocyclylC16 alkyl, ###<Lab6> C312 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C16 alkoxy, ###<Lab9> aralkyloxy, ###<Lab10> heterocyclyloxy, ###<Lab11> heterocyclylC16 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, <Labl4> cyano, ###<Lab15> carboxyl, ###<Lab16> (C16 alkoxy) carbonyl, ###<Lab17> C16 alkylsulfonyl, ###<Lab18> CH2CO2H, ###<Lab19> OR413, ###<Lab20> COR414, ###<Lab21> CO2R413, ###<Lab22> OCOR413, ###<Lab23> CONR415R416, ###<Lab24> OCONR415R416, ###<Lab25> NR415R416, ... <Lab26>NR COR ###<Lab27> NR417CO2R413, ###<Lab28> SR413, ###<Lab29> SOR413, ###<Lab30> SO2R413, ###<Lab31> SO2NR415R416, ###<Lab32> NR417SO2R413 and ###<Lab33> NR417CONR415R416 (R413, R414, R415, R416 and R417 are as defined above); ### (Lba1) O, (Lba2)S, ... (Lba3)CO, ### (Lba4) CO2, ### (Lba5) OCO, ### (Lba6) OCO2, ### (Lba7) SO, ### (Lba8) SO2, ### (Lba9) OSO2, ### (Lba10) SO3, ### (Lba11) NR411, ... (Lbal2)CONR , ### (Lba13) NR411CO, (Lbal4)CSNR, ... (Lbal5)NR41lCS, ### (Lba16) SO2NR411, ### (Lba17) NR411SO2, ### (Lba18) OCONR411, ### (Lba19) NR411CO2, ### (Lba20) NR411CONR412, ### (Lba21) NR411CSNR412, ###(Lba22) NR411SO2NR412 (R411 and R412 are the same or different and each is selected from the following (Lbaal) (Lbaa3)), ####(Lbaa1) hydrogen atom, ####(Lbaa2) C16 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal><Lbaaal3>), #####<Lbaaa1> halogen atom, #####<Lbaaa2> C312 cycloalkyl, ..... <Lbaaa3> hydroxyl, #####<Lbaaa4> C16 alkoxy, #####<Lbaaaa5> C16 alkylthio, #####<Lbaaa6> aryloxy, #####<Lbaaa7> aralkyloxy, #####<Lbaaa8> heterocyclyloxy, #####<Lbaaa9> heterocyclylC16 alkoxy, #####<Lbaaa10> nitro, #####<Lbaaa11> amino, #####<Lbaaa12> cyano, #####<Lbaaa13> carboxyl, and ####(Lbaa3) (CH2)p (p is an integer of 1 to 3) formed by Roll and R412 in combination; and ###(Lba23) 4 to 7membered divalent saturated heterocycle, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

The compound of claim 2, wherein R1 is [A] hydrogen atom, [B] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1><B4>, <B10><B12> and <B14>), #<B1> halogen atom, <B2> C312 cycloalkyl, #<B3> hydroxyl, #<B4> C16 alkoxy, <B10> nitro, #<B11> amino, <B12> cyano and #<B14> X1R11 (R11 and X1 are each as defined in claim 1); or [C] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2>, <C6>, <C7> and <C13><C17>), <C1> halogen atom, #<C2> C16 alkyl, #<C6> hydroxyl, #<C7> Cl_6 alkoxy, #<C13> nitro, #<C14> amino, <C15> cyano, <C16> carboxyl and #<C17> X1R11 (R11 and X1 are as defined above) ; R'i s [F] hydrogen atom, [G] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from <G1><G4>, <G10><G13> and <G16><G18>), #<G1> halogen atom, #<G2> C312 cycloalkyl, #<G3> hydroxyl, #<G4> C16 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, cyano, #<G13> amido, #<G16> PO (OH) zu #<G17> PO (OC16 alkyl)2 and <G18>PO (0aryl) 2 ; or [H] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>, <H2>, <H6>, <H7>, <H13><H16> and <H19><H21>), #<H1> halogen atom, #<H2> C16 alkyl, #<H6> hydroxyl, <H7> Cl6 alkoxy, #<H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, #<H19> PO (OH) 2, #<H20> PO(OC16 alkyl)2 and <H21>PO (Oaryl) 2; R3' is [J] C3_12 cycloalkyl (said cycloalkyl is optionally substitutedby 1 to 3 substituents selected from the following <J1>, <J2>, <J6>, <J7>, <J13><J16> and <J19><J21>), #<J1> halogen atom, #<J2> C16 alkyl, #<J6> hydroxyl, #<J7> C16 alkoxy, #<J13> nitro, #<J14> amino and <J15> cyano <J16> amido, #<J19> PO (OH) 2, #<J20> PO (OC16 alkyl) 2 and <J21>PO (Oaryl) 2; R4' is [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1><L4> and <L10> <L12>), #<L1> halogen atom, #<L2> C312 cycloalkyl, #<L3> hydroxyl, #<L4> C16 alkoxy, #<L10> nitro, #<L11> amino and <L12> cyano; [M] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>, <M7>, <M13><M16> and <M18>), #<M1> halogen atom, #<M2> C16 alkyl, #<M6> hydroxyl, #<M7> C16 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano and #<M18> Y42R41' (R41' is as defined in claim 2, y42 is as defined in claim 1); [P] 3 to 7membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>, <N2>, <N7>, <N8>, <N14><N16> and <N18>), #<N1> halogen atom, #<N2> C16 alkyl, #<N7> hydroxyl, #<N8> C1_6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano and *<N18> carboxyl; or [S] (R42 and R43 are each as defined in claim 1 and m and n are each independently an integer of 0 to 3) formed by R4'and R5'in combination; and R5' is [T] hydrogen atom, [U] C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1><U4> and <U10> <U12>), #<U1> halogen atom, #<U2> C312 cycloalkyl, <U3> hydroxyl, #<U4> C16 alkoxy, #<U10> nitro, <U11> amino and #<U12> cyano; or [V] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>, <V2>, <V6>, <V7> and <V13><V15>), #<V1> halogen atom, <V2> Cl6 alkyl, #<V6> hydroxyl, #<V7> C16 alkoxy, #<V13> nitro, #<V14> amino and #<V15> cyano provided that, when R1 and R2' are hydrogen atoms and R3 is cyclopropyl, then the combination of one of R 4'and R5'being isopropyl or tertbutyl, and the other being hydrogen atom does not occur, and when R1 and R2 are hydrogen atoms and R3' is cyclobutyl, then the combination of one of R4 and R5 being tert butyl, and the other being hydrogen atom does not occur, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A compound represented by the formula [III] wherein R2a is [F] hydrogen atom or [G] C16 alkyl, R4a is selected from the following [MabbO], [Mabbl] and [Mabbl8], [MabbO] hydrogen atom, [Mabb1] halogen atom and [Mabb18] X4cR4c (R4c is selected from the following (Mabbal) (Mabba4), X4C is selected from the following (Mabbbl) (Mabbb9)), # (Mabbal) hydrogen atom, # (Mabba2) C16 alkyl, (Mabba3) aryl and (Mabba4) aralkyl (said alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Mabbaal><Mabbaa4>), ##<Mabbaa1> halogen atom, ##<Mabbaa2> carboxyl, ##<Mabbaa3> (C16 alkoxy) carbonyl and ##<Mabbaa4> C16 alkylsulfonyl; ' (Mabbbl) single bond, (Mabbb2) CO, (Mabbb3) CO2, (Mabbb4)OCO, (Mabbb5) CONR41c, (Mabbb6) NR41cCO, (Mabbb7) SO2, # (Mabbb8) SO2NR41c and (Mabbb9) NR41cSO2 (R41c is hydrogen atom or C16 alkyl) ; X4a is selected from the following [Lba1] [Lba3], [Lba8], [Lba11] [Lbal3], [Lba16] [Lba19] and [Lba21], [Lbal]0, [Lba2]S, [Lba3]CO, [Lba8] SO2, [Lba11] NR41a, [Lba12] CONR41a, [Lba13] NR41aCO, [Lba16] SO2NR41a, [Lba17] NR41aSO2, [Lba18] OCONR41a, [Lbal9]NR41aC02and [Lba21] NR41aCONR41d (R41a and R41d are the same or different and each is hydrogen atom or C16 alkyl) ; R4b is selected from the following [La1], [La2], [La5] and [La6], [Lal] hydrogen atom, [La2] Cl6 alkyl, [La5]aryl and [La6] aralkyl (said alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>, <Lab2>, <Lab7>, <Lab8>, <Labl2><Labl7>, <Lab31> and <Lab32>) ; #<Lab1> halogen atom, #<Lab2> C16 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from C16 alkoxy, SO2C16 alkyl, SO2aryl, NHSO2C1_6 alkyl andNHSO2haloCi_6 alkyl), #<Lab7> hydroxyl, #<Lab8> C16 alkoxy, #<Lab12> nitro, #<Lab13> amino, #<Lab14> cyano, <Labl5> carboxyl, #<Lab16> (C16 alkoxy) carbonyl, #<Lab17> Cri6 alkylsulfonyl, #<Lab31> SO2NR41fR41g and #<Lab32> NR41fSO2R41h (R41f, R41g are the same or different and each is hydrogen atom or C16 alkyl and R41h is C1_6 alkyl) ; X4b is selected from the following [Maal] [Maa6], [Maa9], [Maal2] [Maal6] and [Maa19] [Maa21], [Maa1] single bond, [Maa2]0, [Maa3] S, [Maa4]CO, [Maa5] CO2, [Maa6] OCO, [Maa9] SO2, [Maa12] NR41b, [Maa13] CONR41b, [Maa14] NR41bCO, [Maa15] NR41bCO2, [Maa16] OCONR41b, [Maal9]S02NR41b [Maa20] NR41bSO2 and [Maa21] NR41bCONR41e (R41b and R41e are the same or different and each is hydrogen atom or Cl_6 alkyl, or show (CH2) z, (CHz) 3, (CH2) 4or (CH2) s together with R4b) ; (A) is [Mabl] [Mab2] [Mab5] (R4d is hydrogen atom or C16 alkyl), a is an integer of 1 to 4, b is an integer of 0 to 4, c is an integer of 0 to 2 and d is an integer of 0 to 4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

6.	The compound of claim 5, wherein (A) is [Mam CH, [Mab2] [Mab5] or a stereoisomer thereof, a pharmaceutically acceptable salt ther eof or a solvate thereof.

7.	A compound represented by the formula [IV] wherein each symbol is as defined in claim 5, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

8.	A compound represented by the formula [V] wherein each symbol is as defined in claim 5, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

9.	A compound represented by the formula [VI] wherein each symbol is as defined in claim 5, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

10.

A compound selected from 2 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid, 2 {trans4[(S)amino(NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl}5methylbenzoic acid, 3 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl}5 dimethylaminobenzoic acid, 4 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxy}3fluorobenzoic acid, 2 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl}4methoxybenzoic acid, 2 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl}5fluorobenzoic acid, 3 {trans4[(S)amino(NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid, 3 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxy}2methylbenzoic acid ; 3{trans4[(S)amino(NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxy}5methylbenzOic acid, 3 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxy}5dimethylaminobenzoic acid, 4 {trans4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexylmethoxy}2methylbenzoic acid and trans 4 [ (S)amino (NcyclobutylN methylcarbamoyl) methyl] cyclohexanecarboxylic acid (2 methanesulfonyl) phenylamide, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

11.	2 {trans4 [ (S)Amino (NcyclobutylNmethyl carbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

12.	2 {trans4 [ (S)Amino (NcyclobutylNmethyl carbamoyl) methyl] cyclohexylmethoxymethyl}5methylbenzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

13.	3 {trans4 [ (S)Amino (NcyclobutylNmethyl carbamoyl) methyl] cyclohexylmethoxymethyl}5dimethylaminobenzOic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

14.	4 {trans4 [ (S)Amino (NcyclobutylNmethyl carbamoyl) methyl] cyclohexylmethoxy}3fluorobenzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

15.	trans 4[(S)Amino(NcyclobutylN methylcarbamoyl) methyl] cyclohexanecarboxylic acid (2 methanesulfonyl) phenylamide or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

16.	A pharmaceutical composition comprising the compound of any of claims 2 to 15, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.

17.	A drug for the treatment of diabetes, which comprises the compound of any of claims 2 to 15, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

18.	A DPPIV inhibitor, which comprises a compound of any of claims 2 to 15, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

19.	The pharmaceutical composition of claim 16, which is used in combination with a different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an antiobesity drug.

20.

The pharmaceutical compossition of claim 19, wherein the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the antiobesity drug is selected from insulin preparations (injection), lowmolecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, aglucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARr receptor agonists/antagonists, PPARb receptor agonists, tGLP1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose1, 6bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domain containing inositol phosphatase (SHIP2) inhibitors, AMPactivated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llpHSD1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMGCoA reductase inhibitors, B3 adrenaline receptor agonists, apolipoproteinA1 (ApoA1) inducers, lipoprotein lipase (LPL) activators, glucose dependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS3) agonists, perilipin inhibitors, acetylCoA carboxylase 1 (ACC1) inhibitors, acetylCoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase B (PKCR) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose6phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

21.	A method for treating diabetes, which comprises administering an effective amount of the compound of any of claims 2 to 15 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, to a mammal.

22.	A method for inhibiting DPPIV, comprising using the compound of claim 2 to 15, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

23.	The method of claim 21, which is used in combination with a . different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an antiobesity drug.

24.

The method of claim 23, wherein the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the antiobesity drug is selected from insulin preparations (injection), lowmolecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, aglucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARy receptor agonists/antagonists, PPARg receptor agonists, tGLP1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose1,6 bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domaincontaining inositol phosphatase (SHIP2) inhibitors, AMPactivated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llpHSD1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMGCoA reductase inhibitors, 03 adrenaline receptor agonists, apolipoproteinA1 (ApoA1) inducers, lipoprotein lipase (LPL) activators, glucosedependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS3) agonists, perilipin inhibitors, acetylCoA carboxylase 1 (ACC1) inhibitors, acetylCoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase B (PKCß) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose6phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

25.	Use of the compound of any of claims 2 to 15 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a drug for the treatment of diabetes.

26.	Use of the compound of claim 2 to 15 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for inhibiting DPPIV.

27.	Use of claim 25, which is used in combination with a different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an anti obesity drug.

28.

Use of claim 27, wherein the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the antiobesity drug is selected from insulin preparations (injection), lowmolecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, aglucosidase inhibitors, insulin sensitizers, APPARU receptor agonists, PPARy receptor agonists/antagonists, PPAPZ receptor agonists, tGLP1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose1,6 bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domaincontaining inositol phosphatase (SHIP2) inhibitors, AMPactivated protein kinase (AMPK) activators, glycogen . phosphorylase (GP) inhibitors, glucokinase activators, 11RHSD1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMGCoA reductase inhibitors, p3 adrenaline receptor agonists, apolipoproteinA1 (ApoA1) inducers, lipoprotein lipase (LPL) activators, glucosedependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS3) agonists, perilipin inhibitors, acetylCoA carboxylase 1 (ACC1) inhibitors, acetylCoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase ß (PKC) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose6phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

29.	A commercial package comprising the pharmaceutical composition of any of claims 16,19 and 20 and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating diabetes.

Description:

DESCRIPTION DIPEPTIDYL PEPTIDASE IV INHIBITOR TECHNICAL FIELD The present invention relates to a compound useful as a dipeptidyl peptidase IV inhibitor and a dipeptidyl peptidase IV inhibitor.

BACKGROUND ART Aminopeptidase in a wide sense, which liberates the N- terminal amino acid from proteins and peptides, includes aminopeptidase (hereinafter to be abbreviated as"AP") that liberates one residue, dipeptidyl peptidase (hereinafter to be abbreviated as"DPP") that liberates two residues, and tripeptidyl peptidase (hereinafter to be abbreviated as"TPP") that liberates three residues.

AP is classified into arginyl aminopeptidase, methionyl aminopeptidase, aspartyl aminopeptidase, alanyl aminopeptidase, glutamyl aminopeptidase, prolyl aminopeptidase, leucyl aminopeptidase and cystinyl aminopeptidase based on the substrate specificity. In general, the substrate specificities of these often overlap with each other.

DPP includes four kinds of enzymes of DPP-I, DPP-II, DPP-III and DPP-IV, based on the differences in the substrate specificity thereof, physicochemical properties and intracellular localization.

Moreover, the presence of DPP-VI, DPP-VIII, DPP-IX and DPP-X has been recently reported in a literature. TPP includes two kinds of enzymes of TPP-I and TPP-II, based on the differences in the substrate specificity, molecular weight and intracellular localization.

Dipeptidyl peptidase IV (EC3.4. 14.5, hereinafter to be abbreviated as"DPP-IV") is a glycoprotein on a cell surface, which has been found as a T cell activated antigen and which is a serine protease that cleaves the second peptide bond on C-terminal from N-terminal of protein and peptide having an X-Pro or X-Ala structure on the N-terminus. DPP-IV is widely distributed in the

kidney, liver, salivary glands, connective tissues and the like, and is also present in body fluids such as serum, urine, saliva and the like. In the immune system, moreover, it has been clarified that DPP-IV is the same molecule as a T cell activated antigen CD26.

Various physiological roles of DPP-IV have been reported, such as degradation of neuropeptide, activation of T cell, adhesion of metastatic tumor cell to endothelium, penetration of HIV virus into lymphocytes and the like. Notably, the role of inactivating glucagons-like peptide-1 (hereinafter to be abbreviated as"GLP-1") has been attracting attention.

GLP-1 is released from enteroendocrine L-cells in the distal small intestine and colon in response to oral ingestion of nutrients. Active GLP-1 is rapidly converted to inactive GLP-1 by the action of DPP-IV that cleaves the N-terminal dipeptide (His- Ala) of active GLP-1. It is considered that this inactive GLP-1 acts as an antagonist and shows an antagonistic action against GLP-1 receptor, thus suppressing the function of GLP-1 (see, Journal of Clinical Endocrinology and Metabolism, 80 (3), 952-957 (1995), American Journal of Physiology, 271, E458-E464 (1996), European Journal of Pharmacology, 318,429-435 (1996), Diabetes, 47 (11), 1663-1670 (1998)).

Suppression of degradation of GLP-1 by inhibiting DPP-IV is considered to be the most preferable method as a means to enhance GLP-1 action. That is, reports have documented that a DPP-IV inhibitor can enhance glucose-dependent insulin secretion and improve glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM) and in various diabetic animal models, and it can be a superior pharmaceutical agent that improve postprandial hyperglycemia, which is unaccompanied by side effects such as persistent hypoglycemia and the like.

As a DPP-IV inhibitor, the following compounds are known.

[compound (A): W095/15309, JP-A-9-509921, USP5939560, EP731789A, compound (B): W099/67278, US2002/049164A, EP1087991A, compound (C): USP6124305, compound (D): WO00/34241, JP-A-2002-531547, USP6166063, EP1137635A, compound (E): W001/81304, EP1282600A, compound (F): W001/55105, JP-A-2003-520849, US2001/031780A, USP6380398, EP1254113A, compound (G): W001/68603, US2002/019411A, USP6395767, EP1261586A, compound (H): W002/38541, compound (J): W002/14271, EP1308439A, compound (K): W002/30890, EP1323710A, compound (L): W002/051836]

[compound (M): W003/024942, compound (N): W003/037327, compound (O) : W003/035067, compound (P): W003/045228] All of these have proline or a derivative thereof as a basic structure and is essentially different from the present invention.

Besides these, the following compounds having a completely different structure from the present invention are also known.

[compound (Q): W099/46272, JP-A-2002-506075, US2002/061839A, EP1062222A, compound (R): W002/02560, US2002/161001A, EP1301187A, compound (S): W003/055881] On the other hand, is described as an intermediate for the production of a protease inhibitor in W098/45330, JP-A-2002-504094, USP6291687, US2001/044547A, USP6489364 and EP1005493A.

Furthermore, is described as an intermediate for the production of a matrix metalloproteinase inhibitor in W096/06074, JP-A-10-504821, USP5763621, EP777646A and EP777646B.

Moreover,

is described as an intermediate for the production of a cathepsins inhibitor in W003/029200.

DISCLOSURE OF THE INVENTION The present invention aims at providing a superior DPP-IV inhibitor. In addition, the present invention aims at providing a compound showing a DPP-IV inhibitory activity and effective for the treatment of diabetes, especially type II diabetes, as well as hyperglycemia, hypoglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases thereof, anxiety, eating disorders, neurodegenerative diseases, as well as various immunomodulatory diseases including psoriasis, multiple sclerosis, rheumatoid arthritis, and chronic inflammatory bowel disease, for organ transplantation, and the like.

The present inventors have conducted intensive studies to solve the above-mentioned problems and found that a compound represented by the following formula [I] (hereinafter sometimes to be referred to as"compound [I]") has a superior DPP-IV inhibitory activity, which resulted in the completion of the present invention. While many of the conventionally known DPP-IV inhibitors have proline as a basic structure, the present invention is a DPP-IV inhibitor having a completely new structure wherein a 5-membered ring of proline is cleaved.

More particularly, the present invention provides the following (1) to (29).

(1) A DPP-IV inhibitor comprising a compound represented by the formula [I]

wherein R1 is selected from the following [A]- [E] : [A] hydrogen atom, [B] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B14>), <B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, #<B5> C1-6 alkylthio, #<B6> aryloxy, #<B7> aralkyloxy, #<B8> heterocyclyloxy, #<B9> heterocyclyl-C1-6 alkoxy, <B10> nitro, #<B11> amino, <B12> cyano, #<B13> carboxyl and #<B14> -X1-R11 (R11 is selected from the following (Bal) and (Ba2) and Xi is selected from the following (Bb1) - (Bb23)), ## (Ba1) aryl and ## (Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Baal>-<Baal7>), ###<Baa1> halogen atom, ###<Baa2> C1-6 alkyl, ###<Baa3> Halo-C1-6 alkyl, ###<Baa4> C3-12 cycloalkyl, ###<Baa5> aralkyl, ###<Baa6> heterocyclyl-C1-6 alkyl, '"<Baa7> hydroxyl, ###<Baa8> C1-6 alkoxy, ###<Baa9> C1-6 alkylthio, ###<Baa10> aryloxy,

###<Baa11> aralkyloxy, ###<Baa12> heterocyclyloxy, ###<Baa13> heterocyclyl-C1-6 alkoxy, ###<Baa14> nitro, ###<Baa15> amino, --<Baal6> cyano and ###<Baa17> carboxyl; ### (Bb1) single bond, " (Bb2)-0-, ## (Bb3) -S-, ## (Bb4) -NH-, ## (Bb5) -CO-, ## (Bb6) -CO2-, ## (Bb7) -OCO-, ## (Bb8) -OCO2-, ## (Bb9) -SO-, -(BblO)-SO2-, ## (Bb11) -OSO2-, ## (Bb12) -SO3-, ## (Bb13) -CONH-, ## (Bb14) -NHCO-, ## (Bb15) -CSNH-, ## (Bb16) -NHCS-, ## (Bb17) -NHSO2-, ## (Bb18) -SO2NH-, ## (Bb19) -NHCO2-, ## (Bb20) -OCONH-, ## (Bb21) -NHCONH-, ## (Bb22) -NHCSNH- and ## (Bb23) -NHSO2NH-; [C] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>-<C17>), <C1> halogen atom, <C2> C1_6 alkyl,

#<C3> halo-C1-6 alkyl, #<C4> aralkyl, #<C5> heterocyclyl-C1-6 alkyl, <C6> hydroxyl, #<C7> C1-6 alkoxy, -<C8> Cl-6 alkylthio, #<C9> aryloxy, #<C10> aralkyloxy, #<C11> heterocyclyloxy, <C12> heterocyclyl-C1_6 alkoxy, #<C13> nitro, #<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> -X1-R11 (R11 and X1 are as defined above) ; [D] -X1-R11 (R11 and X1 are as defined above); or [E] wherein R12 and R13 are each independently selected from the following (El)- (E3), j and k are each independently an integer of 0 to 3, which is formed by R1 and R4 in combination, (E1) hydrogen atom, - (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2), X12 is selected from the following (Eb1) - (Eb24)), ## (Ea1) aryl and ## (Ea2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Eaal>-<Eaal7>), ###<Eaa1> halogen atom, ... <Eaa2> CI-6 alkyl, ###<Eaa3> halo-C1-6 alkyl,

... <Eaa4> C3-12 cycloalkyl, ###<Eaa5> aralkyl, ###<Eaa6> heterocyclyl-C1-6 alkyl, ###<Eaa7> hydroxyl, ###<Eaa8> C1-6 alkoxy, ... <Eaa9> CI-6 alkylthio, ###<Eaa10> aryloxy, ###<Eaa11> aralkyloxy, ###<Eaa12> heterocyclyloxy, ##<Eaa13> heterocyclyl-C1-6 alkoxy, ###<Eaa14> nitro, ###<Eaa15> amino, ###<Eaa16> cyano and --<Eaal7> carboxyl; -(Ebl) single bond, ## (Eb2) -O-, ## (Eb3) -S-, ## (Eb4) -NH-, ## (Eb5) -CO-, ## (EB6) -CO2-, ## (EB7) -OCO-, -(Eb8)-OCO2-, ## (Eb9) -SO-, ## (Eb10) -SO2-, ## (Eb11) -OSO2-, ## (Eb12) -SO3-, ## (Eb13) -CONH-, .. (Ebl4)-NHCO-, ## (Eb15) -CNSH-, ## (Eb16) -NHCS-, ## (Eb17) -NHSO2-, ## (Eb18) -SO2NH-, ## (Eb19) -NHCO2-, ## (Eb20) -OCONH-,

## (Eb21) -NHCONH-, ## (Eb22) -NHCSNH-, ## (Eb23) -NHSO2NH- and ## (Eb24) 4 to 7-membered divalent saturated heterocycle; or (E3) benzene ring formed by R and R13 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ecl>-<Ecl7>), ##<Ec1> halogen atom, ##<Ec2> C1-6 alkyl ##<Ec3> halo-C1-6 alkyl, ##<Ec4> C3-12 cycloalkyl, ##<Ec5> aralkyl, ##<Ec6> heterocyclyl-C1-6 alkyl, ##<Ec7> hydroxyl, ##<Ec8> C1-6 alkoxy, ##<Ec9> C1-6 alkylthio, "<EclO> aryloxy, ##<Ec11> aralkyloxy, "<Ecl2> heterocyclyloxy, '-<Ecl3> heterocyclyl-Ci-6 alkoxy, "<Ecl4> nitro, "<Ecl5> amino, ##<Ec16> cyano and ##<Ec17> carboxyl; R2 is selected from the following [F]- [H] : [F] hydrogen atom, [G] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1>-<G18>), #<G1> halogen atom, #<G2> C3-12 cycloalkyl, #<G3> hydroxyl, - <G4> Ci-e alkoxy, #<G5> C1-6 alkylthio,

#<G6> aryloxy, #<G7> aralkyloxy, #<G8> heterocyclyloxy, #<G9> heterocyclyl-C1-6 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, -<G14> =0, #<G15> carboxyl, #<G16> -PO (OH) 2, #<G17> -PO(O-C1-6 alkyl) and -<G18>-PO (O-aryl) 2 ; and [H] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>-<H21>), #<H1> halogen atom, #<H2> C1-6 alkyl, #<H3> halo-C1-6 alkyl, #<H4> aralkyl, #<H5> heterocyclyl-C1-6 alkyl, #<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H8> C1-6 alkylthio, -<H9> aryloxy, #<H10> aralkyloxy, #<H11> heterocyclyloxy, #<H12> heterocyclyl-C1-6 alkoxy, #<H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, -<Hl7> =0, #<H18> carboxyl,

<H19>-PO (OH) 2, <H20>-PO (O-C1_6 alkyl) 2 and #<H21> -PO(O-aryl)2; R3 is selected from the following [I] and [J] [I] Cl-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <I1>-<I18>), #<I1> halogen atom, #<I2> C3-12 cycloalkyl, #<13> hydroxyl, #<14> C1-6 alkoxy, #<15> C1-6 alkylthio, #<16> aryloxy, #<17> aralkyloxy, #<18> heterocyclyloxy, #<19> heterocyclyl-C1-6 alkoxy, #<I10> nitro, #<I11> amino, #<I12> cyano, #<I13> amido, #<I14> =O, #<I15> carboxyl, <I16>-PO (OH) 2, #<I17> -PO(O-C1-6 alkyl) 2 and <I18>-PO (O-aryl) 2 ; and [J] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>-<J21>), #<J1> halogen atom, <J2> C1_6 alkyl, #<J3> halo-C1-6 alkyl, #<J4> aralkyl, #<J5> heterocyclyl-C1-6 alkyl, #<J6> hydroxyl, #<J7> C1-6 alkoxy,

#<J8> C1-6 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heterocyclyloxy, #<J12> heterocyclyl-C1-6 alkoxy, #<J13> nitro, #<J14> amino, #<J15> cyano, #<J16> amido, -<J17> =0, <J18> carboxyl, #<J19> -PO (OH) 2, -<J20>-PO (0-Cl-6 alkyl) 2 and #<J21> -PO(O-aryl)2; R4 is selected from the following [K]- [S] : [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, <L3> hydroxyl, #<L4> C1-6 alkoxy, #<L5> C1-6 alkylthio, #<L6> aryloxy, #<L7> aralkyloxy, #<L8> heterocyclyloxy, #<L9> heterocyclyl-C1-6 alkoxy, #<L10> nitro, #<L11> amino, <L12> cyano, - <L13> carboxyl and #<L14> -Y41-R41 (R41 is selected from the following (La1)-(La8), and Y41 is selected from the following (Lbl) and (Lb2)), -' (Lal) hydrogen atom,

--(La2) C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>), ###<Laa1> halogen atom, ###<Laa2> C3-12 cycloalkyl, ... <Laa3> hydroxyl, ###<Laa4> aralkyloxy, --<Laa5> heterocyclyloxy, "-<Laa6> heterocyclyl-Ci-6 alkoxy, ###<Laa7> nitro, ... <Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> -OR413, ... <Laall>-COR \ ###<Laa12> -CO2R413, ###<Laa13> -OCOR413, ###<Laa14> -CONR415R416, ... <Laal5>-OCONR R ###<Laa16> -NR415R416, ###<Laa17> -NR417COR413, ###<Laa18> -NR417CO2R413, ###<Laa19> -SR413, ###<Laa20> -SOR413, ###<Laa21> -SO2R413, ... <Laa22> 7SO2NR R ###<Laa23> -NR417SO2R413 and ###<Laa24> -NR417CONR415R416 (R413 is C1_6 alkyl, C3-12 cycloalkyl or aryl, R414, R415 and R416 are the same or different and each is hydrogen atom, C1_6 alkyl, 3-12 cycloalkyl or aryl, R417 is hydrogen atom or C1_6 alkyl, or R417 in combination with R413 form C1_4 alkylene); ##(La3) C3-12 cycloalkyl ; ##(La4) C3-12 cycloalkyl-C1-6 alkyl ; (La5) aryl;

.-(La6) aralkyl ; ##(La7) heterocyclyl and -(La8) heterocyclyl-C1_6 alkyl (said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>), ###<Lab1> halogen atom, ###<Lab2> C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C1-6 alkoxy,-SO2-C1_6 alkyl, -SO2-aryl,-NHSO2-C1_6 alkyl and-NHSO2-halo-C1_6 alkyl), -<Lab3> halo-Ci_6 alkyl, -<Lab4> aralkyl, ###<Lab5> heterocyclyl-C1-6 alkyl, ###<Lab6> C3-12 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C1-6 alkoxy, ###<Lab9> aralkyloxy, ###<Lab10> heterocyclyloxy, ###<Lab11> heterocyclyl-C1-6 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, ###<Lab14> cyano, ###<Lab15> carboxyl, ... <Labl6> (CI-6 alkoxy) carbonyl, ###<Lab17> C1-6 alkylsulfonyl, ###<Lab18> -CH2CO2H, ###<Lab19> -OR413, ###<Lab20> -COR414, ###<Lab21> -CO2R413, ###<Lab22> -OCOR413, ###<Lab23> -CONR415R416, ... <Lab24>-OCONR R ###<Lab25> -NR415R416, ###<Lab26> -NR417COR413,

... <Lab27>-NR'C02R ... <Lab28>-SR413, ###<Lab29> -SOR413, ###<Lab30> -SO2R413, ###<Lab31> -SO2NR415R416, ###<Lab32> -NR417SO2R413 and ###<Lab33> -NR417CONR415R416 (R413, R414, R415, R416 and R417 are as defined above) ; ##(Lb1) single bond and ##(Lb2) X41 (X41 is -(CHR418)c-X41a-(CHR419)d-, X41a is selected from the following (Lba1)-(Lba23), R418 and R419 are the same or different and each is hydrogen atom or C1_6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4), ### (Lba1) -O-, ### (Lba2) -S-, ### (Lba3) -CO-, .-. (Lba4)-C02-, ### (Lba5) -OCO-, ### (Lba6) -OCO2-, ### (Lba7) -SO-, ### (Lba8) -SO2-, ... (Lba9)-OSO2-, ### (Lba10) -SO3-, ### (Lba11) -NR411-, (Lbal2)-CONR ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ### (Lba15) -NR411CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-, ### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-, ### (Lba21) -NR411CSNR412-,

###(Lba22) -NR411SO2NR412- (R411 and R412 are the. same or different and each is selected from the following (Lbaa1)-(Lbaa3)), ####(Lbaa1) hydrogen atom, ####(Lbaa2) C1-6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal4>), #####<Lbaaa1> halogen atom, #####<Lbaaa2> C3-12 cycloalkyl, #####<Lbaaa3> hydroxyl, -""<Lbaaa4> Ci-e alkoxy, #####<Lbaaa5> C1-6 alkylthio, #####<Lbaaa6> aryloxy, #####<Lbaaa7> aralkyloxy, #####<Lbaaa8> heterocyclyloxy, #####<Lbaaa9> heterocyclyl-C1-6 alkoxy, <LbaaalO> nitro, #####<Lbaaa11> amino, #####<Lbaaa12> cyano, ..... <Lbaaal3> carboxyl, #####<Lbaaa14> oxo; and ####(Lbaa3) -(CH2) p- (p is an integer of 1 to 3) formed by R411 and R412 in combination; and ###(Lba23) 4 to 7-membered divalent saturated heterocycle; [M] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>), #<M1> halogen atom, #<M2> C1-6 alkyl, #<M3> halo-C1-6 alkyl, <M4> aralkyl, #<M5> heterocyclyl-C1-6 alkyl, <M6> hydroxyl, #<M7> C1-6 alkoxy, #<M8> C1-6 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy,

<M11> heterocyclyloxy, - <M12> heterocyclyl-Ci-6 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, <M17> carboxyl and #<M18> -Y42-R41 (R41 is as defined above, and Y42 is selected from the following (Ma1)-(Ma12)), ## (Ma1) single bond, ## (Ma2) -X41-, ## (Ma3) -Z41-, ## (Ma4) -Z41-Z42-, ## (Ma5) -X41-Z41-, ## (Ma6) -Z41-X41-, (Ma7) _X41_Z41_X42_, ## (Ma8) -X41-Z41-Z42-, ## (Ma9) -Z41-X41-Z42-, ## (Ma10) -Z41-Z42-X41-, '- (Mall) and ## (Ma12) (X41 is as defined above, X42 and X43 are each independently - (CHR420) (CHR selected from the following (Maal)- (Maa23), R420 and R421 are the same or different and each is hydrogen atom or C1_6 alkyl, e and f are each independently an integer of 0 to 2, Z41 and Z42 are the same or different and each is selected from the following (Mab1)-(Mab6), and Z43 is selected

. from the following (Mac1)-(Mac5)), ###(Maa1) single bond, ### (Maa2) -O-, ### (Maa3) -S-, ### (Maa4) -CO-, ### (Maa5) -CO2-, ### (Maa6) -OCO-, ### (Maa7) -OCO2-, ### (Maa8) -SO-, ... (Maa9)-SO2-, ### (Maa10) -SOS2-, ### (Maa11) -SO3-, ### (Maa12) -NR411-, ### (Maa13) -CONR411-, ### (Maa14) -NR411CO-, ... (Maal5)-NR411CO2-, ### (Maa16) -OCONR411-, ### (Maa17) -CSNR411-, ### (Maa18) -NR411CS-, (Maal9)-SO2NR41l- ### (Maa20) -NR411SO2-, ### (Maa21) -NR411CONR412-, ### (Maa22) -NR411CSNR412- and ### (Maa23) -NR411 SO2NR412- (R411 and R412 are as defined above) ; ### (Mab1) C1-6 alkylene, ### (Mab2) C2-6 alkenylene, ### (Mab3) C2-6 alkynylene (said alkylene, alkenylene and alkynylene are optionally substituted by 1 to 3 substituents selected from the following <Mabal>-<Mabal3>), ####<Maba1> halogen atom, ####<Maba2> C3-12 cycloalkyl, ""<Maba3> hydroxyl, ####<Maba4> C1-6 alkoxy, ####<Maba5> C1-6 alkylthio,

####<Maba6> aryloxy, ####<Maba7> aralkyloxy, ####<Maba8> heterocyclyloxy, ####<Maba9> heterocyclyl-C1-6 alkoxy, ####<Maba10> nitro, ####<Maba11> amino, ####<Maba12> cyano and ####<Maba13> carboxyl; ### (Mab4) C3-12 cycloalkylene, ### (Mab5) arylene and --(Mab6) divalent heterocycle (said cycloalkylene, arylene and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Mabbl>-<Mabbl8>), ####<Mabb1> halogen atom, ####<Mabb2> C1-6 alkyl, ####<Mabb3> halo-C1-6 alkyl, ####<Mabb4> aralkyl, ####<Mabb5> heterocyclyl-C1-6 alkyl, ####<Mabb6> C3-12 cycloalkyl, ####<Mabb7> hydroxyl, ####<Mabb8> C1-6 alkoxy, ."-<Mabb9> Ci-e alkylthio, ####<Mabb10> aryloxy, ####<Mabb11> aralkyloxy, ####<Mabb12> heterocyclyloxy, ####<Mabb13> heterocyclyl-C1-6 alkoxy, ""<Mabbl4> nitro, ####<Mabb15> amino, ####<Mabb16> cyano, .... <Mabbl7>, carboxyl and ####<Mabb18> -X4c-R4c (R4c is selected from the following (Mabbal)- (Mabba4), and X4, is selected from the following (Mabbbl)- (Mabbb9)), ##### (Mabba1) hydrogen atom, #### (Mabba2) C1-6 alkyl,

##### (Mabba3) aryl and ----(Mabba4) aralkyl (alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Mabbaal>-<Mabbaa4>) ...... <Mabbaal> halogen atom, ######<Mabbaa2> carboxyl, ######<Mabbaa3> (C1-6 alkoxy) carbonyl and ######<Mabbaa4> C1-6 alkylsulfonyl; ##### (Mabbb1) single bond, ##### (Mabbb2) -CO-, ..... (Mabbb3)-CO2-, ..... (Mabbb4) -OCO-, ##### (Mabbb5) -CONR41c-, ##### (Mabbb6) -NR41cCO-, ##### (Mabbb7) -SO2-, ##### (Mabbb8) -SO2NR41c- and ##### (Mabbbb9) -NR41cSO2- (R41c is hydrogen atom or Cl_6 alkyl) ; ### (Mac1) C1-6 alkanetriyl, ### (Mac2) C2-6 alkenetriyl (said alkanetriyl and alkenetriyl are optionally substituted by 1 to 3 substituents selected from the following <Macal>-<Macal3>) ""<Macal> halogen atom, ####<Maca2> C3-12 cycloalkyl, ####<Maca3> hydroxyl, ####<Maca4> C1-6 alkoxy, ####<Maca5> C1-6 alkylthio, .... <Maca6> aryloxy, ####<Maca7> aralkyloxy, ####<Maca8> heterocyclyloxy, ###<Maca9> heterocyclyl-C1-6 alkoxy, ####<Maca10> nitro, ####<Maca11> amino, ####<Maca12> cyano and .... <Macal3> carboxyl;

.--(Mac3) C3_12 cycloalkanetriyl, ." (Mac4) arenetriyl and ### (Mac5) trivalent heterocycle (said cycloalkanetriyl, arenetriyl and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Macbl>-<Macbl8>), ####<Macb1> halogen atom, ####<Macb2> C1-6 alkyl, ####<Macb3> halo-C1-6 alkyl, ####<Macb4> aralkyl, ""<Macb5> heterocyclyl-Ci-6 alkyi, ####<Macb6> C3-12 cycloalkyl, ####<Macb7> hydroxyl, ####<Macb8> C1-6 alkoxy, ####<Macb9> C1-6 alkylthio, ####<Macb10> aryloxy, <Macbll> aralkyloxy, ####<Macb12> heterocyclyloxy, ###<Macb13> heterocyclyl-C1-6 alkoxy, ""<Macbl4> nitro, ####<Macb15> amino, ""<Macbl6> cyano, ####<Macb17> carboxyl and ####<Macb18> -CH2CO2H ; [N] aryl, [0] aralkyl, [P] heterocyclyl, [Q] heterocyclyl-C1-6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-C1-6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <N1>-<N19>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N3> C3-12 cycloalkyl, #<N4> halo-C1-6 alkyl, -<N5> aralkyl,

#<N6> heterocyclyl-C1-6 alkyl, <N7> hydroxyl, #<N8> C1-6 alkoxy, #<N9> C1-6 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, <N12> heterocyclyloxy, #<N13> heterocyclyl-C1-6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano, -<Nl7> =0, #<N18> carboxyl and #<N19> -Y42-R41 (R41 and Y42 are as defined above); [R] -Y41-R41 (R41 and Y41 are asdefined above), or [S] (R42 and R43 are each independently selected from the following (S1)-(S3), and m and n are each independently an integer of 0 to 3) formed by R4 and R in combination, (S1) hydrogen atom, (S2)-Y41-R44 (R44 is selected from the following (Sal) and (Sa2) and y41 are as defined above), ##(Sa1) aryl and ##(Sa2) heterocyclyl (aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Saal>-<Saal7>), ###<Saa1> halogen atom, ###<Saa2> C1-6 alkyl, ... <Saa3> halO-Cl-6 alkyl, --<Saa4> aralkyl,

###<Saa5> heterocyclyl-C1-6 alkyl, ###<Saa6> C3-12 cycloalkyl, -"<Saa7> hydroxyl, ###<Saa8> C1-6 alkoxy, ###<Saa9> C1-6 alkylthio, ###<Saa10> aryloxy, ###<Saa11> aralkyloxy, ###<Saa12> heterocyclyloxy, ###<Saa13> heterocyclyl-C1-6 alkoxy, ###<Saa14> nitro, ###<Saa15> amino, ###<Saa16> cyano and ###<Saa17> carboxyl; or (S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl>-<Scl7>), ##<Sc1> halogen atom, ##<Sc2> C1-6 alkyl, --<Sc3> halo-Cl-6 alkyl, ##<Sc4> aralkyl, ##<Sc5> heterocyclyl-C1-6 alkyl, ##<Sc5> C3-12 cycloalkyl, ##<Sc7> hydroxyl, ##<Sc8> C1-6 alkoxy, <Sc9> C1_6 alkylthio, ##<Sc10> aryloxy, ##<Sc11> aralkyloxy, ##<Sc12> heterocyclyloxy, ##<Sc13> heterocyclyl-C1-6 alkoxy, ##<Sc14> nitro, "<Scl5> amino, "<Scl6> cyano and "<Scl7> carboxyl;

R5 is selected from the following [T]- [BB], [T] hydrogen atom, [U] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1>-<U14>), -<Ul> halogen atom, -<U2> C3-12 cycloalkyl, -<U3> hydroxyl, #<U4> C1-6 alkoxy, -<U5> CI-6 alkylthio, <U6> aryloxy, #<U7> aralkyloxy, -<U8> heterocyclyloxy, #<U9> heterocyclyl-C1-6 alkoxy, #<U10> nitro, #<U11> amino, #<U12> cyano, #<U13> carboxyl and #<U14> -X44-R45 (R45 is selected from the following (Ual) and (Ua2), and X44 is selected from the following (Ub1) - (Ub23)), ##(Ua1) aryl and ##(Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Uaal>-<Uaal7>) ###<Uaa1> halogen atom, ###<Uaa2> C1-6 alkyl, ###<Uaa3> halo-C1-6 alkyl, ###<Uaa4> C3-12 cycloalkyl, ###<Uaa5> aralkyl, '"<Uaa6> heterocyclyl-C1-6 alkyl, ###<Uaa7> hydroxy1, ###<Uaa8> C1-6 alkoxy, ###<Uaa9> C1-6 alkylthio, ###<Uaa10> aryloxy, ###<Uaa11> aralkyloxy,

###<Uaa12> heterocyclyloxy, ###<Uaa13> heterocyclyl-C1-6 alkoxy, .<Uaal4> nitro, ###<Uaa15> amino, .--<Uaal6> cyano and ###<Uaa17> carboxyl; ##(Ub1) single bond, ## (Ub2) -O-, .. (Ub3)-S-, ## (Ub4) -NH-, ## (Ub5) -CO-, ## (Ub6) -CO2-, ## (Ub7) -OCO-, ## (Ub8) -OCO2-, ## (Ub9) -SO-, ## (Ub10) -SO2-, ## (Ub11) -OSO2-, ## (Ub12) -SO3-, .. (Ubl3)-CONH-, ## (Ub14) -NHCO-, ## (Ub15) -CSNH-, ## (Ub16) -NHCS-, ## (Ub17) -NHSO2-, ## (Ub18) -SO2NH-, ## (Ub19) -NHCO2-, ## (Ub20) -OCONH-, ## (Ub21) -NHCONH-, ## (Ub22) -NHCSNH- and ## (Ub23) -NHSO2NH-; [V] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>-<V17>), <V1> halogen atom, #<V2> C1-6 alkyl, #<V3> halo-C1-6 alkyl,

#<V4> aralkyl, #<V5> heterocyclyl-C1-6 alkyl, #<V6> hydroxyl, #<V7> C1-6 alkoxy, #<V8> C1-6 alkylthio, #<V9> aryloxy, #<V10> aralkyloxy, #<V11> heterocyclyloxy, #<V12> heterocyclyl-C1-6 alkoxy, #<V13> nitro, #<V14> amino, #<V15> cyano, #<V16> carboxyl and <V17>-X44-R45 (R45 and X44 are as defined above); [W] 3 to 7-membered saturated heterocycle, [X] aryl, [Y] heterocyclyl, [Z] aralkyl, [AA] heterocyclyl-C1-6 alkyl (said saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclyl-C1_6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <W1>-<W16>), #<W1> halogen atom, -<W2> Cl-6 alkyl, #<W3> C3-12 cycloalkyl, #<W4> aralkyl, #<W5> heterocyclyl-C1-6 alkyl, #<W6> hydroxyl, #<W7> C1-6 alkoxy, -<W8> Cl-6 alkylthio, '<N9> aryloxy, #<W10> aralkyloxy, #<W11> heterocyclyloxy, #<W12> heterocyclyl-C1-6 alkoxy,

<W13> nitro, #<W14> amino, #<W15> cyano and <W16> carboxyl; and [BB]-X44-R45 (R45 and X44 are as defined above), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(2) A compound represented by the formula [II] wherein R1 is selected from the following [A]- [E] : [A] hydrogen atom, [B] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B14>), #<B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, #<B5> C1_6 alkylthio, #<B6> aryloxy, #<B7> aralkyloxy, #<B8> heterocyclyloxy, - <B9> heterocyclyl-Ci-e alkoxy, #<B10> nitro, #<B11> amino, #<B12> cyano, #<B13> carboxyl and #<B14> -X1-R11 (R11 and X1 are defined in the above-mentioned (1)) ; [C] C312 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>-<C17>), #<C1> halogen atom, #<C2> C1-6 alkyl,

#<C3> halo-C1-6 alkyl, #<C4> aralkyl, <C5> heterocyclyl-Cl-6 alkyl, #<C6> hydroxyl, #<C7> C1-6 alkoxy, #<C8> C1-6 alkylthio, #<C9> aryloxy, #<C10> aralkyloxy, #<C11> heterocyclyloxy, #<C12> heterocyclyl-C1-6 alkoxy, #<C13> nitro, #<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> -X1-R11 (R11 and X1 are as defined in the above-mentioned (1) ) ; [D] -X1-R11 (R1l and Xi are as defined in the above-mentioned (1)) ; or [E] wherein R12, R13, j and k are as defined in the above-mentioned (1), which is formed by R1 and R4 in combination; R2 is selected from the following [F] - [H], [F] hydrogen atom, [G] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1>-<G18>), #<G1> halogen atom, #<G2> C3-12 cycloalkyl, #<G3> hydroxyl, #<G4> C1-6 alkoxy, #<G5> C1-6 alkylthio,

-<G6> aryloxy, #<G7> aralkyloxy, #<G8> heterocyclyloxy, #<G9> heterocyclyl-C1-6 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, -<Gl4> =0, #<G15> carboxyl, -<G16>-PO (OH) 2, #<G17> -PO(O-C1-6 alkyl)2 and <G18>-PO (O-aryl) 2 ; [H] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>-<H16> and <H18>-<H21>), -<Hl> halogen atom, #<H2> C1-6 alkyl, #<H3> halo-C1-6 alkyl, #<H4> aralkyl, #<H5> heterocyclyl-C1-6 alkyl, #<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H8> C1-6 alkylthio, <H9> aryloxy, #<H10> aralkyloxy, #<H11> heterocyclyloxy, #<H12> heterocyclyl-C1-6 alkoxy, #<H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, #<H18> carboxyl, #<H19> -PO (OH) 2,

#<H20> -PO(O-C1-6 alkyl) 2 and #<H21> -PO(O-aryl)2 ; R3 is the following [J] [J] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>-<J16> and <J18>-<J21>), #<J1> halogen atom, #<J2> C1-6 alkyl, #<J3> halo-C1-6 alkyl, #<J4> aralkyl, #<J5> heterocyclyl-C1-6 alkyl, #<J6> hydroxyl, #<J7> C1-6 alkoxy, #<J8> C1-6 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heterocyclyloxy, #<J12> heterocyclyl-C1-6 alkoxy, #<J13> nitro, #<J14> amino, #<J15> cyano, #<J16> amido, #<J18> carboxyl, #<J19> -PO (OH) 2, #<J20> -PO(O-C1-6 alkyl) 2 and #<J21> -PO(O-aryl)2; R4 is selected from the following [K]- [M], [P], [R] and [S], [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>) <L1> halogen atom, #<L2> C3-12 cycloalkyl, #<L3> hydroxyl, <L4> C1_6 alkoxy,

<L5> C1_6 alkylthio, <L6> aryloxy, #<L7> aralkyloxy, #<L8> heterocyclyloxy, #<L9> heterocyclyl-C1-6 alkoxy, #<L10> nitro, #<L11> amino, <L12> cyano, #<L13> carboxyl and #<L14> -Y41-R41' (R41' is selected from the following (Lal), (La2), (La5) and (La7), and y41 is as defined in the above-mentioned (1)), ##(La1) hydrogen atom, ##(La2) C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>), ###<Laa1> halogen atom, ###<Laa2> C3-12 cycloalkyl, ###<Laa3> hydroxyl, ###<Laa4> aralkyloxy, ###<Laa5> heterocyclyloxy, ###<Laa6> heterocyclyl-C16 alkoxy, ###<Laa7> nitro, "-<Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> -OR413, ###<Laa11> -COR414, ###<Laa12> -CO2R413, ###<Laa13> -OCOR413, ###<Laa14> -CONR415R416, ... <Laal5>-OCONR415R416, ###<Laa16> -NR415R416, ###<Laa17> -NR417COR413, ###<Laa18> -NR417CO2R413, ###<Laa19> -SR413, ###<Laa20> -SOR413,

###<Laa21> -SO2R413, ###<Laa22> -SO2NR415R416, ###<Laa23> -NR417SO2R413 and ###<Laa24> -NR417CONR415R416 (R413, R414, R415, R416 and R417 is as defined in the above-mentioned (1) ) ; ##(La5) aryl and ##(La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>), ###<Lab1> halogen atom, ###<Lab2> C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, Cl_6 alkoxy,-SO2-Ci_6 alkyl, -SO2-aryl, -NHSO2-C1-6 alkyl and -NHSO2-halo-C1-6 alkyl), ###<Lab3> halo-C1-6 alkyl, -<Lab4> aralkyl, ###<Lab5> heterocyclyl-C1-6 alkyl, ###<Lab6> C3-12 cycloalkyl, --<Lab7> hydroxyl, ###<Lab8> C1-6 alkoxy, ###<Lab9> aralkyloxy, ###<Lab10> heterocyclyloxy, ###<Lab11> heterocyclyl-C106 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, ###<Lab14> cyano, ###<Lab15> carboxyl, ... <Labl6> (CI-6 alkoxy) carbonyl, ###<Lab17> C1-6 alkylsulfonyl, ###<Lab18> -CH2CO2H, ###<Lab19> -OR413, ###<Lab20> -COR414, ###<Lab21> -CO2R413, ###<Lab22> -OCOR413,

###<Lab23> -CONR415R416, ###<Lab24> -OCONR415R416, ###<Lab25> -NR415R416, ###<Lab26> -NR417COR413, ###<Lab27> -NR417CO2R413, ... <Lab28>-SR ... <Lab29>-SOR ###<Lab30> -SO2R413, ... <Lab3l>-S02NR R ###<Lab32> -NR417SO2R413 and ###<Lab33> -NR417CONR415R416 (R413, R414, R415, R416 and R417 are as defined in the above-mentioned (1) ) ; [M] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>), #<M1> halogen atom, -<M2> Cl-6 alkyl, #<M3> halo-C1-6 alkyl, -<M4> aralkyl, #<M5> heterocyclyl-C1-6 alkyl, #<M6> hydroxyl, #<M7> C1_6 alkoxy, #<M8> C1-6 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heterocyclyloxy, #<M12> heterocyclyl-C1_6 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, #<M17> carboxyl and #<M18> -Y42-R41' (R41' is as defined above and Y42 is as defined in the the above-mentioned (1));

3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>-<N16> and <N18>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N3> C3-12 cycloalkyl, #<N4> halo-C1-6 alkyl, #<N5> aralkyl, - <N6> heterocyclyl-Ci-6 alkyi, #<N7> hydroxyl, #<N8> C1-6 alkoxy, #<N9> Cri-6 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heterocyclyloxy, #<N13> heterocyclyl-C16 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano and <N18> carboxyl; [R] -Y41-R41' (R41' and Y41 are as defined above), or [S] (R42 and R43 are each as defined in the above-mentioned (1), m and n are each independently an integer of 0 to 3) formed by R4' and R5' in combination, R5 is selected from the following [T]- [W] and [BB], [T] hydrogen atom, [U] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1>-<U14>), #<U1> halogen atom,

#<U2> C3-12 cycloalkyl, #<U3> hydroxyl, #<U4> C16 alkoxy, #<U5> C1-6 alkylthio, -<U6> aryloxy, -<U7> aralkyloxy, #<U8> heterocyclyloxy, '<U9> heterocyclyl-Ci-6 alkoxy, #<U10> nitro, #<U11> amino, #<U12> cyano, #<U13> carboxyl and #<U14> -X44-R45 (R45 and X44 are as defined in the above-mentioned (1) ) ; [V] C3_12 cycloalkyl (cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>-<V17>), #<V1> halogen atom, #<V2> C1-6 alkyl, -<V3> halO-Cl-6 alkyl, #<V4> aralkyl, #<V5> heterocyclyl-C1-6 alkyl, #<V6> hydroxyl, #<V7> C1-6 alkoxy, #<V8> Cul-6 alkylthio, #<V9> aryloxy, <V10> aralkyloxy, #<V11> heterocyclyloxy, #<V12> heterocyclyl-C1-6 alkoxy, #<V13> nitro, #<V14> amino, #<V15> cyano, #<V16> carboxyl and #<V17> -X44-R45 (R45 and X44 are as defined in the above-mentioned (1))

[W] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <W1>-<W16>), #<W1> halogen atom, #<W2> C1-6 alkyl, #<W3> C3-12 cycloalkyl, #<W4> aralkyl, #<W5> heterocyclyl-C1-6 alkyl, #<W6> hydroxyl, -<W7> CI-6 alkoxy, '<W8> C1-6 alkylthio, #<W9> aryloxy, #<W10> aralkyloxy, #<W11> heterocyclyloxy, #<W12> heterocyclyl-C1-6 alkoxy, #<W13> nitro, #<W14> amino, #<W15> cyano and <W16> carboxyl; [BB] -X44-R45 (R45 and X44 are as defined in the above-mentioned (1)), provided that, when R1 and R2 are hydrogen atoms and R3 is cyclopropyl, then the combination of one of R4 and R5 being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R1 and R2 are hydrogen atoms and R3 is cyclobutyl, then the combination of one of R4 and R5 being tert- butyl, and the other being hydrogen atom does not occur, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(3) The compound of the above-mentioned (2), wherein R41 is selected from the following (Lal), (La2), (La5) and (La7), X41a is selected from the following (Lbal)- (Lba23), and other symbols are as defined in the above-mentioned (2), ##(La1) hydrogen atom, ##(La2) C1-6 alkyl (said alkyl is optionally substituted by 1 to 3

substituents selected from the following <Laal>-<Laa24>), ###<Laa1> halogen atom, <Laa2> C3-12 cycloalkyl, -<Laa3> hydroxyl, ###<Laa4> aralkyloxy, ... <Laa5> heterocyclyloxy, ###<Laa6> heterocyclyl-C1-6 alkoxy, ###<Laa7> nitro, ###<Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> -OR413, ###<Laa11> -COR414, ###<Laa12> -CO2R413, ###<Laa13> -OCOR413, ###<Laa14> -CONR415R416, ###<Laa15> -OCONR415R416, ###<Laa16> -NR415R416, ###<Laa17> -NR417COR413, ###<Laa18> -NR417CO2R413, ###<Laa19> -SR413, ###<Laa20> -SOR413, ###<Laa21> -SO2R413, ###<Laa22> -SO2NR415R416, ###<Laa23> -NR417SO2R413 and ###<LaA24> -NR417CONR415R416 (R413 is C1_6 alkyl, C3_12 cycloalkyl or aryl, R414, R and R416 are the same or different and each is hydrogen atom, C1-6 alkyl, C3_12 cycloalkyl or aryl, R417 is hydrogen atom or R1-6 alkyl) ; ##(La5) aryl and ##(La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>), ###<Lab1> halogen atom,

... <Lab2> CI-6 alkyl, ####Lab3# halo-C1-6 alkyl, ####Lab4# aralkyl, ####Lab5# heterocyclyl-C1-6 alkyl, ####Lab6# C3-12 cycloalkyl, ####Lab7# hydroxyl, ... <Lab8> CI-6 alkoxy, ####Lab9# aralkyloxy, ####Lab10# heterocyclyloxy, ####Lab11# heterocyclyl-C1-6 alkoxy, ####Lab12# nitro, ####Lab13# amino, ####Lab14# cyano, ####Lab15# carboxyl, ####Lab16# (C1-6 alkoxy) carbonyl, <Labl7> C1_6 alkylsulfonyl, ####Lab18# -CH2CO2H, ####Lab19# -OR413, ####Lab20# -COR414, ... <Lab2l>-C02R41', ####Lab22# -OCOR413, ####Lab23# -CONR415R416, ... <Lab24>-OCONR R ####Lab25# -NR415R416, ####Lab26# -NR417COR413, ####Lab27# -NR417CO2R413, ####Lab28# -SR413, ####Lab29# -SOR413, ####Lab30# -SO2R413, ####Lab31# -SO2NR415R416, ####Lab32# -NR417SO2R413 and ####Lab33# -NR417CONR415R416 R413 R414 R415 R416 and R are as defined above); ### (Lba1) -O-,

,... (Lba2)-s-, ... (Lba3)-CO-, ### (Lba4) -CO2-, (Lba5)-OCO-, ### (Lba6) -OCO2-, ### (Lba7) -SO-, ### (Lba8) -SO2-, ### (Lba9) -OSO2-, ### (Lba10) -SO3-, ### (Lba11) -NR411-, ### (Lba12) -CONR411-, ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ... (Lbal5)-NR41lCS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, (Lbal8)-OCONR-, ### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-, ### (Lba21) -NR411CSNR412-, ### (Lba22) -NR411SO2NR412- (R411 and R412 are the same or different and each is selected from the following (Lbaal)- (Lbaa3)), #### (Lbaa1) hydrogen atom, #### (Lbaa2) C1-6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal3>), ######Lbaaa1# halogen atom, ######Lbaaa2# C3-12 cycloalkyl, ..... <Lbaaa3> hydroxyl, ######Lbaaa4# C1-6 alkoxy, <Lbaaa5> CI-6 alkylthio, ######Lbaaa6# aryloxy, ######Lbaaa7# aralkyloxy, ######Lbaaa8# heterocyclyloxy, ######Lbaaa9# heterocyclyl-C1-6 alkoxy,

######Lbaaa10# nitro, ..... <Lbaaall> amino, -""<Lbaaal2> cyano, ######Lbaaa13# carboxyl, and #### (Lbaa3) - (CH2) p- (p is an integer of 1 to 3) formed by R411 and R412 in combination; and ### (Lba23) 4 to 7-membered divalent saturated heterocycle, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(4) The compound of the above-mentioned (2), wherein R1 is [A] hydrogen atom, [B] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B4>, <B10>-<B12> and #B14#), <B1> halogen atom, ##B2# C3-12 cycloalkyl, ##B3# hydroxyl, ##B4# C1-6 alkoxy, ##B10# nitro, ##B11# amino, ##B12# cyano and ##B14# -X1-R11 (R11 and X1 are each as defined in the above- mentioned (1) ) ; or [C] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2>, <C6>, <C7> and <C13>-<C17>), <C1> halogen atom, <C2> C1_6 alkyl, ##C6# hydroxyl, ##C7# C1_6 alkoxy, ##C13# nitro, ##C14# amino, ##C15# cyano, ##C16# carboxyl and

##C17# -X1-R11 (R11 and X1 are as defined above) ; R2' is [F] hydrogen atom, [G] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from <G1>-<G4>, <G10>-<G13> and <G16>-<G18>), ##G1# halogen atom, ##G2# C3-12 cycloalkyl, ##G3# hydroxyl, ##G4# C1-6 alkoxy, ##G10# nitro, ##G11# amino, ##G12# cyano, ##G13# amido, <G16>-PO (OH) 2, ##G17# -PO(O-C1-6 alkyl) 2 and -<G18>-PO (O-aryl) 2 ; or [H] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>, <H2>, <H6>, <H7>, <H13>-<H16> and <H19>-<H21>), ##H1# halogen atom, ##H2# C1-6 alkyl, <H6> hydroxyl, ##H7# C1-6 alkoxy, ##H13# nitro, ##H14# amino, ##H15# cyano, ##H16# amido, ##H19# -PO (OH) 2, ##H20# -PO (O-C1-6 alkyl)2 and ##H21# -PO (O-aryl) 2; R3 i [J] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>, <J2>, <J6>, <J7>, <J13>-<J16> and <J19>-<J21>),

##J1# halogen atom, ##J2# C1-6 alkyl, ##J6# hydroxyl, ##J7# C1-6 alkoxy, ##J13# nitro, ##J14# amino and <J15> cyano <J16> amido, ##J19# -PO (OH) 2, ##J20# -PO(O-C1-6 alkyl) and -<J21>-PO (0-aryl) 2 ; R4' is [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following #L1#-#L4# and <L10>- <L12>), ##L1# halogen atom, ##L2# C3-12 cycloalkyl, ##L3# hydroxyl, ##L4# C1-6 alkoxy, ##L10# nitro, ##L11# amino and <L12> cyano; [M] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>, <M7>, <M13>-<M16> and <M18>), ##M1# halogen atom, ##M2# C1-6 alkyl, ##M6# hydroxyl, ##M7# C1-6 alkoxy, ##M13# azido, ##M14# nitro, ##M15# amino, ##M16# cyano and

##M18# -Y42-R41' (R41' is as defined in the above-mentioned (2), Y42 is as defined in the above-mentioned (1) ) ; [P] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>, <N2>, <N7>, <N8>, <N14>-<N16> and <N18>), ##N1# halogen atom, -<N2> Cl-6 alkyl, ##N7# hydroxyl, ##N8# C1-6 alkoxy, ##N14# nitro, ##N15# amino, ##N16# cyano and <N18> carboxyl; or [S] (R42 and R43 are each as defined in the above-mentioned (1) and m and n are each independently an integer of 0 to 3) formed by R4' and R5'in combination; and R5' is [T] hydrogen atom, [U] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1>-<U4> and <U10>- <U12>), <U1> halogen atom, ##U2# C3-12 cycloalkyl, ##U3# hydroxyl, -<U4> Cl-6 alkoxy, ##U10# nitro, ##U11# amino and <U12> cyano; or

[V] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>, <V2>, <V6>, <V7> and #V13#-#V15#), ##V1# halogen atom, ##V2# C1-6 alkyl, ##V6# hydroxyl, -<V7> Cl-6 alkoxy, ##V13# nitro, ##V14# amino and <V15> cyano provided that, when R1 and R2 are hydrogen atoms and R3 is cyclopropyl, then the combination of one of R4 and R5 being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R1 and R2' are hydrogen atoms and R3 is cyclobutyl, then the combination of one of R4 and R5 being tert- butyl, and the other being hydrogen atom does not occur, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(5) A compound represented by the formula [III]

wherein R2a is [F] hydrogen atom or [G] C1-6 alkyl, R4a is selected from the following [MabbO], [Mabbl] and [Mabbl8], [MabbO] hydrogen atom, [Mabbl] halogen atom and [Mabb18] -X4c-R4c (R4c is selected from the following (Mabbal)- (Mabba4), X4, is selected from the following (Mabbbl)- (Mabbb9)),

. (Mabbal) hydrogen atom, . (Mabba2) Ci_6 alkyl, . (Mabba3) aryl and - (Mabba4) aralkyl (said alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Mabbaal>-<Mabbaa4>), ###Mabbaa1# halogen atom, ###Mabbaa2# carboxyl, ###Mabbaa3# (C1-6 alkoxy) carbonyl and ###Mabbaa4# C1-6 alkylsulfonyl; # (Mabbbl) single bond, . (Mabbb2)-CO-, . (Mabbb3)-CO2-, . (Mabbb4)-OCO-, # (Mabbb5) -CONR41c-, . (MAbbb6) -NR41cCO-, . (Mabbb7) -SO2-, . (Mabbb8) -SO2NR41c- and . (Mabbb9) -NR41cSO2- (R41c is hydrogen atom or CI-6 alkyl) ; X4a is selected from the following. [Lba1]-[Lba3], [Lba8], [Lba11]- [Lba13], [Lbal6]- [Lbal9] and [Lba21], [Lbal]-0-, [Lba2]-S-, [Lba3]-CO-, [Lba8]-S02-, [Lba11] -NR41a-, [Lbal2]-CONR [Lba13] -NR41aCO-, [Lba16] -SO2NR41a-, [Lbal7]-NR41aSo2-, [Lba18] -OCONR41a-, [Lba19] -NR41aCO2- and [Lba21] -NR41aCONR41d- (R41a and R41d are the same or different and each is hydrogen atom

, or C1_6 alkyl) ; R4b is selected from the following [Lal], [La2], [La5] and [La6], [Lal] hydrogen atom, [La2] C1_6 alkyl, [La5] aryl and [La6] aralkyl (said alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>, <Lab2>, <Lab7>, <Lab8>, <Labl2>-<Labl7>, <Lab31> and <Lab32>); ##Lab1# halogen atom, ##Lab2# C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from C1_6 alkoxy,-SO2-C1_6 alkyl,-SO2-aryl,- NHSO2-C1_6 alkyl and -NHSO2-halo-C1-6 alkyl), ##Lab7# hydroxyl, ##Lab8# C1-6 alkoxy, -<Labl2> nitro, ##Lab13# amino, ##Lab14# cyano, ##Lab15# carboxyl, ##Lab16# (C1-6 alkoxy) carbonyl, ##Lab17# C1-6 alkylsulfonyl, ##Lab31# -SO2NR41fR41g and ##Lab32# -NR41fSO2R41h (R41f, R41g are the same or different and each is hydrogen atom or C1_6 alkyl and R41h is C1-6 alkyl) ; X4b is selected from the following [Maa1]-[Maa6], [Maa9], [Maal2]- [Maal6] and [Maa19]-[Maa21], [Maa1] single bond, [Maa2]-0-, [Maa3] -S-, [Maa4]-CO-, [Maa5] -CO2-, [Maa6]-OCO-, [Maa9] -SO2-,

[Maal2]-NR41b- [Maa13] -CONR14b-, [Maal4]-NR4 [Maa15] -NR41bCO2-, [Maa16] -OCONR14b-, [Maa19] -SO2NR41b-, [Maa20]-NR41bS02-and [Maa21] -NR41bCONR41e- (R41b and R4le are the same or different and each is hydrogen atom or C1-6 alkyl, or show -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5- together with R4b) ; (A) is [Mab1] [Mab2] [Mab5]

(R4d is hydrogen atom or C1-6 alkyl), a is an integer of 1 to 4, b is an integer of 0 to 4, c is an integer of 0 to 2 and d is an integer of 0 to 4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(6) The compound of the above-mentioned (5), wherein (A) is [Mab1] CH, [Mab2]

or a stereoisomer thereof, a pharmaceutically acceptable salt ther eof or a solvate thereof.

(7) A compound represented by the formula [IV]

wherein each symbol is as defined in the above-mentioned (5), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(8) A compound represented by the formula [V]

wherein each symbol is as defined in the above-mentioned (5), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(9) A compound represented by the formula [VI]

wherein each symbol is as defined in the above-mentioned (5), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(10) A compound selected from 2-{trans-4-[(S)-amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid, 2- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid, 3- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5- dimethylaminobenzoic acid, 4- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid, 2- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-4-methoxybenzoic acid, 2- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-fluorobenzoic acid, 3- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl]cyclohexylmethoxymethyl}benzoic acid, 3-{trans-4-[(S)-amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-2-methylbenzoic acid, 3- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) Methyl]cyclohexylmethoxy}-5-methylbenzoic acid, 3-{trans-4-[(S)-amino-(N-cyclobutyl-N

methylcarbamoyl) methyl] cyclohexylmethoxy}-5-dimethylaminobenzOic acid, 4- {trans-4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-2-methylbenzoic acid and trans 4- [ (S)-amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexanecarboxylic acid (2- methanesulfonyl) phenylamide, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(11) 2-{trans-4-[(S)-Amino-(N-cyclobutyl-N-methyl- carbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(12) 2-{trans-4-[(S)-Amino-(N-cyclobutyl-N-methyl- carbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(13) 3- {trans-4- [ (S)-Amino- (N-cyclobutyl-N-methyl- carbamoyl) methyl] cyclohexylmethoxymethyl}-5-dimethylaminobenzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(14) 4- {trans-4- [ (S)-Amino- (N-cyclobutyl-N-methyl- carbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(15) trans 4-[(S)-Amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexanecarboxylic acid (2- methanesulfonyl) phenylamide or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(16) A pharmaceutical composition comprising the compound of any of the above-mentioned (2) to (15), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.

(17) A drug for the treatment of diabetes, which comprises the

compound of any of the above-mentioned (2) to (15), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(18) A DPP-IV inhibitor, which comprises a compound of any of the above-mentioned (2) to (15), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(19) The pharmaceutical composition of the above-mentioned (16), which is used in combination with a different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an anti-obesity drug.

(20) The pharmaceutical compossition of the above-mentioned (19), wherein the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the anti-obesity drug is selected from insulin preparations (injection), low-molecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, a-glucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARy receptor agonists/antagonists, PPARg receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose-1,6- bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llß-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors, B3 adrenaline receptor agonists, apolipoprotein-A1 (Apo-A1) inducers, lipoprotein lipase (LPL) activators, glucose-dependent insulinotropic polypeptide (GIP)

. receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS-3) agonists, perilipin inhibitors, acetyl-CoA carboxylase 1 (ACC1) inhibitors, acetyl-CoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase ß (PKCß) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose-6-phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

(21) A method for treating diabetes, which comprises administering an effective amount of the compound of any of the above-mentioned (2) to (15) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, to a mammal.

(22) A method for inhibiting DPP-IV, comprising using the compound of the above-mentioned (2) to (15), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

(23) The method of the above-mentioned (21), which is used in combination with a different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an anti-obesity drug.

(24) The method of the above-mentioned (23), wherein the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the anti- obesity drug is selected from insulin preparations (injection), low-molecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, a-glucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARy receptor agonists/antagonists, PPARb receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose-1, 6-bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors, ; phosphoenolpyruvate

carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, 11R-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors, R3 adrenaline receptor agonists, apolipoprotein-A1 (Apo-A1) inducers, lipoprotein lipase (LPL) activators, glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS-3) agonists, perilipin inhibitors, acetyl- CoA carboxylase 1 (ACC1) inhibitors, acetyl-CoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase R (PKCß) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose-6-phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

(25) Use of the compound of any of the above-mentioned (2) to (15) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a drug for the treatment of diabetes.

(26) Use of the compound of the above-mentioned (2) to (15) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for inhibiting DPP-IV.

(27) Use of the above-mentioned (25), which is used in combination with a different therapeutic drug for diabetes, a therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an anti-obesity drug.

(28) Use of the above-mentioned (27), wherein. the different therapeutic drug for diabetes, the therapeutic drug for diabetic complication, the therapeutic drug for hyperlipidemia or the anti- obesity drug is selected from insulin preparations (injection), low-molecular insulin preparations (oral agent), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues, a-glucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARy receptor agonists/antagonists, PPARb receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose-1, 6-bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llp-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors, ß3 adrenaline receptor agonists, apolipoprotein-A1 (Apo-A1) inducers, lipoprotein lipase (LPL) activators, glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 3 (BRS-3) agonists, perilipin inhibitors, acetyl- CoA carboxylase 1 (ACC1) inhibitors, acetyl-CoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase ß (PKC) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose-6-phosphate aminotransferase (GFAT) inhibitors and uncoupling protein (UCP) inducers/activators.

(29) A commercial package comprising the pharmaceutical composition of any of the above-mentioned (16), (19) and (20) and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating diabetes.

The present invention includes the following embodiments.

(30) A DPP-IV inhibitor comprising a compound of the formula [I], wherein R4 is selected from the following [K]- [S], or a salt thereof.

[K] hydrogen atom, [L] C1_6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, <L3> hydroxyl, -<L4> CI-6 alkoxy, -<L5> Cl-6 alkylthio, <L6> aryloxy, #<L7> aralkyloxy, <L8> heterocyclyloxy, #<L9> heterocyclyl-C1-6 alkoxy, <L10> nitro, #<L11> amino, #<L12> cyano, <L13> carboxyl and <L14>-Y41-R4l (R41 is selected from the following (La2) and (La4)- (La7), and Y41 is selected from the following (Lbl) and (Lb2)), ##(La2) C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<LaalO>, <Laal6> and <Laal9>), ###<Laa1> halogen atom, ###<Laa2> C3-12 cycloalkyl, ###<Laa3> hydroxyl, ... <Laa4> aralkyloxy,

###<Laa5> heterocyclyloxy, ###<aa6> heterocyclyl-C1-6 alkoxy, ... <Laa7> nitro, .. *<Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> C1-6 alkoxy, aryloxy, ###<Laa16> amino and ###<Laa19> C1-6 alkylthio; ## (La4) C3-12 cycloalkyl-C1-6 alkyl, ## (La5) aryl, ## (La6) aralkyl and ## (La7) heterocyclyl (said aryl, aralkyl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Labl5>, <Labl9> and <Lab28>), ###<Lab1> halogen atom, ###<Lab2> C1-6 alkyl, <Lab3> halo-C1_6 alkyl, --<Lab4> aralkyl, ###<Lab5> heterocyclyl-C1-6 alkyl, ###<Lab6> C3-12 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C1-6 alkoxy, ###<Lab9> aralkyloxy, ... <LablO> heterocyclyloxy, ###<Lab11> heterocyclyl-C1-6 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, "-<Labl4> cyano, ###<Lab15> carboxyl, ###<Lab19> aryloxy and ###<Lab28> C1-6 alkylthio; ## (Lb1) single bond and -(Lb2) X41 (X41 is selected from the following (Lbal)- (Lba23)), (Lbal)-O-,-OCH2-,-OCH2CH2-,-CH20-,-CH2CH20-,

### (Lba2) -S-, -SCH2-, -SCH2CH2-, -CH2S-, -CH2CH2S-, ### (Lba3) -CO-, -COCH2-, -COCH2CH2-, -CH2CO-, -CH2CH2CO-, ### (Lba4) -CO2-, ### (Lba5) -OCO-, ... (Lba6)-OC02-, ... (Lba7)-SO-,-SOCH2-,-SOCH2CH2-,-CH2SO-,-CH2CH2SO-, ### (Lba8) -SO2-, -SO2CH2-, -SO2CH2CH2-, -CH2SO2-, -CH2CH2SO2-, ### (Lba9) -OSO2-, ### (Lba10) -SO3-, ### (Lba11) -NR411-, -NR411CH2-, -NR411CH2CH2-, -CH2NR411-, -CH2CH2NR411-, ### (Lab12) -CONR411-, ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ### (Lba15) -NR411CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-, ### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-, ### (Lba21) -NR411CSNR412-, ### (Lba22) -NR411SO2NR412- (R411, R412 are the same or different and each is selected from the following (Lbaal)- (Lbaa3)), #### (Lbaa1) hydrogen atom, #### (Lbaa2) C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal3>), #####<Lbaaa1> halogen atom, * *,,, <Lbaaa2> C3-12 cycloalkyl, #####<Lbaaa3> hydroxyl, ""'<Lbaaa4> Ci-g alkoxy, #####<Lbaaa5> C1-6 alkylthio, #####<Lbaaa6> aryloxy, #####<Lbaaa7> aralkyloxy, #####<Lbaaa8> heterocyclyloxy, #####<Lbaaa9> heterocyclyl-C1-6 alkoxy,

#####<Lbaaa10> nitro, #####<Lbaaa11> amino, #####<Lbaaa12> cyano and #####<Lbaaa13> carboxyl; and #### (Lbaa3) -(CH2)p- (p is an integer of 1 to 3) formed by R411 and R412 in combination); and ### (Lba23) 4 to 7-membered divalent saturated heterocycle; [M] Cs-iz cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>), <M1> halogen atom, <M2> C1_6 alkyl, #<M3> halo-C1-6 alkyl, -<M4> aralkyl, #<M5> heterocyclyl-C1-6 alkyl, <M6> hydroxyl, #<M7> C1-6 alkoxy, #<M8> C1-6 alkylthio, #<M9> aryloxy, <M10> aralkyloxy, #<M11> heterocyclyloxy, #<M12> heterocyclyl-C1-6 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, #<M17> carboxyl and #<M18> -Y42-R41 (R41 is as defined above, and y42 is selected from the following (Mal)- (Mal2)), ## (Mal) single bond, ## (Ma2) -X41-, ## (Ma3) Z41-, ## (Ma4) -Z41-Z42-, ## (Ma5) -X41-Z41-, ## (Ma6) -Z41-X41-,

## (Ma7) -X41-Z41-X42-, ## (Ma8) -X41-Z41-Z42-, ## (Ma9) -Z41-X41-Z42-, ## (Ma10) -Z41-Z42-X41-, ## (Ma11) or ## (Ma12) (X41 is as defined above, X42 and X43 are the same as X41, Z41 and Z42 are the same or different and each is selected from the following (Mab1), (Mab3)- (Mab6) and Z43 is selected from the following (Mac1), (Mac3)- (Mac5)), --- (Mabl) Cl-6 alkylene, ### (Mab2) C2-6 alkenylene (said alkylene and alkenylene is optionally substituted by 1 to 3 substituents selected from the following <Mabal>-<Mabal3>), ""<Mabal> halogen atom, ####<Maba2> C3-12 cycloalkyl, ####<Maba3> hydroxyl, ####<Maba4> C1-6 alkoxy, ####<Maba5> C1-6 alkylthio, ####<Maba6> aryloxy, ####<Maba7> aralkyloxy, ####<Maba8> heterocyclyloxy, ####<Maba9> heterocyclyl-C1-6 alkoxy, <MabalO> nitro,

####<Maba11> amino, ####<Maba12> cyano and ""<Mabal3> carboxyl; ### (Mab4) C3-12 cycloalkylene, --(Mab5) arylene and "' (Mab6) divalent heterocycle (said cycloalkylene, arylene and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Mabbl>-<Mabbl7>), ####<Mabb1> halogen atom, <Mabb2> C1_6 alkyl, ####<Mabb3> halo-C1-6 alkyl, .... <Mabb4> aralkyl, ####<Mabb5> heterocyclyl-C1-6 alkyl, ####<Mabb6> C3-12 cycloalkyl, ####<Mabb7> hydroxyl, ####<Mabb8> C1-6 alkoxy, .... <Mabb9> Cl-6 alkylthio, ####<Mabb10> aryloxy, <Mabbll> aralkyloxy, ####<Mabb12> heterocyclyloxy, ""<Mabbl3> heterocyclyl-Ci-g alkoxy, .... <Mabbl4> nitro, ####<Mabb15> amino, ####<Mabb16> cyano and ####<Mabb17> carboxyl; ### (Mac1) C1-6 alkanetriyl (said alkanetriyl is optionally substituted by 1 to 3 substituents selected from the following <Macal>-<Macal3>), ####<Maca1> halogen atom, ####<Maca2> C3-12 cycloalkyl, ####<Maca3> hydroxyl, ####<Maca4> C1-6 alkoxy, ####<Maca5> C1-6 alkylthio, ####<Maca6> aryloxy,

..-"<Maca7> aralkyloxy, ####<Maca8> heterocyclyloxy, ####<Maca9> heterocyclyl-C1-6 alkoxy, ""<MacalO> nitro, ####<Maca11> amino, ####<Maca12> cyano and -'"<Macal3> carboxyl; ### (Mac3) C3-12 cycloalkanetriyl, ### (Mac4) arenetriyl and ### (Mac5) trivalent heterocycle (asid cycloalkanetriyl, arenetriyl and heterocycle are optionally substituted by 1 to 3 substituents selected from the following <Macbl>-<Macbl7>), ####<Macb1> halogen atom, ####<Macb2> C1-6 alkyl, ####<Macb3> halo-C1-6 alkyl, ...<Macb4> aralkyl, ""<Macb5> heterocyclyl-Ci-6 alkyi, ####<Macb6> C3-12 cycloalkyl, ####<Macb7> hydroxyl, ####<Macb8> C1-6 alkoxy, ####<Macb9> C1-6 alkylthio, ####<Macb10> aryloxy, ####<Macb11> aralkyloxy, ####<Macb12> heterocyclyloxy, ####<Macb13> heterocyclyl-C1-6 alkoxy, ####<Macb14> nitro, ####<Macb15> amino, ####<Macb16> cyano and ####<Macb17> carboxyl; [N] aryl, [O] aralkyl, [P] heterocyclyl, [Q] heterocyclyl-C1-6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-C1-6 alkyl are optionally substituted by 1 to 3

substituents selected from the following <N1>-<N19>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N3> C3-12 cycloalkyl, #<N4> halo-C1-6 alkyl, -<N5> aralkyl, #<N6> heterocyclyl-C1-6 alkyl, #<N7> hydroxyl, #<N8> C1-6 alkoxy, #<N9> C1-6 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heterocyclyloxy, #<N13> heterocyclyl-C1_6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano, <N17> =O, #<N18> carboxyl and #<N19> -Y42-R41 (R41 and y42 are as defined above); [R] -Y41-R41 (R41 and Y41 are as defined above), or [S] (R42 and R43 are each independently selected from the following (S1)-(S3) and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination, (S1) hydrogen atom, #(S2) -Y41-R44 (R44 is selected from the following (Sal) and (Sa2) and Y41 is as defined above), ##(Sal) aryl and

20 (Sa2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Saal>-<Saal7>), ###<Saa1> halogen atom, ###<Saa2> C1-6 alkyl, ###<Saa3> halo-C1-6 alkyl, ###<Saa4> aralkyl, <Saa5> heterocyclyl-C1_6 alkyl, <Saa6> C3_12 cycloalkyl, "'<Saa7> hydroxyl, ###<Saa8> C1-6 alkoxy, ###<Saa9> C1-6 alkylthio, ###<Saa10> aryloxy, ###<Saa11> aralkyloxy, ###<Saa12> heterocyclyloxy, ###<Saa13> heterocyclyl-C1-6 alkoxy, ###<Saa14> nitro, ###<Saa15> amino, ###<Saa16> cyano and ###<Saa17> carboxyl; or - (S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl>-<Scl7>), ##<Sc1> halogen atom, ##<Sc2> C1-6 alkyl, <Sc3> halo-C16 alkyl, ##<Sc4> aralkyl, ##<Sc5> heterocyclyl-C1_6 alkyl, ##<Sc6> C3-12 cycloalkyl, ##<Sc7> hydroxyl, ##<Sc8> C1-6 alkoxy, ##<Sc9> C1-6 alkylthio, ##<Sc10> aryloxy,

"<Scll> aralkyloxy, ##<Sc12> heterocyclyloxy, ##<Sc13> heterocyclyl-C1-6 alkoxy, ##<Sc14> nitro, ##<Sc15> amino, ##<Sc16> cyano and ##<Sc17> carboxyl.

(31) A compound wherein, in the formula [II], R4'is selected from the following [K]-[M], [P], [R] and [S], or a salt thereof : [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, <L3> hydroxyl, #<L4> C1-6 alkoxy, #<L5> C1-6 alkylthio, <L6> aryloxy, <L7> aralkyloxy, <L8> heterocyclyloxy, #<L9> heterocyclyl-C16 alkoxy, #<L10> nitro, #<L11> amino, #<L12> cyano, #<L13> carboxyl and #<L14> -Y41-R41, (R41, is selected from the following (La2), (La5) and (La7), Y41 is as defined in the above-mentioned (30)), ##(La2) C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<LaalO>, <Laal6> and <Laal9>), ###<Laa1> halogen atom, ###<Laa2> C3-12 cycloalkyl, ###<Laa3> hydroxyl,

."-<Laa4> aralkyloxy, ###<Laa5> heterocyclyloxy, ###<Laa6> heterocyclyl-C1-6 alkoxy, ###<Laa7> nitro, ###<Laa8> cyano, ###<Laa9> carboxyl, ###<Laa10> C1-6 alkoxy, aryloxy, ###<Laa16> amino and ###<Laa19> C1-6 alkylthio; ##(La5) aryl and ##(La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Labl5>, <Labl9> and <Lab28>), ###<Lab1> halogen atom, --<Lab2> C1_6 alkyl, ... <Lab3> halo-CI-6 alkyl, ###<Lab4> aralkyl, ###<Lab5> heterocyclyl-C1-6 alkyl, ... <Lab6> C3-12 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C1-6 alkoxy, ###<Lab9> aralkyloxy, <Labl0> heterocyclyloxy, ###<Lab11> heterocyclyl-C1-6 alkoxy, ###<Lab12> nitro, ###<Lab13> amino, ###<Lab14> cyano, ###<Lab15> carboxyl, ###<Lab19> aryloxy and ###<Lab28> C1-6 alkylthio; [M] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>), <M1> halogen atom, #<M2> C1-6 alkyl,

#<M3> halo-C1-6 alkyl, . <M4> aralkyl, #<M5> heterocyclyl-C1-6 alkyl, #<M6> hydroxyl, #<M7> C1-6 alkoxy, #<M8> C1-6 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heterocyclyloxy, #<M12> heterocyclyl-C1-6 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano, <M17> carboxyl and #<M18> -Y42-R41, (R41, is as defined above, y42 is as defined in the above-mentioned (30) ) ; [P] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>-<N16> and <N18>), #<N1> halogen atom, #<N2> C1-6 alkyl, -<N3> C3-12 cycloalkyl, #<N4> halo-C1-6 alkyl, -<N5> aralkyl, #<N6> heterocyclyl-C1-6 alkyl, #<N7> hydroxyl, #<N8> C1-6 alkoxy, #<N9> Cl_6 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heterocyclyloxy, #<N13> heterocyclyl-C1-6 alkoxy, #<N14> nitro,

. <N15> amino, #<N16> cyano and #<N18> carboxyl; [R] -Y41-R41, (R41, and Y41 are as defined above), or [S] (R42 and R43 are each as defined in the above-mentioned (30) and m and n are each independently an integer of 0 to 3) formed by R4' and R5'in combination, provided that, when R1 and R2'are hydrogen atoms and R3'is cyclopropyl, then the combination of one of R4'and R5'being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R1 and R'are hydrogen atoms and R3'is cyclobutyl, then the combination of one of R4'and R5'being tert- butyl, and the other being hydrogen atom does not occur.

(32) The compound of the above-mentioned (31), wherein R1 is [A] hydrogen atom, [B] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B4>, <B10>-<B12> and <B14>), #<B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, #<B10> nitro, -<Bll> amino, #<B12> cyano and #<B14> -X1-R11 (R11 and X1 are each as defined in the above- mentioned (1) ) ;

or [C] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2>, <C6>, <C7> and <C13>-<C17>), #<C1> halogen atom, #<C2> C1-6 alkyl, #<C6> hydroxyl, -<C7> CI-6 alkoxy, #<C13> nitro, #<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> -X1-R11 (R11 and X1 are as defined above) ; R2'is [F] hydrogen atom, [G] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from <G1>-<G4>, <G10>-<G13> and <G16>-<G18>), #<G1> halogen atom, #<G2> C3-12 cycloalkyl, #<G3> hydroxyl, #<G4> C1-6 alkoxy, <G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, #<G16> -PO (OH) 2, #<G17> -PO (O-C1-6 alkyl) 2 and -<Gl8>-PO (0-aryl) 2 ; or [H] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>, <H2>, <H6>, <H7>, <H13>-<H16> and <H19>-<H21>), <H1> halogen atom, #<H2> C1-6 alkyl,

<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, #<H19> -PO (OH) 2, #<H20> -PO (O-C1-6 alkyl) 2 and #<H21> -PO (O-aryl)2 ; R3'is [J] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>, <J2>, <J6>, <J7>, <J13>-<J16> and <J19>-<J21>), #<J1> halogen atom, #<J2> C1-6 alkyl, #<J6> hydroxyl, #<J7> C1-6 alkoxy, #<J13> nitro, #<J14> amino and #<J15> cyano, #<J16> amido, #<J19> -PO (OH) 2, #<J20> -PO (O-C1-6 alkyl) 2 and #<J21> -PO (O-aryl)2; R4} iS [K] hydrogen atom, [L] Cri-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L4> and <L10>- <L12>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, #<L3> hydroxyl, #<L4> C1-6 alkoxy, #<L10> nitro,

<L11> amino and '<L12> cyano; [M] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>, <M7>, <M13>-<M16> and <M18>) <M1> halogen atom, #<M2> C1-6 alkyl, #<M6> hydroxyl, #<M6> C1-6 alkoxy, #<M13> azido, #<M14> nitro, #<M15> amino, #<M16> cyano and #<M18> -Y42-R41, (R41, is as defined in the above-mentioned (31), and y42 is as defined in the above-mentioned (30) ) ; [P] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>, <N2>, <N7>, <N8>, <N14>-<N16> and <N18>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N7> hydroxyl, #<N8> C1-6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano and <N18> carboxyl; or [S]

(R42 and R43 are as defined in the above-mentioned (30) and m and n are each independently an integer of 0 to 3) formed by R4'and R5' in combination ; R5 is [T] hydrogen atom, [U] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <U1>-<U4> and <U10>- <U12>) <U1> halogen atom, #<U2> C3-12 cycloalkyl, #<U3> hydroxyl, -<U4> CI-6 alkoxy, #<U10> nitro, #<U11> amino and <U12> cyano; or [V] Cl-in cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>, <V2>, <V6>, <V7> and <V13>-<V15>), #<V1> halogen atom, #<V2> C1-6 alkyl, #<V6> hydroxyl, #<V7> C1-6 alkoxy, -<Vl3> nitro, #<V14> amino and #<V15> cyano, provided that, when R1 and R2'are hydrogen atoms and R3'is cyclopropyl, then the combination of one of R4'and R5'being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R1 and R2, are hydrogen atoms and R3'is cyclobutyl, then the combination of one of R4'and R5'being tert- butyl, and the other being hydrogen atom does not occur, or a salt thereof.

(33) A DPP-IV inhibitor comprising a compound of the formula [I], wherein R1 is [A] hydrogen atom, [B] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B14>), <B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, #<B5> C1-6 alkylthio, #<B6> aryloxy, #<B7> aralkyloxy, <B8> heteroaryloxy, #<B9> heteroaryl-C1-6 alkoxy, <B10> nitro, #<B11> amino, <B12> cyano, #<B13> carboxyl and #<B14> -X1-R11 (R11 is selected from the following (Bal) and (Ba2), and Xl is selected from the following (Bb1)-(Bb5) and (Bbl3)- (Bb22) ), '' (Bal) aryl and ##(Ba2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Baal>, <Baa2>, <Baa4> and <Baa7>-<Baal7>), ###<Baa1> halogen atom, ###<Baa2> C1-6 alkyl, ###<Baa4> C3-12 cycloalkyl, ###<Baa7> hydroxyl, ###<Baa8> C1-6 alkoxy, -<Baa9> C1_6 alkylthio, ###<Baa10> aryloxy, ###<Baa11> aralkyloxy,

###<Baa12> heteroaryloxy, ###<Baa13> heteroaryl-C1-6 alkoxy, ###<Baa14> nitro, ###<Baa15> amino, ###<Baa16> cyano and ###<Baa17> carboxyl; ##(Bb1) single bond, " (Bb2)-0-, ## (Bb3) -S-, ## (Bb4) -NH-, ## (Bb5) -CO-, ## (Bb13) -CONH-, ## (Bb14) -NHCO-, ## (Bb15) -CSNH-, ## (Bb16) -NHCS-, ## (Bb17) -NHSO2-, ## (Bb18) -SO2NH-, ## (Bb19) -NHCO2-, ## (Bb20) -OCONH-, ## (Bb21) -NHCONH- and .. (Bb22)-NHCSNH- ; [C] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2> and <C6>-<C17>), #<C1> halogen atom, <C2> C16 alkyl, #<C6> hydroxyl, #<C7> C1-6 alkoxy, -<C8> Cl-6 alkylthio, #<C9> aryloxy, #<C10> aralkyloxy, #<C11> heteroaryloxy, #<C12> heteroaryl-C1-6 alkoxy, #<C13> nitro,

<C14> amino, #<C15> cyano, #<C16> carboxyl and #<C17> -X1-R11 (R11 and X1 are as defined above); [D]-X1-Rll (R1l and Xl are as defined above) or [E] (R12 and R13 are each independently selected from the following (El)- (E3), and j and k are each independently an integer of 0 to 3) formed by R and R4 in combination, #(E1) hydrogen atom, # (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2), and X12 is selected from the following (Eb1)-(Eb5), (Eb13) - (Eb22) and (Eb24)), '' (Eal) aryl and ##(Ea2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Eaal>-<Eaa4>, <Eaa7>-<Eaal7>), ###<Eaal> halogen atom, ###<Eaa2> C1-6 alkyl, ###<Eaa3> halo-C1-6 alkyl, ###<Eaa4> C3-12 cycloalkyl, ###<Eaa7> hydroxyl, ###<Eaa8> C1-6 alkoxy, ###<Eaa9> C1-6 alkylthio, ###<Eaa10> aryloxy, ###<Eaa11> aralkyloxy, <Eaa12> heteroaryloxy, ###<Eaa13> heteroaryl-C1-6 alkoxy, ###<Eaa14> nitro,

###<Eaa15> amino, ###<Eaa16> cyano and ###<Eaa17> carboxyl; ##(Eb1) single bond, ## (Eb2) -O-, ## (Eb3) -S-, ## (Eb4) -NH-, ## (Eb5) -CO-, ## (Eb13) -CONH-, ## (Eb14) -NHCO-, ## (Eb15) -CSNH-, ## (Eb16) -NHCS-, ## (Eb17) -NHSO2-, ## (Eb18) -SO2NH-, ## (Eb19) -NHCO2-, ## (Eb20) -OCONH-, ## (Eb21) -NHCONH-, ## (Eb22) -NHCSNH- and ##(Eb24) 4 to 7-membered divalent saturated heterocycle; or ' (E3) benzene ring formed by Ri and R13 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ecl>-<Ec4> and <Ec7>- <Ecl7>), ##<Ec1> halogen atom, ##<Ec2> C1-6 alkyl, ##<Ec3> halo-C1-6 alkyl, <Ec4> C3_12 cycloalkyl, ##<Ec7> hydroxyl, <Ec8> C1_6 alkoxy, ##<Ec9> C1-6 alkylthio, "<EclO> aryloxy, ##<Ec11> aralkyloxy, "<Ecl2> heteroaryloxy,

##<Ec13> heteroaryl-C1-6 alkoxy, ##<Ec14> nitro, ##<Ec15> amino, ##<Ec16> cyano and ##<Ec17> carboxyl; R2 is [F] hydrogen atom, [G] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1>-<G16>) <G1> halogen atom, #<G2> C3-12 cycloalkyl, <G3> hydroxyl, #<G4> C1-6 alkoxy, -<G5> Cl-6 alkylthio, #<G6> aryloxy, #<G7> aralkyloxy, #<G8> heteroaryloxy, #<G9> heteroaryl-C1-6 alkoxy, #<G10> nitro, #<G11> amino, #<G12> cyano, #<G13> amido, -<Gl4> =0, #<G15> carboxyl and #<G16> -PO (OH) 2; or [H] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>, <H2> and <H6>-<H19>), #<H1> halogen atom, #<H2> Ci-6 alkyl, #<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H8> C1-6 alkylthio,

. <H9> aryloxy, #<H10> aralkyloxy, #<H11> heteroaryloxy, #<H12> heteroaryl-C1-6 alkoxy, #<H13> nitro, #<H14> amino, #<H15> cyano, #<H16> amido, -<Hl7> =0, #<H18> carboxyl and #<H19> -PO (OH)2 ; R3 is [I] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <I1>-<I16>), <I1> halogen atom, #<I2> C3-12 cycloalkyl, #<I3> hydroxyl, -<14> Ci-Ei alkoxy, #<I5> C1-6 alkylthio, #<I6> aryloxy, #<I7> aralkyloxy, #<I8> heteroaryloxy, #<I9> heteroaryl-C1-6 alkoxy, #<I10> nitro, #<I11> amino, #<I12> cyano, #<I13> amido, -<Il4> =0, #<I15> carboxyl and -<116>-PO (OH) 2 ; or [J] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>, <J2> and <J6>-<J19>),

. <J1> halogen atom, . <J2> C1-6 alkyl, #<J6> hydroxyl, #<J7> C1-6 alkoxy, - <J8> Ci-6 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heteroaryloxy, <J12> heteroaryl-Cl-6 alkoxy, <J13> nitro, #<J14> amino, #<J15> cyano, <J16> amido, #<J17> = O, #<J18> carboxyl and #<J19> -PO (OH) 2 ; R4 and R5 are each independently, [K] hydrogen atom, [L] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, #<L3> hydroxyl, #<L4> C1-6 alkoxy, #<L5> C1-6 alkylthio, #<L6> aryloxy, #<L7> aralkyloxy, #<L8> heteroaryloxy, #<L9> heteroaryl-C16 alkoxy, #<L10> nitro, #<L11> amino, #<L12> cyano, #<L13> carboxyl and #<L14> -Y41-R41 (R41 is selected from the following (La5) and (La7),

and Y41 is selected from the following (Lbl) and (Lb2) ) ##(La5) aryl and ##(La7) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Labl>, <Lab2>, <Lab6>-<Labl5>, <Labl9> and <Lab28>), ###<Lab1> halogen atom, ###<Lab2> C1-6 alkyl, ... <Lab6> C3-12 cycloalkyl, ###<Lab7> hydroxyl, <Lab8> C1_6 alkoxy, ... <Lab9> aralkyloxy, <Labl0> heteroaryloxy, ###<Lab11> heteroaryl-C1-6 alkoxy, ... <Labl2> nitro, <Labl3> amino, ###<Lab14> cyano, <Labl5> carboxyl, ###<Lab19> aryloxy and ###<Lab28> C1-6 alkylthio; '' (Lbl) single bond and ##(Lb2) X41 (X41 is selected from the following (Lba1)-(Lba3) and (Lball)- (Lba21)), ### (Lbal) -O-, ... (Lba2)-S-, ### (Lba3) -CO-, ### (Lba11) -NR411-, ### (Lba12) -CONR411-, ... (Lbal3)-NR411Co-, ### (Lba14) -CSNR411-, ... (Lbal5)-NR41"CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-, ### (Lba19) -NR411CO2-,

### (Lba20) -NR411CONR412- and ###(Lba21) -NR411CSNR412- (R411, R412 are each hydrogen atom); [M] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>- <M12> and <M14>-<M18>), <M1> halogen atom, #<M2> C1-6 alkyl, <M6> hydroxyl, <M7> C16 alkoxy, #<M8> C1-6 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heteroaryloxy, #<M12> heteroaryl-C1-6 alkoxy, #<M14> nitro, #<M15> amino, #<M16> cyano, #<M17> carboxyl and #<M18> -Y42-R41 (R41 is as defined above, and y42 iS selected from the following (Mal) and (Ma2)), ##(Ma1) single bond and ##(Ma2) X41 (X41 are as defined above) ; [N] aryl, [O] aralkyl, [P] 3 to 7-membered saturated heterocycle or heteroaryl, [Q] heteroaryl-C1-6 alkyl (said aryl, aralkyl, saturated heterocycle, heteroaryl and heteroaryl-C1-6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <N1>-<N3>, <N7>-<N16> and <N18>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N3> C3-12 cycloalkyl, <N7> hydroxyl, #<N8> C1-6 alkoxy,

#<N9> C1-6 alkylthio, <N10> aryloxy, #<N11> aralkyloxy, <N12> heteroaryloxy, #<N13> heteroaryl-C1-6 alkoxy, #<N14> nitro, <N15> amino, <N16> cyano and <N18> carboxyl; [R] R41-Y41- (R41 and Y41 are as defined above), or [S] (R42 and R43 are each independently selected from the following (S1)-(S3), and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination, #(S1) hydrogen atom, #(S2) -Y411-R44 (R44 is selected from the following (Sal) and (Sa2), and y411 is selected from the following (Lbl) and (Lb2)) ##(Sa1) aryl and ##(Sa2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Saal>-<Saa3> and <Saa6>-<Saal7>), ###<Saa1> halogen atom, ###<Saa2> C1-6 alkyl, ###<Saa3> halo-C1-6 alkyl, ###<Saa6> C3-12 cycloalkyl, ###<Saa7> hydroxyl, ###<Saa8> C1-6 alkoxy, ###<Saa9> C1-6 alkylthio, <Saal0> aryloxy,

."<Saall> aralkyloxy, ###<Saa12> heteroaryloxy, ... <Saal3> heteroaryl-Cl-6 alkoxy, .<Saal4> nitro, ###<Saa15> amino, ###<Saa16> cyano and ###<Saa17> carboxyl; ##<Lb1> single bond and ##<Lb2> X411 (X411 is selected from the following (Lba1)-(Lba3), (Lba11)-(Lba21) and (Lba23)), ... (Lbal)-0-, ### (Lba2) -S-, ### (Lba3) -CO-, ### (Lba11) -NR411-, ### (Lba12) -CONR411-, ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ... (Lbal5)-NR41lCS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-, ### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-, ###(Lba21) -NR411CSNR412- (R411, R412 are each hydrogen atom), and ###(Lba23) 4 to 7-membered divalent saturated heterocycle; or #(S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl>-<Sc3> and <Sc6>- <Scl7>), ##<Sc1> halogen atom, ##<Sc2> C1-6 alkyl, ##<Sc3> halo-C1-6 alkyl,

<Sc6> C3_12 cycloalkyl, ##<Sc7> hydroxyl, ##<Sc8> C1-6 alkoxy, ##<Sc9> C1-6 alkylthio, ##<Sc10> aryloxy, ##<Sc11> aralkyloxy, "<Scl2> heteroaryloxy, ##<Sc13> heteroaryl-C1-6 alkoxy, ##<Sc14> nitro, "<Scl5> amino, "<Scl6> cyano and "<Scl7> carboxyl, or a salt thereof.

(34) A compound represented by the formula [IV] wherein Ri'is the following [A]- [E] : [A] hydrogen atom, [B] Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B12> and <B14>), #<B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, #<B5> C1-6 alkylthio, #<B6> aryloxy, #<B7> aralkyloxy, #<B8> heteroaryloxy, #<B9> heteroaryl-C1-6 alkoxy, #<B10> nitro, #<B11> amino,

<B12> cyano and <B14>-Xl-R" (R"is selected from the following (Bal) and (Ba2), and Xl is selected from the following (Bb1) - (Bb5) and (Bbl3)- (Bb22)), ##(Ba1) aryl and ##(Ba2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Baal>, <Baa2>, <Baa4> and <Baa7>-<Baal7>) ###<Baa1> halogen atom, ###<Baa2> C1-6 alkyl, ###<Baa4> C3-12 cycloalkyl, ###<Baa7> hydroxyl, ... <Baa8> CI-6 alkoxy, ###<Baa9> C1-6 alkylthio, <Baal0> aryloxy, ###<Baa11> aralkyloxy, ###<Baa12> heteroaryloxy, ###<Baa13> heteroaryl-C1-6 alkoxy, ###<Baa14> nitro, ###<Baa15> amino, ###<Baa16> cyano and ###<Baa17> carboxyl; ##(Bb1) single bond, " (Bb2)-0-, -(Bb3)-S-, ## (Bb4) -NH-, ## (Bb5) -CO-, ## (Bb13) -CONH-, (Bbl4)-NHCO-, ## (Bb15) -CSNH-, ## (Bb16) -NHCS-, ## (Bb17) -NHSO2-, ## (Bb18) -SO2NH-, ## (Bb19) -NHCO2-,

.-(Bb20)-OCONH-, ## (Bb21) -NHCONH- and ## (Bb22) -NHCSNH-; [C] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2>, <C6>- <C15> and <C17>), #<C1> halogen atom, -<C2> CI-6 alkyl, #<C6> hydroxyl, #<C7> C1-6 alkoxy, #<C8> C1-6 alkylthio, #<C9> aryloxy, #<C10> aralkyloxy, #<C11> heteroaryloxy, #<C12> heteroaryl-C1-6 alkoxy, #<C13> nitro, #<C14> amino, #<C15> cyano and #<C17> -X1-R11 (R11 and X1 are as defined above) ; [D] -X1-R11 (R11 and X1 are as defined above) or [E] (R12 and R13 are each independently selected from the following (El)- (E3), and j and k are each independently an integer of 0 to 3) formed by R1'and R4'in combination, (E1) hydrogen atom, #(E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2), and X12 is selected from the following (Eb1) - (Eb5), (Eb13) - (Eb22) and (Eb24)), -- (Eal) aryl and

##(Ea2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Eaal>-<Eaa4> and <Eaa7>-<Eaal7>), ###<Eaa1> halogen atom, ###<Eaa2> C1-6 alkyl, ###<Eaa3> halo-C1-6 alkyl, ###<Eaa4> C3-12 cycloalkyl, ###<Eaa7> hydroxyl, ###<Eaa8> C1-6 alkoxy, ... <Eaa9> Cl-6 alkylthio, <Eaal0> aryloxy, <Eaall> aralkyloxy, <Eaal2> heteroaryloxy, ###<Eaa13> heteroaryl-C1-6 alkoxy, ###<Eaa14> nitro, ###<Eaa15> amino, ###<Eaa16> cyano and ###<Eaa17> carboxyl; ##(Eb1) single bond, ## (Eb2) -O-, ## (Eb3) -S-, ## (Eb4) -NH-, ## (Eb5) -CO-, ## (Eb13) -CONH-, ## (Eb14) -NHCO-, 0 (Ebl5) -CSNH-, ## (Eb16) -NHCS-, ## (Eb17) -NHSO2-, ## (Eb18) -SO2NH-, ## (Eb19) -NHCO2-, ## (Eb20) -OCONH-, ## (Eb21) -NHCONH-, ## (Eb22) -NHCSNH- and ##(Eb24) 4 to 7-membered divalent saturated heterocycle;

or (E3) benzene ring formed by R12 and R13 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ecl>-<Ec4> and <Ec7>- <Ecl7>), ##<Ec1> halogen atom, ##<Ec2> C1-6 alkyl, ##<Ec3> halo-C1-6 alkyl, ##<Ec4> C3-12 cycloalkyl, ##<Ec7> hydroxyl, ##<Ec8> C1-6 alkoxy, ##<Ec9> C1-6 alkylthio, "<EclO> aryloxy, ##<Ec11> aralkyloxy, ##<Ec12> heteroaryloxy, ##<Ec13> heteroaryl-C1-6 alkoxy, "<Ecl4> nitro, "<Ecl5> amino, ##<Ec16> cyano and "<Ecl7> carboxyl; R2'is selected from the following [F]- [H] : [F] hydrogen atom, [G] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <G1>-<G12>), #<G1> halogen atom, #<G2> C3-12 cycloalkyl, #<G3> hydroxyl, #<G4> C1-6 alkoxy, #<G5> C1-6 alkylthio, #<G6> aryloxy, #<G7> aralkyloxy, #<G8> heteroaryloxy, #<G9> heteroaryl-C1-6 alkoxy, #<G10> nitro,

#<G11> amino and <G12> cyano; and [H] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following. <H1>, <H2> and <H6>-<H15>), <H1> halogen atom, #<H2> C1-6 alkyl, #<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H8> C1-6 alkylthio, -<H9> aryloxy, #<H10> aralkyloxy, #<H11> heteroaryloxy, #<H12> heteroaryl-C1-6 alkoxy, #<H13> nitro, #<H14> amino and <H15> cyano; R3'is the following [J] : [J] C3_12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>, <J2> and <J6>-<J15>), #<J1> halogen atom, #<J2> C1-6 alkyl, #<J6> hydroxyl, #<J7> C1-6 alkoxy, #<J8> C1-6 alkylthio, #<J9> aryloxy, #<J10> aralkyloxy, #<J11> heteroaryloxy, #<J12> heteroaryl-C1-6 alkoxy, #<J13> nitro, #<J14> amino and <J15> cyano;

R4'and R5'are each independently selected from the following [K]- [M], [P], [R] and [S] : [K] hydrogen atom, [L] C1_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L12> and <L14>), #<L1> halogen atom, #<L2> C3-12 cycloalkyl, #<L3> hydroxyl, #<L4> C1-6 alkoxy, #<L5> C1-6 alkylthio, #<L6> aryloxy, #<L7> aralkyloxy, #<L8> heteroaryloxy, #<L9> heteroaryl-C1-6 alkoxy, <L10> nitro, #<L11> amino, #<L12> cyano and #<L14> -Y41-R41' (R41' is selected from the following (La5) and (La7), and y41 is selected from (Lbl) and (Lb2)), -' (La5) aryl and ##(La7) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Labl>, <Lab2>, <Lab6>-<Labl5>, <Labl9> and <Lab28>), --<Labl> halogen atom, ###<Lab2> C1-6 alkyol, ... <Lab6> C3-12 cycloalkyl, ###<Lab7> hydroxyl, ###<Lab8> C1-6 alkoxy, ###<Lab9> aralkyloxy, ###<Lab10> heteroaryloxy, ###<Lab11> heteroaryl-C1-6 alkoxy, ... <Labl2> nitro, ... <Labl3> amino, ###<Lab14> cyano,

. -<Labl5> carboxyl, .--<Labl9> aryloxy and ###<Lab28> C1-6 alkylthio; ##(Lb1) single bond and ## (Lb2) X41 (X41 is selected from the following (Lba1) - (Lba3) and (Lba11) - (Lba21)), ... (Lbal)-0-, ... (Lba2)-S-, ### (Lba3) -CO-, ### (Lba11) -NR411-, ### (Lba12) -CONR411-, ### (Lba13) -NR411CO-, ... (Lbal4)-CSNR4"-, ### (Lba15) -NR411CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-, ... (Lbal9)-NR'11C02-, ### (Lba20) -NR411CONR412- and ###(Lba21) -NR411CSNR412- (R411, R412 are each hydrogen atom) ; [M] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>- <M12>, <M14>-<M16> and <M18>), #<M1> halogen atom, #<M2> C1-6 alkyl, <M6> hydroxyl, #<M7> C1-6 alkoxy, #<M8> Cl_6 alkylthio, #<M9> aryloxy, #<M10> aralkyloxy, #<M11> heteroaryloxy, -<Ml2> heteroaryl-CI-6 alkoxy, #<M14> nitro, #<M15> amino,

#<M16> cyano and #<M18> -Y42-R41'(R41' is as defined above, and Y42 is as defined for Y y41) ; [P] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following <N1>-<N3>, <N7>-<N16> and <N18>), #<N1> halogen atom, #<N2> C1-6 alkyl, #<N3> C3-12 cycloalkyl, #<N7> hydroxyl, #<N8> C1-6 alkoxy, '<N9> Ci-6 alkylthio, #<N10> aryloxy, #<N11> aralkyloxy, #<N12> heteroaryloxy, -<Nl3> heteroaryl-CI-6 alkoxy, #<N14> nitro, #<N15> amino, #<N16> cyano and -<N18> carboxyl; [R] -Y41-R41' (R41' and Y41 are as defined above), or [S] (R and and are each independently selected from the following (S1) - (S3), and m and n are each independently an integer of 0 to 3) formed by R4'and R'in combination, (S1) hydrogen atom, #(S2) -Y411-R44 (R44 is selected from the following (Sal) and (Sa2), and y411 is selected from the following (Lbl) and (Lb2)), ##(Sa1) aryl and

##(Sa2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Saal>-<Saa3> and <Saa6>-<Saal7>), ##<Saal> halogen atom, <Saa2> C1_6 alkyl, ###<Saa3> halo-C1-6 alkyl, <Saa6> C3_12 cycloalkyl, ###<Saa7> hydroxyl, ... <Saa8> CI-6 alkoxy, ... <Saa9> Cl-6 alkylthio, ###<Saa10> aryloxy, ###<Saa11> aralkyloxy, ###<Saa12> heteroaryloxy, --. <Saal3> heteroaryl-CI-6 alkoxy, --<Saal4> nitro, ###<Saa15> amino, ###<Saa16> cyano and ###<Saa17> carboxyl -(Lbl) single bond and ##(Lb2) X411 (X411 is selected from the following (Lba1)-(Lba3), (Lball)- (Lba21) and (Lba23)), ### (Lba1) -O-, ### (Lba2) -S-, ### (Lba3) -CO-, ### (Lba11) -NR411-, ### (Lba12) -CONR411-, ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ### (Lba15) -NR411CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ... (Lba18) -OCONR411-, ### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-,

###(Lba21) -NR411CSNR412- (R411, R412 are each hydrogen atom) and ###(Lba23) 4 to 7-membered divalent saturated heterocycle; or (S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl>-<Sc3> and <Sc6>- <Sc17>), ##<Sc1> halogen atom, <Sc2> C1_6 alkyl, ##<Sc3> halo-C1-6 alkyl, ##<Sc6> C3-12 cycloalkyl, ##<Sc7> hydroxyl, ##<Sc8> C1-6 alkoxy, ##<Sc9> C1-6 alkylthio, "<SclO> aryloxy, ##<Sc11> aralkyloxy, "<Scl2> heteroaryloxy, ##<Sc13> heteroaryl-C1-6 alkoxy, "<Scl4> nitro, "<Scl5> amino, "<Scl6> cyano and "<Scl7> carboxyl ; provided that, when R'and R 'are hydrogen atoms and R3'is cyclopropyl, then the combination of one of R4'and Being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R1'and R2'are hydrogen atoms and R3'is cyclobutyl, then the combination of one of R4'and R5'being tert- butyl, and the other being hydrogen atom does not occur, or a salt thereof.

(35) A compound of the formula [IV], wherein Rois [A] hydrogen atom,

[B] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <B1>-<B4>, <B10>-<B12> and <B14>), <B1> halogen atom, #<B2> C3-12 cycloalkyl, #<B3> hydroxyl, #<B4> C1-6 alkoxy, <B10> nitro, <B11> amino, <B12> cyano and #<B14> -X1-R11 (R11 is selected from the following (Bal) and (Ba2), Xi vis selected from the following (Bb1)-(Bb5) and (Bb13)-(Bb22)) ##(Ba1) aryl and ##(Ba2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Baal>, <Baa2>, <Baa4>, <Baa7>, <Baa8> and <Baal4>-<Baal7>) ###<Baa1> halogen atom, ###<Baa2> C1-6 alkyl, ... <Baa4> C3-12 cycloalkyl, ###<Baa7> hydroxyl, ###<Baa8> C1-6 alkoxy, ###<Baa14> nitro, ###<Baa15> amino, ###<Baa16> cyano and ###<Baa17> carboxyl; ##(Bb1) single bond, " (Bb2)-0-, -(Bb3)-S-, ## (Bb4) -NH-, ## (Bb5) -CO-, ## (Bb13) -CONH-, ## (Bb14) -NHCO-, ## (Bb15) -CSNH-, ## (Bb16) -NHCS-,

## (Bb17) -NHSO2-, .-(Bbl8)-SO2NH-, ## (Bb19) -NHCO2-, .' (Bb20)-OCONH-, ## (Bb21) -NHCONH- and ## (Bb22) -NHCSNH-; [C] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2>, <C6>, <C7>, <C13>-<C15> and <C17>), #<C1> halogen atom, <C2> C1_6 alkyl, #<C6> hydroxyl, #<C7> C1-6 alkoxy, #<C13> nitro, #<C14> amino, #<C15> cyano and #<C17> -X1-R11 (R11 and X1 are as defined above); or [E] (R12 and R13 are each independently selected from the following (E1)-(E3), and j and k are each independently an integer of 0 to 3) formed by R1'and in combination, (E1) hydrogen atom, (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2), and X12 is selected from the following (Eb1)-(Eb5), (Eb13)-(Eb22) and (Eb24)), -' (Eal) aryl and ##(Ea2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Eaal>-<Eaa4>, <Eaa7>, <Eaa8> and <Eaal4>-<Eaal7>),

.--<Eaal> halogen atom, ###<Eaa2> C1-6 alkyl, ###<Eaa3> halo-C1-6 alkyl, ###<Eaa4> C3-12 cycloalkyl, -"<Eaa7> hydroxyl, ###<Eaa8> C1-6 alkoxy, ###<Eaa14> nitro, ###<Eaa15> amino, ###<Eaa16> cyano and ###<Eaa17> carboxyl; ##(Eb1) single bond, ## (Eb2) -O-, ## (Eb3) -S-, .. (Eb4)-NH-, ## (Eb5) -CO-, ## (Eb13) -CONH-, ## (Eb14) -NHCO-, ## (Eb15) -CSNH-, ## (Eb16) -NHCS-, ## (Eb17) -NHSO2-, ## (Eb18) -SO2NH-, ## (Eb19) -NHCO2-, ## (Eb20) -OCONH-, ## (Eb21) -NHCONH-, ## (Eb22) -NHCSNH- and ##(Eb24) 4 to 7-membered divalent saturated heterocycle; or ' (E3) benzene ring formed by Ri2 and R13 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ec1>-<Ec4>, <Ec7>, <Ec8> and <Ecl4>-<Ecl7>), ##<Ecl> halogen atom, <Ec2> C1_6 alkyl, <Ec3> halo-Cl6 alkyl,

##<Ec4> C3-12 cycloalkyl, ##<Ec7> hydroxyl, ##<Ec8> C1-6 alkoxy, "<Ecl4> nitro, "<Ecl5> amino, "<Ecl6> cyano and "<Ecl7> carboxyl; Ra'is [F] hydrogen atom, [G] C1-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from <G1>-<G4> and <G10>-<G12>), #<G1> halogen atom, #<G2> C3-12 cycloalkyl, #<G3> hydroxyl, #<G4> C1-6 alkoxy, #<G10> nitro, #<G11> amino and <G12> cyano; or [H] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>, <H2>, <H6>, <H7> and <H13>-<H15>), <H1> halogen atom, #<H2> C1-6 alkyl, #<H6> hydroxyl, #<H7> C1-6 alkoxy, #<H13> nitro, #<H14> amino and <H15> cyano; R3'is [J] 3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <J1>, <J2>, <J6>, <J7> and <J13>-<J15>), #<J1> halogen atom, #<J2> C1-6 alkyl,

#<J6> dydroxyl, #<J7> C1-6 alkoxy, . <Jl3> nitro, #<J14> amino and <J15> cyano; R4'and R5' are each independently [K] hydrogen atom, [L] Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L4> and <L10>- <L12>) <L1> halogen atom, #<L2> C3-12 cycloalkyl, #<L3> hydroxyl, #<L4> C1-6 alkoxy, #<L10> nitro, #<L11> amino and <L12> cyano; [M] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>, <M2>, <M6>, <M7> and <M14>-<M16>), #<M1> halogen atom, #<M2> C1-6 alkyl, #<M6> hydroxyl, #<M7> C1-6 alkoxy, #<M14> nitro, #<M15> amino and <M16> cyano; or [S]

(R42 and R43 are each independently selected from the following (Sl)- (S3), and m and n are each independently an integer of 0 to 3) formed by R4'and R5'in combination, #(S1) hydrogen atom, #(S2) -Y411-R44 (R44 is selected from the following (Sal) and (Sa2), and y411 is selected from the following (Lbl) and (Lb2)), '' (Sal) aryl and ##(Sa2) heteroaryl (said aryl and heteroaryl are optionally substituted by 1 to 3 substituents selected from the following <Saal>-<Saa3>, <Saa6>-<Saa8> and <Saal4>-<Saal7>), ###<Saa1> halogen atom, ###<Saa2> C1-6 alkyl, ###<Saa3> halo-C1-6 alkyl, ###<Saa6> C3-12 cycloalkyl, ###<Saa7> hydroxyl, <Saa8> C1_6 alkoxy, ###<Saa14> nitro, ###<Saa15> amino, ###<Saa16> cyano and --<Saal7> carboxyl ##(Lb1) single bond and ##(Lb2) x411 (x411 is selected from the following (Lbal)- (Lba3), (Lba11)-(Lba21) and (Lba23)), ¢ (Lba1) -O-, ... (Lba2)-S-, ### (Lba3) -CO-, ... (Lball)-NR4ll-, ### (Lba12) -CONR411-, ### (Lba13) -NR411CO-, ### (Lba14) -CSNR411-, ### (Lba15) -NR411CS-, ### (Lba16) -SO2NR411-, ### (Lba17) -NR411SO2-, ### (Lba18) -OCONR411-,

### (Lba19) -NR411CO2-, ### (Lba20) -NR411CONR412-, ###(Lba21) -NR411CSNR412- (R411, R412 are each hydrogen atom) and ###(Lba23) 4 to 7-membered divalent saturated heterocycle; or (S3) benzene ring formed by R42 and R43 together with the adjacent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Scl>-<Sc3>, <Sc6>- <Sc8> and <Scl4>-<Scl7>), ##<Sc1> halogen atom, ##<Sc2> C1-6 alkyl, ##<Sc3> halo-C1-6 alkyl, ##<Sc6> C3-12 cycloalkyl, ##<Sc7> hydroxyl, ##<Sc8> C1-6 alkoxy, "<Scl4> nitro, "<Scl5> amino, "<Scl6> cyano and "<Scl7> carboxyl; provided that, when R''and R'are hydrogen atoms and R3'is cyclopropyl, then the combination of one of R4'and R5'being isopropyl or tert-butyl, and the other being hydrogen atom does not occur, and when R''and R2'are hydrogen atoms and R3'is cyclobutyl, then the combination of one of R4'and R5'being tert- butyl, and the other being hydrogen atom does not occur, or a salt thereof.

The compound of the present invention and a salt thereof encompasses a prodrug and a solvate thereof.

In the compounds [I] of the present invention, R, is preferably hydrogen atom, Cl_6 alkyl or 3-12 cycloalkyl, more preferably hydrogen atom, Cl-4 alkyl, C3-6 cycloalkyl or adamantyl, particularly preferably hydrogen atom.

R is preferably hydrogen atom, C1-6 alkyl or C3_l2 cycloalkyl, particularly preferably CI-4 alkyl.

R3 is preferably C1-6 alkyl or 03-1. 2 cycloalkyl, particularly

preferably C3-5 cycloalkyl.

R4 is preferably hydrogen atom, C1-6 alkyl or 3-12 cycloalkyl (cycloalkyl is preferably further substituted by-Y42-R41), particularly preferably substituted C3-1. 2 cycloalkyl.

R5 is preferably hydrogen atom, C1-6 alkyl or C3-12 cycloalkyl, particularly preferably hydrogen atom.

Of R\ R"and R , at least one is preferably a group other than hydrogen atom, and the group is preferably Cl_4 alkyl, C3-6 cycloalkyl or adamantyl.

The form of the compound of the present invention is a compound per se, a prodrug of the compound, a salt of the compound, a salt of a prodrug of the compound, a solvate of the compound, a solvate of a salt of the compound, a solvate of a prodrug of the compound or a solvate of a salt of a prodrug of the compound, preferably a compound per se, a salt of the compound, a solvate of the compound, or a solvate of a salt of the compound, particularly preferably a compound per se or a salt of the compound.

The definition of the terms used in the present specification are as follows.

The"Cl_6 alkyl"means a straight chain or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like, with preference given to Cri-4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The"halogen atom"is fluorine atom, chlorine atom, bromine atom or iodine atom. Preferred are fluorine atom, chlorine atom and bromine atom and particularly preferred is fluorine atom.

The"C3-12 cycloalkyl"means cyclic alkyl having 3 to 12 carbon atoms and may be a fused ring. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like can be mentioned, with preference given to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl.

The"3-12 cycloalkyl Cl_6 alkyl"; means a group wherein the

aforementioned"Ci-g alkyl"'is substituted by the aforementioned "3-12 cycloalkyl", such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, adamantylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, adamantylethyl and the like.

The"Cl-6 alkoxy"used alone or in a compound word means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- butoxy, tert-butoxy, pentyloxy, tert-pentyloxy or hexyloxy and the like, with preference given to Cl-4 alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy.

The"Cl_6 alkylthio"means a straight chain or branched chain alkylthio having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, tert-pentylthio, hexylthio and the like, with preference given to C1-4 alkylthio selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio and tert-butylthio.

The C1_6 alkylene"means a straight chain or branched chain alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethane-1, 1-diyl, 1-methylethane-1, 1-diyl and the like, with preference given to C14alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethane-1, 1-diyl, 1-methylethane-1, 1-diyl and the like.

The"2-6 alkenylene"is a straight chain or branched chain alkenylene having 2 to 6 carbon atoms, such as-CH=CH-,-CH=CH- CH2-,-CH2-CH=CH-,-C (CH3) =CH-CH2-,-CH=CH-CH2-CH2-,-CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=C(CH3)-CH2-, pentenylene, hexenylene and the like, preferably C2_4 alkenylene such as-CH=CH-,-CH=CH-CH2-,-CH2- CH=CH-, -C (CH3) =CH-CH2-,-CH=CH-CH2-CH2-,-CH2-CH=CH-CH2-,-CH2-CH2- CH=CH-,-CH=C (CH3)-CH2-and the like.

The "C2-6 alkynylene" is a straight chain or branched chain

alkynylene having 2 to 6 carbon atoms, such as ethynylene, 1- propyn-1, 3-diyl and the like, with preference given to C2-4 alkynylene.

The"3-12 cycloalkylene"is a cyclic alkylene having 3 to 12 carbon atoms and may be a fused ring. For example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, adamantanediyl and the like can be mentioned, with preference given to cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and adamantanediyl.

The"C1_6 alkanetriyl"is a straight chain or branched chain alkanetriyl having 1 to 6 carbon atoms, such as methanetriyl, ethane-1, 1, 2-triyl, ethane-1, 1, 1-triyl, propane-1, 1, 3-triyl, propane-1, 2,3-triyl, 1-methylethane-1, 1, 2-triyl, propane-1,1, 1- triyl, butane-1, 1, 4-triyl, butane-1, 2,4-triyl, butane-l, 1, 1-triyl, pentane-1, 3,5-triyl, hexane-1, 3,6-triyl and the like, with preference given to C1_4alkanetriyl.

The"C2_6 alkenetriyl"is a straight chain or branched chain alkenetriyl having 2 to 6 carbon atoms, such as and the like, with preference given to 2-4 alkenetriyl.

The C3_12 cycloalkanetriyl"is a cyclic alkanetriyl having 3 to 12 carbon atoms and may be a fused ring. For example, cyclopropanetriyl, cyclobutanetriyl, cyclopentanetriyl, cyclohexanetriyl, cycloheptaneriyl, adamantanetriyl and the like can be mentioned, with preference given to cyclopropanetriyl, cyclobutanetriyl, cyclopentanetriyl, cyclohexanetriyl and adamantanetriyl.

The"aryl"is an aromatic hydrocarbon group having 6 to 12 carbon atoms, and may be partially saturated. For example, phenyl, biphenyl, indenyl, naphthyl and the like can be mentioned.

Preferred are phenyl and naphthyl, and particularly preferred is.

phenyl. The position of binding of aryl and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The"arylene"is a divalent aromatic hydrocarbon group having 6 to 12 carbon atoms and may be partially saturated. For example, phenylene, biphenyldiyl, naphthalenediyl and the like can be mentioned. Preferred are phenylene and naphthalenediyl, and particularly preferred phenylene. The position of binding of arylene and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The"arenetriyl"is a trivalent aromatic hydrocarbon group having 6 to 12 carbon atoms, and may be partially saturated. For example, benzenetriyl, biphenyltriyl, naphthalenetriyl and the like can be mentioned. Preferred are benzenetriyl and naphthalenetriyl, and particularly preferred is benzenetriyl. The position of binding of arenetriyl and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The"aryloxy"is a group wherein the aforementioned"aryl" is bonded via an oxygen atom. For example, phenyloxy, biphenyloxy, indenyloxy, naphthyloxy and the like can be mentioned. Preferred are phenyloxy and naphthyloxy and particularly preferred is phenyloxy. When the aryloxy has a substituent, the position of substituent is not particularly limited as long as it is chemically acceptable.

The"aralkyl"is a group wherein the aforementioned C1_ 6alkyl"is substituted by the aforementioned"aryl". For example, benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2- phenylpropyl, 4-phenylbutyl, indenylmethyl, naphthylmethyl, 2- naphthylethyl, 4-biphenylmethyl, 3- (4-biphenyl) propyl, 2,3- dihydroindenylmethyl, 1,2, 3, 4-tetrahydronaphthylmethyl and the like can be mentioned, with preference given to benzyl and phenethyl. When the aralkyl has a substituent, the position of

substituent is not particularly limited as long as it is chemically acceptable.

The"aralkyloxy"is a group wherein the aforementioned"Cl- 6alkoxy"is substituted by the aforementioned"aryl". For example, benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3-phenylpropoxy, 2-phenylpropoxy, 4-phenylbutoxy, indenylmethoxy, naphthylmethoxy, 2-naphthylethoxy, 4-biphenylmethoxy, 3- (4-biphenyl) propoxy, 2,3- dihydroindenylmethoxy, 1,2, 3,4-tetrahydronaphthylmethoxy and the like can be mentioned, with preference given to benzyloxy and phenethyloxy.

The"heteroaryl"used alone or in a compound word means a 5- or 6-membered unsaturated ring group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom in the ring, and may be a fused ring with a benzene ring or other heterocycle. As the heteroaryl, for example, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl and the like can be mentioned, with preference given to benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, pyridyl and quinolyl. The position of binding of heteroaryl and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The"heteroaryloxy"is a group wherein the aforementioned "heteroaryl"is bonded via oxygen atom, such as pyrrolyloxy, furyloxy, thienyloxy, imidazolyloxy, oxazolyloxy, thiazolyloxy, pyrazolyloxy, isoxazolyloxy, isothiazolyloxy, oxadiazolyloxy, triazolyloxy, indolyloxy, tetrazolyloxy, benzofuryloxy, benzothienyloxy, benzimidazolyloxy, benzoxazolyloxy, benzothiazolyloxy, pyridyloxy, pyrimidinyloxy, pyridazinyloxy, pyrazinyloxy, quinolyloxy, isoquinolyloxy and the like, with preference given to benzofuryloxy, benzothienyloxy,

benzoxazolyloxy, benzothiazolyloxy, pyridyloxy and quinolyloxy. The position of binding of heteroaryloxy and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The heteroaryl-C16 alkyl"is a group wherein the aforementioned"C1_6 alkyl"is substituted by the aforementioned "heteroaryl". For example, pyrrolylmethyl, pyrrolylethyl, furylmethyl, furylethyl, imidazolylmethyl, imidazolylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, pyrazolylmethyl, pyrazolylethyl, isoxazolylmethyl, isoxazolylethyl, isothiazolylmethyl, isothiazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, indolylmethyl, indolylethyl, benzofurylmethyl, benzofurylethyl, benzothienylmethyl, benzothienylethyl, benzimidazolylmethyl, benzimidazolylethyl, benzoxazolylmethyl, benzoxazolylethyl, benzothiazolylmethyl, benzothiazolylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyridazinylmethyl, pyridazinylethyl, pyrazinylmethyl, pyrazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl and the like can be mentioned.

The heteroaryl-C1_6 alkoxy"is a group wherein the aforementioned C1_6 alkoxy"is substituted by the aforementioned "heteroaryl". For example, pyrrolylmethoxy, pyrrolylethoxy, furylmethoxy, furylethoxy, imidazolylmethoxy, imidazolylethoxy, oxazolylmethoxy, oxazolylethoxy, thiazolylmethoxy, thiazolylethoxy, pyrazolylmethoxy, pyrazolylethoxy, isoxazolylmethoxy, isoxazolylethoxy, isothiazolylmethoxy, isothiazolylethoxy, oxadiazolylmethoxy, oxadiazolylethoxy, triazolylmethoxy, triazolylethoxy, tetrazolylmethoxy, tetrazolylethoxy, indolylmethoxy, indolylethoxy, benzofurylmethoxy, benzofurylethoxy, benzothienylmethoxy, benzothienylethoxy, benzimidazolylmethoxy, benzimidazolylethoxy, benzoxazolylmethoxy, benzoxazolylethoxy, benzothiazolylmethoxy, benzothiazolylethoxy, pyridylmethoxy,

. pyridylethoxy, pyrimidinylmethoxy, pyrimidinylethoxy, pyridazinylmethoxy, pyridazinylethoxy, pyrazinylmethoxy, pyrazinylethoxy, quinolylmethoxy, quinolylethoxy, isoquinolylmethoxy, isoquinolylethoxy and the like can be mentioned.

The halo-C16 alkyl"is a haloalkyl wherein the aforementioned"C1_6 alkyl"is substituted by the aforementioned "one or more halogen atoms", wherein the position of substitution of the halogen atom is not particularly limited as long as it is chemically acceptable. As the halo-C1_6 alkyl", for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2, 2-trifluoroethyl, 2- chloroethyl, 2,2-dichloroethyl, 2, 2,2-trichloroethyl, 2- bromomethyl, 2,2-dibromomethyl, 2,2, 2-tribromomethyl, 3- chloropropyl or 4-chlorobutyl and the like can be mentioned, with preference given to halo-C12 alkyl selected from trifluoromethyl and 2,2, 2-trichloroethyl.

The"3-to 7-membered saturated heterocycle"is a ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. For example, aziridine, azetidine, pyrrolidine, piperidine and hexahydroazepine and the like having one nitrogen atom as the hetero atom, and oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, morpholine, thiomorpholine, piperazine, tetrahydrooxazepine, tetrahydrothiazepine, hexahydrodiazepine and the like, which further have oxygen atom, sulfur atom and/or nitrogen atom as hetero atom (s), can be mentioned. The position of binding of heterocycle and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The"4 to 7-membered saturated heterocycle"is a ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and.

. sulfur atom. For example, azetidine, pyrrolidine, piperidine and hexahydroazepine and the like having one nitrogen atom as a hetero atom, and oxazolidine, thiazolidine, imidazolidine, morpholine, thiomorpholine, piperazine, tetrahydrooxazepine, tetrahydrothiazepine, hexahydrodiazepine and the like, which further have oxygen atom, sulfur atom and/or nitrogen atom as hetero atom (s), can be mentioned. The position of binding of heterocycle is not particularly limited as long as it is chemically acceptable.

The"heterocycle"is a ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, may be saturated or unsaturated, and may be a fused ring with a carbon ring, which is preferably 3-to 12-membered, more preferably 4-to 10-membered heterocycle.

As a monocyclic saturated heterocycle, a 3-to 7-membered saturated heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom can be mentioned. For example, a 3-to 7-membered (preferably 5-or 6-membered) saturated heterocycle having 1 to 3 nitrogen atoms (e. g., aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, hexahydroazepine, hexahydrodiazepine and the like), a 3-to 7-membered (preferably 5 or 6-membered) saturated heterocycle having 1 or 2 nitrogen atoms and one hetero atom selected from oxygen atom and sulfur atom (e. g., oxazolidine, thiazolidine, morpholine, thiomorpholine, tetrahydrooxazepine, tetrahydrothiazepine and the like), and a 3-to 7-membered (preferably 5-or 6-membered) saturated heterocycle having 1 or 2 hetero atoms selected from oxygen atom and sulfur atom (e. g., tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, tetrahydropyran, tetrahydrothiophene and the like) can be mentioned.

As the monocyclic saturated heterocycle, preferred is a 5- or 6-membered saturated heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, more preferred are pyrrolidine, pyrazolidine, piperidine, imidazolidine,

morpholine, thiomorpholine, piperazine and the like.

As a monocyclic unsaturated heterocycle, a 3-to 7-membered unsaturated heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom can be mentioned. For example, a 3-to 7-membered (preferably 5-or 6-membered) unsaturated heterocycle having 1 to 3 nitrogen atoms (e. g., pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrroline, imidazoline, pyrazoline and the like), a 3-to 7-membered (preferably 5-or 6- membered) unsaturated heterocycle having 1 or 2 nitrogen atoms and one hetero atom selected from oxygen atom and sulfur atom (e. g., oxazole, thiazole, isoxazole, isothiazole, oxadiazole, thiadiazole, oxazoline, thiazoline and the like), and a 3-to 7-membered (preferably 5 or 6-membered) unsaturated heterocycle having 1 or 2 hetero atoms selected from oxygen atom and sulfur atom (e. g., furan, thiophene and the like) can be mentioned.

As the monocyclic unsaturated heterocycle, preferred is a 5- or 6-membered aromatic heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, more preferred are imidazole, thiazole, oxazole, tetrazole, pyridine, pyrimidine, pyrazine and the like.

As a fused heterocycle, a 8-to 12-membered saturated or unsaturated fused heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom can be mentioned.

It may be a fused ring of a saturated or unsaturated heterocycle and a saturated or unsaturated carbon ring such as a benzene ring, a cyclopentane ring, a cyclohexane ring and the like, or a fused ring of saturated or unsaturated heterocycles. For example, a 8- to 12-membered (preferably 9-or 10-membered) saturated or unsaturated fused heterocycle having 1 to 3 nitrogen atoms (e. g., indole, isoindole, benzimidazole, benzotriazole, indazole, indolizine, quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, phthalazine, quinolizine, naphthyridine, pyrazolopyridine, pyrazolopyrimidine, ; imidazopyridine, indoline,

. isoindoline, 2, 3- dihydrobenzimidazole, 1,2, 3-, 4- tetrahydroquinoline, 1,2, 3,4-tetrahydroisoquinoline, 4,5, 6,7- tetrahydroindole, 4,5, 6,7-tetrahydroisoindole, 4,5, 6,7- tetrahydrobenzimidazole and the like), a 8-to 12-membered (preferably 9-or 10-membered) saturated or unsaturated fused heterocycle having 1 or 2 nitrogen atoms and one hetero atom selected from oxygen atom and sulfur atom (e. g. , benzoxazole, benzothiazole, 2,3-dihydrobenzoxazole, 2,3-dihydrobenzothiazole, 4,5, 6,7-tetrahydrobenzoxazole, 4,5, 6,7-tetrahydrobenzothiazole and the like), a 8-to 12-membered (preferably 9-or 10-membered) saturated or unsaturated fused heterocycle having 1 or 2 hetero atoms selected from oxygen atom and sulfur atom (e. g. , benzofuran, benzothiophene, 2,3-dihydrobenzofuran, 2, 3-dihydrobenzothiophene, 4,5, 6,7-tetrahydrobenzofuran, 4,5, 6,7-tetrahydrobenzothiophene, chroman, isochroman and the like) can be mentioned.

As the fused heterocycle, preferred is a 9-or 10-membered saturated or unsaturated fused heterocycle having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and more preferred are benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, quinoline, 3a, 4,5, 6,7, 7a- hexahydrobenzothiazole, 3a, 4,5, 6,7, 7a-hexahydrobenzoxazole, octahydrobenzoxazole, octahydrobenzothiazole and the like.

The"heterocyclyl"is preferably the aforementioned "heteroaryl", and more preferably benzofuryl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, pyridyl or quinolyl.

The"divalent heterocycle"is the aforementioned "heterocycle"having two bonds, and the"trivalent heterocycle"is the aforementioned"heterocycle"having three bonds.

The position of binding of heterocycle and the position of substituent, when a substituent is present, are not particularly limited as long as they are chemically acceptable.

The heterocyclyl-C1_6 alkyl"is a group wherein the aforementioned C1_6 alkyl"is substituted by the aforementioned "heterocyclyl", and, for example, those exemplified as the

aforementioned "heteroaryl-C1-6 alkyl" can be mentioned. The "heterocyclyl-Cl_6 alkyl"is preferably the aforementioned heteroaryl-C1_6 alkyl".

The"heterocyclyl-C1_6 alkoxy"is a group wherein the aforementioned"Ci_6 alkoxy"is substituted by the aforementioned "heterocyclyl". For example, those exemplified as the aforementioned"heteroaryl-C16 alkoxy"can be mentioned. The "heterocyclyl-C1_6 alkoxy"is preferably the aforementioned "heteroaryl-Cl_6 alkoxy".

The"heterocyclyloxy"is a group wherein the aforementioned "heterocyclyl"is bonded via oxygen atom. For example, those exemplified as the aforementioned"heteroaryloxy"can be mentioned.

The"heterocyclyloxy"is preferably the aforementioned "heteroaryloxy".

The"amido"is a group represented by-NHCO-R21 (R21 is hydrogen atom, C1_6 alkyl or aryl). For example, formamido, acetamido, propaneamido, butaneamido, pentaneamido, hexaneamido, benzamido and the like can be mentioned.

A"prodrug"of a compound means a group chemically or metabolically decomposed and a derivative of the compound of the present invention that shows pharmaceutical activity after hydrolysis or solvolysis, or decomposition under physiological conditions. An ester of carboxylic acid and/or phosphoric acid of the compound [I] of the present invention can be a prodrug, and can be convered to carboxylic acid and/or phosphoric acid in living organisms.

A"pharmaceutically acceptable salt"of the compound or prodrug includes, but not limited to, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate and the like ; organic acid addition salts such as acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, ascorbate and the like; amino acid addition salts such as aspartat, glutamate and the

like; salts with inorganic base such as sodium, potassium, calcium, magnesium, zinc and the like; salts with organic base such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, tris (hydroxymethylamino) methane, dicyclohexylamine, ethylenediamine, guanidine, meglumine, 2- aminoethanol and the like; and salts with amino acid such as aspartic acid, glutamic acid, arginine, histidine, lysin and the like.

The present invention encompasses a solvate. As used herein, a"solvate"of a compound or a prodrug or a salt thereof means, in a solid state of crystal, amorphous form and the like or a solution, one wherein the compound of the present invention is bound with a solvent molecule of water, alcohol and the like, by a relatively weak bond of van der Waals force, electrostatic interaction, hydrogen bond, charge-transfer bond, coordinate bond and the like. In some cases, the solvate may be one wherein a solvent is taken into a solid state such as a water-containing product, an alcohol-containing product and the like. As the "solvate"of the compound, preferred is a hydrate.

As the"therapeutic drug for diabetes, therapeutic drug for diabetic complication, therapeutic drug for hyperlipidemia or anti-obesity drug", insulin preparation (injection), low-molecular insulin preparation (oral agent), sulfonylurea receptor agonist (SU drugs), rapid acting insulin secretion promoter (e. g., nateglide), a-glucosidase inhibitor, insulin sensitivity enhancer, PPARo, receptor agonist, PPARy receptor agonist/antagonist, PPAR8 receptor agonist, tGLP-1 receptor agonist, glucagon receptor antagonist, glucocorticoid receptor antagonist, biguanide, SGLUT inhibitor, fructose-1, 6-bisphosphatases (FBPase) inhibitor, glycogen synthase kinase 3 (GSK-3) inhibitor, phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, protein tyrosine phosphatase 1B (PTPase 1B) inhibitor, SH2 domain-containing inositol phosphatase (SHIP2) inhibitor, AMP-activated protein kinase (AMPK) activator, glycogen phosphorylase (GP) inhibitor, glucokinase activator, llß-

HSD-1 inhibitor, GPR40 receptor agonist, pyruvate dehydrogenase kinase (PDHK) inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, diacylglycerol acyltransferase (DGAT) inhibitor, cholesteryl ester transfer protein (CETP) inhibitor, HMG-CoA reductase inhibitor, p3 adrenaline receptor agonist, apolipoprotein-A1 (Apo-A1) inducer, lipoprotein lipase (LPL) activator, glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist, leptin receptor agonist, bombesin receptor subtype 3 (BRS-3) agonist, perilipin inhibitor, acetyl-CoA carboxylase 1 (ACC1) inhibitor, acetyl-CoA carboxylase 2 (ACC2) inhibitor, melanocortin (MC) receptor agonist, neuropeptide Y5 (NPY5) receptor antagonist, adiponectin receptor agonist, protein kinase ß (PKCß) inhibitor, endothelial lipase inhibitor, angiotensin II receptor antagonist, aldose reductase inhibitor, angiotensin conversion enzyme (ACE) inhibitor, advanced glycation end products (AGE) production suppressant, glutamine/fructose-6- phosphate aminotransferase (GFAT) inhibitor, uncoupling protein (UCP) inducer/activator and the like can be mentioned.

The compound [I] of the present invention may contain various isomers, such as optical isomers, stereoisomers such as trans or cis isomers or S or R optical isomers or enantiomeric or diastereomeric forms or in mixtures thereof, geometric isomers, tautomers and the like. The present invention encompasses all of these isomers and mixtures thereof.

Now, the production methods of compound [I] of the present invention are specifically explained. It is needless to say that the present invention is not limited by these production methods.

For production of the compound of the present invention, the production can be started from a part that permits easily production. When a reactive functional group is involved in each step, protection and deprotection are appropriately performed, and to promote progress of the reaction, a reagent other than the exemplified reagents can be appropriately used. In some cases, a reagent immobilized on polystyrene or silica gel may be used to

facilitate the work-up. The compound obtained in each step can be isolated and purified by conventional methods (e. g. , extraction, concentration, filtration, recrystallization, column chromatography, thin layer chromatography etc. ). Where desired, the compound may be used in the next step without isolation and purification.

Scheme 1 H L 'K RNH2 s te 1 2 R 6 L1 3 3 step 1 step wherein L1 is a leaving group such as halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy and the like, and other symbols are as defined above.

Step 1 Compound (6) can be obtained by reacting compound (2) or compound (3) with compound (4) or compound (5) in a solvent such as N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane and the like in the presence of a base, such as amines (e. g. , triethylamine, diisopropylethylamine and the like) or an inorganic base (e. g., potassium carbonate, sodium hydrogen carbonate and the like), or using compound (2) or compound (3) itself as a base. In this case, a reaction additive such as sodium iodide and the like can be added to promote the reaction. The reaction is carried out at 0°C to 100°C.

Step 2 Compound [I] can be obtained from compound (6) and compound

. (7) using a conventional amidation reaction. A solvent such as N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. Examples of the amidation agent include 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, O-benzotriazol-1-yl-N, N, N', N'- tetramethyluronium hexafluorophosphate, (benzotriazol-1- yloxy) tripyrrolidinophosphonium hexafluorophosphate, carbonyl diimidazole, carbodiimide resin and the like. In some cases, an activator such as 1-hydroxybenzotriazole, hydroxysuccinimide, 4- dimethylaminopyridine and the like can be used. In this case, a base can be used and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, and inorganic bases such as potassium carbonate, sodium hydrogen carbonate and the like. The reaction can be carried out at-50°C to 50°C.

Compound [I] can be also obtained by treating compound (7) with a halogenating agent such as thionyl chloride, phosphorus trichloride and the like to give an acid halide, which is then condensed with compound (6). In this case, a base can be used, and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as potassium carbonate, sodium hydrogen carbonate and the like, and the like. A solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. When a base is a liquid, the base itself can be used as a solvent. The reaction can be carried out at-50°C to 50°C.

In addition, compound [I] can be obtained by reacting compound (7) with chlorocarbonate, pivaloy chloride, p- toluenesulfonyl chloride and the like to give a mixed acid anhydride, which is then amidated with compound (6). In this case, a base can be used, and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as potassium carbonate, sodium hydrogen

carbonate and the like, and the like. A solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. The reaction can be carried out at-50°C to 50°C.

Scheme 2 R=0 R30 R2 2 step 1'R2 HN 2 1 2 9 W-N 3 wherein each symbol is as defined above.

Step 1' Compound (6) can be prepared by reacting compound (2) or compound (3) with compound (8) or compound (9), followed by reduction. As the reduction, for example, a method using a reducting agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like, a hydrogenation reaction using a metal catalyst such as palladium and the like can be mentioned. Optionally, an acid such as acetic acid and the like may be added to promote the reaction. A solvent that does not affect the reaction, such as ethanol, methanol, tetrahydrofuran, dioxane, water, chloroform and the like can be mentioned. The reaction can be carried out at-20°C to 100°C.

Scheme 3

wherein R2"is hydrogen atom or C1_5 alkyl, and R3 is as defined above.

Compound (12), which is a compound (6) wherein R2 is CI-6 alkyl, can be obtained by reduction of compound (11). As the reducing agent, lithium aluminum hydride, sodium borohydride, borane and the like can be mentioned. A solvent such as diethyl ether, dioxane, tetrahydrofuran and the like can be used. The reaction can be carried out at 0°C to 100°C.

Scheme 4 H R, NCO, razz Fe 13 H 2 H NI R step 3 R 6 H R1 Ruz 13 step (I) wherein Rp1 is an amino protecting group such as tert- butoxycarbonyl, benzyloxycarbonyl and the like, L is a leaving group such as halogen atom, methanesulfonyloxy, p- toluenesulfonyloxy and the like and other symbols are as defined above.

Step 2' Compound (14) can be obtained by reacting under the same conditions as described in Step 2 and using compound (13) instead of compound (7) shown in Step 2 of the aforementioned Scheme 1.

Step 3 Compound (16) can be obtained by reacting compound (14) and compound (15) under the same conditions as described in Step 1 of the aforementioned Scheme 1.

Step 4 In this step, compound [I] is introduced by removing an amino protecting group Rpl, and a conventional deprotection method can be used. For example, when Rpl is a group deprotected by an acid, such as tert-butoxycarbonyl, trityl, o-nitrobenzenesulfenyl and the like, the deprotection can be performed using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. A solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, acetic acid, N, N- dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like can be mentioned. In this case, the deprotection can be performed using an acid appropriately diluted with or dissolved in an organic solvent or water. The reaction can be carried out at-50°C to 50°C.

When, Rpl is a group deprotected by a hydrogenation reaction using benzyloxycarbonyl and the like, it can be deprotected by a hydrogenation reaction using metal catalyst such as palladium and the like. A solvent that does not affect the reaction, such as ethanol, methanol, tetrahydrofuran, ethyl acetate, acetic acid and the like can be used. The reaction can be also carried out using ammonium formate, cyclohexene and the like, besides a method using a hydrogen gas under atomospheric pressure or under pressure condition. The reaction can be carried out at 0°C to 100°C.

When, Rpl is a protecting group deprotected by a base such as fluorenylmethoxycarbonyl and the like, it can be deprotected using a base such as diethylamine, piperidine, ammonia, sodium hydroxide, potassium carbonate and the like. These bases can be used as they are, or after dilution with, dissolution in or suspending in a solvent. A solvent such as water, ethanol,

methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like can be used. The reaction can be carried out at 0°C to 100°C.

When, Rpl is a group deprotected by a metal catalyst such as allyloxycarbonyl and the like, it can be deprotected using tetrakis (triphenylphosphine) palladium and the like as a catalyst or reagent. In this case, a solvent that dose not affect the reaction (e. g. , dichloromethane, chloroform, tetrahydrofuran and the like) is used. The reaction can be carried out at 0°C to 100°C.

Scheme 5 wherein is, of the parts represented by R4, a part that is bonded to and also adjacent to -CONR411-, -NR411CO-, -CSNR411-, 15 NR411CS-, -NR411SO2-, -SO2NR411-, -NR411CO2-, -OCONR411-, -NR411CONR412- or -NR411CSNR412-, is, of the parts represented by R4, a part t

on the end via -CONR411-, -NR411CO-, -CSNR411-, -NR411CS-, -NR411SO2-, -SO2NR411-, -NR411CO2-, -OCONR411-, -NR411CONR412- or -NR411CSNR412-, R411, is hydrogen atom or optionally substituted Cl_6alkyl, R4ll''is optionally substituted Cl_6alkyl, and other symbols are as defined above.

Compound (19) can be obtained by reduction of compound (17) or (18). In the case of compound (17), compound (19) can be obtained by a method comprising hydrogenation using a catalyst such as palladium on carbon, palladium black, palladium hydroxide on carbon and the like, a method comprising combining a metal, such as iron, zinc, tin chloride and the like, and an acid, such as hydrochloric acid, acetic acid, ammonium chloride and the like, a method using sodium hydrosulfite, and the like. As the solvent, a solvent that does not influence the reaction, such as methanol, ethanol, tetrahydrofuran, water, ethyl acetate and the like, can be used. The reaction can be carried out at 0°C to 100°C.

In the case of compound (18), compound (19) can be obtained by a method comprising hydrogenation using a catalyst such as palladium on carbon, palladium black, palladium hydroxide on carbon and the like, a method using a reducing agent such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, a method using triphenylphosphine as a reducing agent, and the like. A solvent that does not affect the reaction, such as methanol, ethanol, tetrahydrofuran, water, ethyl acetate and the like can be used, The reaction can be carried out at 0°C to 100°C.

When a compound wherein R411 is optionally substituted Ci_ 6alkyl is desired, compound (21) can be obtained by the method shown in the aforementioned Scheme 2, Step 1'and using compound (19) and compound (20).

Compound (23) can be obtained by the method shown in the aforementioned Scheme 1, Step 2 and using compound (19) or compound (21) and compound (22).

Scheme 6

wherein each symbol is as defined above.

Compound (26) can be obtained by the method shown in the aforementioned Scheme 1, Step 2, and using compound (24) and compound (25).

Scheme 7 wherein each symbol is as defined above.

Compound (27) can be obtained by reacting a sulfidizing agent such as Lawesson's reagent, phosphorus pentasulfide and the like with compound (23). In this case, a solvent that does not affect the reaction such as methanol, tetrahydrofuran, dioxane and the like can be used as a solvent. The reaction can be carried out at 0°C to 100°C. The moiety easily affected by this reaction can be appropriately protected in advance. In addition, the order of production may be changed as appropriate.

Scheme 8

wherein each symbol is as defined above.

Compound (28) can be obtained by the method shown in the aforementioned Scheme 7 and using compound (26).

Scheme 9

wherein L3 is a leaving group such as halogen atom and the like and other symbols are as defined above.

Compound (31) can be obtained by reacting compound (21) with compound (30). In this case, a base can be used, and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as potassium carbonate, sodium hydrogen carbonate and the like, and the like. A solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. When the base is a liquid, the base itself can be used as a solvent. The reaction can be carried out at-50°C to 50°C.

Scheme 10

wherein each symbol is as defined above.

Compound (34) can be obtained by reacting carbamoyl halide (32) obtained from compound (21), or isocyanate (36) obtained from compound (24) with compound (33).

In the case of compound (21), phosgene, triphosgene, 1, 1'- carbonyldiimidazole and the like are reacted to give compound (32), which is then reacted with compound (33) to give compound (34).

In this case, a base can be used, and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as potassium carbonate, sodium hydrogen carbonate and the like, and the like. A solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. The reaction can be carried out at-50°C to 50°C.

Compound (34) can be also obtained by the method shown in the aforementioned Scheme 1, Step 1, and using compound (21) and compound (35).

In the case of compound (24), compound (38) can be obtained by reacting compound (33) with compound (36) obtained by reacting lithium azide or sodium azide with an acid halide obtained by

treating a halogenation agent such as thionyl chloride, phosphorus trichloride and the like or a mixed acid anhydride obtained by reacting with chlorocarbonate, pivaloyl chloride, p- toluenesulfonyl chloride and the like, or by heating acid azide obtained by reacting diphenylphosphoryl azide with compound (24).

In this case, a base can be used, and examples of the base include amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as potassium carbonate, sodium hydrogen carbonate and the like, and the like can be mentioned. A solvent such as tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl acetate and the like can be used. The reaction can be carried out at 0°C to 100°C.

When a compound wherein R41l is optionally substituted C1_ 6alkyl is desired, compound (34) can be obtained by the method shown in the aforementioned Scheme 1, Step 1, and using compound (38) and compound (37).

Scheme 11 wherein each symbol is as defined above.

Compound (42) can be obtained by the method shown in the aforementioned Scheme 10, and using compound (39) and compound (40) or compound (41).

Compound (40) can be obtained from compound (25) by the same

method to obtain compound (32) as shown in the aforementioned Scheme 10. In addition, Compound (41) can be obtained from compound (22) by the same method to obtain compound (36) as shown in the aforementioned Scheme 10.

Scheme 12

wehrien R412'is hydrogen atom or optionally substituted C1_6alkyl, R4l2 « is optionally substituted Cl_6alkyl and other symbols are as defined above.

Compound (43) can be obtained by the same method as shown in the aforementioned Scheme 10 and using compound (41) to compound (21).

When a compound wherein R412 is optionally substituted Cl_ 6alkyl is desired, compound (45) can be obtained by reacting compound (43) with compound (44) in the presence of a base. A base such as n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hydride and the like can be used. In addition, sodium iodide and the like may be added to accerelate the reaction. A solvent that does not affect the reaction, such

as tetrahydrofuran, dioxane, diethyl ether, toluene and the like, can be used. The reaction can be carried out at-100°C to 100°C.

Compound (45) can be also obtained by a method comprising reacting compound (21) and compound (46) with phosgene.

Scheme 13

wherein each symbol is as defined above.

Of compounds (45), when compound (47) wherein R411 is hydrogen is desired, it can be obtained by the same method to obtain compound (38) as shown in the aforementioned Scheme 10 and using compound (36) and compound (46).

Scheme 14

wherein each symbol is as defined above.

Compound (50) can be obtained by reacting compound (21) with compound (49). Compound (49) can be obtained by a method using carbon disulfide to compound (48).

When a compound wherein R412 is optionally substituted C1_ 6alkyl is desired, compound (51) can be also obtained by the same method to obtain compound (45) as shown in the aforementioned Scheme 12 and using compound (50) and compound (44).

Scheme 15

wherein each symbol is as defined above.

Compound (51) can be obtained by reacting compound (21) and compound (46) with thiophosgene, or from compound (45) in the same manner as in Scheme 7.

Scheme 16

wherein Rp2 is a carboxyl protecting group such as methyl, benzyl, tert-butyl and the like, and other symbols are as defined above.

Compound (53) can be obtained by oxidation of compound (52).

As an oxidation method, a conventional method for oxidizing alcohol such as a method using dimethyl sulfoxide and oxalyl chloride, a method using dimethyl sulfoxide and a sulfur trioxide- pyridine complex, a method using Dess-Martin reagent, a method using a Jones reagent and the like can be used. When dimethyl

sulfoxide is used, it can be used as a solvent. Alternatively, a solvent that dose not affect the reaction such as dichloromethane, chloroform, acetonitrile, water, tert-butanol and the like can be used. The reaction can be carried out at-78°C to 50°C.

Compound (54) can be obtained by removing the carboxyl protecting group Rp2 of compound (53). As the deprotection method, a conventional deprotection method can be used as long as the amino protecting group Rp1 is not deprotected. For example, when Rpl is a tert-butoxycarbonyl and Rp2 is a protecting group such as methyl, benzyl and the like, which is deprotected by a base, deprotection can be performed using a base such as ammonia, sodium hydroxide, potassium carbonate and the like. These bases can be used as they are, or after dilution, dissolution or suspendeding in a solvent. In this case, as the solvent, water, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like can be used. The reaction can be carried out at 0°C to 100°C.

Compound (55) can be obtained under the similar conditions as the method shown in the aforementioned Scheme 1, Step 2 and using compound (54) and compound (6).

Scheme 17 each symbol is as defined above.

Compound (59) can be obtained by hydrolyzing compound (57)

or isomerizing compound (58).

Compound (57) can be obtained by reacting compound (56) with methoxymethyl triphenylphosphonium chloride, dimethyl (1-diazo-2- oxopropyl) phosphonate and the like in the presence of a base. A base such as sodium dimsyl, n-butyl lithium, 1,8- diazabicyclo [5. 4.0] undec-7-ene, sodium hydride, potassium carbonate, sodium hydroxide and the like can be used. A solvent that dose not affect the reaction such as tetrahydrofuran, dioxane, toluene, methanol, dimethyl sulfoxide, N, N-dimethylformamide and the like can be used. The reaction can be carried out at 0°C to 100°C.

Compound (59) can be obtained by reacting compound (57) with trichloroacetic acid, trifluoroacetic acid, trimethylsilyl iodide and the like. As the solvent, a solvent that is not involved in the reaction such as tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform and the like can be used. The reaction can be carried out at 0°C to 100°C.

Compound (58) can be obtained by reacting compound (56) with trimethylsulfonium chloride, trimethylsulfoxonium chloride and the like in the presence of a base. A base such as sodium dimsyl, n- butyl lithium, 1, 8-diazabicyclo [5.4. 0] undec-7-ene, sodium hydride and the like can be used, and as the solvent, a solvent that dose not affect the reaction such as tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, N, N-dimethylformamide and the like can be used.

The reaction can be carried out at-78°C to-100°C.

Compound (59) can be obtained by reacting compound (58) with a Lewis acid such as boron trifluoride, aluminum chloride, magnesium bromide, titanium tetrachloride and the like. As the solvent, a solvent that is not involved in the reaction such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, dioxane and the like can be used. The reaction can be carried out at 0°C to 100°C.

Scheme 18

wherein each symbol is as defined above.

Compound (60) can be obtained by reduction of compound (59).

A reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, diisopropylaluminum hydride and the like can be used. A solvent that dose not affect the reaction such as methanol, tetrahydrofuran, diethyl ether, toluene, benzene and the like can be used. The reaction can be carried out at 0°C to 100°C.

Scheme 19 is, of the parts represented by R4, a part that is bonded to and also adjacent to-CH2-O-(CH2) d-,-CH2-S- (CH2) d-or-CH2-SO2-(CH2) d-and is, of the parts represented by R4, a part on the end via-CH2-0- (CH2) d-,-CH2-S- (CH2) d-or-CH2- S°2- (CH2) d-, and other symbols are as defined above.

Compound (62) can be obtained by reacting compound (60) with compound (61). In this case, the reaction can be carried out in the presence of one or both of a silver compound such as silver oxide, silver trifluoromethanesulfonate and the like, and a base such as sodium hydride, potassium tert-butoxide, 2,6-lutidine,

2,6-di-tert-butyl-4-methylpyridine and the like. A solvent that dose not affect the reaction such as dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethoxyethane, toluene, benzene, N, N- dimethylformamide and the like can be used. The reaction can be carried out at 0°C to 100°C.

Scheme 20 wherein each symbol is as defined above.

Compound (64) can be obtained by Mitsunobu reaction using compound (60) and compound (63), triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate. A solvent that dose not affect the reaction such as dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethoxyethane and the like can be used. The reaction can be carried out at 0°C to 100°C.

Compound (65) can be obtained by oxidation of compound (64).

As the oxidant, peroxy acids such as m-chloroperoxybenzoic acid, peroxyacetic acid and the like or potassium permanganate can be used. A solvent that dose not affect the reaction such as dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethoxyethane and the like can be used. The reaction can be carried out at 0°C to 100°C.

Scheme 21

wherein each symbol is as defined above.

Compound (67) means compound (62) wherein d is 0. In this case, the following method may be used.

Compound (67) can be obtained by subjecting compound (60) to Mitsunobu reaction using compound (66), triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate. A solvent that dose not affect the reaction such as dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethoxyethane, and the like can be used. The reaction can be carried out at 0°C to 100°C.

In each of the above-mentioned production methods, a compound wherein suitable substituent R1 has been introduced can be produced by producing a compound wherein R1 is an amino protecting group Rpl, and reacting the obtained amino-protected form under the same conditions as for the method shown in Step 3 and Step 4 of the aforementioned Scheme 4. In addition, a compound wherein R1 is hydrogen atom can be obtained by removing the amino protecting group Rp1 from the deprotected amino form under the same conditions as for the method shown in the aforementioned Scheme 4, Step 4.

The thus-obtained compound [I] of the present invention has a superior DPP-IV inhibitory activity. When the compound of the present invention is used as a therapeutic drug for type II diabetes, especially type II diabetes, as well as hyperglycemia, hypoglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases thereof, anxiety, eating disorders, neurodegenerative diseases, as well as various immunomodulatory diseases including psoriasis, multiple sclerosis, rheumatoid arthritis, and chronic inflammatory bowel disease, for

organ transplantation, it is generally administered systemically, or topical, orally or parenterally.

While the dose varies depending on the age, body weight, symptoms, treatment effect, administration method, treatment time and the like, it is generally from 0.01 mg to 10 g, preferably 1 mg to 1 g, for an adult per day, which is orally or parenterally administered once a day to several portions a day.

When the compound of the present invention is processed to give a solid composition for oral administration, a dosage form such as tablet, pill, powder, granule and the like can be employed.

In such a solid composition, one or more active substance is admixed with at least one inactive diluent, dispersant, adsorbent and the like, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminometasilicate, slicon dioxide powder and the like. The composition may be mixed with an additive other than a diluent according to conventional methods.

When a tablet or a pill is to be prepared, it may be coated with a film made from an enteric or gastrosoluble substance as necessary such as sucrose, gelatin, hydroxypropyl cellulose, hydroxymethylcellulose phthalate and the like, or coated with two or more layers. In addition, a capsule made from a substance such as gelatin or ethyl cellulose can be produced.

When a liquid composition for oral administration is desired, a dosage form such as a pharmaceutically acceptable emulsifier, solubilizer, suspension, syrup, elixir and the like can be employed. As the diluent to be used, for example, purified water, ethanol, vegetable oil, emulsifier and the like can be mentioned.

The composition may further contain an auxiliary agent other than diluent, such as humectant, suspension, sweetening agent, flavor, aromatic, preservative and the like.

When an injection for parenteral administration is to be prepared, a sterile aqueous or non-aqueous solution, solubilizer, suspension or emulsifier can be used. ; As an aqueous solution,

solubilizer or suspension, for example, distillated water for injection, physiological saline, cyclodextrin and derivative thereof, organic amines such as triethanolamine, diethanolamine, monoethanolamine, triethylamine and the like, inorganic alkaline solution and the like can be mentioned.

When a water-soluble solution is desired, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol and the like may be also used. As a solubilizer, for example, surfactants (for forming mixed micelle) such as polyoxyethylene hydrogenated castor oil, sucrose esters, fatty acids and the like, or lecithin or hydrogenated lecithin (for forming liposome) and the like can be used. In addition, an emulsion preparation comprising a non-water-soluble solubilizer such as vegetable oil and the like, and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropyleneglycol and the like can be also prepared.

As other composition for parenteral administration, a coating agent such as external liquid and ointment, suppository, pessary and the like, which contains one or more active substances and which can be prepared by a method known per se can be produced.

Compound [I] can be used alone for the treatment of diabetes and may be used in combination with other pharmaceutical components including other therapeutic drugs for diabetes, therapeutic drugs for diabetic complications, therapeutic drugs for hyperlipidemia or anti-obesity drugs. In this case, these compounds are preferably administered as oral preparations, and where necessary, they may be administered in the form of a suppository and the like.

As used herein, the mode of the combined use of compound [I] with the other pharmaceutical components is not particularly limited. For example, it includes both the administration of a pharmaceutical composition containing the compound [I] and the other pharmaceutical components, and the simultaneous or staggered administration of respective preparations produced separately

without mixing.

While the dose of the other pharmaceutical components varies depending on the age, body weight, symptoms, treatment effect, administration method, treatment time and the like, it is generally from 0.01 mg to 10 g, preferably 1 mg to 1 g, for an adult per day, which is orally or parenterally administered once a day to several portions a day.

In this case, as a therapeutic drug for diabetes, a therapeutic drug for diabetic complications, a therapeutic drug for hyperlipidemia and an anti-obesity drug, that can be combined, for example, insulin preparations (injections), low-molecular weight insulin preparations (oral agents), sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues (e. g., nateglide), a-glucosidase inhibitors, insulin sensitizers, PPARa receptor agonists, PPARy receptor agonists/antagonists, PPARb receptor agonists, tGLP-1 receptor agonists, glucagon receptor antagonists, glucocorticoid receptor antagonists, biguanides, SGLUT inhibitors, fructose-1, 6-bisphosphatases (FBPase) inhibitors, glycogen synthase kinase 3 (GSK-3) inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase 1B (PTPase 1B) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llß-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors, p3 adrenaline receptor agonists, apolipoprotein-A1 (Apo-A1) inducers, lipoprotein lipase (LPL) activators, glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists, leptin receptor agonists, bombesin receptor subtype 33 (BRS-3) agonists, perilipin inhibitors, acetyl-CoA carboxylase 1 (ACC1) inhibitors, acetyl-CoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists,

neuropeptide Y5 (NPY5) receptor antagonists,-adiponectin receptor agonists, protein kinase (PKCß) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutamine/fructose-6-phosphate aminotransferase (GFAT) inhibitors, uncoupling protein (UCP) inducers/activators and the like can be mentioned.

Examples The compound [I] and the production method therof of the present invention are explained in detail by referring to the following Examples, which are not to be construed as limitative.

Example 1 Step 1 (2S)-N-Cyclobutyl-N-methyl-2- (tert-butoxycarbonylamino)-2- cyclohexylacetamide N-Methylcyclobutylamine hydrochloride (159 mg) synthesized by the method described in Journal of Medicinal Chemistry, 1994, 37,3482 was dissolved in N, N-dimethylformamide (4 ml), and L- tert-butoxycarbonylcyclohexylglycine hydrate (159 mg), (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (676 mg) and diisopropylethylamine (0.453 ml) were added. The mixture was stirred overnight at room temperature.

The mixture was poured into water and extracted with ethyl acetate.

The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane : ethyl acetate=3: 1) to give

the title compound.

1H-NMR (8ppm, CDC13) 1.13-1. 37 (5H, m), 1.42 (9H, s), 1.59-1. 71 (9H, m), 2.10-2. 29 (4H, m), 4.39-4. 55 (lH, m), 4.80-4. 90 (0. 4H, m), 5.25- 5.33 (0.6H, m).

Step 2 (2S) -N-Cyclobutyl-N-methyl-2-amino-2-cyclohexylacetamide hydrochloride (2S)-N-Cyclobutyl-N-methyl-2- (tert-butoxycarbonylamino)-2- cyclohexylacetamide (280 mg) was suspended in ethyl acetate (1 ml), and a solution of 4N-hydrogen chloride in ethyl acetate was added.

The mixture was stirred for 5 hr at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue and the mixture was stirred. The precipitated solid was collected by filteration, washed with ethyl acetate and dried under reduced pressure to give the title compound.

H-NMR (6ppm, DMSO-d6) 1.03-1. 18 (5H, m), 1.59-1. 73 (8H, m), 1.99- 2.28 (4H, m), 2.88 (1. 7H, s), 2.98 (1. 3H, s), 4.10 (0.4H, d, J=5. 4Hz), 4.26 (0.6H, d, J=5. 4Hz), 4.42-4. 58 (0.6H, m), 4.69-4. 80 (0.4H, m), 8.12 (3H, brs).

Example 29 Step 1 (S)- [ (trans-4-Azidocyclohexyl)- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (S)-N-tert-Butoxycarbonyl- (trans-4-azidocyclohexyl) glycine

(2.72 g) synthesized in accordance with the method described in W002/076450, N-methylcyclobutylamine hydrochloride (1.1 g) synthesized in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and triethylamine (3.17 ml) were dissolved in N, N-dimethylformamide (25 ml), and (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (5.2 g) was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate: hexane=2: 5-1: 2) to give the title compound (2.84 g).

1H-NMR (6ppm, CDCl3) 1.06-1. 37 (4H, m), 1.42 (9H, s), 1.45-1. 80 (5H, m), 1.97-2. 34 (6H, m), 2.92 (1. 8H, s), 2.99 (1. 2H, s), 3.13-3. 24 (lH, m), 4.36-4. 48 (lH, m), 4.51-4. 58 (0.6H, m), 4.78-4. 89 (0.4H, m), 5.26- 5.37 (lH, m).

Step 2 (S)-[(trans-4-Aminocyclohexyl)-(N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (S)- [ (trans-4-Azidocyclohexyl)- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (2.78 g) obtained in Step 1 was dissolved in tetrahydrofuran (55ml)-water (5. 5ml), and triphenylphosphine (2.19g) was added. The mixture was stirred for 17 hrs at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (chloroform: methanol=10: 1-.

chloroform: methanol: 28% aqueous ammonia=10 : 1 :-0. 1) to give the title compound.

1H-NMR (ppm, CDCl3) 0.92-1. 21 (4H, m), 1.42 (9H, s), 1.31-1. 58 (3H, m), 1.58-1. 77 (4H, m), 1.80-1. 92 (2H, m), 2.00-2. 32 (4H, m), 2.51-2. 63 (lH, m), 2.92 (1. 8H, s), 2.99 (1. 2H, s), 4.36-4. 49 (lH, m), 4.50-4. 57 (0.6H, m), 4.78-4. 90 (0.4H, m), 5.23-5. 36 (lH, m).

Step 3 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- (4- nitrobenzenesulfonylamino) cyclohexyl] methyl] carbamic acid tert- butyl ester A solution of (S)- [ (trans-4-aminocyclohexyl)- (N-cyclobutyl- N-methylcarbamoyl) methyl] carbamic acid ter-butyl ester (1.0 g) obtained in Step 2 and triethylamine (614 pu) in chloroform (10 ml) was cooled to 0°C, and a solution of 4-nitrobenzenesulfonyl chloride (783 mg) in chloroform (5 ml) was added dropwise. The mixture was warmed to room temperature with stirring. The reaction mixture was washed with 5% aqueous citric acid solution and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 1-2: 3) to give the title compound (1.7 g).

1H-NMR (8ppm, CDCl3) 0.94-1. 22 (4H, m), 1.30-1. 80 (14H, m), 1.80- 1.93 (2H, m), 1.95-2. 35 (4H, m), 2.84-3. 01 (3H, s), 3.05-3. 23 (lH, m), 4.27-4. 55 (1. 57H, m), 4.59-4. 73 (0.98H, m), 4. 73-4. 92 (0.50H, m), 5.13- 5.35 (0.95H, m), 7.99-8. 10 (2H, d, J=8.8Hz), 8.27-8. 40 (2H, d, J=8.8Hz).

Step 4 (S)- [ [trans-4- (4-Aminobenzenesulfonylamino) cyclohexyl]- (N- cyclobutyl-N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester

To a solution of (S)-[(N-cyclobutyl-N-methylcarbamoyl)- [trans-4- (4-nitrobenzenesulfonylamino) cyclohexyl] methyl] carbamic acid tert-butyl ester (1.6 g) obtained in Step 3 in ethanol (15 ml), 5% palladium on carbon (300 mg) was added. The mixture was stirred overnight under hydrogen atmosphere. The insoluble material was filtered off through celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 3-1 : 5) to give the title compound (1.376 g).

H-NMR (6ppm, CDC13) 0.92-1. 19 (4H, m), 1.21-1. 94 (16H, m), 1.94- 2.32 (4H, m), 2.84-3. 05 (4H, m), 4.11 (2H, s), 4.23-4. 53 (2.66H, m), 4.73- 4.88 (0.42H, m), 5.18-5. 33 (0.92H, m), 6.59-6. 74 (2H, d, J=8.8Hz), 7.53- 7.71 (2H, d, J=8.8Hz).

Step 5 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2, 2,2- trifluoroethanesulfonylamino) benzenesulfonylamino] cyclohexyl]- methyl] carbamic acid tert-butyl ester A solution of (S)- [ [trans-4- (4- aminobenzenesulfonylamino) cyclohexyl]- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (150 mg) obtained in Step 4 and pyridine (50 nl) in chloroform (1.5 ml) were cooled to 0°C, and 2,2, 2-trifluoroethanesulfonyl chloride (41

nl) was added thereto. The mixture was warmed to room temperature with stirring. The reaction mixture was washed with 5% aqueous citric acid solution and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 2) to give the title compound (185 mg).

1H-NMR (8ppm, CDC13) 0.97-1. 20 (4H, m), 1.30-1. 92 (16H, m), 1.96- 2.32 (4H, m), 2. 85-3.00 (3H, s), 3.00-3. 14 (lH, m), 3.79- 3.93 (2H, q, J=8. OHz), 4.30-4. 60 (2.76H, m), 4.73-4. 86 (0.36H, m), 5.24- 5.38 (0.88H, m), 7.29-7. 44 (2H, d, J=8. 8Hz), 7.75-7. 94 (2H, d, J=8.8Hz).

Step 6 (2S)-2-Amino-N-cyclobutyl-N-methyl-2- [trans-4- [4- (2, 2,2- trifluoroethanesulfonylamino) benzenesulfonylamino] cyclohexyl]- acetamid hydrochloride (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2, 2, 2- trifluoroethanesulfonylamino) benzenesulfonylamino] cycloheXyl]- methyl] carbamic acid tert-butyl ester (185 mg) obtained in Step 5 was suspended in ethyl acetate (4 ml), a solution of 4N-hydrogen chloride in ethyl acetate was added. The mixture was stirred for 2 hrs at room temperature. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue and the mixture was stirred. The precipitated solid was collected by filteration, washed with ethyl acetate and dried under reduced pressure to give the title compound (132.1 mg).

1H-NMR (6ppm, DMSO-d6) 0.88-1. 21 (4H, m), 1.33-1. 76 (7H, m), 1.84- 2.36 (4H, m), 2.67-2. 96 (4H, m), 3.97-4. 10 (0.45H, m), 4.14- 4. 26 (0.55H, m), 4.35-4. 49 (0.55H, m), 4. 61-4. 78 (2.45H, m), 7.27-

7.38 (2H, d, J=8.8Hz), 7. 54-7.66 (lH, m), 7. 68-7. 78 (2H, d, J=8.8Hz), 7.85-8. 08 (3H, m), 10.88-11. 15 (lH, s).

Example 33 Step 1 (S)-2- (tert-Butoxycarbonylamino)-2- (4-oxocyclohexyl) acetic acid methyl ester A solution of oxalyl chloride (34.9 ml) in dichloromethane (500 ml) was cooled to-78°C, a solution of dimethyl sulfoxide (56.8 ml) in dichloromethane (100 ml) was added dropwise thereto.

The mixture was stirred for 5 min at the same temperature. A solution of (S)-2- (tert-butoxycarbonylamino)-2- (4- hydroxycyclohexyl) acetic acid methyl ester (63 g) synthesized by the method described in W002/076450 in dichloromethane (300 ml) was added dropwise and the mixture was stirred for 30 min at the same temperature. Triethylamine (250 ml) was added dropwise to the reaction mixture. Water (400 ml) was added at 0°C, and the organic layer was separated, washed successively with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane: ethyl acetate=3: 2-1 : 1) to give the title compound (45 g).

1H-NMR (8ppm, CDCl3) 1.34-1. 68 (12H, m), 1.83-2. 11 (2H, m), 2.17- 2.51 (4H, m), 3.76 (3H, s), 4.06-4. 17 (lH, m), 5.05-5. 18 (lH, m).

Step 2 (S)-2- (tert-Butoxycarbonylamino)-2- (4-oxocyclohexyl) acetic acid

A solution of (S)-2- (tert-butoxycarbonylamino)-2- (4- oxocyclohexyl) acetic acid methyl ester (30 g) obtained in Step 1 in tetrahydrofuran (84 ml) and methanol (84 ml) was cooled to 0°C.

2N aqueous sodium hydroxide solution (84.1 ml) was added dropwise, and the mixture was stirred for 2 hr at room temperature. A mixture of hexane: diethyl ether (1: 1) was added to the reaction mixture to be separated, and the aqueous layer was neutralized with 5% aqueous potassium hydrogen sulfate solution and evaporated under reduced pressure. 5% Aqueous potassium hydrogen sulfate solution was added to adjust pH to 1-2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (29.47 g).

H-NMR ($ppm, CDC13) 1.25-1. 65 (llH, m), 1.72-1. 94 (2H, m), 2.04- 2.24 (3H, m), 2. 24-2.45 (2H, m), 3.72-3. 82 (0.2H, br), 3.88- 3.96 (0. 8H, dd, J=8Hz), 6.70-6. 81 (0.2H, br), 7.09 (0.8H, d, J=8Hz), 12.35-12. 80 (lH, br).

Step 3 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- (4- oxocyclohexyl) methyl] carbamic acid tert-butyl ester A solution of (S)-2- (tert-butoxycarbonylamino)-2- (4- oxocyclohexyl) acetic acid (29.47 g) obtained in Step 2 in N, N- dimethylformamide (150 ml) was cooledto 0OC. N-

hydrochloride (19. 1 g) synthesized in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and diisopropylethylamine (35.07 ml) were added, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (59.84 g) was gradually added. After the completion of the addition, the mixture was allowed to warm to room temperature. Water (150 ml) was added and the mixture was extracted with a mixture of ethyl acetate-hexane. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 3) to give the title compound (23.5 g).

H-NMR (8ppm, CDCl3) 1.23-2. 49 (24H, m), 2.88-3. 09 (3H, s), 4.30- 4.58 (lH, m), 4.58-4. 75 (0.6H, m), 4.76-4. 93 (0.4H, m), 5.26-5. 49 (lH, m).

Step 4 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- (4- methoxymethylenecyclohexyl) methyl] carbamic acid tert-butyl ester To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (4- oxocyclohexyl) methyl] carbamic acid tert-butyl ester (22.10 g) obtained in Step 3 in methanol (180 ml) was added dropwise a solution of dimethyl (1-diazo-2-oxopropyl) phosphonate (19.07 g) in methanol (40 ml) under an argon atmosphere at 0°C. Potassium carbonate (18.08 g) was added by small portions at 0°C and the mixture was stirred at 0°C for 45 min. A saturated aqueous ammonium chloride solution (200 ml) was added to the reaction

mixture at 0°C to adjust the mixture to pH 8.-The solvent was evaporated under reduced pressure, and the aqueous layer was extracted with a mixture of hexane: ethyl acetate (1: 1). The organic layer was washed with brine, and dried over sodium sulfate.

The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2.5 : 1-1.5 : 1) to give the title compound (24.93 g).

1H-NMR (6ppm, CDCl3) 0. 91-2. 40 (23H, m), 2.70-2. 85 (lH, m), 2.86- 3.05 (3H, s), 3.51 (3H, s), 4.27-4. 62 (2.3H, m), 4.77-4. 93 (0.7H, m), 5.19-5. 38 (lH, m), 5.68-5. 80 (lH, m).

Step 5 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- (trans-4- formylcyclohexyl) methyl] carbamic acid tert-butyl ester A solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (4- methoxymethylenecyclohexyl) methyl] carbamic acid tert-butyl ester (22. 88 g) obtained in Step 4 in dichloromethane (500 ml) was cooled to 0°C under an argon atmosphere. Thereto was added dropwise a solution of trichloroacetic acid (40.80 g) in dichloromethane (150 ml) at 0°C over 15 min and the mixture was stirred at 0°C for 30 min. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture at 0°C to adjust to pH 8 and the organic layer was separated. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Of the residue, 13 g was dissolved in acetone (65 ml), 5% aqueous potassium hydrogen sulfate solution (65 ml) was added and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and

separated from ethyl acetate-water. The organic layer was dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water-methanol (1: 1), potassium carbonate (16.2 g) was added and the mixture was stirred at room temperature for 1.5 hr. The filtrate was concentrated under reduced pressure and separated from ethyl acetate-water. The organic layer was washed with saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (10.2 g). lH-NMR (6ppm, CDCl3) 1.09-1. 28 (4H, m), 1.43 (9H, s), 1.53-1. 81 (7H, m), 2.01-2. 31 (5H, m), 2.94 (1. 74H, s), 3.01 (1. 26H, s), 4.35-4. 61 (1. 58H, m), 4.86 (0. 42H, m), 5.35 (lH, m), 9.60 (lH, s).

Step 6 (S)-[(N-Cyclobutyl-N-methylcarbamoyl)-(trans-4- hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (trans-4-formylcyclohexyl) methyl] carbamic acid tert-butyl ester (2.11 g) obtained in Step 5 in methanol (20 ml) was added sodium borohydride (227 mg) at 0°C. The mixture was stirred for 2 hr at 0°C. Water (10 ml) and acetic acid (one drop) were added threrto and stirred for 30 min at room temperature. The solvent was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 1-ethyl acetate) to give

. the title compound (1.64 g).

H-NMR (8ppm, CDC13) 0.82-1. 00 (2H, m), 1.03-1. 12 (2H, m), 1.42 (9H, s), 1.42-1. 50 (2H, m), 1.62-1. 87 (6H, m), 2. 06-2. 32 (4H, m), 2. 93 (1. 6H, s), 3.01 (1. 4H, s), 3.40-3. 46 (2H, m), 4.40-4. 60 (1. 6H, m), 4. 78- 4.90 (0.5H, m), 5.25-5. 40 (0.9H, m).

Step 7 (S)-[(trans-4-Benzyloxymethylcyclohexyl)-(N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester A solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (trans- 4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester (30 mg) obtained in Step 6,2, 6-di-tert-butyl-4-methylpyridine (21 mg) and silver trifluoromethanesulfonate (24 mg) in dichloromethane (600 1) was cooled to 0°C, benzyl bromide (11.1 jj. 1) was added thereto, and the mixtrure was stirred for 1 hr at 0°C. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=3: 1) to give the title compound (28 mg).

H-NMR (6ppm, CDCl3) 0.80-1. 19 (4H, m), 1.33-1. 78 (6H, m), 1.42 (9H, s), 1.79-1. 91 (2H, m), 1.98-2. 35 (4H, m), 2.93 (1. 73H, s), 3.00 (1. 27H, s), 3.21-3. 29 (2H, d, J=6.2Hz), 4.37-4. 58 (1. 58H, m), 4.47 (2H, s), 4.79- 4.92 (0.42H, m), 5.24-5. 38 (lH, m), 7.22-7. 38 (5H, m).

. Step 8 (2S)-2-Amino-2- (trans-4-benzyloxymethylcyclohexyl)-N-cyclobutyl-N- methylacetamide hydrochloride

- HC I (S)-[(trans-4-Benzyloxymethylcyclohexyl)-(N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (28 mg) obtained in Step 7 was dissolved in 4N-hydrogen chloride ethyl acetate solution (1 ml), and the solution was sttired for 1.5 hr at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (19 mg).

1H-NMR (6ppm, DMSO-d6) 0.77-1. 01 (4H, m), 1.36-1. 85 (8H, m), 1.93- 2.36 (4H, m), 2.88 (1. 73H, s), 2.97 (1. 27H, s), 3.22 (2H, d, J=6.2Hz), 4. 13 (0.42H, d, J=5.8Hz), 4.28 (0.58H, d, J=4. 8Hz), 4.42 (2H, s), 4.47- 4.59 (0.58H, m), 4.70-4. 83 (0.42H, m), 7.22-7. 38 (5H, m), 8.05 (3H, brs).

Example 34 Step 1 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- (4- nitrophenylsulfanylmethyl) cyclohexyl] methyl] carbamic acid tert- butyl ester To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)-

(trans-4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester (177 mg) obtained in Step 6 of Example 33,4-nitrothiophenol (0.55 ml) and triphenylphosphine (0.60 ml) in tetrahydrofuran (2 ml), was added diisopropyl azodicarboxylate (0.60 ml) under ice cooling and argon atomosphere. After allowing the reaction mixture to room temperature, the mixture was stirred overnight.

The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1-1 : 1) to give the title compound (290 mg) as a yellow amorphous form.

1H-NMR (8ppm, CDC13) 0.96-1. 20 (4H, m), 1.42 (9H, s), 1.47-1. 79 (6H, m), 1.94-2. 33 (6H, m), 2.88 (2H, d, J=6.9Hz), 2.93 (1. 74H, s), 3.00 (1. 26H, s), 4.38-4. 46 (0.42H, m), 4.48-4. 61 (0.58H, m), 4.79-4. 90 (0.58H, m), 4.91- 5.03 (0.42H, m), 5.24-5. 38 (lH, m), 6.30 (lH, brs), 7.28 (2H, d, J=8. 8Hz), 8.10 (2H, d, J=8. 8Hz).

Step 2 (S)- [ [trans-4- (4-Aminophenylsulfanylmethyl) cyclohexyl]- (N- cyclobutyl-N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester Using (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- [trans-4- (4- nitrophenylsulfanylmethyl) cyclohexyl] methyl] carbamic acid tert- butyl ester obtained in Step 1, the title compound was obtained in the same manner as in Step 4 of Example 29.

Step 3 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2, 2,2- trifluoroethanesulfonylamino) benzenesulfanylmethyl] cyclohexyl]- methyl] carbamic acid tert-butyl ester

Using (S)- [ [trans-4- (4- aminophenylsulfanylmethyl) cyclohexyl]- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester obtained in Step 2, the title compound was obtained in the same manner as in Step 5 of Example 29.

Step 4 (S)- [ (N-Cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2, 2,2- trifluoroethanesulfonylamino) benzenesulfonylmethyl] cyclohexyl]- methyl] carbamic acid tert-butyl ester To a solution of (S)-[(N-cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2, 2,2-trifluoroethanesulfonylamino)- benzenesulfanylmethyl] cyclohexyl] methyl] carbamic acid tert-butyl ester (123 mg) obtained in Step 3 in chloroform (5 ml) was added m-chloroperoxybenzoic acid (110 mg), and the mixture was stirred for 3.5 hr at room temperature. The reaction mixture was diluted with a mixture of chloroform-lM aqueous potassium carbonate solution, and partitioned. The organic layer was washed with saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer.

chromatography (hexane: ethyl acetate=1 : 2) to give the title compound (95 mg).

1H-NMR (6ppm, CDCl3) 1.01-1. 15 (4H, m), 1.40-1. 76 (6H, m), 1.42 (4H, s), 1.91-2. 28 (6H, m), 2.93 (1. 74H, s), 2.95 (2H, d, J=6.9Hz), 3.00 (1. 26H, s), 3.89 (2H, q, J=8.8Hz), 4.35-4. 60 (1. 58H, m), 4.75-4. 90 (0.42H, m), 5.25- 5.35 (lH, m), 7.41 (2H, d, J=8.6Hz), 7.89 (2H, d, J=8.6Hz).

Step 5 (2S)-2-Amino-N-cyclobutyl-N-methyl-2- [trans-4- [4- (2, 2,2- trifluoroethanesulfonylamino) benzenesulfonylmethyl] cyclohexyl]- acetamide hydrochloride Using (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- [trans-4- [4- (2,2, 2-trifluoroethanesulfonylamino) benzenesulfonylmethyl]- cyclohexyl] methyl] carbamic acid tert-butyl ester obtained in Step 4, the title compound was obtained in the same manner as in Step 6 of Example 29.

1H-NMR (6ppm, DMSO-d6) 0.94-1. 24 (4H, m), 1.48-1. 72 (6H, m), 1.78- 1.88 (2H, m), 1.96-2. 39 (4H, m), 2.87 (1. 74H, s), 2.96 (1. 26H, s), 3.17 (2H, d, J=6. OHz), 4.11 (0.42H, brs), 4.25 (0.58H, brs), 4.50 (0.58H, m), 4.74 (2H, q, J=9.7Hz), 4.70-4. 87 (0.42H, m), 7.40 (2H, d, J=8.6Hz), 7.83 (2H, d, J=8.6Hz), 8. 02 (3H, brs), 11.17 (lH, brs).

Example 212 Step 1 2- (Benzoyloxymethyl) benzyl alcohol

1, 2-Benzenedimethanol (5.00 g) was dissolved in tetrahydrofuran (60ml), and triethylamine (4.20 ml) and benzoyl chloride (5.04 ml) were added dropwise thereto under cooling.

After stirring for 2 hr at room temperature, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 2- 1: 3) to give the title compound (4. 49 g).

H-NMR (8ppm, CDC13) 2.13 (1H, brs), 4. 86 (2H, s), 5.51 (2H, s), 7. 33- 7.59 (7H, m), 8.06 (2H, d, J=4.6Hz).

Step 2 2- (Benzoyloxymethyl) benzyl bromide 2- (Benzoyloxymethyl) benzyl alcohol (4.49 g) was dissolved in chloroform (45 ml), and triphenylphosphine (5.34 g) and carbon tetrabromide (6.76 g) was added thereto under ice-cooling. After stirring for 1 hr at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue purified by silica gel chromatography (hexane: ethyl acetate=9: 1) to give the title compound (5.08 g).

H-NMR (8ppm, CDC13) 4.67 (2H, s), 5.53 (2H, s), 7.34-7. 60 (7H, m), 8.08 (2H, d, J=7.6Hz).

Step 3 (S)- [ (trans-4- [2- (Benzoyloxymethyl) benzyloxymethyl] cyclohexyl)- (N- cyclobutyl-N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester

To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (trans-4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester (4.00 g) obtained in Step 6 of Example 33 and 2,6-di-tert- butyl-4-methylpyridine (2. 78 g) in chloroform (40 ml) was added dropwise a solution of 2- (benzoyloxymethyl) benzylbromide (3.78 g) in chloroform (40 ml) under ice-cooling, and then silver trifluoromethanesulfonate (3.19 g) was added. After stirring for 1 hr at room temperature, the insoluble substance was filtered off using celite, and the filtrate was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the residue, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=3: 1-2: 1) to give the title compound (4.89 g).

1H-NMR (8ppm, CDC13) 0.87-1. 23 (4H, m), 1.43 (9H, s), 1.51-1. 73 (10H, m), 1.80-1. 85 (2H, m), 2.08-2. 28 (4H, m), 2.93 (1. 7H, s), 3.00 (1. 3H, s), 3.28 (2H, t, J=3.2Hz), 4.40-4. 56 (1H, m), 4.61 (2H, s), 4.86 (0.4H, t, J=9. OHz), 5.30 (0.7H, dd, J=14. 4Hz, 9.3Hz), 5.45 (2H, s), 7.31- 7.59 (7H, m), 8.06-8. 08 (2H, m).

Step 4 (S)-[(trans-4-[2-(Hydroxymethyl) benzyloxymethyl] cycloheXyl)-(N- cyclobutyl-N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester

To a solution of (S)- [ (trans-4- [2- (benzoyloxymethyl) benzyloxymethyl] cyclohexyl)- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (4.89 g) obtained in Step 3 in tetrahydrofuran (24 ml) and methanol (24 ml) was added dropwise 1N aqueous sodium hydroxide solution (16.9 ml) at room temperature, and the mixture was stirred for 30 min at room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=1 : 1-2 : 3) to give the title compound (3.76 g).

H-NMR (8ppm, CDC13) 0.85-1. 18 (4H, m), 1.42 (9H, s), 1.62-1. 73 (4H, m), 1.76-1. 82 (2H, m), 2.01-2. 29 (6H, m), 2.92 (1. 7H, s), 2.97 (1. 3H, s), 3.24 (1H, brs), 3.30-3. 33 (2H, m), 4.40-4. 55 (1H, m), 4.58 (2H, s), 4.65 (2H, s), 4.84 (0.3H, q, J=8.6Hz), 5.30 (0.7H, dd, J=14.6Hz, 9.5Hz), 7.30-7. 40 (4H, m).

Step 5 (S)- [ (trans-4- [2-Formylbenzyloxymethyl] cyclohexyl)- (N-cyclobutyl- N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester

To a mixture of (S)- [ (trans-4- [2- (hydroxymethyl) benzyloxymethyl] cyclohexyl)- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (3.76 g) obtained in Step 4, molecular sieves 4A (1.4 g) and chloroform (38 ml) was added successively N-methylmorpholine N-oxide (1.39 g) and tetrapropylammonium perruthenate (139 mg) under ice-cooling.

After stirring for 1 hr at room temperature, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1-3: 2) to give the title compound (2.92 g).

H-NMR (6ppm, CDCl3) 0.88-1. 17 (5H, m), 1. 42 (9H, s), 1.63-1. 72 (5H, m), 1.85 (2H, d, J=13. 0Hz), 2.08-2. 31 (4H, m), 2.93 (1. 7H, s), 3.01 (1. 3H, s), 3.36 (2H, d, J=6. 0Hz), 4.49-4. 58 (2H, m), 4.88 (2H, s), 5.32 (1H, t, J=11. 8Hz), 7.46 (1H, t, J=7.4Hz), 7.57-7. 63 (2H, m), 7.86 (1H, d, J=7.4Hz), 10. 21 (1H, s).

Step 6 2-{trans-4-[(S)-tert-Butoxycarbonylamino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid

To a solution of (S)- [ (trans-4- [2- formylbenzyloxymethyl] cyclohexyl)- (N-cyclobutyl-N- methylcarbamoyl) methyl] carbamic acid ter-butyl ester (2.92 g) obtained in Step 5 in tetrahydrofuran (45 ml) was added a solution of sulfamic acid (780 mg) in water (9 ml) at room temperature.

After cooling with ice-bath, a solution of sodium chlorite (726 mg) in water (9 ml) solution was added dropwise over about 5 min to the reaction mixture. After stirring for 10 min at 0°C, sodium sulfite (1.2 g) was added to the reaction mixture. The mixture was stirred for 15 min and poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate.

The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol=10: 1) to give the title compound (2.98 g).

H-NMR (8ppm, CDC13) 0. 90-1. 21 (4H, m), 1. 43 (9H, s), 1. 60-1. 75 (6H, m), 1.87 (2H, d, J=11.6Hz), 2.05-2. 31 (4H, m), 2.94 (1. 7H, s), 3.02 (1. 3H, s), 3.38 (2H, d, J=6. 0Hz), 4.26-4. 63 (1H, m), 4.80-4. 85 (2H, m), 5.40-5. 47 (1H, m), 7.38-7. 42 (1H, m), 7.52-7. 61 (2H, m), 8.06 (1H, t, J=3.9Hz).

Step 7 2-{trans-4-[(S)-Amino-(N-cyclobutyl-N- methylcarbamoyl) methyllcyclohexylmethoxymethyllbenzoic acid hydrochloride

2- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl} benzoic acid (2. 98 g) obtained in Step 6 was dissolved in a solution of 4N-hydrogen chloride in ethyl acetate (15 ml), and the solution was stirred for 45 min at room temperature. Ethyl acetate (150 ml) was added thereto and the mixture was stirred for 40 min. The solid was collected by filtration and dried under reduced pressure to give the title compound (2.14 g). lH-NMR (8ppm, DMSO-d6) 0.88-1. 21 (4H, m), 1.40-1. 70 (7H, m), 1.79 (2H, brs), 1.99-2. 30 (4H, m), 2.88 (1. 8H, s), 2.97 (1. 2H, s), 3.27 (2H, d, J=6. OHz), 4.14 (0.4H, brs), 4.52 (0.6H, brs), 4. 52 (0.6H, t, J=8. 6Hz), 4.70-4. 80 (2. 4H, m), 7.34-7. 38 (1H, m), 7.51-7. 63 (2H, m), 7.82 (1H, d, J=7.9Hz), 8.05 (3H, brs).

Example 238 Step 1 3-Fluoro-4-hydroxybenzoic acid ethyl ester To a solution of 3-fluoro-4-hydroxybenzoic acid (300 mg) in ethanol (3 ml) was added a several drop of concentrated sulfuric acid under an argon atmosphere, and the mixture was refluxed under heating for 5 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution

and dried over magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (337 mg) as a white solid.

H-NMR (8ppm, DMSO-d6) 1.29 (3H, t, J=7. 0Hz), 4.26 (2H, q, J=7. 0Hz), 7.04 (1H, t, J=8.6Hz), 7.61-7. 64 (1H, m), 7.66 (1H, s), 10.83 (1H, brs).

Step 2 4- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzOic acid ethyl ester To a solution of (S)-[(N-cyclobutyl-N-methylcarbamoyl)- (trans-4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester (70 mg) obtained in Step 6 of Example 33 in tetrahydrofuran (700 p, l) was added 3-fluoro-4-hydroxybenzoic acid ethyl ester (44 mg), triphenylphosphine (62 mg) and diisopropyl azodicarboxylate (46.5 pi) under an argon atmosphere. After stirring for about 1.5 hr at room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=4 : 1-3: 1) to give the title compound (122 mg) as a colorless oil.

Step 3 4-{trans-4-[(S)-tert-Butoxycarbonylamino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid

To a solution of 4-{trans-4-[(S)-tert-butoxycarbonylamino- (N-cyclobutyl-N-methylcarbamoyl) methyl] cyclohexylmethoxy}-3- fluorobenzoic acid ethyl ester (122.2 mg) obtained in Step 2 in tetrahydrofuran (1 ml) and methanol (1 ml) was added dropwise 1N aqueous sodium hydroxide solution (936 pl) under an argon atmosphere, the mixture was stirred overnight at room temperature.

5% Aqueous potassium hydrogen sulfate solution was added to the reaction mixture to adjust to pH 2-3. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1-chloroform : methanol=40: 1-10: 1) to give the title compound (88 mg) as white amorphous.

H-NMR (8ppm, CDC13) 0.95-1. 30 (4H, m), 1.43 (9H, s), 1.50-1. 89 (6H, m), 1.91-2. 01 (2H, m), 2.03-2. 36 (4H, m), 2.95 (1. 74H, s), 3.03 (1. 26H, s), 3.88 (2H, d, J=9. OHz), 4.35-4. 65 (1. 58H, m), 4.78-4. 95 (0.42H, m), 5.31-5. 47 (1H, m), 6.96 (1H, t, J=7.5Hz), 7.78 (1H, dd, J=3. 0Hz, 12. OHz), 7.84 (1H, d, J=9. OHz), Step 4 4-{trans-4-[(S)-Amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid hydrochloride

4- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid (88 mg) obtained in Step 3 was dissolved in 4N-hydrogen chloride ethyl acetate solution (1 ml), and the mixture was stirred for 6 hr at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was collected by filteration, and drying under vacuum to give the title compound (63.5 g).

H-NMR (6ppm, DMSO-d6) 0.94-1. 34 (4H, m), 1.54-1. 79 (6H, m), 1.81- 1.94 (2H, m), 1.97-2. 37 (4H, m), 2.90 (1. 71H, s), 2.99 (1. 29H, s), 3.94 (2H, d, J=6. OHz), 4.11-4. 19 (0.43H, m), 4.27-4. 34 (0.57H, m), 4.47-4. 61 (0. 57H, m), 4.70-4. 85 (0.43H, m), 7.25 (1H, t, J=9. OHz), 7.66 (1H, dd, J=3. 0Hz, 12. 0Hz), 7.74 (1H, d, J=9. OHz), 8.11 (3H, brs).

Example 242 Step 1 2-Bromomethyl-5-methylbenzoic acid To a solution of 2,5-dimethylbenzoic acid (10.0 g) in carbon tetrachloride (200 ml), were added N-bromosuccinimide (12.45 g) and benzoyl peroxide (1.0 g) under an argon atmosphere, and the mixture was heated under reflux for 1 hr. The insoluble material was filtered off and washed with carbon tetrachloride (50 ml).

About 125 ml of the solvent was evaporated from the filtrate, and the concentrated solution was stirred for 3.5 hr at room temperature. The precipitated solid was collected by filtration.

. and dried under reduced pressure to give the title compound (5.48 g) as a white solid.

Step 2 2-Bromomethyl-5-methylbenzoic acid methyl ester

To a solution of 2-bromomethyl-5-methylbenzoic acid (4.59 g) obtained in Step 1 in tetrahydrofuran (100 ml) and methanol (40ml), was added dropwise 2M trimethylsilyl diazomethane-hexane solution (11 ml) over 10 min under an argon atmosphere. After stirring for 3.5 hr at room temperature, acetic acid was added dropwise to the reaction mixture until the color (yellow) of the mixture disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=100 : 1) to give the title compound (3.40 g) as a colorless oil. lH-NMR (8ppm, CDC13) 2.38 (3H, s), 3.94 (3H, s), 4.93 (2H, s), 7.30 (1H, d, J=9. OHz), 7.35 (1H, d, J=9. OHz), 7.78 (1H, s).

Step 3 2-{trans-4-[(S)-tert-Butoxycarbonylamino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid methyl ester To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (trans-4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl ester (1.00 g) obtained in Step 6 of Example 33 and 2-bromomethyl-

5-methylDenzoic acid methyl ester (1.23 g) in dichloromethane (15 ml), were added 2, 6-di-tert-butyl-4-methylpyridine (955 mg, 4.7 mmol) and silver trifluoromethanesulfonate (1.20 g, 4.7 mmol) under ice-cooling and an argon atmosphere. After stirring for 2 hr under ice-cooling, the mixture was stirred for 2.5 hr at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=5: 1-4: 1-3: 1) to give the title compound (851 mg).

1H-NMR (8ppm, CDC13) 0.79-1. 24 (4H, m), 1.42 (9H, s), 1.58-1. 78 (6H, m), 1.80-1. 92 (2H, m), 2.01-2. 32 (4H, m), 2.36 (3H, s), 2.93 (1. 77H, s), 3.01 (1. 23H, s), 3.31 (2H, d, J=9. OHz), 3.87 (3H, s), 4.36-4. 60 (1. 59H, m), 4.80 (2H, s), 4.82-4. 95 (0.41H, m), 5.23-5. 38 (1H, m), 7.32 (1H, d, J=9. OHz), 7.51 (1H, d, J=9. OHz), 7.72 (1H, s).

Step 4 2-{trans-4-[(S)-tert-Butoxycarbonylamino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid A solution of 2-{trans-4-[(S)-tert-butoxycarbonylamino-(N- cyclobutyl-N-methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5- methylbenzoic acid methyl ester (851mg) obtained in Step 3 in tetrahydrofuran (4.3 ml) and methanol (4.3 ml) was cooled under ice-bath, and 2N aqueous sodium hydroxide solution (3. 30ml) was added dropwise thereto under an argon atmosphere, and the mixture

. was stirred overnight at room temperature. The reaction mixture was cooled under ice-bath, and after adding 1N hydrochloric acid (6.6 ml), 5% aqueous potassium hydrogen sulfate was further added to the reaction mixture to adjust pH to 2. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was filtered off, and the filtrate was concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1-1: 1) to give the title compound (702 mg) as white amorphous.

1H-NMR (6ppm, CDC13) 0.84-1. 22 (4H, m), 1.42 (9H, s), 1.48-1. 78 (6H, m), 1.79-1. 91 (2H, m), 2.01-2. 32 (4H, m), 2.39 (3H, s), 2.93 (1. 75H, s), 3. 01 (1. 25H, s), 3.36 (2H, d, J=6. 0Hz), 4.38-4. 60 (1. 58H, m), 4.74 (2H, s), 4.77-4. 93 (0.42H, m), 5.31-5. 43 (1H, m), 7.33 (1H, d, J=9. OHz), 7.38 (1H, d, J=9. OHz), 7.87 (1H, s).

Step 5 2-{trans-4-[(S)-Amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid hydrochloride 2-{trans-4-[(S)-tert-Butoxycarbonylamino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid (702 mg) obtained in Step 4 was dissolved in a solution (7 ml) of 4N-hydrogen chloride in ethyl acetate under ice-cooling, and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was concentrated under reduced pressure, and a mixed solution of diethyl ether-ethyl acetate (3: 1) was added

. thereto. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (545 mg) as a white solid.

H-NMR (8ppm, DMSO-d6) 0.81-1. 02 (2H, m), 1.03-1. 28 (2H, m), 1.37- 1.73 (6H, m), 1.74-1. 87 (2H, m), 1. 94-2. 38 (4H, m), 2.33 (3H, s), 2.89 (1. 68H, s), 2.98 (1. 32H, s), 3.26 (2H, d, J=6. 0Hz), 4.10- 4.18 (0.44H, m), 4. 25-4. 32 (0.56H, m), 4.42-4. 62 (0.56H, m), 4.66- 4.85 (0.44H, m), 4.71 (2H, s), 7.36 (1H, d, J=6. 0Hz), 7.45 (1H, d, J=6. OHz), 7.64 (1H, s), 8.17 (3H, brs).

Example 297 Step 1 5-Methoxymethoxyisophthalic acid dimethyl ester To a solution of 5-hydroxyisophthalic acid dimethyl ester (5.00 g) in N, N-dimethylformamide (25 ml), was added potassium carbonate (4.27 g), and then methoxymethyl chloride (1.99 ml) was added dropwise under ice-cooling. After stirring for 2.5 hr at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over sodium sulfate.

The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=3: 1-2: 1) to give the title compound (4.21g).

1H-NMR (8ppm, CDC13) 8.34 (1H, s), 7.88 (2H, d, J=1. 5Hz), 5.25 (2H, s), 3.94 (6H, s), 3.49 (3H, s).

Step 2 3-Methoxycarbonyl-5-methoxymethoxybenzoic acid

To a solution of 5-methoxymethoxyisophthalic acid dimethyl ester (4.21 g) obtained in Step 1 in tetrahydrofuran (15 ml) and methanol (35 ml), was added aqueous solution of lithium hydroxide monohydrate (695 mg), and the mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue, and partitioned. 5% Aqueous potassium hydrogen sulfate solution was added to the aqueous layer to adjust pH to 2-3. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (2.90 g).

1H-NMR (8ppm, CDC13) 8.41 (1H, s), 7.94 (2H, d, J=1. 5Hz), 5. 27 (2H, s), 3.96 (3H, s), 3.50 (3H, s).

Step 3 3-Benzyloxycarbonylamino-5-methoxymethoxybenzoic acid methyl ester To a solution of 3-methoxycarbonyl-5-methoxymethoxybenzoic acid (890 mg) obtained in Step 2 in tetrahydrofuran (4 ml) and toluene (15 ml), was added triethylamine (1.03 ml) and then diphenylphosphoryl azide (0.959 ml) was added dropwise under ice- cooling. After stirring for 1 hr at room temperature, the mixture was heated for 1 hr at 80°C. Benzyl alcohol was added dropwise to the reaction mixture and the mixture was further heated for 2 hr.

The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=3: 1) to give the title compound (645 mg).

H-NMR (5ppm, CDCIs) 7.58 (1H, s), 7.50 (1H, s), 7. 43-7.34 (6H, m), 6.76 (1H, s), 5. 22 (2H, s), 5.21 (2H, s), 3.90 (3H, s), 3.49 (3H, s).

Step 4 3-Benzyloxycarbonylamino-5-hydroxybenzoic acid methyl ester

To 3-benzyloxycarbonylamino-5-methoxymethoxybenzoic acid methyl ester (200 mg) obtained in Step 3 was added a solution (2 ml) of 4N-hydrogen chloride in 1,4-dioxane, and the mixture was stirred for 20 min at room temperature. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue. The solution was concentrated under reduced pressure and dried to give the title compound (175 mg).

H-NMR (#ppm, DMSO-d6) 9.87 (1H, s), 9.80 (1H, s), 7.58 (1H, s), 7.41- 7.35 (5H, m), 7.22 (1H, t, J=2.3Hz), 6.99 (1H, t, J=1. 7Hz), 5.15 (2H, s), 3.81 (3H, s).

Step 5 3-Benzyloxycarbonylamino-5- {trans-4-[(S)-tert-butoxycarbonylamino- (N-cyclobutyl-N-methylcarbamoyl) methyl] cyclohexylmethoxy} benzoic acid methyl ester To a solution of (S)- [ (N-cyclobutyl-N-methylcarbamoyl)- (trans-4-hydroxymethylcyclohexyl) methyl] carbamic acid tert-butyl

. ester (141 mg) obtained in Step 6 of Example 33,3- benzyloxycarbonylamino-5-hydroxybenzoic acid methyl ester (100 mg) obtained in Step 4 and triphenylphosphine (113 mg) in tetrahydrofuran (2 ml), was added diisopropyl azodicarboxylate (85.1 pl) under ice-cooling. After stirring for 3.5 hr at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1-3: 2) to give the title compound (162 mg).

H-NMR (8ppm, CDC13) 7.39-7. 36 (7H, m), 7.27-7. 23 (1H, m), 6.74 (1H, s), 5.34 (1H, t, J=8.7Hz), 5.19 (2H, d, J=7.5Hz), 4.87 (0.41H, t, J=8.7Hz), 4.60-4. 42 (1. 59H, m), 3.89 (3H, s), 3.77 (2H, d, J=6. OHz), 3.03 (1. 22H, s), 2.96 (1. 78H, s), 2.31-2. 08 (4H, m), 1.92 (2H, d, J=11.7Hz), 1.75-1. 63 (4H, m), 1.62-1. 38 (2H, m), 1.43 (9H, s), 1. 28- 0.98 (4H, m).

Step 6 3-Amino-5-{trans-4-[(S)-tert-butoxycarbonylamino-(N-cyclobut yl-N- methylcarbamoyl) methyl] cyclohexylmethoxy} benzoic acid methyl ester To a solution of 3-benzyloxycarbonylamino-5- {trans-4- [ (S)- tert-butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy} benzoic acid methyl ester (162 mg) obtained in Step 5 in methanol (5 ml), added 5% palladium on carbon (16 mg), and the mixture was stirred under ambient hydrogen atmosphere for 1.5 hr at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (119 mg).

H-NMR (8ppm, CDC13) 6.95-6. 94 (2H, m), 6.39 (1H, t, J = 2.1 Hz), 5.33 (1H, t, J = 9.2 Hz), 4.87 (0.59H, t, J = 8. 5 Hz), 4.56- 4.46 (1. 41H, m), 3.87 (3H, s), 3.71 (2H, t, J = 10. 0 Hz), 3.02 (1. 22H, s), 2.94 (1. 78H, s), 2.27-2. 14 (4H, m), 1. 89 (2H, t, J = 14.1 Hz), 1.73 (4H, q, J = 8.9 Hz), 1.53-1. 46 (2H, m), 1.43 (9H, s), 1.19- 1.08 (4H, m).

Step 7 3- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-5-dimethylaminobenzoic acid methyl ester To a solution of 3-amino-5-{trans-4-[(S)-tert- butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy} benzoic acid methyl ester (119 mg) obtained in Step 6 in acetonitrile (38ml), were added 37% aqueous formaldehyde solution (0.105 ml) and sodium triacetoxyborohydride (312 mg) under ice-cooling, and the mixture was stirred for 30 min at room temperature. After filtrating off the insoluble material, the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and partitioned. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was filtrated off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 1) to give the title compound (123 mg). lH-NMR (8ppm, CDC13) 8 : 7.04 (1H, s), 6.89 (1H, s), 6.41 (1H, t, J=2. 4Hz), 5.33 (1H, t, J=10. OHz), 4. 87 (0. 40H, t, J=9.2Hz), 4.58-

. 4. 45 (1. 60H, m), 3.89 (3H, s), 3.77 (2H, d, J=6.4Hz), 3.02 (1. 21H, s), 2.96 (6H, s), 2.94 (1. 79H, s), 2.31-2. 13 (4H, m), 1.95 (2H, d, J=11.7Hz), 1.74-1. 50 (6H, m), 1.40 (9H, s), 1.28-1. 09 (4H, m).

Step 8 3- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-5-dimethylaminobenzoic acid To a solution of 3- {trans-4- [ (S) -tert-butoxycarbonylamino- (N-cyclobutyl-N-methylcarbamoyl) methyl] cyclohexylmethoxy}-5- dimethylaminobenzoic acid methyl ester (123 mg) obtained in Step 7 in tetrahydrofuran (0.5 ml) and methanol (1 ml), was added dropwise 4N aqueous sodium hydroxide solution (0.22 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue, and partitioned. The aqueous layer was washed with diethyl-ether, and 5% aqueous potassium hydrogen sulfate solution (2.5 ml) was added thereto to adjust pH to 4-6, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg). lH-NMR (8ppm, CDCl3) 7.09 (1H, s), 6.93 (1H, d, J=10.9Hz), 6.44 (1H, t, J=2. lHz), 5.40 (1H, t, J=7.2Hz), 4.87 (0.42H, t, J=8.7Hz), 4.61- 4.43 (1. 58H, m), 3.78 (2H, d, J=6. 0Hz), 3.03 (1. 26H, s), 2.97 (6H, s), 2.95 (1. 74H, s), 2.27-2. 15 (4H, m), 1.95 (2H, d, J=11.3Hz), 1.64- 1. 43 (6H, m), 1. 43 (9H, s), 1.19-1. 09 (4H, m).

Step 9 3-{trans-4-[(S)-Amino-(N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5- dimethylaminobenzoic acid hydrochloride

3- {trans-4- [ (S)-tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-5-dimethylaminobenzoic acid (60 mg) obtained in Step 8 was dissolved a solution (2 ml) of 4N-hydrogen chloride in ethyl acetate under ice-cooling, and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added thereto. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (45 mg).

1H-NMR (8ppm, DMSO-d6) 8.05 (3H, s), 6.92 (1H, s), 6.78 (1H, s), 6.44 (1H, s), 4.77 (0.45H, t, J = 7.9 Hz), 4.44-4. 24 (1.55H, m), 3.79 (2H, d, J = 6.0 Hz), 2.99 (1.35H, s), 2.92 (6H, s), 2.90 (1.65H, s), 2.27-1. 97 (4H, m), 1.91-1. 85 (2H, m), 1.73-1. 67 (6H, m), 1.28-0. 98 (4H, m).

The following compounds were obtained in the same manner as in Examples 1,29, 33,34, 212,238, 242 and 297.

Table 1-1 Example Example NMR No. 1H-NMR (6ppm, DMSO-d6) 0. 84- 0. 94 (2H, m), 1. 00-1. 17 (7H, m), 0 1. 19-1. 30 (1H, m), 2. 03-2. 20 (1H, H2NN 2. 90-2. 95 (1H, m), 4. 32 (1H, Example d, J=13. 2Hz), 4. 30-4. 35 (1H, 2 57 (1H, d, J=13. 2Hz), 8. 61 (3H, brs). HCI H 0. 95- Me 00 (4H, m), 1. 30 (9H, s), 2. 96- Example Me 3. 03 (1H, m), 4. 07 (2H, brs), CN 4. 46 (2H, s), 8. 94 (2H, brs). HCI - 0 0. 89-0. 96 Example 06 (2H, m), N 48-1. 85 (14H, m), 2. 28 (2H, 4 "L 2. 48-2. 83 (1H, m), 3. 64 (2H, s), 4. 29 (2H, s). 0 A 92 H2N - (2H, m), 1. 06-1. 23 (7H, m), Example 1. 61-1. 93 (6H, m), 2. 92-2. 95 (1H, 5 < d, J=8Hz), W 37 (1H, d, J=12Hz), 8. 32 (3H, HCI 1H-NMR (8ppm, DMSO-d6) 0. 88- 0 91 (3H, m), 0. 95-0. 98 (3H, m), j) 1. 55-1. 67 (2H, m), 1. 90-2. 32 (5H, Example 2. 88 (1. 5H, s), 2. 98 (1. 5H, N 6 s), 4. 08-4. 18 (0. 5H, m), 4. 25- Me 4. 33 (0. 5H, m), 4. 48-4. 60 (0. 5H, m), 4. 70-4. 82 (0. 5H, m), 8. 19 (3H, brs).

Table 1-2 H-NMR (6ppm, CDC13) 0. 81-0. 90 (2H, m), 0. 99-1. 04 (2H, m), H 0 1. 20-1. 40 (3H, m), 1. 90-2. 04 Example m), 2. 10-2. 16 (2H, m), 7 , 46-2. 50 (1H, m), 2. 78-2. 83 7 CN 3. 74 (2H, s), 3. 90-4. 03 (1H, m), 4. 23 (2H, s), 5. 93 (1H, d, J=8. 0Hz), 7. 37-7. 50 (3H, m), 7. 65-7. 77 (2H, m). O 0. 85 (2H, m), 0. 90-1. 22 (7H, m), Example, 55-1. 63 (2H, m), 1. 72-1. 81 (4H, 8 2. 78-2. 82 (1H, m), 2. 87 (3H, HCI 4. 26 (1H, d, J=6. 4Hz), 8. 08 (3H, brs). lH-NMR (8ppm, DMSO-d6) 0. 75- 87 (2H, m), 0. 92-1. 23 (1OH, Example 2 1. 58-1. 62 (2H, m), 1. 65- 9 85 (4H, m), 2. 73-2. 80 (1H, m), Me 00-3. 10 (1H, m), 3. 70-3. 78 (1H, ka HCI m), 4. 25 (1H, d, J=6. 4Hz), 8. 18 (3H, brs). O 0. 96- H 21 (5H, m), 1. 55-1. 73 (8H, m), Example 1. 87-1. 99 (2H, m), 2. 13-2. 21 (2H, 10 m), 3. 47 (1H, d, J=6. 3Hz), 4. 17- HCI 25 (1H, m), 8. 17 (3H, brs), 8. 80 (1H, d, J=4. 2Hz). p ppm, 0. 93- HN. /1. (5H, m), 1. 37-1. 83 (14H, Example N 3. 49 (1H, d, J=6. 3Hz), 3. 97- 11-H 08 (1H, m), 8. 16 (3H, brs), HCI 8. 45 (1H, d, J=7. 1Hz).

Table 1-3 1H-NMR (8ppm, DMSO-d6) 0. jj 90 (5H, m), 1. 97-1. 30 (7H, m), Example 1. 42-1. 52 (1H, m), 1. 56-1. 88 (7H, amp 75-2. 80 (1H, m), 2. 83- 2. 95 (1H, m), 3. 68-3. 77 (1H, m), Me 30 (1H, d, J=6. 3Hz), 8. 30 (3H, HCI brs). 0 A 0. 83- H 30 (15H, m), 1. 55-1. 80 (6H, Example 2 2. 60-2. 70 (1H, m), 4. 08- 13 Me 4. 18 (1H, m), 4. 30 (1H, d, W 3Hz), 8. 17 (3H, brs). HCI 0-H-NMR H2 21 (5H, m), 1. 56-1. 78 (8H, m), Example N 05-2. 20 (2H, m), 2. 25-2. 37 (2H, 14 CN m), 4. 30-4. 40 (1H, m), 4. 63 (2H, s), 4. 65-4. 70 (1H, m), 8. 29 (3H, HCI brs). 1H-NMR (8ppm, DMSO-d6) 0. 90 (3H, 0 d, J=6. 9Hz), 0. 97 (3H, d, Example 9Hz), 1. 55-1. 70 (2H, m), 15 N 1. 17 (3H, m), 2. 30-2. 37 Me 41 (1H, d, J=5. 6Hz), 4. 55 (2H, s), 4. 56-4. 68 (1H, m),. 8. 23 (3H, brs). 0 1. 01- H 17 (8H, m), 1. 57-1. 75 (8H, m), Example N 2. 00-2. 25 (4H, m), 3. 30-3. 50 (2H, 16 3. 92 (0. 35H, d, J=6. 1Hz), HCI 4. 18 (0. 65H, d, J=5. 6Hz), 4. 36- 4. 47 (1H, m), 8. 09 (3H, brs).

Table 1-4 O 0. 98- H Sx 1. 23 (5H, m), 1. 55-1. 80 (10H, Example H2Ns, m), 2. 05-2. 20 (4H, m), 3. 64 (1H, 17 H d, J=6. 0Hz), 8. 30 (3H, brs), C 0 0. 95-1. 80 H2N (16H, m), 1. 90-2. 00 (1H, m), Example 23 (1H, d, J=3. 6Hz), 7. 91 (1H, 18 S). 1H-NMR (8ppm, DMSO-d6) 0. 96 0 (5. 4H, s), 0. 98 (3. 6H, s), 1. 63- Example N."A (2H, m), 1. 99-2. 30 (4H, m), 19-Me 2. 88 (1. 7H, s), 3. 01 (1. 3H, s), Me'tMe 4. 11 (0. 4H, s), 4. 30 (0. 6H, s), Me 4. 70-4. 75 (1H, m), 8. 05 (3H, brs). 0 1H-NMR (8ppm, DMSO-d6) 0. 38- H 55 (2H, m), 0. 61-0. 70 (2H, m), Example ? 0. 97-1. 19 m), 1. 52-1. 75 (6H, 20 H 2. 65-2. 71 (1H, m), 3. 43 (1H, HCI J=6. 5Hz), 8. 18 (3H, brs), _ 63 (1H, d, J=4. 2Hz). 0 H-NMR DMSO-d6) 0. H NS, (6H, m), 1. 45-1. 80 (9H, m), Example 2-N s), 3. 11 (2. 4H, s), 21 12 (1H, d, J=5. 6Hz), 8. 28 (3H, HCI brs). 1H-NMR (8ppm, CDC13) 1. 55-1. 75 H (8H, m), 1. 86 (1H, s), 2. 04- Example 30 (6H, m), 2. 88 (1. 5H, s), 22 2. 93 (1. 5H, s), 3. 37 (1H, s), Me 3. 42 (1H, s), 4. 18-4. 29 (0. 5H, m), 4. 89-5. 00 (0. 5H, m).

Table 1-5 H-NMR 0. 87 (3H, m), 0. 91-0. 94 (3H, m), ° 06-1. 15 (1H, m), 1. 57-1. 84 (3H, Example '1. 23 88 (1. 8H, s), 2. 98 (1. 2H, s), 23 Me 4. 15 (0. 4H, d, J=5. 3Hz), HCI 4. 30 (0. 6H, d, J=5. 1Hz), 4. 47- 4. 55 (0. 6H, m), 4. 70-4. 79 (0. 4H, m), 8. 11 1H-NMR (8ppm, DMSO-d6) 1. 03- 0 1. 18 (5H, m), 1. 59-1. 73 (8H, m), H2N 99-2. 28 (4H, m), 2. 88 (1. 7H, Example 2 2. 98 (1. 3H, s), 4. 10 (0. 4H, 24 Me Me 4Hz), 4. 26 (0. 6H, d, HCI J=5. 4Hz), 4. 42-4. 58 (0. 6H, m), 4. 69-4. 80 (0. 4H, m), 8. 12 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 1. 58- 0 66 (2H, m), 2. 00-2. 30 (4H, m), 2. 87 (1. 8H, s), 2. 99 (1. 2H, s), 2 51-3. 62 (1H, m), 3. 65-3. 75 (1H, 25/Me 4. 24-4. 29 (0. 5H, m), 4. 38- HO HCI 4. 41 (0. 5H, m), 4. 47-4. 56 (0. 5H, m), 4. 74-4. 82 (0. 5H, m), 5. 52 (1H, brs), 8. 16 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. p 0. 95 (2H, m), 1. 10-1. 25 (4H, m), H2N 40-1. 67 (8H, m), 1. 82-1. 87 (1H, Example N 95-2. 20 (3H, m), 2. 25- 26 Me 2. 33 (lH, m), 2. 87 (1. 5H, s), hui 94 (1. 5H, s), 4. 21-4. 26 (0. 5H, xp) \ f/f t f HCI 4. 30-4. 42 (1H, m), 4. 71- 7. 83 (0. 5H, m), 8. 15 (3H, brs).

Table 1-6 1H-NMR (8ppm, DMSO-d6) 1. 55- 0 1. 68 (2H, m), 1. 96-2. 05 (1H, m), Example MENEZ J- (3H, m), 2. 53 (1. 5H, NEZ s), 2. 87 (3H, s), 3. 95 (1H, s), Me 00 (1H, s), 4. 15-4. 22 (0. 5H, m), 77-4. 89 (0. 5H, m), 8. 92 (3H, brs). 1H-NMR (8ppm, CDC13) 1. 51-1. 77 0 (14H, m), 1. 88 (2H, brs), 2. 05- Example fl, 30 (6H, m), 2. 88 (1. 5H, s), HO . 93 (1. 5H, s), 3. 37 (1H, s), Me s), 4. 15-4. 25 (0. 5H, m), 4. 90-4. 97 (0. 5H, m). Table 1-7 1H-NMR 1. 11-1. 40 H m), 1. 54-1. 80 (5H, m)., 1. 93- N 2. 35 (6H, m), 2. 78-2. 91 (1H, m), Example Me 2. 88 (1. 65H, s), 2. 98 (1. 35H, s), 30 4. 13 (0. 45H, d, J=5. 6Hz), Y (0. 55H, d, J=5. 8Hz), 4. 47- NH2 4. 58 (0. 55H, m), 4. 68-4. 79 (0. 45H, m), 8. 15 (6H, bs). 0 0. 96-1. 20 H2N,, > m), 1. 35-1. 77 (7H, m), 1. 84- N 31 (4H, m), 2. 79-2. 94 (4H, m), Me 4. 01-4. 07 (0. 45H, d, J=4Hz), Example NO 4. 15-4. 21 (0. 55H, d, J=4Hz), 2 (0. 55H, m), 4. 62-4. 76 HNo 45H, m), 7. 90-8. 15 (6H, m), NN. w , 32-8. 47 (2H, d, J=8. 8Hz). O O 0-H-NMR 0. 91-1. 21 H2N N (4H, m), 1. 32-1. 71 (7H, m), 1. 84- 2. 34 (4H, m), 2. 57-2. 72 (1H, m), Example Me 95 (3H, s), 3. 88-4. 33 32/NH (3. 28H, m), 4. 61-4. 77 (0. 72H, m), 6. 48-6. 73 (2H, d, J=8. 8Hz), 7. 04- HN 26 (1H, m), 7. 31-7. 51 (2H, d, k 8Hz), 7. 87-8. 14 (3H, m). 0 0 2. 06-2. 30Table 1-8 0 1. 16-1. 46 (4H, m), 1. 51-1. 82 (5H, m), 2N 83-2. 42 (6H, m), 2. 91 (1. 75H, Me s), 3. 02 (1. 25H, s), 3. 62-3. 85 Example (1H, m), 4. 19 (0. 42H, d, 35 J=5. 3Hz), 4. 34 (0. 58H, d, J 4. 49-4. 67 (0. 58H, m), HN 4. 71-4. 86 (0. 42H, m), 7. 35-7. 50 \ m), 7. 97-8. 06 (1H, m), . 14 (3H, brs), 8. 25-8. 47 (3H, m). 0 0. 78-1. 32 HNA, -- 1. 39-1. 86 (8H, m), N 1. 93-2. 37 (4H, m), 2. 88 (1. 72H, Me 2. 98 (1. 28H, s), 3. 23 (2H, d, Example 3Hz), 4. 13 (0. 42H, d, 36 J=5. 4. 28 (0. 58H, d, 4Hz), 4. 45 (2H, s), 4. 47- 0 60 (0. 58H, m), 4. 69-4. 83 (0. 42H, m), 7. 03-7. 21 (3H, m), 7. 32-7. 44 (1H, m), 8. 06 (3H, - HCI brs). O 1H-NMR (8ppm, DMSO-d6) 1. 00-1. 30 H2N (4H, m), 1. 55-1. 65 (5H, m), 1. 75 N (3H, s), 1. 75-1. 81 (2H, m), Me 95-2. 35 (4H, m), 2. 05 (3H, s), Me Example HCI 3. 38-3. 43 (1H, m), 4. 12-4. 16 37 (0. 4H, m), 4. 21-4. 25 (0. 6H, m), 4. 52-4. 56 (0. 6H, m), 4. 73-4. 77 HN,,,,,-YMe (0. 4H, m), 5. 58 (1H, d, 0 8Hz), 7. 62 (1H, d, J=8Hz), o 14 (3H, brs). 0 1. 25-1. 55 H m), 1. 60-1. 85 (5H, m), N 97-2. 35 (6H, m), 2. 91 (1. 74H, Me 26H, s), 4. 21 (0. 42H, Me Example d, J=6. 0Hz), 4. 35 (0. 58H, d, 38 4. 56 (0. 58H, m), 4. 78 (1. 42H, m), 7. 51 (2H, dd, o 4Hz, 7. 2Hz), 7. 65 (2H, t, 0 HCI J=7. 7. 93 (2H, d, J=8. 4Hz), 8. brs).

Table 1-9 _ u.. 95 (2H, m), 1. 00-1. 40 (3H, m), N 1. 55-1. 80 (7H, m), 1. 95-2. 35 (4H, m), Example Mu 39 18 (2H, t-like), 4. 13 (0. 42H, d, J=5. 2Hz), 4. 27 T 58H, d, J=5. 2Hz), 4. 39 (1H, t, "HCI J=4 : 4. 53 (0. 58H, m), 4. 77 (0. m) 8. 03 (3H, brs). 0 0. 85-1. 00 (2H, m), 1. 07 (3H, t, J=7. 2Hz), H2N 10-1. 20 (2H, m), 1. 35-1. 80 (8H, m), 1. 90-2. 30 (4H, m), 2. 86 Me Example s), 2. 95 (1. 26H, s), 3. 26 40 10 (0. 42H, d, 0\\/o J=5. 6Hz), 4. 25 (0. 58H, d, SMe J=5. 6Hz), 4. 53 (2H, s), 4. 45- 4. 55 (0. 58H, m), 4. 75 (0. 42H, m), - 63 (2H, m), 7. 77 (2H, m), 7. (3H, brs). 0 0. 85-1. 00 (2H, m), 1. 06 (3H, t, J=7. 2Hz), N 1. 10-1. 25 (2H, m), 1. 45-1. 85 (8H, Me 1. 90-2. 35 (4H, m), 2. 86 Me (1. 74H, s), 2. 95 (1. 26H, s), 3. 25 Example (4H, m), 4. 11 (0. 42H, d, 41 J=5. 6Hz), 4. 26 (0. 58H, d, 0 4. 54 (2H, s), 4. 45- Me 60 (0. 58H, m), 4. 74 (0. 42H, J=8. OHz), 7. 82 (2H, d, J=8. OHz), 8. 00 (3H, o 1H-NMR 0. 85-1. 00 (2H, m), 1. 09 (3H, t, J=7. 2Hz), H2N-N 10-1. 25 (2H, m), 1. 45-1. 85 (8H, X 1. 95-2. 35 (4H, m), 2. 88 Example Me s), 2. 98 (1. 26H, s), 3. 33 0 13 (0. 42H, d, 0-, Me J=5. 6Hz), 4. 28 (0. 58H, d, J=5. 6Hz), 4. 52 (0. 58H, m), 4. 75 0 42H, m), 4. 82 (2H, s), 7. 55- 9 7. 76 (3H, m), 7. 89 (1H, d, J=7. 6Hz), 03 (3H, brs).

Table 1-10 1H-NMR (8ppm, DMSO-d6) 0. (2H, m), 1. 05-1. 25 (2H, m), 1. 40- H2N 80 (8H, m), 1. 95-2. 35 (4H, m), z 88 (1. 74H, s), 2. 97 (3H, s), Me 98 (1. 26H, s), 3. 24 (2H, d, Example 4Hz), 4. 13 (0. 42H, d, 43 Me 4. 28 (0. 58H, d, 0 6Hz), 4. 56 (2H, s), 4. 59 (2H, s), 4. 45-4. 60 (0. 58H, m), 4. 76 HC I @ 42H, m), 7. 31-7. 41 (4H, m), 8. 01 brs). 0 0. 80-1. 00 H2N-"A m), 1. 00-1. 25 (2H, m), 1. 46 I m), 1. 63 (4H, m), 1. 78 (2H, Me m), 1. 95-2. 35 (4H, m), 2. 88 (1. 74H, t 2. 97 (1. 26H, s), 3. 21 (2H, d, Example J=6. 4Hz), 4. 14 (0. 42H, brs), 44 . 4. 30 (0. 58H, brs), 4. 38 (2H, s), 4. 49 (2H, q, J=9. 6Hz), 4. 76 /NSCF3 m), 7. 18 (2H, d, J=8. 8Hz), 7. 27 H d, J=8. 8Hz), 8. 04 (3H, brs), - HCI 10. 43 (1H, brs). 0 1. 05-1. 35 (4H, m), 1. 53-1. 75 (5H, m), 1. 84- N 2. 38 (6H, m), 2. 90 (1. 74H, s), Me 2. 99 (1. 26H, s), 3. 16-3. 33 (1H, Example 15 (0. 42H, d, J=5. 1Hz), 4. 29 (0. 58H, d, J=5. 5Hz), 4. 46- 4. 62 (0. 58H, m), 4. 69-4. 83 (0. 42H, HN\/0 m), 7. 07 (2H, d, J=7. 7Hz), 11 19 (1H, dd, J=7. 4Hz, 7. 1Hz), 7. 37 (2H, dd, J=7. 7, 7. 3Hz), 7. 63 '7g m), 7. 78-8. 56 (3H, brs). ° 1. 20-1. 44 H2N m), 1. 56-1. 78 (5H, m), 1. 92- i 36 (6H, m), 2. 91 (1. 74H, s), Me 3. 01 s), 3. 70-3. 83 (1H, m), Example 4. 15-4. 23 (0. 42H, m), 4. 29-4. 38 46 (0. 58H, m), 4. 51-4. 62 (0. 58H, m), HN 4. 71-4. 83 (0. 42H, m), 7. 48-7. 58 11 m), 7. 92-8. 02 (2H, m), 8. 06- 8. 20 (4H, m), 8. 36-8. 44 (1H, m). HCI Table 1-11 H-NMR (8ppm, CDC13) 0. 86-1. 29 (4H, m), 1. 35-1. 78 (7H, m), 1. 79 0-1. 95 (3H, m), 2. 00-2. 35 (4H, H 2. 94 (1. 74H, s), 2. 95 N 26H, s), 3. 30 (2H, d, Me 5Hz), 3. 43 (0. 42H, d, Example J=5. 8Hz), 3. 53 (0. 58H, d, 47Me 3. 81 s), 4. 32- 4. 43 (0. 58H, m), 4. 52 (2H, s), 0 86-4. 97 (0. 42H, m), 6. 83 (1H, d, 6. 93 (1H, dd, J=7. 5Hz, 7. 5Hz), 7. 23 (1H, dd, J=8. 1Hz, 7. 5Hz), 7. 35 (lui, d, J=7. 4Hz). 1H-NMR (8ppm, DMSO-d6) 0. 93-1. 33 0 (4H, m), 1. 55-1. 77 (6H, m), 1. 82 -2. 36 (6H, m), 2. 89 (1. 74H, s), N 99 (1. 26H, s), 3. 14 (3H, s), I 88 (2H, d, J=6. 3Hz), 4. Example Me 48 42H, d, J=5. 3Hz), 4. 30 (0. 58H, d, J=5. 5Hz), 4. 49-4. 60 Me 58H, m), 4. 71-4. 83 (0. 42H, m), 7. 13 (2H, d, J=8. 8Hz), 7. 81 O d, J=8. 8Hz), 7. 91-8. 25 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 1. 01-1. 31 0 (4H, m), 1. 55-1. 80 (6H, m), 1. 86-2. 37 (6H, m), 2. 90 (1. 74H, Me s), 3. 00 , Example 4. 16 (0. 42H, d, J=5. 8Hz), 4. 32 49/I (0. 58H, d, J=5. 1Hz), 4. 50-4. 61 (0. 58H, m), 4. 72-4. 84 (0. 42H, \ 7. 13 (1H, dd, J=7. 5Hz, °tS 4Hz), 7. 25 (1H, d, J=8. 6Hz), aI 66 (1H, dd, J=7. 9Hz, 8. 2Hz), 0 J=7. 7Hz), 8. 00- 8. 21 (3H, brs).

Table 1-12 H-NMR (Sppm, DMSO-d6) 0. 79-1. 29 0 m), 1. 40-1. 86 (8H, m), H 93-2. 37 (4H, m), 2. 04 (3H, s), 22N 88 (1. 74H, s), 2. 97 (1. 26H, s), I Me 3. 22 (2H, d, J=5. 5Hz), 4. 09-4. 19 Example 42H, m), 4. 24-4. 34 (0. 58H, 50 m), 4. 43 (2H, s). 4. 48-4. 58 HN Me (0. 58H, m), 4. 70-4. 83 (0. 42H, m), 13 (1H, dd, J=7. 4, 7. 0Hz), 7. 24 (1H, dd, J=8. lHz, 7. 7Hz), HCI 34 (1H, d, J=7. 8Hz), 7. 46 (1H, d, J=7. 7Hz), 7. 94-8. 18 (3H, brs), 9. 28 (1H, s). 0 0. 80-1. 31 H N m), 1. 42-1. 85 (8H, m), N 36 (4H, m), 2. 88 (1. 74H, i Me s), 2. 98 (4. 26H, s), 3. 25 (2H, d, Example t 0 2Hz), 4. 10-4. 19 (0. 42H, m), 51 ism 25-4. 34 (0. 58H, m), 4. 46-4. 62 HN Me (0. 58H, m), 4. 56 (2H, s), 4. 70- 4. 83 (0. 42H, m), 7. 20-7. 36 (3H, m), 7. 40 (1H, d, J=7. 5Hz), 7. 94- w 8. 17 (3H, brs), 8. 94 (1H, s). 1H-DdMR (8ppm, DMSO-d6) 0. 94-1. 33 0- m), 1. 56-1. 81 (6H, m), H2N 1. 83-2. 36 (6H, m), 2. 89 (1. 74H, {s), 2. 99 (1. 26H, s), 3. 21 (3H, Me 3. 87 (2H, d, J=6. 2Hz), 4. 16 Example (0. 42H, d, J=5. 6Hz), 4. 31 52 58H, d, J=5. 3Hz), 4. 48-4. 61 , Me 58H, m), 4. 71-4. 84 (0. 42H, m) 26 (1H, d, J=7. 9Hz), 7. 38 0 d, J=1. 9Hz), 7. 47 (1H, d, 7. 54 (1H, dd, J=7. 9Hz, 7. 9Hz), 7. 96-8. 24 (3H, brs).

Table 1-13 1H-NMR 0. 91-1. 38 R 1. 46-1. (5H, m), H2 1. 79-2. 38 (6H, m), 2. 83-3. 00 (3H, z 3. 68 (3H, s), 3. 22-3. 40 (1H, Example 08-4. 21 (0. 4H, m), 4. 29- Example 4. 36 (0. 6H, m), 4. 44-4. 61 (0. 6H, H 4. 66-4. 83 (0. 4H, m), H HN>N<OMe 6. 19 (1H, d, J=8Hz), 6. 41 (1H, m), 6. 78 (1H, d, J=8Hz), 6. 96- O 15 (2H, m), 7. 90-8. 21 (3H, br), 8. 55 (1H, s). 0 DMSO-d6) 0. 87-1. 39 HZNI"A (4H, m), 1. 49-1. 77 (5H, m), | 37 (9H, m), 2. 83-3. 02 (1H, Me 3. 19-3. 42 (1H, m), 4. 08-4. 21 Example (0. 4H, m), 4. 23-4. 36 (0. 6H, m), 54 H 4. 45-4. 59 (0. 6H, m), 4. 68-4. 81 Han (0. 4H, m), 6. 11 (1H, d, J=8Hz), l 6. 97 (2H, d, J=8Hz), 7. 20' (2H, d, Me J=8Hz), 7. 91-8. 18 (3H, br), HCI 8. 38 (1H, s). 0 0. 86-1. 42 H2N,, m), 1. 48-2. 38 (11H, m), . 76-3. 04 (3H, s), 2. 12-3. 30 (1H, Example Me m), 4. 05-4. 15 (0. 4H, d, J=4Hz), 55 19-4. 31 (0. 6H, d, J=4Hz), 4. 40-4. 59 (1. 6H, m), 4. 67-4. 80 OH (0. 4H, m), 7. 84-8. 20 (3H, br). 0 1. 11-1. 42 H m), 1. 49-1. 76 (5H, m), nul 76-1. 92 (9H, m), 2. 82-3. 06 (3H, Me s), 3. 56-3. 77 (1H, m), 4. 09-4. 20 Example Example 4H, d, J=4Hz), 4. 25-4. 36 (0. 6H, d, J=4Hz), 4. 47-4. 64 HN (0. 6H, m), 4. 67-4. 84 (0. 4H, m), ; 21 (2H, d, J=8Hz), 7. 70 (2H, d, 0-HCI 7. 93-8. 25 (4H, br).

Table 1-14 0 0. 84-1. 18 H2NUs 41-1. 84 (7H, m), N 1. 99-2. 32 (4H, m), 2. 89 (1. 68H, i Me 2. 98 (1. 32H, s), 3. 27 (2H, d, Example 0 J=6. 78Hz), 4. 16 (0. 44H, m), 57 9 4. 32 (0. 56H, m), 4. 52 (2H, d, J=9. 42Hz), 4. 56 (2H, s), 4. 46- 4. 60 (0. 44H, m), 4. 78 (0. 56H, m), CJ 30-7. 45 (4H, m), 8. 02 (3H, . 9. 68 (1H, s). Table 1-15 1H-NMR 1. 09-1. 19 (4H, 54-2. 33 (12H, m), H2N"IN 88 (1. 60H, s), 2. 97 (1. 40H, 4. 09-4. 19 (0. 46H, m), 4. 25- Example \ 3 34 (0. 64H, m), 4. 46-4. 56 58 (0. 50H, m), 4. 56 (2H, s), 4. 70- 4. m), 7. 46 (1H, t, 0 7. 54 (1H, d, / 9Hz), 7. 83 (1H, d, 0 4Hz), 7. 88 (1H, s), 8. 05 0 (3H, s). O 1. 09-1. 18 11/~7 (4H, m), 1. 54-2. 31 (12H, m), N 2. 87 (1. 79H, s), 2. 96 (1. 21H, s), 3. 28 (2H, s), 4. 09-4. 18 Example < CH3 (0. 40H, m), 4. 25-4. 32 (0. 60H, 59 m), 4. 45-4. 56 (0. 56H, m), 4. 57 ON 81 (0. 44H, m), 7. 41 (2H, d, J=8. 3Hz), 7. 90 0 d, J=8. 3Hz), 7. 99 (3H, brs). 0 1H-NMR H N (4H, 1. 69-2. 12 (12H, m), N 2. 88 (1. 83H, s), 2. 96 (1. 17H, ~ 3. 31 (2H, s), 4. 07-4. 20 Example 49H, m), 4. 24-4. 34 (0. 51H, Example 49-4. 62 (2. 55H, m), 4. 68- 60 Y 4. 82 (0. 45H, m), 7. 55-7. 58 (1H, %, 7. 83-7. 86 (1H, m), 8. 01- 0 8. 03 (4H, m). Cl Table 1-16 0 1H-NMR 0. 85-1. 20 HN < 46-2. 29 (12H, m), N 87 (1. 85H, s), 2. 94 (1. 15H, -CH HCI 3. 22 (2H, d, J=6. 0Hz), CH3 Example 07-4. 17 (0. 49H, m), 4. 22-4. 31 61 (0. 51H, m), 4. 44-4. 54 (2. 58H, OH m), 4. 70-4. 80 (0. 42H, m), 7. 41- 7. 45 (1H, m), 7. 48-7. 52 (1H, 0 7. 68-7. m), 8. 05 (3H, brs). CI 0 1H-NMR 0. 82-1. 27 H N m), 1. 47-2. 30 (12H, m), N 2. 84 (1. 86H, s), 2. 94 (1. 14H, 'HCI s), 3. 27 (2H, d, J=8. 1Hz), CH3 example 08-4. 22 (0. 47H, m), 4. 21-4. 31 62 45-4. 58 (2. 53H, OH m), 4. 66-4. 79 (0. 47H, m), 7. 27- 7. 32 (1H, m), 7. 87-7. 92 0 m), 7. 98-8. 01 (1H, m), 8. 10 1 brs). F 0 H-NMR 0. 99-1. 13 H m), 1. 36-2. 31 (12H, m), N 2. 88 (1. 79H, s), 2. 97 (1. 21H, ~ HCI s), 3. 17-3. 21 (2H, m), 4. 08- CH3 Example 18 (0. 50H, m), 4. 23-4. 33 63 (0. 50H, m), 4. 35 (2H, s), 4. 49- OH 4. 60 (0. 44H, m), 4. 70-4. 81 (0. 56H, m), 6. 93-6. 98 (1H, m), 0 7. 42-7. 47 (1H, m), 7. 70-7. 74 (1H, m), 8. 12 (3H, brs). OH Table 1-17 0 1H-NMR 0. 81-1. 22 H 34-2. 28 (12H, m), 2. 87 (1. 83H, s), 2. 96 (1. 17H, ~ 3. 22 (2H, d, J=6. 0Hz), Example 4. 12-4. 16 (0. 43H, m), 4. 21-4. 31 64 (0. 57H, m), 4. 41 (2H, s), 4. 46- 4. 56 (0. 55H, m), 4. 68-4. 79 0 45H, m), 6. 56 (1H, d, 0 J=3. 2Hz), 7. 14 (1H, d, 0 J=3. 2Hz), 8. 10 (3H, brs). 0 1. 23 (4H, m), 1. 75-2. 02 (12H, m), (1. 7H, s), 2. 98 (1. 3H, s), 3. 25 (2H, d, J=6. 0Hz), CH 4. 09-4. 19 (0. 37H, m), 4. 23-4. 33 (0. 63H, m), 4. 45-4. 56 (4. 6H, Example OH m), 4. 70-4. 80 (0. 4H, m), 7. 48 65 s), 7. 74 (1H, s), 7. 82 0<~0 8. 08 (3H, brs). OH OH lH-NMR 0. 86-1. 22 (4H, m), 1. 48-2. 32 (12H, m), H2N 88 (1. 66H, s), 2. 95 (1. 34H, s), 3. 24 (2H, d, J=5. 3Hz), 3. 30 CH3 s), 4. 08-4. 17 (0. 39H, m), 4. 22-4. 31 (0. 61H, m), 4. 40-4. 57 Example (4. 52H, m), 4. 68-4. 79 (0. 48H, 66 m), 7. 45-7. 49 (1H, m), 7. 73- 90/T 83 OMe (8ppm, DMSO-d6)Table 1-18 0'H-NMR 1. 00- H2N 22 (4H, m), 1. 63-2. 31 (16H, m), 2. 89 (1. 80H, s), 2. 98 (1. 20H, A 4. 16 (0. 40H, d, J=4. 6Hz), CH Example 4. 30 (0. 60H, d, J=4. 6Hz), 4. 48- 67 F 58 (0. 48H, m), 4. 71- 4. 82 (0. 52H, m), 7. 15-7. 25 (3H, OH m), 8. 00 (3H, brs). 0 0 0 H-NMR 1. 05-1. H m), 1. 56-2. 31 (12H, m), N 88 (1. 60H, s), 2. 98 (1. 40H, A 3. 15 (2H, d, J=4. 6Hz), 3. 86 Example (2H, d, J=6. 0Hz), 4. 15 (0. 41H, 68 d, J=5. 6Hz), 4. 30 (0. 59H, d, J=5. 6Hz), 4. 48-4. 58 (0. 53H, m), OH 70-4. 80 (0. 47H, m), 7 13-7. 19 ( m), 7. 32-7. 36 (2H, m), F 8. 06 (3H, brs). 0 1. 11-1. 19 H2N 1. 65-2. 33 (12H, m), N 2. 90 (1. 9H, s), 3. 00 i CH3 3. 77-3. 87 (2H, Example 4. 13-4. 21 (0. 5H, m), 4. 26- 69 35 (0. 5H, m), 4. 50-4. 60 (0. 74H, m), 4. 68 (2H, s), 4. 73- OH (0. 26H, m), 7. 11-7. 16 (1H, r m), 7. 20-7. 24 (1H, m), 7. 31- J 36 (1H, m), 8. 12 (3H, brs). MeO 0 H-NMR (8ppm, 1. 09- 1. 51 (7H, m), 1. 53-2. 38 (8H, m), N 2. 86 (1. 72H, s), 2. 99 (1. 28H, s), Example 3. 17 (3H, s), 3. 38 (1H, m), 70 HCI 43H, m), 4. 26 (0. 57H, m), 4. 77 (0. 43H, m), 8. 12 (3H, brs). OMe Table 1-19 0 0. 88- ll 1. 32 (4H, m), 1. 50-1. 76 (5H, m), N 92-2. 34 (6H, m), N 2. 89 (1. 49H, s), 2. 97 (1. 51H, s), Example CH 16 (3H, s), 3. 31 s), 71 14 (0. 44H, d, J=5. 6Hz), 4. 29 (0. 56H, d, J=5. 6Hz), 4. 56 (0. 56H, m), 4. 76 (0. 44H, m), OMe 02 (3H, brs). 0/ H-NMR 0. 92- . 1. 27 (4H, m), 1. 38-1. 76 (7H, m), N 1. 89-2. 38 (4H, m), 2. 78- ~ 2. 90 (2. 72H, m), 2. 91- Example CH3 2. 96 (1. 27H, s), 4. 06 (0. 43H, d, oc J=5. 6Hz), 4. 20 (0. 57H, d, J=0. 56Hz), 4. 47 (0. 43H, m), HN 4. 72 (0. 43H, m), 7. 55-7. 63 (2H, "S 7. 84-7. 96 (3H, m), 8. 05 (3H, 0 _ 0. 95-1. 22 (4H, R 1. 39-1. 74 (7H, m), 1. 88- 2. 36 (7H, m), 2. 75 (1H, m), 2. 94 (1. 31H, s), 2. 85 (1. 69H, s), Example 0X/CH3 4. 05 (0. 44H, d, J=5. 6Hz), Example Example 20 (0. 56H, d, J=5. 6Hz), NH 4. 45 (0. 56H, d, J=5. 6Hz), 4. 72 (0. 44H, m), 7. 53 (1H, m), HNs 70 (2H, d, J=8. 8Hz), 7. 76 (2H, d, J=8. 8Hz), 7. 98 (3H, brs), 10. 41 (1H, s). 0 1H-NMR (8ppm, DMSO-d6) 0. 95- 1. 20 (4H, m), 1. 38 (7H, m), H2N 92 (4H, m), 2. 76 (1H, m), 1 86 (1. 73H, s), 2. 93 (1. 27H, s), CH3, 3. 12 (3H, s), 4. 07 (0. 42H, d, J=5. 4. 21 (0. 58H, d, J 4. 46 (0. 58H, m), 4. 72 (0. 42H, m), 7. 55-7. 64 (1H, HN/ 7. 32 (2H, d, J=8. 8Hz), 7. (2H, d, J=8. 8Hz), 8. 00 (3H, brs).

Table 1-20 0 H-NMR 1. 32- 2. 39 (15H, m), 2. 89 (1. 81H, s), N 3. 02 (1. 19H, s), 3. 31 (1H, m), Example 10 (0. 39H, m), 4. 26 (0. 61H, m), Example CH3 75 77 (0. 39H, m), 8. 23 (6H, brs). NH2 2 0 1. 15- 1. 42 (4H, m), 1. 53-1. 78 (5H, m), N 1. 78-1. 94 (2H, m), 1. 94-2. 40 (7H, ~ HCI m), 2. 90 (1. 81H, s), 3. 01 (1. 19H, CH3 Example s), 3. 69 (1H, m), 4. 17 (0. 41H, d, 76 6Hz), 4. 32 (0. 59H, d, J=5. 6Hz), 4. 57 (0. 59H, m), HN 4. 77 (0. 41H, m), 7. 24 (2H, d, J=8. 3Hz), 7. 73 (2H, d, J=8. 3Hz), 0 8. 12 (4H, brs). 0 P-n 1. 13- H2N 43 (4H, m), 1. 50-1. 79 (5H, m), N 1. 81-2. 41 (6H, m), 2. 90 (1. 81H, -CH3 3. 00 (1. 19H, s), 3. 70H (1H, CH3 Example m), 4. 16H (0. 40H, d, J=5. 6Hz), CF3 32 (0. 60H, d, J=5. 6Hz), 4. 57 (0. 60H, m), 4. 77 (0. 40H, m), HN 83 (2H, d, 8. 8Hz), 7. 95- HCI 8. 29 (5H, brs), 8. 53 (1H, m). 0 0 1H-NMR 1. 13- H 45 (4H, m), 1. 51-1. 78 (6H, m), N 1. 79-2. 40 (6H, m), 2. 91 (1. 80H, HCI 3. 00 (1. 20H, s), 3. 67 (1H, Example < 3. 79 (3H, s), 4. 18 (0. 40H, OMe 4. 33 (0. 60H, brs), 4. 57 (0. 60H, m), (4. 78H, m), HN 97 (2H, d, J=9. 3Hz), 7. 80 (2H, Y J=9. 3Hz), 8. 11 brs). 0 Table 1-21 0 H-NMR 0. 94- H 20 (4H, m), 1. 40-1. 72 (7H, m), N 1. 72-2. 43 (7H, m), 2. 76 (1H, s), CH HCI 2. 85 (1. 68H, s), 2. 93 (1. 32H, s), Example 4. 05 (0. 44H, d, J=5. 6Hz), 79 4 4. 19 (0. 56H, d, J=5. 6Hz), 4. 46 (0. 56H, m), 4. 72 (0. 44H, m), HN 7. 38 (2H, d, J=8. 3), 7. 61 (1H, //Sb 7. 68 (2H, d, J=8. 3Hz), 0 07. 95 (3H, brs). 0 P-n 0. 90- H N, m), 1. 38-1. 79 (7H, m), N 1. 87-2. 40 (4H, m), 2. 73-3. 06 (4H, m), 4. 06 (0. 44H, d, CH Example < 4. 21 (0. 56d, J=5. 6Hz), 80 Cl3 46 (0. 56H, m), 4. 72 (0. 44H, m), 7. 84-8. 12 (4H, brs). HN. Jk HN,, O//Sto 0 H-NMR DMSO-d6) 0. 92- H 1. 27 (4H, m), 1. 39-1. 74 (7H, m), N 1. 92-2. 38 (4H, m), 2. 75 ~ 76H, s), 2. 94 (1. 24H, s), Example 3. 83 (3H, s), 4. 04 (0. 42H, d, 81 OMe J=5. 1Hz), 4. 19 (0. 58H, d, T 4. 47 (0. 58H, m), HN w 73 (0. 42H, m), 7. 10 (2H, d, //Sb 8Hz), 7. 52 (1H, m), 7. 72 (2H, 0 \0 J=8. 8Hz), 7. 86 (3H, brs). p 1H-NMR 0. 94- H 43 (4H, m), 1. 51-1. 80 (5H, m), 2-N 81-2. 39 (6H, m), 2. 89 (1. 70H, CH 3. 00 (1. 30H, s), 3. 36 (1H, CH3 4. 18 (0. 43H, m), 4. 32 (0. 57H, Example 4. 54 (0. 57H, m), 4. 77 (0. 43H, 82 6. 42 (1H, d, J=7. 9Hz), H 55 (1H, m), 8. 07 (3H, brs), HN s). 0 CF3 Table 1-22 Q 0. 95- HaN 42 (4H, m), 1. 50-1. 79 (5H, m), 2 81-2. 41 (6H, m), 2. 90 (1. 73H, i 3. 00 (1. 27H, s), 3. 36 (1H, CH3 Example 3. 67 (3H, s), 4. 17 (0. 42H, 83 4. 32 (0. 58H, m), 4. 54 (0. 58H, "r 4. 77 (0. 42H, m), 6. 06 (1H, d, HN 6. 79 (2H, m), 7. 25 (2H, m), 8. 08 (3H, brs), 8. 31 (1H, s). O OMe 0 1. 34-1. 71 H2N/ m), 1. 72-1. 95 (3H, m), -IN 95-2. 41 (4H, m), 2. 91 (1. 65H, CH3 03 (1. 39H, s), 4. 06 (1H, Example 14 (0. 46H, d, J=6. 5Hz), 84 30 (0. 54H, d, J=6. 5Hz), 4. 55 (0. 54H, m), 4. 78 (0. 46H, m), HN 7. 40-7. 56 (3H, m), 7. 85 (3H, m), 8. 15 (3H, brs). 0 0 1H-NMR 1. 13- H 78 (lah, m), 1. 93-2. 40 (4H, m), N 2. 88 (1. 73H, s), 2. 99 (1. 27H, s), C 22 (1H, m), 4. 05 (0. 43H, d, CH 4. 21 (0. 57H, d, Example hui 3. 85 J=7. 4. 51 m), 4. 76 (0. 43H, m), 7. 49-7. 68 (4H, HN m), 7. 83 (2H, m), 8. 08 (3H, brs). O//So 0 0 0 1H-NMR 1. 25- 1. 85 (11H, m), 1. 93-2. 39 (4H, m), N 2. 91 (1. 78H, s), 3. 03 (1. 22H, s), cl3 79 (1H, m), 4. 12 (0. 41H, d, CH3 Example 4. 28 (0. 59H, d, 86 L 5Hz), 4. 59 (0. 59H, m), 86 80 (0. 59H, m), 6. 71 (1H, m), HN N 6. 86 (1H, J=7. 4Hz), 7. 20 (2H, t, 9Hz), 7. 37 (2H, d, 0 3Hz), 8. 12 (3H, brs).

Table 1-23 0 1H-NMR (8ppm, DMSO-d6) 0. 94- H , 30 (7H, m), 1. 17-1. 75 (7H, m), HC I 4H m 8 1H m 2 92-2. 37 (4H, 2. 78 (1H, 2. 86 (1. 65H, s), 2. 93 (1. 35H, s), CHUS Example 3. 22 (2H, q, J=7. 3Hz), NH 07 (0. 45H, m), 4. 21 (0. 55H, m), 4. 46 (0. 55H, m), 4. 72 (0. 45H, m), HNs 7. 34 (2H, d, J=8. 8Hz), 7. 59 (1H, , 7. 73 (2H, d, J=8. 8Hz), 0 7. 99 (3H, brs), 10. 37 (1H, s). 0 r-lH-NMR 0. 89- H2N,,), 28 (4H, m), 1. 38-1. 74 (7H, m), | 93-2. 40 (4H, m), 2. 71 (1H, m), 0 CH3 86 (1. 73H, s), 2. 96 (1. 27H, s), Eample 4. 07 (0. 42H, m), 4. 23 (0. 58H, m), 88 4. 48 (0. 58, m), 4. 75 (0. 42H, m), hui HCI (2H, d, J=8. 8Hz), 7. 46- Hiss 70 (6H, m), 7. 80 (2H, d,. 0 J=8. 8Hz), 8. 01 (3H, brs). 0 0 1H-NMR 0. 92- H 1. 32 (4H, m), 1. 40-1. 79 (7H, m), "V '1. 77-3. 02 (4H, N 1. 88-2. 34 (4H, m), m), 06 (0. 45H, d, Example J=5. 6Hz), 4. 20 (0. 55H, d, 89 J=5. 6Hz), 4. 46 (0. 55H, m), 4. 72 (0. 45H, m), 7. 44 (1H, m), HN 7. 52 (2H, m), 7. 69-7. 80 (3H, m), /St 7. 81-8. 12 (7H, m). O 0 1H-NMR 0. 95- HN 19 (4H, m), 1. 22 (6H, d, HCI 5Hz), 1. 40-1. 78 (7H, m), 1. 92-2. 40 (4H, m), 2. 70-3. 07 (5H, Example CH3 4. 06 (0. 45H, d, J=5. 6Hz), 90 4. 20 (0. 55H, d, J=5. 6Hz), 4. 47 (0. 55H, m), 4. 73 (0. 45H, m), HNs 45 (2H, d, J=8. 3Hz), 7. 61 (1H, /Sb m), 7. 71 (2H, d, J=8. 3Hz), 0 07. 93 (3H, brs).

Table 1-24 0-H-NMR 1. 06- H N-1" 36 (4H, m), 1. 44-1. 85 (7H, m), 2 93-2. 39 (4H, m), 2. 88 (1. 78H, CH 2. 99 (1. 22H, s), 3. 51 (1H, CH3 Example m), 3. 75 (2H, d, J=5. 6Hz), 91 14 (0. 41H, d, J=5. 6Hz), 4. 29 (0. 59H, d, J=5. 6Hz), HN 4. 53 (0. 59H, m), 4. 77 (0. 41H, m), m), 7. 48 (1H, m), 0 02 (3H, brs). H-NMR 0. 95- HCI 1. 20 (4H, m), 1. 26 (6H, d, J=7. , 1. 41-1. 77 (7H, m), I 1. 92-2. 39 (4H, m), 2. 76 (1H, s), CH3 86 (1. 70H, s), 2. 95 (1. 30H, s), 2 3. 36 (1H, sep, J=7. 0Hz), NH 08 (0. 43H, m), 4. 23 (0. 57H, m), 4. 47 (0. 57H, m), 4. 73 (0. 4. m), HNs/9 7. 35 (2H, d, J=8. 8Hz), 7. 58 (1H, "S, (2H, d, J=8. 8Hz), 7. 90 (3H, brs), 10. 32 (1H, s). 0 H-NMR 0. 94 (3H, t, 4Hz), 0. 98-1. 21 (4H, m), 2 39-1. 80 (9H, m), 1. 92- -CH 38 (4H, m), 2. 69- 00 (4H, m), Example 19 (2H, t, J=7. 4Hz), 93 4. 07 (0. 45H, m), 4. 22 (0. 55H, m), 4. 4 (0. 55H, m), 4. 72 (0. 45H, m), HNX '7. 33 (2H, d, J=8. 8Hz), 7. 59 (1H, "St 7. 73 (2H, d, J=8. 8Hz), 8. 00 (3H, brs), 10. 38 0 1H-NMR 1. 02- H 35 (4H, m), 1. 44-1. 86 (7H, m), N 2. 88 (1. 80H, 1 r I | 2. 97 (1. 20H, s), 3. 13 (3H, CH3. 3. 36 (1H, m), 4. 14 (0. 40H, Example 4. 29 (0. 60H, m), 4. 52 (0. 60H, Y 4. 76 (0. 40H, m), 5. 66 (1H, X 7. 12-7. 26 (3H, m), 7. 35 (2H, HN m), 08 (3H, brs). I 1 0 Table 1-25 1H-NMR (8ppm, DMSO-d6) 0. 87 (3H, Q t, J=7. 1Hz), 0. 96-1. 40 (4H, m), ll 42-1. 80 (7H, m), 1. 81- H2N 36 (6H, m), 2. 45 (2H, i J=7. 4Hz), 2. 90 (1. 74H, s), Example L 01 (1. 26H, s), 3. 35 (1H, m), 95 17 (0. 42H, d, J=5. 6Hz), H 31 (0. 58H, d, J=5. 6Hz), HN 4. 55 (0. 58H, m), 4. 76 (0. 42H, m), 6. 16 (1H, d, J=7. 4Hz), 7. 00 (2H, d, J=8. 3Hz), 7. 25 (2H, d, J=8. 3Hz), 8. 07 (3H, brs), 8. 44 (1H, s). 0 H-NMR 0. 85 (6H, d, J=6. 5Hz), 0. 96-1. 40 (4H, m), H2N 1. 43 (14H, m), 2. 89 (1. 73H, l 2. 99 (1. 27H, s), 3. 33 (1H, CH3 17 (0. 42H, m), 4. 32 96 m), 4. 54 (0. 58H, m), T 4. 77 (0. 42H, m), 6. 22 (1H, d, HN N J=7. 4Hz), 6. 65 (1H, d, J=7. 4Hz), 7. 08 (1H, t, J=7. 4Hz), 7. 12- 0 19 (2H, m), 8. 09 (3H, brs), 8. 51 (1H, s). O 0. 92- HN 42 (7H, m), 1. 51-1. 80 (5H, m), N 83-2. 39 (6H, m), 2. 50 (2H, q, ~ 2. 89 (1. 72H, s), Example 28H, s), 3. 52 (1H, m), Example HC1 97 l 4. 31 (0. 57H, T 4. 54 (0. 57H, m), HN N 4. 77 (0. 43H, m), 6. 22 (1H, m), y 02 (2H, d, J=8. 3Hz), 7. 25 (2H, 0 d, J=8. 3Hz), 8. 12 (3H, brs), 8. 51 (1H, s).

Table 1-26 0 1H-NMR Han N JlX 1. 42 (7H, m), 1. 48-1. 79 (5H, m), N 1. 83-2. 39 (6H, m), 2. 53 (2H, q, CH3 2. 89 (1. 72H, s), Example 3. 00 (1. 28H, s), 3. 33 (1H, m), 98 4. 17 (0. 43H, m), 4. 30 (0. 57H, m), H 55 (0. 57H, m), 4. 77 (0. 43H, m), HN N 6. 25 (1H, d, J=7. 9Hz), 6. 71 (1H, d, 4Hz), 7. 03-7. 25 (3H, m), 0 brs), 8. 55 (1H, s). 0 0. 87- Han HCI 1. 30 (10H, m), 1. 39-1. 78 (7H, m), N 1. 88-2. 40 (5H, m), 2. 70-3. 00 (4H, CH3 //m), 11 (2H, d, J=6. 5Hz), 0 (0. 44H, m), 4. 21 (0. 56H, m), 99 NH 4. 47 (0. 56H, m), 4. 72 (0. 44H, m), 7. 59 (1H, ll 7. 32 (2H, d, J=8. 8Hz), S 7. 73 (2H, d, J=8. 8Hz)', 0 04 (3H, brs), 10. 41 (1H, s). 0 H-NMR 0. 87- H2N,,, 1. 43 (4H, m), 1. 50-1. 77 (5H, m), N 1. 87-2. 40 (6H, m), 2. 89 (1. 72H, -CHS 00 (1. 28H, s), 3. 32 (1H, Example m), 16 (0. 43H, m), 4. 30 (0. 57H, 100 4. 54 (0. 57H, m), 4. 76 (0. 43H, H m), 7. 06 (1H, d, J=7. 4Hz), Han 7. 15 (1H, t, 7. 7Hz), 7. 52- 7. 62 (2H, m), 7. 94 (1H, d, 0 3Hz), 8. 12 (3H, brs). 0 1H-NMR 0. 97- H2N,, 43 (4H, m), 1. 45-1. 79 (5H, m), N 1. 83-2. 40 (6H, m), 2. 90 (1. 73H, ~ 3. 00 (1. 27H, s), 3. 33 (1H, HCI 17 (0. 42H, m), 4. 31 (0. 58H, Example 101 4. 54 (0. 58H, m), 4. 70 (0. 42H, T 6. 44 (1H, d, J=7. 4Hz), HN 19 (1H, d, J=7. 4Hz), 7. 35- HN. /N/CF3 7. 50 (2H, m), 7. 95 (1H, s), 8. (3H, brs), 9. 14 (1H, s).

Table 1-27 0 H-NMR 0. 88- H 41 (4H, m), 1. 49-1. 79 (5H, m), N 1. 82-2. 40 (6H, m), 2. 90 (1. 68H, < 3. 00 (1. 32H, s), 3. 81 Example 4. 17 (0. 44H, m), 4. 31 (0. 56H, Example 102 4. 54 (0. 56H, m), 4. 77 (0. 44H, T m), 6. 74-6. 88 (3H, m), 6. 93 (1H, HN 7. 79 (1H, m), 7. 97-8. 21 (4H, Y 0 0 0. 93- H2N (7H, m), 1. 40-1. 77 (8H, m), IN 77-3. 00 (4H, m), 3. 38 (2H, q, - 4Hz), 4. 05 (0. 45H, d, CH3 Example J=5. 4. 20 (0. 55H, d, J=5. 4. 45 (0. 55H, m), 4. 71 (0. 45H, m), 7. 88-8. 14 (8H, HNsS 0// 0 0 0 H2N 1. 25 (4H, m), 1. 41-1. 76 (7H, m), N 37 (4H, m), 2. 79-3. 00 (4H, i CH3 4. 06 (0. 47H, d, J=5. 1Hz), Example 0\\//0 4. 21 (0. 53H, d, J=5. 1Hz), S*-CF3 4. 45 (0. 53H, m), 4. 71 (0. 47H, m), 5. 11 (2H, q, J=9. 9Hz), 7. 80- HNsS ~ (8H, m). os 1H-NMR 0. 78-1. 26 (4H, H N,, 1. 39-1. 86 (7H, m), 1. 93- N 37 (5H, m), 2. 85-2. 91 (4. 71H, i CH3 m), 2. 96 (1. 29H, s), 3. 22 (2H, d, Example J=6. 0Hz), 4. 13 (0. 43H, m), 105 4. 28 (0. 57H, m), 4. 40- 4. 57 (4. 57H, m), 4. 75 (0. 43H, m), 0 26-7. 11 (4H, m), 8. 05 (3H, brs). CH3 Table 1-28 0 1H-NMR (8ppm, DMSO-d6) 0. 76- H2N,,, k"10 1. 26 (3H, m), 1. 40-1. 87 (8H, m), 2 92-2. 36 (5H, m), 2. 84- CH3 2. 91 (4. 76H, m), 2. 97 (1. 24H, s), Example HCI 3. 22 (2H, d, J=6. OHz), 106 4. 13 (0. 41H, d, J=5. lHz), 4. (0. 59H, d, J=5. 1z), 4. 37- oYs$ 4. 59 (4. 59H, m), 4. 75 (0. 41H, m), 0 22-7. 43 (4H, m), 8. 05 (3H, brs). 0 0. 97- H m), 1. 48-1. 78 (5H, m), N 92-2. 36 (6H, m), 2. 87 (1. 80H, Example 2. 98 (1. 20H, s), 3. 20 (1H, Example 3 HC I 107 4. 12 (0. 40H, d, J=5. 6Hz), 4. 28 (0. 60H, d, J=5. 6Hz), 4. 41- 4. 58 (2. 60H, m), 4. 75 (0. 40H, m), 0 09-7. 41 (5H, m), 8. 13 (3H, brs). 0 1H-NMR (8ppm, DMSO-d6) 0. 73- H2N,,, N 1. 32 (7H, m), 1. 38-1. 87 (8H, m), N 1. 92-2. 40 (4H, m), 2. 88 (1. 71H, CH3-HCI s), 2. 97 (1. 29H, s), 3. 12 (2H, q, CH3 HC I J=7. 4Hz), 3. 24 (2H, d, J=6. OHz), Example 4. 14 (0. 43H, d, J=5. lHz), 108 Y 0 4. 29 (0. 57H, d, J=5. 1Hz), 4. 43- 0 66 (4. 57H, m), 4. 76 (0. 3H, m), 7. 47 (4H, m), 8. 05 (3H, brs). 0 r 0. 76- HN k 1. 30 (7H, m), 1. 37-1. 86 (10H, m), N 1. 92-2. 38 (4H, m), 2. 88 (1. 70H, i CH s), 2. 97 (1. 30H, s), 3. 04- 3. 14 (2H, m), 3. 23 (2H, d, Example J 4. 14 (0. 43H, m), 109 0 J=5. lHz), 4. 29 (0. 57H, d, J=5. 4. 47-4. 63 (4. 57H, m), 4. 76 (0. 43H, m), 7. 28-7. 49 (4H, /I 8. 03 (4H, brs).

Table 1-29 0 (8ppm, DMSO-d6) 0. 78- , 1. 35 (10H, m), 1. 38-1. 87 (8H, m), N 1. 92-2. 38 (4H, m), 2. 88 (1. 73H, CH3 2. 97 (1. 27H, s), 3. 23 (2H, d, J=6. 5Hz), 3. 34 (1H, sep, Example 2 4Hz), 4. 14 (0. 42H, d, 110 6Hz), 4. 29 (0. 58H, d, 0 6Hz), 4. 45-4. 64 (4. 58H, m), 4. 77 (0. 42H, m), 7. 27-7. 44 (4H, m), 8. 06 (3H, brs). 1H-NMR (5ppm, DMSO-d6) 1. 04- 1. 49 (4H, m), 1. 54-1. 93 (7H, m), H2N,, , 1. 94-2. 40 (5H, m), 2. 90 (1. 72H, s), 2. 96 (3H, s), 3. 00 (1. 28H, i Example CH-HCI 4. 21 (0. 43H, m), 4. 35 (0. 57H, 111 m), 4. 56 (0. 57H, m), 4. 78 (0. 43H, m), 84 (1H, d, J=7. 9Hz), j 0+"0 t, J=8. 1Hz), 7. 36 (1H, d, J=8. 8Hz), 7. 53 (1H, s), 0 N N CH3 H H 05 (3H, brs), 9. 72 (1H, brs), 9. 92 (1H, s). 0 1. 06- 1. 51 (4H, m), 1. 55-1. 94 (7H, m), a NI HCI 1. 96-2. 40 (5H, m), 2. 89 (4. 81H, Example CH3 3. 00 (1. 19H, s), 4. 19 (0. 40H, 112 4. 55 (0. 60H, NSCH3 m), 4. 78 (0. 40H, m), 7. 12 (2H, d, & 8Hz), 7. 54 (2H, d, J=8. 8Hz), /0 brs), 9. 53 (1H, brs), H 85 (1H, s). H 0 g-1H-NME 1. 50 (4H, m), 1. 52-1. 84 (5H, m), N 87-2. 42 (7H, m), 2. 90 (1. 80H, ~ 2. 92 (3H, s), 3. 00 (1. 20H, CH3 -HCI 4. 20 (0. 40H, d, J=5. 6Hz), Example 4. 35 (0. 60H, d, J=5. 6Hz), 13 4. 56 (0. 60H, m), 4. 78 (0. 40H, m), 7. 12-7. 27 (2H, m), 7. 35 (1H, d, N 64 (1H, d, J=6. 5Hz), 8. 08 (3H, brs), 9. 54 (1H, s). CH3 C"3 CH3 Table 1-30 0 1H-NMR 0. 74- "-0 1. 31 (4H, m), 1. 32-1. 85 (8H, m), N 1. 91-2. 37 (4H, m), 2. 88 (1. 72H, -CH"HCI 2. 97 (1. 28H, s), 3. 22 (2H, d, Example 4. 14 (0. 43H, m), Example 29 (0. 57H, m), 4. 41- 114 OH 4. 59 (4. 57H, m), 4. 76 (0. 43H, m), 5. 06 (1H, brs), 7. 16-7. 48 (4H, 0 I (3H, brs). 0 r_ 0. 71- 1. 29 (4H, m), 1. 32-1. 86 (8H, m), N 38 (4H, m), 2. 87 (1. 76H, CH 2. 96 (1. 24H, s), 3. 19 (2H, d, Example Eample J=5. 6Hz), 3. 61 (2H, s), 115 12 (0. 41H, m), 4. 26 (0. 59H, m), OH 33-4. 60 (2. 59H, m), 4. 75 (0. 41H, m), 7. 00-7. 45 (4H, 0 m), 8. 10 (3H, brs). O lH-NMR 0. 75- H 1. 28 (4H, m), 1. 33-1. 89 (8H, m), N 1. 92-2. 39 (4H, m), 2. 89 (1. 73H, HC I I-HCI 2. 93-3. 09 (3. 27H, m), CH3 15 (0. 42H, d, J=5. 6Hz), Example 30 (0. 58H, d, J=5. 6Hz), 116 0 OH 0 53 (0. 58H, m), 4. 77 (0. 42H, m), 7. 38 (1H, d, J=7. 4Hz), 7. 44- N 58 (2H, m), 7. 73 (1H, d, H 4Hz), 8. 04 (3H, brs),, 8. 28 (1H, t, J=5. 6Hz). 0 1H-NMR 0. 75- H 30 (4H, m), 1. 36-1. 87 (8H, m), N 1. 91-2. 39 (4H, m), 2. 88 (1. 73H, -CH 2. 97 (1. 27H, s), 3. 09 (2H, Example m), 4. 15 (0. 42H, m), 4. 30 (0. 58H, 117 m), 4. 52 (0. 58H, m), 4. 76 (0. 42H, 0 7. 58 (1H, t, J=7. 9Hz), 7. 87- 8. m), 8. 40 (1H, m), N 67 (1H, m). v Table 1-31 0 1H-NMR 0. 76- , 27 (4H, m), 1. 38-1. 86 (8H, m), N 1. 91-2. 38 (4H, m), 2. 89 (1. 77H, CH3 2. 97 (1. 23H, s), 3. 01 (2H, CH3 HCI m), 4. 14 (0. 41H, m), 4. 29 (0. 59H, Example 4 4. 52 (0. 59H, m), 4. 75 (0. 41H, 118 m), 7. 92 (2H, d, J=7. 9Hz), 7. 99 (2H, d, J=7. 9Hz), 8. 05 (3H, N 8. 64 (1H, t, J=5. 8Hz), H 18 (1H, brs). OH 0 0. 70- 1. 33 (4H, m), 1. 36-1. 91 (8H, m), NI 92-2. 40 (4H, m), 2. 88 (1. 70H, HC I CH3 2. 97 (1. 30H, s), 3. 22 (2H, Example brs), 3. 55 (2H, s), 4. 13 (0. 43H, 119 0 OH m), 4. 28 (0. 57H, m), 4. 34- 4. 63 (2. 57H, m), 4. 76 (0. 43H, m), 0 45 (7H, m). 0 0. 73- H2N 28 (4H, m), 1. 31-1. 86 (8H, m), 1. (4H, m), 2. 88 (1. 75H, gwsß HCI s), 2. 97 (1. 25H, s), 3. 20 (2H, d, Example 3. 54 (2H, s), 120 13 (0. 42H, d, J=5. lHz), 4. 28 (0. 58H, d, J=5. lHz), 0 1l 4. 40 (2H, s), 4. 52 (0. 58H, OH 4. 76 (0. 42H, m), 7. 22 (4H, m). 0 94- HN 1. 49-1. 76 (6H, m), N 1. 77-1. 91 (2H, m), 1. 77-2. 37 (4H, , HCI 2. 89 (1. 79H, s), 2. 99 (1. 21H, CH3 HC I s), 3. 47 (2H, s), 3. 75 (2H, d, Example J=5. 6Hz), 4. 15 (0. 40H, d, 121 J=5. 6Hz), 4. 31 (0. 60H, d, J=5. 6Hz), 4. 53 (0. 60H, m), 0 78 (0. 40H, m), 6. 79-6. 94 (2H, OH 10-7. 26 (2H, m), 8. 08 (3H, brs). 0 Table 1-32 O r_ 0. 84- H N 37 (4H, m), 1. 48-1. 78 (6H, m), N 1. 79-2. 40 (6H, m), 2. 89 (1. 76H, -CH"HCI 98 (1. 24H, s), 3. 51 (2H, s), Example 3. 74 (2H, d, J=6. OHz), 4. 16 (0. 41H, m), 4. 29 (0. 59H, m), 0 54 (0. 59H, m), 4. 78 (0. 41H, m), 6. 71-6. 87 (3H, m), 7. 19 (1H, t, 0 9Hz). -H-NMR 0. 83- 1. 33 (4H, m), 1. 49-1. 77 (6H, m), HM"-. 1. 78-2. 39 (6H, m), 88 (1. 74H, N 2. 98 (1.. 26H, s), 3. 46 (2H, Example 3. 74 (2H, d, J=6. OHz), 123 OH 15 (0. 42H, d, J=5. lHz), 4. 29 (0. 58H, d, J=5. lHz), 4. 54 (0. 58H, m), 4. 77 (0. 42H, m), 0 83 (2H, d, J=7. 9Hz), 7. 13 (2H, 0 d, 9Hz), 8. 17 (3H, brs). 0 1H-NMR han 1. 30 (4H, m), 1. 44-1. 75 (6H, m), 2---, 1. 77-2. 37 (6H, m), 2. 87 (1. 76H, s), 2. 95 (1. 24H, s), 3. 29 (2, d, Example CH3 J=6. 5Hz), 4. 11 (0. 41H, d, 124 4. 25 (0. 59H, d, J=5. 4. 50 (0. 59H, m), OH 75 (0. 41H, m), 7. 80 (1H, t, /OH 9Hz), 8. 06 (3H, brs), 0 13 (1H, d, J=7. 9Hz), 8. 26 (1H, d, J=7. 9Hz), 8. 36 (1H, s). 0 H-NMR H 33 (4H, m), 1. 49-1. 72 (5H, m), N 75-2. 37 (7H, m), 2. 88 (1. 74H, ~ 2. 97 (1. 26H, s), 3. 08 (2H, d, CH3 Example J=6. 5Hz), 3. 76 (2H, s,), 125 13 (0. 41H, d, J=5. lHz) OH 4. 28 (0. 59H, d, J=5. 1Hz), 4. 44- 4. 60 (2. 59H, m), 4. 76 (0. 41H, m), 7. 22-7. 40 (4H, m). zu Table 1-33 0 1H-NMR 0. 88- H2N 10 33 (4H, m), 1. 46-2. 38 (12H, m), N 2 2. 88 (1. 74H, s), 2. 94 (2H, d, CH3 J=6. 0Hz), 2. 96 (1. 26H, s), Example 4. 12 (0. 41H, d, J=5. lHz), 126 0 4. 27 (0. 59H, d, J=5. lHz), 4. 59H, m), 4. 76 (0. 41H, m), 5. 00 (2H, s), 7. 43-7. 54 (2H, m), sot 58 (1H, m), 7. 90 (1H, m). H-NMR (8ppm, DMSO-d6) 0. Han 1. 30 (4H, m), 1. 49-1. 71 (5H, m), N-HCI 1. 73-2. 37 (7H, m), 2. 88 (1. 76H, m), CH 93-3. 00 (3. 24H, m), 4. 12 (0. 42H, CH3 Example d, J=5. 6Hz), 4. 27 (0. 58H, d, 127 J=5. 6Hz), 4. 44-4. 64. (2. 58H, m), 0 75 (0. 42H, m), 7. 53 (1H, t, OH 7Hz), 7. 62 (1H, d, J=7 "SSB t, J=7. 4Hz), 7. 99 (1H, O s). 0 0. 89- H m), 1. 49-1. 71 (5H, m), 2 1. 73-2. 37 (7H, m), 2. 87 (1. 74H, s), i CH 2. 90-3. 02 (3. 26H, m), 4. 12 (0. 42H, d, J=5. 1Hz), 4. 27 (0. 58H, d, Example J=5. 4. 44-4. 64 (2. 58H, m), 128 4. 76 (0. 42H, m), 7. 51 (2H, d, s 3Hz), 7. 95 (2H, d, J=8. 3Hz). 0 i 0 lH-NMR (8ppm, DMSO-d6) 0. 89- ° 28 (4H, m), 1. 45-1. 75 (6H, m), 1. 77-2. 37 (6H, m), 2. 87 (1. 76H, s), 2 24H, s), 3. 19 (2H, d, J 4. 10 (0. 41, d, J=5. 6Hz), Example 4. 25 (0. 59H, d, J=5. 6Hz), 4. 50 129 (0. 59H, m), 4. 60 (2H, d, J=6. 0Hz), 4. 75 (0. 41H, m), 5. 47 (1H, t, J=6. 7. 60 (1H, t, J=7. 7Hz), S 66 (1H, d, J=7. 9Hz), 7. 75 (1H, d, 0 0 J=7. 4Hz), 7. 84 (1H, s), 7. 96 (3H, brs).

(8ppm, DMSO-d6). Table 1-34 0 IH-NMR 1. 08 (3H, H 2Hz), 1. 12-1. 48 (4H, m), N 1. 51-1. 83 (5H, m), 1. 88-2. 39 (7H, CH3 HCI 2. 90 (1. 76H, s), 3. 00 (1. 24H, s), 3. 37 (2H, q, J=7. 2Hz), Example 4. 18 (0. 41H, d, J=5. lHz), 130 4. 33 (0. 59H, d, J=5. 1Hz), 4. 55 (0. 59H, m), 4. 78 (0. 41H, m), N 40 (1H, m), 7. 72 (1H, m), H 84 (1H, m), 8. 00-8. 16 (4H, "s'brs), 9. 64 (1H, s). 0 0 -H-NMR H2. 48 (4H, m), 1. 52-1. 83 (5H, m), N 1. 88-2. 37 (7H, m), 2. 63 (6H, s), CH3 2. 90 (1. 72H, s), 3. 00 (1. 28H, s), 4. 17 (0. 43H, d, J=5. 6Hz), Example 33 (0. 57H, d, J=5. 6Hz), 131 (0. 57H, m), 4. 78 (0. 43H, m), A 35 (1H, m), 7. 67 (1H, m), 0 7. 74 (1H, d, J=7. 9Hz), 8. 04 (3H, brs), 16 (1H, d, J=7. 9Hz), 9. cl, CH 0 1H-NMR 63- HzN_ 1. 00 (2H, m), 1. 16-1. 80 (8H, s), 2 1. 86-2. 35 (6H, m), 2. 82 (1. 72H, CH 89 (1. 28H, s), 3. 08 (3H, Example 3 4. 02 (0. 43H, m), 4. 15 (0. 57H, 132 4. 44 (0. 57H, m), 4. 70 (0. 43H, m), 15-7. 64 (5H, m), 7. 96 (3H, O 0 ON CH3 0 0. 61- 1. 03 (2H, m), 1. 12-1. 74 (8H, m), N 1. 76-2. 37 (6H, m), 2. 83 (1. 69H, -CH 2. 89 (1. 31H, s), 3. 02 (3H, Example 4. 15 (0. 56H, 133 4. 42 (0. 56H, m), 4. 71 (0. 44H, m), d, J=7. 7Hz), 7. 51 (1H, t, J=7. 7Hz), 7. 66 (1H, 0 N t, J=7. 7Hz), 7. 83-7. 99 (4H, m). CL30 Table 1-35 1H-NMR 1. 03- H (4H, m), 1. 51-1. 80 (5H, m), N 1. 81-2. 40 (7H, m), CH 89 (1. 72H, s), 2. 99 (1. 28H, s), Example 4. 19 (0. 43H, d, J=5. lHz), 134 34 (0. 57H, d, J=5. 1Hz), 4. 55 (0. 57H, m), 4. 76 (0. 43H, m), 7. 34-7. 48 (2H, m), 7. 65 (1H, t, 0 7. 71 d, J=7. 7Hz), H 09 (3H, brs), 9. 49 (1H, s). O 1. 03- 1. 49 (4H, m), 1. 53-1 (5H, m), 2 N 43 (7H, m), 2. 89 (1. 72H, N s), 2. 99 (1. 28H, s), 4. 19 (0. 43H, Example CH3 d, J=5. lHz), 4. 34 (0. 57H, d, 135 4. 55 (0. 57H, m), 4. 76 (0. 43H, m), 7. 17 (1H, t, J=7. 9Hz), 7. 29 (1H, t, J=7. 9Hz), 7. 46 (1H, d, J=7. 9Hz), 7. 60 (1H, H J=7. 9Hz), 8. 09 (3H, brs), 9. 43 (1H, s). 0 H-NMR DMSO-d6) 0. 50- H 38 (16H, m), 2. 82 (1. 23H, s), , i J H2N -, N 89 (1. 46H, s), 2. 99 (0. 37H, s), - 04 (0. 68H, s), 3. 11 3 HCI 3. 25 (3H, s), 3. 99 (0. 35H, d, Example J=5. 4. 07-4. 19 (0. 65H, m), 136 4. 25-4. 86 (1H, m), 7. 38 (0. 27H, d, 7. 56-8. 15 (6. 73H, o"oo . va XSCH3 v 0 0. 65- H N 1. 03 (2H, m), 1. 16-1. 83 (8H, m), 1. 85-2. 34 (6H, m), 2. 83 (1. 75H, ~ 2. 90 (1. 25H, s), 3. 17 (3H, CH3 3. 25 (3H, s), 4. 03 (0. 42H, Example 137 m), 17 (0. 58H, m), 4. 44 (0. 58H, m), 70 (0. 42H, m), 7. 64- 7. 78 (2H,. m), 7. 80-8. 06 (5H, m). 0 0 N S CH, CH3 Table 1-36 lH-NMR 0. 77- H2N, 1. 12 (2H, m), 1. 17-1. 83 (8H, m), N 1. 86-2. 35 (6H, m), 2. 83 (1. 70H, CH3 s), 30H, s), 3. 16 (3H, Example F 0 brs), 3. 25 (3H, s), 4. 03 (0. 43H, d, 2Hz), 4. 17 (0. 57H, m), 138 S 138 4. 44 (0. 57H, m), 4. 71 (0. 43H, m), 7. d, J=8. 3Hz), 7. 93 (3H, 0 7. 98 (2H, d, J=8. 3Hz). CH3 0 0. 87- H2N 1. 38 (4H, m), 1. 46-1. 77 (6H, m), N 79-2. 38 (6H, m), 2. 89 (1. 73H, CH 2. 98 (1. 27H, s), 3. 77 (3H, s), Example Ç 80 (2H, d, J=6. 5Hz), zea 4. 15 (0. 42H, d, J=5. 1Hz), 4. 30 (0. 58H, d, J=5. 1Hz), OH 4. 54 (0. 58H, m), 4. 77 (0. 42H, m), 0 6. 70 (1H, s), 6. 99-7. 06 (2H, m), 0 09 (3H, brs). Q lH-NMR 88- 1. 38 (4H, m), 1. 48-1. 77 (6H, m), 2 38 (6H, m), 2. 89 (1. 69H, -iCH 2. 98 (1. 31H, s), 3. 79 (3H, s), Example < (2H, d, J=6. 5Hz), Example 15 (0. 44H, d, J=5. lHz), 140 OH 30 (0. 56H, m), 4. 54 (0. 56H, m), 4. 77 (0. 44H, m), 7. 01 (1H, d, 0 3Hz), 7. 43 (1H, d, J=1. 9Hz), 7. 52 (1H, dd, J=8. 3, 1. 9Hz), OMe 09 (3H, brs). 0 0. 74- HNA. LJ 1. 25 (4H, m), 1. 34-1. 83 (8H, m), N 1. 87-2. 39 (7H, m), 2. 80 (1. 71H, A 2. 95 (1. 29H, s), 3. 21 (2H, d, J=6. 4. 11 43H, d, Example 6Hz), 4. 26 (0. 57H, d, 141 6Hz), 4. 43 (2H, s), 0 50 (0. 57H, m), 4. 73 (0. 43H, m), 0 32 (1H, s), 7. 65 (2H, s), 06 (3H, brs). CH3 Table 1-37 0 1H-NMR (8ppm, DMSO-d6) 0. 92-1. 32 (4H, m), 1. 85 (7H, m), N 94-2. 36 (4H, m), 2. 88 (1. 74H, CH3 2. 98 (1. 26H, s), 3. 32-3. 46 CH3 Example m), 4. 09-4. 17 (0. 42H, m), 142 4. 24-4. 33 (0. 58H, m), 4. 47-4. 59 (0. 58H, m), 4. 69-4. 81 (0. 42H, HN CH3 8. 13 (3H, Y 0 1H-NMR (8ppm, DMSO-d6) 1. 20-1. 39 0 m), 1. 58-1. 76 (5H, m), H2N"10 83-1. 93 (2H, m), 1. 97-2. 36 . m), 2. 90 (1. 74H, s), 3. 00 i CH3-HCI 26H, s), 3. 64-3. 75 (1H, m), Example 14-4. 19 (0. 42H, m), 4. 29-4. 35 143 (0. m), 4. 51-4. 61 (0. 58H, m), 4. 71-4. 82 (0. 42H, m)., 7. 43 HN (2H, J=7. 2, 7. 2Hz), 7. 49 1-l d, J=7. 2Hz), 7. 81 (2H, d, 0 J=7. 2Hz), 8. 13 (3H, brs), 8. 22 (1H, m). 0 1H-NMR (8ppm, DMSO-d6) 1. 06-1. 32 H2N,,) m), 1. 50-1. 72 (5H, m), N 1. 86-2. 36 (6H, m), 2. 88 (1. 74H, CH. s), 2. 89 (3H, s), 2. 93-3. 04 Example HCI m), 2. 97 (1. s), 144 10-4. 16 (0. 42H, m), 4. 25-4. 31 (0. 58H, m), 4. 47-4. 58 (0. 58H, HN CH m), 4. 69-4. 80 (0. 42H, m), 6. 96- Sb 7. 04 (1H, m), 8. 11 (3H, brs). O 0 20 \ 1. 43-1. 70 (7H, m), 2 92-2. 31 (4H, m), 2. 74-2. 87 ~ (1. 74H, s), 2. 92 Example 3 26H, s), 4. 05 (0. 42H, d, 145 J=5. 3Hz), 4. 20 (0. 58H, d, J=5. 3Hz), 4. 40-4. 51 (0. 58H, m), HN 4. 65-4. 76 (0. 42H, m), 7. 54-7. 82 "St (5H, m), 8. 03 (3H, brs). O Table 1-38 1H-NMR 0. 90-1. 32 H m), 0. 95 (3H, t, J=7. 2Hz), H2N. N 1. 57-1. 72 (5H, m), 1. 76-1. 87 (2H, CH 1. 94-2. 35 (4H, m), 2. 88 Example 3-HCI (1. 74H, s), 2. 97 (2H, q, J=7. 2Hz), 146 2. 98 (1. 26H, s), 3. 17-3. 27 (1H, T 4. 07-4. 18 (0. 42H, m), 4. 23- HN 4. 34 (0. 58H, m), 4. 47-4. 58 (0. 58H, Y 4. 69-4. 80 (0. 42H, m), 5. 30- 0 6. 01 (2H, m), 8. 09 (3H, brs). 1H-NMR 0. 98-1. 38 (4H, m), 1. 53-1. 77 (5H, m), 1. 85- H2 2. 37 (6H, m), 2. 89 (1. 74H, s), Nl 99 (1. 26H, s), 3. 26-3. 45 (1H, CH3 4. 13-4. 21 (0. 42H, m), 4. 26- Example-HCI 35 (0. 58H, m), 4. 48-4. 59 (0. 58H, 147 m), 4. 70-4. 82 (0. 42H, m), 6. 21 H d, J=8. 1Hz), 6. 85 (1H, dd, HN 2Hz, 7. 2Hz), 7. 18 (2H, dd, § 4, 7. 2Hz), 7. 35 (2H, d, 0 J=7. 4Hz), 8. 08 (3H, brs), 8. 55 (1H, s). 0 IH-NMR 1. 01-1. 32 H2N", 51-1. 71 (5H, m), 1. 75- N 1. 86 (2H, m), 1. 93-2. 36 (4H, m), CH 74H, s), 2. 97 (1. 26H, s), Example HCI 3. 08-3. 20 (1H, m), 3. 49 (3H, s), 148 4. 13 (0. 42H, d, J=5. 1Hz), 4. 28 (0. d, J=5. lHz), 4. 47-4. 58 HN OMe (0. 58H, m), 4. 69-4. 80 (0. 42H, m), y 98-7. 08 (1H, m), 8. 12 (3H, brs). 0 O 0. 92-1. 30 48-1. 79 (7H, m), 1. 92- H2N 2. 34 (4H, m), 2. 29 (2H, t, N "HCI 7Hz), 2. 76 (2H, t, J=7. 7Hz), Example CH3 (1. 74H, s), 2. 96 (1. 26H, s), 149 33-3. 45 (1H, m), 4. 06-4. 15 (0. 42H, m), 4. 22-4. 31 (0. 58H, m), HN 45-4. 56 (0. 58H, m), 4. 67-4. 78 (0. 42H, m), 7. 09-7. 27 (5H, m), 0 68 (1H, d, J=7. 7Hz), 8. 08 (3H, brs).

Table 1-39 0 1H-NMR 1. 19-1. 43 H 1. 55-1. 78 (5H, m), 1. 84- N 36 (6H, m), 2. 89 (1. 74H, s), ~ s), 3. 67-3. 81 (1H, Example m), 4. 13-4. 21 (0. 42H, m), 4. 28- 150 4. 37 (0. 58H, m), 4. 50-4. 62 (0. 58H, m), 4. 70-4. 82 (0. 42H, m), HN 7. 51-7. 62 (2H, m), 7. 85-8. 02 (4H, v 11 (3H, brs), 8. 33-8. 44 0 m). 0 0. 97-1. 34 HN H2N 52-1. 71 (5H, m), 1. 74-1. 85 (2H, N I 1. 93-2. 33 (4H, m), 2. 87 Example CH3 HCI 151 (2H, s), 3. 27-3. 44 (1H, m), 4. 03 (2H, q, J=7. 1Hz), 4. 09-4. 17 (0. 42H, m), 4. 23-4. 31 (0. 58H, m), n'"4. 45-4. 56 (0. 58H, m), 4. 67-4. 79 0 42H, m), 7. 94-8. 01 (1H, m), 0 (3H, brs). 0 0. 96-1. 30 11 50-1. 70 (5H, m), 1. 71- 2 82 (2H, m), 1. 92-2. 32 (4H, m), N HCI t, J=6. 9Hz), 2. 45 (2H, Example < 9Hz), 2. 86 (1. 74H, s), 152 96 (1. 26H, s), 3. 31-3. 43 (1H, < 3. 54 (3H, s), 4. 08-4. 16 Han (0. 42H, m), 4. 22-4. 32 (0. 58H, m), OMe 4. 45-4. 57 (0. 58H, m), 4. 67-4. 79 (0. 42H, m), 7. 70-7. 78 (1H, m), 0 07 (3H, brs). 0 0. 95-1. 30 H m), 1. 49-1. 82 (9H, m), 1. 92- N 2. 34 (4H, m), 2. 02 (2H, t, -. 3Hz), 2. 25 (2H, t, J=7. 4Hz), Example-HCI 2. 86 (1. 74H, s), 2. 96 (1. 26H, s), 153 3. 33-3. 45 (1H, m), 3. 55 (3H, s), 4. 08-4. 16 (0. 42H, m), 4. 22-4. 31 HN 58H, m), 4. 45-4. 56 (0. 58H, m), 4. 67-4. 79 (0. 42H, m), 7. 64-7. 72 0 0 (1H, m), 8. 07 (3H, brs).

Table 1-40 0'H-NMR 0. 96-1. 30 H (4H, m), 1. 50-1. 82 (9H, m), 1. 91- IN 2. 33 (4H, m), 2. 01 (2H, t, CH3 6Hz), 2. 51 (2H, t, J=7. 7Hz), CH3 Example (1 154 3. 33-3. 46 (1H, m), 4. 08-4. 16 (0. 42H, m), 4. 22-4. 31 (0. 58H, m), HN 46-4. 57 (0. 58H, m), 4. 67-4. 78 (0. 42H, m), 7. 10-7. 18 (3H, m), 0 7. 21-7. 28 (2H, m), 7. 62-7. 69 (1H, m), 8. 08 (3H, brs). 0'H-NMR 0. 97-1. 32 "10 50-1. 71 (5H, m), 1. 74- N 1. 86 (2H, m), 1. 92-2. 33 (4H, m), cl3 87 (1. 74H, s), 2. 96 (1. 26H, s), CH3 Example 3. 05 (2H, s), 3. 33-3. 45 (1H, m), 155 4. 09-4. 16 (0. 42H, m), 4. 22-4. 31 (0. 58H, m), 4. 45-4. 56 (0. 58H, m), HN OH 79 (0. 42H, m), 7. 91-7. 98 < m), 8. 07 (3H, brs), 12. 25 0 0 (1H, brs). O 0. 95-1. 30 0 1. 49-1. 70 (5H, m), 1. 70- 1. 83 (2H, m), 1. 91-2. 32 (4H, m), N I 24 (2H, t, J=7. 0Hz), 2. 37 (2H, Example (1. 74H, s), Example 2. 96 (1. 26H, s), 3. 31-3. 43 (1H, 156 "Y 4. 07-4. 16 (0. 42H, m), 4. 22- HN 4. 31 (0. 58H, m), 4. 45-4. 56 OH (0. 58H, m), 4. 68-4. 79 (0. 42H, m), 0 66-7. 75 (1H, m), 8. 05 (3H, brs). 0'H-NMR 30 H m), 1. 50-1. 83 (9H, m), 1. 91- 2. 35 (4H, m), 2. 02 (2H, t, CH3-HCI 3Hz), 2. 16 (2H, t, J=7. 4Hz), CH3 NC I Example 2. 86 (1. 74H, s), 2. 96 (1. 26H, s), 157 30-3. 42 (1H, m), 4. 08-4. 16 (0. m), 4. 23-4. 31 (0. 58H, m), HN 4. 45-4. 57 (0. 58H, m), 4. 68-4. 79 (0. m), 7. 62-7. 71 (1H, m), 0 0 8. 06 (3H, brs).

Table 1-41 0 0. 96-1. 31 HZN m), 1. 50-1. 72 (5H, m), 1. 72- N 1. 84 (2H, m), 1. 91-2. 33 (4H, m), 2. 55 (3H, d, J=4. 6Hz), 2. 87 Example 3-HCI (1. 74H, s), 2. 94 (2H, s), 2. 96 158 (1. 26H, s), 3. 32-3. 44 (1H, m), H 08-4. 16 (0. 42H, m), 4. 23-4. 31 HN (0. 58H, m), 4. 45-4. 56 (0. 58H, m), CH3 4. 68-4. 78 (0. 42H, m), 7. 85-7. 95 0 0 (2H, m), 8. 08 (3H, brs). ° (8ppm, DMSO-d6) 0. 95-1. 31 HN"10 (4H, m), 1. 49-1. 70 (5H, m), 1. 70- 2 1. 81 (2H, m), 1. 92-2. 33 (4H, m), i -CH 2. 23 (4H, s), 2. 51 (3H, d, Example < 4Hz), 2. 86 (1. 74H, s), 2. 96 159 (1. 26H, s), 3. 30-3. 43 (1H, m), 0 4. 07-4. 16 (0. 42H, m), 4. 22-4. 31 HN, 58H, m), 4. 45-4. 57 (0. 58H, m), N 4. 67-4. 79 (0. 42H, m), 7. 64-7. 76 0 m), 8. 07 (3H, brs). 0 Fn 1. 18-1. 42 HN (4H, m), 1. 54-1. 79 (5H, m), 1. 92- N 33 (6H, m), 2. 87 (1. 74H, s), cl3 98 (1. 26H, s), 4. 16 (0. 42H, d, CH3 Example 4. 30 (0. 58H, d, 160 4. 41-4. 58 (1. 58H, m), H 80 (0. 42H, m), 6. 94 (1H, 0 J=7. 4, 7. 4Hz), 7. 23 (2H, dd, J=8. 1, 7. 4Hz), 7. 35 (2H, d, 0 8. 09 (3H, brs), 9. 54 (1H, s). ° 0. 96-1. 30 (4H, m), 1. 50-1. 82 (9H, m), 1. 91- N 33 (8H, m), 52 (3H, d, i CH3 J=4. 6Hz), 2. 86 (1. 74H, s), 2. 96 Example S (1. 26H, s), 3. 32-3. 45 (1H, m), 161 08-4. 16 (0. 42H, m), 4. 23-4. 31 H (0. 58H, m), 4. 45-4. 56 (0. 58H, m), HNo, 78 (0. 42H, m), 7. 59-7. 73 0 m), 8. 08 (3H, brs). 00 Table 1-42 0 0. 87-1. 12 (4H, H 35-1. 64 (7H, m), 1. 86-2. 27 N (4H, m), 2. 74-2. 86 (1H, m), 2. 80 (1. R s), 2. 87 (1. 26H, s), 3. 99 Example f 42H, d, J=5. 6Hz), 4. 14 (0. 58H, 162 d, 6Hz), 4. 34-4. 45 (0. 58H, m), 4. 60-4. 71 (0. 42H, m), 7. 57-7. 71 HN 7. 92-8. 01 (1H, m), 7. 97 (3H, 8. 06, (1H, d, J=7. 4Hz), 0 0 8. 12 (1H, d, J=7. 2Hz), 8. 19 (1H, d, J=8. 8. 60 (1H, d, J=8. lHz). 0 0. 89-1. 18 (4H, , N 1. 38-1. 68 (7H, m), 1. 87-2. 27 N (4H, m), 2. 75-2. 86 (1H, m), 2. 81 CH 74H, s), 2. 88 (1. 26H, s), 4. 00 CH Example (0. 42H, d, J=5. 6Hz), 4. 15 (0. 58H, 163 d, J=5. 6Hz), 4. 35-4. 46 (0. 58H, m), 4. 62-4. 72 (0. 42H, m), 7. 60-7. 71 HN,, m), 7. 74-7. 83 (2H, m), 93 , brs), 8. 01, (1H, d, J=7. 7Hz), 0 8. 07-8. 16 (2H, m), 8. 41 (1H, s). ° 1. 11-1. 38 (4H, H 52-1. 74 (5H, m), 1. 81-2. 36 N N m), 2. 28 (3H, s), 2. 88 (1. 74H, C (1. 26H, s), 3. 55-3. 69 (1H, Example m), 4. 10-4. 20 (0. 42H, m), 4. 24-4. 35 164 (0. 58H, m), 4. 47-4. 59 (0. 58H, m), 4. 68-4. 81 (0. 42H, m), 7. 13-7. 31 HN (4H, m), 8. 00-8. 18 (4H, m). I 0 CH3 0 1H-NMR (8ppm, DMSO-d6) 1. 14-1. 38 (4H, HN m), 53-1. 75 (5H, m), 1. 78-1. 92 N (2H, m), 1. 93-2.. 36 (4H, m), 2. 32 -. 2. 88 (1. 74H, s), 2. 98 Example 26H, s), 3. 60-3. 74 (1H, m), 165 4. 19 (0. 42H, m), 4. 25-4. 35 (0. 58H, m), 4. 48-4. 60 (0. 58H, m), HN 4. 69-4. 81 (0. 42H, m), 7. 23-7. 33 X (2H, m), 7. 53-7. 64 (2H, m), 8. 01- _ 22 (4H, m).

Table 1-43 1H-NMR 1. 10-1. 34 (4H, 1. 52-1. 72 (5H, m), H2N 1. 82-1. 92 (2H, m), 1. 93-2. 34 I m), 2. 14 (3H, s), 2. 22 CH3-HCI 2. 88 (1. 74H, s), 2. 97 Example (1. 26H, s), 3. 54-3. 68 (1H, m), 166 4. 11-4. 19 (0. 42H, m), 4. 26-4. 34 (0. 58H, m), 4. 47-4. 58 (0. 58H, m), 68-4. 80 (0. 42H, m), 7. 01 > d, J=7. 5Hz), 7. 06 (1H, dd, 0 CH3 J=7. 5, 7. 2Hz), 7. 16 (1H, d, J=7. 2Hz), 7. 99-8. 18 (4H, m). 1H-NMR 0. 93-1. 24 (4H, m), 1. 17 (3H, t, J=7. 6Hz), H2N-"A 1. 40-1. 68 (7H, m), 1. 88-2. 32 N HCI (4H, m), 2. 66 (2H, q, J=7. 6Hz), CH3 2. 71-2. 86 (1H, m), 2. 82 (1. 74H, Example s), 2. 90 (1. 26H, s), 4. 03 167 t0. 42H, d, J=5. 6Hz), 4. 17 T (0. 58H, d, J=5. 6Hz), 4. 38-4. 49 (0. 58H, m), 4. 63-4. 75 (0. 42H, "se m), d, J=8. 2Hz) 0 7. 55-7. 63 (1H, m), 7. 67 (2H, d, J=8. 2Hz), 7. 97 (3H, brs). H-NMR (8ppm, DMSO-d6) 0. 94-1. 15 0 m), 1. 40-1. 68 (7H, m), H 1. 90-2. 29 (4H, m), 2. 68-2. 81 2 m), 2. 83 (1. 74H, s), 2. 90 HC I CH 26H, s), 3. 98-4. 07 (0. 42H, Example e 4. 01 (2H, s), 4. 13-4. 21 168 (0. 58H, m), 4. 37-4. 48 (0. 58H, m), 63-4. 75 (0. 42H, m), 7. 14- HNX N 7. 31 (5H, m), 7. 40 (2H, d, "S\\ 7. 56-7. 64 (1H, m), 0 0 7. 68 (2H, d, J=8. 3Hz), 8. 00 (3H, brs).

Table 1-44 1H-NMR 0. 96-1. 36 (m, 4H), 1. 54-1. 75 (m, 5H), H 1. 85-2. 33 (m, 6H), 2. 14 (s, I 2. 88 (s, 1. 74H), 2. 97 (s, CH3. 1. 26H), 3. 23-3. 36 (m, 1H), Example 4. 10-4. 19 (m, 0. 42H), 4. 25-4. 33 169 CH3 0. 58H), 4. 47-4. 58 (m, T 0. 58H), 4. 69-4. 80 (m, 0. 42H), HN 6. 66 (bs, 1H), 6. 80 (dd, 1H, | J=7. 4, 7. 4Hz), 6. 99-7. 09 (m, 0 7. 63 (bs, 1H), 7. 79 (d, 1H, J=8. 4Hz), 8. 07 (bs, 3H). 1H-NMR (6ppm, DMSO-d6) 0. 96-1. 36 0 , m), 1. 52-1. 76 (5H, m), H"10 81-2. 34 (6H, m), 2. 20 (3H, 2 2. 87 (1. 74H, s), 2. 97 I 26H, s), 3. 22-3. 36 (1H, m), CH3 34 Example 170 ."t J (0. 58H, m), 4. 46-4. 57 (0 : 58H, X 4. 69-4. 80 (0. 42H, m), 6. 11- HN 6. 65 (1H, d, J=7. 7Hz), 7. 04 (1H, d, J=7. 7, 0 7Hz), 7. 12 (1H, d, J=7. 7Hz), 7. 16 (1H, s), 8. 05 (3H, brs), 8. 43 (1H, s). 1H-NMR (8ppm, DMSO-d6) 1. 00-1. 39 0 (4H, m), 1. 54-1. 78 (5H, m), 1. 90-2. 34 (6H, m), 2. 88 (1. 74H, N 2. 98 (1. 26H, s), 3. 30-3. 44 ~ HCI m), 4. 12-4. 20 (0. 42H, m), CN3 Example 4. 27-4. 35 (0. 58H, m), 4. 48-4. 58 171 58H, m), 4. 70-4. 81 (0. 42H, Y m), brs), 7. 36 (1H, dd, J=7. 9, 7. 9Hz), 7. 43-7. 53 Y 80-7. 88 (1H, m), (3H, IL1), 0 98 (1H, d, J=7. 7Hz), 8. 07 (3H, brs), 8. 15 (1H, d, J=7. 7Hz), 8. 61 (1H, s).

Table 1-45 0 0. 86-1. 30 H2N A (m, 9H), 1. 42-1. 73 (m, 10H), N 1. 74-1. 87 (m, 2H), 1. 92-2. 34 i CH3 4H), 2. 86 (s, 1. 74H), 2. 96 Example HCI 26H), 3. 12-3. 24 (m, 1H), 172 24-3. 34 (m, 1H), 4. 06-4. 15 T 0. 42H), 4. 21-4. 31 (m, HN N 4. 44-4. 56 (m, 0. 58H), 4. 66-4. 80 (m, 0. 42H), 5. 56 (bs, 0 06 (bs, 3H). 0 1H-NMR DMSO-d6) 0. 86 (3H, t, J=7. 3Hz), 0. 95-1. 14 (4H, m), H2N 1. 66 (9H, m), 1. 89-2. 28 N (4H, m), 2. 61 (2H, t, J=7. 2Hz), CH3'HCI 69-2. 80 (1H, m), 2. 83 (1. 74H, Example s), 2. 90 (1. 26H, s), 4. 04 173 (0. 42H, d, J=5. 6Hz), 4. 17 han 58H, d, J=5. 6Hz), 4. 38-4. 49 (0. 58H, m), 4. 63-4. 74 (0. 42H,. 0 7. 36 (2H, d, J=8. 3Hz), 7. 54-7. 62 (1H, m), 7. 67 (2H, d, J=8. 3Hz), 7. 98 (3H, brs). O 0. 83 (6H, d, J=6. 7Hz), 0. 89-1. 14 (4H, m), H2N 1. 38-1. 66 (7H, m), 1. 78-2. 29 N I (5H, m), 2. 50 (2H, t, J=7. 6Hz), CH3CHCI 69-2. 80 (1H, m), 2. 82 (1. 74H, Example s), 2. 90 (1. 26H, s), 4. 03 174 (0. 42H, d, J=5. 3Hz), 4. 17 -Y 58H, d, J=5. 3Hz), 4. 37-4. 49 HNsSo (0. 58H, m), 4. 63-4. 74 (0. 42H, m), 7. 33 (2H, d, J=8. 1Hz), 7. 53-7. 61 (1H, m), 7. 67 (2H, d, J=8. 1Hz), 7. 97 (3H, brs).

Table 1-46 lH-NMR (8ppm, DMSO-d6) 0. 98-1. 19 0 (4H, m), 1. 43-1. 73 (7H, m), H2No/0o N (IH, m), 2. 85 (1. 74H, s), 2. 93 Example CH3 4. 02-4. 11 (0. 42H, t 4. 16-4. 25 (0. 58H, m), 4. 39- 4. 51 (0. 58H, m), 4. 65-4. 77 (0. 42H, m), 7. 28-7. 36 (2H, m), "S 37-7. 46 (3H, m), 7. 60-7. 73 0 0 (3H, m), 7. 74-7. 82 (4H, m), 8. 02 (3H, brs). lH-NMR (8ppm, DMSO-d6) 0. 96-1. 19 0 (4H, m), 1. 42-1. 69 (7H, m), H 91-2. 32 (4H, m), 2. 70-2. 83 N 2. 83-2. 99 (4H, m), cl3 (1. 74H, s), 2. 93 (1. 26H, Ex3 Example 176 21 (0. 58H, d, J=5. 6Hz), 4. 41- 4. 52 (0. 58H, m), 4. 67-4 : 77 HNs, (0. 42H, m), 7. 12-7. 19 (3H, m), I's', 20-7. 28 (2H, m), 7. 38 (2H, d, J=8. 2Hz), 7. 57-7. 63 (1H, m), 7. 67 (2H, d, J=8. 2Hz), 8. 02 (3H, brs) H-NMR 1. 12-1. 38 (4H, 1. 55-1. 75 (5H, m), H2N 83-1. 94 (2H, m), 1. 96-2. 37 I m), 2. 27 (6H, s), 2. 90 CH3 74H, s), 2. 99 (1. 26H, s), Example 3. 55-3. 69 (1H, m), 4. 13-4. 21 177 (0. 42H, m), 4. 27-4. 37 (0. 58H, m), 4. 50-4. 61 (0. 58H, m), 4. 71- HN 4. 81 (0. 42H, m), 6. 96-7. 04 (2H, m), 7. 15 (1H, d, J= 7. 6Hz), 0 CH3 7. 94-8. 03 (1H, m), 8. 12 (3H, brs).

Table 1-47 0 H-NMR DMSO-d6) 1. 13-1. 38 H2N", 75 (5H, m), N 94 (2H, m), 1. 97-2. 36 CH-HCI (4H, m), 2. 24 (3H, s), 2. 26 Example 178 26H, s), 3. 55-3. 69 (1H, m), 4. 22 (0. 42H, m), 4. 27-4. 37 HIN 58H, m), 4. 49-4. 61 (0. 58H, m), 70-4. 82 (0. 42H, m), 7. 02- 0 23 (3H, m), 7. 99-8. 22 (4H, . 0 1. 11-1. 40 H 54-1. 75 (5H, m), N 1. 84-1. 95 (2H, m), 1. 95-2. 37 CH3 (4H, m), 2. 19 (6H, s), 2. 89 C s), 2. 99 (1. 26H, s), Example 3. 60-3. 73 (1H, m), 4. 13-4. 22 (0. 42H, m), 4. 28-4. 36 (0. 58H, HN 0 m), 49-4. 61 (0. 58H, m)', 4. 69- 4. 81 (0. 42H, m), 7. 01 (2H, d, H J=7. 6Hz), 7. 15 (1H, dd, J= 7. 6, 7. 6Hz), 8. 03-8. 22 (4H, m). W H-NMR (8ppm, DMSO-d6) 0. (3H, t, J=7. 3Hz), 0. 99-1. 38 (4H, m), 1. 44-1. 78 (7H, m), 1. 86-2. 38 H2N (6H, m), 2. 51 (2H, t, J=7. 2Hz), . 90 (1. 74H, s), 3. 00 (1. 26H, CH3 3. 25-3. 38 (1H, m), 4. 12- Example I 21 (0. 42H, m), 4. 27-4. 36 180 (0. 58H, m), 4. 49-4. 60 (0. 58H, H 4. 72-4. 82 (0. 42H, m), 6. 61- HN 76 (1H, m), 6. 87 (1H, dd, l 7. 01-7. 10 (2H, 0 w 7. 58-7. 65 (1H, m), 7. 76 (1H, d, J=8. 2Hz), 8. 10 (3H, brs).

Table 1-48 -NMR (6ppm, DMsO-d6) 0. 98-1. 37 (4H, 1. 14 (6H, d, J=. 7Hz), 1. 55-1. 78 (5H, m), 1. 87-2. 37 H2N, (6H, m), 2. 90 (1. s), 2. 99 I (1. 26H, s), 3. 05-3. 15 (1H, m), C 3. 25-3. 38 (1H, m), 4. 12-4. 21 Example (0. 42H, m), 4. 27-4. 36 (0. 58H, 181 H3C m), 4. 48-4. 60 (0. 58H, m), 4. 70- H 83 (0. 42H, m), 6. 57 (1H, HN 6. 95 dd, J=8. 1, sIf 9Hz), 7. 05 (1H, dd, J=7. 9, 0 7. 4Hz), 7. 19 (1H, d, J=7. 4Hz), 7. 58-7. 72 (2H, m), 8. 10 (3H, brs). 1H-NMR 87-1. 30 (4H, m), 1. 35-1. 79 (7H, m), H2N oN 1. 79-1. 94 (3H, m), 2. 02-2. 20 (3H, m), 2. 20-2. 34 (1H, m), A (1. 74H, s), 2. 95 (1. 26H, Example l 3. 26 (2H, d, J=6. 5Hz), 182 3. 41-3. 45 (0. 42H, m), 3. 50-3. 55 (0. 58H, m), 3. 80 (3H, s), 4. 32- /OMe 4. 43 (0. 58H, m), 4. 46 (2H, s), 4. 85-4. 98 (0. 42H, m), 6. 78-6. 83 (1H, m), 6. 86-6. 92 (2H, m), 7. 24 (1H, dd, J=8. 3, 7. 9Hz). -NMR (ppm, DMSO-d6) 0. 81-1. 01 (2H, m), 1. 01-1. 53 (3H, m), 1. 53-1. 73 (5H, m), 1. 74-1. 84 H m), 1. 93-2. 35 (4H, m), 2. 88 (1. 74H, s), 2. 96 (3H, s), n 2. 98 (1. 26H, s), 3. 22 (2H, d, Example l J=6. 5Hz), 4. 08-4. 15 (0. 42H, m), 183 4. 20-4. 30 (0. 58H, m), 4. 40 (2H, _ 4. 45-4. 56 (0. 58H, m), 4. 69- NH 4. m), 7. 01 (1H, d, J=7. 7Hz), 7. 11 (1H, d, J=7. 5Hz), 7. 17 (1H, s), 7. 28 (1H, dd, J=7. 7, 7, 5Hz), 8. 07 (3H, brs), 9. 75 (1H, s).

Table 1-49 1H-NMR (8ppm, DMSO-d6) 0. 92-1. 0 (4H, m), 1. 31-1. 77 (6H, m), H 82-1. 93 (2H, m), 1. 94-2. 36 (4H, m), 2. 89 (1. 74H, s), 2. 99 CH3 s), 3. 74 (2H, d, Example J=6. 4. 14-4. 18 (0. 42H, m), 184 4. 28-4. 33 (0. 58H, m), 4. 45-4. 59 t . m), 4. 72-4. 83 (0. 42H, 0 3 m), 6. 69 (1H, d, J=7. 9Hz), H 74-6. 80 (2H, m), 7. 22 (1H, dd, J=8. 2, 7, 9Hz), 8. 14 (3H, bs). H-NMR (5ppm, DMSO-d6) 0. 80-1. 03 (2H, m), 1. 03-1. 53 (3H, m), 0 1. 53-1. 72 (5H, m), 1. 74-1. 84 H m), 1. 93-2. 35 (4H, m), 2. 88 (1. 74H, s), 2. 97 (1. 26H, CH3 3. 22 (2H, d, J=6. 2Hz), Example 3 11-4. 17 (0. 42H, m), 4. 31 185 0=S=0 . 58H, m), 4. 36-4. 58 (2. 58H, I, 4. 41 (2H, s), 4. 70-4. 83 0 (0. 42H, m), 7. 05 (1H, d, J=7. 7Hz), 7. 11 (1H, d, J=7. 9Hz), 7. 18 (1H, s), 7. 30 (1H, dd, J=7. 9, 7, 7Hz), 8. 15 (3H, brs). 0/ 0. 96-1. 28 H2N 1. 44-1. 70 (7H, m), 1. 89-2. 35 (4H, m), 2. 84 (1. 74H, N s), 2. 89-3. 04 (1H, m), 2. 92 CH3 ci3 26H, s), 3. 45 (3H, s), 4. 03- ! 4. 09 (0. 42H, m), 4. 18-4. 24 Example (0. 58H, m), 4. 39-4. 51 (0. 58H, 186 m), 4. 65-4. 77 (0. 42H, m), 6. 76 HNss 7. 87-8. 09 (5H, m), OO 8. 13-8. 27 (2H, m). H3C 3 Table 1-50 ° 0. 98-1. 25 z m), 1. 45-1. 74 (7H, m), 2 1. 91-2. 34 (4H, m), 2. 83-2. 96 i CH m), 2. 85 (1. 74H, s), 2. 93 Example 0 0 (1. 26H, s), 3. 33 (3H, s), 4. 03- 187 (0. 42H, m), 4. 18-4. 24 T (0. 58H, m), 4. 41-4. 52 (0. 58H, H 4. 66-4. 77 (0. 42H, m), 7. 97- , 10 (6H, m), 8. 11-8. 27 (2H, 0 0 0 1. 00-1. 25 (4H, m), 1. 44-1. 70 (7H, m), H N""A 1. 92-2. 31 (4H, m), 2. 81-2. 96 (1H, m), 2. 85 (1. 74H, s), 2. 93 i CH (1. 26H, s), 3. 32 (3H, s), 4. 02- Example 4. 10 (0. 42H, m), 4. 16-4. 25 188 (0. 58H, m), 4. 41-4. 52 (0. 58H, m), 4. 66-4. 76 (0. 42H, m), 7. 89 (1H, 9, 7. 9Hz), 97- S 8. 10 (4H, m), 8. 13 (1H, d, 0 9Hz), 8. 19 (1H, d, J=7. 9Hz), 8. 29 (1H, s). 1H-NMR (6ppm, DMSO-d6) 0. 98-1. 29 0 m), 1. 29-1. 86 (8H, m), 1. 93-2. 37 (4H, m), 2. 04 (3H, H2N > 2. 88 (1. 74H, s), 2. 97 (1. 26H, s), 3. 22 (2H, d, CH J=5. 5Hz), 4. 09-4. 19 (0. 42H, m), Example 4. 24-4. 34 (0. 58H, m), 4. 43 (2H, 189 HN) 48-4. 58 (0. 58H, m), 4. 70- C (0. 42H, m), 7. 14 (1H, dd, J=7. 4, 6. 7Hz), 7. 24 (1H, dd, J=7. 9, 6. 7Hz), 7. 34 (1H, d, < 4Hz), 7. 46 (1H, d, J=7. 9Hz), 8. 07 (3H, brs), 9. 28 (1H, brs).

Table 1-51 _ 1. 00-1. 29 11 6 m), 1. 56-1. 77 (6H, m), N 86-1. 95 (2H, m), 1. 96-2. 35 N (4H, m), 2. 84 (3H, s), 2. 90 CH3-HCI (1. 74H, s), 3. 00 (1. 26H, s), Example 3 J=5. 8Hz), 4. 16 190 42H, d, J=5. 5Hz), 4. 31 (0. 58H, d, J=5. 5Hz), 4. 41 (2H, 0 4. 50-4. 60 (0. 58H, m), 4. 73- I 83 (0. 42H, m), 6. 95 (1H, dd, s"J=7. 4, 7. 2Hz), 7. 03 (1H, d, CH J=8. 1Hz), 7. 29-7. 37 (2H, m), 8. 06 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 96-1. 29 0 (4H, m), 1. 57-1. 77 (6H, m), H 83-1. 94 (2H, m), 1. 95-2. 35 N2N (4H, m), 2. 88 (3H, s), 2. 89 HCI (1. 74H, s), 2. 99 (1. 26H, s), Example < 3. 77 (2H, d, J=6. 2Hz), 4. 16 191 t 42H, d, J=4. 9Hz), 4. 31 (0. 58H, d, J=4. 9Hz), 4. 43 (2H, t cl s), 4. 49-4. 59 (0. 58H, m), 4. 72- 0 4. 83 (0. 42H, m), 6. 89-7. 00 (3H, m), 7. 28 (1H, dd, J=8. 1, 7. 9Hz), 8. 0 (3H, brs). lH-NMR (8ppm, DMSO-d6) 0. 94-1. 30 O m), 1. 55-1. 75 (6H, m), 1. 82-1. 94 (2H, m), 1. 95-2. 35 H2N m), 2. 85 (3H, s), 2. 89 I-HCI (1. 74H, s), 2. 99 (1. 26H, s), Example CH3 (2H, d, J=6. 3Hz), 4. 16 192 l (0. 42H, d, J=5. 1Hz), 4. 30 (0. 58H, d, J=5. 1Hz), 4. 37 (2H, f 4. 49-4. 59 (0. 58H, m), 4. 72- 4. 82 (0. 42H, m), 6. 92 (2H, d, J=8. 6Hz), 7. 29 (2H, d, J=8. 6Hz), 8. 06 (3H, brs).

Table 1-52 1H-NMR 96 (2H, m), 1. 02-1. 51 (3H, m), 0 1. 51-1. (7H, m), 1. 95-2. 36 88 (1. 74H, s), 2. 97 N 26H, s), 3. 16 (2H, d, A J=6. 3Hz), 4. 14 (0. 42H, d, Example 0,'J==5. 4. 29 (0. 58H, d, 193 S, 4. 36 (2H, s), 4. 46- 0 (0. 58H, m), 4. 71 (2H, s), 0 4. 72-4. 82 (0. 42H, m), 7. 06 (1H, d, J=7. 4Hz), 7. 17-7. 24 (1H, m), 7. 27-7. 36 (2H, m), 7. 56-7. 65 (2H, m), 7. 67-7. 77 (3H, m), 8. 03 (3H, bs). H-NMR (8ppm, DMSO-d6) 0. 82-1. 00 (2H, m), 1. 03-1. 52 (3H, m), O 52-1. 71 (5H, m), 1. 73-1. 85 HAN N (2H, m), 1. 95-2. 45 (6H, m), N 89 (1. 74H, s), 2. 98 (26H, CH3'HCI 23 (2H, d, J=6. 3Hz), 3. 51 Example (2H, t, J=7. 4Hz), 3. 73 (2H, t, 194 7Hz), 4. 11-4. 19 (0. 42H, m), 4. 26-4. 33 (0. 58H, m), 4. 43 (2H, s), 4. 48-4. 58 (0. 58H, m), 4. 71- s 83 (0. 42H, m), 7. 03 (1H, d, J=7. 9Hz), 7. 09 (1H, d, J=7. 8Hz), 7. 17 (1H, s), 7. 34 (1H, dd, J=7. 9, 7. 8Hz), 8. 07 (3H, brs). 0 0. 80-1. 29 11 85 (8H, m), 2 N HCI 93-2. 35 (4H, m), 2. 89 (1. 74H, N HCI... ~ 2. 93 (3H, s), 2. 98 (1. 26H, < 3. 00 (3H, s), 3. 26 (2H, d, J=6. 2Hz), 4. 13-4. 17 (0. 42H, m), Example 4. 27-4. 32 (0. 58H, m), 4. 44-4. 56 195 0 58H, m), 4. 53 (2H, s), 4. 58 0 (2H, s), 4. 61 (2H, s), 4. 72-4. 83 (0. 42H, m), 7. 36 (1H, d, J=7. 7Hz), 7. 43 (1H, d, J=7. 7Hz), 7. 46 (1H, s), 8. 05 (3H, brs). 0 Table 1-53 0 HN 49-1. 75 (6H, m), 2 83-2. 36 (6H, m), 2. 89 (1. 74H, I 2. 93-3. 02 (2H, m), 2. 98 Example s), 4. 10-4. 19 (0. 42H, Example 196 m), 4. 25-4. 34 (0. 58H, m), 4. 48- 4. (0. 58H, m), 4. 71-4. 83 (0. 42H, m), 6. 75-7. 39 (5H, m), N 10 (3H, brs). N H 0 IH-NMR DMSO-d6) 0. 75-1. 31 (5H, 51-1. 79 (7H, m), 1. 73 N (3H, s), 1. 92-2. 34 (4H, m), 2. 87 I 74H, s), 2. 96 (1. 26H, s), CH3 50 (2H, d, J=7. OHz), 4. 06-4. 15 Example (0. m), 4. 21-4. 31 (0. 58H, 197 m), 4. 44-4. 56 (0. 58H, m), 4. 69- 4. 81 (0. 42H, m), 7. 26-7. 39 (3H, Nw 7. 41-7. 50 (2H, m), 8. 05 (3H, brs). H 3 1H-NMR (8ppm, DMSO-d6) 1. 14-1. 39 0 (4H, m), 1. 55-1. 76 (5H, m), H2N-"A 81-1. 93 (2H, m), 1. 95-2. 39 N HCI (4H, m), 2. 91 (1. 74H, s), 3. 01 ^ (1. 26H, s), 3. 04 (3H, s), 3. 61- Example H 75 (1H, m), 4. 14-4. 23 (0. 42H, 198 N Ns/, 4. 29-4. 38 (0. 58H, m), 4. 51- t 4. 63 (0. 58H, m), 4. 73-4. 84 HN 7. 23 (2H, d, ll 7. 41 (2H, d, J=8. 8Hz), 0 8. 05-8. 22 (4H, m), 10. 11 (1H, brs). 0 1H-NMR (8ppm, DMSO-d6) 1. 11-1. 49 H2N-" 1. 56-1. 83 (5H, m), N 1. 86-2. 40 (7H, m), 2. 91 (1. 74H, -CH 3. 01 (1. 26H, s), 3. 15 (3H, Example fA 0 s), 4. 18-4. 24 (0. 42H, m), 4. 33- 199 SiCHa (0. 58H, m), 4. 51-4. 63 (0. 58H, m), 4. 72-4. 84 (0. 42H, m), 7. 79-7. 90 (4H, m), 8. 12 (3H, 0 brs), 10. 46 (1H, brs). H Table 1-54 0 1H-NMR 1. 12-1. 51 H2N 57-1. 82 (5H, m), N 86-2. 37 (7H, m), 2. 91 (1. 74H, s), 3. 01 (1. 26H, s), 3. 18 (3H, Example 4. 18-4. 24 (0. 42H, m), 4. 33- 200 4. 39 (0. 58H, m), 4. 51-4. 63 (0. 58H, m), 4. 72-4. 84 (0. 42H, m), 7. 53-7. 61 (2H, m), 7. 82- 0 H brs). 0 1H-NMR (8ppm, DMSO-d6) 1. 12-1. 48 H (4H, 1. 56-1. 83 (5H, m), H2N/ 7 1. 38 (7H, m), 2. 91 (1. 74H, I 3. 01 (1. 26H, s), 3. 25 (3H, CH3 4. 17-4. 22 (0. 42H, m), 4. 32- Example 4. 38 (0. 58H, m), 4. 50-4. 62 201 v/% 58H, m), 4. 73-4. 84 (0. 42H, m), 7. 41 (1H, dd, J=7. 9, /7. 7. 72 (1H, dd, J=8. 2, 0 5Hz), 7. 90 d, J=7. 9Hz), 0==su 8. 01 (1H, d, J=8. 2Hz), 8. 09 3 (3H, brs), 9. 63 (1H, brs). 0 1H-NMR (8ppm, DMSO-d6) 0. 90-1. 0 (4H, m), 1. 53-1. 77 (6H, m), HN"10 1. 80-1. 93 (2H, m), 1. 95-2. 37 2-,- 2. 90 (1. 74H, s), 2. 99 (4H, I (1. 26H, s), 3. 69 (2H, d, Example CH3-HCI J=6. 3Hz), 4. 16 (0. 42H, d, 202 3Hz), 4. 31 (0. 58H, d, J=5. 3Hz), 4. 49-4. 60 (0. 58H, m), 4. 72-4. 84 (0. 42H, m), 6. 26-6. 38 (3H, 7. 02 (1H, dd, J=8. 1, 0 OH 7. 9Hz), 8. 07 (3H, brs), 9. 38 (1H, s).

Table 1-55 0 1H-NMR (8ppm, DMSO-d6) 0. 80-1. 30 H2N 42-1. 74 (6H, m), N 1. 74-1. 87 (2H, m), 1. 94-2. 37 (4H,. 2. 89 (1. 74H, s), 2. 98 0 (1. 26H, s), 3. 01 (3H, s), 3. 29 Example \/zSX (2H, J=6. 5Hz), 4. 15 (0. 42H, 203 HN 4. 30 (0. 58H, d, /J=5. 4. 47-4. 59 (0. 58H, m), 4. 63 (2H, s), 4. 72-4. 84 (0. 42H, OH m), 7. 54 (1H, d, J=8. 1Hz), 7. 82 (1H, J=8. 1Hz), 7. 88 (1H, s), 0 05 (3H, brs). 0 0. 82-1. 31 H2N-" (4H, 88 (8H, m), -IN 37 (4H, m), 2. 89 (1. 74H, CH 2. 98 (1. 26H, s), 3. 08 (3H, I 3. 28 (2H, d, J=6. 0Hz), 4. 15 L 42H, d, J=5. 0Hz), 4. 30 Example HN (0. 58H, d, J=5. 0Hz), 4. 47-4. 59 204 3 m), 4. 60 (2H, s), 4. 72- 0 (0. 42H, m), 7. 47 (lui, d, J=8. 7. 87 (1H, dd, J=8. 4, 2. 7. 97 (1H, d, J=2. 1Hz) 8. 05 (3H, brs). 0 0 1H-NMR 1. 06-1. 50 HN"0 1. 57-1. 82 (5H, m), N HCI u m), 2. 91 (1. 74H, _ 3. 01 (1. 26H, s), 4. 17-4. 23 Example < 4. 32-4. 38 (0. 58H, 205 4. 52-4. 63 (0. 58H, m), 4. 73- Y/% (0. 42H, m), 7. 40 (1H, dd, J=7. 9, 7. 9Hz), 7. 59 (1H, d, OH 9Hz), 7, 82 (1H, d, H 9Hz), 8. 24 (1H, s), 10. 12 0 (1H, brs).

Table 1-56 0'H-NMR 1. 14-1. 49 (4H, 56-1. 82 (5H, m), N 94-2. 36 (7H, m), 2. 91 (1. 74H, _ 3. 01 (1. 26H, s), 4. 16-4. 25 L (0. 42H, m), 4. 31-4. 38 (0. 58H, Example m), 4. 50-4. 61 (0. 58H, m), 4. 73- 206 (0. 42H, m), 7. 13 (1H, dd, J=8. 4, 7. 6Hz), 7. 56 (1H, dd, 0 6Hz), 7. 98 (1H, d, " 8. 06 (3H, brs), 8. 48 H d, J=8. 4Hz), 11. 27 (1H, 0 OH 13. 56 (1H, brs). 0 1H-NMR 1. 06-1. 50 H m), 1. 57-1. 82 (5H, m), 2 85-2. 40 (7H, m), 2. 91 (1. 74H, I 3. 01 (1. 26H, s), 4. 21 Example 3 (0. 42H, d, J=5. 1Hz), 4. 36 207 58H, d, J=5. 1Hz), 4. 51-4. 63 OH 58H, m), 4. 73-4. 84 (0. 42H, m), 7. 72 (2H, d, J=8. 8Hz), 7. 87 0 N d, J=8. 8Hz), 8. 10 (3H, H brs), 10. 26 (1H, brs). H 0 r- H-NMR 0. 95-1. 32 H2N N"10 1. 55-1. 77 (6H, m), < 84-2. 37 (6H, m), 2. 90 (1. 74H, I 2. 99 (1. 26H, s), 3. 83 (2H, CH d, J=5. 7Hz), 4. 13-4. 19 (0. 42H, Example m), 4. 28-4. 34 (0. 58H, m), 4. 49- 208 (0. 58H, m), 4. 72-4. 85 (0. 42H, m), 6. 97 (1H, dd, J=7. 4, 7. 4Hz), 7. 07 (1H, d, 0 7. 46 (1H, dd, J=8. 1, 7. 4Hz), 7. 60 (1H, d, J=7. 4Hz), 0 OH 08 (3H, brs).

Table 1-57 1H-NMR 0. 90-1. 34 H 52-1. 79 (6H, m), 1. 80-2. 38 (6H, m), 2. 90 (1. 74H, I 99 (1. 26H, s), 3.. 85 (2H, Example < 0 9Hz), 4. 12-4. 20 (0. 42H, 209 m), 4. 27-4. 36 (0. 58H, m), 4. 48- OH 4. 58H, m), 4. 72-4. 85 (0. 42H, m), 6. 99 (2H, d, J=7. 9Hz), 7. 87 (2H, d, J=7. 9Hz), 8. 07 (3H, brs). 0 1H-NMR (8ppm, DMSO-d6) 0. 81-1. 29 H2N (4H, 41-1. 86 (8H, m), N 1. 94-2. 36 (4H, m), 2. 89 (1. 74H, I CH3 s), 2. 98 (1. 26H, s), 3. 25 (2H, d, J=6. 3Hz), 4. 14 (0. 42H, d, d= Example 5. 2Hz), 4. 29 (0. 58H, d, 210 J=5. 2Hz), 4. 46-4. 59 (0. 58H, m), 4. 52 (2H, s), 4. 71-4. 83 (0. 42H, m), 7. 42 (2H, d, J=8. 4Hz), 7. 92 OH (2H, d, J=8. 4Hz), 8. 06 (3H, brs). 0 0 DMSO-d6) 0. 81-1. 29 n m), 1. 41-1. 86 (8H, m), H2N-N 1. 94-2. 35 (4H, m), 2. 89 (1. 74H, I 98 (1. 26H, s), 3. 25 (2H, < d, J=6. 5Hz), 4. 14 (0. 42H, d, d= Example HCI 5. 1Hz), 4. 29 (0. 58H, d, 211 0 4. 44-4. 60 (0. 58H, m), 4. 50 (2H, s), 4. 71-4. 83 (0. 42H, m J=7. 4, 7. 4Hz), 7. 55 (1H, d, J=7. 4Hz), 7. 85 (1H, d, J=7. 4Hz), 7. 88 (1H, s), 8. 07 (3H, brs). 0 H-NMR 1. 04-1. 35 HN 1. 52-1. 78 (5H, m), : 87-2. 37 (7H, m), 2. 89 (1. 74H, s), 2. 98 (1. 26H, s), 4. 15 Example < (0. 42H, d, J=5. 2Hz), 4. 30 213-HCI d, J=5. 2Hz), 4. 48-4. 59 (0. 58H, m), 4. 71-4. 83 (0. 42H, m), 8. 14 (3H, brs). 0 Table 1-58 1H-NMR 1. 15-1. 39 0 m), 1. 56-1. 77 (5H, m), H2N-""0 82-1. 94 (2H, m), 1. 97-2. 38 N m), 2. 91 (1. 74H, s), 3. 01 3. 62 (2H, s), 3. 65- Example 3. 76 (1H, m), 4. 18 (0. 42H, d, 214 7Hz), 4. 34 (0. 58H, d, T 7Hz), 4. 51-4. 63 (0. 58H, m), HN I/4. (0. 42H, m), 7. 35-7. 42 X 7. 68-7. 74 (2H, m), 0 8. 10 (3H, brs), 8. 22 (1H, d, J=7. 9Hz). 1H-NMR (8ppm, DMSO-d6) 1. 14-1. 40 0 m), 1. 57-1. 77 (5H, m), it 6 82-1. 94 (2H, m), 1. 97-2. 38 (4H, m), 2. 91 (1. 74H, s), 3. 01 I 26H, s), 3. 63 (2H, s), 3. 65- z 23 (0. 42H, m), 30-4. 38 (0. 58H, m), 4. 51- 4. (0. 58H, m), 4. 73-4. 84 HN . 42H, m), 7. 33 (2H, d, J=8. 7. 77 (2H, d, 11 4Hz), 8. 12 (3H, brs), 8. 20 (1H, d, J=8. 4Hz), 12. 35 (1H, bs). O 0. 79-1. 26 H2N (4H, m), 1. 40-1. 85 (8H, m), 1. 36 (4H, m), 2. 89 (1. 74H, I 2. 98 (1. 26H, s), 3. 04-3. 14 Example Example 216 4. 31 T" 58H, d, J=5. 1Hz), 4. 47-4. 59 OH m), 4. 71-4. 83 (0. 42H, N 7. 35-7. 45 (2H, m), 7. 68- < 76 (2H, m), 8. 07 (3H, brs), 8. 42-8. 49 (1H, m).

Table 1-59 0 1H-NMR 0. 78-1. 30 1. 38-1. 87 (8H, m), N 93-2. 36 (4H, m), 2. 89 (1. 74H, -CH3 s), 3. 03-3. 15 Example 3. 63 (2H, s), 4. 11- Example 217 20 (0. 42H, m), 4. 26-4. 36 0 58H, m), 4. 46-4. 61 (0. 58H, m), 4. 69-4. 83 (0. 42H, m), 7. 33 H d, J=7. 4Hz), 7. 77 (2H, d, OH J=7. 4Hz), 8. 05 (3H, brs), 8. 38- 8. 51 (1H, m). 0 1. 13-1. 35 HN (4H, m), 1. 55-1. 74 (5H, m), N 82-1. 93 (2H, m), 1. 96-2. 36 N I m), 2. 90 (1. 74H, s), 3. 00 < HCI s), 3. 55-3. 66 (1H, m), 3. 75 (2H, s), 4. 18 (0. 42H, d, Example J=5. 4. 32 (0. 58H, d, 218 1 4. 51-4. 63 (0. 58H, m), Han/4. 72-4. 83 (0. 42H, m), 7. 26-7. 42 (4H, m), 8. 08 (3H, bs), 8. 20- 0 8. 26 (1H, m). 0 0'H-NMR 0. 91-1. 31 HN 0 1. 47-1. 77 (5H, m), N 80-2. 36 (7H, m), 2. 88 (1. 74H, I 2. 96 (1. 26H, s), 3. 12-3. 22 CH3 HCI m), 4. 06 (2H, s), 4. 07- 4. 16 (0. 42H, m), 4. 22-4. 31 Example (0. 58H, m), 4. 45-4. 57 (0. 58H, l 4. 69-4. 82 (0. 42H, m), 7. 44- 7. 61 (2H, m), 7. 64-7. 75 (1H, m), 90 (1H, d, J=7. 2Hz), 8. 07 pH 0 Table 1-60 O 1. 13-1. 49 jj / m), 1. 56-1. 83 (5H, m), 2 93-2. 37 (7H, m), 2. 62 (3H, N I 2. 91 (1. 74H, s), 3. 01 CH3 (1. 26H, s), 4. 16-4. 23 (0. 42H, Example m), 30-4. 39 (0. 58H, m), 4. 51- 220 4. 62 (0. 58H, m), 4. 73-4. 84 (0. 42H, m), 7. 20 (1H, dd, J=8. 1, 7. 4Hz), 7. 59 (1H, dd, 0 4, 7. 4Hz), 800 (1H, d, H J=8. lHz), 8. 13 (3H, bs), 8. 36. 0 J=8. 4Hz), 11. 35 (1H, s). 0 0. 76-1. 05 (2H, 1. 21-1. 45 (2H, m), HN . HC I HCI 45-1. 80 (8H, m), 1. 88-2. 35 (4H, m), 2. 86 (1. 74H, s), 2. 92 CH3 26H, s), 3. 16 (3H, s), 3. 98- Example. 08 (0. 42H, m), 4. 14-4. 24 221 58H, m), 4. 39-4. 52 (0. 58H, 0 m), 4. 67-4. 80 (0. 42H, m), 7. 46 0+/\+ d, J=8. 2Hz), 7. 97 (3H, 0 brs), 8. 01 (2H, d, J=8. 2Hz). CH3 0 0. 71-1. 04 11 22-1. 78 (8H, m), 2-" 89-2. 37 (6H, m), 2. 85 (1. 74H, I 2. 92 (1. 26H, s), 3. 15 (3H, CH3-KCI 3. 97-4. 09 (0. 42H, m), 4. 13- Example 4. (0. 58H, m), 4. 38-4. 52 222 58H, m), 4. 66-4. 80 (0. 42H, m), 7. 53-7. 67 (2H, m), 7. 77- OH m), 7. 87 (3H, brs), 0 IN 7. 94 (1H, s). CH3 0 Table 1-61 0'H-NMP, 0. 72-1. 03 j/ -1. 44 (2H, m), 2 44-1. 79 (7H, m), 1. 87-2. 37 I m), 2. 85 (1. 74H, s), 2. 92 ( 26H, s), 3. 99-4. 07 (0. 42H, m), 4. 14-4. 24 (0. 58H, m), 4. 20 Example (2H, 4. 39-4. 51 (0. 58H, m), 223 4. 66-4. 79 (0. 42H, m), 7. 33-7. 53 0 . (3H, bs). ON 0 0 0 0. 76-1. 05 H2N-" 21-1. 42 (2H, m), N 1. 43-1. 74 (8H, m), 1. 93-2. 32 CH3 CH3 (4H, 2. 85 (1. 74H, s), 2. 92 Example H (1. 26H, s), 3. 06 (3H, s)., 3. 08 224 N,, NX CH3 (3H, s), 4. 01-4. 08 (0. 42H, m), 0//\\o 15-4. 22 (0. 58H, m), 4. 39-4. 52 0 (0. 58H, m), 4. 67-4. 80 (0. 42H, I 7. 22-7. 34 (4H, m), 7. 94 CH3 (3H, bs). 1H-NMR (8ppm, DMSO-d6) 0. 75-1. 05 0 m), 1. 23-1. 45 (2H, m), 1. 45-1. 78 (8H, m), 1. 88-2. 35 -Nl m), 2. 86 (1. 74H, s), 2. 93 < (1. 26H, s), 3. 04 (3H, s), 3. 11 Example (3H, s), 3. 97-4. 09 (0. 42H, m), 225 4. 15-4. 24 (0. 58H, m), 4. 40-4. 52 j 58H, m), 4. 67-4. 81 (0. 42H, NiS. H 7. 07 (1H, d, J=7. 4Hz), 7. 11 I H 0 J=7. 7Hz), CH3 7. 43 (1H, dd, J=7. 7, 7. 4Hz), 7. 94 (3H, brs).

Table 1-62 0 1H-NMR DMSO-d6) 0. 66-1. 04 HN 13-1. 77 (8H, m), 2 77-2. 36 (6H, m), 2. 85 (1. 74H, s), 2. 92 (1. 26H, s), 3. 04 (3H, < 3. 15 (3H, s), 3. 96-4. 10 (0. 42H, m), 4. 11-4. 24 (0. 58H, Example 4. 39-4. 53 (0. 58H, m), 4. 66- 226 4. 82 (0. 42H, m), 7. 22 (1H, dd, \ 5, 7. 4Hz), 7. 32 (1H, d, 0 N 5Hz), 7. 38 (1H, dd, J=8. 1, CH3 4Hz), 7. 53 (1H, d, J=8. 1Hz), So 7. 99 (3H, brs), 9. 51 (1H, brs). CH3 0 1H-NMR 75-1. 04 HN m), 1. 20-1. 43 (2H, m), : 43-1. 77 (7H, m), 1. 89-2. 39 HCI m), 2. 33 (3H, s), 2. 85 L (1. 74H, s), 2. 92 (1. 26H s), 4. 00-4. 06 (0. 42H, m), 4. 14-4. 22 Example CH3 (0. 58H, m), 4. 16 (2H, s), 4. 40- 227 227 (0. 58H, m), 4. 66-4. 78 (0. 42H, m), 7. 21-7. 33 (4H, m), 0 11 (3H, brs). OH 0 0 J 0. 78-1. 06 H 1. 21-1. 42 (2H, m), 2 44-1. 76 (7H, m), 1. 92-2. 32 HCI m), 2. 85 (1. 74H, s), 2. 92 L (1. 26H, s), 4. 01-4. 05 (0. 42H, m), 4. 14-4. 18 (0. 58H, m), 4. 20 Example (2H, s), 4. 40-4. 51 (0. 58H, m), 28 228 67-4. 78 (0. 42H, m), 7. 43 (2H, d, 9Hz), 7. 55 (2H, d, 0 N J=7. 9Hz). OH f 0 Table 1-63 0 0. 73-1. 07 HN 1. 13-1. 44 (2H, m), 2 45-1. 83 (7H, m), 1. 89-2. 36 N (5H, m), 2. 85 (1. 74H, s), 2. 92 UH3-HCI s), 3. 99-4. 08 (0. 42H, m), 4. 14-4. 21 (0. 58H, m), 4. 26 Example 3 (2H, s), 4. 38-4. 54 (0. 58H, m), 229 4. 66-4. 79 (0. 42H, m), 7. 54-7. 71 0 N (2H, m), 7. 78-7. 93 (2H, m), 8. 02 (3H, brs). OH 0 0 H-NMR 0. 75-1. 05 HN"10 1. 22-1. 44 (2H, m), N 45-1. 78 (7H, m), 1. 92-2. 37 I 33 (3H, s), 2. 85 UH3-HCI (1. 74H, s), 2. 92 (1. 26H,, s), Example 01-4. 07 (0. 42H, m), 4. 14-4. 21 Example 58H, m), 4. 17 (2H, s), 4. 40- 230 4. 52 (0. 58H, m), 4. 67-4. 78 0 42H, m), 7. 12-7. 25 (3H, m), 0 dd, J=8. 1, 7. 7Hz), OH 8. 11 (3H, brs). 0 0 0 0. 77-1. 06 HN"10 21-1. 44 (2H, m),. 2 46-1. 79 (7H, m), 1. 92-2. 36 (5H, m), 2. 86 (1. 74H, s), 2. 93 cl3 26H, s), 4. 02-4. 07 (0. 42H, m), 4. 15-4. 21 (0. 58H, m), 4. 22 Example (2H, s), 4. 41-4. 53 (0. 58H, m), 231 4. 67-4. 79 (0. 42H, m), 7. 35-7. 43 (IH, m), 7. 45-7. 57 (3H, m), 0 (3H, brs). OH 0 Table 1-64 0 1H-NMR 72-1. 04 H 1. 14-1. 45 (2H, m), 2 46-1. 81 (7H, m), 1. 89-2. 35 HCI m), 2. 85 (1. 74H, s), 2. 92 L (1. 26H, s), 4. 00-4. 08 (0. 42H, m), 4. 14-4. 21 (0. 58H, m), 4. 27 Example s), 4. 39-4. 53 (0. 58H, m), 232 s 65-4. 79 (0. 42H, m), 7. 66-7. 86 0 y oh 0 O DMSO-d6) 0. 80-1. 28 0 m), 1. 41-1. 88 (8H, m) H2N 94-2. 36 (4H, m), 2. 88 (1. 74H, I 2. 97 (1. 26H, s), 3. 28 (2H, f CH3 J=6. 0Hz), 3. 75 (3H, s), 4. 12 Example (0. 42H, d, J=5. 3Hz), 4. 27 233 9 58H, d, J=5. 3Hz), 4. 43-4. 58 OMe 0 (0. 58H, m), 4. 48 (2H, s), 4. 70- 0 (0. 42H, m), 7. 19 (1H, dd, J=7. 7, 7. 4Hz), 7. 53 (1H, d, J=7. 4Hz), 7. 63 (1H, d, J=7. 7Hz). 0 1H-NMR 0. 75- H2N-'A 0. 96 (2H, m), 0. 98-1. 30 (2H, m), N 1. 32-1. 48 (1H, m), 1. 49-1. 84 (7H, ~ HCI m), 1. 89-2. 38 (4H, m), CH3 Example 88 (1. 74H, s), 2. 97 (1. 26H, s), 3. 18 (2H, d, J=6. 0Hz), 4. 09-4. 17 234 0 OH (0. 42H, m), 4. 23-4. 32 (0. 58H, t 4. 44-4. 59 (0. 58H, m), O 4. 73 (2H, s), 4. 75-4. 83 (0. 42H, m), 7. 62 (1H, t, J=7. 5Hz), 7. 83- CF3 7. 90 (2H, m), 8. 04 (3H, brs).

Table 1-65 0 11/m 99 (2H, m), 1. 02-1. 33 (2H, m), H2NN 1. 35-1. 51 (1H, m), 1. 52-1. 85 (7H, m), 36 (4H, m), 2. 29 (3H, \ 89 (1. 70H, s), 2. 98 (1. 30H, Example s), 3. 18 (2H, d, J=6. 0Hz), 4. 10- 235 OH 4. 22 (0. 43H, m), 4. 24- 4. 36 (0. 57H, m), 4. 45 (2H, s), Wo 4. 48-4. 60 (0. 43H, m), 4. 70- 4. 84 (0. 57H, m), 7. 16-7. 24 (2H, w 7. 25-7. 34 (1H, m), 8. 04 (3H, brs), 13. 03 (1H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 0 34 (4H, m), 1. 55-1. 78 (6H, m), ij/7 93 (2H, m), 1. 95-2. 37 (4H, 2 m), 2. 90 (1. 65H, s), 2. 99 (1. 35H, I 87 (2H, d, J=6. 0Hz), 4. 12- Example n 19 (0. 45H, m), 4. 26- 236 55H, m), 4. 47- OH 4. 61 (0. 55H, m), 4. 70-4. 84 (0. 45H, m), 6. 97 (1H, dd, J=3. 0, 0 9. OHz), 7. 07 d, J=3. OHz), 7. 83 (1H, d, J=9. OHz), 8. 09 (3H, brs). lH-lIMR 0. 97- 1. 35 (4H, m), 1. 51-1. 80 (6H, m), H2NJ 82-1. 96 (2H, m), 1. 97-2. 39 (4H, N HCI m), 2. 90 (1. 70H, s), 3. 00 (1. 30H, CH s), 3. 96 (2H, d, J=6. 0Hz), 4 13- Example 0 4. 19 (0. 43H, m), 4. 27- 237 4. 34 (0. 57H, m), 4. 48- OH 63 (0. 57H, m), 4. 72-4. 85 (0. 43H, m), 7. 23 (1H, d, 0 7. 88 (1H, dd, J=9. 0, Cl 7. 89 (1H, s), 8. 17 (3H, brs).

Table 1-66 _ 0. 95-1. 35 (4H, 1. 53-1. 80 (6H, m), ' 83-1. 95 (2H, m), 1. 97-2. 39 (4H, m), 2. 18 (3H, s), 2. 90 CH (1. 73H, s), 3. 00 (1. 27H, s), Example | J=6. 0Hz), 4. 15 239 (0. 42H, d, J=6. 0Hz), 4. 30 (0. 58H, d, J=6. 0Hz), 4. 47-4. 63 0 (0. 58H, m), 4. 68-4. 85 (0. 42H, m), 6. 98 (1H, d, J=9. OHz), 7. 72 CH3 (1H, s), 7. 76 (1H, dd, J=9. 0, 3. 0Hz), 8. 13 (3H, brs). 0 1H-NMR 0. 88-1. 34 53-1. 79 (6H, m), 2 80-1. 94 (2H, m), 1. 96-2. 38 N (4H, m), 2. 90 (1. 69H, s), 2. 99 Example ( (1. 31H, s), 3. 83 (2H, d, 240 J=6. 4. 11-4. 19 (0. 44H, m), OH < 34 (0. 56H, m), 4. 46-4. 62 (0. 56H, m), 4. 69-4. 85 (0. 44H, 0 6. 74-6. 88 (2H, m), 7. 82 (1H, d, J=9. OHz). 0 p HN 1. 36 (4H, m), 1. 52-1. 80 (6H, m), N 95 (2H, m), 1. 96-2. 39 (4H, m), 28 (6H, s), 2. 90 (1. 71H, s), CH3 Example CH3 3. 00 (1. 29H, s), 3. 79 (2H, d, 241 4. 10-4. 19 (0. 43H, m), 4. 26-4. 34 (0. 57H, m), 4. 47-4. 62 OH (0. 57H, m), 4. 69-4. 86 (0. 43H, m), T 6. 92 (1H, s), 7. 11 (1H, s), CH3 25 (3H, brs). CH3 0 0 1H-NMR DMSO-d6) 0. 89- 1. 34 (4H, m), 52-1. 78 (6H, m), N HCI 93 (2H, m), 1. 94-2. 40 (4H, CH 90 (1. 70H, s), 2. 99 (1. 30H, 243 87 (2H, d, J=6. 0Hz), 4. 11- 4. 19 (0. 43H, m), 4. 25-4. 35 (0. 57H, OH m), 4. 45-4. 63 (0. 57H, m), 4. 67- % 86 (0. 43H, m), 6. 77-6. 93 (2H, 0 m), 7. 81 (1H, t, J=9. OHz).

Table 1-67 1H-NMR (8ppm, DMSO-d6) 10. 39 (1H, 0 s), 7. 98 (3H, s), 7. 70 (2H, d, H2N HCI J=8. 7Hz), 7. 58 (1H, t, N 7Hz), 7. 34-7. 33 (3H, m), i Ci3 27-7. 25 (4H, m), 4. 72 (0. 42H, Example J=9. 2Hz), 4. 60 (2H, s), 4. 45 244 H 58H, t, J=8. 9Hz), 4. 22 (0. 58H, s), 4. 05-4. 03 (0. 42H, HN/ "ss, m), 2. 93 (1. 27H, s), 2. 85 0 73H, s), 2. 76-2. 73 (1H, m), 2. 21-2. 06 (4H, m), 1. 64-1. 52 (7H, m), 1. 17-1. 09 (4H, m). 1H-NMR (8ppm, DMSO-d6) 8. 08 O/, 09H, s), 7. 77 (1H, d, H2N N,,, J=6. 8Hz), 7. 30 (5H, tt, J=12. 4, 'IN 4. 3Hz), 4. 76 (0. 45H, t, A HCI J=8. 9Hz), 4. 54 (0. 55H, t, CH3 Example J=8. 9Hz), 4. 44 (2H, s), 4. 32- 245 55H, m), 4. 17-4 : 13 I 45H, m), 3. 62 (2H, t, HN R,,-O 2Hz), 3. 44-3. 41 (1H, m), 2. 98 (1. 34H, s), 2. 89 (1. 56H, 0 2. 33-1. 99 (6H, m), 1. 78 (2H, s), 1. 63 (5H, d, J=4. 1Hz), 1. 25-1. 03 (4H, m). O lH-NMR 8. 09 (3H, HN A s), 7. 6Hz), 4. 75 N (0. 41H, t, J=7. 9Hz), 4. 53 -cl 59H, t, J=8. 8Hz), 4. 29 CH3 Example HC I 246 3. 59-3. 57 (2H, m), 3. 43 (1H, brs), 2. 98 (1. 24H, s), HN (1. 76H, s), 2. 22-2. 11 (6H, m), 1. 79 (2H, brs), 1. 63 (5H, brs), 1. 35-1. 05 (4H, m). 0 Table 1-68 H-NMR 7. 96 (3H, brs), 7. 25 (2H, t, J=7. 9Hz), H2N 6. 90 (3H, dt, J=6. 8, 2. 6Hz), 4. 76 (0. 42H, t, J=9. 2Hz), 4. 57- CH 4. 49 (0. 58H, m), 4. 31-4. 29 Example (0. 52H, m), 4. 16-4. 11 (0. 42H, 247 m), 3. 96 (2H, J=6. 2Hz), 2. 99 (1. 25H, s), 2. 88 (1. 75H, s), 2. 30-2. 21 (1H, m), 2. 10-1. 99 ll m), 1. 78-1. 61 (9H, m), 1. 36-1. 33 (2H, m), 1. 04 (3H, ddd, J=67. 6, 25. 1, 13. 6Hz). O DMSO-d6) 8. 04 (3H, brs), 7. 33-7. 14 (5H, m), 4. 77 H 43H, t, J=8. 9Hz), 4. 53 I 57H, t, J=8. 3Hz), 4. 30 Example CH3 HCI 57H, d, J=4. 9Hz), 4. 16 248 (0. d, J=5. 3Hz), 3. 82 (2H, s), (1. 30H, s), 2. 8-8 (1. 70H, s), 2. 26-2. 04 (7H, m), 0 64-1. 55 (5H, m), 1. 20-1. 16 (4H, m). lH-NMR 8. 01 (3H, brs), 7. 26 (2H, t, J=7. 3Hz), H2N+N 7. 17 (3H, d, J=7. 2Hz), 4. 77 (0. 42H, t, J=9. OHz), 4. 52 CH3 (0. 58H, t, J=8. 7Hz), 4. 28 Example (0. 58H, d, J=5. 3Hz), 4. 13 249 (0. 42H, d, J=4. 9Hz), 2. 97 (1. 27H, s), 2. 88 (1. 73H, s), 2. 56-2. 47 (2H, m), 2. 31-2. 04 (4H, m), 1. 73-1. 61 (9H, m), 1. 23-1. 06 (5H, m), 0. 84-0. 80 (2H, m).

Table 1-69 1H-NMR 8. 06 (3H, J=7. 9Hz) 0 brs), 7. 27 (2H, t, H 92-6. 90 (3H, m), 4. 77 (0. 42H, 2 t, J=9. OHz), 4. 53 (0. 58H, t, CH 4. 29 (0. 58H, d, CH3 Example 9Hz), 4. 14 (0. 42H, brs), 250 98 (2H, t, J=6. 4Hz), 2. 98 (1. 25H, s), 2. 89 (1. 75H, s), 2. 25-2. 11 (4H, m), 1. 81 (2H, d, J=11. 1. 60 (7H, dd, J=13. 8, 7. 3Hz), 1. 40-1. 36 (1H, m), 1. 21-1. 11 (2H, m), 0. 93- 0. 89 (2H, m). 0 1H-NMR 9. 72 (1H, s), 8. 07 (3H, brs), 7. 21 (1H, N J=8. 5Hz), 6. 77-6. 76 (2H, m), cl3 65 (1H, d, J=9. OHz), 4. 78 CH3 (0. 45H, t, J=9. OHz), 4. 55 4 55H, t, J=7. 9Hz), 4. 32 Example 55H, s), 4. 18 (0. 45H, s), 251 3. 74 (2H, d, J=6. 4Hz), 2. 99 0 (1. 36H, s), 2. 97 (3H, s), 2. 90 (1. 64H, s), 2. 29-2. 06 (4H, m), 1. 89-1. 87 (2H, m), 1. 65-1. 55 Ow, 0 N m), 1. 16-1. 03 (4H, m). N CH, H lH-NMR 8. 27 (1H, t, 8. 05 (3H, brs), H2N N-"A 31-7. 28 (2H, m), 7. 23-7. 19 (3H, m), 4. 76 (0. 40H, t, Cfig 4. 53 (0. 60H, t, Example HCI 4. 32 (0. 60H, brs), 252 4. 23 (2H, d, J=6. 0Hz), 4. 17 (0. 40H, brs), 2. 98 (1. 21H, s), 2. (1. 79H, s), 2. 32-2. 28 (1H, 0 2. 17-2. 08 (4H, m), 1. 82- 1. m), 1. 63-1. 61 (5H, m), 1. 39-1. 07 (4H, m).

Table 1-70 lH-NMR (8ppm, DMSO-d6) 9. 87 (1H, 0 r-_ 08 (3H, brs), 7. 58 (2H, H J=7. 9Hz), 7. 26 (2H, t, N 9Hz), 7. 00 (1H, t, - 4Hz), 4. 77 (0. 44H, t, Example < 7Hz), 4. 56 (0. 56H, t, 253 J=8. 35 (0. 56H, d, J=4. 6Hz), 4. 20 (0. 44H, d, A 3. 00 (1. 32H, s), 2. 90 0 68H, s), 2. 31-2. 06 (5H, m), H 90-1. 86 (2H, m), 1. 75-1. 58. (5H, m), 1. 36-1. 14 (4H, m). 1H-NMR (§ppm, DMSO-d6) 8. 00 (3H, brs), 7. 50-7. 37 (4H, m), 4. 77 han 42H, t, J=8. 3Hz), 4. 56-4. 50 2 (0. 58H, m), 4. 56 (2H, s), 4. 30 (0. 58H, d, J=5. 3Hz), 4. 15 CH3 (0. 42H, d, J=4. 1Hz), 3. 61 (2H, Example t, J=6. 6Hz), 3. 41 (2H, t, 254 < J=7. 5Hz), 3. 26 (2H, d, J=6. 2. 98 (1. 25H, s), 2. 89 O (1. 75H, s), 2. 41 (2H, t, J=7. 3Hz), 2. 22-2. 05 (4H, m), 1. 82-1. 79 (2H, m), 1. 64-1. 49 (6H, m), 1. 28-1. 07 (2H, m), 0. 93-0. 89 (2H, m). 1H-NMR (8ppm, DMSO-d6) 7. 36 (1H, cl, J=7. 9Hz), 7. 27 (1H, s), 7. 17 HCI d, J=8. 3Hz), 4. 79 (0. 40H, i J=8. 7Hz), 4. 56 (2H, s), A 56-4. 53 (0. 60H, m), 4. 53 (2H, Example 4. 04-4. 02 (0. 60H, m), 3. 92- 255 CN3 3. 88 (0. 40H, m), 3. 22 (2H, d, J=6. 3. 01 (3H, s), 3. 00 ° 0 (3H, 2. 96 (1. 21H, s), 2. 87 "--'NCH 2. 23-2. 06 (4H, m), H 76-1. 46 (8H, m), 1. 13-0. 99 (4H, m).

Table 1-71 O 11. 06 (1H, d, 5Hz), 8. 62 (1H, d, 2 8. 10 (3H, brs), 7. 81 l 7. 52 (2H, t, 3-HCI 7. 19 (1H, brs), 4. 79 Example 40H, t, J=8. 9Hz), 4. 57 256 (0. 60H, t, J=7. 9Hz), 4. 35 'J. 60H, brs), 4. 20 (0. 40H, brs), 3. 71 (1H, brs), 3. 11 (3H, O s), 3. 01 (1. 20H, s), 2. 91 S-0 s), 2. 21-2. 01 (6H, m), W 68-1. 65 (5H, m), 1. 31-1. 27 cH3 CH3 0 r_ 8. 46 (1H, t, J=5. 7Hz), 8. 05 (3H, brs), N 83 (2H, d, J=7. 2Hz), 7. 54- 7. 43 (3H, m), 4. 77 (0. 41H, t, CH3 Example 4. 53 (0. 59H, t, Example 257 3Hz), 4. 31 (0. 59H, brs), 0 4. 16 (0. 41H, brs), 3. 09 (2H, t, J=6. 2. 98 (1. 23H,. 2. 89 N 76H, s), 2. 23-2. 14 (4H, m), H 1. 80-1. 76 (2H, m), 1. 60-1. 51 (6H, m), 1. 13-0. 92 (4H, m). lH-NMR (8ppm, DMSO-d6) 8. 04 (3H, brs), 7. 51 (1H, d, J=7. 5Hz), H2N 40-7. 39 (2H, m), 7. 17 (1H, N J=8. 5, 1. 7Hz), 4. 78 (0. 42H, CH3 HCI t, J=9. OHz), 4. 55 (0. 58H, t, Example 9Hz), 4. 32 (0. 58H, d, 258 5Hz), 4. 17 (0. 42H, d, 5 9Hz), 3. 83 (2H, d, OH 2. 99 (1. 27H, s), 2. 90 0)) 73H, s), 2. 22-2. 10 (3H, m), 0 1. 91-1. 88 (2H, m), 1. 68-1. 65 (6H, m), 1. 22-1. 09 (5H, m).

Table 1-72 MP 0 8. 03 (3H, brs), 7. 42-7. 33 AN (4H, m), 7. 06-7. 05 (1H, m), 4. 81-4. 77 (0. 42H, m), 4. 58-4. 51 Example 4. 36-4. 34 (0. 58H, Example m), 4. 19-4. 15 (0. 42H, m), 3. 259 (2H, 5Hz), 2. 99 (1. 26H, NH2 2. 90 (1. 74H, s), 2. 32-2. 27 d .. m), 0 1. 94-1. (2H, m), 1. 76-1. 56 (6H, 1. 28-0. 97 (5H, m). 'H-NMR (8ppm, DMSO-d6) 8. 40 (1H, ° J=4. 5Hz), 8. 04 (3H, brs), H2N 41-7. 31 (3H, m), 7. 06-7. 03 Nl m), 4. 80-4. 78 (0. 40H, m), 4. 55-4. 52 (0. 60H, m), 4. 32 Example (0. 60H, s), 4. 19 (0. 40H, s), 260 82 (2H, d, J=6. 4Hz), 3. 00 H 20H, s), 2. 90 (1. 80H,-s), N . 2. 27- 2. 05 (3H, m), 1. 91 (2H, s), 0 1. 65 (6H, s), 1. 28-0. 99 (5H, m). 1H-NMR (8ppm, DMSO-d6) 8. 04 (3H, 0 7. 32 (1H, t, J=7. 9Hz), H2N 6. 98-6. 89 (3H, m), 4. 78 (0. 40H, H2N J=7. 9Hz), 4. 54 (0. 60H, t, | 4. 31 (0. 60H, d, Example < 4. 17 (0. 40H, d, 261 J=4. 9Hz), 3. 80 (2H, d, CH J=6. 0Hz), 2. 99 (1. 20H, s), 2. 96 (3H, N,, (3H, brs), 2. 22-2. 04 (4H, " 1. 91-1. 87 (2H, m), 1. 66- 1. 61 (6H, m), 1. 27-0. 98 (4H, m).

Table 1-73 0'H-NMR DMSO-d6) 9. 88 (1H, HN 8. 03 (3H, brs), 7. 58 (2H, H2N N d, J=7. 5Hz), 7. 27 (3H, t, - 9Hz), 7. 02 (1H, t, CH3 42H, t, Example J=9. 2Hz), 4. 53 (0. 58H, t, ) 4. 31 (0. 58H, brs), 4. 16 (0. 42H, brs), 2. 98 (1. 27H, s), 2. 89 (1. 73H, s), 2. 27-2. 11 ou (5H, m), 1. 77-1. 64 (8H, m), 1. 24-0. 86 (4H, m). O 11. 18 (1H, s), 8. 89 (1H, s), 8. 04 (3H, s), H 7. 83 (1H, d, J=8. 3Hz), 7. 54- X 53 (2H, m), 7. 21-7. 16 (1H, CH3 m), 4. 77 (0. 42H, t, J=9. OHz), Example 0 4. 53 (0. 58H, t, J=7. 7Hz), 4. 30 263'J rH (0. 58H, brs), 4. 17 (0. 42H, brs), 3. 13-3. 10 (2H, m), 11 N s), 2. 89 H 75H, s), 2. 23-2. 09 (4H, m), 1. 81-1. 50 (8H, m), 1. 11-0. 96 (4H, m). H-EMR (6ppm, DMSO-d6) 9. 88 (1H, s), 8. 48 (1H, t, J=5. 3Hz), 8. 04 O (3H, brs), 7. 65 (1H, s), 7. 55 H2N-"A 2Hz), 7. 41 (1H, N J=7. 7Hz), 7. 34 (1H, d, CH3 HCI 4. 77 (0. 44H, t, Example J=7. 9Hz), 4. 53 (0. 56H, 264 0 J=7. 9Hz), 4. 30 (0. 56H, brs), H 16 (0. 44H, brs), 3. 08 (2H, t, N J=6. 2Hz), 3. 01 (3H, s), 2. 98 H U (1. 31H, s), 2. 89 (1. 69H, s), 2. 32-2. 00 (4H, m), 1. 78-1. 63 (7H, m), 1. 46 (1H, s), 1. 15- 0. 89 (4H, m).

Table 1-74 1H-NMR (8ppm, DMSO-d6) 10. 0 s), 8. 37 (1H, brs), 8. 03 (3H, brs), 7. 81 (2H, d, J=8. 7Hz), N 7. 23 (2H, d, J=8. 7Hz), 4. 77 CH t, J=9. 6Hz), 4. 53 Example 59H, brs), 4. 31 (0. 59H, 265 4. 16 (0. 41H, brs), 3. 07- 3. 05 (2H, m), 3. 05 (3H, s), Nu 98 (1. 22H, s), 2. 89 (1. 78H, H 2. 32-2. 00 (4H, m), 1. 78- N 1. 63 (7H, m), 1. 46-1. 43 (1H, H 1. 18-1. 08 (3H, m), 0. 92- 0. 88 (1H, m). 0 H-NMR 8. 14-8. 05 HN (4H, J=7. 5Hz), N 54-7. 50 (2H, m), 7. 35 (1H, dd, lHz), 4. 80-4. 76 r ""' m), 4. 57-4. 54 (0. 57H, Example m), (0. 57H, brs), 4. 20 266 43H, brs), 3. 61-3. 57 (1H, HN 3. 00 (1. 29H, s), 2. 91 Y s), 2. 35-1. 91 (6H, m), 1. 66-1. 65 (5H, m), 1. 29-1. 07 0 (4H, m). H-NMR (8ppm, DMSO-d6) 8. 46 (1H, d, J=7. 9Hz), 8. 39 (1H, d, 0 J=1. 9Hz), 8. 05 (1H, dd, J=7. 7, H 6Hz), 8. 05 (3H, brs), 7. 58 N t, J=7. 7Hz), 4. 78 (0. 40H, t, 4. 56 (0. 60H, t, HC 1 Example 4. 33 (0. 60H, d, 267 6Hz), 4. 18 (0. 40H, d, T 3. 71 (1H, brs), 3. 00 HO (1. 19H, s), 2. 90 (1. 81H, s), 2. 30-2. 28 (1H, m), 2. 21-2. 06 0 0 (3H, m), 1. 90-1. 88 (2H, m), 1. 65-1. 64 (5H, m), 1. 30-1. 27 (4H, m).

Table 1-75 1H-NMR (8ppm, DMSO-d6) 8. 41 (1H, 0 d, J=8. 3Hz), 7. 99 (2H, d, H2 7. 95 (3H, brs), 7. 91 N d, J=8. 3Hz), 4. 79-4. 77 i CH3 (0. 38H, m), 4. 57-4. 55 (0. 62H, Example 4. 33 (0. 62H, d, J=5. 6Hz), 268 18 (0. 38H, d, J=5. 6Hz), 3. 71 s 3. 00 (1. 14H, s), HN 2. 90 (1. 86H, s), 2. 30-2. 28 (1H, m), 2. 15-2. 04 (3H, m), 1. 90- 1. 88 (2H, m), 1. 65-1. 64 (5H, m), 1. 26-1. 19 (4H, m). 0 8. 04 (4H, H N 79-4. 75 (0. m), 4. 55- 2-N 52 (0. 53H, m), 4. 31 (0. 53H, CH 4. 18 (0. 47H, brs), 3. 43 Example 3 J=6. 4Hz), 3. 21 (2H, t, 269 J=6. 4Hz), 2. 26-1. 99 (4H, m), 0 71-1. 65 (8H, m), 1. 261. 14 (4H, m). ONX H 0, H-NMR 8. 04 (3H, H N N 4. 77-4. 74 (0. 57H, m), 4. 55-4. 52 (0. 43H, m), 4. 33 (0. 57H, brs), Example 3. 4. 19 (0. 43H, brs), 3. 20 (2H, q, 270 J=6. 7Hz), 2. 98 (1. 30H, s), 2. 89 (1. 70H, s), 2. 49 (2H, t, J=6. 7Hz), 2. 27-1. 99 (5H, m), O CHg 2. 05 (3H, s), 1. 76-1. 64 (7H, H 1. 32-1. 09 (4H, m). O 8. 03 (3H, H 7. 85 (1H, t, J=6. 4Hz), N 79-4. 76 (0. 48H, m), 4. 55-4. 52 -cl 52H, m), 4. 32 (0. 52H, brs), Example le HCI 4. 18 (0. 48H, brs), 3. 13-3. 06 HCI 271 (4H, m), 2. 99 (1. 43H, s), 2. 95 (3H, s), 2. 90 (1. 57H, s), 2. 23- 'cl3 03 (5H, m), 1. 77-1. 63 (9H, ON/"S, 1. 29-1. 09 (4H, m). H H 0 Table 1-76 1H-NMR 04 (3H, brs), 7. 76 (1H, t, J=5. 8Hz), H2 t, J=8. lHz), 4. 54 (0. 59H, t, J=7. 9Hz), 4. 33 Example CH3 272'HCI 3. 08 (2H, q, J=6. 5Hz), 2. 98 (1. 24H, s), 2. 89 (1. 76H, s), 2. 43 43 t, J=7. 3Hz), 2. 32-1. 95 0 SH3 m), 2. 02 (3H, s), 1. 76-1. 60 H m), 1. 23 (4H, tt, J=30. 3, 11. 9Hz). 0 8. 05 (3H, brs), 7. 85 (1H, t, J=5. 7Hz), H2N 05 (1H, t, J=6. 2Hz), 4. 79-4. 76 l 37H, m), 4. 54-4. 52 (0. 63H, CN3CH3t Example 273 37H, brs), 3. 11 (2H, q, J=6. 4Hz), 2. 98 (1. 11H, s), 2. 96 H (2H, t, J=7. 3Hz), 2. 89 (1-. 89H, 0 . s), 2. 88 (3H, s), 2. 30-2. 00 (5H, H 77-1. 64 (7H, m), 1. 32-1. 07 (4H, m). 1H-NMR (8ppm, DMSO-d6) 8. 05 (3H, 0 brs), 7. 76 (1H, brs), 6. 94 (1H, t, 3Hz), 4. 78-4. 76 (0. 44H, m) 4. 56-4. 53 (0. 56H, m), 4. 32 Example < 56H, brs), 4. 18 (0. 44H, brs), 274 05 (2H, q, J=6. 3Hz), 2. 98 (1. 32H, s), 2. 90 (2H, q,. J=7. ), 2. 89 (1. 68H, s), 2. 87 O s), 2. 23-2. 06 (5H, m), H H 1. 71-1. 57 (9H, m), 1. 24-1. 13 (4H, m). 0 12. 16 (1H, NZN N t, J=5. 5Hz), 4. 78-4. 75 (0. 41H, m), 54-4. 51 (0. 59H, m), 4. 32 Example L (0. 59H, brs), 4. 17 (0. 41H, brs), 275 t 20 (2H, q, J=6. 3Hz), 2. 98 O 23H, s), 2. 89 (1. 77H, s), 2. 34 (2H, t, J=6. 8Hz), 2. 26-2. 10 0 m), 1. 75-1. 60 (8H, m), 1. 23-1. 14 (4H, m).

Table 1-77 0 1H-NMR 8. 09 (2. 46H, H J=6. 0Hz), 8. 05 (3H, brs), 4. 77 2 41H, t, J=9. 2Hz), 4. 54 (0. 59H, CH J=8. 5Hz), 4. 32 (0. 59H, d, Example J=3. 8Hz), 4. 17 (0. 41H, d, 276 J=5. 3. 70 (2H, d, J=5. 7Hz), 2. 99 (1. 23H, s), 2. 90 (1. 77H, s), Xs 05 (5H, m), 1. 73-1. 66 (7H, 0 1. 24-1. 15 (4H, m). H 0 12. 04 (1H, brs), 8. 04 (3H, brs), 7. 74 (1H, t, J=5. 7Hz), 4. 77 (0. 43H, t, CH J=8. 5Hz), 4. 54 (0. 57H, t, Example J=7. 9Hz), 4. 33 (0. 57H, brs), 4. 18 277 43H, brs), 3. 01 (2H, q, J=6. 2. 98 (1. 29H, s), 2. 89 OH 71H, s), 2. 27-1. 91 (5H, 0 19-2. 16 (2H, m), 1. 72-1. 60 (9H, H 1. 24-1. 15 (4H, m). 1H-NMR 8. 34-8. 32 H NJk 7. 50-7. 42 N (4H, m), 4. 79 (2H, s), 4. 77-4. 73 I 4. 57-4. 54 (0. 57H, m), 4. 33 (0. 57H, brs), 4. 20 (0. 43H, Example brs), 3. 63 (1H, brs), 3. 00 (1. 30H, 278 s), 2. 91 (1. 70H, s), 2. 86 (3H, s), HN 2. 16-2. 03 (6H, m), 1. 67-1. 66 (5H, m), 1. 30-1. 26 (4H, m). 0 <, 0 1H-NMR (8ppm, DMSO-d6) 8. 30 (1H, d, brs) 7. 86- O, J=7. 9Hz), 8. 10 (3H, HN Nss 7. 83 (2H, m), 7. 55 (1H, d, N J=7. 5Hz), 7. 48 (1H, t, J=7. 3Hz), --CH (0. 36H, d, J=8. 7Hz), 4. 60- CH3 Example 4. 54 (0. 64H, m), 4. 54 (2H, s), 279 4. 34 (0. 64H, brs), 4. 19 (0. 36H, I//o 3. 73 (1H, brs), 3. 01 (1. 07H, HN s), 2. 93 (3H, s), 2. 91 (1. 93H, s), ! 2. 30-2. 00 (4H, m), 1. 91-1. 89 (2H, 0 1. 68-1. 64 (5H, m), 1. 30-1. 26 (4H, m).

(8ppm, DMSO-d6)Table 1-78 1H-NMR (8ppm, DMSO-d6) 8. 27 (1H, 0 d, J=7. 9Hz), 8. 08 (3H, brs), H2NsJk 84 (2H, d, J=7. 9Hz), 7. 48 . HCI d, J=8. 3Hz), 4. 79 (0. 35H, i CH3 t, J=9. OHz), 4. 57-4. 53 (0. 65H, Example S 55 (2H, s), 4. 35 (0. 65H, 280 k/% e, brs), 4. 20 (0. 35H, brs), 3. 71 (1H, 3. 01 (1. 05H, s), HN 91 (4. 95H, s), 2. 23-2. 07 (4H, m), 1. 91-1. m), 1. 68- 0 65 (5H, m), 1. 30-1. 27 (4H, m). lH-NMR (8ppm, DMSO-d6) 8. 05 (3H, brs), 7. 73 (1H, t, J=5. 8Hz), H2N-", 94 (1H, t, J=5. 7Hz), 4. 77- N 4. 74 (0. 44H, m), 4. 57-4. 54 Example CH3 (0. 56H, m), 4. 31 (0. 56H, brs), 281 18 (0. 44H, brs), 3. 01-2. 98 (2H, m), 2. 98 (1. 32H, s) 2. 89- N 86 (2H, 2. 89 (1. 68H, s), N CH3 0 So 86 (3H, s), 2. 21-2. 03 (5H, "0 1. 69-1. 64 (7H, m), 1. 30- 1. 18 (8H, m). 1H-NMR (8ppm, DMSO-d6) 9. 0 8. 03 (3H, brs), 7. 51 (2H, d, J=8. 7Hz), 7. 15 (2H, d, s HCI J=8. 7Hz), 4. 79-4. 77 (0. 45H, m), z Example CH3 4. 58-4. 55 (0. 55H, m), 4. 37-4. 37 (0. 55H, m), 4. 24-4. 21 (0. 44H, OH m), 3. 49 (2H, s), 3. 00 (1. 35H, I s), 2. 91 (1. 65H, s), 2. 28-1. 99 O+Nw 91-1. 86 (2H, m), H 68-1. 65 (5H, m), 1. 41-1. 07 (4H, m).

Table 1-79 1H-NMR (8ppm, DMSO-d6) 9. 84 (1H, 0 s), 8. 15 (3H, brs), 7. 51 (1H, HN 9Hz), 7. 21 2 t, J=7. 7Hz), 6. 91 (1H, d, - 2Hz), 4. 80-4. 77 (0. 43H, m), Example 4. 58-4. 55 (0. 57H, m), 4. 35 283 (0. 57H, d, J=4. 9Hz), 4. 21 0 43H, d, J=5. 3Hz), 3. 50 (2H, » (1. 28H, s), 2. 91 0 (1. 72H, s), 2. 20-2. 10 (5H, m), H 86 (2H, m), 1. 68-1. 64 (5H, m), 1. 42-1. 07 (4H, m). 0 1H-NMR 9. 32 (1H, HN 8. 03 (3H, brs), 7. 33 (1H, N d, J=7. 9Hz), 7. 24-7. 21 (2H, m), 7. t, J=7. 3Hz), 4. 79- 4. (0. 39H, m), 4. 57-4. 54 Example (0. 61H, m), 4. 36 (0. 61H, brs), 284 (0. 39H, brs), 3. 57^ s), 3. 01 (1. 18H, s), 2. 91 N (1. 82H, s), 2. 27-1. 99 (5H, m), H 87 (2H, m), 1. 68-1. 64 (5H, m), 1. 30-1. 14 (4H, m). 0 1H-NMR (8ppm, DMSO-d6) 8. 03-7. 97 m), 7. 22-7. 20 (1H, m), 7. 13-7. 10 (3H, m), 4. 78-4. 76 ~ 39H, m), 4. 55-4. 51 (0. 61H, Example m), 285 39H, brs), 3. 54-3. 52 (1H, m), 3. 52 (2H, s), 3. 33 (2H, s), HN 16H, s), 2. 89 (1. 84H, s), 2. 28-1. 99 (4H, m), 1. 85- 0 82 (2H, m), 1. 63-1. 60 (5H, m), 1. 17-1. 09 (4H, m).

Table 1-80 lH-NMR 7. 99 (3H, brs), 7. 84 (2H, d, J=7. 9Hz), H2N-"AN 54 (2H, d, J=8. 3Hz), 4. 77- HCI 4. 74 (0. 42H, m), 4. 52-4. 49 Example H3 286 11 (0. 42H, brs), 3. 74 (2H, OH 3. 21 (2H, d, J=6. 4Hz), 2. 96 (1. s), 2. 88 (1. 74H, s), 0 23-2. 04 (4H, m), 1. 89-1. 86 (2H, m), 1. 62-1. 59 (6H, m), 1. 20-1. 07 (4H, m). 1H-NMR 8. 00 (3H, brs), 7. 80-7. 78 (2H, m), 7. 61- H2N-"AN 7. 59 (2H, m), 4. 77-4. 74 (0. 41H, -HCI 4. 53-4. 51 (0. 59H, m), 4. 26 Example H3 9Hz), 4. 12 287 41H, d, J=4. 9Hz), 3. 75 (2H, 9 s), 7Hz), 2. 96 (1. 23H, s), 2. 88 (1. 77H ; s), OH 22-2. 05 (4H, m), 1. 88-1. 85 (2H, m), 1. 66-1. 55 (6H, m), 1. 20-1. 01 (4H, m). 0 9. 96 (1H, HN 8. 09 (1H, d, J=2. 3Hz), 8. 00 N brs), 7. 66 (1H, d, CH3 J=8. 7Hz), 7. 20 (1H, d, Example 4. 79-4. 76 (0. 42H, m), 4. 56-4. 53 (0. 58H, m), 4. 30 H 58H, brs), 4. 17 (0. 42H, brs), 2. 98 (1. 26H, s), 2. 89 | s), 2. 44 (3H, s), 2. 32- O (6H, m), 1. 76-1. 63 (6H, CH m), 1. 14-1. 02 (4H, m).

Table 1-81 1H-NMR (8ppm, DMSO-d6) 7. 98 (3H, 7. 90 (2H, d,, 0 brs), Han 7. 76 (1H, t, J=7. 3Hz), 7. 66 2 t, J=7. 3Hz), 4. 77-4. 74 i -CH 43H, m), 4. 52-4. 48 (0. 57H, Example 4. 26 (0. 57H, d, J=3. 8Hz), 289 4. 12 (0. 43H, d, J=4. 5Hz), 3. 22 (2H, 7Hz), 2. 96 (1. 28H, s), 2. 88 (1. 72H, s), 2. 23-2. 09 "St (4H, m), 1. 87-1. 84 (2H, m), 0 1. 62-1. 58 (6H, m), 1. 15-1. 05 (4H, m). 0 1H-NMR DMSO-d6) 8. 00 (3H, brs), N s), 7. 10 (1H, s), 4. 79-4. 76 CH3-HCI (0. 42H, m), 4. 53-4. 47 (0. 58H, m), 4. 50 (2H, s), 4. 29 (0. 58H, Example d, J=4. 5Hz), 4. 15 (0. 42H, d, 290 0 3Hz), 3. 80 (3H, s),-3. 24 (2H, d, J=6. 0Hz), 2. 98 (1. 27H, 0 OH s), 2. 89 (1. 73H, s), 2. 23-2. 09 4v m), 1. 82-1. 48 (8H, m), 1. 18-1. 07 (2H, m), 0. 93-0. 89 OMe (2H, 1H-NMR (8ppm, DMSO-d6) 7. 99 (3H, brs), 7. 46 (1H, s), 7. 31 (1H, N m), 4. (0. 57H, I Example J4541Hz) Example 291 J=3. 7Hz), 3. 82 (2H, d, J=6. 3. 29 (3H, s), 2. 98 OH (1. 28H, s), 2. 89 (1. 72H, s), 0 26-2. 13 (4H, m), 1. 89-1. 87 0 (2H, m), 1. 64 (6H, m), 1. 22-1. 02 (4H, m).

Table 1-82 lH-NMR (8ppm, DMSO-d6) 8. 06 (3H, brs), 7. 48 (1H, s), 7. 26 (1H, H2N 7. 09 (1H, s), 5. 30 (1H, t, z J=5. 4. 77-4. 75 (0. 43H, m), CH3 OH 4. 55-4. 50 (0. 57H, m), 4. 50 (2H, Example'HCI d, J=5. 6Hz), 4. 30 (0. 57H, d, 292 J=5. 6Hz), 4. 15 (0. 43H, d, J=5. 3. 80 (2H, d, OH J=6. 0Hz), 2. 98 (1. 30H, s), 2. 89 0 70H, s), 2. 32-2. 05 (4H, m), 0 1. 89-1. 86 (2H, m), 1. 66-1. 64 (6H, m), 1. 26-0. (4H, m). 0 lH-NMR 8. 04 (3H, HN 2 6. 98 (1H, s), 4. 78-4. 76 N -HCI 43H, m), 4. 54-4. 52 (0. 57H, HCI Example CH3CH3 (0. 57H, d, J=5. 1Hz), 293 15 (0. 43H, d, J=5. 1Hz), 3. 79 (2H, 2. 98 (1. 29H, OH 89 (1. 71H, s), 2. 35-2. 04 Y 1. 88- 1. 86 (2H, m), 1. 65-1. 63 (6H, m), 1. 26-0. 97 (4H, m). 0 8. 05 (3H, brs), 7. 26 (2H, brs), 6. 97 (1i1, 2-4. 74 (0. 44H, m), CH3 4. 52-4. 50 (0. 56H, m), 4. 43 (2H, s), 4. 28 (0. 56H, brs), Example 4. 4. 44H, brs), 3. 22 (2H, d, 294 2. 96 (1. 31H, s), 2. (6H, s), 2. 87 (1. 69H, s), 0 OH 2. 31-1. 93 (4H, m), 1. 79-1. 76 (2H, 9 1. 64-1. 46 (6H, m), 1. 12- 0. 95 (4H, m). H3C Table 1-83 0 1F3-NMR 8. 07 (3H, brs), 7. 17-7. (2H, m), 7. 07 N t, J=7. 9Hz), 4. 81-4. 72 -CH 42H, m), 4. 56-4. 54 (0. 58H, A m), 4. 30 (0. 58H, d, J=5. 1Hz), Example 4. 15 (0. 42H, d, J=5. 1Hz), 3. 81 (2H, J=5. 6Hz), 3. 75 (3H, s), OH (1. 25H, s), 2. 89 (1. 75H, 0 31-1. 97 (4H, m), 1. 90- OMe 0 1. 88 (2H, m), 1. 64-1. 62 (6H, m), 1. 19-1. (4H, m). IH-NMR 8. 06 (3H, 0 s), 7. 67 (1H, d, J=8. 3Hz), 6. 56 ll d, J=1. 9Hz), 6. 53 (1H, dd, 2 6, 2. 1Hz), 4. 77-4. I m), 4. 54-4. 52 (0. 57H, Example < m), 4. 31 (0. 57H, brs), 4. 16 296 (0. 43H, brs), 3. 83 (2H, d, OH 3. 78 (3H, s), 2. 98 (1. 29H, s), 2. 89 (1. 71H, s), 0/OMe 05 (4H, m), 1. 88-1. 86 (2H, m), 1. 65-1. 58 (6H, m), 1. 22-0. 97 (4H, m). 0 > 0. 75-0-. H2N-'A 1. 05-1. 21 (3H, m), N 62-1. 65 (7H, m), 1. 91-2. 30 ~ m), 2. 56 (2H, d, CH3 Example-HCI 65Hz), 2. 88 (1. 65H, s), 298 2. 4. 11-4. 15 0 0 (0. 45H, m), 4. 26-4. 29 (0. 55H, m), 4. 51-4. 54 (0. 55H, m), 4. 74- 4. (0. 45H, m), 7. 59-7. 61 (4H, H 7. 78 (2H, d, J=6. 78Hz), 8. 07 (3H, brs).

Table 1-84 0 lH-NMR (8ppm, DMSO-d6) 0. 46-0. 62 (1H, 97-1. 16 (3H, m), H2N 31 N 42-1. 84 (8H, m), 1. 98-2. -CH m), 2. 88-3. 02 (6H, m), CH3 31 (2H, m), 4. 07-4. 35 Example HCI 299 (1H, 4. 46-4. 59 (0. 55H, m), Y 4. 70-4. 81 (0. 45H, m), 7. 32-7. 42 (5H, m), 8. 12 (3H, brs). N I CH3 0 H-NMR 0. 60-0. 78 H m), 1. 01-1. 25 (3H, m), 1. 45-1. 72 (8H, m), 1. 82-2. 32 CH m), 2. 87 (1. 65H, s), 2. 95 CH3. (1. 35H, s), 3. 15 (3H, s), 4. 08- Example 4. 4. 24-4. 26 300 CH3 (0. 55H, m), 4. 45-4. 54 (0. 55H, t 4. 69-4. 80 (0. 45H, m), 7. 20- 7. 53 (5H, m), 8. 12 (3H, brs). 0 v O 28 (4H, m), 1. 34-1. 49 (1H, m), H2N>N 1. 53-1. 89 (9H, m), 1. 96-2. 37 I m), 2. 89 (1. 65H, s), 2. 98 A 35H, s), 3. 99-4. 19 (2. 45H, Example m), 4. 25-4. 35 (0. 55H, m), 4. 48- 301 0 4. 60 (0. 55H, m), 4. 70-4. 83 (0. 45H, m), 6. 97 (1H, t, 0 7. 11 (1H, d, J=7. 7. 46 (1H, t, w 7. 59 (1H, d, J=7. 40Hz), 8. 10 (3H, brs).

Table 1-85 1H-NMR (8ppm, DMSO-d6) 0. 85-1. 0 m), 1. 06-1. 26 (2H, m), 1. 31-1. 47 (1H, m), 1. 54-1. 86 H2N 1. 98-2. 36 (4H, m), N (1. 65H, s), 3. 00 (1. 35H, CH3 3. 59 (2H, d, J=6. 13Hz), Example 302 OH 13Hz), 4. 14-4. 17 (0. 45H, m), 4. 30-4. 33 (0. 55H, m), 4. 50- 0 61 (0. 55H, m), 4. 71-4. 84 (0. 45H, m), 6. 88 (1H, t, < 35Hz), 6. 96 (1H, d, J=8. 29Hz), 7. 15-7. 28 (2H, m), 8. 15 (3H, brs). 0 1H-NMR (8ppm, DMSO-d6) 0. 86-1. 00 H2N"A (2H, 06-1. 25 (2H, m), N 1. 44-1. 85 (8H, m), 1. 97-2. 34 É HCI (4H, m), 2. 89 (1. 65H, s), 2. 98 CH3 (1. 35H, s), 3. 26 (2H, d, Example J=6. 03Hz), 4. 12-4. 18 (0. 45H, 303 OH 4. 27-4. 33 (0. 55H, m), 4. 50- 4. 57 (2. 55H, m), 4. 70-4. 82 O (0. 45H, m), 7. 61 (1H, 7. 80 (lu, s), 7. 83 (1H, s), 8. 05 (3H, ci 1H-NMR (8ppm, DMSO-d6) 0. 96-1. 26 ° m), 1. 57-1. 75 (6H, m), H2N 82-1. 91 (2H, m), 1. 97-2. 36 IN m), 2. 90 (1. 65H, s), 2. 99 I CH HCI (1. 35H, s), 3. 76 (2H, d, Example) J=5. 10Hz), 4. 15-4. 18 (0. 45H, 304 4. 30-4. 33 (0. 55H, m), 4. 50- 4. 59 (0. 45H, m), 4. 73-4. 82 OH (0. 55H, m), 6. 53 (1H, s), 6. 88 0 s), 6. 95 (1H, s), 8. 09 0 brs), 9. 80 (1H, s), 12. 83 (1H, brs).

Table 1-86 1H-NMR (8ppm, DMSO-d6) 1. 02-1. 29 0 (4H, m), 1. 59-1. 76 (6H, m), HN I1 k (2H, m), 1. 97-2. 35 2 2. 90 (1. 65H, s), 2. 99 (1. 35H, s), 3. 90 (2H, d, Example UH 57Hz), 4. 15-4. 18 (0. 45H, 305 4. 30-4. 33 (0. 55H, m), 4. 50- 4. 55H, m), 4. 74-4. 82 (0. 45H, m), 7. 25 (1H, dd, OH 42, 2. 78Hz), 7. 25 (1H, dd, ! 42, 2. 78Hz), 7. 34 (1H, t, ci J=7. 42Hz), 8. 08 (3H, brs), 13. 34 (1H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 72-0. 87 0 (2H, m), 1. 02-1. 22 (1H, m), H2NI-I 31-1. 40 (1H, m), 1. 52-1. 69 H2N/w/ (8H, m), 1. 96-2. 33 (4H, m), 2. 88 (1. 65H, s), 2. 97 (1. 35H, CH Example J=6. 49Hz), 306 4. 11-4. 13 (0. 45H, m), 4. 26-4. 28 (0. 55H, m), 4. 48-4. 56 (0. 55H, m), 4. 73-4. 79 (2. 45H, m), 7. 50 O t, J=7. 65Hz), 7. 59 (1H, t, J=7. 65Hz), 7. 64 (1H, d, J=7. 65Hz), 7. 76 (1H, d, J=7. 65Hz), 8. 10 (3H, brs). lH-NMR (8ppm, DMSO-d6) 0. 86-1. 00 0 m), 1. 07-1. 27 (2H, m), han 47-1. 71 (6H, m), 1. 78-1. 86 (2H, 1. 97-2. 33 (4H, m), -CH"HCI (1. 65H, s), 2. 98 (1. 35H, Example CHS J=6. 03Hz), 307 4. 13-4. 15 (0. 45H, m), 4. 28-4. 30 oU/ M HN''N. (0. 55H, m), 4. 52-4. 56 (2. 55H, /N 4. 72-4. 81 (0. 45H, m), 7. 51 0m d, J=7. 42Hz), 7. 58 (1H, t, J=7. 65Hz), 8. 02 (1H, d, J=7. 88Hz), 8. 06 (1H, s), 8. 13 (2H, brs).

Table 1-87 H-NMR (8ppm, DMSO-d6) 0. 86-1. (2H, m), 1. 08-1. (2H, m), 1. 47-1. 72 (6H, m), 1. 77-1. 85 H2N (2H, m), 1. 95-2. (3H, m), 2. 23-2. 33 (1H, m), 2. 88 (1. 65H, i CH3 2. 98 (1. 35H, s), 3. 32 (2H, Example d, J=6. 49Hz), 4. 12-4. 14 (0. 45H, 308 ei 4. 27-4. 30 (0. 55H, m), 4. 52- 4. 56 (2. 55H, m), 4. 71-4. 80 0 (0. 45H, m), 7. 43 (1H, t, J=7. 65Hz), 7. 61 (1H, d, J=7. 88Hz), 7. 64 (1H, dd, J=7. 65, 1. 62Hz), 8. 16 (3H, brs), 13. 41 (1H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 95-1. 31 0 m), 1. 58-1. 75 (7H, m), H2N 84-1. 91 (2H, m), 1. 98-2. 21 N m), 2. 23-2. 34 (1H, m), 'HCI (1. 65H, s), 2. 99 (1. 35H, CH3 Example 3. 86 (2H, d, J=6. 03Hz), 309 4. 14-4. 16 (0. 45H, m), 4. 29-4. 32 (0. 55H, m), 4. 51-4. 59 (0. 55H, m), 4. 73-4. 82 (0. 45H, m), 7. 28 0 s), 7. 36 (1H, s), 7. 46 0 (1H, s), 8. 15 (3H, brs), 13. 35 (1H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 96-1. 30 0 m), 1. 58-1. 76 (6H, m), HN 83-1. 91 (2H, m), 1. 98-2. 21 2 2. 23-2. 34 (1H, m), ~ 43 (3H, d, J=2. 32Hz), 2. 90 Example CH3 s), 2. 99 (1. 35H, s), 310 3. 91 (2H, d, J=6. 49Hz), 4. 14- 0 17 (0. 45H, 4. 29-4. 32 (0. 55H, m) 4. 51-4. 59 (0. 55H, 0 4. 73-4. 81 (0. 45H, m), 7. 05 (1H, t, J=8. 58Hz), 7. 68 (1H, dd, J=8. 58, 2. 32Hz), 8. 14 (3H, brs), 12. 73 (1H, brs).

Table 1-88 lH-NMR (8ppm, DMSO-d6) 0. 82-0. 97 0 m), 1. 05-1. 29 (2H, m), 1. 40-1. 50 (1H, m), 1. 56-1. 81 H2N-IA m), 1. 95-2. 33 (4H, m), HCI 2. 88 (1. 65H, s), 2. 97 (1. 35H, CH s), 3. 20 (2H, d, J=7. 42Hz), Example 3. 81 (3H, s), 4. 11-4. 14 (0. 45H, 311 OH 4. 26-4. 29 (0. 55H, m), 4. 38 (2H, 4. 49-4. 57 (0. 55H, m), 0 4. 71-4. 80 (0. 45H, m), 7. 09 (1H, d, J=8. 35Hz), 7. 43 (1H, dd, OMe 35, 1. 86Hz), 7. 57 (1H, d, J=1. 86Hz), 8. 15 (3H, brs), 12. 59 (1H, brs). H-NMR (8ppm, DMSO-d6) 0. 85-1. 00 (2H, m), 1. 06-1. 26 (2H, m), 0 1. 43-1. 52 (1H, m), 1. 57-1. 70 HN (5H, m), 1. 75-1. 83 (2H, m), N 1. 96-2. 33 (4H, m), 2. 41- (3H, HCI 2. 88 (1. 65H, s), 2. 98 CH3 Example 35H, s), 3. 26 (2H, d, 312 4. 12-4. 14 (0. 45H, CH3 OH m), 4. 27-4. 29 (0. 55H, m), 4. 47 (3H, s), 4. 50-4. 57 (0. 55H, m), 0 4. 71-4. 80 (0. 45H, m), 7. 24 (1. 08H, t, J=7. 65Hz), 7. 46 (1. 06H, d, J=7. 42Hz), 7. 63 (1H, d, J=7. 88Hz), 8. 11 (3H, brs), 12. 86 (1H, brs). 1H-NMR DMSO-d6) 1. 08-1. 39 (4H, m), 1. 59-1. 89 (6H, m), H2N 1. 96-2. 37 (6H, m), 2. 90 (1. 74H, l 3. 02 (1. 26H, s), 3. 97 (2H, CH3 HCI d, J=6. 0Hz), 4. 18 (0. 42H, d, Example J=5. 33 (0. 58H, d, 313 J=5. 6Hz), 4. 52-4. 63 (0. 58H, m), 4. 72-4. 87 (0. 42H, m), 6. 93 (1H, d, 4Hz), 7. 35-7. 59 (4H, m), 7. 86 (1H, dd, J=7. 2, 2. 1Hz), 8. 8. (3H, brs), 8. 15 (1H, d, J=7. 9Hz).

Table 1-89 0 DMSO-d6) 0. 83-1. 27 (4H, H 43-1. 52 (1H, m), 1. 55-1. 72 2 (5H, m), 1. 75-1. 84 (2H, m), 1. 97- 1 2. (3H, m), 2. 22-2. 35 (1H, m), Example (1. 74H, s), 2. 98 (1. 26H, s), 314 23 (2H, d, J=6. 5Hz), 4. 13 (0. 42H, d, J=5. lHz), 4. 28 (0. 58H, d, J=5. 4. 43 (2H, s), 4. 49-4. 59 (0. 58H, m), 4. 72-4. 83 (0. 42H, m), 7. 25-7. 36 (5H, m), 7. 98 (3H, brs). 0 g-lH-NMR 0. 98-1. 27 (4H, HN"10 1. 58-1. 73 (6H, m), 1. 82-1. 96 Y m), 1. 96-2. 38 (4H, m), 2. 90 1 s), 2. 99 (1. 26H, s), 3. 77 315 d, J=6. 5Hz), 4. 16 (0. 42H, d, l, 4. 30 (0. 58H, d, J=5. 1Hz), 4. 50-4. 59 (0. 4. 72-4. 82 (0. 42H, m), 6. 86-6. 95 (3H, m), 7. 27 0 (2H, t, J=7. 9Hz), 8. 00 (3H, brs). 0 0. 79-1. 23 (4H, m), 1. 41-1. 48 (2H, m), 1. 54-1. 71 H2N N (6H, m), 1. 74-1. 85 (2H, m), 1. 96- 2. 33 (4H, m), 2. 57 (2H, Example CH3 J=7. 9Hz), 2. 88 (1. 74H, s), 2. 97 316 (1. 26H, s), 4. 12 (0. 42H, d, J=5. 6Hz), 4. 27 (0. 58H, d, J=5. 6Hz), f 47-4. 57 (0. 58H, m), 4. 73-4. 79 (0. 42H, m), 7. 13-7. 17 (3H, m), 7. 25 (2H, t, J=7. 4Hz), 7. 99 (3H, brs). 0 H-NMR 0. 81-1. 30 (4H, HN N,, A m), 1. 43-1. 52 (1H, m), 1. 53-1. 72 N (5H, m), 1. 73-1. 83 (2H, m), 1. 95- ~ (4H, m), 2. 88 (1. 74H, s), 2. 98 Example 26H, s), 3. 22 (2H, d, J=6. 5Hz), 317 14 (0. 42H, d, J=5. 6Hz), 4. 29 317 58H, d, J=5. 6Hz), 4. 44 (2H, s), 4. 49-4. 59 (0. 58H, m), 4. 71-4. 83 (0. 42H, m), 7. 32 (2H, d, J=8. 3Hz), 7. 40 (2H, d, J=8. 3Hz), 8. 02 (3H, Cl s).

Table 1-90 0 0. 83-1. 29 H2N-"A 1. 42-1. 54 (1H, m), N 1. 54-1. 74 (5H, m), 1. 73-1. 86 CH (2H, m), 1. 96-2. 35 (4H, m), Example 2. s), 2. 98 (1. 26H, 318 3. 24 (2H, d, J=6. 0Hz), 4. 14 (0. 42H, d, J=5. lHz), 4. 29 (0. 58H, d, J=5. lHz), 4. 45 (2H, ° s), 4. 49-4. 57 (0. 58H, m), 4. 71- 4. 84 (0. 42H, m), 7. 24-7. 41 (4H, m), 8. 00 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 84-1. 28 0 (3H, m), 1. 44-1. 55 (1H, m), H 58-1. 74 (4H, m), 1. 76-1. 85 N (2H, m), 1. 98-2. 36 (4H, m), CH. 2. 89 (1. 74H, s), 2. 98 (1. 26H, S 3. 33 Example 319 s), 4. 14 (0. 42H, d, T 6Hz), 4. 29 (0. 58H, d-, J=5. 6Hz), 4. 51 (2H, s), 4. 51- ° 4. 58 (0. 58H, m), 4. 74-4. 84 (0. 42H, m), 7. 29-7. 39 (2H, m), 7. 40-7. 50 (2H, m), 8. 00 (3H, s). H-NMR (8ppm, DMSO-d6) 0. 92-1. 31 (4H, m), 1. 56-1. 82 (6H, m), S/~7 83-1. 94 (2H, m), 1. 96-2. 37 H2NN (4H, m), 2. 87 (3H, s), 2. 90 X (1. 74H, s), 2. 99 (1. 26H, s), Example < 3. 74 (2H, d, J=6. 5Hz), 4. 16 320 ß 42H, d, J=5. 1Hz), 4. 31 \/eNsSzCH3 58H, d, J=5. lHz), 4. 48-4. 61 0'/'o 58H, m), 4. 70-4. 84 (0. 42H, p 88 (2H, d, J=8. 8Hz), 7. 12 (2H, d, J=8. 8Hz), 7. 98 (3H, brs), 9. 35 (1H, brs).

Table 1-91 1H-NMR (5ppm, DMSO-d6) 0. 85-1. 26 (4H, m), 1. 30-1. 40 (1H, m), 11 1. 53-1. 74 (5H, m), 1. 86-2. 35 HCI HC I Example 88 (1. 74H, s), 2. 96 (1. 26H, 321 4. 11 (0. 42H, d, J=5. 1Hz), /N 26 (0. 58H, d, J=5. 1Hz), 4. 44- 4. (2. 58H, m), 4. 71-4. 85 (0. 42H, m), 7. 15 (2H, d, J=8. 8Hz), 7. 29 (2H, d, J=8. 8Hz), 8. 14 (3H, brs). 1H-NMR (5ppm, DMSO-d6) 0. 67-1. 22 0 r-. m), 1. 41-1. 71 (8H, m), 1. 96-2. 33 (4H, m), 2. 85 (1. 74H, É 2. 92 (1. 26H, s), 3. 00 (2H, e J=7. OHz), 4. 02-4. 56 (5. 58H, 322 4. 65-4. 80 (0. 42H, m), 6. 67 (1H, d, J=7. 9Hz), 6. 76 (1H, d, '0N-, 9Hz), 6. 80 (1H, s),-7. 12 0 O O (1H, J=7. 9Hz), 7. 92 (3H, brs), 9. 45 (1H, s). 1H-NMR (8ppm, DMSO-d6) 1. 10-1. 46 0 (4H, 1. 48-1. 70 (5H, m), H2N 94-2. 37 (6H, m), 2. 65 (3H, Nl 2. 87 (1. 74H, s), 2. 95 Example CH3 3. 50-3. 60 (1H, m), 323 4. 12 (0. 42H, d, J=4. 6Hz), 4. 27 N-, d, J=4. 6Hz), 4. 42-4. 55 0 N-~ 58H, m), 4. 62-4. 81 (2. 42H, H3C"S 7. 35 (2H, d, J=8. 8Hz), 7. 72 O (2H, d, J=8. 8Hz), 8. 01 (3H, brs), 11. 10 (1H, brs).

Table 1-92 lH-NMR (8ppm, DMSO-d6) 1. 22-1. 39 0 m), 1. 56-1. 79 (5H, m), Ji. 1. 87-2. 35 (6H, m), 2. 90 (1. 74H, N 3. 00 (1. 26H, s), 3. 26 (3H, N s), 3. 67-3. 79 (1H, m), 4. 17 CH3 4. 32 Example 324 (0. 58H, d, J=5. lHz), 4. 49-4. 61 /I 58H, m), 4. 71-4. 84 (0. 42H, m), J=8. 3Hz), 7. 97 3 brs), 8. 06 (1H, d, O 3Hz), 8. 16 (1H, d, J=8. 3Hz), 8. 35 (1H, s), 8. 57 (1H, d, J=7. 9Hz). 1H-NMR (8ppm, DMSO-d6) 1. 11-1. 37 (4H, m), 1. 56-1. 78 (5H, m), H2N N 1. 91-2. 35 (6H, m), 2. 89 (1. 74H, s), 2. 99 (1. 26H, s), 3. 32 (3H, CH3 HCI 3. 56-3. 67 (1H, m), 4. 16 Example 42H, d, J=6. 0Hz), 4. 30 ,. (0. 58H, d, J=6. 0Hz), 4. 51-4. 59 (0. 58H, m), 4. 73-4. 81 (0. 42H, HN m), 7. 47 (1H, dd, J=7. 7, l. 2Hz), 7. 68 (1H, td, J=7. 7, 00==S-CH3 2Hz), 7. 76 (1H, t, J=7. 7Hz), 0 94 (lH, d, J=7. 7Hz), 7. 99 (OH, s), 8. 48 (1H, t, J=7. 9Hz). 1H-NMR (5ppm, DMSO-d6) 1. 19-1. 38 0 m), 1. 56-1. 75 (5H, m), H HCI 84-1. 95 (2H, m), 1. 96-2. 38 N m), 2. 90 (1. 74H, s), 3. 00 CH (1. 26H, s), 3. 25 (3H, s), 3. 60- Example 0 m), 4. 17 (0. 42H, d, 326 s cii 6Hz), 4. 32 (0. 58H, d, 3 6Hz), 4. 49-4. 62 (0. 58H, m), HN 70-4. 84 (0. 42H, m), 8. 00 (2H, d, J=8. 8Hz), 8. 02 (3H, brs), 0 8. 04 (2H, d, J=8. 8Hz), 8. 52 (1H, d, J=7. 9Hz).

(4H,Table 1-93 1H-NMR (5ppm, DMSO-d6) 1. 21-1. 38 0 (4H, m), 1. 57-1. 74 (6H, m), H2N 1. 93 (2H, m), 2. 00-2. 35 HCI (4H, m), 2. 90 (1. 74H, s), 2. 99 I s), 3. 00 (1. 26H, s), 3. 62- Example (0. 42H, d, 37 31 (0. 58H, d, O 0 J-5. 6Hz), 4. 50-4. 60 (0. 58H, m), 4. 73-4. 83 (0. 42H, m), 7. 30-7. 35 HN S.. H. 7. 39 (1H, t, J=7. 7Hz), "7. 54 (1H, d, J=7. 7Hz), 7. 61- 7. 64 (1H, m), 8. 01 (3H, s), 8. 25 (1H, d, J=7. 9Hz). lH-ND (8ppm, DMSO-d6) 0. 93-1. 23 0 (4H, m), 1. 48-1. 71 (7H, m), ll 81-1. 89 (1H, m), 1. 98-2. 36 2 74H, s), 2. 96 -CH 26H, s), 3. 15 (2H, d, Example H J=6. OHz), 4. 09 (0. 42H, d, 328 X J=5. 6Hz), 4. 23 (0. 58H, d, J=5. 6Hz), 4. 45-4. 58 (0. 58H, m), 9 70-4. 84 (0. 42H, m), 7. 80 (2H, d, J=9. 3Hz), 7. 83 (3H, brs), 7. 84 (2H, d, J=9. 3Hz), 10. 47 (1H, brs). 0 (8ppm, DMSO-d6) 0. 94-1. 23 ll m), 1. 50-1. 72 (7H, m), H2N\/\N"HCI 1. 82-1. 90 (1H, m), 1. 94-2. 37 HCI m), 2. 87 (1. 74H, s), 2. 95 Example CH 3 329 4. 09 (0. 42H, d, OH 6Hz), 4. 23 (0. 58H, d, J=4. 6Hz), 4. 43-4. 55 (0. 58H, m), 4. 70-4. 83 (0. 42H, m), 8. 00 (2H, d, J=8. 3Hz), 8. 15 (2H, d, J=8. 3Hz).

Table 1-94 1H-NMR (8ppm, DMSO-d6) 0. 96-1. 22 0/ 1. 48-1. 71 (7H, m), 1. m), 1. 94-2. 35 N HCI (4H, m), 2. 87 (1. 74H, s), 2. 95 i -CH s), 3. 27 (2H, d, CH Example 0 J=5. 6Hz), 4. 08 (0. 42H, d, 330 J=5. 4. 22 (0. 58H, d, Y 4. 42-4. 58 (0. 58H, m), 4. 68-4. 82 (0. 42H, m), 7. 67 (1H, brs), 7. 90 (3H, brs), 7. 97 (2H, 0 d, J=8. 3Hz), 8. 09 (2H, d, J=8. 3Hz), 8. 23 (1H, brs). H-NMR (8ppm, DMSO-d6) 0. 93-1. 25 (4H, m), 1. 47-1. 72 (6H, m), O 80-1. 89 (2H, m), 1. 93-2. 35 H2N,,, HCI (4H, m), 2. 80 (3H, d, J=4. 6Hz), 2. 85 (1. 74H, s), 2. 95 (1. 26H, Example CH3 s), 3. 27 (2H, d, J=6. 5Hz), 4. 09 331 6Hz), 4. 23 N"CH3 58H, d, J=5. 6Hz), 4. 42-4. 57 H 58H, m), 4. 68-4. 82 (0. 42H, m), 7. 97 (3H, brs), 7. 98 (2H, Ob d, J=8. 3Hz), 8. 05 (2H, d, J=8. 3Hz), 8. 75 (1H, q, J=4. 6Hz). lH-lIMR (8ppm, DMSO-ds) 0. 96-1. 21 0 (4H, m), 1. 52-1. 76 (6H, m), 1. 91 (2H, m), 1. 98-2. 37 N (3H, s), 2. 87 (1. 74H, s), 2. 95 (1. 26H, s), Example CH3 3. 00 (3H, s), 3. 26 (2H, d, 332 Z J=6. 0Hz), 4. 09 (0. 42H, d, N 6Hz), 4. 24 (0. 58H, d, J=5. 6Hz), 4. 41-4. 58 (0. 58H, m), "St 4. 69-4. 85 (0. 42H, m), 7. 65 (2H, d, 7. 93 (3H, brs), 7. 94 (2H, d, J=8. 3Hz).

Table 1-95 0 1H-NMR (8ppm, DMSO-d6) 0. 81-1. 31 (4H, 1. 45-1. 80 (6H, m), N 1. 87-2. 36 (6H, m), 2. 88 (1. 76H, CH3 s), 2. 97 (1. 26H, s), 4. 12 Example (0. 42H, d, J=5. lHz), 4. 27 333 HCI (0. 58H, d, J=5. 6Hz), 4. 43-4. 60 (0. 58H, m), 4. 67-4. 85 (0. 42H, OH 8. 08 (3H, brs). 0 0 1H-NMR (8ppm, DMSO-d6) 0. 84-1. 28 O m), 1. 52-1. 81 (8H, m), H2N"" 93-2. 34 (6H, m), 2. 88 (1. 74H, N (1. 26H, s), 4. 12 i CH3 (0. 42H, d, J=5. 6Hz), 4. 27 Example (0. 58H, d, J=5. lHz), 4. 46-4. 58 334 0 58H, m), 4. 70-4. 84 (0. 42H, t H H m), 7. 39 (1H, t, J=7. 9Hz, 7. 58 H 9 & 8. 16 (3H, 0 d, J=3. 2Hz). lH-NMR (8ppm, DMSO-d6) 0. 86-1. 28 0 1. 54-1. 84 (8H, m), H2N--, 94-2. 36 (6H, m), 2. 89 (1. 74H, N 2. 98 (1. 26H, s), 3. 51 (2H, CH3 4. 13 (0. 42H, d, J=4. 8Hz), Example 4. 28 (0. 58H, d, J=5. 5Hz), 4. 46- 335 4. 60 (0. 58H, m), 4. 69-4. 85 | 42H, m), 6. 91 (1H, d, N 9Hz), 7. 21 (1H, t, 0 U O 9Hz), 7. 48 (1H, d, J=7. 7Hz), 7. 49 (1H, s), 8. 18 (3H, brs), 9. 87 (1H, s).

Table 1-96 1H-NMR 85-1. 28 H2N-I-A (4H, m), 1. 52-1. 79 (8H, N 94-2. 33 (6H, m), 2. 88 (1. 74H, - u 2. 96 (1. 26H, s), 3. 47 (2H, CH3. riC 1 Example s), 42H, d, J=5. 6Hz), 336 4. (0. 58H, d, J=4. 6Hz), 4. 47- H 57 (0. 58H, m), 4. 69-4. 83 N 42H, m), 7. 14 (2H, d, t 7. 50 (2H, d, 0 J=8. 8Hz), 8. 22 (3H, brs), 9. 87 OH (1H, brs). 0 1. 14-1. 47 \ 58-1. 79 (6H, m), N 1. 96-2. 39 (6H, m), 2. 36 (3H, -CH"HCI s), 2. 90 (1. 74H, s), 2. 99 CH3 (1. 26H, s), 3. 20 (3H, s), 4. 17 Example cl3 42H, d, J=5. 1Hz), 4. 32 337 (0. 58H, d, J=5. 6Hz), 4. 50-4. 63 A 58H, m), 4. 74-4. 84 (0. 42H, O m), 7. 51 (1H, d, J=8. 8Hz), 7. 70 H 7. 81 (1H, d, J=8. 8Hz), 7. 99 (3H, brs), 9. 52 (1H, s). CH3 1H-NMR (5ppm, DMSO-d6) 1. 09-1. 43 0 (4H, m), 1. 58-1. 85 (8H, m), H2NoJs A/1. 98-2. 37 (4H, m), 2. 89 (1. 74H, N 2. 98 (1. 26H, s), 3. 52 (2H, CH3 s), 4. 17 (0. 42H, d, J=4. 6Hz), Example 4. (2H, d, J=6. 0Hz), 4. 32 338 (0. 58H, d, J=5. 1Hz), 4. 48-4. 59 OH 58H, m), 4. 71-4. 82 (0. 42H, /OH 7. 05-7. 14 (3H, m), 7. 24 0 N H |X1 t, J=7. 9Hz), 8. 07 (3H, brs), 8. 28 (1H, t, J=6. 0Hz), 12. 29 (1H, brs).

Table 1-97 0 1. 07-1. 42 H 1. 58-1. 85 (8H, m), 1. 99- N 2. 35 (4H, m), 2. 89 (1. 74H, s), I CH3 HCI 98 (1. 26H, s), 3. 52 (2H, s), Example 11-4. 24 (2. 42H, m), 4. 32 (0. 58H, 339 d, J=5. 1Hz), 4. 49-4. 62 (0. 58H, m), 4. 74-4. 85 (0. 42H, m), 7. 14 (2H, d, 0 J=8. 3Hz), 18 (2H, d, J=8. 3Hz), 8. OH J=5. 8Hz), 12. 24 (1H, brs). 0 98-1. 25 H2N 48-1. 92 (8H, m), 1. 96- N 2. 33 (4H, m), 2. 88 (1. 74H, s), 2. 26H, s), 3. 47 (2H, d, CH3 HC I Example J=6. 0Hz), 4. 13 (0. 42H, d, 340 4. 28 (0. 58H, d, J=5. 6Hz), 4. 45-4. 56 (0. 58H, m), 4. 70-4. 82 (0. 42H, m), 7. 65-7. 85 "St (3H, m), 7. 95 (1H, d, J=7. 4Hz), O 02 (3H, brs). 0 0 lH-NMR 0. 91-1. 28 \ 52-1. 95 (8H, m), 1. 96- 2 2. 35 (4H, m), 2. 88 (1. 74H, s), CH 93 (2H, d, J=6. 0Hz), 2. 97 Example (1. 26H, s), 3. 57 (2H, s), 4. 12 341 (0. 42H, d, J=5. 6Hz), 4. 27 (0. 58H, d, J=5. 1Hz), 4. 43 (2H, s), 4. 47- OH (0. 58H, m), 4. 71-4. 82 (0. 42H, o"'o 20-7. 42 (4H, m), 8. 06 (3H, brs). O 0. 96-1. 26 11 (4H, m), 1. 54-1. 95 (8H, m), 2. 00- 2. 33 (4H, m), 2. 88 (1. 74H, s), N 2. 93 (2H, d, J=6. 0Hz), 2. 97 CH3 (1. 26H, s), 3. 58 (2H, s), 4. 13 Example 342 (0. 42H, d, J=5. 6Hz), 4. 28 (0. 58H, d, J=5. 1Hz), 4. 42 (2H, s), 4. 48- s 58 (0. 58H, m), 4. 71-4. 82 (0. 42H, m), 3Hz), 7. 32 OH d, J=8. 3Hz), 8. 04 (3H, brs), 12. 24 (1H, brs).

Table 1-98 H 0. 88-1. 31 11 1. 47-1. 70 (6H, m), H2N 78-1. 87 (2H, m), 1. 95-2. 35 HCI m), 2. 88 (1. 74H, s), 2. 98 CH3 (1. 26H, s), 3. 29 (2H, d, Example 3. 56 (1H, s), 4. 14 343 (0. 42H, d, J=5. lHz), 4. 28 (0. 58H, d, J=5. lHz), 4. 46-4. 60 0 (0. 58H, m), 4. 69-4. 85 (0. 42H, m), s), 6. 90 (1H, dd, J=8. 8, 2. 8Hz), 7. 11 (1H, d, OMe 7. 87 (1H, d, J=8. 8Hz), 8. 06 (3H, brs). O DMSO-d6) 0. 83-1. 30 m), 1. 43-1. 71 (6H, m), H2 1. 85 (2H, m), 1. 94-2. 33 (4H, m), 2. 88 (1. 74H, s), 2. 97 CH3 26H, s), 3. 26 (1H, d, Example J=6. 4. 13 (0. 42H, d-, 344 0 OH J=5. 1Hz), 4. 28 (0. 58H, d, J=5. 4. 47-4. 59 (0. 58H, m), 0/< 68-4. 83 (0. 42H, m), 4. 71 (2H, s), 7. 40 (1H, td, J=8. 3, 2. 8Hz), 7. 54-7. 62 (2H, m), 8. 05 (3H, brs). 0 1H-NMR 0. 74-1. 24 H N m), 1. 33-1. 43 (1H, m), N 1. 48-1. 80 (7H, m), 1. 96-2. 37 HC I I-HCI (4H, m), 2. 87 (1. 74H, s), 2. 95 Example 26H, s), 3. 17 (2H, d, 345 4. 11 (0. 42H, d, J=4. 6Hz), 4. 26 (0. 52H, d, J=5. 4. 46-4. 56 (0. 52H, m), 0 4. 70 (2H, s), 4. 72-4. 79 (0. 42H, m), 7. 35-7. 55 (3H, m), 7. 96 F (3H, brs).

Table 1-99 0 0. 80-1. 29 H 85 (8H, m), 2 93-2. 35 (4H, m), 2. 88 (1. 74H, N 2. 97 (1. 26H, s), 3. 26 (2H, Example J=6. 5Hz), 4. 14 (0. 42H, d, Example 346 4. 29 (0. 58H, d, OH 6Hz), 4. 45-4. 57 (0. 58H, m), 4. 70-4. 84 (0. 42H, m), 4. 74 (2H, 0 7. 17 (1H, d, J=5. lHz), 7. 77 (1H, d, J=5. 1Hz), 8. 01 (3H, brs). O 0. 71-1. 25 m), 1. 32-1. 44 (1H, m), H2Ns 51-1. 80 (7H, m), 1. 98-2. 35 æ m), 2. 88 (1. 74H, s), 2. 96 CH3 (1. 26H, s), 3. 15 (2H, d, Example J=6. 6Hz), 3. 80 (3H, s), 4. 11 347 0 (0. 42H, d, J=4. 8Hz), 4. 26 (0. 58H, d, J=4. 4Hz), 4. 44-4. 58 0 58H, m), 4. 66 (2H, s), 4. 71- 4. 83 (0. 42H, m), 7. 12-7. 25 (2H, MeO m), 7. 35 (1H, t, J=7. 9Hz), 7. 99 (3H, brs). lH-NMR 0. 82-1. 29 (4H, m), 1. 43-1. 85 (8H, m), H2N 98-2. 35 (4H, m), 2. 89 (1. 74H, s), 2. 97 (1. 26H, s), 3. 23 (2H, CH3 HCI J=6. 2Hz), 4. 13 (0. 42H, d, Example J=4. 8Hz), 4. 28 (0. 58H, d, 348 4. 45 (2H, s), 4. 49- 4. 58 (0. 58H, m), 4. 69-4. 87 0 (0. 42H, m), 7. 28 (3H, dd, J=10. 6, 8. 4Hz), 7. 50-7. 60 (1H, R<~F 7. 79 (1H, dd, J=7. 2, 2. 4Hz), 8. 09 (3H, s).

Table 1-100 0'H-NMR 0. 94-1. 28 HN A"10 52-2. 36 (12H, m), N 2. 89 (1. 74H, s), 2. 94 (2H, d, - 9Hz), 2. 97 (1. 26H, s), 4. 12 CH3 Example 42H, d, J=5. lHz), 4. 27 349'HCI (0. 58H, d, J=5. 5Hz), 4. 44-4. 60 (0. 58H, m), 4. 45 (2H, s), 4. 68- 4. 82 (0. 42H, m), 7. 39 (5H, brs), 8. 02 (3H, brs). O 1H-NMR 0. 76-1. 20 n m), 1. 33-1. 45 (1H, m), 1. 49-1. 79 (7H, m), 1. 95-2. 32 I m), 2. 88 (1. 74H, s), 2. 96 CH 26H, s), 3. 19 (2H, d, Example J=6. 4. 13 (0. 42H, d, 350'0 J=5. 1Hz), 4. 28 (0. 58H, d, J=4. 6Hz), 4. 46-4. 57 (0. 58H, m), 0 72-4. 83 (0. 42H, m), 4. 77 (2H, l 7. 42 (1H, t, J=7. 9Hz), Cl 60-7. 62 (2H, m), 8. 01 (3H, brs). 0 sH-NMR 89-1. 28 H 47-1. 86 (8H, m), N 1. 95-2. 36 (4H, m), 2. 89 (1. 74H, CH3'HCI 98 (1. 26H, s), 3. 32 (2H, d, J=6. 0Hz), 4. 14 (0. 42H, d, Example 0 OH J=5. 6Hz), 4. 29 (0. 58H, d, 351 J=5. 6Hz), 4. 48-4. 59 (0. 58H, m), 4. 69-4. 83 (0. 42H, m), 4. 77 (2H, 0 s), 7. 45 (1H, d, J=8. 3Hz), 7. 59 6 s), 7. 86 (1H, d, J=8. 3Hz), 7. 98 (3H, brs). ci Table 1-101 1H-NMR 0. 85-1. 25 n m), 1. 45-1. 85 (8H, m), N 97-2. 34 (4H, m), 2. 89 (1. 74H, E-C 98 (1. 26H, s), 3. 28 (2H, CH3 J=6. 0Hz), 4. 14 (0. 42H, d, Example J=5. 6Hz), 4. 29 (0. 58H, d, 352 0 OH 6Hz), 4. 48-4. 59 (0. 58H, m), 4. 69-4. 82 (0. 42H, m), 4. 73 (2H, /s), 8Hz), 7. 63 (1H, dd, J=8. 8, 2. 1Hz), 7. 79 9 d, J=2. 1Hz), 8. 08 (3H, brs). 0 1H-NMR H2N " 1. 50-1. 87 (8H, m), N 2. 00-2. 28 (4H, m), 2. 90 (1. 74H, I -CH (1. 26H, s), 4. 15 (0. 42H, d, J=5. lHz), 4. 29 Example 0 OH 58H, d, J=5. 1Hz), 4. 48-4. 62 353 (0. 58H, m), 4. 74-4. 87 (0-. 42H, m), 4. 79 (2H, s), 7. 21 (1H, t, 0 4Hz), 7. 35 (1H, d, J=10. 6Hz), 7. 95 (1H, dd, J=8. 4, 6. 8. 13 (3H, brs). F 0 1H-NMR 0. 85-1. 22 HN A"10 (4H, m), 1. 45-1. 85 (8H, m), N 95-2. 30 (4H, m), 2. 87 (1. 74H, I HCI 2. 96 (1. 26H, s), 4. 15 CH3 HCI (0. 42H, d, J=5. 1Hz), 4. 27 Example (0. d, J=5. lHz), 4. 50-4. 60 354 0 OH 354 58H, m), 4. 70-4. 80 (0. 42H, m), 4. 82 (2H, s), 7. 82 (1H, d, p/I 4Hz), 7. 91 (1H, d, J=8. 4Hz), 8. 00 (3H, brs), 8. 07 >'CF3 s).

Table 1-102 0 1H-NMR 0. 77-1. 23 H2N 1. 33-1. 79 (8H, m), 1. 91-2. 29 (4H, m), 2. 82 (1. 74H, s), 2. 91 (1. 26H, s), 3. 20 (2H, Example N3 5Hz), 4. 07 (0. 42H, d, 355 4. 21 (0. 58H, d, J=5. 6Hz), 4. 41-4. 50 (0. 58H, m), OH 4. 57 (2H, s), 4. 65-4. 78 (0. 42H, 09 6. 99 (1H, d, J=3. 2Hz), 7. 53 \ d, J=3. 2Hz), 7. 98 (3H, brs). 0 1H-NMR 29 H 55-1. 77 (6H, m), N 1. 84-2. 35 (6H, m), 2. 89 (1. 74H, - 2. 98 (1. 26H, s), 3. 92 (2H, d, J=6. 0Hz), 4. 15 (0. 42H, d, J=5. 4. 30 (0. 58H, d, Example. I J=5. lHz), 4. 52-4. 55 (0. 58H, m), 356 4. 76-4. 78 (0. 42H, m), 7 55 0 (3H, m), 8. 05 (3H, brs). ci OH 0 0 O/1H-NMR 0. 92-1. 28 H 52-1. 76 (6H, m), 2 35 (6H, m), 2. 88 (1. 74H, s), 2. 97 (1. 26H, s), 3. 80 (2H, EH3'H J=6. OHz), 4. 16 (0. 42H, brs), Example 357 30 (0. 58H, brs), 4. 46-4. 59 cri 58H, m), 4. 71-4. 81 (0. 42H, m), 7. 07 (1H, dd, J=8. 8, OH 2. 8Hz), 7. J=2. 8Hz), 7. 40 (1H, d, J=8. 8Hz), 8. 04 (3H, s).

Table 1-103 0 1H-NMR (8ppm, DMSO-d6) 0. 95-1. 30 H2N"A m), 1. 56-1. 77 (6H, m), N N 81-2. 34 (6H, m), 2. 89 (1. 74H, s), 2. 99 (1. 26H, s), 3. 91 (2H, CH3 J=6. 0Hz), 4. 15 (0. 42H, d, J=5. 6Hz), 4. 30 (0. 58H, d, Example 4. 53-4. 55 (0. 58H, m), 358 76-4. 79 (0. 42H, m), 7. 30-7. 33 0 m), 7. 54-7. 59 (2H, m), l 04 (3H, brs). zu kOH 0 O 1. 01-1. 29 (4H, m), 1. 54-1. 75 (6H, m), H2N\+ 1. 85-2. 37 (6H, m), 2. 30 (3H, s), 2. 89 (1. 74H, s), 2. 9-9 CH3-HCI (1. 26H, s), 3. 80 (2H, d, Example J=6. 4. 14 (0. 42H, d, 359 6Hz), 4. 29 (0. 58H, d, J=5. 6Hz), 4. 47-4. 62 (0. 58H, m), OH 4. 72-4. 83 (0. 42H, m), 7. 07 (1H, 0 J=7. 9Hz), 7. 19 (1H, t, CH3 0 J=7. 9Hz), 7. 28 (1H, d, J=7. 4Hz), 8. 05 (3H, brs). 0 1. 00-1. 29 L/ 56-1. 77 (6H, m), z 85-2. 35 (6H, m), 2. 20 (3H, s), 89 (1. 74H, s), 2. 99 CH3 cl 26H, s), 3. 82 (2H, d, J=6. 4. 14 (0. 42H, d, Example J=5. 28 (0. 58H, d, 6Hz), 4. 47-4. 61 (0. 58H, m), 360 0 72-4. 84 (0. 42H, m), 7. 25 (1H, l d, J=7. 9Hz), 7. 37 (1H, s), 7. 43 3 d, J=7. 9Hz), 7. 99 (3H, brs). O 0 Table 1-104 0 g_ 0. 80-1. 27 H (4H, m), 1. 43-1. 84 (8H, m), 2 94-2. 35 (4H, m), 2. 88 (1. 74H, i CH 2. 97 (1. 26H, s), 3. 25 (2H, d, J=6. 0Hz), 4. 13 (0. 42H, d, Example J=5. 4. 27 (0. 58H, d, 361 0 J=5. 6Hz), 4. 45-4. 58 (0. 58H, m), 4. 4. 70-4. 81 (0. 42H, 0 38 (1H, d, J=8. 3Hz), 7. 55 9 d, J=8. 3Hz), 7. 72 (1H, s), 8. 05 (3H, brs). F 1H-NMR DMSO-d6) 0. 79-1. 28 (4H, m), 1. 40-1. 84 (8H, m), H2N 1. 94-2. 34 (4H, m), 2. 88 (1. 74H, -xHCI 2. 97 (1. 26H, s), 3. 23 (2H, 4 3. 77 (3H, s), 4. 13 Example (0. 42H, d, J=5. 6Hz), 4. 28 362 0 OH (0. 58H, d, J=5. 6Hz), 4. 47-4. 57 (0. 58H, m), 4. 66 (2H, s), 4. 72- 0 (0. 42H, m), 7. 10 (1H, dd, J=8. 3, 2. 8Hz), 7. 30 (1H, d, OMe J=2. 8Hz), 7. 44 (1H, d, J=8. 3Hz), 8. 03 (3H, brs). lH-NMR (ppm, DMSO-d6) 0. 97-1. 25 0 m), 1. 60-1. 63 (6H, m), H2N 86-1. 89 (2H, m), 1. 97-2. 19 E HCI (3H, m), 2. 28-2. 30 (1H, m), CH3 2. 50 (3H, s), 2. 88 (1. 74H, s), Example g) 0 2. 98 (1. 26H, s), 3. 91 (2H, d, 363 J=6. 5Hz), 4. 14 (0. 42H, d, J 4. 29 (0. 58H, d, J=5. 4. 52-4. 54 (0. 58H, m), ° 75-4. 78 (0. 42H, m), 7. 06 (1H, F J=8. 3Hz), 7. 59 (1H, d, J=12. 5Hz), 8. 05 (1H, brs).

Table 1-105 lH-NMR (8ppm, DMSO-d6) 0. 91-1. 33 8 1. 54-1. 72 (6H, m), H (2H, m), 1. 95-2. 23 Nl 2. 21-2. 36 (1H, m), I < (1. 74H, s), 2. 98 (1. 26H, Example F s), 3. 84 (2H, d, J=6. 5Hz), 4. 14 364 (0. 42H, d, J=5. 6Hz), 4. 29 (0. 58H, d, J=5. 6Hz), 4. 47-4. 60 OH (0. 58H, m), 4. 69-4. 81 (0. 42H, O 7. 07 (1H, dt, J=10. 7, 0 2. 3Hz), 7. 21 (1H, d, J=8. 8Hz), 7. 25 (1H, brs), 8. 05 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 93-1. 28 O m), 1. 53-1. 74 (6H, m), jj/'/1. 80-1. 91 (2H, m), 1. 95-2. 21 2N (3H, m), 2. 21-2. 34 (1H, m), t HCI 39 (3H, s), 2. 88 (1. 74H, s), CH3 (1. 26H, s), 3. 76 (2H, d, Example J=6. 0Hz), 4. 14 (0. 42H, d, Y J=5. 1Hz), 4. 29 (0. 58H, d, J=5. 4. 46-4. 60 (0. 58H, m), 4. 68-4. 83 (0. 42H, m), 6. 99 (1H, dd, J=8. 3, 2. 8Hz), 7. 17 (1H, d, J=8. 3Hz), 7. 29 (1H, d, J=2. 8Hz), 8. 07 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 88-1. 31 0 m), 1. 53-1. 74 (6H, m), H2N AN", 80-1. 92 (2H, m), 1. 94-2. 19 (3H, m), 2. 21-2. 33 (1H, m), Example CH3 74H, s), 2. 97 (1. 26H, 366 3. 73 (2H, d, J=8. 2Hz), 3. 74 OMe (3H, s), 4. 14 (0. 42H, d, J=5. 4. 29 (0. 58H, d, OH J=5. 1Hz), 4. 45-4. 60 (0. 58H, m), 0j 66-4. 84 (0. 42H, m), 6. 99-7. 09 0 (2H, m), 7. 12 (1H, d, J=2. 8Hz), 8. 08 (3H, brs).

Table 1-106 0 , 0. 93- H 43 (9H, m), 1. 47-1. 85 (12H, m), 2 1. 93-2. 40 (5H, m), 2. 89 (1. 7H, s) 2. 98 (1. 3H, s), 3. 27- CH3 Example 3. 51 (1H, m), 4. 08-4. 21 (0. 4H, 367 21-4. 39 (0. 6H, m), 4. 44- 4. 62 (0. 6H, m), 4. 66-4. 85 (0. 4H, HN m), 52 (1H, d, J=7. 9Hz), 8. 10 (3H, brs). 0 0 1H-NMR (8ppm, DMSO-d6) 0. 98- 1. 35 (4H, m), 1. 48-1. 88 (7H, N 93-2. 39 (4H, m), 2. 89 (1. 7H, CH s), 3H, s), 3. 29- Example 3. 50 (3H, m), 4. 08-4. 21 4H, 368-HCI m), 4. 22-4. 37 (0. 6H, m), 4. 44- 4. 63 (0. 6H, m), 4. 66-4. 85 (0. 4H, HN 12-7. 36 (5H, m), 8. 00 (1H, d, 9Hz), 8. 10 (3H, brs). O 0 1. 06 (9H, H2N 10-1. 32 (4H, m), 1. 48- N 83 (7H, m), 1. 94-2. 39 (4H, m), L 2. 89 (1. 8H, s), 2. 99 (1. 2H, s), Example 3. 28-3. 60 (1H, m), 4. 08- 369 4. 22 (0. 4H, m), 4. 22-4. 38 (0. 6H, T 47-4. 64 (0. 6H, m), 4. 68- HN 85 (0. 4H, m), 7. 12 (1H, d, CH3 J=8. 3Hz), 8. 11 (3H, brs). O 0 1H-NMR 0. 99- H o 38 (4H, m), 1. 49-1. 89 (7H, m), N 1. 92-2. 40 (4H, m), 2. 89 (1. 8H, É 2. 99 (1. 2H, s), 3. 36- CH3 3. 59 (3H, m), 4. 08-4. 19 (0. 4H, 2HCI 4. 22-4. 34 (0. 6H, m), 4. 42- 370 4. 64 (0. 6H, m), 4. 65-4. 85 (0. 4H, HN 0 m), 8. 15 (5H, brs), 8. 35- 8. 50 (1H, m). NH2 Table 1-107 o 1. 00- H2N ,. 1. 34 (4H, m), 1. 48-1. 88 (7H, m), NI 1. 93-2. 37 (4H, m), 2. 45 (2H, t, CH3 2Hz), 2. 80-3. 05 (5H, m), Example 54 (1H, m), 4. 06-4. 20 371 (0. 4H, m), 4. 21-4. 38 (0. 6H, m), 4. 43-4. 63 (0. 6H, m), 4. 66-4. 86 HN (0. 4H, m), 7. 80-8. 29 (7H, m). 0 ii 0 0 H nua 1. 36 (4H, m), 1. 48-1. 90 (9H, m), N 1. 90-2. 40 (6H, m), 2. 65-2. 81 (2H, ~ 2. 89 (1. 8H, s), 2. 98 (1. 2H, CH3 Example 2HCI 3. 31-3. 52 (1H, m), 4. 03- 372 44 (1H, m), 4. 45-4. 63 (0. 6H, m), 4. 66-4. 84 (0. 4H, m), 7. 82- NH2 (7H, m). O 0 0 1H-NMR 0. 95- H2N 33 (4H, m), 1. 48-1. 87 (7H, m), N 1. 77 (3H, s), 1. 91-2. 41 (6H, m), cl3 89 (1. 8H, s), 2. 98 (1. 2H, CH3 Example HCI 3. 12-3. 25 (2H, m), 3. 31-3. 54 (1H, 373 m), 4. 06-4. 20 (0. 4H, m), 4. 20- H 37 (0. 6H, m), 4. 45-4. 64 (0. 6H, HO lr, CH3 7. 77 (1H, d, J=8. 7. 87 (1H, brs), 8. 13 0 0 0 H 1. 33 (4H, m), 1. 47-1. 87 (9H, m), N 1. 78 (3H, s), 1. 91-2. 38 (6H, m), CH3 2. 89 (1. 8H, s), 2. 92-3. 04 (3. 2H, Example HCI m), 3. 31-3. 51 (1H, m), 4. 07- 374 4. 21 (0. 4H, m), 4. 22-4. 36 (0. 6H, 0 4. 44-4. 63 (0. 6H, m), 4. 67- HN ~ 4. 84 (0. 4H, m), 7. 66-7. 80 (1H, H 7. 87 (1H, brs), 8. 12 (3H, brs).

Table 1-108 0 H-NMR H2 36 (4H, m), 1. 45-1. 88 (7H, m), 1. 83 (3H, s), 1. 89-2. 39 (4H, m), CH3 2. 89 (1. 8H, s), 2. 98 (1. 2H, s), Example'HCI 3. 34-3. 52 (1H, m), 3. 55-3. 65 (2H, 375 m), 4. 08-4. 21 (0. 4H, m), 4. 22- T 4. 35 (0. 6H, m), 4. 44-4. 61 (0. 6H, HN m), 67-4. 83 (0. 4H, m), 7. 66- HN T 7. 80 (1H, m), 7. 90-8. 24 (4H, m). 0 ° H2N 37 (4H, m), 1. 49-1. 88 (7H, m), N 1. 92-2. 39 (4H, m), 2. 89 (1. 8H, s), cl3 91 (3H, s), 2. 98 (1. 2H, s), 3. 31- C Example 3. 45 (1H, m), 4. 08-4. 20 (0. 4H, m), 376 4. 22-4. 37 (0. 6H, m), 4. 46- 0 0 4. 61 (0. 6H, m), 4. 68-4. 83 (0. 4H, m), 30 (1H, t, J=6. 0Hz), 7. 77- 7. 89 (1H, m), 8. 10 (3H, brs). õ 0 1H-NMR 96- HN 1. 35 (4H, m), 1. 49-1. 88 (7H, m), N 1. 92-2. 38 (6H, m), 2. 87 (3H, s), 2. 89 (1. 8H, s), 2. 98 (1. 2H, s), Example < 06-3. 17 (2H, m), 3. 34-3. 51 (1H, 377 4. 08-4. 20 (0. 4H, m), 4. 23- H 35 (0. 6H, m), 4. 45-4. 62 (0. 6H, HN 4. 67-4. 84 (0. 4H, m), 6. 88- cii 03 (1H, m), 7. 75-7. 87 (1H, m), 0 10 (3H, brs). 0 0 0 0. 94- H 37 (4H, m), 1. 48-1. 87 (9H, m), 2 1. 92-2. 39 (6H, m), 2. 79-2. 95 (2H, i A Example 378 4 08-4. 21 (0. 4H, m), 4. 23- 3 34 (0. 6H, m), 4. 45-4. 61 (0. 6H, HN own m), 4. 67-4. 84 (0. 4H, m), 6. 97 (1H, brs), 7. 65-7. 78 (1H, m), 8. 10 (3H, brs).

Table 1-109 0'H-NMR 0. 97 (3H, t, J=7. 1. 02-1. 35 (4H, m), 1. 50- IN 86 (7H, m), 1. 92-2. 37 (4H, m), -CH 89 (1. 8H, s), 2. 98 (1. 2H, s), Example 99 (2H, q, J=7. 2Hz), 3. 35- P 379 3. 50 (1H, m), 3. 55 (2H, s), 4. 07- 0 4. 19 (0. 4H, m), 4. 23-4. 35 (0. 6H, HN 4. 45-4. 61 (0. 6H, m), 4. 67- T 4. 83 (0. 4H, m), 7. 64-7. 73 (1H, m), 0 10 (3H, brs). 0 0'H-NMR 0. 96 (3H, t, H2N J=7. 2Hz), 1. 00-1. 34 (4H, m), 1. 49- N 87 (7H, m), 1. 92-2. 38 (6H, m), 2. 88 (1. 8H, s), 2. 97 (2H, q, CH3 Example J=7. 2Hz), 2. 98 (1. 2H, s), 3. 09- 380 3. m), 3. 34-3. 51 (1H, m), H 07-4. 19 (0. 4H, m), 4. 21-4. 36 HN" (0. 6H, m), 4. 45-4. 61 (0. 6H,. 4. 67-4. 83 (0. 4H, m), 7. 69-7. 82 (1H, 0 0 m), 8. 11 brs). 0 1H-NMR 0. 96 (3H, t, H2N"10 1. 01-1. 34 (4H, m), 1. 46- 1 1. 92-2. 38 (6H, m), Example 83-3. 05 (7H, m), 3. 33-3. 50 (1H, 381 m), 4. 07-4. 20 (0. 4H, m), 4. 22- 0 35 (0. 6H, m), 4. 46-4. 61 (0. 6H, HN N Et m), 4. 68-4. 83 (0. 4H, m), 7. 70- R N H 7. 82 (1H, m), 8. 12 (3H, brs). 0 0 0. 94- HN zu 1. 35 (4H, m), 1. 49-1. 72 (5H, m), N 1. 72-1. 86 (2H, m), 1. 92-2. 38 (6H, -CH 88 (1. 8H, s), 2. 98 (1. 2H, s), Example 3. 07-3. 21 (2H, m), 3. 32-3. 61 (1H, 382 3. 50 (3H, s), 4. 08-4. 18 (0. 4H, T 4. 24-4. 34 (0. 6H, m), 4. 46- HN N 4. 61 6H, m), 4. 68-4. 83 (0. 4H, < 7. 06 (1H, brs), 7. 68-7. 83 (1H, 0 8. 10 (3H, brs).

Table 1-110 1H-NMR 0. 94- 1. 35 (4H, m), 1. 49-1. 72 (7H, m), 1. 1. 91-2. 37 (6H, ~ 2. 81-3. 03 (2H, m), Example '2. 88 (1. 8H, s), 2. 98 (1. 2H, s), 383 3. 32-3. 59 (1H, m), 3. 50 (3H, s), 0 4. 06-4. 19 (0. 4H, m), 4. 22- 'it, 36 (0. 6H, m), 4. 46-4. 61 (0. 6H, N N m), 4. 67-4. 82 (0. 4H, m), 0 10 (1H, brs), 7. 63-7. 76 (1H, m), 8. 13 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 94- 0 1. 22 (4H, m), 1. 13 (3H, t, HNl"kN 5Hz), 1. 36-1. 74 (7H, m), N 1. 88-2. 33 (4H, m), 2. 39 (2H, q, CH J=7. 5Hz), 2. 69-2. 90 (1H, m), Example HCI 2. 85 (1. 8H, s), 2. 93 (1. 2H, s), 384 3. 82 (2H, s), 4. 00-4. 11 (0. 4H, HN2 m), 4. 14-4. 26 (0. 6H, m), 36- 4. 56 (0. 6H, m), 4. 62-4. 83 (0. 4H, m), 52 (2H, d, J=8. 3Hz), 7. 60- \ CH3 . 0 m), 7. 74 (2H, d, J=8. 3Hz), 8. 00 (3H, brs). 1H-NMR (8ppm, DMSO-d6) 0. 95- O 1. 18 (4H, m), 1. : (3H, t, J=7. 5Hz), 1. 41-1. 74 (7H, m), N 89-2. 32 (4H, m), 2. 75-2. 90 A m), 2. 85 (1. 8H, s), Example 2. 93 (1. 2H, s), 3. 07 (2H, q, 385 5Hz), 3. 99-4. 12 (0. 4H, m), , 4. 14-4. 28 (0. 6H, m), 4. 38-4. 54 HN (0. 6H, m), 4. 60 (2H, s), 4. 64- 0 | (0. 4H, m), 7. 60 (2H, d, CH3 3Hz), 7. 71-7. 80 O 7. 83 (2H, d, J=8. 3Hz), 8. 03 (3H, brs).

Table 1-111 1H-NMR 0. 93- HN 1. 26 (4H, m), 1. 39 (3H, t, N 5Hz), 1. 44-1. 76 (7H, m), CH 91 (1H, m), 2. 86 (1. 8H, s), Example 2. 93 (1. 2H, s), 3. 62 (2H, q, 386 J=7. 5Hz), 4. 01-4. 12 (0. 4H, m), 3 17-4. 26 (0. 6H, m), 4. 37-4. 56 , (0. 6H, m), 4. 63-4. 81 (0. 4H, m), 0 CH 7. 54 (2H, d, J=8. 7Hz), 7. 77-7. 89 \ S m), 7. 90 (2H, d, J=8. 7Hz), 0-.--8. 02 (3H, brs). 0 1H-NMR 0. 75- 1. m), 1. 01-1. 27 (2H, m), N 1. 35-1. 85 (8H, m), 1. 92-2. 36 (4H, -CH 2. 88 (1. 8H, s), 2. 97 (1. 2H, CH3 Example 3. 24 (2H, d, J=6. 0Hz), 4. 07- 4. 4. 23-4. 33 (0. 6H, < 4. 43-4. 60 (0. 6H, m), 4. 48 (2H, s), 4. 68-4. 84 (0 4H, m), 7. 11-7. 25 (2H, m), 7. 29- 7. 48 (2H, m), 8. 06 (3H, brs). F 0 lH-NMR (8ppm, DMSO-d6) 0. 78- 1. 00 (2H, m), 1. 00-1. 29 (2H, m), N 1. 35-1. 84 (8H, m), 1. 92-2. 36 (4H, ~ 2. 88 (1. 8H, s), 2. 97 (1. 2H, CH3 Example 3. 21 (2H, d, J=6. 2Hz), 4. 09- 388 m), 4. 24-4. 32 (0. 6H, < 4. 40 (2H, s), 4. 46-4. 60 (0. 6H, m), 4. 68-4. 83 (0. 4H, m), 0 7. 10-7. 21 (2H, m), 7. 27-7. 39 (2H, zJo 8. 06 (3H, brs). v 0 1H-NMR (8ppm, DMSO-d6) 0. 86- H 33 (4H, m), 1. 50-1. 82 (6H, m), N 1. 85-2. 40 (6H, m), 2. 90 (1. 8H, s), -CH 00 (1. 2H, s), 3. 81 (2H, d, CH3 J=6. 4Hz), 4. 10-4. 24 (0. 4H, m), Example 26-4. 47 (2. 6H, m), 4. 47-4. 67 zizi (0. 6H, m), 4. 67-4. 90 (0. 4H, m), 6. 92 (1H, dd, J=7. 5Hz, 7. 9Hz), 0 7. 04 (1H, d, J=7. 9Hz), 7. 15-7. 34 HNs' , 0 Table 1-112 0 8. 04 (3H, HN s), 4. 85- N 4. 70 (0. 47H, m), 4. 60-4. 50 (0. 53H, CH3 m), 4. 35-4. 25 (0. 47H, m), 4. 20- Example. 4. 10 (0. 53H, m), 2. 98 (1. 2H, s), 390 2. 89 (1. 8H, s), 2. 61 (1H, s), 2. 31 (1H, m), 2. 19-1. 75 (8H, HN 1. 70- 53 (6H, m), 1. 31- OH 1. 00 (7H, m). 0 0 8. 06 (3H, HN N 3Hz), 7. 57 2 d, J=3. 7Hz), 7. 11-7. 04 I m), 6. 91-6. 87 (1H, m), CH3-HCI 6. 58 (1H, d, J=7. 0Hz), 4. 85- Example 4. 72 (0. 42H, s), 4. 59-4. 50 391 (0. 59H, m), 4. 35-4. 27 (0. 59H, , 4. 20-4. 15 (0. 41H, m), 3. 00 HN (1. 3H, s), 2. 90 (1. 7H, s), 2. 53 (2H, q, J=7. 4Hz), 2. 33-1. 91 (7H, m), 1. 75-1. 57 (5H, m), CH3 33-1. 04 (7H, m). CHg H-NMR (6ppm, DMSO-d6) 8. 05 (3H, s), 7. 60 (1H, s), 7. 51 (1H, d, 0 J=7. 9Hz), 6. 94 (1H, t, H N J=7. 7Hz), 6. 79 (1H, d, N J=7. 9Hz), 6. 45 (1H, s), 4. 83- CH3 2 4H, m), 4. 57-4. 48 Example (0. 6H, m), 4. 35-4. 25 (0. 6H, m), 392 20-4. 17 (0. 4H, m), 3. 37-3. 29 H (2H, m), 2. 99 (1. 3H, s), 2. 90 HN N CH3 s), 2. 31 (1H, t, J=9. 3Hz), 2. 21 (3H, s), 2. 19- 0 , 2. 10-1. 97 (5H, m), 1. 95-1. 88 (3H, m), 1. 70- 1. 55 (5H, m), 1. 29-1. 18 (3H, m).

Table 1-113 O 8. 07 (3H, s), 7. 65 (1H, s), 7. 55 (1H, d, H2N J=3. 7Hz), 6. 95 (1H, d, I 6. 65 (1H, d, CH3 4Hz), 6. 60 (1H, d, J=6. 5Hz), 4. 82-4. 75 (0. 4H, m), Example CH 60-4. 50 (0. 6H, m), 4. 35-4. 29 393 H 3 6H, m), 4. 20-4. 15 (0. 4H, m), HN 37-3. 25 (2H, m), 3. 00 (1. 3H, | s), 2. 90 (1. 7H, s), 2. 33-2. 24 I I 0 m), 2. 20 (3H, s), 2. 14 (1H, t, J=7. 2Hz), 2. 11 (3H, s), CH3 2. 10-1. 88 (4H, m), 1. 70-1. 55 (5H, m), 1. 30-1. 05 (4H, m). 0 lH-NMR DMSO-d6) 8. 06 (3H, HN 7. 02-6. 96 2""N (3H, m), 5. 99 (1H, s), 4. 82- r r v 4. (0. 4H, m), 4. 64-4. 46 (0. 6H, CH3 4. 31 (0. 6H, brs), 4. Example (0. 4H, brs), 3. 30 (1H, brs), 394 < 2. 99 (1. 3H, s), 2. 89 (1. 7H, s), HN 32-2. 16 (1H, m), 2. 12 (6H, s 10-1. 97 (3H, m), 1. 95-1. 85 (2H, m), 1. 70-1. 53 (5H, m), H3C 1. 30-1. 06 (4H, m). 0 1H-NMR (8ppm, DMSO-d6) 8. 04 (2H, brs), 7. 18 (2H, d, J=7. 7Hz), H2N A"10 14 (2H, d, J=7. 7Hz), 4. 77 nul 4H, t, J=8. 8Hz), 4. 53 (0. 6H, I CH3 J=8. 1Hz), 4. 39 (2H, s), 4. 29 Example 6H, d, J=4. 6Hz), 4. 14 (0. 4H, 395 d, 3. 18 (2H, dd, J=9. 7, 5. 6Hz), 2. 98 (1. 3H, s), 2. 89 (1. 7H, s), 2. 30 (4H, brs), 2. 20-2. 01 (3H, brs), 1. 73-1. 50 (5H, m), 1. 49- 3 1. 41 (1H, m), 1. 29-1. 10 (3H, m), 0. 95-0. 85 (2H, m).

Table 1-114 1H-NMR (8ppm, DMSO-d6) 8. 06 (2H, brs), 7. 26 (1H, d, J=6. 5Hz), 7. 18-7. 13 (3H, m), 4. 77 (0. 4H, H2N N"10 t, J=9. 3Hz), 4. 53 (0. 6H, t, J=8. 4. 43 (2H, s), 4. 30 CH3 (0. 4H, brs), 4. 13 (0. 6H, brs), Example 3. 24 (1. 5H, d, J=6. 0Hz), 3. 17 396 CH 5H, d, J=4. 6Hz), 2. 98 (1. 3H, 3 s), 2. 89 (1. 7H, s), 2. 30-2. 23 0 (5H, 2. 20-1. 95 (3H, m), 1. 83-1. 72 (2H, m), 1. 70-1. 55 (6H, m), 1. 53-1. 40 (1H, m), 1. 22-1. 10 (2H, m), 0. 98-0. 85 (1H, m). 1H-NMR (8ppm, DMSO-d6) 8. 01 (2H, 0 brs), 7. 22 (1H, t, J=7. 2Hz), Han A 7. 12-7. 06 (3H, m), 4. 77 (0. 4H, N t, J=8. 1Hz), 4. 53 (0. 6H, t, - lHz), 4. 39 (2H, s), 4. 31- CH3 16-4. 12 Example 397 4H, m), 3. 21 (2H, d, J=6. 2. 98 (1. 3H, s), 2. 89 ci3 7H, s), 2. 30 (3H, s), 2. 25- 0 2. 00 (4H, m), 1. 85-1. 75 (2H, s 1. 70-1. 52 (5H, m), 1. 50- 1. 40 (1H, m), 1. 25-0. 80 (5H, m). 0 1H-NMR 8. 00 (3H, HN brs), 7. 41-7. 22 (4H, m), 4. 82- HCI 4. 60-4. 55 (0. 6H, i HCI 4. 77 (0. 4H,). (, CH3 m), 4. 45 (2H, s), 4. 37- Example 4. 30 (0. 6H, m), 4. 21-4. 15 (0. 4H, 398 k 3. 22 (3H, s), 2. 98 (1. 2H, s), 2. 93 (3H, s), 2. 89 (1. 8H, s), 0/1 S 2. 38-2. 00 (4H, m), 1. 85-1. 75 (2H, CH3 73-1. 45 (6H, m), 1. 08- 0. 85 (3H, m).

Table 1-115 lH-NMR DMSO-d6) 8. 00 (2H, H 7. 50-7. 45 (2H, m), 7. 40- N hui 35 (2H, m), 4. 82-4. 70 (0. 3H, N NCI o m), 4. 60-4. 45 (0. 7H, m), 4. 35- CH3 25 (0. 7H, m), 4. 20-4. 10 Example 399 \NSCH3 m), 3. 25 (2H, d, J 3. 13 (3H, s), 3. 04 (3H, s), 2. 97 (1. 2H, s), 2. 88 0 (1. 8H, s), 2. 30-2. 00 (3H, m), 1. 77 (2H, m), 1. 70-1. 40 (6H, m), 1. 25-0. 80 (3H, m). 'H-NMR (8ppm, DMSO-d6) 8. 39 (1H, 0 J=5. 8Hz), 8. 09 (3H, brs), 7. 7. 32 N (2H, d, J=8. 3Hz), 4. 76 (0. 4H, Ex 8Hz), 4. 54 (0. 5H, t, Example 400 6Hz), 4. 45-4. 27 (3. 6H, m), 0 20-4. 15 (0. 4H, m), 2. 98 (1. 4H, t s), 2. 89 (1. 6H, s), 2. 28-2. 02 0 1. 85-1. 77 (3H, m), H 0 1. 70-1. 55 (6H, m), 1. 42-1. 23 (3H, m). 1H-NMR (8ppm, DMSO-d6) 9. 99 (1H, 0 8. 10 (3H, brs), 7. 60 (2H, 1I d, 3Hz), 7. 30 (2H, d, H2N J=8. 8Hz), 4. 77 (0. 5H, t, ICI 3Hz), 4. 56 (0. 5H, t, Example i 4. 38 (3H, s), 4. 30- 401 4. 15 (1H, m), 3. 00 (1. 2H, s), ol S,, 2. 90 (1. 8H, s), 2. 85 (3H, s), 3 2. 83-2. 80 (lH, m), 2. 33-2. 06 0 N (4H, m), 1. 91-1. 40 (3H, m), 1. 75-1. 60 (5H, m), 1. 43-1. 21 (2H, m).

Table 1-116 1H-NMR DMSO-d6) 8. 39 (1H, t, HNN 8Hz), 8. 09 (3H, brs), 7. 87 7. 32 (2H, d, H , A 4. 76 (0. 4H, t, J=8. 6Hz), 4. 54 (0. 6H, t, Example J=8. 6Hz), 4. 31-4. 27 (2. 4H, m), 4. 17 (0. 6H, brs), 2. 98 (1. 2H, s), 0 89 (1. 8H, s), 2. 29-2. 00 (6H, H OH 85-1. 75 (3H, m), 1. 70-1. 58 (6H, m), 1. 41-1. 20 (3H, m). 0 0'H-NMR DMSO-d6) 8. 35 (1H, s), H 05 (3H, brs), 7. 77 (2H, t, J=2. 8Hz), 7. 41 (2H, dt, J=13. 0, ~ 2Hz), 4. 74 (0. 4H, t, J=8. 6Hz), goss 6Hz), 4. 29 Example -403 6H, brs), 4. 26 (2H, d, OH J=6. 0Hz), 4. 15 (0. 4H, brs), 2. 96 (1. 4H, s), 2. 87 (1. 6H, s), 30- 0 2. 00 (6H, m), 1. 80-1. 73 (3H, m), H 62-1. 53 (6H, m), 1. 40-1. 20 (3H, m). 0 r-_ 8. 04 (3H, H 95 (1H, d, J=7. 0Hz), 7. 19- N 13 (4H, m), 4. 73 (0. 4H, t, l 4. 50 (0. 6H, t, J= EH3 4. 27 (0. 6H, brs), Example 13 (0. 4H, brs), 3. 63 (2H, s), 404 0 (2H, brs), 2. 95 (1. 2H, s), 2. 8H, s), 2. 30-2. 00 (4H, m), 1. 85-1. 75 (3H, m), 1. 70-1. 55 (5H, 0 1. 25-1. 05 (4H, m). 0 (8ppm, DMSO-d6) 8. 13 (lH, t, HN 8Hz), 8. 02 (3H, brs), 7. 22- HCI (0. 5H, t, ~ 7Hz), 4. 52 (0. 5H, t, J=7. 7Hz), CH3 4. 30 (0. 5H, brs), 4. 20 (2H, d, 405 4. 16 (0. 5H, brs), 3. 61 405 (2H, s), 2. 87 (1. 7H, s), 2. 26-1. 92 (6H, m), /1. 85-1. 70 (3H, m), 1. 65-1. 50 (5H, H m), 1. 36-1. 05 (5H, m).

The present invention also comprises, but is not limited to, the following compounds.

[Experimental Example] Then, the biological activity of the compound of the present invention was examined.

Experimental Example 1: evaluation of human DPP-IV enzyme inhibitory activity A test compound (10 L/well) and D'PBS (70 µL/well, Dulbecco's Phosphate Buffered Saline, calcium, magnesium free, Sanko Junyaku Co., Ltd.) were added to a 96-well plate (FALCON) and stirred. Thereto was added 5 mM of synthetic substrate, Gly- Pro-pNA (Glycine-Proline-p-nitroaniline, PEPTIDE INSTITUTE, Inc.) at 10 pL/well and the mixture was stirred. Human DPP-IV purified enzyme was added at 10 L/well, and after sufficient stirring, incubated at 37°C for 90 min.

The test compound was dissolved in dimethyl sulfoxide (Nacalai Tesque, Inc. ) and the final concentration of dimethyl sulfoxide in reaction mixture was 0.1%.

After the completion of the reaction, the absorbance at (O. D.

405 nm)- (O. D. 650 nm) was measured using a microplate reader (Versa Max, Molecular Devices). The p-nitroaniline amount produced by DPP-IV enzyme was calculated from the standard curve of p-nitroaniline amount (Wako Pure Chemical Industries, Ltd.).

Using the following formula, an enzyme inhibition rate (%) was calculated and ICgo value was determined.

Enzyme inhibition rate (%) = p-nitroaniline amount)- of test compound of blank) 1-X100 total amount ofß p-nitroaniline-amount of blank) 0

wherein the p-nitroaniline amount of blank shows the amount of p- nitroaniline of well free of enzyme, the total amount of p- nitroaniline shows the amount of p-nitroaniline of well free of the compound.

The results are shown in Tables 2-1 and 2-13.

Table 2-1 Test compound IC50 (µM) Example 1 < 10 Example 2 < 100 Example 4 < 100 Example 5 < 10 Example 6 < 10 Example 7 < 100 Example 8 < 10 Example 10 < 100 Example 14 < 10 Example 15 < 10 Example 19 < 10 Example 21 < 10 Example 22 < 10 Example 23 < 10 Example 26 < 100 Example 28 < 10 Example 29 < 10 Example 30 < 10 Example 31 < 10 Example 32 < 10 Example 33 < 10 Example 34 < 10 Example 35 < 10 Example 36 < 10 Example 37 < 10 Example 38 < 10 Example 39 < 10 Example 40 < 10 Example 41 < 10 Example 42 < 10 Example 43 < 10 Example 44 < 10 Example 45 < 10 Example 46 < 10 Example 47 < 10 Example 48 < 10 Example 49 < 10 Table 2-2 Test compound IC50 (µM) Example 50 < 10 Example 51 < 10 Example 52 < 10 Example 53 < 10 Example 54 < 10 Example 55 < 10 Example 56 < 10 Example 57 < 10 Table 2-3 Test compound IC50 (AM) Example 58 < 10 Example 59 < 10 Example 60 < 10 Example 61 < 10 Example 62 < 10 Example 63 < 10 Example 64 < 10 Example 65 < 10 Example 66 < 10 Example 67 < 10 Example 68 < 10 Example 69 < 10 Example 70 < 10 Example 71 < 10 Example 72 < 10 Example 73 < 10 Example 74 < 10 Example 75 < 10 Example 76 < 10 Example 77 < 10 Example 78 < 10 Example 79 < 10 Example 80 < 10

Table 2-4 Test compound _ L M) Example 81 < 10 Example 82 < 10 Example 83 < 10 Example 84 < 10 Example 85 < 10 Example 86 < 10 Example 87 < 10 Example 88 < 10 Example 89 < 10 Example 90 < 10 Example 91 < 10 Example 92 < 10 Example 93 < 10 Example 94 < 10 Example 95 < 10 Example 96 < 10 Example 97 < 10 Example 98 < 10 Example 99 < 10 Example 100 < 10 Example 101 < 10 Example 102 < 10 Example 103 < 10 Example 104 < 10 Example 105 < 10 Example 106 < 10 Example 107 < 10 Example 108 < 10 Example 109 < 10 Example 110 < 10 Example 111 < 10 Example 112 < 10 Example 113 < 10 Table 2-5 Test compound ICsp ( M) Example 114 < 10 Example 115 < 10 Example 116 < 10 Example 117 < 10 Example 118 < 10 Example 119 < 10 Example 120 < 10 Example 121 < 10 Example 122 < 10 Example 123 < 10 Example 124 < 10 Example 125 < 10 Example 126 < 10 Example 127 < 10 Example 128 < 10 Example 129 < 10 Example 130 < 10 Example 131 < 10 Example 132 < 10 Example 133 < 10 Example 134 < 10 Example 135 < 10 Example 136 < 10 Example 137 < 10 Example 138 < 10 Example 139 < 10 Example 140 < 10 Example 141 < 10 Example 142 < 10 Example 143 < 10 Example 144 < 10 Example 145 < 10 Example 146 < 10 Table 2-6 Test compound 50 (µM) Example 147 < 10 Example 148 < 10 Example 149 < 10 Example 150 < 10 Example 151 < 10 Example 152 < 10 Example 153 < 10 Example 154 < 10 Example 155 < 10 Example 156 < 10 Example 157 < 10 Example 158 < 10 Example 159 < 10 Example 160 < 10 Example 161 < 10 Example 162 < 10 Example 163 < 10 Example 164 < 10 Example 165 < 10 Example 166 < 10 Example 167 < 10 Example 168 < 10 Example 169 < 10 Example 170 < 10 Example 171 < 10 Example 172 < 10 Example 173 < 10 Example 174 < 10 Example 175 < 10 Example 176 < 10 Example 177 < 10 Example 178 < 10 Example 179 < 10 Table 2-7 Test compound IC50 (µM) Example 180 < 10 Example 181 < 10 Example 182 < 10 Example 183 < 10 Example 184 < 10 Example 185 < 10 Example 186 < 10 Example 187 < 10 Example 188 < 10 Example 189 < 10 Example 190 < 10 Example 191 < 10 Example 192 < 10 Example 193 < 10 Example 194 < 10 Example 195 < 10 Example 196 < 10 Example 197 < 10 Example 198 < 10 Example 199 < 10 Example 200 < 10 Example 201< 10 Example 202 < 10 Example 203 < 10 Example 204 < 10 Example 205 < 10 Example e 206 < 10 Example 207 < 10 Example 208 < 10 Example 209 < 10 Example 210 < 10 Example 211 < 10 Example 212 < 10 Table 2-8 Test compound IC50 (µM) Example 213 < 10 Example 214 < 10 Example 215 10 Example 216 < 10 Example 217 < 10 Example 218 < 10 Example 219 < 10 Example 220 < 10 Example 221 < 10 Example 222 < 10 Example 223 < 10 Example 224 < 10 Example 225 < 10 Example 226 < 10 Example 227 < 10 Example 228 < 10 Example 229 < 10 Example 230 < 10 Example 231 < 10 Example 232 < 10 Example 233 < 10 Example 234 < 10 Example 235 < 10 Example 236 < 10 Example 237 < 10 Example 238 < 10 Example 239 < 10 Example 240 < 10 Example 241 < 10 Example 242 < 10 Example 243 < 10 Example 244 < 10 Example 245 < 10 Table 2-9 Test compound __ Example 246 < 10 Example 247 < 10 Example 248 < 10 Example 249 < 10 Example 250 < 10 Example 251 < 10 Example 252 < 10 Example 253 < 10 Example 254 < 10 Example 255 < 10 Example 256 < 10 Example 257 < 10 Example 258 < 10 Example 259 < 10 Example 260 < 10 Example 261 < 10 Example 262 < 10 Example 263 < 10 Example 264 < 10 Example 265 < 10 Example 266 < 10 Example 267 < 10 Example 268 < 10 Example 269 < 10 Example 270 < 10 Example 271 < 10 Example 272 < 10 Example 273 < 10 Example 274 < 10 Example 275 < 10 Example 276 < 10 Example 277 < 10 Example 278 < 10 Table 2-10 Test compound IC50 (AM) Example 279 < 10 Example 280 < 10 Example 281 < 10 Example 282 < 10 Example 283 < 10 Example 284 < 10 Example 285 < 10 Example 286 < 10 Example 287 < 10 Example 288 < 10 Example 289 < 10 Example 290 < 10 Example 291 < 10 Example 292 < 10 Example 293 < 10 Example 294 < 10 Example 295 < 10 Example 296 < 10 Example 297 < 10 Example 298 < 10 Example 299 < 10 Example 300 < 10 Example 301 < 10 Example 302 < 10 Example 303 < 10 Example 304 < 10 Example 305 < 10 Example 306 < 10 Example 307 < 10 Example 308 < 10 Example 309 < 10 Example 310 < 10 Example 311 < 10 Table 2-11 Test compound IC50 (µM) Example 312 < 10 Example 313 < 10 Example 314 < 10 Example 315 < 10 Example 316 < 10 Example 317 < 10 Example 318 < 10 Example 319 < 10 Example 320 < 10 Example 321 < 10 Example 322 < 10 Example 323 < 10 Example 324 < 10 Example 325 < 10 Example 326 < 10 Example 327 < 10 Example 328 < 10 Example 329 < 10 Example 330 < 10 Example 331 < 10 Example 332 < 10 Example 333 < 10 Example 334 < 10 Example 335 < 10 Example 336 < 10 Example 337 < 10 Example 338 < 10 Example 339 < 10 Example 340 < 10 Example 341 < 10 Example 342 < 10 Example 343 < 10 Example 344 < 10 Table 2-12 Test compound IC50 (µM) Example 345 < 10 Example 346 < 10 Example 347 < 10 Example 348 < 10 Example 349 < 10 Example 350 < 10 Example 351 < 10 Example 352 < 10 Example 353 < 10 Example 354 < 10 Example 355 < 10 Example 356 < 10 Example 357 < 10 Example 358 < 10 Example 359 < 10 Example 360 < 10 Example 361 < 10 Example 362 < 10 Example 363 < 10 Example 364 < 10 Example 365 < 10 Example 366 < 10 Example 367 < 10 Example 368 < 10 Example 369 < 10 Example 370 < 10 Example 371 < 10 Example 372 < 10 Example 373 < 10 Example 374 < 10 Example 375 < 10 Example 376 < 10 Example 377 < 10 Table 2-13 Test compound IC50 (AM) l Example 378 < 10 Example 379 < 10 Example 380 < 10 Example 381 < 10 Example 382 < 10 Example 383 < 10 Example 384 < 10 Example 385 < 10 Example 386 < 10 Example 387 < 10 Example 388 < 10 Example 389 < 10 Example 390 < 10 Example 391 < 10 Example 392 < 10 Example 393 < 10 Example 394 < 10 Example 395 < 10 Example 396 < 10 Example 397 < 10 Example 398 < 10 Example 399 < 10 Example 400 < 10 Example 401 < 10 Example 402 < 10 Example 403 < 10 Example 404 < 10 Example 405 < 10

Industrial Applicability As is clear from the Experimental Examples described above, compound [I] of the present invention has a superior DPP-IV inhibitory activity. Therefore, it is useful as a therapeutic drug for a disease involving DPP-IV, or type II diabetes, obesity and the like.

This application is based on patent application Nos.

317407/2003, 395879/2003 and 114685/2004 filed in Japan, the contents of which are hereby incorporated by reference.

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