WO2005025554A2 - Dipeptidyl peptidase iv inhibitor - Google Patents

Dipeptidyl peptidase iv inhibitor Download PDF

Info

Publication number
WO2005025554A2
WO2005025554A2 PCT/JP2004/013480 JP2004013480W WO2005025554A2 WO 2005025554 A2 WO2005025554 A2 WO 2005025554A2 JP 2004013480 W JP2004013480 W JP 2004013480W WO 2005025554 A2 WO2005025554 A2 WO 2005025554A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
heterocyclyl
following
cycloalkyl
Prior art date
Application number
PCT/JP2004/013480
Other languages
French (fr)
Other versions
WO2005025554A3 (en
Inventor
Kazuhiro Tsutsumi
Hisashi Shinkai
Yuki Kitao
Masaki Yamashita
Satoru Kobayashi
Kenichi Matsui
Tomohiro Oda
Toshio Taniguchi
Kota Asahina
Original Assignee
Japan Tobacco Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34317220&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005025554(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Japan Tobacco Inc. filed Critical Japan Tobacco Inc.
Publication of WO2005025554A2 publication Critical patent/WO2005025554A2/en
Publication of WO2005025554A3 publication Critical patent/WO2005025554A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a compound useful as a dipeptidyl peptidase IV inhibitor and a dipeptidyl peptidase IV inhibitor.
  • 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 aminopeptidase
  • DPP dipeptidyl peptidase
  • TPP tripeptidyl peptidase
  • 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- ⁇ V 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.
  • GLP-1 glucagons-like peptide-1
  • 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.
  • 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)) .
  • DPP-IV 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.
  • NIDDM non-insulin-dependent diabetes mellitus
  • DPP-IV inhibitor As a DPP-IV inhibitor, the following compounds are known.
  • T is described as an intermediate for the production of a protease inhibitor in WO98/45330, JP-A-2002-504094 , USP6291687, US2001/044547A, USP6489364 and EP1005493A. Furthermore ,
  • (U) (V) is described as an intermediate for the production of a matrix metalloproteinase inhibitor in WO96/06074, JP-A-10-504821 , USP5763621, EP777646A and EP777646B. Moreover, is described as an intermediate for the production of a cathepsins inhibitor in WO03/029200.
  • the present invention aims at providing a superior DPP-IV inhibitor.
  • 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.
  • compound [I] 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.
  • the present invention provides the following (1) to (29) .
  • a DPP-IV inhibitor comprising a compound represented by the formula [I]
  • R 1 is selected from the following [A]-[E]:
  • (Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Baal>- ⁇ Baal7>) , ... ⁇ Baal> halogen atom, ••• ⁇ Baa2> C ⁇ - 6 alkyl, ••• ⁇ Baa3> halo-C_- 6 alkyl, ••• ⁇ Baa4> C 3 - 12 cycloalkyl, ⁇ • ⁇ Baa5> aralkyl, ••• ⁇ Baa6> heterocyclyl-C ⁇ _ 6 alkyl, ⁇ • ⁇ Baa7> hydroxyl , ••• ⁇ Baa8> C1-6 alkoxy, ••• ⁇ Baa9> C ⁇ _ 6 alkylthio, ••• ⁇ Baal0> aryloxy, ⁇ Baall> aralkyloxy,
  • [C] C 3 - ⁇ 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ C1>- ⁇ C17>) , ⁇ ⁇ C1> halogen atom, • ⁇ C2> C ⁇ - 6 alkyl, • ⁇ C3> halo-C ⁇ - 6 alkyl ,
  • R 12 and R 13 are each independently selected from the following (E1)-(E3), j and k are each independently an integer of
  • X 12 is selected from the following (Ebl) - (Eb24) ) , "(Eal) aryl and
  • R 2 is selected from the following [F]-[H]:
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ G1>- ⁇ G18>) ,
  • R 3 is selected from the following [I] and [J]
  • R 4 is selected from the following [K]-[S]:
  • R 41 is selected from the following (Lal)-(La8), and
  • Y 41 is selected from the following (Lbl) and (Lb2) ) ,
  • R 413 is Ci-6 alkyl , C 3 - ⁇ 2 cycloalkyl or aryl ,
  • R 414 R 415 and R 416 are the same or different and each is hydrogen atom, Ci-6 alkyl, C 3 - 12 cycloalkyl or aryl,
  • R is hydrogen atom or C ⁇ - 6 alkyl , or R 417 in combination with R 413 form C ⁇ _ 4 alkylene) ;
  • cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>- ⁇ Lab33>) , ••• ⁇ Labl> halogen atom,
  • Ci_ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, Ci-_ alkoxy, -S0 2 -C ⁇ -6 alkyl, -S0 2 -aryl, -NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-Ci- 6 alkyl) ,
  • X 41 is (CHR 418 ) C - • X 41a -(CHR 419 ) d - X 41a is selected from the following (Lbal) - (Lba23) , R 418 and R 419 are the same or different and each is hydrogen atom or C ⁇ - 6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4) ,
  • R 41 is as defined above, and Y 42 is selected from the following (Mai) - (Mal2) ) , (Mai) single bond,
  • X 2a is selected from the following (Maal) (Maa23)
  • R 420 and R 421 are the same or different and each is hydrogen atom or C ⁇ - 6 alkyl
  • e and f are each independently an integer of 0 to 2
  • Z 41 and Z 42 are the same or different and each is selected from the following (Mabl).- (Mab6)
  • Z 43 is selected.
  • (Mab3) C 2 _ 6 alkynylene (said alkylene, alkenylene and alkynylene are optionally substituted by 1 to 3 substituents selected from the following ⁇ Mabal>- ⁇ Mabal3>) , •" ⁇ ⁇ Mabal> halogen atom, ⁇ Maba2> C 3 - 12 cycloalkyl,
  • (Mabba4) , and X 4c is selected from the following (Mabbbl) - (Mabbb9) ) (Mabbal) hydrogen atom, (Mabba2) C ⁇ _ 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>)
  • (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> C 3 - ⁇ 2 cycloalkyl ,
  • heterocyclyl-C ⁇ - 6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-C ⁇ -6 alkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ N1>- ⁇ N19>) ,
  • R 42 and R 43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to
  • Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ U1>- ⁇ U14>) ,
  • (Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Uaal>- ⁇ Uaal7>) " ⁇ Uaal> halogen atom, "• ⁇ Uaa2> Ci- 6 alkyl, ' ••• ⁇ Uaa3> halo-Ci- 6 alkyl,
  • [V] C 3 -i 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ V1>- ⁇ V17>) , • ⁇ V1> halogen atom, • ⁇ V2> Ci- 6 alkyl, • ⁇ V3> halo-C . - . alkyl, • ⁇ V4> aralkyl,
  • heterocyclyl-C ⁇ - 6 alkyl saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclyl-C ⁇ _ 6 alkyl are optionally substituted by 1 to 3 substituents selected from the following '
  • R 1 is selected from the following [A]-[E]:
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ B1>- ⁇ B14>) ,
  • R 12 , R 13 ,j and k are as defined in the above-mentioned (1) , which is formed by R 1 and R 4' in combination;
  • R 2 ' is selected from the following [F]-[H], [F] hydrogen atom, [G] C ⁇ _ 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,
  • R 3' is the following [J]
  • R 4 ' is selected from the following [K]-[M], [P] , [R] and [S] ,
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ L1>- ⁇ L14>)
  • R 41' is selected from the following (Lai) , (La2) , (La5) and (La7) , and Y 41 is as defined in the above-mentioned (1) ) , (Lai) hydrogen atom,
  • (La2) C ⁇ _ 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laa24>) ,
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C.-e alkoxy, -S0 2 -C ⁇ _ 6 alkyl, -S0 2 -aryl, -NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-C__6 alkyl) ,
  • R 413 , R 414 , R 415 , R 41 ⁇ and R 417 are as defined in the above-mentioned
  • [M] C 3 _ ⁇ 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ M1>- ⁇ M18>) , ⁇ M1> halogen atom, ⁇ M2> Ci-6 alkyl, ⁇ M3> halo-C ⁇ -6 alkyl, ⁇ M4> aralkyl,
  • R 42 and R 43 are each as defined in the above-mentioned (1) , m and n are each independently an integer of 0 to 3) formed by R 4' and R 5 ' in combination,
  • R 5' is selected from the following [T]-[W] and [BB] , [T] hydrogen atom,
  • C ⁇ _ 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> Ci-6 alkoxy, • ⁇ U5> Ci- 6 alkylthio, - ⁇ U6> aryloxy, • ⁇ U7> aralkyloxy, • ⁇ U8> heterocyclyloxy, • ⁇ U9> heterocyclyl-C ⁇ _6 alkoxy, • ⁇ U10> nitro, - ⁇ U11> amino, • ⁇ U12> cyano, • ⁇ U13> carboxyl and • ⁇ U14> -X 44 -R 45 (R 45 and X 44 are as defined in the above-mentioned
  • Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laa24>) , ⁇ Laal> halogen atom, ⁇ Laa2> C3-12 cycloalkyl, ⁇ Laa3> hydroxyl, ⁇ Laa4> aralkyloxy, ⁇ Laa5> heterocyclyloxy, ⁇ Laa6> heterocyclyl-C ⁇ _ 6 alkoxy, ⁇ Laa7> nitro, ⁇ Laa8> cyano, ⁇ Laa9> carboxyl,
  • R is Ci- 6 alkyl , C 3 _ ⁇ 2 cycloalkyl or aryl ,
  • R 414 , R 415 and R 416 are the same or different and each is hydrogen atom, Ci-6 alkyl , C 3 __ 2 cycloalkyl or aryl ,
  • R' 417 is hydrogen atom or G1- 6 alkyl) ;
  • Ci- 6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Lbaaal>- ⁇ Lbaaal3>) , ⁇ " ⁇ Lbaaal> halogen atom,
  • C ⁇ _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,
  • C3_i 2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ C1>, ⁇ C2>, ⁇ C6>,
  • Ci- 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> C 3 -1 2 cycloalkyl, • ⁇ G3> hydroxyl, • ⁇ G4> Ci-e alkoxy, • ⁇ G10> nitro,
  • [L] C ⁇ - 6 alkyl (said alkyl is optionally substituted by 1 to * 3 substituents selected from the following ⁇ L1>- ⁇ L4> and ⁇ L10>-
  • [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>) ,
  • R 42 and R 43 are each as defined in the above-mentioned (1) and m and n are each independently an integer of 0 to 3) formed by R 4 ' and R 5 ' in combination; and R5' is
  • Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ U1>- ⁇ U4> and ⁇ U10>-
  • R 4a is selected from the following [MabbO] , [Mabbl] and [Mabbl ⁇ ] , [MabbO] hydrogen atom, [Mabbl] halogen atom and
  • R 41a and R 41d are the same or different and each is hydrogen atom or C -6 alkyl) ;
  • R 4b is selected from the following [Lai] , [La2] , [La5] and [La6] ,
  • alkyl, aryl and aralkyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>, ⁇ Lab2>, ⁇ Lab7>,
  • Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from C ⁇ _ 6 alkoxy, -S0 2 -C ⁇ - 6 alkyl, -S0 2 -aryl, - NHS0 2 -C ⁇ - 6 alkyl and -NHS0 2 -halo-C ⁇ _ 6 alkyl) ,
  • R 41f , R 1g are the same or different and each is hydrogen atom or Ci-e alkyl and R 41h is C ⁇ _ 6 alkyl) ;
  • X 4b is selected from the following [Maal]- [Maa ⁇ ] , [Maa9] , [Maal2]-
  • R 41b and R 41e are the same or different and each is hydrogen atom or Ci-e alkyl, or show -(CH 2 ) 2 -, -(CH 2 ) 3 -, - (CH 2 ) 4 - or -(CH 2 ) 5 - together with R 4b ) ;
  • R 4d is hydrogen atom or C ⁇ - 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
  • d is an integer of 0 to 4 , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • each symbol is as defined in the above-mentioned (5) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • each symbol is as defined in the above-mentioned (5) , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • 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.
  • 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 , ⁇ -glucosidase inhibitors, insulin sensitizers, PPAR ⁇ receptor agonists, PPAR ⁇ receptor agonists/antagonists, PPAR ⁇ 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 carboxykinas
  • 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.
  • 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.
  • 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 , ⁇ -glucosidase inhibitors , insulin sensitizers , PPAR receptor agonists, PPAR ⁇ receptor agonists/antagonists, PPAR ⁇ 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 ,,.
  • insulin preparations injection
  • oral agent low-molecular insulin preparations
  • SU drugs sulfonylurea
  • PPCK protein tyrosine phosphatase IB
  • SH2 domain-containing inositol phosphatase (SHIP2) inhibitors SH2 domain-containing inositol phosphatase (SHIP2) inhibitors
  • AMPK AMP-activated protein kinase
  • GP glycogen phosphorylase
  • GP glycogen phosphorylase
  • PDHK microsomal triglyceride transfer protein
  • MTP diacylglycerol acyltransferase
  • CETP cholesteryl ester transfer protein
  • HMG-CoA reductase inhibitors ⁇ 3 adrenaline receptor agonists
  • Apo-Al apolipoprotein-Al
  • lipoprotein lipoprotein
  • the present invention includes the following embodiments .
  • a DPP-IV inhibitor comprising a compound of the formula [I] , wherein
  • R 4 is selected from the following [K]-[S], or a salt thereof.
  • R 41 is selected from the following (La2) and (La4)-
  • (La7) , and Y 41 is selected from the following (Lbl) and (Lb2) ) , •• (La2) Ci- 6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following ⁇ Laal>- ⁇ Laal0>, ⁇ Laal6> and ⁇ Laal9>) ,
  • heterocyclyl (said aryl, aralkyl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following ⁇ Labl>- ⁇ Labl5>, ⁇ Labl9> and ⁇ Lab28>) ,
  • (Lb2) X 41 (X q ⁇ is selected from the following (Lbal) - (Lba23) ) , ⁇ (Lbal) -0-, -OCH 2 -, -OCH 2 CH 2 -, -CH2O-, -CH 2 CH 2 0-, (Lba2) -S-, -SCF ⁇ 2 -, -SCH 2 CH 2 -, -CH 2 S-, -CH 2 CH 2 S-,
  • (Lbaa2) C ⁇ - 6 alkyl (said alkyl is optionally substituted by 1 to substituents selected from the following ⁇ Lbaaal>- ⁇ Lbaaal3>) , • ⁇ Lbaaal> halogen atom, • ⁇ Lbaaa2> C 3 - 12 cycloalkyl, ⁇ Lbaaa3> hydroxyl, " ⁇ Lbaaa4> C ⁇ - 6 alkoxy, • ⁇ Lbaaa5> Ci-e alkylthio, • ⁇ Lbaa6> aryloxy, •• ⁇ Lbaaa7> aralkyloxy, • ⁇ Lbaaa8> heterocyclyloxy, • ⁇ Lbaaa9> heterocyclyl-C ⁇ _6 alkoxy r •" ⁇ LbaaalO> nitro,
  • X 41 is as defined above, X 42 and X 43 are the same as X 41 , Z 41 and Z 42 are the same or different and each is selected from the following (Mabl) , (Mab3)-(Mab6) and Z 43 is selected from the following (Macl) ,
  • ⁇ "(Mac5) trivalent heterocycle (asid cycloalkanetriyl, arenetriyl and heterocycle are optionally substituted by 1 to 3 substituents selected from the following ⁇ Macbl>- ⁇ Macbl7>) , •• •• ⁇ Macbl> halogen atom, ⁇ Macb2> Ci-e alkyl , ⁇ Macb3> halo-Ci-e alkyl,

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.

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-ΪV 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.
Figure imgf000004_0001
[compound (A): O95/15309, JP-A-9-509921, USP5939560, EP731789A, compound (B) : 099/67278, US2002/049164A, EP1087991A, compound (C) : USP6124305, compound (D) : WO00/34241, JP-A-2002-531547 , USP6166063, EP1137635A, compound (E) : WO01/81304, EP1282600A, compound (F) : O01/55105, JP-A-2003-520849 , US2001/031780A,
USP6380398, EP1254113A, compound (G) WOOl/68603, US2002/019411A,
USP6395767, EP1261586A, compound (H) WO02/38541, compound (J) : O02/14271, EP1308439A, compound (K) WO02/30890, EP1323710A, compound (L) : WO02/051836]
Figure imgf000004_0002
[compound (M) : WO03/024942, compound (N) : WO03/037327, compound (O): WO03/035067, compound (P) : WO03/045228]
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.
Figure imgf000005_0001
[compound (Q) : W099/46272, JP-A-2002-506075, US2002/061839A, EP1062222A, compound (R) : WO02/02560, US2002/161001A, EP1301187A, compound (S) : WO03/055881] On the other hand,
Figure imgf000005_0002
(T) is described as an intermediate for the production of a protease inhibitor in WO98/45330, JP-A-2002-504094 , USP6291687, US2001/044547A, USP6489364 and EP1005493A. Furthermore ,
Ξ H ϊ H
Me^ e e^Me
Me and Me
(U) (V) is described as an intermediate for the production of a matrix metalloproteinase inhibitor in WO96/06074, JP-A-10-504821 , USP5763621, EP777646A and EP777646B. Moreover,
Figure imgf000006_0001
is described as an intermediate for the production of a cathepsins inhibitor in WO03/029200.
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]
Figure imgf000006_0002
wherein
R1 is selected from the following [A]-[E]:
[A] hydrogen atom,
[B] Cι-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-Cι-6 alkoxy,
<B10> nitro,
<B11> amino,
<B12> cyano,
<B13> carboxyl and
<B14> -XX-R1:L (R11 is selected from the following (Bal) and (Ba2) and X1 is selected from the following (Bbl) - (Bb23) ) , (Bal) aryl and
(Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Baal>-<Baal7>) , ...<Baal> halogen atom, •••<Baa2> Cι-6 alkyl, •••<Baa3> halo-C_-6 alkyl, •••<Baa4> C3-12 cycloalkyl, ■■•<Baa5> aralkyl, •••<Baa6> heterocyclyl-Cι_6 alkyl, ■ • ■<Baa7> hydroxyl , •••<Baa8> C1-6 alkoxy, •••<Baa9> Cι_6 alkylthio, •••<Baal0> aryloxy, ■<Baall> aralkyloxy,
•<Baal2> heterocyclyloxy,
■<Baal3> heterocyclyl-Ci-6 alkoxy,
•<Baal4> nitro,
■<Baal5> amino,
■<Baal6> cyano and
•<Baal7> carboxyl;
(Bbl) single bond,
(Bb2) -0-,
(Bb3) -S-,
(Bb4) -NH-,
(Bb5) -CO-,
(Bb6) -C02-,
(Bb7) -OCO-,
(Bb8) -OC02-,
(Bb9) -SO-,
(BblO) -SO2-,
(Bbll) -OSO2-,
(Bbl2) -S03-,
(Bbl3) -CONH-,
(Bbl4) -NHCO-,
(Bbl5) -CSNH-,
(Bbl6) -NHCS-,
(Bbl7) -NHS02-,
(Bbl8) -SO2NH-,
(Bbl9) -NHC02-,
(Bb20) -OCONH-,
(Bb21) -NHCONH-,
(Bb22) -NHCSNH- and
(Bb23) -NHSO2NH-;
[C] C3-ι2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>-<C17>) , ■<C1> halogen atom, •<C2> Cι-6 alkyl, • <C3> halo-Cι-6 alkyl ,
•<C4> aralkyl,
• <C5> heterocyclyl-Cι_6 alkyl ,
•<C6> hydroxyl,
•<C7> Cι-6 alkoxy,
•<C8> Cι-6 alkylthio,
•<C9> aryloxy,
•<C10> aralkyloxy,
•<C11> heterocyclyloxy,
■<C12> heterocyclyl-Cι-6 alkoxy,
•<C13> nitro,
•<C14> amino,
•<C15> cyano,
•<C16> carboxyl and
•<C17> -X^R11 (R11 and X1 are as defined above) ;
[D] -X^R11 (R11 and X1 are as defined above) ; or
[E]
Figure imgf000009_0001
wherein R12 and R13 are each independently selected from the following (E1)-(E3), j and k are each independently an integer of
0 to 3 , which is formed by R1 and R4 in combination,
• (El) hydrogen atom,
• (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2) ,
X12 is selected from the following (Ebl) - (Eb24) ) , "(Eal) aryl and
•• (Ea2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following
<Eaal>-<Eaal7>) ,
•"<Eaal> halogen atom, ...<Eaa2> Cι_6 alkyl,
•••<Eaa3> halo-Cι-6 alkyl, ••<Eaa4> C3_ι2 cycloalkyl,
••<Eaa5> aralkyl,
•■<Eaa6> heterocyclyl-Cι-6 alkyl,
• ■<Eaa7> hydroxyl , ••<Eaa8> Cι_6 alkoxy, ■•<Eaa9> C_.-6 alkylthio, ■•<Eaal0> aryloxy, ••<Eaall> aralkyloxy, ••<Eaal2> heterocyclyloxy, ••<Eaal3> heterocyclyl-Cι-6 alkoxy, ••<Eaal4> nitro,
••<Eaal5> amino, ••<Eaal6> cyano and ■•<Eaal7> carboxyl; • (Ebl) single bond,
■ (E 2) -0-,
• (Eb3) -S-,
■ (Eb4) -NH-,
■ (Eb5) -CO-,
• (Eb6) -C02-,
• (Eb7) -OCO-,
• (Eb8) -OCO2-,
• (Eb9) -SO-,
• (EblO) -SO2-,
• (Ebll) -OSO2-,
■ (Ebl2) -SO3-,
• (Ebl3) -CONH-,
• (Ebl4) -NHCO-,
■ (Ebl5) -CSNH-,
• (Ebl6) -NHCS-,
• (Ebl7) -NHSO2-,
• (Ebl8) -SO2NH-, •(Ebl9) -NHC02-,
• (Eb20) -OCONH-, ■ • (Eb21 ) -NHCONH- ,
■ • (Eb22 ) -NHCSNH- ,
■ • (Eb23 ) -NHSO2NH- and
• • (Eb24 ) 4 to 7-membered divalent saturated heterocycle ; or
• (E3) benzene ring formed by R12 and R13 together with the adj cent carbon atoms (said benzene ring is optionally substituted by 1 to 3 substituents selected from the following <Ecl>-<Ecl7>) , ••<Ecl> halogen atom, ••<Ec2> C-6 alkyl,
••<Ec3> halo-Cι-6 alkyl, ••<Ec4> C3-12 cycloalkyl, ••<Ec5> aralkyl, "<Ec6> heterocyclyl-Cι-6 alkyl, "<Ec7> hydroxyl, ••<Ec8> Cι_6 alkoxy, -<Ec9> Ci-6 alkylthio,
• •<EclO> aryloxy, "<Ecll> aralkyloxy, "<Ecl2> heterocyclyloxy,
■■<Ecl3> heterocyclyl-Cι-6 alkoxy,
-<Ecl4> nitro,
••<Ecl5> amino,
••<Ecl6> cyano and "<Ecl7> carboxyl;
R2 is selected from the following [F]-[H]:
[F] hydrogen atom,
[G] Ci-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-6 alkoxy, <G5> Ci-6 alkylthio, , -<G6> aryloxy,
■<G7> aralkyloxy,
■<G8> heterocyclyloxy,
•<G9> heterocyclyl-Cι-6 alkoxy, -<G10> nitro,
•<G11> amino,
•<G12> cyano,
•<G13> amido,
•<G14> =0, -<G15> carboxyl,
•<G16> -P0(0H) ,
•<G17> -P0(0-Cι-6 alkyl) 2 and
•<G18> -P0(0-aryl)2; and [H] C3-i2 cycloalkyl (said cycloalkyl is optionally substituted by
1 to 3 substituents selected from the following <H1>-<H21>) ,
•<H1> halogen atom,
•<H2> Ci-6 alkyl,
•<H3> halo-Cι-6 alkyl , -<H4> aralkyl ,
• <H5> heterocyclyl-Cι-6 alkyl ,
•<H6> hydroxyl,
•<H7> Ci-6 alkoxy,
•<H8> Ci-6 alkylthio, •<H9> aryloxy,
•<H10> aralkyloxy,
•<H11> heterocyclyloxy,
•<H12> heterocyclyl-Cι-6 alkoxy,
•<H13> nitro, -<H14> amino,
•<H15> cyano,
•<Hlβ> amido,
•<H17> =0,
•<H18> carboxyl, ■<H19> -PO(OH)2, •<H20> -PO(0-Cι_6 alkyl) 2 and •<H21> -PO(0-aryl)2;
R3 is selected from the following [I] and [J]
[I] Ci-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, ■<I3> hydroxyl, •<I4> Ci-6 alkoxy, •<I5> Ci-6 alkylthio, •<I6> aryloxy, •<I7> aralkyloxy, •<I8> heterocyclyloxy, •<I9> heterocyclyl-Cι-6 alkoxy, •<I10> nitro, •<I11> amino, •<I12> cyano, •<I13> amido, •<I14> =0, •<I15> carboxyl, •<I16> -P0(0H)2, •<I17> -P0(0-Cι-6 alkyl) 2 and •<I18> -P0(0-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> Ci-6 alkyl, •<J3> halo-Cι-6 alkyl, •<J4> aralkyl,
•<J5> heterocyclyl-Ci-e alkyl, •<J6> hydroxyl, •<J7> Ci-6 alkoxy, ,- <J8> Ci-6 alkylthio ,
•<J9> aryloxy,
•<J10> aralkyloxy,
•<J11> heterocyclyloxy, -<J12> heterocyclyl-Cι-6 alkoxy,
•<J13> nitro,
•<J14> amino,
•<J15> cyano,
•<J16> amido, -<J17> =0,
•<J18> carboxyl,
•<J19> -PO(OH)2,
•<J20> -P0(0-Ci_6 alkyl) 2 and
•<J21> -P0(0-aryl)2; R4 is selected from the following [K]-[S]:
[K] hydrogen atom,
[L] Cι_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> Ci-6 alkoxy,
•<L5> Cι_6 alkylthio,
•<L6> aryloxy, -<L7> aralkyloxy,
•<L8> heterocyclyloxy,
• <L9> heterocyclyl-Cι_6 alkoxy,
•<L10> nitro,
•<L11> amino, -<L12> cyano,
■<L13> carboxyl and
•<L14> -Y41-R41 (R41 is selected from the following (Lal)-(La8), and
Y41 is selected from the following (Lbl) and (Lb2) ) ,
••(Lai) hydrogen atom, 1 (La2) Cι_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) , <Laal> halogen atom, <Laa2> C3-ι2 cycloalkyl, <Laa3> hydroxyl, <Laa4> aralkyloxy, <Laa5> heterocyclyloxy, <Laa6> heterocyclyl-Cι-6 alkoxy, <Laa7> nitro, <Laa8> cyano , <Laa9> carboxyl,
<LaalO> -OR 413 <Laall> -COR 414 <Laal2> 413
-C02R'
<Laal3> -OCOR ,4*13 <Laal4> -CONR415R416 , <Laal5> -OCONR 15R416 , <Laal6> -NR415R41S , <Laal7> -NR 17COR413 , <Laal8> -NR417C02R413 , <Laal9> -SR413 , <Laa20> -SOR413 , <Laa21> -S02R413 , <Laa22> -S02NR415R416 , <Laa23> -NR417S02R413 and
<Laa24> -NR417CONR415R416
(R 413 is Ci-6 alkyl , C3-ι2 cycloalkyl or aryl ,
R 414 R415 and R416 are the same or different and each is hydrogen atom, Ci-6 alkyl, C3-12 cycloalkyl or aryl,
417
R is hydrogen atom or Cι-6 alkyl , or R417 in combination with R413 form Cι_4 alkylene) ;
(La3) C3-12 cycloalkyl ;
(La4) C3-12 cycloalkyl-Cι-6 alkyl ;
(La5) aryl ; • • (La6) aralkyl ;
••(La7) heterocyclyl and ••(La8) heterocyclyl-Ci-6 alkyl
(said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>) , •••<Labl> halogen atom,
•"<Lab2> Ci_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, Ci-_ alkoxy, -S02-Cι-6 alkyl, -S02-aryl, -NHS02-Cι-6 alkyl and -NHS02-halo-Ci-6 alkyl) ,
<Lab3> halo-Cι-6 alkyl,
<Lab4> aralkyl,
<Lab5> heterocyclyl-Cι_6 alkyl,
<Lab6> C3-12 cycloalkyl,
<Lab7> hydroxyl,
<Lab8> Cι_6 alkoxy,
<Lab9> aralkyloxy,
<LablO> heterocyclyloxy,
<Labll> heterocyclyl-Cι-6 alkoxy ,
<Labl2> nitro,
<Labl3> amino,
<Labl4> cyano,
<Labl5> carboxyl,
<Labl6> (Ci-6 alkoxy) carbonyl,
<Labl7> Ci-6 alkylsulfonyl ,
<Labl8> -CH2C02H,
Figure imgf000016_0001
<Lab22> -OCOR413, <Lab23> -CONR415R416 , <Lab24> -OCONR415R416 , <Lab25> -NR415R416, <Lab26> -NR17COR413 , •<Lab27> -NR1/C02R"
•<Lab28> -SR413,
•<Lab29> -SOR413,
•<Lab30> -S02R413,
•<Lab31> -S02NR415R416 ,
•<Lab32> -NR417S02R413 and
•<Lab33> -NR417CONR415R416
(R ,4'1"3f R ,4^14% R ,4'15 R416 and R417 are as defined above) ;
•• (Lbl) single bond and
(Lb2) X41 (X41 is (CHR418)C- •X41a-(CHR419)d- X 41a is selected from the following (Lbal) - (Lba23) , R418 and R419 are the same or different and each is hydrogen atom or Cι-6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4) ,
(Lbal) -0-,
(Lba2) -S-,
(Lba3) -CO-,
(Lba4) -C02-,
(Lba5) -OCO-,
(Lba6) -OC02-,
(Lba7) -SO-,
(Lba8) -S02-,
(Lba9) -OS02-,
(LbalO) -SO3-,
(Lball) -NR411-,
(Lbal 2) -CONR411- ,
(Lbal3) -NR411CO-
(Lbal4) -CSNR' 411
(Lbal 5) -NR 44111C,S-,
(Lbal 6) -S02NR' 411 (Lbal 7) NR411S02- ,
(Lbal 8) -OCONR' 411
,411,
(Lbal9) -NRβllC02- (Lba20) -NR411CONR412- , (Lba21) -NR11CSNR412- , .-(Lba22) -NR411S02NR412- (R411 and R412 are the .same or different and each is selected from the following (Lbaal) - (Lbaa3) ) ,
•"•(Lbaal) hydrogen atom,
••••(Lbaa2) Cι_6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal4>) , <Lbaaal> halogen atom, <Lbaaa2> C3-ι2 cycloalkyl, <Lbaaa3> hydroxyl , <Lbaaa4> Ci-e alkoxy, <Lbaaa5> Cι-6 alkylthio, <Lbaaa6> aryloxy, <Lbaaa7> aralkyloxy, <Lbaaa8> heterocyclyloxy, <Lbaaa9> heterocyclyl-Cι-6 alkoxy, <LbaaalO> nitro, <Lbaaall> amino, <Lbaaal2> cyano, <Lbaaal3> carboxyl, <Lbaaal4> 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>) , .<__ halogen atom,
•<M2> Ci-6 alkyl,
■<M3> halo-Cι-6 alkyl,
•<M4> aralkyl,
■<M5> heterocyclyl-Cι-6 alkyl, .<M6> hydroxyl,
•<M7> Cι_6 alkoxy,
•<M8> Ci-6 alkylthio,
•<M9> aryloxy,
•<M10> aralkyloxy, <M11> heterocyclyloxy,
<M12> heterocyclyl-Cι-6 alkoxy, <M13> azido, <M14> nitro, <M15> amino, <M16> cyano, <M17> carboxyl and
<M18> -Y4Z-R41 (R41 is as defined above, and Y42 is selected from the following (Mai) - (Mal2) ) , (Mai) single bond,
(Ma2) -χ41- ,
(Ma3) -Z41- ,
(Ma4) -z41-z42- ,
(Ma5) -X41-Z41- ,
(Ma6 ) -z41-x41- ,
(Ma7) -X41-Z1-X42-, (Ma8) -X41-Z41-Z42-, (Ma9) -Z1-X41-Z42-, (MalO) -Z41-Z2-X41-, (Mall)
Figure imgf000019_0001
and
•• (Mal2)
Figure imgf000019_0002
(χ4i ^s ag ζjg ingζj above, X42 and X43 are each independently
-(CHR420)e-X42a-(CHR421)f-, X2a is selected from the following (Maal) (Maa23) , R420 and R421 are the same or different and each is hydrogen atom or Cι-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 (Mabl).- (Mab6) , and Z43 is selected. from the following (Macl) - (Mac5) ) , (Maal) single bond, (Maa2) -0-, (Maa3) -S-, (Maa4) -CO-, (Maa5) -C02-, (Maaδ) -OCO-, (Maa7) -OC02-, (Maa8) -SO-, (Maa9) -S02-, (MaalO) -OS02-, (Maall) -S03-, (Maal2) -NR411-,
(Maal3 ) -CONR' 411
Figure imgf000020_0001
(Maal 6 ) -OCONR' 411
(Maal7 ) -CSNR ,411 - ,
(Maal 8 ) -NR411CS-
(Maal9 ) S02NR411-
(Maa20 ) -NR411S02- , (Maa21 ) -NR411CONR412- , (Maa22 ) -NR 11CSNR412- and
(Maa23) -NR411S02NR412- (R411 and R412 are as defined above) ;
(Mabl) Ci-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>) , •"■<Mabal> halogen atom, <Maba2> C3-12 cycloalkyl,
• • • •<Maba3> hydroxyl , <Maba4> C_-6 alkoxy, <Maba5> Cι-6 alkylthio, ," " <Maba6> aryloxy,
• • ••<Maba7> aralkyloxy,
....<Maba8> heterocyclyloxy, <Maba9> heterocyclyl-C_.-6 alkoxy,
•••■<MabalO> nitro,
•■••<Maball> amino,
....<Mabal2> cyano and
....<Mabal3> carboxyl ;
•••(Mab4) C3_ι2 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>) ,
••••<Mabbl> halogen atom, <Mabb2> Cι-6 alkyl, <Mabb3> halo-Cι_6 alkyl, <Mabb4> aralkyl,
....<Mabb5> heterocyclyl-Cι-6 alkyl , <Mabb6> C3-ι2 cycloalkyl ,
•• ••<Mabb7> hydroxyl , <Mabb8> C__6 alkoxy, <Mabb9> Cι_6 alkylthio,
"••<MabblO> aryloxy, ••••<Mabbll> aralkyloxy,
• • ••<Mabbl2> heterocyclyloxy,
• •• •<Mabbl3> heterocyclyl-Ci_6 alkoxy, <Mabbl4> nitro,
."••<Mabbl5> amino, •■ ••<Mabbl6> cyano , ••••<Mabbl7>. carboxyl and <Mabbl8> -X4c-R4c (R4c is selected from the following (Mabbal)-
(Mabba4) , and X4c is selected from the following (Mabbbl) - (Mabbb9) ) (Mabbal) hydrogen atom, (Mabba2) Cι_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> (Cι_e alkoxy) carbonyl and
■<Mabbaa4> C__6 alkylsulfonyl;
(Mabbbl) single bond,
(Mabbb2) -CO-,
(Mabbb3) -C02-,
(Mabbb4) -OCO-,
(Mabbb5) -CONR41c-,
(Mabbb6) -NR41cCO-,
(Mabbb7) -S02-,
(Mabbb8) -S02NR 41c and
(Mabbb9) -NR41cS02- (R41c is hydrogen atom or Cι-6 alkyl) ;
(Macl) Ci-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-ι2 cycloalkyl ,
•• ••<Maca3> hydroxyl , <Maca4> Cι_6 alkoxy,
• •• •<Maca5> Cι_6 alkylthio , ••"<Maca6> aryloxy, <Maca7> aralkyloxy,
■•"<Maca8> heterocyclyloxy,
• •"<Maca9> heterocyclyl-Cι-6 alkoxy, <MacalO> nitro,
••"<Macall> amino,
•• ■• <Macal2> cyano and
•"•<Macal3> carboxyl; • • • (Mac3 ) C3_i2 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>) ,
••••<Macbl> halogen atom, <Macb2> Ci-6 alkyl, <Macb3> halo-Cι-6 alkyl, <Macb4> aralkyl ,
• •• •<Macb5> heterocyclyl-Cι-6 alkyl ,
• • ••<Macb6> C3-12 cycloalkyl , •• ••<Macb7> hydroxyl , <Macb8> Ci-6 alkoxy, <Macb9> Ci-6 alkylthio,
• • " <MacblO> aryloxy, • • • • <Macbll> aralkyloxy,
• • • • <Macbl2> heterocyclyloxy , • • " <Macbl3> heterocyclyl-Cι-6 alkoxy, <Macbl4> nitro,
•■•■<Macbl5> amino,
• • ••<Macbl6> cyano, ■••■<Macbl7> carboxyl and <Macbl8> -CH2C02H;
[N] aryl, [0] aralkyl,
[P] heterocyclyl,
[Q] heterocyclyl-Cι-6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-Cι-6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <N1>-<N19>) ,
<N1> halogen atom,
<N2> Cι_6 alkyl,
<N3> C3-12 cycloalkyl ,
<N4> halo-Cι-6 alkyl ,
<N5> aralkyl , <N6> heterocyclyl-Ci-6 alkyl,
<N7> hydroxyl, <N8> Ci-6 alkoxy, <N9> Ci-6 alkylthio, <N10> aryloxy, <N11> aralkyloxy, <N12> heterocyclyloxy, <N13> heterocyclyl-Cι-6 alkoxy, <N14> nitro, <N15> amino, <N16> cyano, <N17> =0,
<N18> carboxyl and
<N19> -γ42-R41 (R41 and Y42 are as defined above) ; [R] -Y41-R41 (R41 and Y41 are as defined above) , or [S]
Figure imgf000024_0001
(R42 and R43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to
3) formed by R4 and R5 in combination,
■ (SI) hydrogen atom,
• (S2) -Y41-R44 (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>) , •••<Saal> halogen atom, •••<Saa2> Ci-6 alkyl,
•<Saa3> halo-Cι-6 alkyl,
•<Saa4> aralkyl, •<Saa5> heterocyclyl-Cι_6 alkyl,
■<Saa6> C3_i2 cycloalkyl,
•<Saa7> hydroxyl,
•<Saa8> Cι_6 alkoxy,
•<Saa9> Cι_6 alkylthio,
•<Saal0> aryloxy,
•<Saall> aralkyloxy,
•<Saal2> heterocyclyloxy,
•<Saal3> heterocyclyl-Cι-6 alkoxy,
•<Saal4> nitro,
•<Saal5> amino,
•<Saal6> cyano and
•<Saal7> 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>) , ■•<Scl> halogen atom, ••<Sc2> Ci-6 alkyl, •■<Sc3> halo-Ci-6 alkyl, ••<Sc4> aralkyl, ••<Sc5> heterocyclyl-Cι_6 alkyl, ••<Sc6> C3-12 cycloalkyl, ••<Sc7> hydroxyl, ••<Sc8> Ci-6 alkoxy, ••<Sc9> Ci-6 alkylthio, ■•<SclO> aryloxy, ••<Scll> aralkyloxy, ••<Scl2> heterocyclyloxy, ••<Scl3> heterocyclyl-Cι_6 alkoxy, ••<Scl4> nitro, ■•<Scl5> amino, ••<Scl6> cyano and ••<Scl7> carboxyl; ,R5 is selected from the following [T]-[BB], [T] hydrogen atom,
[U] Ci-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> Ci-6 alkoxy,
<U5> C-6 alkylthio,
<U6> aryloxy,
<U7> aralkyloxy,
<U8> heterocyclyloxy,
<U9> heterocyclyl-Cι_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 (Ubl) - (Ub23) ) ,
(Ual) aryl and
(Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Uaal>-<Uaal7>) "■<Uaal> halogen atom, "•<Uaa2> Ci-6 alkyl, ' •••<Uaa3> halo-Ci-6 alkyl,
• • -<Uaa4> C3_i2 cycloalkyl , •"<Uaa5> aralkyl,
"•<Uaa6> heterocyclyl-Cι-6 alkyl,
• • •<Uaa7> hydroxyl , •••<Uaa8> Cι_6 alkoxy, •■■<Uaa9> Ci-6 alkylthio, "•<UaalO> aryloxy, •••<Uaall> aralkyloxy, •<Uaal2> heterocyclyloxy, •<Uaal3> heterocyclyl-Cι_6 alkoxy, •<Uaal4> nitro, •<Uaal5> amino, •<Uaal6> cyano and •<Uaal7> carboxyl;
(Ubl) single bond,
(Ub2) -0-,
(Ub3) -S-,
(Ub4) -NH-,
(Ub5) '-CO-,
(Ub6) -C02-,
(Ub7) -OCO-,
(Ub8) -OC02-, -
(Ub9) -SO-,
(UblO) -SO2-,
(Ubll) -OSO2-,
(Ubl2) -SO3-,
(Ubl3) -CONH-,
(Ubl4) -NHCO-,
(Ubl5) -CSNH-,
(Ubl6) -NHCS-,
(Ubl7) -NHS02-,
(Ubl8) -SO2NH-,
(Ubl9) -NHCO2-,
(Ub20) -OCONH-,
(Ub21) -NHCONH-,
(Ub22) -NHCSNH- and
(Ub23) -NHSO2NH-;
[V] C3-i2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <V1>-<V17>) , •<V1> halogen atom, •<V2> Ci-6 alkyl, •<V3> halo-C.-. alkyl, •<V4> aralkyl,
•<V5> heterocyclyl-Cι-6 alkyl,
•<V6> hydroxyl,
•<V7> Ci-6 alkoxy, -<V8> Ci-6 alkylthio,
•<V9> aryloxy,
•<V10> aralkyloxy,
•<V11> heterocyclyloxy,
•<V12> heterocyclyl-Cι_6 alkoxy, -<V13> nitro,
•<V14> amino,
•<V15> cyano,
•<V16> carboxyl and
•<V17> -X -R45 (R45 and X44 are as defined above) ; [W] 3 to 7-membered saturated heterocycle,
[X] aryl,
[Y] heterocyclyl,
[Z] aralkyl,
[AA] heterocyclyl-Cι-6 alkyl (said saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclyl-Cι_6 alkyl are optionally substituted by 1 to 3 substituents selected from the following '
<W1>-<W16>) ,
•<W1> halogen atom,
•<W2> Ci-6 alkyl, -<W3> C3-12 cycloalkyl,
•<W4> aralkyl,
•<W5> heterocyclyl-Ci_6 alkyl,
•<W6> hydroxyl,
•<W7> Ci-6 alkoxy, -<W8> Ci-6 alkylthio,
•<W9> aryloxy,
•<W10> aralkyloxy,
•<W11> heterocyclyloxy,
• <W12> heterocyclyl-Cι_6 alkoxy , •<W13> nitro,
•<W14> amino,
•<W15> cyano and
•<W16> carboxyl; and
[BB] -X4-R45 (R4S 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]
Figure imgf000029_0001
wherein R1 is selected from 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>-<B14>) ,
■<B1> halogen atom, -<B2> C3-12 cycloalkyl,
•<B3> hydroxyl,
•<B4> Ci-6 alkoxy,
•<B5> Ci-6 alkylthio,
•<B6> aryloxy, -<B7> aralkyloxy,
•<B8> heterocyclyloxy,
•<B9> heterocyclyl-Ci-e alkoxy,
•<B10> nitro,
•<B11> amino, -<B12> cyano,
•<B13> carboxyl and
•<B14> -X^R11 (R11 and X1 are defined in the above-mentioned (1)) ; [C] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by
1 to 3 substituents selected from the following <C1>-<C17>) , -<C1> halogen atom,
•<C2> Ci-e alkyl, • <C3> halo-Cι-6 alkyl ,
•<C4> aralkyl,
• <C5> heterocyclyl-Cι-6 alkyl ,
•<C6> hydroxyl,
•<C7> Ci-6 alkoxy,
•<C8> Cι_6 alkylthio,
•<C9> aryloxy,
•<C10> aralkyloxy,
•<C11> heterocyclyloxy,
•<C12> heterocyclyl-Ci-6 alkoxy,
•<C13> nitro,
•<C14> amino,
•<C15> cyano,
•<C16> carboxyl and
•<C17> -X^R11 (R11 and X1 are as defined in the above-mentioned
(D) ;
[D] XK^-R11 (R11 and X1 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] Cι_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> Cι_6 alkoxy,
<G5> Cι_6 alkylthio, ,« <G6> aryloxy ,
•<G7> aralkyloxy,
•<G8> heterocyclyloxy,
•<G9> heterocyclyl-Ci-e alkoxy, -<G10> nitro ,
■<G11> amino,
•<G12> cyano,
•<G13> amido,
•<G14> =0, -<G15> carboxyl,
•<G16> -PO(OH)2,
•<G17> -PO (0-Cι_6 alkyl) 2 and
•<G18> -P0 (0-aryl) 2 ;
[H] C3_i2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>-<H16> and
<H18>-<H21>) ,
•<H1> halogen atom,
■<H2> Cι_6 alkyl,
•<H3> halo-Cι-6 alkyl, -<H4> aralkyl,
•<H5> heterocyclyl-Cι-6 alkyl,
•<H6> hydroxyl,
•<H7> Ci-6 alkoxy,
■<H8> Ci-6 alkylthio, •<H9> aryloxy,
•<H10> aralkyloxy,
■<H11> heterocyclyloxy,
•<H12> heterocyclyl-Cι-6 alkoxy,
■<H13> nitro, -<H14> amino,
•<H15> cyano,
•<H16> amido,
•<H18> carboxyl,
•<H19> -PO(OH)2, ,-<H20> -PO(0-C!_6 alkyl) 2 and
•<H21> -PO(0-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> Ci-6 alkyl,
•<J3> halo-Cι_6 alkyl, .<J4> aralkyl,
•<J5> heterocyclyl-Cι_6 alkyl,
•<J6> hydroxyl,
•<J7> Ci-6 alkoxy,
•<J8> Ci-6 alkylthio, -<J9> aryloxy,
•<J10> aralkyloxy,
•<J11> heterocyclyloxy,
•<J12> heterocyclyl-Cι-6 alkoxy,
■<J13> nitro, -<J14> amino,
■<J15> cyano,
•<J16> amido,
■<J18> carboxyl,
•<J19> -PO(OH)2, -<J20> -P0(0-Cι_6 alkyl) 2 and
•<J21> -PO(0-aryl)2;
R4' is selected from the following [K]-[M], [P] , [R] and [S] ,
[K] hydrogen atom,
[L] Ci-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> Ci-6 alkoxy, <L5> Ci-6 alkylthio, <L6> aryloxy, <L7> aralkyloxy, <L8> heterocyclyloxy, <L9> heterocyclyl-Cι-6 alkoxy, <L10> nitro, <L11> amino, <L12> cyano, <L13> carboxyl and
<L14> -Y41-R41' (R41' is selected from the following (Lai) , (La2) , (La5) and (La7) , and Y41 is as defined in the above-mentioned (1) ) , (Lai) hydrogen atom,
(La2) Cι_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) ,
<Laal> halogen atom,
<Laa2> C3-ι2 cycloalkyl,
<Laa3> hydroxyl ,
<Laa4> aralkyloxy,
<Laa5> heterocyclyloxy,
<Laa6> heterocyclyl-Cι-6 alkoxy ,
<Laa7> nitro,
<Laa8> cyano,
<Laa9> carboxyl ,
<Laal0> -OR413,
<Laall> -COR 414
Figure imgf000033_0001
<Laal3> -OCOR413, <Laal4> -CONR415R416 ,
<Laal5> -OCONR415R416 ,
<Laalβ> -NR415R416 ,
<Laal7> -NR417COR413 ,
<Laal8> -NR 1 C02R413 ,
<Laal9> -SR413 ,
<Laa20> -SOR413 , • • <Laa21> -S02R413 ,
■ • <Laa22> -S02NR415R416 ,
■ <Laa23> -NR 1 S02R4iJ and ■ <Laa24> -NR417CONR415R416 (R ,4^13 , R ,4*14 R' 415 R and R is as defined in the above-mentioned
(D);
• • (La5) aryl and
•• (La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>) ,
•••<Labl> halogen atom,
•••<Lab2> Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C.-e alkoxy, -S02-Cι_6 alkyl, -S02-aryl, -NHS02-Cι-6 alkyl and -NHS02-halo-C__6 alkyl) ,
<Lab3> halo-Cι-6 alkyl,
<Lab4> aralkyl,
<Lab5> heterocyclyl-Cι_6 alkyl,
<Lab6> C3-12 cycloalkyl,
<Lab7> hydroxyl,
<Lab8> Ci-6 alkoxy,
<Lab9> aralkyloxy,
<LablO> heterocyclyloxy,
<Labll> heterocyclyl-Cι_6 alkoxy ,
<Labl2> nitro,
<Labl3> amino,
<Labl4> cyano,
<Labl5> carboxyl,
<Labl6> (Cχ-6 alkoxy) carbonyl ,
<Labl7> Cχ_6 alkylsulfonyl,
<Labl8> -CH2C02H,
<Labl9> -OR' 413 <Lab20> -COR 414 <Lab21> 413
-C02R' <Lab22> -OCOR 413 <Lab23> -C0NR 1SR416 ,
<Lab24> -OCONR415R416 ,
<Lab25> -NR415R416 ,
<Lab26> -NR417COR413 ,
<Lab27> -NR417C02R413 ,
<Lab28> -SR413 ,
<Lab29> -SOR413 ,
<Lab30> -S02R413 ,
<Lab31> -S02NR415R416 , - " <Lab32> -NR417S02R413 and
■ <Lab33> -NR 17CONR415R416
(R413 , R414 , R415 , R41δ and R417 are as defined in the above-mentioned
(D ) ;
[M] C3_ι2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>) , <M1> halogen atom, <M2> Ci-6 alkyl, <M3> halo-Cι-6 alkyl, <M4> aralkyl,
<M5> heterocyclyl-Cι-6 alkyl, <M6> hydroxyl, <M7> Ci-6 alkoxy, <M8> Ci-6 alkylthio, <M9> aryloxy, <M10> aralkyloxy, <M11> heterocyclyloxy, <M12> heterocyclyl-Cι-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) ) ; [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> Cι_6 alkyl,
<N3> C3-12 cycloalkyl ,
<N4> halo-Cι-6 alkyl ,
<N5> aralkyl ,
<N6> heterocyclyl-Ci-e alkyl ,
<N7> hydroxyl,
<N8> Cι_6 alkoxy,
<N9> Cι_6 alkylthio,
<N10> aryloxy,
<N11> aralkyloxy,
<N12> heterocyclyloxy,
<N13> heterocyclyl-Cι-6 alkoxy,
<N14> nitro,
<N15> amino,
<N16> cyano and
<N18> carboxyl;
R] -Y 1-R41 ' (R41 ' and Y41 are as defined above) , or
S]
Figure imgf000036_0001
(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] Cι_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> Ci-6 alkoxy, •<U5> Ci-6 alkylthio, -<U6> aryloxy, •<U7> aralkyloxy, •<U8> heterocyclyloxy, •<U9> heterocyclyl-Cι_6 alkoxy, •<U10> nitro, -<U11> amino, •<U12> cyano, •<U13> carboxyl and •<U14> -X44-R45 (R45 and X44 are as defined in the above-mentioned
(D); [V] C3-12 cycloalkyl (cycloalkyl is optionally substituted by 1 to
3 substituents selected from the following <V1>-<V17>) ,
•<V1> halogen atom,
•<V2> Ci-6 alkyl,
•<V3> halo-Cι-6 alkyl, .<γ4> aralkyl,
•<V5> heterocyclyl-Cι-6 alkyl,
■<V6> hydroxyl,
•<V7> Ci-6 alkoxy,
•<V8> Ci-6 alkylthio, -<V9> aryloxy,
•<V10> aralkyloxy,
■<V11> heterocyclyloxy,
•<V12> heterocyclyl-Cι-6 alkoxy,
•<V13> nitro, .<vl4> amino,
•<V15> cyano,
■<V16> carboxyl and
•<V17> -X44-R45 (R45 and X44 are as defined in the above-mentioned
(D); [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> Cι_6 alkyl,
•<W3> C3-12 cycloalkyl,
•<W4> aralkyl,
•<W5> heterocyclyl-Cχ-6 alkyl ,
•<W6> hydroxyl,
•<W7> Ci-6 alkoxy,
•<W8> Ci-6 alkylthio,
•<W9> aryloxy,
■<W10> aralkyloxy,
•<W11> heterocyclyloxy, .<W12> heterocyclyl-Cι-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 (Lai) , (La2) , (La5) and (La7) , X1a is selected from the following (Lbal) - (Lba23) , and other symbols are as defined in the above-mentioned (2) ,
■•(Lai) hydrogen atom,
•• (La2) Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) , <Laal> halogen atom, <Laa2> C3-12 cycloalkyl, <Laa3> hydroxyl, <Laa4> aralkyloxy, <Laa5> heterocyclyloxy, <Laa6> heterocyclyl-Cι_6 alkoxy, <Laa7> nitro, <Laa8> cyano, <Laa9> carboxyl,
<LaalO> -OR' 413
<Laall> -COR' 414
Figure imgf000039_0001
<Laal3> -OCOR413, <Laal4> CONR^R416 ,
<Laal5> -OCONR415R416 ,
<Laal6> -NR415R416 ,
<Laal7> -NR417COR413 ,
<Laal8> -NR417C02R413 ,
<Laal9> -SR' 413
<Laa20> -SOR 4' 13
<Laa21> -S02R413 ,
<Laa22> ~S02NR 15R416 ,
<Laa23> -NR417S02R413 and
<Laa24> -NR417CONR415R416
(R is Ci-6 alkyl , C3_ι2 cycloalkyl or aryl ,
R414 , R415 and R416 are the same or different and each is hydrogen atom, Ci-6 alkyl , C3__2 cycloalkyl or aryl ,
R' 417 is hydrogen atom or G1-6 alkyl) ;
• • (La5) aryl and
•• (La7) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following
<Labl>-<Lab33>) ,
•••<Labl> halogen atom, <Lab2> Ci-6 alkyl,
<Lab3> halo-Cχ-6 alkyl,
<Lab4> aralkyl,
<Lab5> heterocyclyl-Cι_6 alkyl,
<Lab6> C3-i2 cycloalkyl,
<Lab7> hydroxyl,
<Lab8> Cχ-6 alkoxy,
<Lab9> aralkyloxy,
<LablO> heterocyclyloxy,
<Labll> heterocyclyl-Ci-e alkoxy,
<Labl2> nitro,
<Labl3> amino,
<Labl4> cyano,
<Labl5> carboxyl,
<Labl6> (Ci-6 alkoxy) carbonyl,
<Labl7> Ci-6 alkylsulfonyl ,
<Labl8> -CH2C02H ,
<Labl9 -OR' 413
<Lab20> -COR' 414
<Lab21> -C02R' 413
<Lab22> -OCOR 4' 13
<Lab23> -CONR415R416 ,
<Lab24> -OCONR415R416 ,
<Lab25> -NR 15R416 ,
<Lab26> -NR417COR413 ,
<Lab27> -NR417C02R413 ,
<Lab28> -SR' 413
<Lab29> -SOR' 413
<Lab30> -S02R 4' 13
<Lab31> -S02NR415R416 ,
<Lab32> -NR417S02R413 and
<Lab33> -NR417CONR415R416
413
(R' R414 , R415 , R416 and R417 are as defined above) ;
(Lbal ) -0- , (Lba2) -S-, (Lba3) -CO-, (Lba4) -C02-, (Lba5) -OCO-, (Lba6) -OC02-, (Lba7) -SO-, (Lba8) -S02-, (Lba9) -OS02-, (LbalO) -SO3-, (Lball) -NR411-, (Lbal 2) -CONR411-, (Lbal3) -NR411CO-, (Lbal4) -CSNR411-, (Lbal 5) -NR11CS-, (Lbalβ) -S02NR411-, (Lbal7) -NR411S02-, (Lbal 8) -OCONR411-, (Lbal9) -NR411C02-, ( Lba20 ) -NR411CONR412- , (Lba21) -NR411CSNR412- ,
• (Lba22) -NR411S02NR412- (R411 and R412 are the same or different and each is selected from the following (Lbaal) - (Lbaa3) ) ,
••(Lbaal) hydrogen atom,
•• (Lbaa2) Ci-6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal3>) , ■"<Lbaaal> halogen atom,
• • • <Lbaaa2> C3-ι2 cycloalkyl ,
• • • <Lbaaa3> hydroxyl , •••<Lbaaa4> Ci-e alkoxy, •••<Lbaaa5> C.-6 alkylthio,
• • • <Lbaaa6> aryloxy , ••■<Lbaaa7> aralkyloxy,
• • • <Lbaaa8> heterocyclyloxy , •••<Lbaaa9> heterocyclyl-Ci-s alkoxy,. , <LbaaalO> nitro, <Lbaaall> amino, <Lbaaal2> cyano, <Lbaaal3> 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] Cι_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_i2 cycloalkyl,
•<B3> hydroxyl,
•<B4> Ci-e alkoxy,
•<B10> nitro, •<B11> amino,
■<B12> cyano and
•<B14> -X^R11 (R11 and X1 are each as defined in he above- mentioned (1) ) ; or
[C] C3_i2 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> Ci-6 alkyl, •<C6> hydroxyl, -<C7> Ci-e alkoxy, •<C13> nitro, ■<C14> amino, •<C15> cyano, ■<C16> carboxyl and •<C17> -X^R11 (R11 and X1 are as defined above) ; R2' is
[F] hydrogen atom,
[G] Ci-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> Ci-e alkoxy, •<G10> nitro,
•<G11> amino,
•<G12> cyano,
•<G13> amido,
•<G16> -PO(OH)2, -<G17> -PO(0-Cι_6 alkyl) 2 and
•<G18> -PO(0-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> Ci-e alkyl,
•<H6> hydroxyl ,
•<H7> Ci-e alkoxy,
•<H13> nitro, •<H14> amino,
•<H15> cyano,
•<H16> amido,
•<H19> -PO(OH)2,
•<H20> -PO(0-Cι-6 alkyl) 2 and
•<H21> -PO(p-aryl)2;
R3' is
[J] C3_i2 cycloalkyl (said cycloalkyl is optionally substituted by
1 to 3 substituents selected from the following <J1>, <J2>, <J6>,
<J7>, <J13>-<Jlβ> and <J19>-<J21>) , . •<J1> halogen atom,
•<J2> Ci-e alkyl,
•<J6> hydroxyl, ■<J7> Cι_6 alkoxy, ■<J13> nitro, ■<J14> amino and ■<J15> cyano ■<J16> amido, ■<J19> -PO(OH)2, ■<J20> -PO(0-Ci_6 alkyl) 2 and •<J21> -PO(0-aryl)2;
R4' is
[K] hydrogen atom,
[L] Cχ-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-ι2 cycloalkyl,
•<L3> hydroxyl, -<L4> Ci-e alkoxy,
•<L10> nitro,
•<L11> amino and
•<L12> cyano;
[M] C3_i2 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> Ci-e alkyl,
•<M6> hydroxyl, .< 7> Ci-e 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> Ci-e alkyl,
■<N7> hydroxyl, -<N8> Ci-e alkoxy,
•<N14> nitro,
•<N15> amino,
•<N16> cyano and
•<N18> carboxyl; or [S]
Figure imgf000045_0001
(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] Ci-e 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-e 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> Ci-e alkyl, •<V6> hydroxyl, •<V7> Ci-e 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]
Figure imgf000046_0001
wherein R2a is
[F] hydrogen atom or
[G] Ci-e alkyl,
R4a is selected from the following [MabbO] , [Mabbl] and [Mabblδ] , [MabbO] hydrogen atom, [Mabbl] halogen atom and
[Mabbl8] -Xc-R4c(R4c is selected from the following (Mabbal)- (Mabba4) , X4c is selected from the following (Mabbbl) - (Mabbb9) ) , • (Mabbal) hydrogen atom,
• (Mabba2) C1 5 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>) ,
■<Mabbaal> halogen atom,
•<Mabbaa2> carboxyl,
■<Mabbaa3> (Cι-6 alkoxy) carbonyl and
•<Mabbaa4> Cι_6 alkylsulfonyl;
(Mabbbl) single bond,
(Mabbb2) -CO-,
(Mabbb3) -C02-,
(Mabbb4) -OCO-,
(Mabbb5) -CONR1c-,
(Mabbbδ) -NR41cCO-,
(Mabbb7) -S02-,
(Mabbb8) -S02NR41c- and
(Mabbb9) -NR1cS02- (R41c is hydrogen atom or Cι-6 alkyl) ; X4a is selected from the following [Lbal] - [Lba3] , [Lba8] , [Lball]
Lbal3] , [Lbal6]-[Lbal9] and [Lba21] ,
Lbal] -0-,
Lba2] -S-,
Lba3] -CO-,
Lba8] -S02-,
Lball] -NR1a-,
Lbal2] -CONR41a-,
Lbal3] -NR41aCO-,
Lbal6] -S02NR41a-,
Lbal7] -NR41aS02-,
Lbal8] -OCONR1a-,
Lbal9 ] -NR41aC02- and
Lba21 ] -NR41aCONR 1d-
R41a and R41d are the same or different and each is hydrogen atom or C -6 alkyl) ;
R4b is selected from the following [Lai] , [La2] , [La5] and [La6] ,
[Lai] hydrogen atom,
[La2] Ci-e 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>) ; -<Labl> halogen atom,
•<Lab2> Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from Cι_6 alkoxy, -S02-Cι-6 alkyl, -S02-aryl, - NHS02-Cι-6 alkyl and -NHS02-halo-Cι_6 alkyl) ,
•<Lab7> hydroxyl, -<Lab8> Ci-e alkoxy,
•<Labl2> nitro,
•<Labl3> amino,
•<Labl4> cyano,
•<Labl5> carboxyl, «<Labl6> (Ci-e alkoxy) carbonyl ,
•<Labl7> Ci-6 alkylsulfonyl,
•<Lab31> -S02NR1fR41g and
•<Lab32> -NR41fS02R41h
(R41f, R1g are the same or different and each is hydrogen atom or Ci-e alkyl and R41h is Cι_6 alkyl) ;
X4b is selected from the following [Maal]- [Maaδ] , [Maa9] , [Maal2]-
[Maalδ] and [Maal9] - [Maa21] ,
[Maal] single bond,
[Maa2] -0-, [Maa3] -S-,
[Maa4] -CO-,
[Maa5] -C02-,
[Maa6] -OCO-,
[Maa9] -S02-, [Maal2] -NR41-,
[Maal3] -CONR1b-,
[Maal4] -NR41bCO-,
[Maal5] -NR41bC02-,
[Maal6] -OCONR41b-,
[Maal9] -S02NR1b-,
[Maa20] -NR41bS02- and
[Maa21] -NR41bCONR41e-
(R41b and R41e are the same or different and each is hydrogen atom or Ci-e alkyl, or show -(CH2)2-, -(CH2)3-, - (CH2) 4- or -(CH2)5- together with R4b) ;
(A) is
[Mabl ]
/
Figure imgf000049_0001
[Mab2]
— CH=C or
[Mab5]
Figure imgf000049_0002
(R4d is hydrogen atom or Cι-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 [Mabl] CH,
[Mab2 ] — GH=C
\ or
[Mab5 ]
-CL or a stereoisomer thereof, a pharmaceutically acceptable salt ther eof or a solvate thereof.
(7) A compound represented by the formula [IV]
Figure imgf000050_0001
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]
Figure imgf000050_0002
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]
Figure imgf000051_0001
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- methyIcarbamoyl) methyl] cyclohexylmethoxymethyl Jbenzoic acid,
2-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl) 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- methyIcarbamoyl)methyl] cyclohexylmethoxy}-3-fluorobenzoic acid,
2-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl)methyl] cyclohexylmethoxymethyl}-4-methoxybenzoic acid,
2-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-fluorobenzoic acid,
3-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl Jbenzoic acid,
3-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl) methyl] cyclohexylmethoxy}-2-methylbenzoic acid,
3-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl) 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- methyIcarbamoyl) methyl] cyclohexylmethoxy}-2-methylbenzoic acid and trans 4- [ (S) -amino- (N-cyclobutyl-N- methyIcarbamoyl) methyl] cyclohexanecarboxylie 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 Jbenzoic 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- methyIcarbamoyl) 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 , α-glucosidase inhibitors, insulin sensitizers, PPARα receptor agonists, PPARγ receptor agonists/antagonists, PPAR§ 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 IB (PTPase IB) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators , glycogen phosphorylase (GP) inhibitors, glucokinase activators, llβ-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, β3 adrenaline receptor agonists, apolipoprotein-Al (Apo-Al) 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 β (PKCβ) 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 , α-glucosidase inhibitors , insulin sensitizers , PPAR receptor agonists, PPARγ receptor agonists/antagonists, PPAR§ 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 IB (PTPase IB) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llβ-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, β3 adrenaline receptor agonists, apolipoprotein-Al (Apo-Al) 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 β (PKCβ) 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 , α-glucosidase inhibitors, insulin sensitizers, PPARα receptor agonists, PPARγ receptor agonists/antagonists, PPARδ 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 IB (PTPase IB) inhibitors, SH2 domain-containing inositol phos*phatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llβ-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, β3 adrenaline receptor agonists, apolipoprotein-Al (Apo-Al) 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 β (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] Cι_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-e alkoxy,
<L5> Ci-e alkylthio,
<L6> aryloxy,
<L7> aralkyloxy,
<L8> heterocyclyloxy,
<L9> heterocyclyl-Cι-6 alkoxy ,
<L10> nitro,
<L11> amino,
<L12> cyano,
<L13> carboxyl and
<L14> -Y41-R41 (R41 is selected from the following (La2) and (La4)-
(La7) , and Y41 is selected from the following (Lbl) and (Lb2) ) , •• (La2) Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laal0>, <Laal6> and <Laal9>) ,
•••<Laal> halogen atom,
• • ■<Laa2> C3-12 cycloalkyl ,
• • •<Laa3> hydroxyl , •••<Laa4> aralkyloxy, ■<Laa5> heterocyclyloxy,
■<Laa6> heterocyclyl-Ci-6 alkoxy,
•<Laa7> nitro,
■<Laa8> cyano,
•<Laa9> carboxyl,
><LaalO> Ci-6 alkoxy, aryloxy,
■<Laal6> amino and
•<Laal9> Cι-6 alkylthio;
(La4) C3-12 cycloalkyl-Cι_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>) ,
•<Labl> halogen atom,
•<Lab2> Ci-e alkyl,
•<Lab3> halo-Cι_6 alkyl,
•<Lab4> aralkyl,
•<Lab5> heterocyclyl-Ci-g alkyl,
•<Lab6> C3-12 cycloalkyl,
•<Lab7> hydroxyl ,
•<Lab8> Cι_6 alkoxy,
•<Lab9> aralkyloxy,
•<LablO> heterocyclyloxy,
• <Labll> heterocyclyl-Ci-e alkoxy,
•<Labl2> nitro,
•<Labl3> amino,
•<Labl4> cyano,
•<Labl5> carboxyl ,
•<Labl9> aryloxy and
■<Lab28> Ci-e alkylthio;
(Lbl) single bond and
(Lb2) X41 (Xqι is selected from the following (Lbal) - (Lba23) ) , ■(Lbal) -0-, -OCH2-, -OCH2CH2-, -CH2O-, -CH2CH20-, (Lba2) -S-, -SCFΪ2-, -SCH2CH2-, -CH2S-, -CH2CH2S-,
(Lba3) -CO-, -COCH2-, -COCH2CH2-, -CH2CO-, -CH2CH2CO-,
(Lba4) -C02-,
(Lba5) -OCO-,
(Lba6) -OC02-,
(Lba7) -SO-, -SOCH2-, -SOCH2CH2-, -CH2SO-, -CH2CH2SO-,
(Lba8) -S02-, -S02CH2-, -S02CH2CH2-, -CH2S02-, -CH2CH2S02-,
(Lba9) -OS02-,
(LbalO) -SO3-,
(Lball) -NR411-, -NR411CH2-, -NR411CH2CH2- , -CH2NR411-, -CH2CH2NR411-
(Lbal2) -CONR411-,
(Lbal3) -NR411CO-,
(Lbal4) -CSNR411-,
(Lbal5) -NR411CS-,
(Lbal6) -S02NR411-,
(Lbal7) -NR411S02-,
(Lbal8) -OCONR411-,
(Lbal9) -NR11C02-,
(Lba20) -NR411C0NR412- ,
(Lba21) -NR411CSNR412- ,
• (Lba22) -NR411S02NR412- (R411, R412 are the same or different and each is selected from the following (Lbaal)- (Lbaa3) ) , (Lbaal) hydrogen atom,
(Lbaa2) Cι-6 alkyl (said alkyl is optionally substituted by 1 to substituents selected from the following <Lbaaal>-<Lbaaal3>) , •<Lbaaal> halogen atom, •<Lbaaa2> C3-12 cycloalkyl, ■<Lbaaa3> hydroxyl, "<Lbaaa4> Cι-6 alkoxy, •<Lbaaa5> Ci-e alkylthio, •<Lbaaa6> aryloxy, ••<Lbaaa7> aralkyloxy, •<Lbaaa8> heterocyclyloxy, •<Lbaaa9> heterocyclyl-Cι_6 alkoxy r •"<LbaaalO> nitro,
• • •<Lbaaal1> amino ,
•••<Lbaaal2> cyano and
•"<Lbaaal3> 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] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <M1>-<M18>) , <M1> halogen atom, <M2> Ci-e alkyl, <M3> halo-Ci-e alkyl, <M4> aralkyl,
<M5> heterocyclyl-Ci-e alkyl, <M6> hydroxyl , <M7> Ci-e alkoxy, <M8> Ci-e alkylthio, <M9> aryloxy, <M10> aralkyloxy, <M11> heterocyclyloxy, <M12> heterocyclyl-Ci-e alkoxy, <M13> azido, <M14> nitro, <M15> amino, <M16> cyano, <M17> carboxyl and
<M18> -γ2-R41 (R41 is as defined above, and Y42 is selected from the following (Mai) - (Mal2) ) ,
(Mai) single bond,
(Ma2) -X41-,
(Ma3) -Z41-,
(Ma4) -Z1-Z42-,
(Ma5) -X41-Z41-,
(Ma6) -Z41-X41-, (Ma7) -X41-Z 1-X42-, (Ma8) -X1-Z41-Z42- , (Ma9) -Z41-X41-Z42-, (MalO) -Z 1-Z42-X41-, (Mall)
Z4,H or
(Mal2)
X^Z41H
(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 (Mabl) , (Mab3)-(Mab6) and Z43 is selected from the following (Macl) ,
(Mac3)-(Mac5) ) ,
••• (Mabl) Ci-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_ι2 cycloalkyl,
....<Maba3> hydroxyl , <Maba4> C__6 alkoxy, <Maba5> Cι_6 alkylthio,
....<Maba6> aryloxy,
•• • •<Maba7> aralkyloxy,
•• • •<Maba8> heterocyclyloxy,
••••<Maba9> heterocyclyl-C__6 alkoxy, <MabalO> nitro, <Maball> amino ,
....<Mabal2> cyano and
• •• •<Mabal3> carboxyl ;
•••(Mab4) C3_ι2 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>) ,
••<Mabbl> halogen atom,
••<Mabb2> d-6 alkyl,
••<Mabb3> halo-Cι_6 alkyl,
••<Mabb4> aralkyl,
••<Mabb5> heterocyclyl-Ci-e alkyl,
••<Mabb6> C3_ι2 cycloalkyl,
• •<Mabb7> hydroxyl , ••<Mabb8> Ci-e alkoxy, ••<Mabb9> Cι-6 alkylthio, ••<MabblO> aryloxy,
• •<Mabbl1> aralkyloxy, ••<Mabbl2> heterocyclyloxy, ••<Mabbl3> heterocyclyl-Ci-e alkoxy, -<Mabbl4> nitro, ••<Mabbl5> amino, ••<Mabbl6> cyano and
• ■<Mabbl7> carboxyl ;
• (Macl) Cχ_6 alkanetriyl (said alkanetriyl is optionally substituted by 1 to 3 substituents selected from the following <Macal>-<Macal3>) ,
"••<Macal> halogen atom, <Maca2> C3-_.2 cycloalkyl,
....<Maca3> hydroxyl , <Maca4> Cι-6 alkoxy, <Maca5> C__6 alkylthio ,
•■•■<Maca6> aryloxy, ••••<Maca7> aralkyloxy,
• • •■<Maca8> heterocyclyloxy, <Maca9> heterocyclyl-Ci-6 alkoxy, <MacalO> nitro,
• •• •<Macal1> amino, ••"<Macal2> cyano and •• ••<Macal3> carboxyl ; •••(Mac3) C3_i2 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>) , •• ••<Macbl> halogen atom, <Macb2> Ci-e alkyl , <Macb3> halo-Ci-e alkyl,
"••<Macb4> aralkyl,
•• ••<Macb5> heterocyclyl-Ci-6 alkyl ,
• •• •<Macb6> C3_i2 cycloalkyl , •• ••<Macb7> hydroxyl , <Macb8> Ci-6 alkoxy, <Macb9> Ci-e alkylthio,
••"<MacblO> aryloxy,
"••<Macbll> aralkyloxy,
•• ••<Macbl2> heterocyclyloxy,
•• • •<Macbl3> heterocyclyl-Ci-6 alkoxy, <Macbl4> nitro,
"••<Macbl5> amino,
....<Macbl6> cyano and
•• ••<Macbl7> carboxyl ;
[N] aryl,
[0] aralkyl,
[P] heterocyclyl,
[Q] heterocyclyl-Ci-e alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-Ci-6 alkyl are optionally, substituted by 1 to 3 substituents selected from the following <N1>-<N19>) ,
<N1> halogen atom,
<N2> Ci-e alkyl,
<N3> C3-12 cycloalkyl,
<N4> halo-Ci-6 alkyl,
<N5> aralkyl,
<N6> heterocyclyl-Ci-6 alkyl ,
<N7> hydroxyl,
<N8> Ci-e alkoxy,
<N9> Ci-e alkylthio,
<N10> aryloxy,
<N11> aralkyloxy,
<N12> heterocyclyloxy,
<N13> heterocyclyl-Ci-6 alkoxy,
<N14> nitro,
<N15> amino,
<N16> cyano,
<N17> =0,
<N18> carboxyl and
<N19> -γ42-R41 (R41 and Y42 are as defined above) ; [R] -Y41-R41 (R41 and Y41 are as defined above) , or [S]
Figure imgf000064_0001
(R42 ,and R43 are each independently selected from the following
(SI) -(S3) and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination,
• (SI) hydrogen atom,
• (S2) -Y1-R44 (R44 is selected from the following (Sal) and (Sa2) and Y41 is as defined above) ,
■ • (Sal) aryl and ••(Sa2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following
<Saal>-<Saal7>) ,
•••<Saal> halogen atom,
•••<Saa2> Cι_6 alkyl,
•••<Saa3> halo-Cι-6 alkyl,
•••<Saa4> aralkyl,
■••<Saa5> heterocyclyl-Ci-6 alkyl,
■"<Saa6> C3_ι2 cycloalkyl,
• • •<Saa7> hydroxyl , •"<Saa8> Cχ-6 alkoxy, •••<Saa9> Cι_6 alkylthio, •••<Saal0> aryloxy, •••<Saall> aralkyloxy, "'<Saal2> heterocyclyloxy,
• • •<Saal3> heterocyclyl-Ci-6 alkoxy ,
"•<Saal4> nitro,
•••<Saal5> amino,
•••<Saal6> cyano and -"<Saal7> 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>) , "<Scl> halogen atom, ••<Sc2> Ci-e alkyl, -<Sc3> halo-Cι-6 alkyl, ••<Sc4> aralkyl, ••<Sc5> heterocyclyl-Ci-e alkyl, ••<Sc6> C3-12 cycloalkyl,
• •<Sc7> hydroxyl , ••<Sc8> Ci-6 alkoxy, •■<Sc9> Ci-6 alkylthio, ••<SclO> aryloxy, ••<Scll> aralkyloxy, ••<Scl2> heterocyclyloxy, ••<Scl3> heterocyclyl-Cι-6 alkoxy, ••<Scl4> nitro, "<Scl5> amino, ••<Scl6> cyano and "<Scl7> 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] Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <L1>-<L14>) ,
<L1> halogen atom,
<L2> C3-χ2 cycloalkyl,
<L3> hydroxyl ,
<L4> Ci-e alkoxy,
<L5> Ci-6 alkylthio,
<L6> aryloxy,
<L7> aralkyloxy,
<L8> heterocyclyloxy,
<L9> heterocyclyl-Ci-6 alkoxy,
<L10> nitro,
<L11> amino,
<L12> cyano,
<L13> carboxyl and
<L14> ~γ1-R41' (R41' is selected from the following (La2) , (La5) and (La7) , Y41 is as defined in the above-mentioned (30)), ■•(La2) Cι_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laal0>, <Laal6> and <Laal9>) , •••<Laal> halogen atom, "•<Laa2> C3_ι2 cycloalkyl, • • -<Laa3> hydroxyl , ■<Laa4> aralkyloxy,
•<Laa5> heterocyclyloxy,
•<Laa6> heterocyclyl-Ci_6 alkoxy,
•<Laa7> nitro ,
><Laa8> cyano ,
■<Laa9> carboxyl ,
■<Laal0> Cι_6 alkoxy, aryloxy,
■ <Laal6> amino and
■ <Laal9> C_-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>) , ••<Labl> halogen atom, ■•<Lab2> Ci-6 alkyl, ■■<Lab3> halo-Cι-6 alkyl, ••<Lab4> aralkyl, ••<Lab5> heterocyclyl-Ci-e alkyl, ••<Lab6> C3_ι2 cycloalkyl, • •<Lab7> hydroxyl , ••<Lab8> Ci-6 alkoxy, ••<Lab9> aralkyloxy, ••<LablO> heterocyclyloxy, "<Labll> heterocyclyl-Ci-6 alkoxy, ••<Labl2> nitro, •■<Labl3> amino, ••<Labl4> cyano, ••<Labl5> carboxyl, ••<Labl9> aryloxy and ••<Lab28> Cι_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> Ci-e alkyl, <M3> halo-Cι-6 alkyl ,
<M4> aralkyl,
<M5> heterocyclyl-Ci-6 alkyl,
<M6> hydroxyl,
<M7> Ci-e alkoxy,
<M8> Ci-e alkylthio,
<M9> aryloxy,
<M10> aralkyloxy,
<M11> heterocyclyloxy,
<M12> heterocyclyl-Ci-6 alkoxy, •<M13> azido, •<M14> nitro, •<M15> amino, •<M16> cyano, .<M17> carboxyl and
•<M18> -γ2-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> Ci-e alkyl, •<N3> C3-ι2 cycloalkyl, •<N4> halo-Cχ-6 alkyl, ><N5> aralkyl,
•<N6> heterocyclyl-Ci-6 alkyl, •<N7> hydroxyl, •<N8> Ci-e alkoxy, •<N9> Ci-e alkylthio, -<N10> aryloxy, •<N11> aralkyloxy, •<N12> heterocyclyloxy, •<N13> heterocyclyl-Ci-6 alkoxy, •<N14> nitro, •<N15> amino, •<N16> cyano and •<N18> carboxyl;
[R] -Y41-R4 41
(R and Yr41 are as defined above) , or [S]
Figure imgf000069_0001
(R and R 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 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. (32) The compound of the above-mentioned (31) , wherein R1 is [A] hydrogen atom, [B] Ci-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> Ci-e alkoxy, •<B10> nitro, •<B11> amino, •<B12> cyano and -<B14> -X^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> Ci-6 alkyl,
•<C6> hydroxyl,
•<C7> Ci-e alkoxy,
•<C13> nitro, -<C14> amino,
•<C15> cyano,
•<C16> carboxyl and
•<C17> -X^R11 (R11 and X1 are as defined above) ;
R2' is [F] hydrogen atom,
[G] Ci-e 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-ι2 cycloalkyl, -<G3> hydroxyl,
•<G4> Cι_6 alkoxy,
•<G10> nitro,
•<G11> amino,
•<G12> cyano, -<G13> amido,
•<G16> -PO(OH)2,
•<G17> -PO(0-Cι_6 alkyl) 2 and
•<G18> -PO(0-aryl)2; or [H] C3_i2 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> Ci-e alkyl, •<H6> hydroxyl,
•<H7> Cι_6 alkoxy,
•<H13> nitro,
•<H14> amino, •<H15> cyano,
•<H16> amido,
•<H19> ~PO(OH)2,
•<H20> -P0(0-Cι_6 alkyl) 2 and
•<H21> -P0(0-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> Ci-6 alkyl, •<J6> hydroxyl, •<J7> Ci-6 alkoxy, •<J13> nitro, •<J14> amino and •<J15> cyano, •<J16> amido, ■<J19> -PO(OH)2, •<J20> -P0(0-Cι-6 alkyl) 2 and •<J21> -PO(0-aryl)2; R4' is
[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_i2 cycloalkyl, •<L3> hydroxyl, ■<L4> Ci-e alkoxy, •<L10> nitro, •<L11> amino and
•<L12> cyano;
[M] C3-i2 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> Ci-e alkyl,
•<M6> hydroxyl,
•<M7> Ci-6 alkoxy, -<M13> azido,
•<M14> nitro,
•<M15> amino,
■<M16> cyano and
•<M18> -γ42-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> Ci-e alkyl,
•<N7> hydroxyl,
•<N8> Ci-e alkoxy,
•<N14> nitro, '<N15> amino,
•<N16> cyano and
•<N18> carboxyl; or
[S]
Figure imgf000072_0001
(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] Ci-e 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-e 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> Ci-e alkyl,
•<V6> hydroxyl,
•<V7> Ci-e 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 salt thereof. (33) A DPP-IV inhibitor comprising a compound of the formula [I] , wherein R1 is
[A] hydrogen atom,
[B] Ci-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> Ci-e alkoxy,
<B5> Ci-e alkylthio,
<B6> aryloxy,
<B7> aralkyloxy,
<B8> heteroaryloxy,
<B9> heteroaryl-Cι-6 alkoxy ,
<B10> nitro,
<B11> amino,
<B12> cyano,
<B13> carboxyl and
<B14> -XX-R1:L (R11 is selected from the following (Bal) and (Ba2) , and X1 is selected from the following (Bbl)-(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>) , •••<Baal> halogen atom, "■<Baa2> Cι_6 alkyl, •••<Baa4> C3-ι2 cycloalkyl, ...<Baa7> hydroxyl, •••<Baa8> C.-6 alkoxy, •••<Baa9> Ci-6 alkylthio, •••<BaalO> aryloxy, ■••<Baall> aralkyloxy, •••<Baal2> heteroaryloxy,
■ ••<Baal3> heteroaryl-Ci-6 alkoxy, •••<Baal4> nitro, •••<Baal5> amino, •■■<Baal6> cyano and •••<Baal7> carboxyl; ••(Bbl) single bond, •• (Bb2) -0-, •• (Bb3) -S-, -(Bb4) -NH-,
•• (Bb5) -CO-, ••(Bbl3) -CONH-, •• (Bbl4) -NHCO-, •• (Bbl5) -CSNH-, -(Bbl6) -NHCS-, •• (Bbl7) -NHS02-, ••(Bbl8) -S02NH-,
■ • (Bbl9 ) -NHC02- , •• (Bb20) -OCONH-, •• (Bb21) -NHCONH- and •• (Bb22) -NHCSNH-;
[C] C3_ι2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>, <C2> and <C6>-<C17>) , -<C1> halogen atom, •<C2> Ci-e alkyl, •<C6> hydroxyl, •<C7> Ci-6 alkoxy, ■<C8> Ci-e alkylthio,
<C9> aryloxy,
<C10> aralkyloxy,
<C11> heteroaryloxy,
<C12> heteroaryl-Cι-6 alkoxy ,
<C13> nitro , •<C14> amino,
•<C15> cyano,
•<C16> carboxyl and
•<C17> -X^R11 (R11 and X1 are as defined above) ;
[D] -X^R11 (Ru and X1 are as defined above) or
[E]
Figure imgf000076_0001
(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, • (El) hydrogen atom,
• (E2) -X12-R14 (R is selected from the following (Eal) and (Ea2) , and X12 is selected from the following (Ebl)-(Eb5), (Ebl3) - (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> C_.-6 alkyl,
•••<Eaa3> halo-C_.-6 alkyl,
•■•<Eaa4> C3_ι2 cycloalkyl,
•••<Eaa7> hydroxyl,
•••<Eaa8> C_-6 alkoxy,
•••<Eaa9> Cι_6 alkylthio,
■■•<Eaal0> aryloxy,
"■<Eaall> aralkyloxy,
• • • <Eaal2> heteroarylox , ••.•<Eaal3> heteroaryl-Ci-6 alkoxy, •••<Eaal4> nitro, •••<Eaal5> amino,
■••<Eaal6> cyano and
•••<Eaal7> carboxyl;
••(Ebl) single bond,
•• (Eb2) -0-,
•• (Eb3) -S-,
•• (Eb4) -NH-,
•• (Eb5) -CO-,
•• (Ebl3) -CONH-,
•• (Ebl4) -NHCO-,
•• (Ebl5) -CSNH-,
••(Ebl6) -NHCS-,
••(Ebl7) -NHS02-,
••(Ebl8) -S02NH-, -(Ebl9) -NHC02-,
•• (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>) , "<Ecl> halogen atom, -<Ec2> Ci-e alkyl, ••<Ec3> halo-Cι-6 alkyl, ••<Ec4> C3-ι2 cycloalkyl,
• •<Ec7> hydroxyl , ••<Ec8> Ci-e alkoxy, ••<Ec9> Ci-e alkylthio, •■<EclO> aryloxy, "<Ecll> aralkyloxy, ••<Ecl2> heteroaryloxy, , • •<Ecl3> heteroaryl-Ci-6 alkoxy, ••<Ecl4> nitro, ••<Ecl5> amino, ••<Ecl6> cyano and "<Ecl7> carboxyl; R2 is
[F] hydrogen atom,
[G] Ci-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> Ci-e alkoxy, •<G5> Ci-e alkylthio, -<G6> aryloxy, •<G7> aralkyloxy, •<G8> heteroaryloxy, •<G9> heteroaryl-Ci-6 alkoxy, •<G10> nitro, -<G11> amino, •<G12> cyano, •<G13> amido, •<G14> =0,
•<G15> carboxyl and -<G16> -PO(OH)2; or
[H] C3_ι2 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-e alkyl,
<H6> hydroxyl,
<H7> Ci-e alkoxy,
<H8> Ci-e alkylthio, •<H9> aryloxy,
•<H10> aralkyloxy,
•<H11> heteroaryloxy,
• <H12> heteroaryl-Cι-6 alkoxy ,
•<H13> nitro,
•<H14> amino,
•<H15> cyano,
•<H16> amido,
•<H17> =0,
•<H18> carboxyl and
•<H19> -PO(OH)2;
R3 is
[I] Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <ll>-<116>) , -<I1> halogen atom,
•<I2> C3-12 cycloalkyl,
•<I3> hydroxyl,
•<I4> Ci-e alkoxy,
•<I5> Ci-e alkylthio, «<I6> aryloxy,
•<I7> aralkyloxy,
•<I8> heteroaryloxy,
•<I9> heteroaryl-Ci-6 alkoxy,
•<I10> nitro, -<I11> amino,
•<I12> cyano,
•<I13> amido,
•<I14> =0,
•<I15> carboxyl and -<I16> -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> Ci-e alkyl, •<J6> hydroxyl,
•<J7> Ci-e alkoxy, -<J8> Ci-6 alkylthio, •<J9> aryloxy, •<J10> aralkyloxy, •<J11> heteroaryloxy, •<J12> heteroaryl-Ci-6 alkoxy, -<J13> nitro, •<J14> amino, •<J15> cyano, •<J16> amido,
•<J17> =0, ' . -<J18> carboxyl and ■<J19> -PO(OH)2;
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>-<L14>) ,
<L1> halogen atom,
<L2> C3-12 cycloalkyl,
<L3> hydroxyl,
<L4> Ci-e alkoxy,
<L5> Ci-e alkylthio,
<L6> aryloxy,
<L7> aralkyloxy,
<L8> heteroaryloxy,
<L9> heteroaryl-Ci-6 alkoxy ,
<L10> nitro,
<L11> amino,
<L12> cyano,
<L13> carboxyl and
<L14> -γ41-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>) ,
•<Labl> halogen atom,
•<Lab2> Cι_6 alkyl,
•<Lab6> C3_ι2 cycloalkyl,
•<Lab7> hydroxyl,
•<Lab8> Ci-6 alkoxy,
•<Lab9> aralkyloxy,
•<LablO> heteroaryloxy,
•<Labll> heteroaryl-Ci-6 alkoxy,
•<Labl2> nitro,
•<Labl3> amino,
•<Labl4> cyano,
•<Labl5> carboxyl,
•<Labl9> aryloxy and
•<Lab28> Ci-e alkylthio;
(Lbl) single bond and
(Lb2) X41 (X41 is selected from the following (Lbal)- (Lba3) and (Lball) -(Lba21)) , (Lbal) -0-, (Lba2) -S-, (Lba3) -CO-, (Lball) ~NR411-, (Lbal2) -CONR411-, (Lbal3) -NR411CO-,
Figure imgf000081_0001
(Lbal7) -NR ,44111S,02-, (Lbal8) -OCONR411-,
(Lbal9) -NR 44111iC,02- • • • (Lba20 ) -NR411CONR412- and
• • • (Lba21) -NR 11CSNR412- (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> Cχ-6 alkyl ,
<M6> hydroxyl,
<M7> Ci-6 alkoxy,
<M8> Ci-e alkylthio,
<M9> aryloxy,
<M10> aralkyloxy,
<M11> heteroaryloxy,
<M12> heteroaryl-Ci-6 alkoxy,
<M14> nitro,
<M15> amino,
<M16> cyano,
<M17> carboxyl and
<M18> -γ42-R41 (R41 is as defined above, and Y42 is selected from the following (Mai) and (Ma2)), (Mai) single bond and (Ma2) X41 (X41 are as defined above) ; [N] aryl, [0] aralkyl, [P] 3 to 7-membered saturated heterocycle or heteroaryl, [Q] heteroaryl-Ci-6 alkyl (said aryl, aralkyl, saturated heterocycle, heteroaryl and heteroaryl-Ci-6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <N1>-<N3>, <N7>-<N16> and <N18>) , -<N1> halogen atom, •<N2> Ci-e alkyl, •<N3> C3-i2 cycloalkyl, ■<N7> hydroxyl, •<N8> Ci-e alkoxy, •<N9> Ci-e alkylthio, •<N10> aryloxy, •<N11> aralkyloxy, •<N12> heteroaryloxy, •<N13> heteroaryl-Ci-6 alkoxy, •<N14> nitro, •<N15> amino, ■<N16> cyano and •<N18> carboxyl; [R] R1-Y41- (R41 and Y41 are as defined above) , or [S]
Figure imgf000083_0001
(R42 and R43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination,
• (SI) hydrogen atom,
• (S2) -γ411-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> and <Saa6>-<Saal7>) ,
•••<Saal> halogen atom, "-<Saa2> Ci-e alkyl,
•••<Saa3> halo-Cι-6 alkyl,
■"<Saa6> C3-12 cycloalkyl,
■••<Saa7> hydroxyl,
•"<Saa8> Ci-6 alkoxy,
•"<Saa9> Ci-e alkylthio,
•••<SaalO> aryloxy, ••<Saall> aralkyloxy, ••<Saal2> heteroaryloxy, ••<Saal3> heteroaryl-Ci-6 alkoxy, ••<Saal4> nitro, ••<Saal5> amino, ••<Saal6> cyano and ••<Saal7> carboxyl;
• (Lbl) single bond and
• (Lb2) X411 (X411 is selected from the following (Lbal) - (Lba3) , (Lball) -(Lba21) and (Lba23) ) ,
(Lbal) -0-, (Lba2) -S-, (Lba3) -CO-, (Lball) -NR411-,
(Lbal 2) -CONR' 411
Figure imgf000084_0001
(Lbal4) -CSNR 4^111-
Figure imgf000084_0002
(Lbal 6) -S02NR' 411
(Lbal 7) -NR 4*111XS,02-,
(Lbal 8) -OCONR 4'11 (Lbal9) -NR411C02-, (Lba20) -NR411C0NR412- ,
(Lba21) -NR411CSNR4 - (R4 , R4iZ 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>) ,
••<Scl> halogen atom, ••<Sc2> Cι_6 alkyl, ■•<Sc3> halo-Cι_6 alkyl, • •<Sc6> C3_i2 cycloalkyl, ••<Sc7> hydroxyl,
• •<Sc8> Cι_6 alkoxy, ••<Sc9> Cι_6 alkylthio, ••<SclO> aryloxy, "<Scll> aralkyloxy, ••<Scl2> heteroaryloxy, ••<Scl3> heteroaryl-Ci-6 alkoxy, "<Scl4> nitro,
••<Scl5> amino, "<Scl6> cyano and "<Scl7> carboxyl, or a salt thereof. (34) A compound represented by the formula [IV]
Figure imgf000085_0001
wherein R1 ' 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> Ci-e alkoxy, -<B5> Ci-e alkylthio,
•<B6> aryloxy,
•<B7> aralkyloxy,
•<B8> heteroaryloxy,
• <B9> heteroaryl-Cι_6 alkoxy , -<B10> nitro ,
■<Bll> amino, •<B12> cyano and
•<B14> -X^-R11 (R11 is selected from the following (Bal) and (Ba2) , and X1 is selected from the following (Bbl)-(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>)
•••<Baal> halogen atom,
•••<Baa2> Ci_6 alkyl,
•••<Baa4> C-ι2 cycloalkyl,
• • •<Baa7> hydroxyl , •••<Baa8> Cι_6 alkoxy, •••<Baa9> Cι-6 alkylthio, •••<BaalO> aryloxy,
• ••<Baal1> aralk loxy, •••<Baal2> heteroaryloxy, •••<Baal3> heteroaryl-Ci-6 alkoxy, •••<Baal4> nitro,
• • •<Baal5> amino, •••<Baal6> cyano and •••<Baal7> carboxyl; ••(Bbl) single bond, •• (Bb2) -0-,
•• (Bb3) -S-, •• (Bb4) -NH-, •• (Bb5) -CO-, •• (Bbl3) -CONH-, •• (Bbl4) -NHCO-, - (Bbl5) -CSNH-, •• (Bbl6) -NHCS-, ••(Bbl7) -NHS02-, ■•(Bbl8) -S02NH-, •• (Bbl9) -NHC02-, • • (Bb2'0 ) -OCONH- , • • (Bb21 ) -NHCONH- and
• • (Bb22 ) -NHCSNH- ;
[C] C3-i2 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> Ci-e alkoxy,
•<C8> Ci-6 alkylthio, •<C9> aryloxy, •<C10> aralkyloxy, •<C11> heteroaryloxy, «<C12> heteroaryl-Ci-6 alkoxy, •<C13> nitro, •<C14> amino, •<C15> cyano and •<C17> -X^R11 (R11 and X1 are as defined above) ;
[D] -X^-R11 (R and X1 are as defined above) or [E]
Figure imgf000087_0001
(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, • (El) hydrogen atom,
• (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2) , and X12 is selected from the following (Ebl)-(Eb5), (Ebl3) - (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>) , •••<Eaal> halogen atom, •••<Eaa2> Ci_6 alkyl, •••<Eaa3> halo-Cι-6 alkyl,
• • •<Eaa4> C3-ι2 cycloalkyl , •••<Eaa7> hydroxyl, •••<Eaa8> Cι_6 alkoxy, ••■<Eaa9> Ci-e alkylthio, •••<EaalO> aryloxy, •••<Eaall> aralkyloxy,
• • •<Eaal2> heteroaryloxy, •••<Eaal3> heteroaryl-Ci-6 alkoxy, •••<Eaal4> nitro,
•••<Eaal5> amino,
•••<Eaal6> cyano and
•••<Eaal7> carboxyl;
••(Ebl) single bond,
•• (Eb2) -0-,
- (Eb3) -S-,
•• (Eb4) -NH-,
•• (Eb5) -CO-,
•• (Ebl3) -CONH-,
•• (Ebl4) -NHCO-,
•■ (Ebl5) -CSNH-,
•■ (Ebl6) -NHCS-,
•• (Ebl7) -NHS02-,
••(Ebl8) -S02NH-,
•■ (Ebl9) -NHC02-,
•• (Eb20j -0C0NH-,
•• (Eb21) -NHC0NH-,
"(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>) ,
••<Ecl> halogen atom,
••<Ec2> Cι_6 alkyl,
••<Ec3> halo-Cι-6 alkyl,
••<Ec4> C3_ι2 cycloalkyl, "<Ec7> hydroxyl,
••<Ec8> Ci-e alkoxy,
•■<Ec9> Ci-e alkylthio,
••<Ecl0> aryloxy,
••<Ecll> aralkyloxy, "<Ecl2> heteroaryloxy,
••<Ecl3> heteroaryl-Ci-6 alkoxy,
••<Ecl4> nitro,
••<Ecl5> amino,
••<Ecl6> cyano and "<Ecl7> carboxyl;
R2 ' is selected from the following [F]-[H]:
[F] hydrogen atom,
[G] Cι_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> Ci-e alkoxy,
■<G5> Ci-6 alkylthio, -<G6> aryloxy,
•<G7> aralkyloxy,
•<G8> heteroaryloxy,
• <G9> heteroaryl-Ci-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> Ci-6 alkyl,
•<H6> hydroxyl,
•<H7> Ci-e alkoxy,
•<H8> Ci-e alkylthio,
■<H9> aryloxy,
•<H10> aralkyloxy,
•<H11> heteroaryloxy, •<H12> heteroaryl-Ci-6 alkoxy,
•<H13> nitro,
•<H14> amino and
•<H15> cyano;
R3 ' is the following [J] : [J] C3_i2 cycloalkyl (said cycloalkyl is optionally substituted by
1 to 3 substituents selected from the following <J1>, <J2> and
<J6>-<J15>) ,
•<J1> halogen atom,
•<J2> Ci-6 alkyl, -<J6> hydroxyl,
•<J7> Ci-e alkoxy,
•<J8> Ci-e alkylthio,
•<J9> aryloxy,
•<J10> aralkyloxy,
•<J11> heteroaryloxy,
• <J12> heteroaryl-Cι_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] Ci-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> Ci-6 alkoxy,
<L5> Ci-e alkylthio,
<L6> aryloxy,
<L7> aralkyloxy,
<L8> heteroaryloxy,
<L9> heteroaryl-Ci-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> Ci_6 alkyl,
•••<Lab6> C3_ι2 cycloalkyl, • • •<Lab7> hydroxyl , •••<Lab8> Cι_6 alkoxy, •••<Lab9> aralkyloxy, •••<LablO> heteroaryloxy, "•<Labll> heteroaryl-Ci-6 alkoxy, ■••<Labl2> nitro, •••<Labl3> amino, •••<Labl4> cyano, ■<Labl5> carboxyl, •<Labl9> aryloxy and •<Lab28> Ci-e alkylthio; (Lbl) single bond and
(Lb2) X41 (X41 is selected from the following (Lbal)- (Lba3) and (Lball) - (Lba21) ) ,
(Lbal) -0-,
(Lba2) -S-,
(Lba3) -CO-,
(Lball) -NR411-,
Figure imgf000092_0001
(Lbal3) NR411CO-,
Figure imgf000092_0002
(Lbal6) S02NR411- , (Lbal7) NR411S02- ,
(Lbalδ ) -OCONR 4*11 - ,
(Lbal9 ) -NR411C02- ,
(Lba20) -NR411C0NR412- and
(Lba21 ) -NR4nCSNR412- (R411 , R ,4"11"2 are each hydrogen atom) ; [M] C3-ι2 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> Ci-e alkyl, •<M6> hydroxyl, •<M7> Ci-e alkoxy, •<M8> Ci-e alkylthio, •<M9> aryloxy, •<M10> aralkyloxy, •<M11> heteroaryloxy, ■<M12> heteroaryl-Ci-6 alkoxy, •<M14> nitro, •<M15> amino, •<M16> cyano and
•<M18> -γ42-R41' (R41' is as defined above, and Y42 is as defined for 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> Ci-e alkyl,
•<N3> C3-12 cycloalkyl, -<N7> hydroxyl,
•<N8> Ci-6 alkoxy,
•<N9> Ci-e alkylthio,
•<N10> aryloxy,
•<N11> aralkyloxy, «<N12> heteroaryloxy,
•<N13> heteroaryl-Ci-6 alkoxy,
•<N14> nitro,
•<N15> amino,
•<N16> cyano and -<N18> carboxyl;
[R] -γ41-R41' (R41' and Y41 are as defined above), or
[S]
Figure imgf000093_0001
(R42 and R43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to 3) formed by R4' and R5 ' in combination,
■ (SI) hydrogen atom,
■ (S2) -Y4U-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> and <Saa6>-<Saal7>) , •<Saal> halogen atom, •<Saa2> Ci-e alkyl, •<Saa3> halo-Cι-6 alkyl, •<Saa6> C3-ι2 cycloalkyl, •<Saa7> hydroxyl, •<Saa8> Cι_6 alkoxy, •<Saa9> Ci-6 alkylthio, •<SaalO> aryloxy, •<Saall> aralkyloxy, •<Saal2> heteroaryloxy, •<Saal3> heteroaryl-Ci-6 alkoxy, •<Saal4> nitro, •<Saal5> amino, •<Saal6> cyano and •<Saal7> carboxyl (Lbl) single bond and
(Lb2) X411 (X411 is selected from the following (Lbal) - (Lba3) , (Lball) -(Lba21) and (Lba23) ) ,
(Lbal) -0-,
(Lba2) -S-,
(Lba3) -CO-,
(Lball) -NR411-,
(Lbal2) -CONR411-,
(Lbal3) -NR411CO-,
(Lbal4) -CSNR411-,
(Lbal5) -NR411CS-,
(Lbal6) -S02NR411-,
(Lbal7) -NR411S02-,
(Lbal8) -OCONR411-,
(Lbal9) -NR411C02-,
(Lba20 ) -NR 11CONR412- , % "-(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>) ,
••<Scl> halogen atom, -<Sc2> Ci-6 alkyl,
■•<Sc3> halo-Cι-6 alkyl,
••<Sc6> C3-ι2 cycloalkyl,
• •<Sc7> hydroxyl ,
••<Sc8> Ci-e alkoxy, -<Sc9> Ci-6 alkylthio,
••<SclO> aryloxy,
"<Scll> aralkyloxy,
••<Scl2> heteroaryloxy,
••<Scl3> heteroaryl-Ci-6 alkoxy, -<Scl4> nitro,
••<Scl5> amino,
••<Scl6> cyano and
••<Scl7> carboxyl; provided that, when R1' and R2' are hydrogen atoms and R3' is cyclopropyl , then the combination of one of R ' 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.
(35) A compound of the formula [IV] , wherein
R1' is
[A] hydrogen atom, [B] Ci-e 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-ι2 cycloalkyl,
•<B3> hydroxyl,
•<B4> Ci-e alkoxy,
•<B10> nitro,
•<B11> amino,
•<B12> cyano and
•<B14> -X^R11 (R11 is selected from the following (Bal) and (Ba2) ,
X1 is selected from the following (Bbl)-(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>, <Baa7>, <Baa8> and <Baal4>-<Baal7>) •••<Baal> halogen atom, •••<Baa2> Cι_6 alkyl,
• • •<Baa4> C3_i2 cycloalkyl ,
• • •<Baa7> hydroxyl , •■•<Baa8> Cι_6 alkoxy, •••<Baal4> nitro, •••<Baal5> amino, •••<Baal6> cyano and
• • •<Baal7> carboxyl ; ••(Bbl) single bond, •• (Bb2) -0-, •• (Bb3) -S-, •• (Bb4) -NH-, •• (Bb5) -CO-, •• (Bbl3) -CONH-, ■■ (Bbl4) -NHCO-, •• (Bbl5) -CSNH-, ••(Bbl6) -NHCS-, • • (Bbl 7 ) -NHS02- ,
• • (Bbl8 ) -SO2NH- ,
• • (Bbl9 ) -NHCO2- , • • (Bb20 ) -OCONH- , • • (Bb21) -NHCONH- and
- (Bb22 ) -NHCSNH- ;
[C] C3_i2 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> Ci-e alkyl,
•<C6> hydroxyl,
•<C7> Ci-6 alkoxy,
•<C13> nitro, -<C14> amino,
•<C15> cyano and
•<C17> -X^R11 (R11 and X1 are as defined above) ; or
[E]
Figure imgf000097_0001
(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 R4' in combination,
• (El) hydrogen atom, • (E2) -X12-R14 (R14 is selected from the following (Eal) and (Ea2) , and X12 is selected from the following (Ebl)-(Eb5), (Ebl3)- (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> Ci_6 alkyl, •••<Eaa3> halo-Cι-6 alkyl, •••<Eaa4> C3_ι2 cycloalkyl,
• • •<Eaa7> hydroxyl ,
• ■•<Eaa8> Cι_6 alkoxy, "■<Eaal4> nitro,
• • •<Eaal5> amino , •••<Eaal6> cyano and •••<Eaal7> carboxyl; •• (Ebl) single bond, •• (Eb2) -0-,
•• (Eb3) -S-,
- (Eb4) -NH-, •• (Eb5) -CO-,
- (Ebl3) -CONH-,
- (Ebl4) -NHCO-, ■• (Ebl5) -CSNH-, •• (Ebl6) -NHCS-, •• (Ebl7) -NHS02-, •• (Ebl8) -SOzNH-, " (Ebl9) -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>, <Ec7>, <Ec8> and <Ecl4>-<Ecl7>) ,
■•<Ecl> halogen atom, •*<Ec2> Ci-e alkyl, ••<Ec3> halo-Cι-6 alkyl, " <Ec4> C3_i2 cycloalkyl ,
• • <Ec7> hydroxyl , • • <Ec8> Cι_6 alkoxy , • • <Ecl4> nitro , " <Ecl5> amino , • • <Ecl6> cyano and • • <Ecl7> carboxyl ; R2 ' is
[F] hydrogen atom,
[G] Ci-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> Ci-e 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> Ci-e alkyl,
•<H6> hydroxyl, -<H7> Ci-e alkoxy,
•<H13> nitro,
•<H14> amino and
•<H15> cyano;
R3' is
[J] C3_i2 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> Ci-6 alkyl, •<J6> hydroxyl,
■<J7> Ci-6 alkoxy,
•<J13> 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> Ci-e 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> Ci-e alkyl,
•<M6> hydroxyl,
•<M7> Ci-e alkoxy, -<M14> nitro,
•<M15> amino and
•<M16> cyano; or
[S]
Figure imgf000100_0001
(R42 and R43 are each independently selected from the following (Si) -(S3) , and m and n are each independently an integer of 0 to 3) formed by R4' and R5' in combination,
• (SI) hydrogen atom, • (S2) -Y11-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>) , ■<Saal> halogen atom, ■<Saa2> Ci-e alkyl, ■<Saa3> halo-Cι-6 alkyl, ■<Saaβ> C3_i2 cycloalkyl, ■<Saa7> hydroxyl, •<Saa8> Ci-6 alkoxy, •<Saal4> nitro, •<Saal5> amino, •<Saal6> cyano and ■<Saal7> carboxyl (Lbl) single bond and
(Lb2) X411 (X411 is selected from the following (Lbal) - (Lba3) , (Lball) -(Lba21) and (Lba23) ) ,
(Lbal ) -0- ,
(Lba2 ) -S- ,
(Lba3 ) -CO- ,
(Lball) -NR411- ,
(Lbal2 ) -CONR411- ,
(Lbal3) -NR411CO- ,
(Lbal4) -CSNR411- ,
(Lbal5) -NR 11CS- ,
(Lbal 6 ) -S02NR411- ,
(Lbal 7 ) -NR411S02- ,
(Lbal8 ) -OCONR411- , ■•(Lbal9) -NR411C02-, ■ • ( ba20) -NR411CONR412- ,
■•(Lba21) -NR11CSNR412- (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>) , •■<Scl> halogen atom, ••<Sc2> Ci-e alkyl, ••<Sc3> halo-Cι-6 alkyl, ••<Sc6> C3-12 cycloalkyl, ••<Sc7> hydroxyl, •■<Sc8> Ci-6 alkoxy, ••<Scl4> nitro, ••<Scl5> amino, ••<Scl6> cyano and ••<Scl7> carboxyl; 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.
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, R1 is preferably hydrogen atom, C__6 alkyl or C3-12 cycloalkyl, more preferably hydrogen atom, C_- alkyl, C3-6 cycloalkyl or adamantyl, particularly preferably hydrogen atom.
R2 is preferably hydrogen atom, Cι_6 alkyl or C3-12 cycloalkyl, particularly preferably C1-4 alkyl.
R3 is preferably Cι_e alkyl or G3_ι2 cycloalkyl, particularly preferably C3-5 cycloalkyl.
R4 is preferably hydrogen atom, C_-6 alkyl or CV12 cycloalkyl (cycloalkyl is preferably further substituted by -Y42-R41) , particularly preferably substituted C3-12 cycloalkyl. R5 is preferably hydrogen atom, Cι_e alkyl or C3-ι2 cycloalkyl, particularly preferably hydrogen atom.
Of R1, R4 and R5, at least one is preferably a group other than hydrogen atom, and the group is preferably Cι_4 alkyl, C3-e 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 "Ci-e 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 Cι_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 "C3-12 cycloalkyl Cι-6 alkyl" means a group wherein the • aforementioned "Cι_6 alkyl" is substituted by the aforementioned "C3_i2 cycloalkyl", such as cyclopropylmethyl , cyclobutylmethyl , cyclopentylmethyl , cyclohexylmethyl , cycloheptylmethyl , adamantylme hyl , cyclopropylethyl, cyclobutylethyl, cyclopentylethyl , cyclohexylethyl , cycloheptylethyl , adamantylethyl and the like.
The "Ci-e 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 Cι-4 alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy.
The "Ci-e 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 Cι-_ alkylthio selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio and tert-butylthio. The "Ci-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-l , 1-diyl and the like, with preference given to Cι_4alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethane-1, 1-diyl, 1-methylethane-l, 1-diyl and the like.
The "C2-6 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 "C3-12 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 "Ci-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-l , 1 , 2-triyl , propane-1 ,1 ,1- triyl, butane-1 , 1 , 4-triyl, butane-1 ,2 ,4-triyl, butane-1 ,1 , 1-triyl, pentane-1,3 ,5-triyl, hexane-1 , 3 , 6-triyl and the like, with preference given to Cι_4alkanetriyl.
The "C2-6 alkenetriyl" is a straight chain or branched chain alkenetriyl having 2 to 6 carbon atoms , such as
/ /
—CH=C —CH=CH—HC -CH^-CH=C
and the like, with preference given to C2-4 alkenetriyl.
The "C3-i2 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 "Cι_ 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 "Ci- 6alkoxy" is substituted by the aforementioned "aryl". For example, benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3-phenylpropoxy, 2-phenylpropoxy, 4-phenylbutoxy, indenylmethoxy, naphthylmethoxy, 2-naphthylethoxy, 4-biphenylmethox , 3- (4-biphenyl) propoxy, 2,3- dihydroindenylmethoxy, 1,2,3,4-tetrahydronap thylmethoxy 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, pyrazolylox , isoxazolyloxy, isothiazolyloxy , oxadiazolyloxy, triazolyloxy, indolyloxy, tetrazolyloxy, berizofuryloxy, benzothienyloxy, benzimidazolyloxy, benzoxazolyloxy, benzothiazolyloxy , pyridyloxy, pyrimidinyloxy, pyridazinyloxy, pyrazinyloxy, guinolyloxy, isoquinolyloxy and the like, with preference given to benzofuryloxy, benzothienyloxy, ■ enzimidazolyloxy, benzoxazolyloxy, benzothiazolylox , 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-Ci-6 alkyl" is a group wherein the aforementioned "C_-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 , indolyle hyl , benzofurylmethyl, benzofurylethyl , benzothienylmethyl, benzothienylethyl , benzimidazolylmethyl, benzimidazolylethyl , benzoxazolylmethyl, benzoxazolylethyl, benzothiazolylmethyl, benzothiazolylethyl, pyridyl ethyl , pyridylethyl , pyrimidinylmethyl , pyri idinylethyl , pyridazinylmethyl, pyridazinylethyl, pyrazinylmethyl, pyrazinylethyl, quinolylmethyl , quinolylethyl , isoquinolylmethyl , isoquinolylethyl and the like can be mentioned.
The "heteroaryl-Ci-6 alkoxy" is a group wherein the aforementioned "Cι_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, pyrimidinylmethox , pyrimidinylethox , pyridazinylmethoxy, pyridazinylethoxy, pyrazinylmethoxy, pyrazinylethoxy, quinolylmethoxy, quinolylethoxy, isoquinolyl ethoxy, isoquinolylethoxy and the like can be mentioned.
The "halo-Cι-6 alkyl" is a haloalkyl wherein the aforementioned "Cι_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-Cι_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-Ci_2 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, guinolizine, 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- tetrahydrobenzi idazole 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-Ci-e alkyl" is a group wherein the aforementioned "Cι_6 alkyl" is substituted by the aforementioned "heterocyclyl", and, for example, those exemplified as the aforementioned "heteroaryl-Ci_6 alkyl" can be -mentioned. The "heterocyclyl-Cι_6 alkyl" is preferably the aforementioned "heteroaryl-Ci-6 alkyl".
The "heterocyclyl-Ci-6 alkoxy" is a group wherein the aforementioned "C__6 alkoxy" is substituted by the aforementioned "heterocyclyl".. For example, those exemplified as the aforementioned "heteroaryl-Ci-e alkoxy" can be mentioned. The "heterocyclyl-Ci-6 alkoxy" is preferably the aforementioned "heteroaryl-Cι_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, Cι-6 alkyl or aryl) . For example, formamido, acetamido, propaneamido , butaneamido, pentaneamido , hexaneamido, benza ido 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 aspartate, 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) , -glucosidase inhibitor, insulin sensitivity enhancer, PPARα receptor agonist, PPARγ receptor agonist/antagonist, PPARδ* receptor agonist, tGLP-1 receptor agonist, glucagon receptor antagonist, glucocorticoid receptor antagonist, biguanide, SGLUT inhibitor, fructose-l,6-bisphosphatases (FBPase) inhibitor, glycogen synthase kinase 3 (GSK-3) inhibitor, phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, protein tyrosine phosphatase IB (PTPase IB) inhibitor, SH2 domain-containing inositol phosphatase (SHIP2) inhibitor, AMP-activated protein kinase (AMPK) activator, glycogen phosphorylase (GP) inhibitor, glucokinase activator, llβ- 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, β3 adrenaline receptor agonist, apolipoprotein-Al (Apo-Al) 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 (ACCl) inhibitor, acetyl-CoA carboxylase 2 (ACC2) inhibitor, melanocortin (MC) receptor agonist, neuropeptide Y5 (NPY5) receptor antagonist, adiponectin receptor agonist, protein kinase β (PKCβ) 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
Figure imgf000116_0001
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-dime hylformamide, 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 l-ethyl-3- (3- 5 dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, 0-benzotriazol-l-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 5 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 then0 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-0 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
Figure imgf000118_0001
step 1 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
Figure imgf000119_0001
11 12
wherein R " is hydrogen atom or C1-5 alkyl, and R is as defined above .
Compound (12) , which is a compound (6) wherein R2 is Cι-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
Figure imgf000119_0002
6 14 16
Figure imgf000119_0003
wherein Rp1 is an amino protecting group such as tert- butoxycarbonyl, benzyloxycarbonyl and the like, L2 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 Rp1, and a conventional deprotection method can be used. For example, when Rp1 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, sulf ric acid, trifluoroacetic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. A solvent such as ethanol, methanol, tetrahydrof ran, 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, Rp1 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, Rp1 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, Rp1 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
Figure imgf000121_0001
wherein
(R4)J is, of the parts represented by R , a part that is bonded to
and also adj acent to -CONR4 - ,
Figure imgf000121_0003
, -CSNR ,441i1- , -
Figure imgf000121_0002
NR 11CS- , -NR US02- , -S02NR411- , -NR 11C02- , -OCONR411- , -NR4UCONR' 412
or -NR ,411C,Sr,N,ττR-,4"12-, ((R41)) is, of the parts represented by R% a part . on the end via -CONR411-, -NR411CO-r -CSNR411-, .-NR11CS-, -NR411S02-, -S02NR411-, -NR411C02-, -OCONR411-, -NR411C0NR41Z- or -NR11CSNR412- , R411 • is hydrogen atom or optionally substituted Cι_6alkyl, R411" is optionally substituted Cι_6alkyl, and other symbols are as defined 5 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,5 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 0 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 compound0 (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
Figure imgf000123_0001
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
Figure imgf000123_0002
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
Figure imgf000124_0001
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
Figure imgf000124_0002
wherein L 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 tetrahydrof ran, 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
Figure imgf000125_0001
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 t iethylamine, 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 R411 is optionally substituted Cι_ 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
Figure imgf000126_0001
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
Figure imgf000127_0001
21 wehrien R412 ' is hydrogen atom or optionally substituted Cι_6alkyl, R4i2„ ^s optionally substituted C_-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 Cι_ 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
Figure imgf000128_0001
wherein each symbol is as defined above.
Of compounds (45) , when compound (47) wherein R ,4"11 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
Figure imgf000128_0002
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 C_._ 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
Figure imgf000129_0001
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
R
Figure imgf000129_0002
52 53 54 55 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. 5 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 Rp1 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, 5 methanol, tetrahydrof ran, 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 and0 using compound (54) and compound (6) . Scheme 17
Figure imgf000130_0001
58 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 m thoxymethyl triphenylphosphonium chloride, dimethyl (l-diazo-2- oxopropyl)phosphonate and the like in the presence of a base. A 5 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 in5 the reaction such as tetrahydrof ran, 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 the0 like in the presence of a base. A base such as sodium dimsyl, n- butyl lithium, 1 , 8-diazabicyclo [5. .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.5 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 as0 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
Figure imgf000132_0001
59 60
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
Figure imgf000132_0002
60 62
wherein ((R4)) is, of the parts represented by R , a part that is
bonded to and also adjacent to -CH2-0- (CH2)d-, -CH2-S-
Figure imgf000132_0003
(CH2)d- or -CH2-S02-(CH2) - and ((R4)) is, of the parts represented
by R4, a part on the end via -CH2-0- (CH2) d-f -CH2-S- (CH2) d- or -CH2~ S02-(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
Figure imgf000133_0001
60 64
Figure imgf000133_0002
65 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
Figure imgf000134_0001
60 67 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 Rp1, 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, hyperinsulmemia, 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 5 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, macrocrystalline 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 as0 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,5 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 than0 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 •5 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 drugo 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) , α-ζjlucosidase inhibitors, insulin sensitizers, PPARα5 receptor agonists, PPARγ receptor agonists/antagonists, PPARδ 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, phosphoenolpyruvate0 carboxykinase (PEPCK) inhibitors, protein tyrosine phosphatase IB (PTPase IB) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors , glucokinase activators , llβ-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate 5 dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors, β3 adrenaline receptor agonists, apolipoprotein-Al (Apo-Al) inducers, lipoprotein lipase0 (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 (MO) receptor agonists, . neuropeptide Y5 (NPY5) receptor antagonists, -adiponectin receptor agonists, protein kinaseβ (PKCβ) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, 5 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 5 (2S) -N-Cyclobutyl-N-methyl-2- (tert-butoxycarbonylamino) -2- cyclohexylacetamide
Figure imgf000138_0001
N-Methylcyclobutylamine hydrochloride (159 mg) synthesized by the method described in Journal of Medicinal Chemistry, 1994,0 37, 3482 was dissolved in N,N-dim thylformamide (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.5 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 was0 concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane: ethyl acetate=3:l) to give • , the title compound . 1H-NMR (δppmr CDCl3) 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
Figure imgf000139_0001
(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.
1H-NMR(δppm,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
Figure imgf000139_0002
(S) -N-tert-Butoxycarbonyl- (trans-4-azidocyclohexyl) glycine . (2.72 g) synthesized in accordance with the method described in WO02/076450, 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) 5 were dissolved in N, -dimethylformamide (25 ml) , and (benzotriazole-1-yloxy) ripyrrolidinophosphonium 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) to5 give the title compound (2.84 g) .
^-NMRfδppπ^CDCls) 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) . 0 Step 2
(S) - [ (trans-4-Aminocyclohexyl) - (N-cyclobutyl-N- methyIcarbamoyl)methyl] carbamic acid tert-butyl ester
Figure imgf000140_0001
(S) - [ (trans-4-Azidocyclohexyl) - (N-cyclobutyl-N-5 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 0 purified by silica gel chromatograph (chloroform:methanol=10 : 1- • . chloroform:methanol: 28% aqueous ammonia=10 : 1 : 0.1) to give the title compound.
1H-NMR(δppm,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) , 5 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
Figure imgf000141_0001
A solution of (S) - [ (trans-4-aminocyclohexyl) - (N-cyclobutyl- N-methyIcarbamoyl)methyl] carbamic acid tert-butyl ester (1.0 g) obtained in Step 2 and triethylamine (614 μl) in chloroform (105 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 off0 and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane: ethyl acetate=l : 1-2 : 3) to give the title compound (1.7 g) . 1H-NMR(δppm,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) ,5 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
Figure imgf000142_0001
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=l : 3-1 : 5) to give the title compound (1.376 g) .
^-NMRfδppπ^CDCls) 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. 2H,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) enzenesulfonylamino] cyclohexyl] - methyl] carbamic acid tert-butyl ester
Figure imgf000142_0002
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 μl) in chloroform (1.5 ml) were cooled to 0°C, and 2 ,2 ,2-trifluoroethanesulfonyl chloride (41 . μl) 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=l:2) to give the title compound (185 mg) .
1H-NMR(δpp ,CDCl3) 0.97-1.20 (4H,m) , 1.30-1.92 (16H,m) , 1.96- 2.32(4H,m), 2.85-3.00 (3H,s) , 3.00-3.1 (lH,m) , 3.79- 3.93(2H,q,J=8.0Hz) , 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) enzenesulfonylamino] cyclohexyl] - acetamide hydrochloride
Figure imgf000143_0001
(S) - [ (N-Cyclobutyl-N-methylcarbamoyl) - [trans-4- [4- (2,2 ,2- trifluoroethanesulfonylamino) enzenesulfonylamino] 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 ahd dried under reduced pressure to give the title compound (132.1 mg) .
Figure imgf000143_0002
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. 8 (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
Figure imgf000144_0001
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 WO02/076450 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(δppm,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
Figure imgf000145_0001
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) .
^- Rtδpprr CDC^) 1.25-1.65 (HH,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-methyIcarbamoyl) - (4- oxocyclohexyl) methyl] carbamic acid tert-butyl ester
Figure imgf000145_0002
A solution of (S) -2- (tert-butoxycarbonylamino) -2- (4- oxocyclohexyl) acetic acid (29.47 g) obtatned in Step 2 in N,N- dimethylformamide (150 ml) was cooled, to 0°C. N~ - methylcyclobutylamine 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) . hl-N R(δPFm,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
Figure imgf000146_0001
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 (l-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(δppm,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
t-Buθ
Figure imgf000147_0001
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) 5 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(δppm,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 5 (S) - [ (N-Cyclobutyl-N-methylcarbamoyl) - (trans-4- hydroxymethylcyclohexyl)methyl] carbamic acid tert-butyl ester
Figure imgf000148_0001
To a solution of (S) - [ (N-cyclobutyl-N-methylcarbamoyl) - (trans-4-formylcyclohexyl)methyl] carbamic acid tert-butyl ester0 (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 5 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=l : 1-ethyl acetate) to give • the title compound (1.64 g).
^-NMRfδpprr^CDCls) 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
Figure imgf000149_0001
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 μl) was cooled to 0°C, benzyl bromide (11.1 μl) 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:l) to give the title compound (28 mg) . 1H-NMR(δppm,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- .38 (5H,m) . Step 8
(2S) -2-Amino-2- (trans-4-benzyloxymethylcyclohexyl) -N-cyclobutyl-N- methylacetamide hydrochloride
Figure imgf000150_0001
• HGI
5 (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(δppm,DMSO-d5) 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) , .70-4.83 (0.42H,m) , 7.22-7.38 (5H,m) , 8.05 (3H,brs) .5 Example 34 Step 1
(S) - [ (N-Cyclobutyl-N-methylcarbamoyl) - [trans-4- (4- nitrophenylsulfanyl e hy1) cyclohexyl]methyl] carbamic acid tert- butyl ester
Figure imgf000150_0002
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(δppm,CDCl3) 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-methyIcarbamoyl) ethyl] carbamic acid tert-butyl ester
Figure imgf000151_0001
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
Figure imgf000152_0001
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) enzenesulfonylmethyl] cyclohexyl] - methyl] carbamic acid tert-butyl ester
Figure imgf000152_0002
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=l : 2) to give the title compound (95 mg) .
1H-NMR(δppm,CDCl3) 1.01-1.15 (4H,m) , 1.40-1.76 (6H,m) , 1.42(4H,s), 1.91-2.28(6H,m) , 2. 3 (1.74H,s) , 2.95 (2H,d, =6.9Hz) , 3.00 (1.26H,s) , 5 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, =8.6Hz) . Step 5
(2S) -2-Amino-N-cyclobutyl-N-methyl-2- [trans-4- [4- (2,2,2- trifluoroethanesulfonylamino) benzenesulfonylmethyl] cyclohexyl] -° acetamide hydrochloride
Figure imgf000153_0001
Using (S) - [ (N-cyclobutyl-N-methylcarbamoyl) - [trans-4- [4- (2,2, 2-trifluoroethanesulfonylamino) benzenesulfonylmethyl] - cyclohexyl]methyl] carbamic acid tert-butyl ester obtained in Step5 4, the title compound was obtained in the same manner as in Step 6 of Example 29.
^-NMRfδppπ^DMSO-de) 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=6.0Hz) , 4.11 (0.42H,brs) , 4.25 (0.58H,brs) , 0 4.50(0.58H,m) , 4.74 (2H,q,J=9.7Hz) , .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 5 2- (Benzoyloxymethyl) benzyl alcohol
Figure imgf000154_0001
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=l : 2- 1:3) to give the title compound (4.49 g) .
^-NMRfδppm, CDC13) 2.13 (IH, 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
Figure imgf000154_0002
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:l) to give the title compound (5.08 g). ^-NMRfδppm, 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) benzyloxymethy1] cyclohexyl) - (N- cyclobutyl-N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester
Figure imgf000155_0001
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) . xH-NMR(δppm, 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- .56 (IH, m) , 4.61(2H, s) , 4.86(0.4H, t, J=9.0Hz)f 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) benzyloxymethy1] cyclohexyl) - (N- cyclobutyl-N-methylcarbamoyl) ethyl] carbamic acid tert-butyl ester
Figure imgf000156_0001
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 IN 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=l : 1-2 : 3) to give the title compound (3.76 g) .
1H-NMR(δppm, 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 (IH, 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-Formylbenzyloxymethy1] cyclohexyl) - (N-cyclobutyl- N-methylcarbamoyl) methyl] carbamic acid tert-butyl ester
Figure imgf000157_0001
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) .
1H-NMR(δppm, CDC13) 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 (IH, s) .
Step 6
2-{trans-4- [ (S) -tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethylJbenzoic acid
Figure imgf000158_0001
To a solution of (S)-[ (trans-4- [2- formylbenzyloxymethyl] cyclohexyl) - (N-cyclobutyl-N- methylcarbamoyl)methyl] carbamic acid tert-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:l) to give the title compound (2.98 g) .
1H-NMR(δppm, CDC13) 0.90-1.21 (4H, m) , 1.43(9H, s) , 1.60-1.75 (6H, ) ,
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 (IH, m) , 4.80-4.85 (2H, m) ,
5.40-5.47 (IH, m) , 7.38-7.42 (IH, 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) methyl] cyclohexylmethoxymethyl Jbenzoic acid hydrochloride l
Figure imgf000159_0001
2-{trans-4- [ (S) -tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl Jbenzoic 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) . 1H-NMR(δppm, 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=6.0Hz) , 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 (IH, 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
Figure imgf000159_0002
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.
1H-NMR (δppm, DMS0-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 (IH, 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
Figure imgf000160_0001
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 μl) was added 3-fluoro-4-hydroxybenzoic acid ethyl ester (44 mg) , triphenylphosphine (62 mg) and diisopropyl azodicarboxylate (46.5 μl) 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
Figure imgf000161_0001
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 IN aqueous sodium hydroxide solution (936 μl) 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: l-chloroform:methanol=40 : 1-10 : 1) to give the title compound (88 mg) as white amorphous.
1H-NMR(δppm, 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=9.0Hz), 4.35-4.65 (1.58H, m) , 4.78-4.95 (0.42H, m) , 5.31-5.47(1H, ) , 6.96(1H, t, J=7.5Hz), 7.78(1H, dd, J=3.0Hz , 12.0Hz), 7.84 (IH, d, J=9.0Hz), Step 4
4-{trans-4- [ (S) -Amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxy}-3-fluorobenzoic acid hydrochloride
Figure imgf000162_0001
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) . XH-NMR (δppm, DMS0-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=6.0Hz), 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=9.0Hz), 7.66 (IH, dd, J=3.0Hz , 12.0Hz), 7.74 (IH, d, J=9.0Hz), 8.11 (3H, brs) Example 242 Step 1 2-Bromomethyl-5-methylbenzoic acid
Figure imgf000162_0002
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
Figure imgf000163_0001
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.
^-NMRfδppm, CDC13) 2.38 (3H, s) , 3.94 (3H, s) , 4.93 (2H, s) , 7.30 (IH, d, J=9.0Hz), 7.35 (IH, d, J=9.0Hz), 7.78 (IH, s) .
Step 3
2-{trans-4- [ (S) -tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid methyl ester
Figure imgf000163_0002
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-methylbenzoic 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(δppm, 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) , 3.0K1.23H, s) , 3.31(2H, d, J=9.0Hz), 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 (IH, m) , 7.32(1H, d, J=9.0Hz), 7.51 (IH, d, J=9.0Hz), 7.72 (IH, s) . Step 4
2-{trans-4- [ (S) -tert-Butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl)methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid
Figure imgf000164_0001
A solution of 2-{trans-4- [ (S) -tert-butoxycarbonylamino- (N- cyclobutyl-N-methyIcarbamoyl) methyl] cyclohexylmethoxymethylJ-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 IN 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.
XH-NMR (δppm, CDC13) 0.84-1.22 (4H, m) , 1.42 (9H, s) , 1.48-1.78 (6H, m) , 1.79-1.9K2H, 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 (IH, m) , 7.33(111, d, J=9.0Hz), 7.38(1H, d, J=9.0Hz), 7.87 (IH, s) . Step 5
2-{trans-4- [ (S) -Amino- (N-cyclobutyl-N- methylcarbamoyl)methyl] cyclohexylmethoxymethyl}-5-methylbenzoic acid hydrochloride
Figure imgf000165_0001
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.
^-NMRfδppm, 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=6.0Hz), 7.64 (IH, s) , 8.17 (3H, brs). Example 297 Step 1
5-Methoxymethoxyisophthalic acid dimethyl ester
Figure imgf000166_0001
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). ^-NMRfδppm, CDC13) 8.34 (IH, 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
Figure imgf000167_0001
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) .
XH-NMR (δppm, CDCI3) 8.41 (IH, 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
Figure imgf000167_0002
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:l) to give the title compound (645 mg) . 1H-NMR(δppm, CDC13) 7.58 (IH, s) , 7.50 (IH, s) , -7.43-7.34 (6H, ) , 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
Figure imgf000168_0001
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) . xH-NMR(δppm, DMSO-d6) 9.87 (IH, s) , 9.80 (IH, s) , 7.58 (IH, s) , 7.41- 7.35(5H, m) , 7.22(1H, t, J=2.3Hz), 6.99 (IH, 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 Jbenzoic acid methyl ester
Figure imgf000168_0002
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 triphenylphosphme (113 mg) in tetrahydrofuran (2 ml) , was added diisopropyl azodicarboxylate (85.1 μl) 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) . 1H-NMR(δppm, CDC13) 7.39-7.36 (7H, m) , 7.27-7.23 (IH, m) , 6.74 (IH, 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=6.0Hz), 3.03(1.22H, s) , 2.96(1.78H, s) , 2.31-2.08 (4H, ) , 1.92(2H, d, J=11.7Hz), 1.75-1.63 (4H, m) , 1.62-1.38 (2H, m) , 1.43 (9H, s),' l.28- 0.98(4H, m) . Step 6
3-Amino-5-{ rans-4- [ (S) -tert-butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxyJbenzoic acid methyl ester
Figure imgf000169_0001
To a solution of 3-benzyloxycarbonylamino-5-{trans-4- [ (S) - tert-butoxycarbonylamino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxyJbenzoic 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) . •1H-NMR(δppm, CDC13) 6.95-6. 4 (2H, m) , 6.39(lH,-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, ) , 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
Figure imgf000170_0001
To a solution of 3-amino-5-{trans-4- [ (S) -tert- butoxycarbonylamino- (N-cyclobutyl-N- meth lcarbamoyl)methyl] cyclohexylmethoxyJbenzoic 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:l) to give the title compound (123 mg) . 1H-NMR(δppm, CDCI3) δ: 7.04 (IH, s),.6.89(lH, s) , 6.41 (IH, t, J=2.4Hz), 5.33 (IH, tr J=10.0Hz), 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
Figure imgf000171_0001
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) . 1H-NMR(δppm, CDC13) 7.09 (IH, s) , 6.93 (IH, d, J=10.9Hz), 6.44 (IH, t, J=2.1Hz), 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-cyclobut l-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl}-5- dimethylaminobenzoic acid hydrochloride
Figure imgf000172_0001
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) .
^-NMR (δppm, DMSO-d6) 8.05 (3H, s) , 6.92 (IH, s) , 6.78 (IH, s) , 6.44 (IH, 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, ) , 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
Figure imgf000173_0001
Table 1-2
Figure imgf000174_0001
Table 1-3
Figure imgf000175_0001
Table 1-4
Figure imgf000176_0001
Figure imgf000177_0001
Table 1-6 xH-NMR(δppm, DMSO-d6) 1.55- 1.68(2H, m) , 1.96-2.05 (IH, m) ,
Example 2.06-2.30(3H, m) , 2.53(1.5H, 27
Figure imgf000178_0001
s) , 2.87(3H, s) , 3.95(1H, s) , 4.00(1H, s) , 4.15-4.22(0.5H, HCI m) , 4.77-4.89 (0.5H, m) , 8.92 (3H, brs) . xH-NMR(δppm, CDC13) 1.51-1.77 (14H, m) , 1.88(2H, brs) , 2.05-
Example 2.30(6H, m) , 2.88 (1.5H, s) , 28 ^εW 2.93(1.5H, s) , 3.37 (IH, s) , 3.42(1H, s) , 4.15-4.25 (0.5H, m) , 4.90-4.97 (0.5H, m) .
Table 1-7
Figure imgf000178_0002
Table 1-8
Figure imgf000179_0001
Table 1-9
Figure imgf000180_0001
Table 1-10
Figure imgf000181_0001
Table 1-11
Figure imgf000182_0001
Table 1-12
Figure imgf000183_0001
Table 1-13
Figure imgf000184_0001
Table 1-14
Figure imgf000185_0001
Table 1-15
Figure imgf000185_0002
Table 1-16
Figure imgf000186_0001
Table 1-17
Figure imgf000187_0001
Table 1-18
Figure imgf000188_0001
Table 1-19
Figure imgf000189_0001
Table 1-20
Figure imgf000190_0001
Table 1 — 21
Figure imgf000191_0001
Table 1 — 22
Figure imgf000192_0001
Table 1 — 23
Figure imgf000193_0001
Table 1-24
Figure imgf000194_0001
Table 1 — 25
Figure imgf000195_0001
Table 1-26
Figure imgf000196_0001
Table 1 — 27
Figure imgf000197_0001
Table 1—28
Figure imgf000198_0001
Table 1 — 29
Figure imgf000199_0001
Table 1 — 30
Figure imgf000200_0001
Table 1-31
Figure imgf000201_0001
Table 1-32
Figure imgf000202_0001
Table 1-33
Figure imgf000203_0001
Table 1-34
Figure imgf000204_0001
Table 1-35
Figure imgf000205_0001
Table 1-36
Figure imgf000206_0001
Figure imgf000207_0001
Table 1-38
Figure imgf000208_0001
Table 1-39
Figure imgf000209_0001
Figure imgf000210_0001
Table 1-41
Figure imgf000211_0001
Figure imgf000212_0001
Table 1-43
Figure imgf000213_0001
Table 1-44
Figure imgf000214_0001
Table 1-45
Figure imgf000215_0001
Table 1-46
Figure imgf000216_0001
Table 1-47
Figure imgf000217_0001
Table 1-48
Figure imgf000218_0001
Figure imgf000219_0001
Table 1-50
Figure imgf000220_0001
Table 1-51
Figure imgf000221_0001
Table 1-52
Figure imgf000222_0001
Table 1-53
Figure imgf000223_0001
Table 1-54
Figure imgf000224_0001
Table 1-55
Figure imgf000225_0001
Table 1-56
Figure imgf000226_0001
Figure imgf000227_0001
Table 1-58
Figure imgf000228_0001
Table 1-59
Figure imgf000229_0001
Table 1-60
Figure imgf000230_0001
Table 1-61
Figure imgf000231_0001
Table 1-62
Figure imgf000232_0001
Table 1—63
Figure imgf000233_0001
Table 1—64
Figure imgf000234_0001
Table 1—65
Figure imgf000235_0001
Table 1—66
Figure imgf000236_0001
Table 1 — 67
Figure imgf000237_0001
Table 1—68
Figure imgf000238_0001
Table 1—69
Figure imgf000239_0001
Table 1-70
Figure imgf000240_0001
Table 1 — 71
Figure imgf000241_0001
Table 1—72
Figure imgf000242_0001
Table 1-73
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Table 1-76
Figure imgf000246_0001
Table 1-77
Figure imgf000247_0001
Table 1-78
Figure imgf000248_0001
Table 1-79
Figure imgf000249_0001
Figure imgf000250_0001
Table 1-81
Figure imgf000251_0001
Figure imgf000252_0001
Table 1-83
Figure imgf000253_0001
Table 1 — 84
Figure imgf000254_0001
Table 1—85
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Table 1—88 xH-NMR(δppm, DMSO-d6) 0.82-0.97 (2H, m) , 1.05-1.29 (2H, m) , 1.40-1.50 (IH, m) , 1.56-1.81 (7H, m) , 1.95-2.33 (4H, m) , 2.88 (1.65H, s) , 2.97 (1.35H, s) , 3.20 <2H, d, J=7.42Hz),
Example 3.81 (3H, s) , 4.11-4.14 (0.45H, 311 m) , 4.26-4.29 (0.55H, m) , 4.38 (2H, s) , 4.49-4.57 (0.55H, m) , 4.71-4.80 (0.45H, m) , 7.09 (IH, d, J=8.35Hz), 7.43 (IH, dd, J=8.35, 1.86Hz), 7.57 (IH, d,
Figure imgf000258_0001
J=1.86Hz), 8.15 (3H, brs), 12.59 (IH, brs) . xH-NMR(δppm, DMSO-d6) 0.85-1.00 (2H, m) , 1.06-1.26 (2H, m) ,
1.43-1.52 (IH, m) , 1.57-1.70 (5H, m) , 1.75-1.83 (2H, m) ,
1.96-2.33 (4H, m) , 2.41 -(3H, s) , 2.88 (1.65H, s) , 2.98
Example (1.35H, s) , 3.26 (2H, d, 312 J=6.03Hz), 4.12-4.14 (0.45H, m) , 4.27-4.29 (0.55H, m) , 4.47 (3H, s) , 4.50-4.57 (0.55H, m) ,
4.71-4.80 (0.45H, m) , 7.24 (1.08H, t, J=7.65Hz), 7.46
Figure imgf000258_0002
(1.06H, d, J=7.42Hz), 7.63 (IH, d, J=7.88Hz), 8.11 (3H, brs),
12.86 (IH, brs) . xH-NMR(δppm, DMSO-d6) 1.08-1.39 (4H, m) , 1.59-1.89 (6H, m) , 1.96-2.37 (6H, m) , 2.90 (1.74H, s) , 3.02 (1.26H, s) , 3.97 (2H, d, J=6.0Hz), 4.18 (0.42H, d,
Example J=5.1Hz) , 4.33 (0.58H, d, 313 J=5.6Hz), 4.52-4.63 (0.58H, m) , 4.72-4.87 (0.42H, ra) , 6.93 (IH, d, J=7.4Hz), 7.35-7.59 (4H, m) , 7.86 (IH, dd, J=7.2 , 2.1Hz),
Figure imgf000258_0003
8.07 (3H, brs) , 8.15 (IH, d, J=7.9Hz) .
Figure imgf000259_0001
Figure imgf000260_0001
Table 1 — 91
Figure imgf000261_0001
Table 1 — 92
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Table 1—95
Figure imgf000265_0001
Table 1—96
Figure imgf000266_0001
Table 1—97
Figure imgf000267_0001
Figure imgf000268_0001
Table 1-99
Figure imgf000269_0001
Figure imgf000270_0001
Table 1-101
Figure imgf000271_0001
Table 1-102
Figure imgf000272_0001
Figure imgf000273_0001
Table 1-104
Figure imgf000274_0001
Table 1-105
Figure imgf000275_0001
Table 1-106
Figure imgf000276_0001
Figure imgf000277_0001
Table 1-108
Figure imgf000278_0001
Table 1-109
Figure imgf000279_0001
Figure imgf000280_0001
Table 1-111
Figure imgf000281_0001
Figure imgf000282_0001
Table 1-113
Figure imgf000283_0001
Table 1-114
Figure imgf000284_0001
Table 1-115
Figure imgf000285_0001
Figure imgf000286_0001
The present invention also comprises, but is not limited to, the following compounds .
Figure imgf000287_0001
' Mxe
Figure imgf000287_0002
Figure imgf000287_0003
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000292_0002
[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 μL/well) and D'PBS (70 μL/well, Dulbecco's Phosphate Buffered Saline, calcium, magnesium free, San o 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 μL/well and the mixture was stirred. Human DPP-IV purified enzyme was added at 10 μL/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 IC50 value was determined.
Enzyme inhibition rate (%) =
Figure imgf000293_0001
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
Figure imgf000294_0001
Table 2-2
Figure imgf000295_0001
Table 2-4
Table 2-5
Figure imgf000297_0001
Table 2-6
Figure imgf000298_0001
Table 2-7
Figure imgf000299_0001
Table 2-8
Figure imgf000300_0001
Table 2-9
Figure imgf000301_0001
Table 2-10
Figure imgf000302_0001
Table 2-11
Figure imgf000303_0001
Table 2-12
Table 2-13
Figure imgf000305_0001
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.

Claims

Claims
1. A DPP-IV inhibitor comprising a compound represented by the formula [I]
Figure imgf000306_0001
wherein
Rx is selected from 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>-<B14>) ,
<B1> halogen atom,
<B2> C3_ι2 cycloalkyl,
<B3> hydroxyl,
<B4> Ci-e alkoxy,
<B5> Ci-e alkylthio,
<B6> aryloxy,
<B7> aralkyloxy,
<B8> heterocyclyloxy,
<B9> heterocyclyl-Ci-6 alkoxy,
<B10> nitro,
<B11> amino,
<B12> cyano,
<B13> carboxyl and
<B14> -Xx-Rxx (Rxx is selected from the following (Bal) and (Ba2) and X1 is selected from the following (Bbl) - (Bb23) ) , (Bal) aryl and
(Ba2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Baal>-<Baal7>) , •■•<Baal> halogen atom, •••<Baa2> Ci-6 alkyl, • ■ •<Baa3> halo-Cι-6 alkyl , ••■<Baa4> C3_ι2 cycloalkyl, •<Baa5> aralkyl,
•<Baa6> heterocyclyl-Ci-6 alkyl,
•<Baa7> hydroxyl,
•<Baa8> Cχ-6 alkoxy,
•<Baa9> Cι_6 alkylthio,
•<Baal0> aryloxy,
•<Baall> aralkyloxy,
•<Baal2> heterocyclyloxy,
•<Baal3> heterocyclyl-Ci-6 alkoxy,
•<Baal4> nitro,
■<Baal5> amino,
•<Baal6> cyano and
•<Baal7> carboxyl;
(Bbl) single bond,
(Bb2) -0-,
(Bb3) -S-,
(Bb4) -NH-,
(Bb5) -CO-,
(Bb6) -CO2-,
(Bb7) -OCO-,
(Bb8) -OCO2-,
(Bb9) -SO-,
(BblO) -SO2-,
(Bbll) -OSO2-,
(Bbl2) -SO3-,
(Bbl3) -CONH-,
(Bbl4) -NHCO-,
(Bbl5) -CSNH-,
(Bbl6) -NHCS-,
(Bbl7) -NHSO2-,
(Bbl8) -S02NH-,
(Bbl9) -NHCO2-,
(Bb20) -OCONH-,
(Bb21) -NHCONH-, • • (Bb22) -NHCSNH- and • ■ (Bb23 ) -NHSO2NH- ;
[C] C3-ι2 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>-<C17>) , -<C1> halogen atom,
•<C2> d-6 alkyl,
•<C3> halo-Ci-e alkyl,
•<C4> aralkyl,
•<C5> heterocyclyl-Ci-e alkyl, -<C6> hydroxyl,
•<C7> Ci-e alkoxy,
•<C8> Cι_6 alkylthio,
•<C9> aryloxy,
•<C10> aralkyloxy, •<C11> heterocyclyloxy,
•<C12> heterocyclyl-Ci-e alkoxy,
•<C13> nitro,
•<C14> amino,
•<C15> cyano, '<C16> carboxyl and
•<C17> -XX-RX1 (Rx and X1 are as defined above) ;
[D] -XX-R1:L (Rx and X1 are as defined above) ; or [E]
Figure imgf000308_0001
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,
• (El) hydrogen atom,
• (E2) -Xx2-R14 (R14 is selected from the following (Eal) and (Ea2) , X12 is selected from the following (Ebl) - (Eb24) ) ,
• • (Eal) aryl and ••(Ea2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Eaal>-<Eaal7>) ,
•<Eaal> halogen atom,
■<Eaa2> Cι-6 alkyl,
•<Eaa3> halo-Cι_6 alkyl,
><Eaa4> C3-12 cycloalkyl,
■<Eaa5> aralkyl,
•<Eaa6> heterocyclyl-C_-6 alkyl,
•<Eaa7> hydroxyl,
><Eaa8> Cι-6 alkoxy,
■<Eaa9> Cι-6 alkylthio,
■<EaalO> aryloxy,
■<Eaall> aralkyloxy,
■<Eaal2> heterocyclyloxy,
• <Eaal3> heterocyclyl-Ci_6 alkoxy,
■<Eaal4> nitro,
■<Eaal5> amino,
■<Eaal6> cyano and
><Eaal7> carboxyl;
(Ebl) single bond,
(Eb2) -0-,
(Eb3) -S-,
(Eb4) -NH-,
(Eb5) -CO-,
(Eb6) -CO2-,
(Eb7) -0C0-,
(Eb8) -OCO2-,
(Eb9) -SO-,
(EblO) -SO2-,
(Ebll) -OSO2-,
(Ebl2) -SO3-,
(Ebl3) -C0NH-,
(Ebl4) -NHCO-, (Ebl5 ) -CSNH- ,
(Ebl 6 ) -NHCS- ,
(Ebl7 ) -NHS02- ,
(Ebl 8 ) -S02NH- ,
(Ebl9 ) -NHC02- ,
(Eb20 ) -OCONH- ,
(Eb21 ) -NHCONH- ,
(Eb22 ) -NHCSNH- ,
(Eb23 ) -NHSO2NH- 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>-<Ecl7>) , ••<Ecl> halogen atom, ••<Ec2> Ci-e alkyl, ••<Ec3> halo-Ci-e alkyl, •■<Ec4> C3-12 cycloalkyl, ••<Ec5> aralkyl, ••<Ec6> heterocyclyl-Ci-6 alkyl, ••<Ec7> hydroxyl, ••<Ec8> Ci-e alkoxy, ••<Ec9> Ci-e alkylthio, ••<EclO> aryloxy, ••<Ecll> aralkyloxy,
••<Ecl2> heterocyclyloxy, ••<Ecl3> heterocyclyl-Cι_6 alkoxy, ••<Ecl4> nitro, ••<Ecl5> amino, ••<Ecl6> cyano and ••<Ecl7> carboxyl; R2 is selected from the following [F_-[H]:
[F] hydrogen atom,
[G] Cι_6 alkyl (said alkyl is optionally substituted by 1 to 3 • substituents selected from the following <G1>-<G18>) ,
•<G1> halogen atom,
•<G2> C3_i2 cycloalkyl,
•<G3> hydroxyl,
•<G4> Cι_6 alkoxy,
•<G5> Ci-e alkylthio,
•.<G6> aryloxy,
•<G7> aralkyloxy,
•<G8> heterocyclyloxy,
•<G9> heterocyclyl-Ci-e alkoxy,
•<G10> nitro,
•<G11> amino,
•<G12> cyano,
•<G13> amido, -<G14> =0,
•<G15> carboxyl,
•<G16> -PO(OH)2,
•<G17> -PO(0-Cι-e alkyl) 2 and
•<G18> -PO(0-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> Ci-e alkyl, -<H3> halo-Cι-6 alkyl,
•<H4> aralkyl,
• <H5> heterocyclyl-Cι_6 alkyl ,
•<H6> hydroxyl,
•<H7> Ci-e alkoxy,
•<H8> Ci-e alkylthio,
•<H9> aryloxy,
•<H10> aralkyloxy,
•<H11> heterocyclyloxy,
•<H12> heterocyclyl-Ci-e alkoxy, •<H13> nitro,
•<H14> amino,
•<H15> cyano,
•<H16> amido, -<H17> =0,
•<H18> carboxyl,
•<H19> -PO(OH)2,
•<H20> -PO(0-Cι_6 alkyl) 2 and
•<H21> -PO(0-aryl)2; R3 is selected from the following [I] and [J]
[I] Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <I1>-<I18>) ,
■<I1> halogen atom,
•<I2> C3-12 cycloalkyl, -<I3> hydroxyl,
•<I4> Ci-e alkoxy,
•<I5> Ci-6 alkylthio,
*<I6> aryloxy,
■<I7> aralkyloxy, •<I8> heterocyclyloxy,
•<I9> heterocyclyl-Cι_6 alkoxy,
•<I10> nitro,
•<I11> amino,
•<I12> cyano, •<I13> amido,
•<I14> =0,
■<I15> carboxyl,
•<I16> -P0(0H)2,
•<I17> -P0(0-Cι_e alkyl) 2 and -<I18> -PO(0-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> Ci-e alkyl,
•<J3> halo-Cι_6 alkyl,
•<J4> aralkyl,
•<J5> heterocyclyl-Ci-6 alkyl, -<J6> hydroxyl,
•<J7> Ci-6 alkoxy,
•<J8> Ci-e alkylthio,
•<J9> aryloxy,
•<J10> aralkyloxy, «<J11> heterocyclyloxy,
■<J12> heterocyclyl-Ci-e alkoxy,
•<J13> nitro,
•<J14> amino,
•<J15> cyano, -<J16> amido,
•<J17> =0,
•<J18> carboxyl,
•<J19> -PO(OH)2,
■<J20> -PO(0-Cι-e alkyl) 2 and -<J21> -P0(0-aryl)2;
R4 is selected from the following [K_-[S]:
[K] hydrogen atom,
[L] Cι_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> Ci-e alkoxy,
•<L5> Ci-e alkylthio, '<L6> aryloxy,
•<L7> aralkyloxy,
•<L8> heterocyclyloxy,
•<L9> heterocyclyl-Ci-e alkoxy,
•<L10> nitro, <L11> amino,
<L12> cyano,
<L13> carboxyl and
<L14> -Y1-R4X (R4X is selected from the following (Lal)-( aδ), and
'41 is selected from the following (Lbl) and (Lb2) ) ,
(Lai) hydrogen atom,
(La2) Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) ,
<Laal> halogen atom,
<Laa2> C_ι2 cycloalkyl,
<Laa3> hydroxyl,
<Laa4> aralkyloxy,
<Laa5> heterocyclyloxy,
<Laa6> heterocyclyl-Cι_6 alkoxy,
<Laa7> nitro,
<Laa8> cyano,
<Laa9> carboxyl,
<LaalO> -OR' 413
<Laall> -COR' 414
<Laal2> -C02R 413
<Laal3> -OCOR 4' 13 <Laal4> -C0NR415R416 , <Laal5> -0C0NR4X5R416 , <Laal6> -NR415R416 , <Laal7> -NR X7COR413 , <Laal8> -NR417C02R413 ,
<Laal9> -SR' 413
<Laa20> -SOR' 413
<Laa21> -S02R 4' 13 <Laa22> -S02NR415R416 , <Laa23> -NR4X7S02R413 and <Laa24> -NR4X7CONR X5R416
413
(R' is Ci-e alkyl , C3-12 cycloalkyl or aryl ,
R 414 R415 and R416 are the same or different and each is hydrogen atom, Cχ-6 alkyl , C3-12 cycloalkyl or aryl ,
R417 is hydrogen atom or Cι_6 alkyl , or R417 in combination with R413 form C1-4 alkylene) ;
(La3) C3-12 cycloalkyl ;
(La4) C3-12 cycloalkyl-Cι-6 alkyl ;
(La5) aryl;
(La6) aralkyl;
(La7) heterocyclyl and
(La8) heterocyclyl-Ci-6 alkyl (said cycloalkyl, cycloalkylalkyl, aryl, aralkyl ,,heterocyclyl and heterocyclylalkyl are optionally substituted by 1 to 3 substituents selected from the following <Labl>-<Lab33>) , ■•■<Labl> halogen atom,
•••<Lab2> Ci-e alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from hydroxyl, C_-6 alkoxy, -S02-Cι_6 alkyl, -S02-aryl, -NHS02-Cι-6 alkyl and -NHS02-halo-Cι-6 alkyl) ,
<Lab3> halo-Cι-6 alkyl,
<Lab4> aralkyl,
<Lab5> heterocyclyl-Ci-6 alkyl,
<Lab6> C3-12 cycloalkyl,
<Lab7> hydroxyl,
<Lab8> Cι_6 alkoxy,
<Lab9> aralkyloxy,
<LablO> heterocyclyloxy,
<Labll> heterocyclyl-Ci-6 alkoxy,
<Labl2> nitro,
<Labl3> amino,
<Labl4> cyano,
<Labl5> carboxyl,
<Labl6> (Cι_6 alkoxy) carbonyl ,
<Labl7> Cχ-6 alkylsulfonyl,
<Labl8> -CH2C02H,
Figure imgf000315_0001
<Lab2l> -C02R413 ,
<Lab22> -OCOR413 ,
<Lab23> -C0NR415R416 ,
<Lab24> -0C0NR 15R416 ,
<Lab25> -NR 15R416 ,
<Lab26> -NR417COR413 ,
<Lab27> -NR 4,117',C02R ,4' 13
<Lab28> -SR413 ,
<Lab29> -SOR413 ,
<Lab30> -S02R413 ,
<Lab31> -S02NR 15R416 ,
<Lab32> -NR 4'117Sc 02R ,41 "3 and <Lab33> -NR417CONR415R416
(R 4*1A3 D R4""14* , π R415 R416 and R417 are as defined above) ; (Lbl) single bond and
(Lb2) X ,41 (X ,4*11 is - 1a
Figure imgf000316_0001
X ,4ia is selected from the following (Lbal) - (Lba23) , R418 and R419 are the same or different and each is hydrogen atom or Cι_6 alkyl, c is an integer of 0 to 2, and d is an integer of 0 to 4) ,
(Lbal) -0-,
(Lba2) -S-,
(Lba3) -CO-,
(Lba4) -CO2-,
(Lba5) -OCO-,
(Lba6) -OCO2-,
(Lba7) -SO-,
(Lba8) -SO2-,
(Lba9) -OSO2-,
(LbalO) -S03~,
(Lball) -NR' 411
Figure imgf000316_0002
(Lbal3) -NR 4*1x1l,CO-,
Figure imgf000316_0003
• •• (Lbal 6) -S02NR411-,
•••(Lbal7) -NR411S02~,
••• (Lbal 8) -OCONR411-,
•••(Lbal9) -NR11C02-, • • • ( Lba20 ) -NR411CONR412- ,
•••(Lba21) -NR411CSNR412-,
•••(Lba22) -NR411S02NR412- (R411 and R412 are the same or different and each is selected from the following (Lbaal) - (Lbaa3) ) ,
••••(Lbaal) hydrogen atom, ....(Lbaa2) C.-6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal4>) , <Lbaaal> halogen atom, <Lbaaa2> C3_ι2 cycloalkyl, <Lbaaa3> hydroxyl , <Lbaaa4> C_-6 alkoxy , <Lbaaa5> Cι-6 alkylthio , <Lbaaa6> aryloxy, <Lbaaa7> aralkyloxy, <Lbaaa8> heterocyclyloxy , <Lbaaa9> heterocyclyl-Ci_6 alkoxy, <LbaaalO> nitro, <Lbaaall> amino, <Lbaaal2> cyano, <Lbaaal3> carboxyl, <Lbaaal4> 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> Ci-e alkyl,
•<M3> halo-Ci-6 alkyl,
•<M4> aralkyl, <M5> heterocyclyl-Ci-e alkyl, <M6> hydroxyl, <M7> C.-e alkoxy, <M8> Cι_6 alkylthio, <M9> aryloxy, <M10> aralkyloxy, <M11> heterocyclyloxy, <M12> heterocyclyl-Cι_6 alkoxy, <M13> azido, <M14> nitro, <M15> amino, <M16> cyano, <M17> carboxyl and
<M18> -γ42-R41 (R41 is as defined above, and Y42 is selected "from the following (Mai) - (Mal2) ) ,
(Mai) single bond,
(Ma2) -X41-,
(Ma3) -Z41-,
(Ma4) -Z41-Z42-,
(Ma5) -X1-Z41-,
(Ma6) -Z1-X41-,
(Ma7) -X41-Z41-X42-,
(Ma8) -X41-Z41-Z42-,
(Ma9) -Z41-X41-Z42-,
(MalO) -z41-Z2-X41-,
(Mall)
Figure imgf000318_0001
and
• • (Mal2)
Figure imgf000318_0002
(X41 is as defined above, X42 and X43 are each independently -(CHR420)e-X2a~(CHR421)f-, X42a is selected from the following (Maal) (Maa23) , R420 and R421 are the same or different and each is hydrogen atom or Ci-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 (Mabl) - (Mab6) , and Z43 is selected from the following (Macl) - (Mac5) ) ,
(Maal) single bond,
(Maa2) -0-,
(Maa3) -S-,
(Maa4) -CO-,
(Maa5) -C02-,
(Maa6) -OCO-,
(Maa7) -OC02-,
(Maaδ) -SO-,
(Maa9) -S02-,
(MaalO) -OS02-,
(Maall) -S03-,
(Maal2) -NR411-,
(Maal3) -CONR411-, (Maal4) -NR411CO-
(Maal5) -NR 4'1"1,C02-,
Figure imgf000319_0001
(Maa20) -NR11S02-, (Maa21) -NR411C0NR412- , (Maa22) -NR4UCSNR412- and
(Maa23) -NR11S02NR412- (R411 and R412 are as defined above) ; (Mabl) Cι_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>) , ■•••<Mabal> halogen atom, <Maba2> C3_12 cycloalkyl,
....<Maba3> hydroxyl , <Maba4> C_-6 alkoxy, <Maba5> C.-6 alkylthio ,
....<Maba6> aryloxy,
....<Maba7> aralkyloxy,
....<Maba8> heterocyclyloxy,
• • • •<Maba9> heterocycly1-Cι-e alkoxy, <MabalO> nitro,
....<Maball> amino ,
••••<Mabal2> 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>-<Mabbl8>) , <Mabbl> halogen atom, <Mabb2> Ci-e alkyl, <Mabb3> halo-Cι-6 alkyl , <Mabb4> aralkyl,
• • • •<Mabb5> heterocyclyl-Ci-6 alkyl ,
• • • •<Mabb6> C3_i2 cycloalkyl ,
• • • •<Mabb7> hydroxyl, <Mabb8> Cι-6 alkoxy, <Mabb9> Cι_6 alkylthio, <MabblO> aryloxy, <Mabbll> aralkyloxy,
• • • •<Mabbl2> heterocyclyloxy,
• • • •<Mabbl3> heterocyclyl-Cχ-6 alkoxy, ••••<Mabbl4> nitro, <Mabbl5> amino, •••■<Mabbl6> cyano, <Mabbl7> carboxyl and <Mabbl8> -X4c-Rc (R4c is selected from the following (Mabbal)-
(Mabba4) , and Xc is selected from the following (Mabbbl) - (Mabbb9) ) , (Mabbal) hydrogen atom, (Mabba2) Cι_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> (Cι-6 alkoxy) carbonyl and
•<Mabbaa4> Cι_6 alkylsulfonyl ;
(Mabbbl) single bond,
(Mabbb2) -CO-,
(Mabbb3) -C02-,
(Mabbb4) -OCO-,
(Mabbb5) -C0NR41c-, (Mabbbδ) -NR41cCO-, (Mabbb7) -S02-, (Mabbb8) -S02NR41c- and
(Mabbb9) -NR41cS02- (R41c is hydrogen atom or Cι_6 alkyl) ; (Macl) Ci-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_ι2 cycloalkyl, ••<Maca3> hydroxyl, ••<Maca4> Cι_6 alkoxy, ••<Maca5> Cι_6 alkylthio, • • <Maca6> aryloxy, ••<Maca7> aralkyloxy, •••<Maca8> heterocyclyloxy, <Maca9> heterocyclyl-Cι_6 alkoxy,
• • •<MacalO> nitro ,
• • •<Macal1> amino , •••<Macal2> 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>) ,
••••<Macbl> halogen atom, <Macb2> Ci-e alkyl, <Macb3> halo-d-e alkyl, <Macb4> aralkyl, <Macb5> heterocyclyl-Ci-e alkyl,
••••<Macb6> C3-12 cycloalkyl,
....<Macb7> hydroxyl , <Macb8> Cχ-6 alkoxy, <Macb9> Ci-e alkylthio,
••••<MacblO> aryloxy,
••■•<Macbll> aralkyloxy, <Macbl2> heterocyclyloxy,
••••<Macbl3> heterocyclyl-Ci-6 alkoxy, <Macbl4> nitro,
■ • • •<Macbl5> amino ,
••••<Macbl6> cyano,
••••<Macbl7> carboxyl and <Macbl8> -CH2C02H; [N] aryl,
[0] aralkyl,
[P] heterocyclyl,
[Q] heterocyclyl-Cι_6 alkyl (said aryl, aralkyl, heterocyclyl and heterocyclyl-Ci-6 alkyl are optionally,, substituted by 1 to 3 substituents selected from the following <N1>-<N19>) ,
•<N1> halogen atom,
•<N2> Cι_6 alkyl,
•<N3> C3_ι2 cycloalkyl ,
•<N4> halo-Cι-6 alkyl ,
•<N5> aralkyl,
•<N6> heterocyclyl-Ci-e alkyl,
•<N7> hydroxyl,
•<N8> Ci-e alkoxy,
•<N9> Ci-e alkylthio,
•<N10> aryloxy,
•<N11> aralkyloxy,
•<N12> heterocyclyloxy,
•<N13> heterocyclyl-Ci-e alkoxy,
•<N14> nitro,
•<N15> amino,
•<N16> cyano,
•<N17> =0,
•<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]
Figure imgf000323_0001
(R42 and R43 are each independently selected from the following (SI) -(S3) , and m and n are each independently an integer of 0 to 3) formed by R4 and R5 in combination, • (SI) hydrogen atom,
• (S2) -Y41-R44 (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>) ,
•••<Saal> halogen atom,
•••<Saa2> Ci-6 alkyl,
•••<Saa3> halo-Ci-e alkyl,
•■•<Saa4> aralkyl,
•••<Saa5> heterocyclyl-Ci-6 alkyl,
•••<Saa6> C3-ι2 cycloalkyl,
•••<Saa7> hydroxyl,
•■•<Saaδ> Ci-6 alkoxy,
•••<Saa9> Ci-e alkylthio,
• • •<Saal0> aryloxy,
• • •<Saall> aralkyloxy, •••<Saal2> heterocyclyloxy, •••<Saal3> heterocyclyl-Ci_6 alkoxy, •••<Saal4> nitro, •••<Saal5> amino, •••<Saal6> cyano and •••<Saal7> 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>) , ••<Scl> halogen atom, ••<Sc2> Cα-e alkyl,
••<Sc3> halo-Cι_6 alkyl,
••<Sc4> aralkyl,
••<Sc5> heterocyclyl-Ci-6 alkyl,
••<Sc6> C3_12 cycloalkyl, ••<Sc7> hydroxyl,
••<Scδ> Cχ-6 alkoxy,
••<Sc9> Cχ-6 alkylthio,
••<SclO> aryloxy,
••<Scll> aralkyloxy, ••<Scl2> heterocyclyloxy, ••<Scl3> heterocyclyl-Cι_6 alkoxy, ••<Scl4> nitro, ••<Scl5> amino, ••<Scl6> cyano and • •<Scl7> carboxyl ;
R5 is selected from the following [T]-[BB], [T] hydrogen atom,
[U] Cχ-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> Ci-e alkoxy,
<U5> Cι_6 alkylthio,
<U6> aryloxy,
<U7> aralkyloxy,
<U8> heterocyclyloxy,
<U9> heterocyclyl-Ci-6 alkoxy,
<U10> nitro,
<U11> amino,
<U12i> cyano ,
<U13> carboxyl and
<U14> -X -R45 (R45 is selected from the following (Ual) and (Ua2) , and X44 is selected from the following (Ubl) - (Ub23) ) , (Ual) aryl and
(Ua2) heterocyclyl (said aryl and heterocyclyl are optionally substituted by 1 to 3 substituents selected from the following <Uaal>-<Uaal7>) ...<uaal> halogen atom, •••<Uaa2> Ci-e alkyl, •••<Uaa3> halo-Cχ-6 alkyl, •••<Uaa4> C3-12 cycloalkyl, •••<Uaa5> aralkyl, •<Uaa6> heterocyclyl-Ci-e alkyl ,
■<Uaa7> hydroxyl,
•<Uaa8> Ci-6 alkoxy,
■<Uaa9> Ci-e alkylthio,
•<UaalO> aryloxy,
■<Uaall> aralkyloxy,
•<Uaal2> heterocyclyloxy,
■<Uaal3> heterocyclyl-Ci-6 alkoxy,
•<Uaal4> nitro, •••<Uaal5> amino,
•<Uaal6> cyano and
•<Uaal7> carboxyl;
(Ubl) single bond,
(Ub2) -0-, •• (Ub3) -S-,
(Ub4) -NH-,
(Ub5) -CO-,
(Ub6) -C02-,
(Ub7) -OCO-, --(Ub8) -OC02-,
(Ub9) -SO-,
(UblO) -S02-,
(Ubll) -OSO2-,
(Ubl2) ~S03-, •• (Ubl3) -CONH-,
(Ubl4) -NHCO-,
(Ubl5) -CSNH-,
(Ubl6) -NHCS-,
(Ubl7) -NHSO2-, •• (Ubl8) -SO2NH-,
(Ubl9) -NHCO2-,
(Ub20) -OCONH-,
(Ub21) -NHCONH-,
(Ub22) -NHCSNH- and • • (Ub23 ) -NHSO2NH- ;
[V] C3_i2 cycloalkyl (said cycloalkyl is optionally substituted by
1 to 3 substituents selected from the following <V1>-<V17>) ,
<V1> halogen atom,
<V2> Ci-e alkyl,
<V3> halo-Cι-6 alkyl,
<V4> aralkyl,
<V5> heterocyclyl-Ci-e alkyl,
<V6> hydroxyl,
<V7> Ci-e alkoxy,
<V8> Ci-e alkylthio,
<V9> aryloxy,
<V10> aralkyloxy,
<V11> heterocyclyloxy,
<V12> heterocyclyl-Ci-6 alkoxy,
<V13> nitro,
<V14> amino,
<V15> cyano,
<V16> carboxyl and
<V17> -X4-R45 (R45 and X44 are as defined above) ; [ ] 3 to 7-membered saturated heterocycle, [X] aryl, [Y] heterocyclyl, [Z] aralkyl, [AA] heterocyclyl-Cι-6 alkyl (said saturated heterocycle, aryl, heterocyclyl, aralkyl and heterocyclyl-Ci-6 alkyl are optionally substituted by 1 to 3 substituents selected from the following <W1>-<W16>) , •<W1> halogen atom, -< 2> Ci-e alkyl,
•<W3> C3-12 cycloalkyl, •<W4> aralkyl,
•<W5> heterocyclyl-Ci-e alkyl, •<W6> hydroxyl, •< 7> Ci-e alkoxy,
•<W8> Ci-e alkylthio,
•<W9> aryloxy,
•<W10> aralkyloxy,
•<W11> heterocyclyloxy,
•<W12> heterocyclyl-Ci-6 alkoxy,
•<W13> nitro,
•< 14> amino,
•< 15> 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]
Figure imgf000328_0001
wherein R1 is selected from 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>-<B14>) ,
•<B1> halogen atom,
•<B2> C3-12 cycloalkyl,
•<B3> hydroxyl,
•<B4> Ci-e alkoxy, -<B5> Ci-e alkylthio,
•<B6> aryloxy,
•<B7> aralkyloxy,
•<B8> heterocyclyloxy,
•<B9> heterocyclyl-Cι_6 alkoxy, -<B10> nitro,
•<B11> amino, •<B12> cyano,
•<B13> carboxyl , and
•<B14> -X^R11 (R11 and X1 are defined in claim 1) ;
[C] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <C1>-<C17>) , •<C1> halogen atom, •<C2> Ci-e alkyl, •<C3> halo-Cι-6 alkyl, •<C4> aralkyl,
•<C5> heterocyclyl-Cι_6 alkyl, •<C6> hydroxyl, •<C7> Ci-e alkoxy, •<C8> Ci-e alkylthio, •<C9> aryloxy, "<C10> aralkyloxy,
•<C11> heterocyclyloxy,
• <C12> heterocyclyl-Cι_6 alkoxy ,
•<C13> nitro,
•<C14> amino,
■<C15> cyano,
■<C16> carboxyl and
■<C17> -X^R11 (R11 and X1 are as defined in claim 1) ;
[D] - ^R11 (R11 and X1 are as defined in claim 1) ; or
[E]
Figure imgf000329_0001
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] Cι_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> Ci-e alkylthio,
•<G6> aryloxy,
•<G7> aralkyloxy,
•<G8> heterocyclyloxy,
•<G9> heterocyclyl-Ci-6 alkoxy, -<G10> nitro,
•<G11> amino,
•<G12> cyano,
•<G13> amido,
•<G14> =0, -<G15> carboxyl,
•<G16> -P0(0H)2,
•<G17> -P0(0-Ci-6 alkyl) 2 and
•<Glδ> -P0(0-aryl)2;
[H] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by 1 to 3 substituents selected from the following <H1>-<H16> and
<Hlδ>-<H21>) ,
•<H1> halogen atom,
•<H2> Ci-e alkyl,
•<H3> halo-Cι-6 alkyl, -<H4> aralkyl,
•<H5> heterocyclyl-Ci-6 alkyl,
•<H6> hydroxyl,
■<H7> Ci-e alkoxy,
•<Hδ> Ci-e alkylthio,
•<H9> aryloxy,
•<H10> aralkyloxy,
•<H11> heterocyclyloxy,
• <H12> heterocyclyl-Ci-6 alkoxy,
• <H13> nitro , •<H14> amino,
•<H15> cyano,
•<H16> amido,
•<H18> carboxyl,
•<H19> -PO(OH)2,
•<H20> -PO(0-Cι_6 alkyl) 2 and
•<H21> -PO(0-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> Ci-e alkyl,
•<J3> halo-Ci-e alkyl, .<j4> aralkyl,
•<J5> heterocyclyl-Ci-6 alkyl,
•<J6> hydroxyl,
•<J7> Ci-6 alkoxy,
•<J8> Ci-e alkylthio, *<J9> aryloxy,
•<J10> aralkyloxy,
•<J11> heterocyclyloxy,
•<J12> heterocyclyl-Ci-e alkoxy,
•<J13> nitro, -<J14> amino,
•<J15> cyano,
•<J16> amido,
•<J18> carboxyl,
•<J19> -PO(OH)2,
•<J20> -PO(0-Cι-e alkyl) 2 and
•<J21> -PO(0-aryl)2;
R4' is selected from the following [K]-[M], [P] , [R] and [S] ,
[ ] hydrogen atom,
[L] Ci-e 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> Ci-e alkoxy, <L5> Ci-6 alkylthio, <L6> aryloxy, <L7> aralkyloxy, <L8> heterocyclyloxy, <L9> heterocyclyl-Ci-6 alkoxy, <L10> nitro, <L11> amino, <L12> cyano, <L13> carboxyl and
<L14> -γ41-R41' (R41' is selected from the following (Lai) , (La2) , (La5) and (La7) , and Y41 is as defined in claim 1) ,
(Lai) hydrogen atom,
(La2) Cι_6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) ,
<Laal> halogen atom,
<Laa2> C3_i2 cycloalkyl,
<Laa3> hydroxyl,
<Laa4> aralkyloxy,
<Laa5> heterocyclyloxy,
<Laa6> heterocyclyl-Cι_6 alkoxy,
<Laa7> nitro,
<Laa8> cyano,
<Laa9> carboxyl,
<LaalO> -OR' 413
<Laall> -COR' 414
<Laal2> -C02R' 413
<Laal3> -OCOR 4' 13 <Laal4> -CONR 15R416 , <Laal5> -OCONR415R416 , ■ <Laal6> -NR415R416 ,
■ <Laal7> -NR417COR413 , > <Laal8> -NR417C02R413 ■ <Laal9> -SR413 ,
■ <Laa20> -SOR' 413
■ <Laa21> -S02R 413
•<Laa22> -S02NR415R416 ,
• <Laa23> -NR 17S02R413 and
- <Laa24> -NR 17CONR415R416
413 414
(R' K 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>) ,
•••<Labl> halogen atom,
•••<Lab2> Ci-e alkyl (said alkyl is optionally substituted by 1 to
3 substituents selected from hydroxyl, Cι_6 alkoxy, -S02-Cι_6 alkyl,
-S02- aryl, -NHS02-Cι-e alkyl and -NHS02-halo-Ci_6 alkyl),
•••<Lab3> halo-Cι_6 alkyl,
•••<Lab4> aralkyl,
•••<Lab5> heterocyclyl-Ci-e alkyl,
•••<Lab6> C3-12 cycloalkyl,
• • ■<Lab7> hydroxyl , •••<Lab8> Ci-e alkoxy,
• • •<Lab9> aralkyloxy, ••■<LablO> heterocyclyloxy, •••<Labll> heterocyclyl-Cι_6 alkoxy, •••<Labl2> nitro,
•••<Labl3> amino,
•••<Labl4> cyano,
•••<Labl5> carboxyl,
•■•<Labl6> (Ci-6 alkoxy) carbonyl,
•••<Labl7> Ci-6 alkylsulfonyl ,
•••<Labl8> -CH2C02H, <Labl9> -OR' 413
<Lab20> -COR 414
<Lab21> -C02R' 413
<Lab22> -OCOR 413 <Lab23> -C0NR415R416 , <Lab24> -0C0NR415R416 , <Lab25> -NR415R416 , <Lab26> -NR417C0R413 , <Lab27> -NR417C02R413 , <Lab28> -SR413 , <Lab29> -SOR413 , <Lab30> -S02R413 , <Lab31> -S02NR415R416 , <Lab32> -NR 17S02R413 and <Lab33> -NR 17C0NR415R416
(R ,4*1A3 R ,4'1A4 R ,4"115 R416 and R417 are as defined in claim 1) ;
[M] C3-12 cycloalkyl (said cycloalkyl is optionally substituted by to 3 substituents selected from the following <M1>-<M18>) ,
<M1> halogen atom,
<M2> Ci-e alkyl,
<M3> halo-Ci-e alkyl,
<M4> aralkyl,
<M5> heterocyclyl-Ci-e alkyl ,
<M6> hydroxyl,
<M7> Ci-e alkoxy,
<M8> Ci-e alkylthio,
<M9> aryloxy,
<M10> aralkyloxy,
<M11> heterocyclyloxy,
<M12> heterocyclyl-Ci-e alkoxy,
<M13> azido,
<M14> nitro,
<M15> amino,
<M16 cyano, •<M17> carboxyl and
•<M18> -γ42-R41' (R41' is as defined above and Y42 is as defined in the claim 1) ;
[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 <Nlδ>) , •<N1> halogen atom, •<N2> Ci-e alkyl, •<N3> C3_i2 cycloalkyl, •<N4> halo-Cι-6 alkyl, •<N5> aralkyl,
•<N6> heterocyclyl-Cι_6 alkyl, •<N7> hydroxyl, *<N8> Ci-e alkoxy, •<N9> Ci-e alkylthio, •<N10> aryloxy, •<N11> aralkyloxy, •<N12> heterocyclyloxy, •<N13> heterocyclyl-Ci-e alkoxy, •<N14> nitro, •<N15> amino, •<N16> cyano and •<N18> carboxyl; [R] -γ41-R41' (R41' and Y41 are as defined above) , or
[S]
Figure imgf000335_0001
(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 [T]-[W] and [BB_ , [T] hydrogen atom, [U] Ci-e 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> Ci-e alkoxy,
<U5> Ci-e 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 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> Ci-e alkyl, •<V3> halo-Ci-e alkyl, •<V4> aralkyl,
•<V5> heterocyclyl-Ci-e alkyl, •<V6> hydroxyl, -<V7> Ci-e alkoxy, •<V8> Ci-e alkylthio, •<V9> aryloxy, •<V10> aralkyloxy, •<V11> heterocyclyloxy, •<V12> heterocyclyl-Ci-6 alkoxy, •<V13> nitro, •<V14> amino, •<V15> cyano, •<V16> carboxyl and , -<V17> -X44-R45 (R45 and X44 are as defined in claim 1) ; [ ] 3 to 7-membered saturated heterocycle (said saturated heterocycle is optionally substituted by 1 to 3 substituents selected from the following < 1>-< 16>) , '<W1> halogen atom, •< 2> Ci-e alkyl, •<W3> C3_i2 cycloalkyl, •< 4> aralkyl, •<W5> heterocyclyl-Ci-6 alkyl, -< 6> hydroxyl, •<W7> Cι_6 alkoxy, •< δ> Ci-e alkylthio, •< 9> aryloxy, •< 10> aralkyloxy, -< 11> heterocyclyloxy,
•< 12> heterocyclyl-Ci-e alkoxy, •< 13> nitro, •<W14> amino, •<W15> cyano and -<W16> carboxyl;
[BB] -X4-R45 (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 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 claim 2, wherein R41' is selected from the following (Lai) , (La2) , (La5) and (La7) , X41a is selected from the following (Lbal) - (Lba23) , and other symbols are as defined in claim 2, . (Lai) hydrogen atom,
(La2) Ci-6 alkyl (said alkyl is optionally substituted by 1 to 3 substituents selected from the following <Laal>-<Laa24>) ,
<Laal> halogen atom,
<Laa2> C3_ι2 cycloalkyl,
<Laa3> hydroxyl,
<Laa4> aralkyloxy,
<Laa5> heterocyclyloxy,
<Laa6> heterocyclyl-C_-6 alkoxy,
<Laa7> nitro,
<Laaδ> cyano,
<Laa9> carboxyl,
<LaalO> 413
-OR <Laall> 414
-COR <Laal2> 413
-C02R'
<Laal3> -OCOR413 , <Laal4> CONR4X5R416 ,
<Laal5> -OCONR415R416 , <Laal6> -NR415R416 , <Laal7> -NR417COR413 , <Laalδ> -NR 17C02R413 , <Laal9> -SR413 , <Laa20> -SOR413 , <Laa21> -S02R413 , <Laa22> -S02NR415R416 , <Laa23> -NR 17S02R413 and <Laa24> -NR417CONR415R416
(R' 413 is Ci-6 alkyl , C3-ι2 cycloalkyl or aryl ,
R' 414 R and R are the same or different and each is hydrogen atom, Cι_6 alkyl, C3-12 cycloalkyl or aryl,
R' 417 is hydrogen atom or Cι_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>) ,
<Labl> halogen atom,
<Lab2> Ci-e alkyl,
<Lab3> halo-Ci-e alkyl,
<Lab4> aralkyl,
<Lab5> heterocyclyl-Ci-e alkyl,
<Lab6> C3_ι2 cycloalkyl,
<Lab7> hydroxyl,
<Labδ> Cι_6 alkoxy,
<Lab9> aralkyloxy,
<LablO> heterocyclyloxy,
<Labll> heterocyclyl-Ci-6 alkoxy ,
<Labl2> nitro,
<Labl3> amino,
<Labl4> cyano,
<Labl5> carboxyl ,
<Labl6> (Ci-6 alkoxy) carbonyl,
<Labl7> Ci-6 alkylsulfonyl,
<Lablδ> -CH2C02H,
Figure imgf000339_0001
<Lab20> -COR 4414
<Lab21> -C02R 4413
<Lab22> -OCOR413 , <Lab23> -CONR415R416 , <Lab24> -OCONR 15R416 , <Lab25> -NR415R416 , <Lab26> -NR417COR413 ,
Figure imgf000339_0002
<Lab29> -SOR413,
Figure imgf000339_0003
<Lab31> -S02NR415R416 , <Lab32> -NR417S02R413 and <Lab33> -NR417C0NR415R416 (R413, R414 R415, ] R416 and R417 are as defined above) ;
••• (Lbal) -0-,
••■ (Lba2) -S-,
••• (Lba3) -CO-,
•■• (Lba4) -co2- ,
••• (Lba5) -oco- ,
••• (Lba6) -oco2- ,
••• (Lba7) -so-,
••• (Lbaδ) -so2-,
••• (Lba9) -OS02- ,
••• (LbalO) -S03-,
■(Lball) -NR411-,
• (Lbal2) -CONR411-,
• (Lbal3) -NR411CO-,
• (Lbal4) -CSNR411-,
• (Lbal5) -NR11CS-,
• (Lbal6) -S02NR411-,
• (Lbal7) -NR411S02-,
• (Lbalδ) -OCONR411-,
• (Lbal9) -NR11C02-,
■ (Lba20) -NR411CONR412- ,
• (Lba21) -NR411CSNR412- ,
• (Lba22) -NR411S02NR412- (R411 and R412 are the same or different and each is selected from the following (Lbaal) - (Lbaa3) ) ,
••(Lbaal) hydrogen atom,
■• (Lbaa2) Cι_6 alkyl (alkyl is optionally substituted by 1 to 3 substituents selected from the following <Lbaaal>-<Lbaaal3>) , ■••<Lbaaal> halogen atom,
• • •<Lbaaa2> C3-12 cycloalkyl ,
• • •<Lbaaa3> hydroxyl ,
• • •<Lbaaa4> Q__6 alkoxy ,
• • •<Lbaaa5> Ci-6 alkylthio ,
■ • • <Lbaaa6> aryloxy, •••<Lbaaa7> aralkyloxy, , <Lbaaaδ> heterocyclyloxy, <Lbaaa9> heterocyclyl-Ci_6 alkoxy , <LbaaalO> nitro, <Lbaaall> amino,
5 <Lbaaal2> cyano, <Lbaaal3> 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, 10 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
4. The compound of claim 2, wherein R1 is
[A] hydrogen atom, ϊ5 [B] Ci-e 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, 20 -<B3> hydroxyl,
•<B4> Ci-e alkoxy,
•<B10> nitro,
•<B11> amino,
■<B12> cyano and 5 .<BI4> -XX-R1:L (R11 and X1 are each as defined in claim 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, 30 -<C2> Ci-e alkyl,
•<C6> hydroxyl,
•<C7> Ci-e alkoxy,
•<C13> nitro,
•<C14> amino, •<C15> cyano,
•<C16> carboxyl and
•<C17> -X^R11 (R11 and X1 are as defined above) ;
R2' is [F] hydrogen atom,
[G] Cι_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> Ci-e alkoxy,
•<G10> nitro,
•<G11> amino,
•<G12> cyano, -<G13> amido,
•<G16> -PO(OH)2,
•<G17> -PO(0-Cι-6 alkyl) 2 and
•<G18> -PO(0-aryl)2; or
[H] C3_i2 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> Ci-e alkyl,
•<H6> hydroxyl, -<H7> Ci-e alkoxy,
•<H13> nitro,
•<H14> amino,
•<H15> cyano,
•<H16> amido, -<H19> -P0(0H)2,
■<H20> -P0(0-Ci_6 alkyl) 2 and
•<H21> -P0(0-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> Ci-e alkyl, -<J6> hydroxyl,
•<J7> Ci-6 alkoxy,
•<J13> nitro,
•<J14> amino and
•<J15> cyano -<J16> amido,
•<J19> -PO(OH)2,
■<J20> -PO(0-Cι-e alkyl) 2 and
•<J21> -PO(0-aryl)2;
R4' is [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> Ci-e 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> Ci-e alkyl,
•<M6> hydroxyl,
•<M7> Ci-e alkoxy,
•<M13> azido,
•<M14> nitro, •<M15> amino, •<M16> cyano and
•<M18> -Y42-R41' (R41' is as defined in claim 2, Y42 is as defined in claim 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 <Nlδ>) , •<N1> halogen atom, •<N2> Ci-e alkyl, •<N7> hydroxyl, •<N8> Ci-e alkoxy, •<N14> nitro, •<N15> amino, «<N16> cyano and •<Nlδ> carboxyl; or [S]
Figure imgf000344_0001
(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 combinatio ; and
R5 is
[T] hydrogen atom,
[U] Ci-e 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-e alkoxy,
•<U10> nitro, •<U11> amino and
•<U12> cyano; or
[V] C3-i 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> Ci-e alkyl,
•<V6> hydroxyl,
•<V7> Ci-e 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]
Figure imgf000345_0001
wherein R2a is [F] hydrogen atom or
[G] Ci-e alkyl,
R is selected from the following [MabbO], [Mabbl] and [Mabblδ] ,
[MabbO] hydrogen atom, [Mabbl] halogen atom and
[Mabblβ] -Xc-R4MR4c is selected from the following (Mabbal)-
(Mabba4) , X4c is selected from the following (Mabbbl) - (Mabbb9) ) ,
• (Mabbal) hydrogen atom, • (Mabba2) Cι-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>) , ..<Mabbaal> halogen atom,
• •<Mabbaa2> carboxyl ,
••<Mabbaa3> (Cι_6 alkoxy) carbonyl and
••<Mabbaa4> Cι_6 alkylsulfonyl;
• (Mabbbl) single bond, • (Mabbb2) -CO-,
• (Mabbb3) -C02-,
• (Mabbb4) -0C0-,
•(Mabbb5) -CONR1c-,
• (Mabbb6) -NR41cCO-, • (Mabbb7) -S02-,
• (Mabbbδ) -S02NR41α- and
• (Mabbb9) -NR41cS02- (R1c is hydrogen atom or Cι-6 alkyl) ;
X4a is selected from the following [Lbal]- [Lba3] , [Lba8] , [Lball]-
[Lbal3], [Lbal6]-[Lbal9] and [Lba21] , [Lbal] -0-,
[Lba2] -S-,
[Lba3] -CO-,
[Lbaδ] -S02-,
[Lball] -NR41a-, [Lbal 2] -CONR41a-,
[Lbal3] -NR41aCO-,
[Lbal6] -S02NR41a-,
[Lbal7] -NR41aS02-,
[Lbalδ] -0C0NR41a-, [Lbal9] -NR41aC02~ and
[Lba21] -NR1aC0NR41-
(R1 and R41d are the same or different and each is hydrogen atom or Ci-e alkyl) ; R4b is selected from the following [Lai] , [La2] , [La5] and [La6] ,
[Lai] hydrogen atom,
[La2] Ci-e 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>,
<Labδ>, <Labl2>-<Labl7>, <Lab31> and <Lab32>) ;
•<Labl> halogen atom,
•<Lab2> Ci-6 alkyl (said alkyl is optionally substituted by "1 to 3 substituents selected from Cι_6 alkoxy, -SO2-C1-6 alkyl, -S02-aryl, -
NHS02-Cι_6 alkyl and -NHS02-halo-Cι-e alkyl) ,
•<Lab7> hydroxyl,
•<Lab8> Ci-6 alkoxy,
•<Labl2> nitro, «<Labl3> amino,
•<Labl4> cyano,
•<Labl5> carboxyl,
•<Labl6> (Ci-6 alkoxy) carbonyl,
•<Labl7> Ci-6 alkylsulfonyl , -<Lab31> -S02NR41fR 1g and
• <Lab32> -NR41fS02R41h
(R41f , R41g are the same or different and each is hydrogen atom or
Ci-e alkyl and R41h is Cι_6 alkyl) ;
X4b is selected from the following [Maal ] - [Maa6] , [Maa9 ] , [Maal2 ] - [Maalδ ] and [Maal9 ] - [Maa21] ,
[Maal] single bond,
[Maa2] -0- ,
[Maa3] -S- ,
[Maa4 ] -CO- , , [Maa5] -C02-,
[Maa6] -OCO-,
[Maa9] -S02-,
[Maal2] -NR1b-, [Maal3] -CONR41b-,
[Maal4] -NR1bCO-,
[Maal5] -NR1bC02-,
[Maal6] -OCONR1b-,
[Maal9] -S02NR1b-, [Maa20] -NR41bS02- and
[Maa21] -NR41bCONR41e-
(R41b and R41e are the same or different and each is hydrogen atom or Ci-e alkyl, or show -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5- together with Rb) ; (A) is
[Mabl]
/
4d
R
[Mab2]
—CH=Cχ or
[Mab5]
Figure imgf000348_0001
(R4d is hydrogen atom or Cι-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 claim 5, wherein (A) is [Mabl] CH, [Mab2]
—CH=C A or [Mab5]
-OC or a stereoisomer thereof, a pharmaceutically acceptable salt ther eof or a solvate thereof.
7. A compound represented by the formula [IV]
Figure imgf000349_0001
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]
Figure imgf000349_0002
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]
Figure imgf000350_0001
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-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methylcarbamoyl) methyl] cyclohexylmethoxymethyl Jbenzoic 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 Jbenzoic 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] cyclohexylmethoxyJ-5-methylbenzoic acid, 3-{trans-4- [ (S) -amino- (N-cyclobutyl-N- methylcarbaraoyl) 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- carbaraoyl)methyl] cyclohexylmethoxymethylJbenzoic 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.
3 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. o
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 DPP-IV inhibitor, which comprises a compound of any of 5 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 0 therapeutic drug for diabetic complication, a therapeutic drug for hyperlipidemia or an anti-obesity drug.
20. The pharmaceutical compossition of claim 19 , wherein the different therapeutic drug for diabetes , the therapeutic drug for3 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 , α~glucosidase inhibitors, insulin sensitizers, 0 PPAR receptor agonists, PPARγ receptor agonists/antagonists, PPARδ 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 IB (PTPase IB) inhibitors, SH2 domain- containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators, glycogen phosphorylase (GP) inhibitors, glucokinase activators, llβ-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, β3 adrenaline receptor agonists, apolipoprotein-Al (Apo-Al) 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 (ACCl) inhibitors, acetyl-CoA carboxylase 2 (ACC2) inhibitors, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, adiponectin receptor agonists, protein kinase β (PKCβ) 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 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 DPP-IV, 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 anti-obesity 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 anti-obesity drug is selected from insulin preparations (injection) , low-molecular insulin preparations (oral agent) , sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues , or-glucosidase inhibitors, insulin sensitizers, PPARα receptor agonists, PPARγ receptor agonists/antagonists , PPARδ 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 IB (PTPase IB) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators , glycogen phosphorylase (GP) inhibitors, glucokinase activators, llβ-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 , β3 adrenaline receptor agonists , apolipoprotein-Al (Apo-Al) 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 β (PKCβ) inhibitors, endothelial lipase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, angiotensin conversion enzyme (ACE) inhibitors, advanced glycation end products (AGE) inhibitors, glutaraine/fructose-6-phosphate 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 DPP-IV.
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 anti-obesity drug is selected from insulin preparations (injection) , low-molecular insulin preparations (oral agent) , sulfonylurea receptor agonists (SU drugs), short acting insulin secretagogues , α~glucosidase inhibitors, insulin sensitizers, PPAR receptor agonists, PPARγ receptor agonists/antagonists, PPARδ 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 IB (PTPase IB) inhibitors, SH2 domain-containing inositol phosphatase (SHIP2) inhibitors, AMP-activated protein kinase (AMPK) activators , glycogen
.phosphorylase (GP) inhibitors, glucokinase activators, llβ-HSD-1 inhibitors, GPR40 receptor agonists, pyruvate dehydrogenase kinase (PDHK) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase (DGAT) inhibitors, 5 cholesteryl ester transfer protein (CETP) inhibitors, HMG-CoA reductase inhibitors , β3 adrenaline receptor agonists , apolipoprotein-Al (Apo-Al) 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 β (PKC) inhibitors, endothelial lipase 5 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 .0
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 treating5 diabetes .
PCT/JP2004/013480 2003-09-09 2004-09-09 Dipeptidyl peptidase iv inhibitor WO2005025554A2 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2003317407 2003-09-09
JP2003-317407 2003-09-09
JP2003395879 2003-11-26
JP2003-395879 2003-11-26
JP2004-114685 2004-04-08
JP2004114685 2004-04-08

Publications (2)

Publication Number Publication Date
WO2005025554A2 true WO2005025554A2 (en) 2005-03-24
WO2005025554A3 WO2005025554A3 (en) 2005-07-28

Family

ID=34317220

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/013480 WO2005025554A2 (en) 2003-09-09 2004-09-09 Dipeptidyl peptidase iv inhibitor

Country Status (4)

Country Link
AR (1) AR046330A1 (en)
PE (1) PE20050948A1 (en)
TW (1) TW200530157A (en)
WO (1) WO2005025554A2 (en)

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072083A1 (en) 2005-12-23 2007-06-28 Prosidion Limited Treatment of type 2 diabetes with a combination of dpiv inhibitor and metformin or thiazolidinedione
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
WO2007027225A3 (en) * 2005-04-27 2007-11-22 Arena Pharm Inc Combination therapy for the treatment of obesity and diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood glp-1 level
WO2008020037A1 (en) * 2006-08-16 2008-02-21 Action Medicines, S.L. Use of 2,5-dihydroxybenzene derivatives for treating obesity, hirsutism, hypertricosis and viral warts
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012119941A1 (en) 2011-03-04 2012-09-13 Prozymex A/S Peptidyl nitrilcompounds as peptidase inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20130053364A1 (en) * 2009-10-09 2013-02-28 Hazel J. Dyke Sulphone Compounds and Methods of Making and Using Same
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US8946147B2 (en) 2010-06-24 2015-02-03 Indiana University Research And Technology Corporation Amide-based insulin prodrugs
US8957219B2 (en) 2008-10-17 2015-02-17 Shionogi & Co., Ltd. Acetic acid amide derivative having inhibitory activity on endothelial lipase
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US9089539B2 (en) 2008-01-30 2015-07-28 Indiana University Research And Technology Corporation Ester-based insulin prodrugs
US9187494B2 (en) 2011-05-06 2015-11-17 Zafgen, Inc. Aryl-substituted tricyclic sulfonamides as methionyl aminopeptidase 2 modulators
US9242997B2 (en) 2011-05-06 2016-01-26 Zafgen, Inc. Tricyclic pyrazole sulphonamide compunds and methods of making and using same
US9266896B2 (en) 2010-07-22 2016-02-23 Zafgen, Inc. Tricyclic compounds and methods of making and using same
US9290472B2 (en) 2011-05-06 2016-03-22 Zafgen, Inc. Partially saturated tricyclic compounds and methods of making and using same
US9321740B2 (en) 2011-01-26 2016-04-26 Zafgen, Inc. Tetrazole compounds and methods of making and using same
US9359369B2 (en) 2012-01-18 2016-06-07 Zafgen, Inc. Tricyclic sulfonamide compounds and methods of making and using same
US9440943B2 (en) 2012-01-18 2016-09-13 Zafgen, Inc. Tricyclic sulfone compounds and methods of making and using same
US9561209B2 (en) 2012-11-05 2017-02-07 Zafgen, Inc. Methods of treating liver diseases
US9616037B2 (en) 2008-09-19 2017-04-11 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
WO2017176461A1 (en) * 2016-04-04 2017-10-12 Research Triangle Institute Neuropeptide s receptor (npsr) agonists
JP2017538678A (en) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
US9868717B2 (en) 2012-11-05 2018-01-16 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
US10174009B2 (en) 2012-11-05 2019-01-08 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10654800B1 (en) * 2019-11-21 2020-05-19 King Abdulaziz Univeristy Antidiabetic compounds
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG182004A1 (en) 2003-01-14 2012-07-30 Arena Pharm Inc 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP2146210A1 (en) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
WO2010071807A1 (en) 2008-12-19 2010-06-24 Indiana University Research And Technology Corporation Amide based glucagon superfamily peptide prodrugs

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006074A1 (en) * 1994-08-20 1996-02-29 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
WO1998045330A1 (en) * 1997-04-04 1998-10-15 Medivir Ab Antiviral protease inhibitors
WO2000034241A1 (en) * 1998-12-10 2000-06-15 Novartis Ag N-substituted 2-cyanopyrrolidines
WO2003029200A2 (en) * 2001-10-02 2003-04-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
WO2003045977A2 (en) * 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006074A1 (en) * 1994-08-20 1996-02-29 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
WO1998045330A1 (en) * 1997-04-04 1998-10-15 Medivir Ab Antiviral protease inhibitors
WO2000034241A1 (en) * 1998-12-10 2000-06-15 Novartis Ag N-substituted 2-cyanopyrrolidines
WO2003029200A2 (en) * 2001-10-02 2003-04-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
WO2003045977A2 (en) * 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
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 *
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 *
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 *

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
WO2007027225A3 (en) * 2005-04-27 2007-11-22 Arena Pharm Inc Combination therapy for the treatment of obesity and diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood glp-1 level
US9182414B2 (en) 2005-04-27 2015-11-10 Arena Pharmaceuticals, Inc. Methods for identifying a GLP-1 secretagogue
US8354241B2 (en) 2005-04-27 2013-01-15 Arena Pharmaceuticals, Inc. Methods for identifying a GLP-1 secretagogue
JP2012136554A (en) * 2005-04-27 2012-07-19 Arena Pharmaceuticals Inc Combination therapy for treatment of obesity and diabetes and condition related thereto and for treatment of condition ameliorated by increasing blood glp-1 level
JP2008540336A (en) * 2005-04-27 2008-11-20 アリーナ ファーマシューティカルズ， インコーポレイテッド Combination therapy for the treatment of obesity and diabetes, and conditions associated therewith, and for the treatment of conditions that are alleviated by increasing blood GLP-1 levels
WO2007072083A1 (en) 2005-12-23 2007-06-28 Prosidion Limited Treatment of type 2 diabetes with a combination of dpiv inhibitor and metformin or thiazolidinedione
EP2253311A2 (en) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2008020037A1 (en) * 2006-08-16 2008-02-21 Action Medicines, S.L. Use of 2,5-dihydroxybenzene derivatives for treating obesity, hirsutism, hypertricosis and viral warts
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US9089539B2 (en) 2008-01-30 2015-07-28 Indiana University Research And Technology Corporation Ester-based insulin prodrugs
US9616037B2 (en) 2008-09-19 2017-04-11 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
US8957219B2 (en) 2008-10-17 2015-02-17 Shionogi & Co., Ltd. Acetic acid amide derivative having inhibitory activity on endothelial lipase
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
US9067905B2 (en) 2009-10-09 2015-06-30 Zafgen, Inc. Sulphone compounds and methods of making and using same
US20130053364A1 (en) * 2009-10-09 2013-02-28 Hazel J. Dyke Sulphone Compounds and Methods of Making and Using Same
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8946147B2 (en) 2010-06-24 2015-02-03 Indiana University Research And Technology Corporation Amide-based insulin prodrugs
US9266896B2 (en) 2010-07-22 2016-02-23 Zafgen, Inc. Tricyclic compounds and methods of making and using same
US9839623B2 (en) 2010-07-22 2017-12-12 Zafgen, Inc. Tricyclic compounds and methods of making and using same
EP3323818A1 (en) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9321740B2 (en) 2011-01-26 2016-04-26 Zafgen, Inc. Tetrazole compounds and methods of making and using same
WO2012119941A1 (en) 2011-03-04 2012-09-13 Prozymex A/S Peptidyl nitrilcompounds as peptidase inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9187494B2 (en) 2011-05-06 2015-11-17 Zafgen, Inc. Aryl-substituted tricyclic sulfonamides as methionyl aminopeptidase 2 modulators
US9242997B2 (en) 2011-05-06 2016-01-26 Zafgen, Inc. Tricyclic pyrazole sulphonamide compunds and methods of making and using same
US9617237B2 (en) 2011-05-06 2017-04-11 Zafgen, Inc. Partially saturated tricyclic compounds and methods of making and using same
US9290472B2 (en) 2011-05-06 2016-03-22 Zafgen, Inc. Partially saturated tricyclic compounds and methods of making and using same
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9359369B2 (en) 2012-01-18 2016-06-07 Zafgen, Inc. Tricyclic sulfonamide compounds and methods of making and using same
US9440943B2 (en) 2012-01-18 2016-09-13 Zafgen, Inc. Tricyclic sulfone compounds and methods of making and using same
US9561209B2 (en) 2012-11-05 2017-02-07 Zafgen, Inc. Methods of treating liver diseases
US10174009B2 (en) 2012-11-05 2019-01-08 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
US10064839B2 (en) 2012-11-05 2018-09-04 Zafgen, Inc. Methods of treating liver diseases
US9868717B2 (en) 2012-11-05 2018-01-16 Zafgen, Inc. Tricyclic sulphonamide compounds and methods of making and using same
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US9796670B2 (en) 2013-06-26 2017-10-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10233147B2 (en) 2013-06-26 2019-03-19 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10029979B2 (en) 2013-06-26 2018-07-24 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
JP2017538678A (en) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
EP3215141A4 (en) * 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
WO2017176461A1 (en) * 2016-04-04 2017-10-12 Research Triangle Institute Neuropeptide s receptor (npsr) agonists
US11142546B2 (en) 2016-04-04 2021-10-12 Research Triangle Institute Neuropeptide S receptor (NPSR) agonists
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
US10654800B1 (en) * 2019-11-21 2020-05-19 King Abdulaziz Univeristy Antidiabetic compounds

Also Published As

Publication number Publication date
TW200530157A (en) 2005-09-16
PE20050948A1 (en) 2005-12-16
AR046330A1 (en) 2005-12-07
WO2005025554A3 (en) 2005-07-28

Similar Documents

Publication Publication Date Title
WO2005025554A2 (en) Dipeptidyl peptidase iv inhibitor
US8202859B2 (en) Heterocyclic sulfonamides
US20200109167A1 (en) Small molecule dcn1 inhibitors and therapeutic methods using the same
US9051249B2 (en) Benzylamine derivatives as inhibitors of plasma kallikrein
US7893020B2 (en) Bacterial efflux pump inhibitors and methods of treating bacterial infections
JP5528113B2 (en) Michael System as a transglutaminase inhibitor
US5574017A (en) Antibacterial agents
US6797820B2 (en) Succinate compounds, compositions and methods of use and preparation
JPH04217652A (en) Acetic acid derivative, process for producing same, pharmaceutical preparation containing same and utilization thereof in production of pharmaceutical preparation
TW200920365A (en) Dipeptoid prodrugs and their use
JP2973271B2 (en) Endopeptidase 24.15 inhibitor
EP2379540A1 (en) Dipeptoid prodrugs and the use thereof
WO2012168820A1 (en) Polymyxin derivatives useful as antibacterial agents
WO2004089362A1 (en) 2-cyanopyrroles and their analogues as ddp-iv inhibitors
WO2000006594A1 (en) Novel thiazolidine derivatives
US11186541B2 (en) Potent inhibitors of aspartate N-acetyl-transferase for the treatment of Canavan disease
AU706978B2 (en) Thiol derivatives with metallopeptidase (ACE/NEP) inhibitory activity
AU707570B2 (en) Phosphonic acid derivatives with metallopeptidase inhibitory activity
WO2023249007A1 (en) Calpain inhibitor
EP2797910B1 (en) Quinuclidine esters of 1-azaheterocyclylacetic acid as antimuscarinic agents, process for their preparation and medicinal compositions thereof
JP2000229958A (en) Substituted bezylamines
CA2139305A1 (en) Process for producing pyrrolidine derivative and salt thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BW BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE EG ES FI GB GD GE GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MK MN MW MX MZ NA NI NO NZ PG PH PL PT RO RU SC SD SE SG SK SY TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SZ TZ UG ZM ZW AM AZ BY KG MD RU TJ TM AT BE BG CH CY DE DK EE ES FI FR GB GR HU IE IT MC NL PL PT RO SE SI SK TR BF CF CG CI CM GA GN GQ GW ML MR SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP